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cd9f1df66dfe4a4eb97264bbd8701592	2012+WHO技术规范	冷冻治疗用于治疗宫颈癌前病变以及宫颈癌预防	# WHO technical specificationsCryosurgical equipment forthe treatment of precancerouscervical lesions and preventionof cervical cancer. # . # WHO technical specifications. Cryosurgical equipment for the treatment of precancerous cervical lesions and prevention of cervical cancer. # WHO Library Cataloguing- in- Publication Data. WHO technical specifications: cryosurgical equipment for the treatment of precancerous cervical lesions and prevention of cervical cancer.. 1. Cryosurgery - instrumentation. 2.Uterine cervical diseases - surgery. 3.Precancerous conditions - therapy. 4.Uterine cervical neoplasms - prevention and control. I.World Health Organization.. ISBN 978 92 4 150456 0. (NLM classification: WP 480). \mathfrak{G}. All rights reserved. Publications of the World Health Organization are available on the WHO web site (www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e- mail: bookorders@who.int). Requests for permission to reproduce or translate WHO publications - whether for sale or for noncommercial distribution - should be addressed to WHO Press through the WHO web site (. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.. Printed by the WHO Document Production Services, Geneva, Switzerland. # Acknowledgements. AcknowledgementsThis document is the result of a review of the latest available evidence and an extensive consultative process on the treatment of precancerous cervical lesions by cryosurgery. WHO, UNFPA, and PATH organized a joint meeting of clinical experts in cryosurgery in Seattle, March 30- April 1, 2009. The goal of the meeting was to build consensus on approaches to improving cryosurgical service delivery to prevent cervical cancer. The meeting had two areas of focus: to discuss clinical recommendations in the use of cryosurgery for cervical cancer prevention and to initiate development of technical specifications to facilitate country procurement. Meeting attendees included experts from different countries on obstetrics and gynaecology, and the use of cryosurgery to treat cervical precancerous lesions. Representatives from NGOs and advocacy groups, and representatives from two cryotherapy device manufacturers, Wallach and MedGyn, also attended the meeting.. The first meeting identified several key issues relating to technical specifications for cryosurgery equipment which required follow- up and further development. These included procurement, performance, and maintenance of cryosurgical devices and related equipment, such as gas cylinders and connectors. At that time a framework was developed to address these issues, including the formation of a technical specification working group.. A second meeting re- convened key members from the technical specification working group to finalize the technical basis and make recommendations for the development of a procurement specification to guide the purchase, use, and maintenance of cryosurgical devices. This document is based on the output of the second meeting, together with input from members of the technical specification working group and other experts listed below.. WHO, UNFPA, and PATH have all supported the development of this document and would like to gratefully acknowledge the contributions of the following people and organizations:. Co-authors. Co- authorsWilliam Potter (Consultant/WHO Technical Adviser) drafted the technical specification and supporting documents, with core contributions from Siavoche Mohadjer (WHO Consultant), Margaret Usher- Patel (WHO), Jennifer L. Winkler (PATH), Jered Singleton (PATH), Keith Neroutsos (PATH), and Nathalie Broutet (WHO).. Primary reviewers. Primary reviewersAgnes Chidanyika (UNFPA), Hugo de Vuyst (International Agency for Research on Cancer), Paul Blumenthal (Stanford University School of Medicine), Ricky Lu (Jhpiego), Carlos Santos (Instituto Nacional de Enfermedades Neoplásicas), Jose Jeronimo (PATH), Lisa Hedman (WHO), and Ingegerd Nordin (UNFPA) who provided detailed feedback on the draft documents with input from equipment manufacturers Wallach, Cooper Surgical, ERBE, and CryoPen Inc. In addition, feedback was received from field staff who were asked to comment on issues related to gas used for cryotherapy and to review from a programmatic perspective: Shumet Adnew (Pathfinder), Min Zaw (PSI), Matts Boxshall (PSI), Edward Kumakech (PATH), and Wame Baravilala (UNFPA).. Meeting participants and members of the technical specification working group. Meeting participants and members of the technical specification working groupLinda Alexander (Qiagen), Laura Bell (Qiagen), Paul Blumenthal (Stanford University School of Medicine), Nathalie Broutet (WHO), Linda Cella (Wallach), Agnes Chidanyika (UNFPA), Craig Citron (Wallach), Hugo de Vuyst (International Agency for Research on Cancer), Lauren Ditzian (Basic Health International), Francisco Garcia (American Cancer Society), Lisa Hedman (WHO), Judith Henninger (WHO), Arnynah Janmohamed (PATH), Jose Jeronimo (PATH), Greg Kinley (MedGyn International), Ricky Lu (Jhpiego), Silvana Luciani (WHO), Rachel Masch (Beth Israel Medical Center), Mutsumi Metzler (PATH), Siavoche Mohadjer (WHO Consultant), Katie Richey (WHO), Carlos Santos (Instituto Nacional de Enfermedades Neoplásicas), Jered Singleton (PATH), Gene Spahija (MedGyn International), Maggie Usher- Patel (WHO), and Jennifer Winkler (PATH).. Editing and layoutGreen Ink (www.greenink.co.uk). # iv Cryosurgical equipment for the treatment of precancerous cervical lesions and prevention of cervical cancer. # Contents. ContentsAcknowledgements iiiExecutive Summary viiIntroduction 1Chapter 1. Generic specification of cryosurgical equipment for the treatment of precancerous cervical lesions 3Chapter 2. Advice and guidance regarding gas supplies for cryosurgical treatment of precancerous cervical lesions 10Chapter 3. Recommendations for handling gas cylinders 19Chapter 4. Procurement guidance 22Annex 1. Glossary of terms 27Annex 2. Technical Basis Paper: Cryosurgical equipment for the treatment of precancerous cervical lesions 29Annex 3. WHO guidelines on cryotherapy 38Annex 4. WHO universal precautions for infection prevention 42Annex 5. Details of gas fittings and suppliers by country 46. Figures. FiguresFigure 1: A typical cryosurgical unit 5Figure 2: Illustration of dimensions of cryotips suggested for cryosurgical treatment of precancerous cervical lesions 7Figure 3: Range of high pressure gas cylinder sizes 14Figure 4: Examples of pin- indexed cylinder valves 15Figure 5: The stages of procurement 22Figure A1: A typical cryosurgical unit 31Figure A2: Illustration of dimensions of cryotips suggested for cryosurgery of precancerous cervical lesions 32. Tables. TablesTable 1: Suppliers of cryosurgical equipment suitable for cervical lesions 4Table 2: Values of 1 Bar of pressure in commonly- used units 11Table A1: Suppliers of cryosurgical equipment suitable for cervical lesions 30. # . # Executive Summary. Cervical cancer is a serious and growing global health issue. In 2008, there were approximately 274 000 deaths from the disease, about . This document seeks to assist programme managers, purchasing managers, and other . # . # Introduction. Cervical cancer is a serious and growing global health issue.In 2008,there were an estimated 529 000 new cases of cervical cancer and approximately 274 000 deaths, making it the second most common cancer in women.About . Although it affects women worldwide, cervical cancer mortality is highest in low- resource settings where women have not traditionally had access to organized screening programmes. Infection with human papillomavirus (HPV), the virus that causes cervical cancer, is preventable through vaccination, but the vaccine should be given prior to infection, which often occurs within a few years of sexual debut. For those women already infected, development of cervical cancer is preventable using relatively simple, low- cost screening and treatment approaches that can be implemented at the district, if not primary, health care level. This is particularly true of visual inspection methods such as VIA (visual inspection with acetic acid) combined with cryosurgical treatment, although in certain cases more sophisticated treatment is needed2. In many areas, treatment is provided the same day as a positive screening test, or soon after. It is usually provided without histological confirmation because of the potential loss to followup that would result from the extra diagnostic step. Cervical cancer usually takes decades to . Cryosurgery is appropriate for use in low- resource settings because it is effective . The WHO Reproductive Health Strategy, adapted by Member States during the . That said, a successful programme requires confidence in both the screening method and the equipment necessary to treat lesions. Cryosurgical equipment has not always inspired such confidence. Failure to achieve freezing and gas line blockages are two problems that have been seen in the field. In response, the WHO Department of Reproductive Health and Research (WHO/RHR), in partnership with PATH and UNFPA, mobilized technical advisors, researchers, and manufacturers to develop procurement specifications for cryosurgical equipment, gas, and accessories, along with technical guidance for addressing operational. # challenges and a consensus configuration of a standard cryosurgical package.. For more information about cervical cancer screening and treatment, consult WHO's [C4- GEP] and other documents which can be found in the "Screening" section of the RHO Cervical Cancer Library (www.rho.org).. Who is this document intended for?. This document is intended primarily for any policy- maker, manager, or procurement officer who has responsibility for procuring, supplying, and promoting the early prevention and management of cervical cancer. Individuals working in reproductive health care programmes, particularly STI/HIV/AIDS prevention and family planning programmes at the district and primary health care level, should also review this document to understand why it is vitally important to establish systems which ensure that a quality product is manufactured, procured, and used. Bulk procurement agencies and national regulatory authorities will also need to study this document in preparation for the manufacture, procurement, and supply of cryosurgical equipment and the appropriate . In addition to these primary users, the document will be useful to manufacturers, social marketing programmes, nongovernmental agencies, and policy- makers as they work to improve the acceptability and use of cryosurgery as a means to support cervical cancer prevention and management programmes in their target populations.. Purpose of the document. This document describes a technically sound, systematic process to support the procurement and distribution of cryosurgical equipment that can meet the needs of cervical cancer prevention and management programmes at the district and primary health care levels. It includes advice on technical specifications for purchasers, including the design and performance recommendations necessary to ensure the safety and efficacy of cryosurgical equipment. It also discusses issues related to the sources, storing, and handling of gases used by the equipment, and guidance on how to procure both the equipment and the gases.. # Chapter 1. Generic specification of cryosurgical equipment for the treatment of precancerous cervical lesions. 1.1 Scope. This Generic Specification specifies requirements and recommendations for cryosurgical equipment for the treatment of precancerous cervical lesions in low- resource settings. The specification is based on a series of meetings, surveys, reviews, and studies undertaken between 2008 and 2010 by WHO, PATH, and UNPFA<sup>4</sup>.. 1.2 Background to cryosurgical equipment. Cryotherapy, also known as cryosurgery, has been widely accepted as a practical and effective method of treating precancerous cervical lesions worldwide. Extreme cold is applied to the lesion using a cryoprobe (an extremely cold probe) to freeze the lesion. The World Health Organization Guidelines on the use of cryotherapy for cervical intraepithelial neoplasia strongly recommend the use of cryotherapy over no treatment.. Cryosurgical equipment (also known as cryotherapy equipment) is available from a number of manufacturers, mainly US- based, but with some types available from European and Indian manufacturers. Two main methods are used to cool the cryoprobe: the expansion of . Although current cryosurgical equipment relies on using a compressed gas or a cryogenic liquid to achieve the target probe temperature, new types of equipment with built- in freezer units are beginning to emerge. By eliminating the need for compressed gas supplies, units with built- in freezers may have clear advantages in low- resource environments despite their potentially higher initial purchasing costs. The suitability of this type of equipment for use in low- resource settings still has to be assessed but may well represent an opportunity for the future.. The most widely- used compressed gases for surgery are carbon dioxide and nitrous oxide, and most cryosurgical equipment manufacturers offer the option of using either. The choice of gas has to be made at the time of purchase of the equipment to ensure the proper fittings, and in some cases that the appropriate device is used. In low- resource settings carbon dioxide is often cheaper and more readily available than nitrous oxide.. Examples of some of the main suppliers that have been identified through internet and other searches are given in Table 1.. 1.3 Equipment requirements. Cryosurgical equipment operating on either compressed carbon dioxide or nitrous oxide may be used for the treatment of precancerous. # cervical lesions. In low- resource settings carbon dioxide is generally more readily available and costs less. An example of a typical cryosurgical unit is shown in Figure 1.. The equipment comprises the following components:. A hand unit with a shaft to which detachable probe tips can be attached. The hand unit is made of a material that withstands routine sterilization or disinfection with hospital disinfectants, including bleach solutions or any other disinfectant for surgical instruments. The manufacturers' recommendations for sterilization and disinfection should be followed. The hand unit is fitted with one or more integrated triggers and other controls . # 1. Probe 2. Trigger 3. Handle grip (fiberglass) 4. Yoke 5. Inlet of gas from cylinder 6. Tightening knob 7. Pressure gauge showing cylinder pressure 8. Silencer (outlet) 9. Gas-conveying tube 10. Probe tip. o The trigger mechanism unit should be made of rigid plastic, of a type and grade that will insulate the hand of the user while providing durability. o The hand unit shall permit the removal and attachment of the cryotip and/or the cryoshaft to facilitate cleaning.. A hose assembly attaching the hand unit to a connector/pressure gauge assembly that connects to the high- pressure gas cylinder. The hose assembly comprises: o A high- pressure hose to conduct the gas to the hand unit and a return hose to carry the waste gas back to the pressure gauge assembly to be vented (venting of the gas within the handset is not acceptable). o The high- pressure hose, as required by ASTM F 882- 84 (Reapproved 2002) Standard Performance and Safety Specification for Cryosurgical Medical Instruments5, shall be rated for a pressure that is at least twice the maximum gas cylinder pressure (ca. 2000 psi). o Ideally the hose will comply with the requirements specified in ISO 21969 (2009) High- pressure flexible connections for use with medical gas systems6. o A minimum hose assembly length of . A connector/pressure gauge assembly that connects to the gas cylinder with the following features:. o A gas connector to permit the cryosurgical system to connect to the compressed gas cylinder. The connector is made of metal and should be appropriate for use with pressurized gases, specifically with carbon dioxide and nitrous oxide. Multiple types of connectors are available and compressed gas cylinder valves vary from country to country. It is essential that the proper. # connector is used with the compressed gas cylinder valve. More information on gas fittings and gas supplies are given in Chapter 2. o A pressure gauge to indicate the pressure within the system. The gauge may be colour coded to indicate the safe working pressure range for the device. o A pressure relief valve designed to protect the device, the user and the patient from potentially excessive tank pressure. Typically the valve should have an internal rupture disk which bursts at a set pressure, preventing the device from becoming over- pressurized. The pressure relief valve should be designed to rupture if the maximum pressure rating of the pressure gauge, the hose assembly, or the trigger mechanism is reached. o An exhaust port to which a hose can be connected to vent the exhaust to a place with adequate air circulation. o Optionally the equipment may be fitted with a pressure regulator to maintain a relatively constant pressure within the unit. o Preferably a silencer unit to reduce noise levels. o Active defrosting mechanisms may or may not be incorporated into the operation of the unit. Both active and passive defrost systems are acceptable for the treatment of precancerous cervical lesions. If an active defrosting option is included, it will be integrated into the trigger function or the hand unit to facilitate single handed operation of the equipment. o Optionally the equipment may be fitted with temperature sensors to indicate the probe temperature and a timer to indicate the duration of tissue exposure.. probe shaft shall be removable at its base from the hand unit.. The cryotip shall be made from surgical- grade materials or the manufacturers shall provide evidence that the materials used for the cryotips have been assessed for cytotoxicity according to ISO 10993- 5 (2009), Biological evaluation of medical devices - Part 5: Tests for in vitro cytotoxicity, and for irritation and sensitization potential according to ISO 10993- 10 (2010), Biological evaluation of medical devices - Part 10: Tests for irritation and skin sensitization. Cryotips with a well- established history of safe use are acceptable.. The cryotip shall be made from materials capable of withstanding routine sterilization by autoclave or disinfection with hospital disinfectants, including bleach solutions or any other disinfectant for surgical instruments.. The surface of the cryotip that contacts the cervix should be smooth with no sharp edges.. Only cryotips conforming to the following requirements should be used for the treatment of precancerous cervical lesions:. The cryotips shall be of closed design. Open cryotips apply the cryogen directly to the target tissue and must not be used for treating cervical lesions because of the risk of damage to surrounding healthy tissue. The cryotips shall be rounded in shape and should be . 1.4 Cryotips. The cryotip will be removable to allow interchangeable tips to be used and to facilitate cleaning and disinfection after use. The cryotips may attach directly to the probe shaft or be integral to the probe shaft, in which case the. 1.5 Cryoshaft. The cryoshaft is made from materials capable of withstanding routine sterilization by autoclave or disinfection with hospital disinfectants, including bleach solutions or any. # other disinfectant for surgical instruments. Manufacturers should include information on disinfectants that can be used with the shafts and warn about any that can cause damage. With some designs of equipment it may not be possible to detach the cryoshaft for sterilization. In such cases the manufacturers' procedures for disinfection should be followed.. The overall length of the cryoshaft and cryotip assembly should be between 170 and 200 mm. The cryoshaft should not freeze during normal use; its outer surface should be insulated to prevent accidental freezing of any tissue that it touches.. The cryoshaft should be rigid so that it does not flex during normal use.. The cryotip should provide safe and consistent delivery of gas to the tip as well as gas exhaust back through the interior body of the tube.. 1.6 Performance and safety standards. The cryosurgical equipment is capable of reaching and maintaining a cryotip temperature below . Ideally the cryosurgical system should conform to an appropriate national standard such as ASTM F882- 84 (Reapproved 2002), Standard Performance and Safety Specification for Cryosurgical Medical Instruments. All high- pressure gas fittings incorporated into the cryosurgical unit should comply with regulations for compressed gas fittings in the country where the equipment is manufactured.. 1.7 Regulatory status of cryosurgical equipment. In the US cryosurgical equipment is regulated as a Class II medical device. Before being. # placed on the US market a 510(k) premarket notification has to be submitted to the Food and Drug Administration (FDA) providing information on the safety and effectiveness of the equipment. Manufacturers are required to demonstrate equivalence to a device that was on the US market prior to the introduction of the regulations (i.e. before May 28, 1976) or a device that has been shown to be substantially equivalent to such a device through a previous 510(k) submission. The previously- marketed device is known as the predicate device.. In Europe cryosurgical equipment falls into Class IIa according to classification rule 9 of the European Medical Device Directive (93/42/EEC as amended). Class IIa devices require prior clearance before being placed on the market in Europe by a Notified Body. Once the equipment is cleared for marketing the manufacturer must affix a CE Mark to the device to demonstrate that the product complies with the essential requirements of the directive. If the cryosurgical equipment includes any electrical components then the equipment may also be required to comply with other European regulations relating to the safety and compatibility of electrical equipment.. The regulation of medical devices in other countries and regions tends to vary considerably. Most low- resource countries have very limited, if any, regulation of most medical devices. It is therefore unlikely that product registration for cryosurgical equipment will be required in most low- resource countries but the national regulatory authority may insist on the product having US FDA 510(k) and/or European CE Mark clearance. National regulatory authorities may also require a certificate of free sale for the product in the country of manufacture and may want to review the documents submitted in support of 510(k) or CE mark approval.. A key stage in the procurement or purchase of cryosurgical equipment therefore is an assessment of local regulatory requirements, if any, in the recipient country or countries. Once the . - confirm with the national regulatory authorities whether there are any local regulatory or registration requirements for cryosurgical equipment;- source equipment that has US FDA 510(k) and/or European CE Mark clearance;- ensure that equipment which is not manufactured or distributed in the US or Europe, and does not have 510(k) or CE Mark clearance, has appropriate regulatory approval in the country of manufacture;- ensure, where applicable, that the equipment manufacturer has the appropriate export licences issued in the country of manufacture for the equipment;- ensure that the equipment manufacturers are prepared to supply any necessary documentation that may be required for local regulatory review in the recipient countries, including certificates of free sale.. 1.8 Gas cylinder connector. The connector between the gas cylinder valve and the cryosurgical unit is an integral part of the cryosurgical unit. The connector will be specified when the equipment is purchased and must be compatible with the cylinder valve fitment available in the country where the equipment is to be used. Further advice on gas cylinders and gas connectors is given in Chapter 2, including a list of some of the most common fitments.. Gas cylinder fitments are specific to the type and grade of gas being used as well as the cylinder size. It is essential to determine the type of fitments available in- country before ordering cryosurgical equipment.. Some manufacturers provide an empty gas cylinder with the equipment. In such cases it is essential to confirm that the local gas supplier. # has the correct fittings to be able to refill the cylinder prior to purchase. It is also essential to confirm that the supplied cylinder is of adequate capacity for treating cervical lesions (for further information on gas cylinder fittings and cylinder capacity, refer to Chapter 2).. 1.9 Gas cylinders. A full review of gas supplies for cryosurgical equipment has been completed separately. This includes advice on the selection, procurement, storage, and handling of the gas cylinders (see Chapters 2 and 3).. 1.10 Spare parts. Essential spare parts such as the hose assembly, cryotips, cryoshafts, O- ring, and sealing washers should be purchased from the original equipment manufacturer. Manufacturers should provide a referenced list of spare parts to facilitate ordering.. # Chapter 2. Advice and guidance regarding gas supplies for cryosurgical treatment of precancerous cervical lesions. 2.1 Background. Cryosurgical equipment suitable for the in- clinic treatment of precancerous cervical lesions normally operates from a high- pressure gas cylinder. The most commonly- used gases are carbon dioxide and nitrous oxide. The probe tip is cooled by expansion of the gas through a nozzle, causing cooling by the Joule- Thomson effect. Both nitrous oxide and carbon dioxide have high Joule- Thomson coefficients, making them good gases for this application. Sourcing an appropriate supply of compressed gas can be problematic, especially in low- resource settings. This document provides advice and guidance to procurers and users of cryosurgical equipment in low- resource countries on obtaining, storing, and using suitable gases.. 2.2 Gas quality. Gases are available in many different "grades", including medical, food, industrial, ultrapure, and spectroscopic. Different manufacturers and/or distributors may use different designations for some of these grades.. Medical- grade gases are of very high quality and by necessity are free of any potentially problematic impurities. They are also more expensive than other grades.. Although with the types of cryosurgical equipment that are suitable for treatment of cervical lesions there is no direct contact between the gas and the patient, it is nevertheless recommended that medical- grade gas is used if available and affordable. This is to reduce the risk of equipment blockages due to impurities such as moisture or particulate material in the gas.. Ideally medical- grade gases should be used, but if these are not available locally then food, beverage (for carbon dioxide), or equivalent grades can be considered. Use of "industrial"-. grade gas is discouraged. Gases should never be mixed, nor should any other gas than that specified by the equipment manufacturer be used.. The type of connector between the cylinder valve (which is part of the gas tank and supplied by the distributor) and the device not only depends on the type of gas, but also the grade of gas. It may not be possible therefore to switch between different grades of gas without also changing the fitting on the device. Again this reinforces the need to check the local availability of gas supplies before purchasing cryosurgical equipment.. 2.3 Units used for gas pressure. Different units for pressure are in common use. The official SI (Système international d'unités) derived unit for pressure is the Pascal (Pa) but, to avoid excessively large numbers, it is normally more convenient to use the kilo Pascal (kPa) for gas pressures. A pressure of one Pa is equivalent to one Newton (a measure of force) per square metre. Other common units for pressure include pounds per square inch (psi), atmospheres, bar, and . The gauges used on cryosurgical equipment are commonly colour coded to indicate the acceptable operational range. Red indicates that the gas pressure is too high, green that it is within the acceptable operational range, and yellow that it is too low.. # 2.4 Properties of compressed gases. The properties of compressed gases and the requirements for their safe transport and storage can be confusing and difficult to understand.Different standards, regulations, and requirements apply to gases and gas cylinders depending upon country, region, and application.Some gases turn into liquids when compressed and are stored in the tank in liquid form.Others remain as gases even under very high pressures.If the gas in the cylinder is liquefied, then there are important implications for the storage,handing,and use of the gas which are discussed later in this document.All gases under pressure are potentially hazardous. When dealing with compressed gases it is therefore essential to understand the basic principles behind the purchasing, storage, and use of gases and gas cylinders.. An important concept in understanding the behaviour of gases under pressure is the "critical point".The critical point is the combination of temperature and pressure at which separate liquid and gas or vapour phases effectively cease to exist.Above the critical temperature it is not possible to cause the gas to liquefy no matter how high a pressure is applied to it. In this state the gas is known as supercritical.The pressure required to cause a gas to liquefy at the critical temperature is known as the critical pressure.At temperatures below the critical temperature the gas can be liquefied if sufficient pressure is applied. This is why some gases liquefy at normal ambient temperatures and others do not.. Both carbon dioxide and nitrous oxide have critical temperatures that are a little higher than room temperature.For carbon dioxide the critical temperature is . 1. The pressure within the cylinders will remain largely constant as the gas is used until all the liquid is gone, at which point the gas pressure will start to drop. The gas pressure may also drop during use as the cylinder is approaching empty because the rate of evaporation of the liquid can no longer keep the pressure constant. However, once the treatment is stopped, the pressure may recover. The pressure gauge cannot therefore be relied upon to indicate the amount of gas remaining in the cylinder. If the gas pressure in the cylinder drops during use and then recovers, this should be taken as a warning that the cylinder is approaching empty.. 2. The vapour pressure of the liquid, and therefore the pressure in the cylinder, will depend on temperature to a much greater extent than for cylinders containing compressed gases only (i.e. no liquid). At typical storage temperatures in the range . # high for use with some types of cryosurgical equipment until the cylinder has had time to cool to below . 3. The cylinders must be standing upright in order to deliver gas. If they are used on their side then liquid or a mixture of gas and liquid will be forced into the equipment. Cylinders may be stored upright or on their side, but before use they must be stood upright.. Some cylinders are fitted with a dip tube or siphon. These cylinders are intended to deliver liquid, not gas. Some manufacturers mark siphon cylinders with a white stripe running along the length of the cylinder. If there is any doubt about whether a cylinder contains a siphon tube the supplier should be consulted. Unless it is specifically stated for a specific piece of equipment that a siphon cylinder should be used, then never use a cylinder with a dip tube or siphon. Doing so could cause damage to the equipment leading to leaks, possible cold burns to the user, and even the risk of an explosion.. As gas is drawn from a cylinder containing a liquefied gas, some of the liquid evaporates in order to maintain the constant pressure. This has a cooling effect. If gas withdrawal is rapid this can cause a sufficient drop in temperature for moisture to condense and even for frost to appear on the outside of the cylinder.. If for any reason there is a rapid discharge of gas, for example if a valve leaks or a hose bursts, the valve itself can become very cold and there is a risk of frostbite if the valve is touched.. Gas suppliers always leave space in a cylinder containing liquefied gases, such as nitrous oxide and carbon dioxide, for expansion. Typically cylinders are only filled to about . of the available volume in temperate climates and . Overfilling could lead to excessive cylinder pressures during storage causing the pressure release valve to vent the entire contents of the cylinder. Always use a reputable gas supplier to reduce the risk of being supplied with overfilled cylinders.. If the gas pressure in a cylinder is too high for the specific type of cryosurgical equipment being used, the excess pressure can be vented using the following procedure:. - Close the main cylinder valve.- Ensure that the main cylinder valve opening is facing away from any people and slowly open the valve. Allow a small stream of gas to escape for 8-10 seconds.- Close the main cylinder valve.- Re-connect the cryosurgical system to the cylinder valve.- Open the main cylinder valve again. If the pressure is still too high, repeat the procedure.. If a cylinder containing gas at an excessively high pressure is attached to some types of cryosurgical equipment, the equipment may be damaged. If at all possible try and check cylinder pressures before attaching the cryosurgical unit.. 2.5 Gas cylinders. 2.5.1 General. Pressures within carbon dioxide and nitrous oxide cylinders can be extremely high, typically up to just over 1,000 psi. Cylinders are normally constructed of carbon steel or aluminium. Cylinders containing high- pressure gas are potentially very dangerous. Additionally, using an incorrect gas can cause serious injury and death due to asphyxiation, poisoning, fire, and explosion. For these reasons most countries have stringent regulations controlling the transport, supply, and use of compressed gas cylinders.. # Find out about the regulations regarding transport, supply, and use of compressed gas cylinders in your country.. Depending upon local or regional regulations, the cylinders have to be tested periodically to make certain that they can withstand the high pressures reached in service. The frequency of testing is determined by local regulations in most countries. In general a hydraulic pressure test is required every five to ten years depending upon the type of gas and local regulations. All cylinders should carry an indication of when they were last tested and when a re- test is required, although the code system used may not be obvious. If there is any doubt about the age or condition of a cylinder, consult with the gas supplier to determine when the cylinder was last tested and cleaned.. It is essential that the gas suppliers' recommendations relating to the safe transport, storage, and use of the cylinders are followed. Cylinders must be restrained by suitable chains or holders to prevent them falling over, both in storage and in use.. If a cylinder falls over and the valve is damaged or broken, it can turn the cylinder into a dangerous projectile causing extensive damage, serious injury, and even death. Some guidelines on handling cylinders are included at the end of this chapter.. 2.5.2 Identification of gas cylinders. To assist in the identification of gases, cylinders are usually colour- coded. Unfortunately there are different colour- coding systems in operation depending upon the country, the standards being used, and even the supplier of the gas. In some countries the colour code system may not even be followed.. Find out about the colour coding of gas cylinders used in your country.. Colour coding within the European Union is regulated under European Standard EN 1089- 37, Transportable gas cylinders. Gas cylinder identification (excluding LPG). This standard specifies colour coding for all types of gas cylinders. Colour coding can be related to the hazard properties of the gas or by specific gas contained in the cylinder. Carbon dioxide is indicated by a dusty grey on the cylinder and nitrous oxide by dark blue. Different countries use different colour- coding schemes, although attempts to standardize colours are being made. The colour coding of medical gases is covered by an international standard, ISO 32 (1977), Gas cylinders for medical use - marking for identification of content. This standard applies to medical gases only; not all countries use the standard.. It is therefore essential to check the label of any gas cylinder carefully to make sure the correct gas and the correct grade are being used. If there is any doubt about the contents of a gas cylinder, then either contact the supplier for confirmation or do not use it!. 2.5.3 Cylinder sizes. Cylinders are available in a wide range of sizes (see Figure 3). The size of gas cylinders can be specified by a letter code, by the water capacity expressed in pounds, by internal volume, or by the volume of gas at normal pressure and temperature contained in the cylinder. Common sizes for European medical gas cylinders are size C containing 450 ml of gas, size D containing 900 ml of gas, size E containing 1800 ml of gas, size F containing 3600 ml of. # gas, size G containing 9000 ml of gas and size J containing 18 000 ml of gas.. - The most common and useful sizes for cryosurgery are D and E.. In the US, cylinder capacities are more commonly expressed in pounds (lbs). Commonly- used sizes for cryosurgery are 6 lbs and 20 lbs.. The number of cryosurgical sessions per cylinder will clearly depend upon the size of the cylinder, the type of equipment used, and the duration of the procedure. Wallach, in their sales literature, state that the LL100 Cryosurgical System using a 20 lb nitrous oxide cylinder should provide approximately 80 minutes of use. This would be sufficient for about 20 precancerous cervical lesion treatments. Practical experience, however, suggests that the number of treatments per 20 lb cylinder can vary widely. Contributors to this document commented that in some cases as few as two full treatment sessions have been possible with a 20 lb cylinder whereas in other . Smaller cylinders may only provide sufficient gas for a few procedures and should only be used for emergencies. When deciding on a cylinder size it is essential to take into account such factors as costs, caseload, frequency of use, convenience of resupply, and local transport, storage and handling issues. As a general rule, it is best to opt for the largest cylinder size available subject to practical considerations relating to storage and handling on site.. 2.5.4 Cylinder valves. All cylinders are fitted with a suitable valve to allow attachment to the equipment via an appropriate connector. To prevent the risk of an explosion, should a cylinder overheat during transport or storage, the valve assembly must have a pressure relief valve, normally in the form. # of a rupture disc. These types of release valve do not reset; if for any reason the pressure limit is exceeded they will vent the entire contents of the cylinder.. For this reason transporting cylinders in enclosed vehicles can be extremely dangerous. If the rupture disc is activated then the entire contents of the cylinder will be vented into the vehicle.. 2.6 Connectors. Because of the significant risks associated with using the wrong gas - which include poisoning, asphyxiation, fire, and explosion - different types of cylinder valve connectors are used to prevent the accidental connection of the wrong type of gas cylinder to any equipment. Connectors can be of different types and sizes. Some connectors screw onto the valve directly but the size and shape of the union and the type of thread used vary to prevent connecting the wrong type of connector.. For medical gases the use of pin- indexed yoke connectors is common, particularly for the smaller cylinders (see Figure 4 for examples). The location of the pins determines whether the connector will fit on a specific valve. Larger cylinders of medical- grade gases may use other types of connectors meeting American, British, or French specifications.. Some connectors rely upon a direct fit between the metal parts to form a seal, whereas others contain washers and/or O- rings. Many connectors are designed to be tightened by hand only, whereas others require the use of a spanner or wrench.. It is important to never over- tighten the connection, since this can weaken the joint and eventually lead to failure. O- rings and washers need to be inspected every time the cylinder is changed and replaced regularly.. Figure 4: Examples of pin-indexed cylinder valves. Pin Indexed Cylinder Valves. Source: OHYG BOC Gas Cylindersafety.pdf, p. 10. Never apply any kind of lubricant to the thread or the connected thread; with oxidizing gases this could lead to an explosion.. Do not use Teflon (PTFE) tape to seal the connector to the cylinder valve unless this is a specific requirement for the type of connector used. Most connectors do not need tape or any kind of lubricant.. Open the cylinder valve slowly. Rapidly opening the valve can damage equipment attached to the cylinder and can cause the discharged gas to re- liquefy. This liquid can cause cold burns if in contact with the skin.. Unfortunately, different specifications and standards for connectors are in use around the world. The type of fitting can vary depending on the intended use of the gas and the size of the cylinder. In the US the regulation of the connector is governed by Compressed Gas Association (CGA). For example, carbon. # dioxide connections in the US use CGA type320 connectors (applicable for pressures up to 3000 psi). In Europe, Africa, and much of Australia and New Zealand the connectors comply with British Standard BS431 No.8 (BS 431 is interchangeable with European equivalents DIN477 No.6, SN219505 type 7, French NFE29650 type C, and Australian AS2473 type 30). Similar differences apply to nitrous oxide connectors. For example, BS341 type 13 applies to larger cylinders supplied in the UK, whereas pin- index yoke type connectors apply to smaller D and E size cylinders. In the US CGA326 threaded connections and CGA910 yoke connections can be used, but for ultra- high purity nitrous oxide, CGA712 is used. Further information on gas fittings, cylinders, and suppliers by country is given in Annex 5.. 2.6.1 Specifying connector requirements. Some suppliers of cryosurgical equipment provide a complete package including an empty gas cylinder, whereas others do not. Even in those cases where a cylinder is supplied, it is necessary to confirm that the cylinder can be refilled locally. If not, it may be necessary to obtain the cylinder from a local supplier and ensure that the equipment manufacturer supplies an appropriate connector with the equipment.. - Where a cylinder has to be obtained locally, it is essential to confirm that the cylinder valve fitting is compatible with the connector supplied by the cryosurgical equipment manufacturer.- The recommended procedure is to identify which size of cylinder and which type of fitting can be obtained locally and to provide detailed specification to the cryosurgical equipment manufacturer.. Some cylinders are provided with non- removable valve shields or collars. These shields or collars may interfere with the cryosurgical device connector supplied by the equipment manufacturer.. - It is essential therefore when conferring with gas suppliers to get a full specification of the cylinder including the dimensions of any fitted shield. A photograph would certainly help.. In some circumstances it may be necessary to use an adaptor between the cylinder valve and the cryosurgical device but this should only be done as a last resort. Should it prove necessary, it is essential to check local regulations to determine whether it is permitted.. - The fitting of any adaptors should only be carried out by individuals with the necessary skills and qualifications to undertake such work.- Any adaptors should be selected with great care to make sure that they are safe to use with the gas in question, and the pressures involved.- All materials must be compatible with the gas and all fittings compatible with the device and valve assembly.. 2.7 Gas cylinder maintenance. As already pointed out, the gas in a cylinder is under high pressure and extensive damage and injury can occur if a cylinder ruptures or bursts. It is essential that cylinders are managed carefully and not subjected to excessive heat, mechanical trauma, or misuse. All cylinders should be inspected carefully on receipt to make certain that they are not damaged in any way, and inspected periodically during use. Some degree of wear and tear can be expected - for example, the paint can become scuffed and scratched. But never use a cylinder that has dents, bulges, evidence of fire damage such as scorch marks, or significant signs of corrosion. Further advice on handling cylinders is given in Chapter 3.. # 2.8 Nitrous oxide. Nitrous oxide is available in various sizes of high pressure cylinders. The cylinders are either made from carbon steel or aluminium. Under pressure at room temperature . The smaller sizes of nitrous oxide cylinder intended for medical use are fitted with pin index yoke fittings.Larger sizes will be fitted with a BS341- Type 13 fitting or a CGA326 threaded connector.The cylinders should have a working pressure of at least 137 bar.. Nitrous oxide is an anaesthetic. It can cause asphyxiation in high concentrations and is a strong oxidizing agent, strongly supporting vigorous combustion even with materials that do not normally burn in air. Exposure to the gas causes short- term decreases in mental performance and can cause disorientation, sedation, headache, nausea, vomiting, dizziness and loss of coordination, audio and vision problems, and loss of manual dexterity. The effects are rapidly reversible, but long- term exposure can cause vitamin B12 deficiency (megaloblastic anaemia), agranulocytosis, numbness, reduced fertility, reproductive side- effects in pregnant females, and other harmful side- effects.. Misuse of nitrous oxide, including its recreational use, can be dangerous.Do not play with it. Cylinders must be stored and used in well- ventilated areas. Good ventilation is essential when . performing cryosurgery in small rooms.. The long- term exposure limit (8- hour time- weighted average (TWA)) and workplace exposure limit recommended by the UK Health and Safety Executive in EH40/2005 (as consolidated with amendments 2007) is 100 ppm. The National Institute for Occupational Safety and Health (1992) recommended exposure limit for nitrous oxide is 25 ppm as a TWA for the duration of the exposure. The American Conference of Governmental Industrial Hygienists (1994) assigned nitrous oxide a threshold limit value of 50 ppm as a TWA for a normal 8- hour workday and a 40- hour workweek.. # suppliers. Ethylene propylene diene monomer (EPDM) O- rings, washes and gaskets are, for example, recommended for use with nitrous oxide.. 2.9 Carbon dioxide. Carbon dioxide is a colourless, odourless gas that can cause the nose to sting in high concentrations. It is asphyxiant and toxic in high concentrations. Exposure to carbon dioxide may cause increased respiration, headache, nausea, vomiting, mild narcotic effects, increased blood pressure, increased heart rate, and occasionally unconsciousness. It is slightly corrosive in the presence of moisture. The gas is not combustible and does not support combustion (it is used in fire extinguishers).. - Carbon dioxide is heavier than air. It can therefore collect in ducts, drains, and low-lying areas. Entering a poorly. ventilated room in which carbon dioxide cylinders have been stored is therefore potentially hazardous.. As with nitrous oxide, carbon dioxide liquefies under pressures exceeding 73.8 bar at temperatures below . - It is very important to check any carbon dioxide cylinder to make certain that it does not contain a dip tube before connecting it to cryosurgical equipment. Cylinders containing a dip tube may be marked with a white stripe. If necessary check with the supplier of the cylinder.- Carbon dioxide cylinders should be stored or used in a well-ventilated area.- All O-rings, washers and gaskets must be compatible with the gas.- Only use components recommended by the equipment suppliers. EPDM O-rings, washes and gaskets are recommended for use with carbon dioxide.. # Chapter 3. Recommendations for handling gas cylinders<sup>10</sup>. 3.1 Main hazards from gas cylinders. The main hazards from gas cylinders include:. blast impact, including flying debris, from a gas cylinder explosion or rapid release of compressed gas (cylinder pressures can be as high as 300 bar); impact from parts of gas cylinders, regulators or valves that fail; contact with released gas or fluid which might be toxic or asphyxiating; fire resulting from the escape of flammable gases; impact from falling cylinders (they are very heavy- as much as . 3.2 Main potential causes of gas cylinder accidents. The main potential causes of gas cylinder accidents include:. inadequate training and supervision; poor installation; poor examination and maintenance; faulty equipment and/or design (e.g. badly fitted valves and regulators); poor handling or storage; inadequately- ventilated working conditions; incorrect filling procedure (only use reputable companies to refill cylinders); hidden damage.. 3.3 Inspection and training. All gas cylinders must be initially inspected by a competent person before they are put into service, to ensure they conform to the approved standards.. All gas cylinders must be periodically examined at appropriate intervals to ensure that they remain safe while in service. Anyone who examines or uses a gas cylinder should be suitably trained and have the necessary skills to carry out the job safely. They should understand the risks associated with the gas cylinder and its contents. Users should be able to carry out an external visual inspection of the gas cylinder and any attachments (e.g. valves and regulators) to determine whether they are damaged. Visible indication of damage includes dents, bulges, or evidence of fire damage (scorch marks). Gas cylinder users should satisfy themselves that the cylinders have been properly tested by examining either the written certificate accompanying the gas cylinder or the stamp or mark of relevant inspection body on the gas cylinder itself. The level of control over the quality of cylinders varies from country to country. In some countries certificates may not be routinely available and cylinders may not be stamped or marked. Users should nevertheless take whatever steps they can to confirm with the suppliers that the cylinders are safe and have been subject to testing. Gas cylinders must be clearly marked to show what they contain and the hazards associated with their contents.. 3.4 Handling and use. Gas cylinders should always be used in a vertical position, unless specifically designed to be used otherwise. Gas cylinders should always be securely restrained to prevent them from falling over (for example attached to a wall by a chain or strap). Always double check that the cylinder/gas is the right one for the intended use. Do not remove or discard any batch labels fitted to the cylinder if present. Before connecting a gas cylinder to equipment or pipework, make sure that the. # regulators and pipework are suitable for the type of gas and pressure being used.- Gas cylinders can be heavy and difficult to handle. Wear appropriate personal protective equipment (such as safety shoes, protective overalls, or gowns and protective gloves) when handling gas cylinders, and safety spectacles when using them.- Carefully clean any connector with a clean, oil- free cloth before connecting the regulatory to the cylinder valve.- Never use excessive force when connecting equipment to the cylinder.- After connecting a cylinder, check for any leaks at the cylinder valve, regulator, hose, or any other location where there is potential for leakage to occur.- Should a leak occur between the valve outlet and the connector or manifold yoke, depressurise and remove the fitting and fit an approved sealing washer. Reconnect the fitting to the valve with moderate force only, fitting a replacement regulator or manifold tailpipe as required. If the leak persists, label the cylinder as leaking and return to the company. Sealing or jointing compounds must never be used to cure a leak.- Do not use gas cylinders for any other purpose than the transport and storage of gas.- Never drop, roll, or drag cylinders.- Close the cylinder valve and replace dust caps, where provided, when a gas cylinder is not in use.- Ensure that the valve is protected by a valve cap or collar that the valve has been designed to withstand impact if the cylinder is dropped.. 3.5 Lifting and transport. - Avoid the need for manual handling of gas cylinders whenever possible, for example by using cylinder trolleys.- Do not lift cylinders by their valves, shrouds or caps unless they have been designed and manufactured for this purpose.. - Gas cylinders should not be raised or lowered unless adequate precautions are taken to prevent them from falling.- Fit suitable protective valve caps and covers to cylinders, when necessary, before transporting. This helps to prevent moisture and dirt from gathering in the valve of the cylinder, in addition to providing protection during transport.- Securely stay gas cylinders to prevent them from moving or falling. This is normally in the vertical position, unless instructions for transport state otherwise.- Avoid transport on vehicles where the load space is not separated from the driver's compartment.- Disconnect devices and hoses from cylinders when not being used.. 3.6 Storage. - Gas cylinders should not be stored for excessive periods of time. Only purchase sufficient quantities of gas to cover short-term needs.- Rotate stocks of gas cylinders to ensure first in is first used.- Store gas cylinder in a dry, safe place on a flat surface in the open air. If this is not reasonably practicable, store in an adequately-ventilated building or part of a building specifically designed for this purpose.- Gas cylinders containing flammable gas should not be stored in part of a building used for other purposes.- Protect gas cylinders from external heat sources that may adversely affect their mechanical integrity. This is particularly important in hot climates.- Store gas cylinders at room temperature (i.e. between 20-30 °C [68 - 86 °F]) and away from sunlight.- Gas cylinders should be stored away from sources of ignition and other flammable materials.- Warning notices prohibiting smoking and naked lights should be posted in the cylinder storage area.. # Do not store gas cylinders containing flammable gases with cylinders containing oxidizing gases such as oxygen and nitrous oxide. Avoid storing gas cylinders so that they stand or lie in water or other liquid. Ensure the valves on empty cylinders are closed to prevent contamination entering the cylinder. Store gas cylinders securely when they are not in use. They should be properly restrained, unless designed to be freestanding. Store cylinders where they are not vulnerable to hazards caused by impact (e.g. from vehicles).. 3.7 Reference documents. Safe use of gas cylinders: Guidance issued by the Health and Safety Executive, Issue 1. London, Health and Safety Executive, June 2004. (www.hse.gov.uk). Medical Gas Data Sheet: Medical nitrous oxide, Essential safety information. BOC Healthcare Customer Service Centre, Priestley Road, Worsley, Manchester M128 2UT, UK.. Medical Gas Data Sheet: Medical carbon dioxide, Essential safety information. BOC Healthcare Customer Service Centre, Priestley Road, Worsley, Manchester M128 2UT, UK.. McIntosh N, Blumenthal P, Blouse A, eds. Cervical Cancer Prevention: Guidelines for low- resource settings. Baltimore, MD, Jhpiego Corporation, July 2000.. # Chapter 4. Procurement guidance. This chapter provides information on procurement planning for procuring cryosurgical devices. Prioritizing and planning procurement activities upfront will avoid missed schedule milestones, the procurement of poorly specified equipment, and poor vendor relationships. These problems can cause delays and budget overruns. These are general guidelines and should be used as a complementary resource to local procurement and other regulations.. Procurement is a sequential process that includes seven major, interdependent steps, shown in Figure 6. An efficient and effective procurement procedure will include:. 1. estimating the quantities of cryosurgical equipment, spare parts and gas supplies needed and their costs; 2. defining and verifying the fitness of specifications (i.e. the physical characteristics and performance of the cryosurgical equipment to be procured), taking into account any national regulatory or registration requirements;. 3. preparing documents for competitive bidding and conducting the bidding process; 4. negotiating the details of the procurement with the selected supplier; 5. obtaining approvals and documentation; 6. completing the contract; 7. managing the supplier, delivery, and assuring quality.. 4.1 Planning. Estimating the quantities of cryosurgical equipment, spare parts, and gas supplies needed and their associated costs is a critical first step to initiating procurement actions. This step will define the scope of the procurement. Procurement processes often escalate in formality and time required depending on value and complexity. The quantity estimate is used in confirming financial considerations, procurement methods, and shipping methods.. # Consideration should be taken to calculate the number of facilities that will receive equipment and how many procedures per day will be performed. This information is important in determining the number of devices needed and the number of spare parts kits to include.. The required delivery date is also a critical piece of information that will inform when each procurement step needs to occur. The equipment should always arrive ahead of scheduled training with enough time to assemble and troubleshoot connections to gas. The procurement department will identify the amount of time needed for confirming specifications, conducting bidding, and other processes. Sufficient time should be allocated for the procurement process. Avoiding steps can lead to problems, ranging from bid protests to ordering incorrect or incomplete equipment. Transit time, customs processing, supplier manufacturing, contracting process, approval process, and negotiation should also be included in the timeline.. In some countries cryosurgical equipment may need to be approved and/or registered with the national regulatory authority as a medical device. A certificate of free sale in the country of manufacture may also be required for some recipient countries. In addition, some countries where the equipment is manufactured may required export certificates. Sufficient time and planning must be included to evaluate these regulatory needs and ensure that the manufacturers can supply all the documentation necessary to comply with local regulations where they exist. Failing to comply with this step can lead to the product being rejected or held in customs for long periods of time, and can also include severe penalties.. 4.2 Specifications. Specifications define the physical characteristics and the performance standards of the equipment to be procured. Earlier chapters provide information and guidance that can . Specifications include both minimum criteria for technical selection and optional considerations. If any area is considered optional, it must be clearly noted. Specifications must be clear and complete. When specifications are not complete, they often lead to offers that are difficult to compare and understand. In some cases, incomplete specifications can be considered an indication of a flawed procurement process and they leave the procurer open to a "protest" where suppliers can object to the final supplier selection. This creates delays and adds expense to the process. Specifications may also be used in pre- or post- shipment inspections (where applicable) and in overall acceptance of the final product.. 4.3 Competition. Competitive procurement is an accepted method in the public sector for obtaining the best value for a quality device. In most countries, the procurement of cryosurgical equipment would be conducted along with the procurement of other medical and surgical. # devices. The processes used generally adhere to strict national requirements for bidding, including strict deadlines, evaluation by a procurement committee, and sealed bids. Local procurement regulations generally dictate the selected process and procedure; however, if cryosurgical equipment is procured through more informal methods, including those available to some vertically managed programmes, the process should ensure diligence in planning, competition to ensure a range of options, specification development, and technical evaluation of offers.. 4.3.1 Requesting quotations (invitation to bid). The object of the Request for Quotation (RFQ) or Invitation to Bid is to solicit competitive offers that represent the best combination of technical and cost value. Typical orders for cryosurgical equipment will be under US$ 100 000 and can be procured using the simplified RFQ process described below. Should the procurement value be in excess of US$100 000 then a more formal process is generally required. The formal Invitation to Bid process requires an open invitation, a formal Request for Proposal document, and sealed bids, opened by a bid- opening committee on an established date and time.. The World Bank procurement guidelines offer an internationally accepted formal Invitation to Bid process<sup>11</sup>.. 4.3.2 Simplified request-for-quotation process. The RFQ communicates and establishes the technical requirements for the equipment, as well as all other criteria for awarding the final offer. It must be clear and structured, or resulting offers will lack the detail needed to evaluate the bids. At a minimum, the document should address equipment specifications, . All bids should be received sealed and only opened by the bid- opening committee at a specified time and date after the bid closing date and time. A bid analysis should be performed and documented. A template should be developed to indicate minimum technical and information requirements for the offers. This template should be developed at the same time as the RFQ and verified to ensure that the RFQ requests the required detail. Offers that do not meet the minimum requirements are rejected and only the remaining bids are reviewed for cost and other factors, such as supplier performance references, advantageous warranties, and other pre- established criteria. For a cryosurgical unit, it is appropriate to consider equipment cost, operating costs, delivery terms, warranty, and cost and availability of spare parts packages. Intangibles that would add to the assessment of each manufacturer, such as standardization with existing equipment, should also be included. All these variables should be put into a spreadsheet formatted for presentation to facilitate the analysis and support the final award.. 4.4 Negotiation. Subject to local procurement regulations, negotiation can occur once the evaluation is complete and the supplier has been selected. The ability to negotiate on the content of an offer varies depending on local procurement regulations, but is generally not allowed until after an initial selection as been made. Terms and conditions, delivery, spare parts packages, and service and warranty period are typically the areas where negotiation is considered. In some case, price may also be considered negotiable. The contract should reflect all terms included in the RFQ (noting that the procurer's standard terms and conditions should have been included), as well as any specially negotiated terms. Negotiation does. # not occur without some level of risk. Clear and transparent documentation of any negotiation proceedings must be kept. If the negotiation takes place in a verbal meeting, minutes must be prepared. If it occurs via email, records of all negotiations must be maintained. When the procurer initiates negotiation, it is assumed at that point that the supplier may also attempt to negotiate certain terms. This should be allowed. In any case where negotiation is performed, trained procurement negotiators, attorneys, or contract specialists should always be involved.. 4.5 Approval and documentation. Before releasing a final contract, all elements of the procurement process must be documented and presented for approval to the appropriate body. In most cases, procurement authorities require a system of checks and balances whereby the parties creating technical specifications and conducting bid evaluations are separate from those who review and approve the transaction. This practice safeguards against internal bias towards certain manufacturers and also ensures neutrality in reviewing the key risk elements of entering into a contract. Those who review and authorize the final transaction should be individuals within the procurement department who have the training and authority to commit their organization. The procurement process should document all steps along the way in preparation for this final step. Failing to produce documentation for a specific step in a procurement process is often assumed to imply that the step did not take place or was insufficiently managed. Returning to earlier phases to rework an element that was not properly documented or managed can create problems ranging from delays to cancelling and re- starting the entire process. Organized documentation is important in defending the decisions of the procurement authority and protects the procurer's decision in the event of any liability.. 4.6 Executing contracts. A purchase order (PO) or contract for goods and services is the final document that secures all terms and conditions of the transaction. The PO or contract is normally developed by the procurer and released to the supplier. It should represent all terms and conditions as agreed. The agreement would either be acceptance of all terms and conditions included in the RFQ, or all negotiated terms and conditions. When the PO is released, the supplier generally has a limited period (e.g. 3 working days) to accept or reject the purchase order. Rejection is rare and typically only occurs when the procurer does not accurately represent what has been agreed or adds significant terms that the supplier was not previously aware of.. Once the PO is accepted by the supplier, it represents a legally binding contract and governs the implementation of the transaction from that point forward. It is important to note that the PO governs the implementation of the transaction; however, the transaction must be actively managed to ensure compliance with the terms and conditions.. If a purchase order is altered in any way, a written amendment to the original purchase order must be created and signed by both procurer and supplier, and the documentation must be retained with other procurement documents related to the transaction. Once agreed to, any amendments are binding under the terms of the original purchase order.. 4.7 Managing the supplier delivery and assuring quality. The procurement process should build in steps to assure that the equipment will be of appropriate quality and performance when it finally arrives. POs and contracts have terms that allow them to not accept equipment that fails to meet the specifications, but avoiding such a situation is critical to maintaining timelines and avoiding extra costs. It is good practice to follow up with the supplier in advance of ship-. # ping to ensure the agreed- upon delivery dates will be met. This will allow the receiving organization to properly plan for receipt inspection.. When necessary, equipment can be inspected prior to shipment or upon arrival in a country. This is referred to as pre- or post- shipment inspection and is conducted based on a subset of the specifications. It has limitations, but can be an effective safeguard when needed. An example of a limitation is that an inspector can confirm that contents meet the descriptions of the equipment, but they cannot test it to ensure that it meets performance standards without a specific testing protocol.. Pre- shipment factory testing is one way that many organizations assure the quality of their equipment purchases, particularly if certain tests need special test equipment that the buyer does not possess. In these cases, documentation of the test results is provided. The results are either inspected by an official inspector, or by a competent authority within the procurement agency. Verification that the documents are correct and bone fide is generally part of compliance with current Good Manufacturing Practices (cGMP). If a manufacturer is cGMP certified, the documents can be reasonably expected to be accurate and bone fide. If not, the procurer may opt to visit the factory and witness the testing or accept the documentation of the testing at their own risk.. Inspection criteria should be carefully used and developed. Excessive criteria can add costs, delays, and confusion if they are not implemented by qualified staff.. It is important to perform a comprehensive post- delivery inspection of the equipment after it is delivered to the receiving site. The inspection, which should be done immediately the equipment arrives, should document any damage or non- conformance to specifications. It should be reported immediately to the supplier and remedies should be sought.. A post- delivery inspection is a comprehensive, final inspection of the purchased equipment. The objective of the post- delivery inspection is to find any missing components, damage, or malfunctions.. Preparation for the inspection is done by developing a checklist based on the purchase order specifications. Include the equipment's original specifications in the purchase agreement. The inspection/receipt report should be documented as part of the procurement for the transaction.. If damage or problems are discovered, and the supplier cannot arrange for on- site remedy or repairs, then the equipment should be sent back to the manufacturer. If the schedule cannot accommodate the time required for the reworking, then the procurement department and the vendor will need to negotiate financial reparations or replacement. Payment for the shipment should only be made after the shipment has passed all inspections.. It is also important to track supplier's schedule and quality performance over time. Poorly- performing suppliers should be advised that expectations of their performance have not been met. Performance levels can also become evaluation criteria when considering future business.. Procurement is a crucial process. It ensures good stewardship of funds and supports quality medical care when medical equipment or supplies are involved. An appropriate and well- managed procurement process can take time and resources. The consequences of a poorly- managed procurement process can be devastating to programmes, ranging from delays to irreplaceable losses of limited funding. Procurement professionals are trained to work in conjunction with legal, financial, and technical departments. They work to coordinate a process that protects public funds and ensures the best possible results for those ultimately seeking health services that depend on supplies and equipment.. # Annex 1. Glossary of terms. Active defrost - a mechanism within some cryosystems that accelerates the return of the cryotip towards ambient temperature.. Cryotip - an interchangeable tip designed to fit a specific anatomical site (cervix) for the purpose of freezing the tissue. A closed cryotip will not vent gas or cryogen in the vicinity of the tissue. An open cryotip directly jets the gas or cryogen onto the tissue and is not appropriate for use in treating cervical lesions.. Compressed gas cylinder - a container that is specifically designed to store a gas or liquid under elevated pressure conditions.. Compressed gas cylinder valve - a device specifically designed to receive a connector to the cryosystem. It is pre- attached to a gas cylinder to allow for the proper and safe release of its contents.. Connector to the cryosystem - the fitting between the compressed gas cylinder valve that connects the tank to the cryosystem.. Connection adapter - an extension placed between the compressed gas cylinder valve and the connector to the cryosystem, which is used in cases where there is mismatch between the valve tip and connector to the cryosystem, including the valve being too short, the wrong threading etc.. Cryo- adhesion - cryotip attachment to target tissue.. Cryogen - a substance, such as compressed gas or liquid, used to obtain reduced temperatures. Cryogens are usually classed by their boiling points and their grade. The most common cryogens for precancerous cervical lesions and their respective boiling points are as follows:. Cryonecrosis - destruction of tissue cells using cryogen (see clinical references for additional detail).. Cryoshaft - the component onto which the cryotip is attached. The cryoshaft may be detachable or fixed, and should be thermally insulated.. Cryosystem - collectively, all parts of system necessary to apply cryogen therapeutically, for the treatment of cervical precancer. It excludes the gas and its tank, the compressed gas cylinder valve, and the adaptor.. Defrost - the function of the cryosystem which allows the cryotip to return toward ambient temperature.. EPDM - ethylene propylene diene monomer rubber.. Exhaust hose - a hose that returns the exhaust gas from the cryogun to the regulator assembly for venting.. Exhaust port vent - the vent to which a tube can be attached to safely vent the exhaust gas from the room.. Gasket - a round, flat plastic or rubber ring (that looks like a washer) which is usually placed between the connector to the cryosystem and the compressed gas cylinder valve.. Handle - the part of the cryosystem that is gripped in the hand and that includes the trigger mechanism.. Hose assembly - polymer tubes that carry the cryogen from the regulator to the handle. In cryosystems, it is common to have an assembly in which there may be tubes inside a main hose.. Mechanical integrity - the ability of all components of a cryosystem to withstand the pressures and temperatures that may be encountered during use as recommended by the manufacturer.. Notified Body - in relation to medical devices, an organization authorized by a Competent. # Authority of a European Member State to determine whether a medical device meets the essential requirements of the European Medical Device Directive.. O- ring - a ring of rubber or silicon usually inserted between the cryotip and the cryoshaft to ensure an effective seal to avoid leaking.. Passive defrost - a function of a cryosystem (without active defrost) to return towards ambient temperature. Passive defrost is typically a slower process of defrosting the cryotip than active defrost.. Regulator - a device for maintaining a constant gas pressure. Note that most cryosurgical devices are not equipped with a regulator.. Rupture disc - see safety valve.. Safety valve - a valve, usually a rupture disc, to release excessive pressure in the system. Can also be called a pressure relief valve.. Single- use disposable - any device which is designed to be discarded after one use.. Target tissue - the specific anatomical area of the cervix intended to be treated.. Thermal insulation - a material used to prevent unintended cryonecrosis, inflammatory responses, or cryo- adhesion to non- target tissues.. Thermocouple - a junction of two dissimilar metals that produce an output voltage proportional to the temperature of the junction. The output is directly correlated to the temperature to which the sensing junction is exposed.. Tractive force - the level of attraction between the cryotip and the target tissue during cryo- adhesion, i.e. when the tip freezes to the tissue.. Trigger mechanism - the mechanism that is activated (or squeezed, pressed, or pushed) to release the cryogen into the cryotip. Cryo- systems may also include triggers for active defrosting.. US FDA - United States Food and Drug Administration, an agency within the U.S. Department of Health and Human Services that protects public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products, medical devices, the food supply, cosmetics, dietary supplements, and products that give off radiation.. Washer - see gasket.. # Annex 2. Technical Basis Paper: Cryosurgical equipment for the treatment of precancerous cervical lesions. A1 Introduction and scope. This technical basis paper reviews the types of cryosurgical equipment that are available and discusses some of the key issues in acquiring and using the equipment in low- resource countries. It is intended to summarize the technical discussions undertaken by the WHO Cryotherapy Technical Specification Working Group and provide background information supporting the recommendations made in the Cryotherapy Technical Specifications and Procurement Guidelines. It is not intended for circulation to users of the equipment, but to provide a record for future reference of the issues discussed and rationale for the recommendations made.. A1.1 Research methods. The paper is based on a literature search for information on cryosurgical equipment conducted online using the NML Gateway (a service of the US National Institutes of Health) which accesses multiple retrieval systems including MEDLINE/PubMed.. Information related to cryosurgical devices and equipment has also been collated from the following sources:. - The 2008 WHO/UNFPA/PATH Cryotherapy Market Survey.- Bench testing of four cryosurgical devices with nitrous oxide and carbon dioxide in Peru in 2009.- Discussion held by the Technical Specifications working group during the March 30-April 1, 2009: Building a consensus on approaches to improving cryotherapy service delivery to prevent cervical cancer.- Meeting on Procurement of Cryotherapy Equipment for Cervical Cancer Prevention. September 23rd and 24th, 2010.. A1.2 Cryosurgical equipment. Cryosurgical equipment is available from a number of manufacturers, mainly US- based but with some types available from European and. Indian manufacturers. The equipment is used to treat a wide range of medical conditions in dermatology, ophthalmology, gynaecology, and other disciplines. Not all cryosurgical equipment is suitable for the treatment of precancerous cervical lesions.. Two main methods are used to cool the cryoprobe: the expansion of a compressed gas through a nozzle, causing cooling by the Joule- Thomson effect; and the use of cryogenic liquids such as liquid nitrogen. Because of the risk of damaging surrounding tissue, cryosurgical equipment based on cryogenic liquids is never used in the treatment of precancerous cervical lesions. Additionally, the availability, transport, delivery, storage, and handling of liquid nitrogen can be problematic in low- resource countries. For these reasons this paper only considers cryosurgical equipment that operates on compressed gases such as nitrous oxide and carbon dioxide.. Both nitrous oxide and carbon dioxide have high Joule- Thomson coefficients making them good gases for this purpose. Most cryosurgical equipment manufacturers offer the option of carbon dioxide or nitrous oxide. The choice of gas has to be made at the time of purchase of the equipment to ensure the proper fittings, and in some cases the appropriate device. In low- resource settings carbon dioxide is often cheaper and more readily available.. The recommended temperature most widely cited in the literature for treating precancerous cervical lesions is . # that the equipment is capable of achieving tip temperatures of . Examples of some of the main suppliers that have been identified through internet searches are given in Table A1.. A1.3 Description of a typical cryosurgical unit. A typical cryosurgical unit consists of a hand unit with a shaft to which detachable probe tips can be attached. The hand unit is fitted with one or more triggers and other controls to regulate the temperature and control the freezing/thaw cycle. It is designed such that the controls can be used with just one hand. Some models are fitted with temperature sensors to indicate . The hand unit is attached to a pressure gauge assembly that conducts the high pressure gas to the unit and returns waste gas to be vented.. A1.4 Cryotips. Most manufacturers offer a wide range of interchangeable cryosurgical probe tips (cryotips). These are interchangeable and can be cleaned and disinfected between patients. In some cases the cryotips can be changed without depressurising the system. Some cryotips can be autoclaved whereas others can only be disinfected by treatment with chemical disinfectants. The manufacturers' instruction must. # be followed when determining the cleaning and disinfection cycle for any probe type.. Only closed cryotips can be used for treating cervical lesions. Open cryotips apply the cryogen directly to the target tissue and must not be used for treating cervical lesions because of the risk of damage to surrounding healthy tissue.. The cryotips are usually made from surgical- grade interchangeable metal fittings. Some designs are covered with a plastic sleeve which is removable for cleaning. Based on an assessment of the type and duration of exposure to the cryotips according to ISO 10993- 1 (2009), Biological evaluation of medical devices, it is recommended that the cryotips should be assessed by the manufacturers for cytotoxicity, irritation, and sensitization potential. If medical- grade materials are used for the cryotips, then actual testing may not be necessary. Cryotips with a well- established history of safe use also do not need to be subjected to testing according to ISO 10993- 1.. The cryotip must be removable to allow interchangeable tips to be used and to facilitate cleaning and disinfection after use. In some configurations, the cryotip attaches to the probe shaft with internally threaded surfaces inside the metal tube. Other configurations combine the probe shaft and the cryotip. These are detachable at the base of the probe. Both configurations provide the same intended result and there are no technical reasons to select one over the other, although detachable cryotips may be easier to sterilize by boiling or autoclaving.. Cryotips used for treating precancerous cervical lesions should be rounded in shape and be 19 mm in diameter . # The surface of the cryotip should be smooth with no sharp edges. The material should withstand routine sterilization or disinfecting with hospital disinfectants. It is recommended that the manufacturers' recommendations for cleaning and disinfection are followed. Not all cryotips can be autoclaved or disinfected with some hospital disinfectants.. A1.5 Cryoshaft. The cryoshaft connects the cryotip to the trigger unit. It does not have a required minimum or maximum length but typically the overall length of the cryoshaft and cryotip assembly should be between . The materials used for its construction must be able to withstand routine sterilization or disinfecting with hospital disinfectants, including bleach dilutions or any other disinfectant for surgical instruments.. A1.6 Trigger mechanism. The hand unit should have an integrated trigger or other mechanism to activate the flow of gas. The trigger mechanism should be designed to give the user sensory feedback indicating whether the device is in the on or off position. There should be a latching or ratchet mechanism allowing the user to lock the trigger in the on position. The trigger must also have a release mechanism to unlock the trigger and return the device to the off position.. The trigger mechanism activates the internal valves and switches required to deliver the gas from the attached hose though the gas delivery tube to the cryotip and exhaust gas. # back through the exhaust tube. The trigger mechanism unit should be made of rigid plastic, of a type and grade that will insulate the hand of the user while providing durability.. The material must withstand routine sterilization or disinfecting with hospital disinfectants, including bleach dilutions or any other disinfectant for surgical instruments. The handle should be of a design that allows the user to hold and control the device in one hand, either the left or the right.. Active defrosting mechanisms may or may not be incorporated into the operation of the unit. If an active defrosting option is included, it may be integrated into the trigger function or the handle. Both active and passive defrost systems are acceptable. Whatever system is used, it must be capable of being operated by one hand.. A1.7 Hose assembly. The hose assembly connects the trigger mechanism to the gas supply, both delivering the gas and venting the exhaust gas. The hose assembly should be of sufficient length for comfortable operation while the tank is appropriately secured to a nearby wall or safe portable stand. A minimum of . The hose connection should be integrated into the handle and not designed for removal by the user. The other end of the hose should securely connect to the pressure gauge. The hose assembly should be capable of being pressured to at least twice the maximum cylinder pressure13(ca 2,000 psi).Ideally, hoses complying with the requirements specified . Due to the constant flexing, pressure, and movement during use, the hose assembly should be checked periodically for and signs of damage including leaks or cracks. If damaged, cracked or leaking, the hose assembly must be replaced with replacement part provided by the manufacturer. Most manufactures supply a step- by- step instruction on how to replace the hose assembly.. A1.8 Pressure gauge. The pressure gauge is a visual indicator of the pressure in the tank and should clearly indicate whether the gas pressure is within the appropriate range (minimum to maximum) for the device to function properly. For many cryosurgical devices, the pressure gauges are colour- coded to indicate the safe operational range.. A1.9 Pressure relief valve. The pressure relief valve is designed to protect the device and the user from potential excessive tank pressure. It typically works by having an internal rupture disc which bursts at a set pressure, preventing the device from becoming over- pressurized. The pressure relief valve should be designed to rupture if the maximum pressure rating of the pressure gage, the hose assembly, or the trigger mechanism is reached. Once triggered, the relief valve will completely empty the cylinder.. A1.10 Exhaust port. Since both carbon dioxide and nitrous oxide can be hazardous, cryosurgical units should have an exhaust port that allows the operator to attach a hose to vent the exhaust to a place with adequate air circulation.. A1.11 Gas connector. The gas connector connects the cryosurgical system to the compressed gas cylinder.. # It should be made of metal and should be appropriate for use with pressurized gases, specifically with carbon dioxide and nitrous oxide. There are multiple types of connectors (compressed gas cylinder valves vary from country to country). It is essential that the proper connector is used with the compressed gas cylinder valve. More information on gas fittings and gas supplies are given later in this document and in the document on gas supplies.. A1.12 Performance and Safety Standards. Ideally cryosurgical systems should conform to appropriate standards such as F882- 84 (reapproved 2002) Standard Performance and Safety Specification for Cryosurgical Medical Instruments. This specification covers standards a manufacturer must meet in the designing, manufacturing, testing, labelling, and documenting of cryosurgical medical instruments, but does not cover factors such as production methods, quality control techniques, manufacturer's lot release criteria, or clinical recommendations.. A1.13 Training. All equipment should be fit for the intended purpose of treating precancerous cervical lesions. Each unit should be accompanied by training materials specifying basic operation of all components, assembling the equipment, risks of use, and maintenance.. A1.14 Spare parts. It is imperative that spare parts such as the hose assembly, cryotips and cryoshafts be purchased from the original equipment manufacturer. Due to varying design, replacement parts from other manufactures are not acceptable replacements. Similar comments apply to parts that require inspection and replacement on a regular basis. These include O- rings and sealing washers. A supply of these components should be purchased with and maintained with the equipment.. A2. Bench testing of cryosurgical devices and equipment. Bench testing was conducted in Peru using four different makes of cryosurgical devices and locally obtained nitrous oxide and medical- and industrial- grade carbon dioxide. The temperatures reached by each device when used with each gas were compared using a thermocouple to continuously monitor the temperature of the cryotip. Comparisons across the devices were based on the mean and lowest temperatures reached. The study found that all of the devices tested reached temperatures below . One- way analysis of variance identified the device as the dominant factor determining the differences in temperature, whereas the gas was not a significant determinant of temperature reached. The study concluded that both nitrous oxide and medical- and industrial- grade carbon dioxide reach appropriate freezing temperatures with some cryosurgical devices and that performance of some cryosurgical devices is suboptimal. Given that carbon dioxide is likely to be the preferred gas in low- resource countries since it is generally more readily available and cheaper, the outcome of this study suggest that the choice of a device that can reach the recommended temperature of . A3. Recommendations on gas supplies. A full review of gas supplies for cryosurgical equipment has been completed separately. This includes advice on the selection, procurement, storage and handling of the gas cylinders (See Chapter 2 and 3). Both carbon dioxide and nitrous oxide are liquid at the typical pressures. # found in commercial gas cylinders. This significantly increases the capacity of gas that can be stored in an equivalent- sized cylinder compared to the amount of a gas that does not liquefy under normal cylinder pressure.. Carbon dioxide and nitrous oxide can be obtained in a number of different purity grades and in a wide variety of cylinder sizes. In general, the purer the grade the less likely is the risk of the cryosurgical equipment becoming clogged during use. For this reason medical- grade gases are preferred, with food/beverage grades being acceptable as an alternative.. Cylinders are available in a wide range of sizes. The size of gas cylinders can be specified by a letter code, by the water capacity expressed in pounds, by internal volume, or by the volume of gas at normal pressure and temperature contained in the cylinder. Common sizes for European medical gas cylinders<sup>14</sup> are size C containing . The number of cryosurgical sessions per cylinder will clearly depend upon the size of the cylinder, the type of equipment used and the duration of the procedure. Walach, in their sales literature, state that the LL100 Cryosurgical System using a 20 lb nitrous oxide cylinder should provide approximately 80 minutes of use, i.e. sufficient for about 20 precancerous cervical lesion treatments. Practical experience, however, suggests that the number of treatments per 20 lb cylinder can vary widely ranging from as few as two full treatments per 20 lb cylinder to over 20 treatments. Local temperature conditions and the filling policies of local gas suppliers may have a significant impact on . A3.1 Specifying connector requirements. A major potential problem in using cryosurgical equipment in low- resource settings is ensuring that the fitting on the equipment matches the fitting on the gas cylinder. Different standards apply to gas cylinder connectors in different countries. To prevent accidental use of the wrong gas, cylinder fittings are deliberately designed differently for different gases. Additionally, the type of fitting can change depending upon the grade of gas and the size of the cylinder. All of these factors complicate the purchase and use of cryosurgery in low- resource settings where the availability of gas cylinder fittings may be different to that in the country where the equipment is manufactured. Guidance on the choice of the correct fitting is provided in the document on gas supplies for cryosurgical equipment (See Annex 5).. A3.2 Gas safety. Both carbon dioxide and nitrous oxide can be hazardous if leaks occur or the exhaust from the cryosurgical unit is not vented properly. Additionally, the gas cylinders are under high pressure and can be hazardous in their own right. Appropriate precautions for working with the gases and handling the cylinders are given in Chapters 2 and 3.. A4. Operational procedures. Cryosurgical treatment is a medical procedure that should only be performed by trained clinical providers. Appropriate clinical training should be provided in advance of using the equipment.. Clinical guidelines on the use of cryosurgical equipment are available in the WHO guidelines on cryotherapy (Annex 3).. # General guidelines on the operation of cryosurgical equipment in the treatment of precancerous cervical lesions are given in the Jhpeigo Cervical Cancer Prevention Guidelines for Low- Resource Settings<sup>15</sup>. The guidelines are based on the Wallach LL100 cryotherapy system but nevertheless can be generalized to most equipment types. The general steps required to set up, test, use, clean, and troubleshoot the equipment are described. When using equipment from other manufacturers, however, reference must be made to the manufacturer's own instructions for specific guidelines on setting up, testing, using, cleaning, disinfecting and troubleshooting the equipment.. The guidelines recommend that when using carbon dioxide, the risk of the unit becoming blocked by ice particles can be reduced by using the freeze- clear- freeze technique. Basically this consists of beginning the freeze cycle for 15 seconds and then very briefly pressing the defrost trigger for a second or less before reapplying freezing. This cycle is repeated through the whole of the freezing procedure. This procedure is also known as the cough technique.. Seamans et al<sup>16</sup> demonstrated, however, that when using the cough technique with the Wallach LL100 cryotherapy system (with a T- 2500 2.5 cm diameter flat probe) the minimum tissue temperatures achieved using either nitrous oxide or carbon dioxide were greater than the . Winkler et al<sup>17</sup> reported very similar results, again using the Wallach LL100 cryotherapy system. The temperature of the cryotip did not drop below . In an attempt to overcome blockages due to icing, Seamans et al.<sup>18</sup> reported on the use of a gas conditioner to filter and dry the gas before it enters the cryogun. The conditioner was placed in the in the gas supply line between the cylinder and the Cryogun. It contained a commercial calcium sulphate laboratory desiccant, Drierite (W. A. Hammond Drierite Co. Ltd, Xenia, Ohio). The authors concluded that the gas conditioner showed promise in reducing the incidence of blocking, but it has not yet been made commercially available. Follow up work by Winkler et al.<sup>19</sup>, however, showed that the device only helped with the Wallach LL100,. # which as stated in the previous paragraph has since been recalled and modified. Using the conditioner with other makes of cryosurgical equipment led to increased tip temperatures. The use of a gas conditioner is therefore not recommended.. A5. Cleaning and disinfection. The cryosurgical unit, cryoshaft and cryotip will all require cleaning and disinfection between patients. Disinfection can present a major problem in low- resource countries. WHO recommends that a solution of sodium hypochlorite with . When cleaning equipment without a detachable cryoshaft, special care has to be taken to prevent damage to the hand unit. Such units cannot, for example, be immersed in disinfectant.. Alternative chemical disinfection options are severely limited. Treatment with . Other options for disinfecting the cryotips include boiling or steaming to 20 minutes, autoclaving at . Whatever methods of cleaning and disinfection are used, it is essential that the manufacturers' instructions are followed, otherwise the cryotips could be damaged. Not all manufacturers make cryotips that can be heated or autoclaved and some might be damaged by the chemicals that are used. Read the manufacturers' instructions before use.. # Annex 3. WHO guidelines on cryotherapy. PS 12: Cryotherapy. PRACTICE SHEET 12: CRYOTHERAPY. Cryotherapy is the freezing of the abnormal areas of the cervix by the application of a very cold disc to them. It takes only a few minutes and usually only causes some cramping.. The following materials and equipment are needed for cryotherapy:. speculum, high- level disinfected (it need not be sterile); disposable or high- level disinfected examination gloves (need not be sterile); cotton swabs for wiping the cervix; normal saline solution; colposcope, if used in the particular venue; cryosurgery unit with adequate gas supply (Figure PS12.1).. For basic equipment to perform a pelvic examination refer to PS7.. Source: Sellors JW, Sankaranarayanan R. Colposcopy and treatment of cervical intraepithelial neoplasia: a beginners' manual. Lyon, IARCPress, 2002.. # PERFORMING CRYOTHERAPY. Before the procedure. 1. Explain the procedure, and why it is important to return for further management as requested. Ensure that the woman has understood and obtain informed consent.. PS6 Informed consent PS7 Pelvic exam. 2. Show her the cryotherapy equipment and explain how you will use it to freeze the abnormal areas on the cervix.. 3. Prepare the patient for a gynaecological examination, and perform a speculum examination (see Practice Sheet 7).. 4. If there is no evidence of infection, proceed with cryotherapy.. 5. If there is a cervical infection, provide treatment as described in Annex 8. You may proceed with the cryotherapy, or you may give the patient an appointment to return once the infection is cured.. Procedure. 6. Wipe the cervix with a saline-soaked cotton swab and wait a few minutes. 7. Apply acetic acid to outline the abnormality and wait a further few minutes. 8. Tell the woman she might feel some discomfort or cramping while you are freezing the cervix. 9. Wipe the cryoprobe surface with saline to ensure optimum effectiveness. 10. Apply the cryoprobe tip in the centre of the os and make sure the probe adequately covers the lesion (Figure PS12.2). If the lesion extends more than 2 mm beyond the probe, discontinue the procedure. Explain to the woman why you are doing this and what needs to be done for her as an alternative. 11. Ensure that the vaginal wall is not in contact with the cryoprobe or you may cause a freezing injury to the vagina. 12. Set the timer and release the gas trigger to cool the probe. 13. You will observe the ice forming on the tip of the cryoprobe and on the cervix (Figure PS12.2). When the frozen area extends 4-5 mm beyond the edge of the cryoprobe, freezing is adequate.. # Figure PS12.2 Position of cryoprobe on the cervix and ice forming. 14. Allow two cycles of freezing and thawing: 3 minutes freezing, followed by 5 minutes thawing, followed by a further 3 minutes freezing. 15. Once the second freezing is complete, allow time for thawing before attempting to remove the probe from the cervix. Removing it before it is fully thawed will pull tissue off the cervix. 16. Gently rotate the probe on the cervix to remove it. The area you have frozen will appear white. 17. Examine the cervix for bleeding. If bleeding is noted, apply Monsel's paste. 18. Do not pack the vagina. 19. Remove the speculum.. After the procedure. 20. Provide a sanitary pad.. 21. Instruct the woman to abstain from intercourse and not to use vaginal tampons for 4 weeks, until the discharge stops completely. This to avoid infection.. 22. Provide condoms for use if she cannot abstain from intercourse as instructed. Teach her how to use them.. 23. Invite her to return in 2-6 weeks to be checked for healing, and again in 6 months for a repeat Pap smear and possible colposcopy.. # 24. inform her of possible complications and ask her to return immediately if she notes:. a. fever with temperature higher than . 25. Clean and disinfect the cryoprobe and decontaminate the cryogun, tubing, pressure gauge and gas tank:17. a. Decontaminate the cryotherapy unit, hose and regulator by wiping them with alcohol. b. Wash the cryotip and the plastic sleeve with soap and water until visibly clean. c. Rinse the cryotip and plastic sleeve thoroughly with clean water. d. High-level disinfect (HLD) the cryotip and plastic sleeve by one of the following methods: - boil in water for 20 minutes; or - steam for 20 minutes; or - soak in chemical disinfectant (0.1% chlorine solution or 2-4% glutaral) for 20 minutes and then rinse with boiled water.. e. It is critical that the hollow part of the cryotip is completely dry when next used, otherwise the water will freeze and the probe could crack or the treatment not work.. f. Either use a rubber cap to seal off the hollow part of the cryoprobe during processing, or thoroughly dry the cryoprobe before it is reused.. g. If none of the high-level disinfection options are available, the cryotip and sleeve may be disinfected by soaking in 70-90% ethanol or isopropanol for 20 minutes. Allow to air-dry and then reassemble.. Follow-up. 26. Perform a pelvic examination to check for healing 2-6 weeks after the cryotherapy.. Flowchart precancer. 27. At 6 and 12 months, do a Pap test and a colposcopy and take a biopsy if necessary. Follow up as described in Annex 5.. # Annex 4. WHO universal precautions for infection prevention. Annex 1: Universal precautions for infection prevention. ANNEX 1: UNIVERSAL PRECAUTIONS FOR INFECTION PREVENTION24. Universal precautions are simple measures that help prevent the spread of infection. All health care providers must use universal precautions to protect patients, themselves and other health care workers from the spread of infectious diseases.. The current epidemic spread of bloodborne viruses, including hepatitis B, C and D, and HIV, underscores the importance of paying scrupulous attention to preventing infection in clinical practice. Many transmissible infections are asymptomatic, and it is not always possible to know who is infected. Therefore, precautions against spreading infection should be used with all patients, whether they appear sick or well, and whether their HIV or other infection status is known or not.. Quality control and supervision are essential to ensure that infections are prevented. A pelvic infection after a clinical procedure is an indicator of poor infection- prevention measures.. Infection prevention: universal precautions. Wear latex gloves whenever:. - you handle items or body surfaces that might be contaminated;- you perform clinical examinations or procedures (cryotherapy, biopsy, endocervical curettage and LEEP), or give injections;- you clean the area where the patient has been;- you handle used instruments.. Remember:. - If gloves get damaged, remove them, wash your hands thoroughly, and then put on new gloves.- Gloves are not a substitute for handwashing.. Wash your hands with soap and water for at least 30 seconds:. - before and after contact with each client or patient;- if you touch blood or body fluids;- immediately after you take off latex gloves.. # Handle contaminated disposable items and clinic surfaces as follows:. Discard disposable items that are soiled with blood or body fluids in a tightly sealed plastic bag. Disposable needles need special handling; use your health facility's protocols. Wash linen and reusable cloth items. Use detergent, dry them in the sun, and iron them if possible. Clean and disinfect surfaces such as examination tables and floors.. Process reusable instruments and gloves after each use, as follows:. All instruments that have been in contact with the vagina or cervix (e.g. specula, biopsy forceps, gloves, etc.) should be decontaminated, cleaned, and sterilized or high- level disinfected. Cryoprobes should be decontaminated, cleaned, and high- level disinfected. The examination or procedure table must be decontaminated after each patient. Other instruments (e.g. colposcope, cryogun, torch lights) must be decontaminated at least once a day, and more often if visibly soiled.. Processing instruments25. There are three basic steps for processing instruments used in clinical and surgical procedures, before they can be reused: (1) decontamination, (2) cleaning, and (3) sterilization or high- level disinfection (HLD).. Decontamination. Decontamination is the process by which used instruments and gloves are made safe for handling; this step inactivates hepatitis B and HIV. To decontaminate instruments and gloves immediately after use, immerse them in a large plastic bucket containing . Cleaning. Soon after decontamination, instruments should be cleaned by a person wearing heavy gloves and glasses or goggles. Use a brush to scrub instruments with water and detergent, and rinse thoroughly with boiled water. Special attention must be given to instruments with teeth, joints and screws.. # Sterilization. Sterilization Sterilization destroys all microorganisms and must be used for all instruments that come into contact with sterile parts of the body, e.g. that penetrate the skin or enter the womb.. Sterilization can be achieved by one of the following:. Expose instruments to superheated steam in an autoclave: 20 minutes for unwrapped instruments and 30 minutes for wrapped instruments. Autoclaving is the preferred method of sterilization. Soak instruments in either . High-level disinfection. HLD destroys all organisms except bacterial spores, and is used when sterilization equipment is not available or the instrument is too delicate to be sterilized. One of the following processes can be used for HLD:. Boil instruments for at least 20 minutes in plain tapwater, which is changed at least daily. Make sure that instruments are fully covered by the water, and start timing after the water with the instruments is fully boiling. Do not add anything to the pot once you have started to time. Soak instruments in . Supplies and equipment. The following supplies and equipment are needed for infection prevention (depending on the processing methods used):. clean and boiled water; detergent; household bleach or commercial chlorine powder; one or more sterilizing chemicals (2- 4% glutaral, 8% formaldehyde); one or more HLD chemicals (0.1% chlorine, 2% glutaral, 6% hydrogen peroxide); 60- 90% ethanol or isopropanol; sterile clothes; plastic bucket,. (continued next page). # scrubbing brush; large jars for storage of solutions; heavy gloves for cleaning; sterile or high- level disinfected gloves and long- handled forceps for handling processed instruments; autoclave or vessels for boiling and soaking instruments; closet with light closure to prevent entrance of dust, for storage of processed instruments and supplies.. # # # Additional information on gas suppliers. The following companies supply gases, including medical- grade carbon dioxide, and have local distribution centres around the world:. Linde AG: gas.de/international/web/lg/de/like35lgde.nsf/docbyalias/homepage. Messer: . Tyczka: . Praxair: . # . # For more information, please contact: Department of Reproductive Health and Research World Health Organization Avenue Appia 20, CH- 1211 Geneva 27, Switzerland Fax: +41 22 791 4171 E- mail: reproductivehealth@who.int www.who.int/reproductivehealth.	None	None	None
7deade3b54c74cf4bf972c5b708fb825	2022+JASTRO共识指南	妇科癌症腔内和间质联合近距离放射治疗	# Japanese Society for Radiation Oncology Consensus Guidelines of combined intracavitary and interstitial brachytherapy for gynecological cancers. Naoya Murakami<sup>1</sup>, Tatsuya Ohno<sup>2,3,</sup>, Takafumi Toita<sup>4</sup>, Ken Ando<sup>2</sup>, Noriko Ii<sup>5</sup>, Hiroyuki Okamoto<sup>6</sup>, Toru Kojima<sup>7</sup>, Kayoko Tsujino<sup>8</sup>, Koji Masui<sup>9</sup>, Ken Yoshida<sup>10</sup> and Hitoshi Ikushima<sup>11</sup>. <sup>1</sup>Department of Radiation Oncology, National Cancer Center Hospital, Tokyo 104- 0045, Japan <sup>2</sup>Department of Radiation Oncology, Gunma University Graduate School of Medicine, Gunma 371- 8511, Japan <sup>3</sup>Gunma University Heavy Ion Medical Center, 3- 39- 22 Showa- machi, Maebashi 371- 8511, Japan <sup>4</sup>Radiation Therapy Center, Okinawa Chubu Hospital, Okinawa 904- 2293, Japan <sup>5</sup>Department of Radiation Oncology, Ise Red Cross Hospital, Mie 516- 8512, Japan <sup>6</sup>Radiation Safety and Quality Assurance Division, National Cancer Center Hospital, Tokyo 104- 0045, Japan <sup>7</sup>Department of Radiation Oncology, Saitama Cancer Center, Saitama 362- 0806, Japan <sup>8</sup>Department of Radiation Oncology, Hyogo Cancer Center, Hyogo 673- 8558, Japan <sup>9</sup>Department of Radiology, Kyoto Prefectural University of Medicine, Kyoto 602- 8566, Japan <sup>10</sup>Institute of Radiology, Kansai Medical University Medical Center, Osaka 573- 1191, Japan <sup>11</sup>Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770- 8503, Japan Corresponding author. Department of Radiation Oncology, Gunma University Graduate School of Medicine, Gunma 371- 8511, Japan. tohno@gunma- u.ac.jp (Received 12 December 2021; revised 25 January 2022; editorial decision 23 February 2022). ABSTRACT. It has been postulated that the combination of intracavitary and interstitial brachytherapy (IC/IS) is effective and safe for large and irregularly shaped uterine cervical cancer patients. However, due to its invasiveness compared to conventional intracavitary brachytherapy (ICBT), it has to be said that the implementation speed of IC/IS is slow. Until now, there have been no guidelines for required equipment, human resources, and procedural guide focusing solely on IC/IS. The purpose of this guideline is to provide radiation oncologists and medical physicists who wish to start IC/IS with practical and comprehensive guidance for a safe IC/IS introduction and to help accelerate the spread of the utilization of IC/IS nationwide. This is the English translation of the Japanese IC/IS Guidelines, and it was created in an effort to share the Japanese approach to the management of locally advanced uterine cervical cancer worldwide.. Keywords: JASTRO Guidelines; intracavitary and interstitial brachytherapy (IC/IS); cervical cancer; brachytherapy; consensus guidelines; gynecologic cancers. INTRODUCTION. In the management of uterine cervical cancer with primary radiotherapy, brachytherapy plays a central role that cannot be replaced by other treatment modalities [1]. The point A prescription calculated by orthogonal 2D X- ray images based on the Manchester method became the standard method, and favorable clinical results have been reported [2]. This 2D treatment plan was summarized in detail in the Practical and QA Manual for Sealed Radioactive Source Brachytherapy Based on the Guidelines of the Brachytherapy Committee' published by the Japanese Brachytherapy Society of the Japanese Society for Radiation. Oncology (JASTRO) in 2013 [3], and has greatly contributed to the standardization and equalization of 2D- based intracavitary brachytherapy (ICBT) for cervical cancer. However, point A was not based on the individual tumor morphology. As a result, 2D methods cannot control a large or irregularly shaped tumor. Additionally, dose evaluation of organs at risk (OARs) had not been adequately performed, and only the point dose evaluation had been performed.. Since 2000, 3D image- guided brachytherapy (3D- IGBT) has been introduced in which dose calculation has been performed based on 3D images such as magnetic resonance images (MRI) or. # computed tomography (CT) with intra- uterine/vagina brachytherapy applicators in place [4]. In 3D- IGBT, clinical target volume (CTV) and OARs were delineated, and dose prescription and/or evaluation have been performed based on dose- volume histograms (DVHs). The 3D- IGBT has been rapidly and widely adopted also in Japan, with accumulating reports indicating that it not only enhanced local control but also decreased late toxicities when compared to the 2D era [4, 5]. The Practical and QA Manual for Sealed Radioactive Source Brachytherapy Based on the Guidelines of the Brachytherapy Committee' published in 2013 provided details on standard techniques and dose calculation for 3D- IGBT in cervical cancer [6]. In 2018, the Guidelines for the Introduction of Image- Guided Brachytherapy In . On the other hand, even with the use of 3D- IGBT, it has been elucidated that it is difficult to deliver an adequate tumoricidal dose while sparing surrounding DARs for bulky or irregularly shaped tumors. For such tumors, it is obvious that multi- catheter interstitial brachytherapy (MC- ISBT) should be appropriate due to the superior dose coverage and conformity compared to conventional ICBT. However, because MC- ISBT is highly invasive and requires expertise, the widespread use of this method has been limited. In such circumstances, combined intracavitary and interstitial brachytherapy (IC/IS BT) has been introduced to compensate for the disadvantage of ICBT while integrating the benefits of MC- ISBT. In IC/IS, additional interstitial needles are inserted into the area that cannot be adequately covered by the conventional ICBT, and increasing the ratio of CTV covered by the prescribed dose can be achieved while sparing OARs. IC/IS has also been gradually adopted in several Japanese hospitals, and favorable clinical outcomes have been reported not only from Western countries but also from Japanese hospitals [5, 8, 9]. This method can be adopted not only for cervical cancer but also for other gynecologic malignancies such as endometrioid carcinoma or vaginal cancer, and international recommendations advocate applying IC/IS for selective other gynecologic malignancies [10- 13].. Although IC/IS is less invasive compared to MC- ISBT, several interstitial needles are used. Therefore, appropriate preparation and additional attention should be paid to avoid adverse events related to needle insertion. In addition, extra attention should be paid to dose calculations specific to IC/IS. As a result, it could be said that the speed of the spread of implementation of IC/IS is rather slow compared to the effectiveness of this method. It can easily be imagined that radiation oncologists who can perform ICBT hesitate to start IC/IS due to its invasiveness, as mentioned above. In such circumstances, there exist no guidelines for required equipment, human resources, or procedural guide focusing solely on IC/IS. It is true that there are many institutions which can perform ICBT. The purpose of this guideline is to provide radiation oncologists and medical physicists who wish to start IC/IS with practical and comprehensive guidance for a safe IC/IS introduction and help to accelerate the spread of the utilization of IC/IS nationwide.. This guideline was approved by JASTRO in July 2021. This is the English translation of the Japanese IC/IS Guidelines, and it was created in an effort to share the Japanese approach to the management of locally advanced uterine cervical cancer worldwide.. MATERIALS AND METHODS. The members involved in the development of this guideline are radiation oncologists who specialize in gynecologic malignancies and medical physicists. A thorough literature review regarding IC/IS for gynecologic malignancies was initially performed by two radiation oncologists. Two hundred three papers were extracted by PubMed between January 2000 and December 2020 using the following keywords; 'uterine cervical neoplasms,' 'endometrial neoplasms,' vaginal neoplasms,' vulval neoplasms,' image- guided brachytherapy' or 'image- based brachytherapy,' 'intracavitary and interstitial,' and 'guideline.' Among the 203 papers, 33 papers were further carefully selected, which were deemed highly important.. Definition of IC/IS. Based on the conventional ICBT, additional interstitial needles are inserted to cover the area where adequate doses cannot be delivered only by ICBT.. Patient selection. IC/IS should be adopted for uterine or vaginal tumors in which an adequate dose cannot be delivered to the entire high- risk CTV . Preparation. - Pelvic examination preferably performed under anesthesia should be done by the start of IC/IS, and it is recommended that the obtained information be drawn using a drawing template (Fig. 1).- Pelvic MRI soon before the start of IC/IS- Electrocardiogram- Blood tests including blood count, biochemistry, coagulation, and cross-match for transfusion. Note the bleeding tendency in patients with platelets less than . # Antibiotics may be considered if there is a retained pyometra and postoperative infection is highly anticipated or if a postoperative infection has occurred during previous treatment.. Equipment required for pain control and sedation General anesthesia or lumber spinal anesthesia managed by an anesthesiologist is preferable. Even if such anesthesia is not available, a moderate level of sedation should be performed because interstitial needle insertion is applied. It is recommended that a sedation/analgesia plan be prepared after conducting a pre- patient evaluation in advance, referring to 'the 2020 Guidelines for Sedation and Anesthesia in Gynecologic Brachytherapy' [16] and that the patient's consent for sedation be obtained beforehand. The following is the equipment required for pain control and sedation.. Sedative agents (benzodiazepines, propofol, etc.) Analgesics (pentazocine, opioids, etc.) Equipment for continuous measurement of patient vitals during the procedure Essential: continuous blood pressure monitor, pulse oximeter, electrocardiogram. Recommended: Capnometer (measuring end- expiratory carbon dioxide . Items to be used in an emergency. Respiratory support/artificial respiration: nasal airway, Ambu bag, endotracheal tube, etc. Medications: Flumazenil, naloxone, catecholamine, etc., which are antagonists for an overdose of sedative/analgesic drugs.. Equipment and applicators used. Transrectal ultrasound (TRUS), transabdominal ultrasound (TAUS). X- ray fluoroscopy X- ray in the same room or in a separate room, or MRI in a separate room:. If patients need to be moved to the other room to take images, care must be taken in fixing the applicators and interstitial needles, and in the way of transferring the patient to prevent displacement of the applicators and interstitial needles. The use of a patient transfer system dedicated to brachytherapy is also beneficial.. Applicator for intracavitary irradiation:. When performing MRI- based 3D- IGBT, use an MRI- compatible applicator; even for CT- based 3D- IGBT, an MRI- compatible applicator has fewer CT artifacts than a metal applicator. There is also an applicator for IC/IS that is equipped with an interstitial needle insertion template and with holes for interstitial needles in vaginal voids/ring.. Interstitial needle:. Interstitial needles are either made of metal (reusable) or plastic (disposable). The characteristics of each material are described later.. Examples of combined use: Tandem + ovoid + interstitial needles Tandem + interstitial needles Tandem + vaginal cylinder + interstitial needles Applicator dedicated for IC/IS, etc.. Personnel requirements for performing IC/IS. Because IC/IS involves a more invasive technique than conventional ICBT, at least the personnel required by the guidelines for the introduction of 3D- IGBT should be secured [7]. When performing IC/IS, it is necessary to have sufficient experience with 3D- IGBT for gynecologic tumors or to perform the procedure under the supervision of a person who is proficient in 3D- IGBT.. # In addition to the above, it is desirable to assign a full- time physician or nurse (person in charge of the management of sedation and analgesia) who continuously manages and monitors the patient's condition separately from the brachytherapists.. The medical safety system. Vaginal bleeding during and after procedures can often be stopped with tamponade with gauze. However, it is important to establish a system to obtain the cooperation of gynecologists and interventional radiologists (IVR) in advance, assuming that suturing for vaginal wall lacerations . IC/IS procedure. 1. Pretreatment. To prevent vomiting during sedation, abstain from food for 6 hours and water for 2 hours before the treatment. Also, explain that the patient should have defecated beforehand.. 2. Sedation and analgesia. Start sedation and analgesia based on the sedation and analgesia plan prepared before treatment. Since the depth of sedation and analgesia changes over time, check the depth of sedation, analgesia, and vital signs as treatment progresses.. 3. Insertion of the irradiation needle into the tissue. A) Selection of insertion route. There are two routes for insertion of the intratissue irradiation needle: the transvaginal approach and the transperineal approach (Fig. 2). The advantages and disadvantages of each are shown in Table 1. To prevent postoperative infection, thoroughly disinfect the vaginal (or perineal) site of insertion.. A-1) Transvaginal approach. The advantage of the transvaginal approach is that the distance until the needle reaches the tumor is shorter than that of the transperineal approach, the penetration into the tumor is much easier, and it does not require a high degree of analgesia compared to the transperineal approach. Therefore, it is a relatively easy technique to obtain. On the other hand, there is a limit to the reach of the interstitial needle due to the space limitation of the vagina, and there are cases where it is difficult to treat large tumors or tumors with complex shapes. In addition, there is interference between other vaginal applicators and the interstitial needles, which can make insertion difficult, especially in patients with narrow vaginas.. A-2) Perineal approach. The advantage of this approach is that it has high flexibility in terms of the reach and angulation of the interstitial needles and the extent to which they can be inserted. It can easily be used even for large tumors and tumors with complex shapes. However, because it requires a high degree of sedation, such as saddle block, and the path to the tumor is long, it should be performed under the supervision of an experienced brachytherapist at least in the beginning.. B) Selecting an interstitial needle. There are two types of materials for interstitial needles: plastic and metal. Each has advantages and disadvantages as shown in Table 2, and should be selected according to the preference of each brachytherapist and their level of proficiency in the method. Regardless of which type of needle is used, visually confirm that there is no damage to the interstitial needle before insertion, and use an appropriate obturator to maintain needle strength during insertion.. B-1) Plastic needle. There are two types of plastic needles (sharp and round). Because it has only been short period of time since round plastic needles were available in Japan and not so much information or experience has accumulated regarding the round plastic needle, only sharp plastic needles are described in this guideline. When MRI- based 3D- IGBT is performed, metallic needles cannot be used unless they are made of. # titanium. Plastic needle has the advantage of being less artifactual, even when CT- based. They are disposable, but at the time of the development of this guideline, Japanese public insurance does not cover plastic needle costs. To determine the first stopping point in the treatment planning system, the offset value (distance from the applicator tip to the closest stopping point) obtained by the dummy source or the value obtained from commissioning performed in advance is used.. B-2) Metallic needle. Although the metallic needle has the advantage of easy puncture and better real- time ultrasound visualization during needle insertion, it has a sharper tip, so be careful of the risk of damaging blood vessels or bowels. In addition, the offset value is longer than that of the plastic needle, so care must be taken with the depth of the needle. To determine the first stopping point in the treatment planning system, use the offset value obtained from the dummy source or commissioning performed in advance.. C) Interstitial needle insertion procedure. The interstitial needle is inserted aiming at the tumor portion where the dose is insufficient in the dose distribution of normal ICBT. For insertion, it is essential to have an image in mind of the insertion site, angle, depth, etc., in advance using MRI images before IC/IS and TRUS or TAUS while inserting a sonde into the uterine cavity, as described before. In addition, pelvic examination findings on the day of the procedure and modalities to assist the insertion as described below are used as appropriate. The insertion is performed with the utmost care. The following is an overview of the insertion method by different approaches.. C-1) Transvaginal approach. First, the regular ICBT applicator insertion is performed, followed by the insertion of the interstitial needles. Although needle insertion after insertion of the ovoid is easy and the ovoid serves as a guide for the insertion site, it has the disadvantage of limiting the space and range of needle insertion due to interference with the ovoid. If the interstitial needle is inserted into the tissue before inserting the ovoid, there is more freedom in the needle insertion site and direction, but the needle must be inserted from the side of the vagina to avoid interference so that the ovoid can be inserted after insertion.. There are two methods of needle insertion from the vaginal wall: freehand insertion and insertion using the applicator for IC/IS as a template. Freehand needle insertion offers a wide range of applicability with a high degree of freedom in the insertion site and angulation, but it is difficult to ensure reproducibility. When a template (ring or ovoid with holes) is used, the insertion site and direction are restricted according to the template, but it has the advantage of high reproducibility.. When puncturing the vaginal wall, it is recommended that the vaginal wall be sufficiently stretched after the insertion of the ICBT applicator and that the needle be inserted into the vaginal wall as vertically as possible in order to avoid vaginal wall lacerations caused by the interstitial needle penetrating the vaginal wall at an angle.. C-2) Transperineal approach. The patient should be in the extended lithotomy position to avoid pubic bone interference. Because the ovoid and the interstitial needle. # may interfere with each other in the transperineal approach, it is often possible to perform the procedure smoothly by inserting the interstitial needles first and then the ICBT applicators. In some cases, the interstitial needle may be excessively bent by the ovoid inserted after the interstitial needles. In such a case, confirm that the source path is not blocked by using a dummy source and consider replacing it with a smaller size ovoid. Meanwhile, inserting the tandem first may make it easier to insert the interstitial needle because it serves as an indicator of the insertion site of the interstitial needle.. In the transperineal approach, there is a risk that the needle tip may point in an unexpected direction due to the high degree of flexibility in the angle of the interstitial needle in the tissues, so it is recommended that the needle tip be confirmed in real- time by TRUS during insertion. If TRUS is not used, it is safer to use a perineal template where the needle angle is prefixed.. To avoid damage to the vaginal wall due to the long penetration route, be careful not to expose the interstitial needle in the vagina. If the position of the needle tip cannot be confirmed by TRUS, it is safer to insert a finger into the vagina and use the finger to palpate and guide the needle tip under the vaginal mucosa as it moves deeper. If it is necessary to insert the needle into a deeper plane against the vaginal wall surface, the needle under the vaginal mucosa serves as a marker, making it easier to insert the needle into the deeper planes.. When the ICBT applicator is inserted after insertion of the interstitial needles, the interstitial needles may come out slightly. Check and modify the tip of the interstitial needle again with TRUS before vaginal gauze packing is performed.. C-3) Modalities that can assist interstitial needle insertion. When freehand needle insertion is performed, it is possible that the needle will go in an unintended direction. Since organ damage associated with the insertion of an interstitial needle can lead to serious adverse events such as bleeding, infection, and bowel perforation, it is necessary to perform the insertion under real- time image guidance such as TRUS with X- ray assistance or frequent use of CT to avoid unnecessary normal organ injury and to always pay attention to the position of the needle tip while inserting the needle and keeping it inside the . TAUS guidance: Inject about . TRUS guidance: Real- time confirmation of needle position and depth is safer and has the advantage of completing the procedure more quickly than CT guidance, but unlike prostate brachytherapy under TRUS guidance, experience is required to recognize the TRUS images in the female pelvis. The range of images is limited to the depth of the transrectal probe, so the needle tip needs to be confirmed by CT or TAUS for deeper needle insertion.. CT- guided . C-4) Precautions after needle insertion. When multiple interstitial needles are used, it is possible to mistake the channel number of the transfer tube to be connected or to misidentify the channel number when the applicator is reconfigured in the treatment planning system. When multiple interstitial needles cross each other or the needle passes the air cavity of the vagina, and it is difficult to identify them, insert a dummy source that helps indicates the source path and confirm it. In addition, it is desirable to take measures such as attaching number stickers to all interstitial needles so that they can be easily identified.. If it takes a long time until the start of irradiation after the insertion is completed, consider inserting an obturator into the interstitial needle to prevent blood or disinfectant contamination. If the connection point of the interstitial needle is faulty, or if blood or other substances have contaminated the inside of the catheter and cannot be removed, cut the faulty point of the needle using a dedicated instrument. In such a case, measure the length of the interstitial needle again and reflect it in the applicator reconstruction of the treatment plan.. Needle retraction or displacement can happen, especially when patients need to be moved to another room for image acquisition. To avoid such circumstances, when needed, needle fixation using a button sutured to the skin could be considered.. D) Treatment plan image acquisition. After implantation and insertion of the ICBT applicator and the interstitial needles are completed, CT and/or MRI for treatment planning should be taken. When image acquisition is required in a room separate from the brachytherapy room, care should be taken to ensure that the positional relationship between the applicators and the interstitial needle is not displaced or retracted during transportation, such as by fixing the applicators with tape, etc. During MRI imaging, care should be taken to ensure that the interstitial needle does not move due to the weight or pressure of the MRI coil. After confirming the obtained images and confirming that the applicators and interstitial needles are in the appropriate locations and depths and that there are no excessively bent parts in the interstitial needles, move on to treatment planning.. E) Treatment Planning/Dose calculation. Dose calculation of IC/IS is performed based on the Practical and QA Manual for Sealed Radioactive Source Brachytherapy Based on the Guidelines of the Brachytherapy Committee [6] or Guidelines for the Introduction of Image- Guided Brachytherapy in 2018 [7]. In particular, in the case of IC/IS, the length to the first stopping point and the offset value differ depending on the type of interstitial needle. Therefore, attention should be paid to using the correct offset value, which is acquired with commissioning in advance.. For contouring of high- risk CTV . Calculate and record the bilateral point A doses, . # \mathbf{D}_{2\mathrm{cm3}}. Evaluate the International Commission on Radiation Units and Measurements (ICRU) recto- vaginal reference point dose [22] (Figure 3). Vaginal . In calculating dose distributions, the standard Manchester method dose distribution based on the point A prescription is first prepared. Then, the dose distribution is modified by adding doses to the areas in the . The biological equivalent dose is calculated using the LQ model to add the dose from each IC/IS session . \mathrm{D_{90\%}}. In the standard external radiation schedule in Japan, central shielding (CS) is used as the tumor shrinks. According to the definition of . If sedation and analgesia are not sufficiently obtained, the position of the applicator and the interstitial needle may shift due to the patient's unintentional body movement. Therefore, monitor the patient carefully during treatment planning, and connect the applicator to the transfer tube immediately before treatment.. (F) Indication. When connecting the interstitial needle to the transfer tube, be careful because the weight of the transfer tube can pull the interstitial needle toward the outside of the body. It would be helpful to use some kind of support stand to prevent needle displacement due to the transfer tube weight.. When multiple interstitial needles are inserted, be careful not to connect the wrong transfer tube to the wrong interstitial needle. Use a dummy source to confirm the applicator passage in advance to avoid errors during irradiation.. Visually confirm that there is no significant change in the applicator position before and after treatment.. G) Needle removal. Bleeding often occurs during needle removal, so paramount attention should be paid to bleeding during the removal of the interstitial needle.. In general, the transvaginal approach is more likely to cause bleeding than the transperineal approach because of the abundant blood flow in the vaginal wall. However, if the point of bleeding is well identified and pressure is applied to the bleeding point for a sufficient time, hemostasis can often be achieved. In addition to focused hemostasis, filling the vagina with gauze (or iodoform gauze) and applying continuous pressure to the entire vagina is also effective. If the outside of the gauze does not turn red after a while, it is likely that hemostasis has been obtained.. Even in cases where minor bleeding persists, and multiple gauze changes are required, overnight tamponade with gauze will almost always stop bleeding the next day. However, if arterial bleeding or bleeding of more than moderate severity is suspected, do not attempt to handle the situation alone, but do not hesitate to ask for help from a gynecologist or IVR physician.. # Note that intra- abdominal hemorrhage may occur in rare cases when the tip of the needle is beyond the . Confirming the position of uterine arteries by prior MRI is also useful in avoiding bleeding. Intraoperative Doppler ultrasonography is also helpful in identifying vessels in a real- time manner.. The above description focuses on IC/IS for curative cases of uterine cervical cancer. However, it is possible to apply the same procedure for other gynecological malignancies, such as postoperative vaginal recurrences thicker than . Effectiveness and safety of IC/IS. In 3D- IGBT for cervical cancer, randomized controlled trials comparing ICBT versus IC/IS have not yet been reported.. A large retrospective multicenter study comparing the results of both treatment methods has been conducted by the External beam radiochemotherapy and MRI- based adaptive brachytherapy in locally advanced cervical cancer (EMBRACE) group [8]. In this study, the local control rate, late adverse events, and DVH were evaluated in 300 patients in the IC/IS group and 310 patients in the ICBT group. The 5- year local control rate was . In the EMBRACE study mentioned above, DVH parameters were compared between the tandem plus ovoid group and the tandem plus ring applicator group, and in both groups, . A case with severe bleeding treated by transcatheter arterial embolization was reported in which an obturator artery was injured by an interstitial needle inserted using an ovoid with holes as a template. The lessons learned from this case include inserting the needle under image guidance and, if CT preplanning is used to determine needle position beforehand, paying attention to anatomical changes during the treatment period, such as tumor shrinkage due to treatment [18].. The initial treatment results of a novel applicator dedicated to IC/IS were reported from the United States. The median . The results of 42 cases of IC/IS using the standard radiotherapy schedule in Japan were reported [9]. The median . In conclusion, IC/IS has clear advantages in terms of dose distribution compared to ICBT. It is recommended because of its clinical advantages in cases in which the conventional ICBT does not provide sufficient dose to cover the entire . QA/QC. A) Quality assurance and control of treatment devices, treatment planning systems, and applicators. For quality control and commissioning of treatment devices and treatment planning systems, refer to the Practical and QA Manual for Sealed Radioactive Source Brachytherapy Based on the Guidelines of the Brachytherapy Committee [3, 35], and for quality assurance required for the initiation of IGBT, refer to the Guidelines for the Introduction of Image- Guided Brachytherapy (IGBT) [7].. B) Applicator and catheter quality control. The novel applicator dedicated to IC/IS has a complex structure with many components, so it should be checked periodically for missing or damaged parts. Since applicators such as disposable plastic interstitial needles cannot be sterilized at their own facility, it is not possible to confirm the position of the radiation source using an actual radiation source beforehand. Therefore, before the start of clinical use, an applicator for QA that is not used for actual patients must be introduced separately to confirm the source anchorage position (referring to the commissioning of applicator reconstruction).. It is advisable to visually confirm that there are no abnormalities such as bends or indentations each time it is used.. DISCUSSION. Since the introduction of 3D- IGBT, the clinical outcome has dramatically improved compared to the 2D era [19, 36]. However, it was elucidated that even with 3D- IGBT, it is challenging to achieve the recommended dose constraints for . # due to its invasiveness. Although the clinical results of IC/IS have been reported, until now, there have been no guidelines for required equipment, human resources, and procedural guides focusing solely on IC/IS. Therefore, to help spread IC/IS, JASTRO decided to create a practical and comprehensive guide dedicated to IC/IS. Because IC/IS is more invasive than conventional ICBT and deeper sedation is required, when the conditions in each institution allow, it is recommended that radiation oncologists conduct sedation, at least initially, in collaboration with anesthesiologists. This guideline deals with practical patient selection, preparation, procedures, and evidence supporting the effectiveness and safety of IC/IS. The authors hope that this article will help radiation oncologists and medical physicists who wish to start IC/IS and contribute to improving the clinical outcomes of patients suffering from this devastating disease.. Even though the incidence of uterine cervical cancer could be reduced by human papillomavirus vaccination [37], it will be long before most countries are fullvaccinated and it will be one of the major health problems for the next several decades in most countries. In such circumstances, this guideline will help promote IC/IS and increase the curative rate of definitive radiotherapy.. The limitations of this guideline are that most of the information described above is not based on phase III clinical trials but on expert opinions or retrospective studies. However, because of the paucity of phase III clinical trials in the field of brachytherapy, the authors believe that collecting such expert opinions and results from retrospective studies and creating this kind of clinical guideline is valuable.. ACKNOWLEDGEMENT. The authors appreciate Takahito Chiba for drawing the figures for this article.. FUNDING. This work was supported by Research Funding of Gunma University Heavy Ion Medical Center.. CONFLICT OF INTEREST. Dr. Yoshida reports personal fees from Chiyoda Technol, outside the submitted work. The other authors have no conflict of interest to declare.. REFERENCES. 1. Chino J, Annunziata CM, Beriwal S et al. 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efe878c001314c1bb82293693e7ad37f	2024+AAN／AES／SMFM实践指南	子宫内暴露于抗癫痫药物后的畸形、围产期和神经发育结局	# Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication. Practice Guideline From the AAN, AES, and SMFM. Alison M. Pack, MD, MPH, Maryam Oskoui, MD, MSc, Shawniqua Williams Roberson, MEng, MD, Diane K. Donley, MD, Jacqueline French, MD, Elizabeth E. Gerard, MD, David Gloss, MD, MPH&TM, Wendy R. Miller, PhD, RN, CCRN, Heidi M. Munger Clary, MD, MPH, Sarah S. Osmundson, MD, MS, Brandy McFadden, Kaitlyn Parrott, MBBS (Hons 1), Page B. Pennell, MD, George Saade, MD, Don B. Smith, MD, Kelly Sullivan, PhD, Sanjeev V. Thomas, MD, DM, Torbjörn Tomson, MD, Mary Dolan O'Brien, MLIS, PMP, Kylie Botchway- Doe, Heather M. Silsbee, MWC, and Mark R. Keezer, MDCM, PhD. Neurology 2024;102:e209779. doi:10.1212/WNL.0000000000209279. Abstract. This practice guideline provides updated evidence- based conclusions and recommendations regarding the effects of antiseizure medications (ASMs) and folic acid supplementation on the prevalence of major congenital malformations (MCMs), adverse perinatal outcomes, and neurodevelopmental outcomes in children born to people with epilepsy of childbearing potential (PWECP). A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies through August 2022. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. The following are some of the major recommendations. When treating PWECP, clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes should pregnancy occur, at the earliest possible opportunity preconceptionally. Clinicians must minimize the occurrence of convulsive seizures in PWECP during pregnancy to minimize potential risks to the birth parent and to the fetus. Once a PWECP is already pregnant, clinicians should exercise caution in attempting to remove or replace an ASM that is effective in controlling generalized tonic- clonic or focal- to- bilateral tonic- clonic seizures. Clinicians must consider using lamotrigine, levetiracetam, or oxcarbazepine in PWECP when appropriate based on the patient's epilepsy syndrome, likelihood of achieving seizure control, and comorbidities, to minimize the risk of MCMs. Clinicians must avoid the use of valproic acid in PWECP to minimize the risk of MCMs or neural tube defects (NTDs), if clinically feasible. Clinicians should avoid the use of valproic acid or topiramate in PWECP to minimize the risk of offspring being born small for gestational age, if clinically feasible. To reduce the risk of poor neurodevelopmental outcomes, including autism spectrum disorder and lower IQ, in children born to PWECP, clinicians must avoid the use of valproic acid in PWECP, if clinically feasible. Clinicians should prescribe at least . Correspondence American Academy of Neurology guidelines@aan.com. # Glossary. \mathbf{AAN} =. Epilepsy is one of the most common neurologic disorders, affecting more than 50 million people worldwide. One in 5 of those affected are people of childbearing potential, based on extrapolations from the proportion of the 2022 US female population aged 15- 45 years. Infants born to people with epilepsy are at increased risk of major congenital malformations (MCMs), adverse perinatal outcomes, and adverse neurodevelopmental outcomes. Multiple factors are associated with this risk, including genetic differences, environmental factors, seizure control, and intrauterine exposure to antiseizure medications (ASMs). The role of folic acid supplementation in mitigating these risks is unclear. Optimizing the treatment of epilepsy is necessary to achieve the most favorable outcomes for persons with epilepsy and their offspring.. In 2009, the American Academy of Neurology (AAN) published the guideline "Practice Parameter update: Management issues for women with epilepsy- Focus on pregnancy: Teratogenesis and perinatal outcomes." The authors concluded that treatment with valproic acid carries a higher risk of MCMs in the offspring of women with epilepsy than treatment with carbamazepine, phenytoin, and phenobarbital, especially if taken in polytherapy. The risk associated with other commonly used ASMs, such as levetiracetam or topiramate, was not evaluated because of limited available evidence. The authors concluded that treatment with valproic acid carried the highest risk of adverse cognitive outcomes in the offspring of women with epilepsy as compared with carbamazepine, although the risk of autism spectrum disorder (ASD) was not addressed because this association was not yet reported in the literature. Infants exposed to any ASM in utero had a higher risk of being born small for gestational age (SGA), but there was no evidence of an increased risk of fetal death.. A separate 2009 practice guideline recommended that preconception folic acid supplementation "may be considered to reduce the risk of MCMs," but did not provide further guidance on supplementation dosage. Since 2009, new studies have been published related to the risk of MCMs associated with several ASMs, the association between different ASMs and adverse perinatal or neurodevelopmental outcomes, and the effect of folic acid supplementation.. While the 2009 guidelines described the affected population as "women with epilepsy," this phrasing does not recognize the important difference between biological sex and sociocultural gender. In this update, we refer to the affected population with the gender- neutral language, "people with epilepsy of childbearing potential" (PWECP).. In this practice guideline update, we aim to provide guidance to clinicians when choosing an ASMs in monotherapy or polytherapy, in this patient population. We also aim to clarify the potential role of folic acid supplementation among PWECP. This guideline specifically addresses the following 4 clinical questions:. 1. What is the prevalence of MCMs associated with intrauterine exposure to specific ASMs, and how does this vary between ASMs in monotherapy vs polytherapy, and at high doses vs low-medium doses of ASMs, in children born to PWECP? 2. What is the prevalence of adverse perinatal outcomes associated with intrauterine exposure to specific ASMs, and how does this vary between ASMs in monotherapy vs polytherapy, and at high doses vs low-medium doses of ASMs, in children born to PWECP? 3. What is the prevalence of adverse neurodevelopmental outcomes associated with intrauterine exposure to specific ASMs, and how does this vary between ASMs in monotherapy vs polytherapy, and at high vs low-medium doses of ASMs, in children born to PWECP? 4. What is the effect of intrauterine exposure to folic acid on the prevalence of MCMs, adverse perinatal outcomes, and neurodevelopmental outcomes, and how does this vary by folic acid dose in children born to PWECP treated with ASMs?. Description of the Analytic Process. The development of this practice guideline followed the 2017 edition of the AAN's guideline development process manual. In March 2018, a multidisciplinary panel was recruited to develop the protocol for this guideline. The authors include content experts, methodologists, Guidelines Subcommittee members, an AAN epilepsy quality measure workgroup representative, physician representatives for the American Epilepsy Society and the Society for Maternal- Fetal Medicine, and patient advocates. In accordance with AAN policy, the current lead developer (A.M.P.), and the majority of the panel, has no conflicts of interest (COIs). Five of the 19 guideline developers (J.F., E.G., K.P., G.S., and T.T.) were determined to have COIs, but each COI was judged to be not significant enough to preclude authorship. These 5 developers were not permitted to review or rate the evidence; they served in an advisory capacity to help with the validation of the key. # questions, the scope of the literature search, and the identification of seminal articles. They also participated in the recommendation development process. The full author panel was solely responsible for final decisions about the design, analysis, and reporting of this guideline.. This article is a summary of the key findings of the guideline. The complete guideline, including the literature search strategy, details about evidence classification, and the full systematic review of the evidence, is available in eAppendix 1.. Systematic Review of the Evidence. The panel searched Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, Ovid Embase, CINAHL, the Database of Abstracts of Reviews of Effects, ClinicalTrials.gov, and the US Food and Drug Administration literature databases from June 1, 2007, to February 15, 2019, for relevant peer- reviewed articles that met inclusion criteria. The initial search after duplicates were removed yielded 4,039 articles. Using a systematic process detailed in the AAN's guideline development process manual,5 2 review panel members (not the same pair for all articles) independently reviewed the article titles and abstracts for relevance and then reviewed the full text of the articles determined to be relevant. (Figure). Disagreements about inclusion were resolved through discussion between the 2 panelists, with a third reviewer included to break ties when necessary. One hundred eighty- three articles were selected and rated for risk of bias by 2 panel members using the AAN criteria for the classification of causation studies. Class I studies have the lowest risk of bias, and Class IV studies have the highest risk of bias. As per predefined exclusion criteria that are laid out in the process manual,5 the panel excluded articles that were assessed as Class IV . An updated literature search was completed to identify additional relevant articles published between February 15, 2019, and August 1, 2022. The initial search after duplicates were removed yielded 128 articles. The abstracts and full- text articles were reviewed following the same process as the first literature review, which resulted in 13 articles being added to the systematic review (Figure). The primary findings of the systematic review are summarized in Tables 1- 7. Additional data are presented in eTables 1 and 2.. As detailed in the AAN's guideline development process manual, a modified version of the grading of Recommendations. # Assessment, Development and Evaluation process was used to develop conclusions after the analysis of evidence. The evidence was analyzed based on parameters pertaining to risk of bias, . # # # Continued. # different studies) and, at best, classified as Class III evidence to address causation, the initial confidence rating for most conclusions was anchored as low if at least 2 Class III or at least 1 Class I or II studies informed each estimate used in the comparisons. The initial confidence rating was set to very low if one of the contributing estimates was informed by a single Class III study.. In the second step, the classification of evidence was upgraded or downgraded according to criteria specified in the process manual (e.g., upgraded for large magnitude of effect, downgraded for lack of statistical precision). For estimates obtained through indirect comparisons, confidence in the evidence was downgraded for precision when the width of the . # # statistical significance were not upgraded for magnitude of effect.. The authors formulated a rationale for each recommendation based on the evidence systematically reviewed and stipulated axiomatic principles of care, related evidence, and inferences. The recommendation development process is described in further detail in the complete guideline (eAppendix 1) and the AAN's guideline development process manual.5. Clinical Context. The goal of this guideline is to assist clinicians (e.g., physicians, nurses, and advanced practice providers) in the pharmacologic management of PWECP to limit risk of adverse congenital, perinatal, and neurodevelopmental outcomes. Given the many variables that may confound the outcomes we examined (e.g., genetic conditions, pregnancy conditions, and socioeconomic contexts), we weighted evidence more strongly where analyses could be adjusted for these and other potential confounders (i.e., Class I studies). Demonstration of . The available evidence on the association between in utero ASM exposure and neurodevelopmental outcomes is rapidly expanding. Although valproic acid exposure shows a strong effect, data from our preplanned analyses on adverse neurodevelopmental outcomes were insufficient to demonstrate an effect; thus, caution in counseling is warranted. While we could not extract sufficient data on topiramate exposure, the SCAN- AED study49 found even higher prevalences of ASD and intellectual disability with exposure to topiramate than. # valproic acid. Their adjusted hazard ratios (aHRs), however, used prevalence in the general population of children as a comparator group (aHRs for ASD and intellectual disability after topiramate exposure were 2.8 . Folic acid prescribing practices for PWECP are variable.. Practice Recommendations. General. Recommendation 1 Rationale. The overarching goals of care for PWECP are to optimize health outcomes both for individuals and their future offspring. In many cases, in utero ASM exposure may be associated with increased risks to the fetus. There are also risks associated with discontinuing or changing ASMs in PWECP.. Recommendation 1 Statements. 1(A) Clinicians should engage in joint decision- making with PWECP, taking individual preferences into account when selecting ASMs and monitoring their dosing (Level B).. 1(B) When treating PWECP, clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes should pregnancy occur, at the earliest possible opportunity preconceptionally (e.g., at the time of starting an ASM in a person post- menarche) (Level B).. Recommendation 2 Rationale. The odds of mortality during pregnancy is 5- 12 times greater among PWECP as compared with pregnant people without epilepsy, according to an analysis of a Danish cohort of more than 2 million pregnancies and a US cohort of more than 20 million participants.. In an analysis of the EURAP study including 1,956 pregnancies among 1,882 participants, there was no statistical association between seizures during pregnancy and spontaneous abortion or stillbirth. However, the 1 stillbirth that occurred soon after a seizure was an episode of convulsive status epilepticus.. Valproic acid is one of the most effective ASMs at obtaining adequate seizure control among people with idiopathic generalized epilepsy.. The serum concentration of most ASMs has a defined therapeutic window for effective seizure control. The serum concentration of some ASMs (in particular, lamotrigine and levetiracetam) decreases during pregnancy. These decreases may occur at any point during the pregnancy.. There are limited data available on epilepsy- related outcomes during pregnancy among PWECP for numerous ASMs, including but not limited to acetazolamide, eslicarbazepine, ethosuximide, lacosamide, nitrazepam, perampanel, piracetam, pregabalin, rufinamide, stiripentol, tiagabine, and vigabatrin.. # Recommendation 2 Statements. 2A. Clinicians must minimize the occurrence of convulsive seizures (generalized tonic-clonic seizures and focal-tobilateral tonic-clonic seizures) in PWECP during pregnancy to minimize potential risks to the birth parent (e.g., seizurerelated mortality) and to the fetus (Level A).. 2B. Once a PWECP is already pregnant, clinicians should exercise caution in attempting to remove or replace an ASM that is effective in controlling generalized tonic-clonic or focal-tobilateral tonic-clonic seizures, even if it is not an optimal choice with regards to the risk to the fetus (e.g., valproic acid) (Level B).. 2C. Clinicians should monitor ASM levels in PWECP throughout pregnancy as guided by individual ASM pharmacokinetics and patient clinical presentation (Level B).. 2D. Clinicians should adjust the dose of ASMs at their clinical discretion during the pregnancy in response to (1) decreasing serum ASM levels or (2) worsening seizure control (observed or anticipated based on the clinician's judgment and known pharmacokinetics of ASMs in the pregnant state) (Level B).. 2E. Clinicians treating PWECP using acetazolamide, eslicarbazepine, ethosuximide, lacosamide, nitrazepam, perampanel, piracetam, pregabalin, rufinamide, stiripentol, tiagabine, or vigabatrin should counsel their patients that there are limited data on pregnancy-related outcomes for these drugs (Level B).. Antiseizure Medications: Major Congenital Malformations. Recommendation 3 Rationale. The unadjusted birth prevalence of any MCM among children born to people without epilepsy is approximately . Valproic acid is associated with the highest unadjusted birth prevalence of neural tube defects (NTDs) . A detailed anatomical ultrasound of the fetus can enable earlier diagnosis of MCMs,e20- e24 Early detection of severe . Recommendation 3 Statements. 3A. Clinicians must counsel their patients with epilepsy that the birth prevalence of any MCM in the general population is approximately . 3B. Clinicians must consider using lamotrigine, levetiracetam, or oxcarbazepine in PWECP when appropriate based on the patient's epilepsy syndrome, likelihood of achieving seizure control, and comorbidities, to minimize the risk of MCMs (Level A).. 3C. Clinicians must avoid the use of valproic acid in PWECP to minimize the risk of MCMs (composite outcome) or NTDs, if clinically feasible (Level A).. 3D. Clinicians must counsel PWECP who are treated with, or are considering starting, valproic acid that the risk of any MCM is the highest with valproic acid as compared with other studied ASMs (Level A).. 3E. To reduce the risk of cardiac malformations, clinicians must avoid the use of phenobarbital in PWECP, if clinically feasible (Level A).. 3F. To reduce the risk of oral clefts, clinicians should avoid the use of phenobarbital and topiramate in PWECP, if clinically feasible (Level B).. 3G. To reduce the risk of urogenital and renal malformations, clinicians should avoid the use of valproic acid in PWECP, if clinically feasible (Level B).. 3H. To enable early detection and timely intervention of MCMs, obstetricians should recommend fetal screening for MCMs (e.g., a detailed anatomical ultrasound, where available) for PWECP who are treated with any ASM during pregnancy (Level B).. 3I. To enable early detection and timely intervention of congenital heart defects, obstetricians should recommend screening cardiac investigations of the fetus among PWECP who are treated with phenobarbital during pregnancy (Level B).. Antiseizure Medications: Perinatal Outcomes. Recommendation 4 Rationale. Among children exposed to ASMs in utero and born to PWECP, the prevalence of intrauterine death is highly likely. # not to differ across ASMs when used in monotherapy and the prevalence of prematurity is possibly no different across ASMs when used in monotherapy (eTable 2). The risk of intrauterine death is likely higher with polytherapy exposure compared with monotherapy exposure. Fetal growth restriction increases the risk of perinatal morbidity and mortality.. Recommendation 4 Statements. 4A. Clinicians should counsel PWECP that the prevalence of intrauterine death does not differ among different ASM exposures in monotherapy (Level B).. 4B. Clinicians should avoid the use of valproic acid or topiramate in PWECP to minimize the risk of offspring being born SGA, if clinically feasible (Level B).. 4C. To enable early identification of fetal growth restriction, obstetricians should recommend screening of fetal growth throughout pregnancy among PWECP who are treated with valproic acid or topiramate (Level B).. Antiseizure Medications: Neurodevelopmental Outcomes. Recommendation 5 Rationale. Among children born to PWECP, in utero exposure to valproic acid is likely associated with a decrease in full scale IQ at age 6 years compared with gabapentin and lamotrigine in monotherapy; valproic acid is possibly associated with a decrease as compared with carbamazepine, levetiracetam, and topiramate in monotherapy; and there is possibly no difference in full scale IQ with valproic acid as compared with phenytoin in monotherapy.. Among children born to PWECP, in utero exposure to valproic acid is likely associated with a decrease in verbal IQ at age 6 years compared with gabapentin, lamotrigine, levetiracetam, and phenytoin in monotherapy, and possibly associated with a decrease as compared with carbamazepine and topiramate in monotherapy.. Among children born to PWECP, in utero exposure to valproic acid is possibly associated with a decrease in non- verbal IQ at age 6 years compared with carbamazepine and phenytoin in monotherapy, but there is possibly no difference as compared with gabapentin, lamotrigine, levetiracetam, and topiramate in monotherapy.. Among children born to PWECP, in utero exposure to valproic acid throughout the pregnancy is possibly associated with an increased risk of ASD and autistic traits compared with other studied ASMs (i.e., carbamazepine, clonazepam, lamotrigine, and levetiracetam) used in monotherapy.. Numerous ASMs have limited available data on neurodevelopmental outcomes. These neurodevelopmental outcomes are determined during both early and later stages of pregnancy.. Recommendation 5 Statements. 5A. To reduce the risk of poor neurodevelopmental outcomes, including ASD and lower . 5B. Clinicians must counsel PWECP who are treated with, or are considering starting, valproic acid that in utero exposure to valproic acid is likely or possibly associated with a decrease in full scale, verbal, and non-verbal . 5C. Clinicians must counsel PWECP who are treated with, or are considering starting, valproic acid that in utero exposure to valproic acid is possibly associated with an increased risk of ASD as compared with other studied ASMs (i.e., carbamazepine, clonazepam, levetiracetam, and lamotrigine) (Level A).. 5D. Clinicians should implement age- appropriate developmental screening in children exposed to any ASM in utero born to PWECP (Level B).. Folic Acid. Recommendation 6 Rationale. The optimal dosing and timing of folic acid supplementation are unknown in PWECP. There is likely no demonstrated benefit of folic acid supplementation (at least . # Preconception folic acid supplementation is possibly associated with better neurodevelopmental outcomes among children born to PWECP. Folic acid supplementation of at least . Recommendation 6 Statements. 6A. Clinicians should prescribe at least . 6B. Clinicians must prescribe at least . 6C. Clinicians should counsel PWECP treated with an ASM that adherence to recommended folic acid supplementation preconceptionally and during pregnancy is important to minimize the risk of MCMs and poor neurodevelopmental outcomes (Level B).. Suggestions for Future Research. The findings of this systematic review highlight several knowledge gaps that should be addressed in future research to . There is considerable practice variation in the dosing of folic acid supplementation. High- quality studies, including randomized controlled trials where possible, will be required to definitively clarify the optimal dose and timing with respect to conception.. The impact of screening for fetal anomalies and growth restriction on perinatal outcomes needs to be established. Clarification of the impact of socioeconomic status on pregnancy outcomes in PWECP will inform social service priorities. To better clarify the potentially diverse needs of underrepresented groups, future studies should work to include diverse ethnic and racial groups, people from low and middle- income countries, as well as transgender, nonbinary, and intersex PWECP. Altogether, these lines of research will help identify pregnancies at greatest risk of adverse outcomes and inform new, targeted interventions to improve parental, fetal, perinatal, and neurodevelopmental outcomes.. Disclaimer. Clinical practice guidelines, practice advisories, systematic reviews, and other guidance published by the American Academy of Neurology (AAN) and its affiliates are assessments of current scientific and clinical information provided as an educational service. The information (1) should not be considered inclusive of all proper treatments or methods of care or as a statement of the standard of care; (2) is not continually updated and may not reflect the most recent evidence (new evidence may emerge between the time information is developed and when it is published or read); (3) addresses only the question(s) specifically identified; (4) does. # not mandate any particular course of medical care; and (5) is not intended to substitute for the independent professional judgment of the treating provider because the information does not account for individual variation among patients. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. The AAN provides this information on an "as is" basis and makes no warranty, expressed or implied, regarding the information. The AAN specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. AAN assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions.. Conflict of Interest. The American Academy of Neurology (AAN) is committed to producing independent, critical, and trustworthy clinical practice guidelines (CPGs) and evidence- based documents. Significant efforts are made to minimize the potential for conflicts of interest to influence the recommendations of this evidence- based document. Management and disclosure of document developer relationships is conducted in compliance with the 2017 AAN process manual section titled, "Implementing the AAN Conflict of Interest Policy for Guidelines and Case Definitions," which can be viewed at aan.com.. Acknowledgment. Coauthor Sanjeev V. Thomas, MD, died February 4, 2024. The authors are grateful for his contributions to this guideline and to the field of neurology. The authors thank former lead developer Cynthia L. Harden, MD, for drafting the protocol and clinical questions and former AAN staff member Shannon Merillat, MLIS, for her assistance during the guideline development process.. Study Funding. This practice guideline was developed with financial support from the American Academy of Neurology (AAN). Authors who have served as AAN subcommittee members (A.M.P., M.O., S.W.R., D.K.D., J.F., K.S., M.K.), or as methodologists (M.O., D.B.S.), or who are or were AAN staff members (M.D.O., K.B.D., H.M.S.) were reimbursed by the AAN for expenses related to travel to subcommittee meetings where drafts of manuscripts were reviewed.. Disclosure. A.M. Pack serves on the editorial board for the journal Epilepsy Currents, receives royalties from UpToDate, receives funding from the NIH for serving as coinvestigator and site PI for the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, and receives funding from Bayer for serving as a co-investigator on a study on women with epilepsy initiating a progestin IUD. An immediate family member of A.M. Pack has received personal compensation for serving as an employee of. REGENEXBIO. M. Oskoui has received personal compensation in the range of . # Consortium, the Epilepsy Foundation, Angelini Pharma, Biohaven Pharmaceuticals, Cerebral Therapeutics, Neurelis, Neurocrine, Praxis, Rapport, SK Life Science, Stoke, Takeda, and Xenon. E.E. Gerard has received personal compensation in the range of . Parratt receives funding from Zynebba for serving as a subinvestigator for the study Cannabidiol ZYNN2- CL- 04 and ZYNN2- CL- 04 for arterial onset seizures, receives funding from SK Life Science for serving as a subinvestigator for the study Cenobamate YKP3089C021 for partial onset seizures, has received funding from Eisai Inc. for the study Perampanel E2007- G00- 335 for partial onset seizures, has received funding from Marinus Pharmaceuticals for the study Ganaxolone 10420603 for partial onset seizures, and has received honoraria from Eisai for a dinner meeting lecture. P.B. Pennell's institution has received research support from the NINDS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development for observational studies of people with epilepsy of childbearing potential and their children. The institution of an immediate family member of P.B. Pennell has received research support from the U.S. Department of Defense, the Environmental Protection Agency, the NIH, and Advanced Energy Consortium. P.B. Pennell has received publishing royalties from UpToDate, a publication relating to health care. P.B. Pennell has received honoraria and/or travel reimbursements from the AES, the AAN, and various academic medical institutions for CME lectures. She has received honoraria for grant reviews from the NIH and Harvard Catalyst. She has received honoraria for serving on the scientific advisory board for BRAINS, an NIH- funded study. G. Saade has received personal compensation in the range of . # India, and served on the editorial board of the journal Epilepsy Research. T. Tomson's institution has received personal compensation in the range of . Publication History. Received by Neurology October 17, 2023. Accepted in final form February 21, 2024. Submitted and externally peer reviewed. The handling editor was Editor- in- Chief Jose Merino, MD, MPhil, FAAN.. # References. 1. US Census Bureau. National Population by Characteristics: 2020-2022 [online]. Accessed January 3, 2022. census.gov/data/tables/time-series/demo/popest/2020s-national-detail.html. 2. Stephen LJ, Harden C, Tomson T, Brodie MJ. Management of epilepsy in women. Lancet Neurol. 2019;18(5):481-491. doi:10.1016/S1474-4422(18)30495-2 3. Harden C, Pennell P, Koppel B, et al. 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b617694dff3640acb36c4975008f87f1	2024+AIRO意见书	妇科恶性肿瘤放疗相关毒性的预防和管理	# Prevention and management of radiotherapy-related toxicities in gynecological malignancies. Position paper on behalf of AIRO (Italian Association of Radiotherapy and Clinical Oncology). Elisabetta Perrucci. Received: 7 March 2024 / Accepted: 1 July 2024 © The Author(s) 2024. Abstract. Multi- modal therapies for gynecological cancers management may determine a wide range of side effects which depend on therapy- related factors and patient characteristics and comorbidities. Curative or adjuvant pelvic radiotherapy is linked with acute and late toxicity due to irradiation of organs at risk, as small and large bowel, rectum, bladder, pelvic bone, vagina and bone marrow. Successful toxicity management varies with its severity, Radiation Centre practice and experience and skills of radiation oncologists. This position paper was designed by the Italian Association of Radiation and Clinical Oncology Gynecology Study Group to provide radiation oncologists with evidence- based strategies to prevent and manage acute and late toxicities and follow- up recommendations for gynecological cancer patients submitted radiotherapy. Six workgroups of radiation oncologists with over 5 years of experience in gynecologic cancers were setup to investigate radiotherapy- related toxicities. For each topic, PubMed database was searched for relevant English language papers from January 2005 to December 2022. Titles and abstracts of results were checked to verify suitability for the document. Reference lists of selected studies and review papers were added if pertinent. Data on incidence, etiopathogenesis, prevention, treatment and follow- up of acute and late side effects for each organ at risk are presented and discussed.. Keywords Gynecological cancers · Radiotherapy · Acute late toxicity · Prevention · Treatment · Follow- up. Introduction. Today's multi- modal therapies for gynecological cancers management including surgery, chemotherapy (CHT), external beam radiotherapy (EBRT) and interventional radiotherapy (IR), also called brachytherapy, may determine a wide range of underestimated side effects [1, 2], the development of which depends on therapy- related factors such as radiation therapy (RT) modality and dose, and patient characteristics and comorbidities. Pelvic RT, in the curative or adjuvant setting, is linked with acute and late toxicity due to irradiation of organs at risk (OARs), such as the small and large bowel, rectum, bladder, and femoral heads, . # management varies with its severity, Radiation Centre practice and the experience and skills of the radiation oncologists which may be limited by a lack of physician education [1]. The present position paper was designed by the Italian Association of Radiation and Clinical Oncology Gynecology Study Group (AIRO Gyn) to provide radiation oncologists with evidence- based strategies to prevent and manage acute and chronic toxicities and follow- up recommendations for patients with gynecological cancers who underwent RT.. Methods. With AIRO Steering Committee endorsement, 6 workgroups of radiation oncologists, each including physicians with over 5 years of experience in gynecologic cancer, were setup to investigate early and late RT- related toxicities in the bowel (AB, AP, EG, JDM, AF), rectum (SC, EM, CM, ADA, PF), bladder (FT, RL, GC, AS), bone (EP, CA, MPP, VE), blood (FT, RL, GC, AS), and vagina (MC, VDS, FT, CL) after adjuvant or curative EBRT, with or without BT and/or CHT. The choice of taking part to each group was based on the preference and interest of the single specialists in the specific field of investigation; each group was established during the preparatory meeting. For each topic, PubMed database was searched for relevant English language papers published from January 2005 to December 2023. Search strategy included the following keywords: "cervical cancer" OR "cervical neoplasm" OR "cervix cancer" OR "cervix neoplasm" OR "uterine cancer" OR "uterine neoplasm" OR "vaginal cancer" OR "vaginal neoplasm" OR "vulva* cancer" OR "vulva neoplasm" OR "endometrial cancer" OR "endometrial neoplasm" OR "ovarian cancer" OR "ovarian neoplasm*" OR "Genital Neoplasms, Female" [Mesh]. An example of search strategy referring to bone toxicity is shown in Table 1. Titles and abstracts of literature search results were checked to verify suitability for the document. Reference lists of selected studies and review papers were manually searched for additional pertinent publications. Editorial, abstract from international meetings and case reports/series were excluded. Results . Results. Bowel toxicity. Incidence and etiopathogenesis. Overall, small bowel toxicity develops in up to . # serious side effects, i.e., ischemia, progressive intestinal fibrosis, stenosis and/or fistulas. Etiopathogenesis of bowel toxicity is shown in Fig. 1.. Prevention. Pharmacological and RT techniques may prevent small bowel toxicity. Several studies demonstrated that probiotics during treatment significantly reduced acute toxicity [11]. A double- blinded study of 54 patients who underwent pelvic RT assessed probiotics against placebo [12]. During EBRT and in the three weeks afterward, episodes of diarrhea and abdominal pain were evaluated through interviews and questionnaires and scored on the CTCAE scale [5]. Probiotics significantly reduced not only the incidence of diarrhea more than placebo (53.8 vs 82.1%, . Small bowel toxicity is reduced by modern RT techniques such as IMRT, volumetric modulated arc therapy (VMAT), tomotherapy and proton beam RT [16, 17, 25- 31]. On the other hand, changes in setup positions (supine vs prone) yielded discordant results [32- 35].. Hoover et al. found that visceral adipose- corrected bowel bag dosimetric constraints correlated better with acute bowel toxicity than the current standard practice of considering V45 cc and V40% [36]. Using image- guided radiotherapy (IGRT), Xin et al. [37] evaluated setup errors and their effects on acute bowel toxicity and treatment efficacy in 170 cervical cancer patients who underwent IMRT ± IGRT. Response rates were similar in both groups, but IGRT significantly corrected and reduced setup errors during treatment and enhanced the accuracy of dosage distribution within OARs (such as targeted regions), thus reducing RT- related toxicity [33]. Park et al. [38] found bladder filling associated with the use of personalized immobilization devices and the adoption of the prone position in 3D- CRT displaced the small bowel continuously away from the irradiated field in cervical cancer patients. Adopting these precautions decreases the amount of intestine exposed to radiation and consequently can decrease the frequency and severity of onset of side effects [38].. # Treatment. TreatmentSmall bowel toxicity may have an impact on treatment compliance, requiring symptomatic therapy when necessary. Treatment of acute small bowel toxicity can require probiotics to restore intestinal microbiota, loperamide and dietary counseling, bearing in mind that nutrient malabsorption may occur as a late side effect [39].. Follow-up. During follow- up, all patients should be evaluated to assess late toxicity for early intervention by a specialist multidisciplinary team (e.g., gastroenterologist, nutritionist, surgeon). Patients recovering from initial complications remain at risk of late and persistent adverse events [40].. Summary of evidences is shown in Table 2.. Rectal toxicity. Incidence and etiopathogenesis. Rectal toxicityIncidence and etiopathogenesisRT- related proctitis, a common complication of pelvic RT, is due to the rectal proximity to pelvic organs and its fixed position [41]. Although the incidence is not clear, due to a lack of consensus on its definition and reporting methodologies, large irradiated volume, RT dose (<45 Gy or above 70 Gy), older RT technique (3D- CRT vs IMRT), are generally agreed to be risk factors [42]. Acute RT- related proctitis occurs almost immediately after starting RT and lasts for up to 3 months. It is an inflammatory process affecting the superficial mucosa and its symptoms usually include diarrhea, cramps, tenesmus, urgency, mucus discharge, and minor bleeding which typically resolve spontaneously following completion of treatment [43]. Even though chronic RT- related proctitis may begin during the acute phase of radiation proctitis, symptoms may not become apparent until a median of 8- 12 months after completing RT [42]. It is histologically characterized by arteriole endarteritis, submucosal connective tissue fibrosis and neoangiogenesis followed by telangiectasias [44]. Bleeding is the most common symptom; strictures, perforation, fistula and rectal obstruction may also occur [41, 45]. In some cases, loss of distensibility, due to rectal wall fibrosis, results in tenesmus or defecation difficulties. Etiopathogenesis of rectal toxicity is shown in Fig. 2.. Prevention. Rectal toxicity should be prevented because it may interrupt treatment, limit the delivered RT dose with a consequent reduction in treatment efficacy and worsen the patient's QoL [46]. Prevention should begin by assessing the individual . RT- related rectal toxicity is reduced by decreasing the dose delivered to the rectum and by adopting strategies that modulate cellular and tissue responses to RT, thus reducing radiosensitivity [14, 47].. Several trials demonstrated that IMRT was associated with less rectal toxicity than 3D- CRT [48- 50].A prospective, phase III trial was conducted on 234 patients with cervical or endometrial cancer who were randomized to post- operative RT with IMRT or 3D- CRT. IMRT was associated with significantly fewer episodes of diarrhea and fecal incontinence [51]. The Post- operative Adjuvant Radiation in Cervical Cancer (PARCER) phase III randomized trial, which compared late toxicity in women with cervical cancer undergoing post- operative RT with IGRT- IMRT or 3D- CRT, demonstrated that IGRT- IMRT significantly reduced late toxicity with no difference in disease outcomes [52].. Although clinical target volume- planning target volume (CTV- PTV) margin shrinkage might reduce RT- related toxicity, too narrow margins could increase the risk of geographic miss, especially with IMRT/VMAT techniques with highly conformal doses to the target volume [53- 55]. IGRT reduces the risks of target miss and/or OARs overdose during RT delivery [56]. The role of cone- beam computed tomography (CT) [57] was evaluated in 170 patients with cervical cancer to check setup errors and their effects on acute toxicity and RT efficacy. The results showed it corrected and reduced setup errors, improved dose distribution accuracy in the target area and OARs, significantly reduced toxicity and improved efficacy [57]. Even though prone and supine positions were not associated with any differences in dosimetry and rectal toxicity with IMRT, the supine position is preferred because of fewer setup uncertainties and greater patient stability during treatment [33].. Several drugs have been used to prevent RT- related toxicity by modulating the radiosensitivity of normal tissues [47]. Administered intravenously, subcutaneously or intrarectally (the most effective route) [44], amifostine exerts radioprotective efficacy through diverse complex and not fully understood molecular and cellular processes, which are hypothesized to include free- radical scavenging, DNA protection, DNA repair acceleration, and induction of cellular hypoxia [58]. It may up- regulate the expression of proteins that repair DNA and inhibit apoptosis through Bcl- 2 and hypoxia- inducible factor- 1 [59]. Several small, single- center controlled trials suggested that amifostine may reduce acute gastrointestinal toxicity during pelvic RT, while there does not appear to be any meaning reduction in late morbidity. Thus, despite many studies [14, 60, 61] which. # # # a recent review judged to be at high risk of bias [62], due to methodological limitations and very uncertain evidence, amifostine has not been associated with sufficiently reduced side effects to satisfy FDA regulatory requirements [59].. The present position concurs with the MASCC panel's recommendation that cytoprotective agents like Sucralfate, non- steroid anti- inflammatory agents like balsalazide, mesalazine and prostaglandin analog like misoprostol should not be treatment of choice to prevent radiation- induced proctitis, due to conflicting evidence on their efficacy [63].. Treatment. Grade 1/2 proctitis responds to topical anti- inflammatory products, such as sulfasalazine or mesalazine alone or combined with steroids [64].. Hyperbaric oxygen which induces neo- vascularization, tissue re- oxygenation, collagen neo- deposition and fibroblast proliferation, elicited responses in the majority of patients with soft tissue necrosis or chronic proctitis [65- 67]. A review evidenced that hyperbaric oxygen therapy may improve outcomes, but further studies are necessary to establish the correct patient's selection [68]. Potassium titanyl phosphate, Argon and YAG lasers are used to treat superficial injuries [69]. Repeated applications of Argon Plasma Coagulation resolved . Follow-up. Sigmoidoscopy is recommended for investigating patient- reported bleeding or evidence of occult fecal blood [73, 74]. Summary of evidences is shown in Table 2.. Urinary toxicity. Incidence and etiopathogenesis. After pelvic RT for gynecologic malignancies about . The bladder and urethra frequently show signs of late radiation damage, leading to urinary sequelae like infection, discomfort, and hematuria. Reduced bladder capacity leading to frequent urination is due to damage to bladder vasculature and smooth muscle fibers, resulting in edema, cell death and fibrosis [2, 3].. Bladder dysfunction occurring many years after RT, affects the patient's QoL and includes urgency, frequency and incontinence due to high dose bladder neck irradiation. # (26\%). The risk of late genitourinary toxicity increased with a history of abdominal surgery, pelvic inflammatory disease, hypertension, diabetes mellitus and smoking [76]. Older age significantly impacted incontinence, because shorter vaginal lengths can result in higher bladder neck doses. Obesity and overweight were risk factors for incontinence and frequency [77].. Most RT- related ureteral strictures caused by RT affect the distal portion of the ureter, and it was demonstrated that delaying the clearance of ureteral blockage increases the risk of serious long- term morbidity, including infections, kidney damage, and arterial hypertension. The risk of ureteral stricture in patients with locally advanced cervical cancer and hydronephrosis at diagnosis was . Diverse urinary morbidity endpoints exhibit different temporal trends, as shown by the EMBRACE research [78]. This suggests that a wide range of intricate physiological mechanisms develop during radiation. The exposure of various organ sub- volumes to RT, the differences in dose- effect relationships for various symptoms, the potential reversibility of some late effects, and the effective management of late effects are additional factors that influence the development of treatment- related morbidity. Etiopathogenesis of urinary toxicity is shown in Fig. 3.. Prevention. Different IMRT modalities may reduce the rate of acute and late high- grade toxicity [79, 80]. On the other hand, Droge et al. reported that patients treated with VMAT experienced acute . In patients with locally advanced cervical cancer, who were treated with EBRT, CHT and IR the investigators of EMBRACE Collaborative Group found ICRU bladder point (ICRU- BP) dose . Treatment. Guidelines for managing urinary toxicity are lacking. For acute symptoms, the workup should include urine analysis and urine culture. Low- grade urinary symptoms are managed with non- steroidal anti- inflammatory drugs, anticholinergic agents such as oxybutynin, or analgesics such as phenazopyridine. Botulinum toxin A injection into the detrusor muscle may be used when drug therapy is ineffective [2]. Symptoms are generally self- limited, and drugs can be discontinued as symptoms improve. Treatment for hemorrhagic cystitis includes hydration, hyperbaric oxygen, clot evacuation, endoscopic fulguration and bladder irrigation with a variety of substances [84]. Surgery should be evaluated in case of refractory disease. Infection and primary bladder malignancy must also be evaluated.. # Ureteral strictures, if not due to recurrent disease, are repaired with endoscopy or open surgery including percutaneous nephrostomy or ureteral stent or ileal ureteral substitution [84] which can be challenging due to the poor vascularity and wound healing following radiation. Vesicovaginal fistulae, not related to disease, may require fulguration and drainage or surgery [84].. Follow-up. In addition to the clinical examination, the accurate anamnesis guides the specialist in any ulterior investigation with further instrumental tests for urinary tract dysfunction. Bladder cystitis and bleeding may reach a peak prevalence rate at about 30 months, after which prevalence rates fell to baseline, indicating healing [85].. Summary of evidences is shown in Table 2.. Bone toxicity. Incidence and etiopathogenesis. Surgery with ovary removal, CHT and RT may have detrimental effects on bone mineral density (BMD) leading to osteoporosis and fractures which impact on quality of life and life expectancy [86- 89]. The incidence of bone toxicity after RT or CRT is largely underestimated because attention has only recently focused on long- term cancer survivors [90].. RT is hypothesized to be linked to osteoblast death and less activity as well as increased osteoclast activity and inflammatory cytokine release. Consequences include bone marrow adiposity, trabecular bone loss [91, 92], reduced BMD, osteoporosis, and pelvic insufficiency fractures (PIF) [1, 90, 93- 98].. The incidence of PIF after RT ranges from 10 to . PIF is diagnosed on evidence from X- rays, bone scans, CT scans, or magnetic resonance imaging (MRI), with MRI being the most reliable tool [92, 93, 95, 103]. The sacrum, sacroiliac joint and pubis are the most frequently affected sites [97, 99, 101]; more than 1 PIF can occur [95]. About . # Prevention. Before RT, primary prevention of PIF is based on accurate evaluations of BMD and risk factors, particularly in postmenopausal women and in patients over 50 years old [89], as lower pre- treatment CT bone density was found in patients developing PIF [104, 105, 107] and a global reduction of BMD was reported after RT or CRT, even though there is no consensus on whether adding CHT to RT increases the risk of PIF [86, 95, 102, 109- 112]. When necessary, therapy should be prescribed, e.g., vitamin D, calcium, bisphosphonate and, in selected cases, hormone replacement therapy [89, 113].. RT- related bone toxicity should be minimized even though to date modalities and doses have not yet been clearly defined and no dosimetric constraints are available for the pelvic bone dose to reduce the incidence of bone toxicity and PIF [114]. In cervical cancer patients treated with curative intent, IMRT plus IR was associated with less PIF than 3D/ CRT plus IR [100, 102, 110, 115]. This difference did not emerge in the adjuvant setting [109], due to the lower doses administered in the post- operative treatment.. Controversial results were achieved when a simultaneous integrated boost (SIB) was administered by IMRT [96, 103]. Bazire et al. [96] found maximum doses were significantly higher at fracture sites than in pelvic bones without PIF; while, Mir et al. [103] reported 60 Gy SIB did not impact fracture sites. Ramlov et al. [95] found sacrum . Treatment. Management of bone toxicities and PIF requires a multidisciplinary approach. Preventive therapy for low BMD and osteoporosis should continue throughout treatment and follow- up [2]. PIF is generally treated with no steroidal anti- inflammatory drugs, analgesics or opioids, if necessary; treatment can take many months [99]. Bed rest is indicated . Follow-up. Follow- up examinations should include regular BMD assessment and drug therapy for patients at risk [93, 97, 112, 116]. Attention should be paid to patient- reported musculoskeletal symptoms, which are often overlooked as specific QoL questionnaires do not investigate RT- related bone toxicity [114]. Imaging studies, particularly MRI, should be prescribed for symptomatic patients, taking care to differentiate PIF from metastases [117, 118].. Summary of evidences is shown in Table 2.. Hematological toxicity. Incidence and etiopathogenesis. Hematological toxicityIncidence and etiopathogenesisDue to the heterogeneity of gynecological cancers and the range of treatments (EBRT alone, IR alone, or combined, with or without CHT), no studies have defined the impact of each factor on the incidence of hematological toxicity. Several studies reported that bone marrow (BM) acted as a parallel organ and emphasized the need for sparing a threshold of its volume. Predictors contributing to hematological toxicity were: baseline white blood cells, absolute neutrophil count, hemoglobin and platelets; use of para- aortic irradiation; body mass index. No associations were found between hematological toxicity and race, age, comorbidity, performance status, smoking history, stage, BM volume, pre- treatment transfusions [119, 120]. Hematological toxicity might depend on the association of RT and a myelosuppressive CHT regimen [121]. In the setting of CRT for various pelvic cancers, including cervical cancer [122- 125], myelosuppressive CHT was identified as the primary cause of anemia, leukopenia, and neutropenia [122- 125] which, together with thrombocytopenia, are common and, at times, life- threatening side effects of oncologic treatments for pelvic malignancies [122- 127]. Huang et al. showed hematological toxicity grade 2 or higher in . # during RT [130, 131], with the decline and regeneration of active, red BM (aBM) being RT dose- dependent [124]. Patients with a low pre- treatment aBM volume, identified by 18F- FDG- PET- CT and the technetium- . aBM, half of which is located within pelvic bones and lumbar vertebrae [122, 124, 125], is highly radiosensitive as just 4 Gy reduces its volume by . Even though avoiding BM during RT appears to be a factor in preserving aBM and decreasing hematological toxicity [139], BM tolerance remains poorly understood [121]. Moreover, BM was excluded from normal tissue dose constraint guidelines such as "the Emami table" [140] or Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) [141]. Furthermore, the Lyman- Kutcher- Burman model, the most widely used normal tissue complication probability (NTCP) model, does not consider BM . Prevention. Currently, the development of effective pelvic BM sparing RT techniques is limited due to a lack of knowledge on the spatial location of BM to be saved and the required degree of sparing that is essential [143]. In the future proton therapy may be beneficial to enable BM sparing due to its physical characteristics and ability to achieve satisfactory target dose distribution [144].. A systematic review investigating the clinical benefit of aBM sparing in cervical cancer patients receiving CRT evidenced decreasing incidence of hematological toxicity [145]. Since functional imaging to identify aBM by 18F- FDGPET- CT and the technetium- . # 149], and . A significant relationship emerged between the dose received by pelvic bone and nadirs of blood cells, including white blood cells, absolute neutrophil count, hemoglobin, and platelets [151]. Only V10 and V20 were significantly correlated with hemoglobin nadirs, while no dosimetric parameters were associated with platelets nadirs [124]. In cervical cancer patients who were treated with CRT, Elicin et al. found the volume of BM and aBM exposed to low doses RT were associated with white blood cells decrease. In particular, aBM V30 correlated with reduced aBM SUV and impacted the white blood cells count three months after treatment and during late follow- up [152].. In patients with cervical cancer who had no lymph node metastasis detected during surgery or by preoperative imaging, and met the criteria, reduced- volume pelvic RT, rather than whole pelvis RT, relieved acute and late radiation damage, especially myelosuppression. With a decreased CTV and significantly lower V10 and V20, reduced- volume pelvic RT did not affect long- term survival. Compared with whole pelvis RT the incidence of decreased hemoglobin associated with . Treatment. During CRT, routine blood and biochemistry investigations are indicated. Myelosuppression, which can increase infection and hospitalization rates may require transfusions and administration of growth factors. It is also linked with treatment interruptions that significantly worsen outcomes [123, 125, 151].. Follow-up. Slow immune recovery and abnormal white blood cells count at three months post- treatment and/or at the last follow- up, underline the need to lower the incidence of hematological toxicity [152]. Low lymphocyte counts persisting for one year after RT [154] might be associated with a higher risk of decreased survival. Patients with hematological toxicity should be evaluated by a multidisciplinary team, including a hematologist. Routine analysis should include blood and biochemistry tests other than CT Scan, USG abdomen, ECG, and chest X- ray.. Summary of evidences is shown in Table 2.. Vaginal Toxicity. Incidence and etiopathogenesis. Little attention is paid to vaginal toxicity and the ensuing sexual complications that women may experience after RT. In cervical cancer patients a systematic review reported more sexual dysfunction and vaginal toxicity after RT. [155]. Modifications in sexuality were due not only to physical and treatment- linked factors, but also to physiological and social causes [155]. Vaginal atrophy in up to . A . Prevention. Two dosimetric studies [158, 160] showed that improving RT techniques could prevent vaginal toxicity. Vaginal dose de- escalation at EBRT with IMRT as well as at IR is expected to reduce vaginal morbidity and thus help prevent sexual dysfunction [161]. According to data on the dose- response relationship [162], de- escalating the dose to the ICRU rectovaginal point from 75 to 65 Gy reduced grade 2 or more vaginal stenosis by . # Created with PowerPoint. changes significantly reduced vaginal toxicity more than the non- vaginal dose de- escalated plan [158].. The gonadal function might be preserved in selected cases. Ovarian preservation with IMRT is technically challenging, due to poor ovary visualization at CT planning and high oocyte radiosensitivity. Indeed, sterilization is predicted in 5 and . Treatment. Topical application of hyaluronic acid, along with vitamin E and A [9, 167- 170] prevented acute and late vaginal toxicities thanks to their role in cellular differentiation, keratinocyte proliferation, antioxidative properties and support to the extracellular matrix of the vaginal epithelium [167, 168]. They reduced dyspareunia, vaginal mucosal inflammation, vaginal dryness, bleeding, fibrosis and cellular atypia. Regular use of vaginal moisturizers to hydrate the vaginal mucosa and lubricants to minimize dryness and pain during sexual practice is indicated. Further studies are needed to confirm whether local application of mitomycin C prevents vaginal vault narrowing after treatment, as fewer vaginal adhesions . Toxicity, deriving from hypoestrogenism, includes the genitourinary menopause syndrome, i.e., the set of vulvovaginal signs and symptoms, involving changes in the major/ minor lips, clitoris, vestibule, vagina, urethra and bladder [172].. Hormone replacement therapy (HRT), as administered in diverse formulations, effectively treats genitourinary menopause syndrome [173] and is useful in managing post- RT menopausal symptoms [165]. Despite the few studies, systemic or local estrogen therapy is a valid option for acute RT- related changes and preventing the development of later vaginal complications, thanks to its direct effect on epithelial regeneration and anti- inflammatory properties. Vaginal estrogens reduce superficial dyspareunia [9] and relieve urogenital symptoms related to vaginal atrophy and are safe in cervical cancer patients because of minimal systemic absorption through the atrophic mucosa [165]. Although estrogen and progesterone receptors are expressed in . # HRT usage and the risk of endometrial cancer recurrence [178].. Pelvic floor muscle exercises help relieve vaginal pain and enhance clitoral blood flow, thus promoting better sexual function. Pelvic floor muscle training, alone or in combination with other treatments, seemed effective, even though more studies are needed [179].. Laser therapy was described as promising in the management of vaginal atrophy after RT as intravaginal . There is no consensus on the use of vaginal dilators. Even though some authors suggest they prevent the onset and worsening of vaginal stenosis [9, 181], a systematic review [182] concluded that evidence was insufficient to recommend them, and that dilation was associated with recovaginal fistulae and psychological consequences. Despite these findings, vaginal dilators are commonly accepted as a strategy for preventing vaginal stenosis [183]. Furthermore, their long- term use is indicated to reduce G2 late vaginal stenosis in 3D- vaginal cuff IR [184] but poor compliance might underlie minimal improvement in vaginal symptoms [185].. Follow-up. During follow- up visits, attention should be reserved for vaginal and sexual symptoms reported by the patients and active interventions by a multi- specialist team should be undertaken, if possible.. Summary of evidences is shown in Table 2.. Conclusions and recommendations. Treatment of gynecological cancers may have an important impact on women's overall health and QoL. Other than the psychological aspect linked to the diagnosis of cancer [186] patients may experience a wide range of side effects due to the multi- modal therapeutic approach which includes surgery, CHT, RT and IR. RT alone or combined with CHT as adjuvant or definitive treatment plays a crucial role in the treatment of gynecological cancers and achieves better outcomes and long- term survival of patients. However, the occurrence of acute and late side effects related to pelvic RT can negatively impact overall outcomes and patients' QoL [187, 188].. This position paper, conceived in the AIRO Gyn Group, aimed at providing radiation oncologists with a succinct, but comprehensive view of RT- related toxicities in gynecological cancers. Aims were not only to describe the incidence and pathogenesis of specific toxicities but also, above all, to disseminate evidence for the prevention and treatment of such treatment- related side effects [3]. The ultimate goal was . Since there are no standard guidelines for narrative reviews, we decided to search PubMed, one of the largest free- access biomedical databases. We started our analysis with the year 2005, when IMRT for gynecologic tumors became standard in routine clinical practice in most Radiation Oncology Centers [189].. In our opinion, prevention of toxicity should aim at improving the therapeutic index of RT treatment, possibly by adopting IMRT/VMAT, Tomotherapy along with IGRT, which reduce the occurrence and severity of toxicity [190, 191]. Treatment planning should be done with great care, following guidelines, indications and dose constraints for OARs even though, unfortunately, dose constraints are not standardized for each specific OAR. Furthermore, to prevent the onset of toxicity, and/or reduce its severity before, during and after RT, knowledge of patient and disease features aid radiation oncologists in prescribing drugs and non- pharmacological interventions.. Moreover, patients should be carefully informed and trained if a particular preparation is required during RT treatment to avoid side effects, i.e., bladder filling or dietary recommendations if indicated. During RT treatment, patients should be followed with routine visits to early assess the occurrence and grade of toxicities, reported and graded by specific scales [4- 6]. At present it is unknown if one specific scale is better than others in assessing RT- related adverse events [192]. The administration of questionnaires as PRO might be useful to recognize and prevent acute toxicity, as suggested by Chan et al. [193]. If needed, pharmacological therapy should be prescribed along with eventual replanning.. Long- term follow- up is needed to investigate not only the clinical outcome of the disease, but the occurrence of late RT- induced toxicity. Management of late toxicity can require a multidisciplinary approach and interventions should be based on shared decisions.. New evidences suggest other fields of research and interventions. Recent studies focused on the role of gut microbiome in determining gastrointestinal side effects [1, 114] and possibly treatment outcomes, indicating the need for attention to this aspect during RT. Bone health in menopausal women should not be overlooked, as bone toxicity negatively affects patients QoL. Lastly, sexual problems in women undergoing treatment for gynecological cancer have been investigated more recently [155] and the real occurrence is underestimated, as PRO revealed that patients did not respond to these specific questions [193]. Patients needing RT should be fully informed about sexual dysfunctions linked to treatment and approaches for reducing discomfort [155].. # Therefore, RT techniques advance, respect for OAR constraints, knowledge of causes and treatment options for RT side effects along with patient care can guide radiation oncologists to offer the best RT modalities and support women during treatment and follow- up.. Finally, well- designed, specific investigations are needed to answer the not yet solved problems in order to improve the quality of treatment delivered to patients who will receive radiation therapy for gynecological cancers.. Acknowledgements The Authors thank the Scientific Committee and Board of the AIRO for the critical revision and final approval of the manuscript (Nr. 1/2024).. Author contributions All authors contributed equally.. Funding Open access funding provided by Università degli Studi di Perugia within the CRUI- CARE Agreement. The authors have not disclosed any funding.. Declarations. Conflict of interest Authors disclose no conflicts of interest.. Ethics approval Institutional Review Board approval was not required because this study does not involve human subjects.. Consent to participate Informed consent was not applicable for this study.. Consent for publication All authors agreed on the content of the paper.. 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Bodner K, Laubichler P, Kimberger O, Czerwenka K, Zeillinger R, Bodner-Adler B (2010) Oestrogen and progesterone receptor expression in patients with adenocarcinoma of the uterine cervix and correlation with various clinicopathological parameters. Anticancer Res 30:1341-1345175. Everhov AH, Nyberg T, Bergmark K, Citarella A, Radestad AF, Hirschberg AL, Smedby KE (2015) Hormone therapy after uterine cervical cancer treatment: a Swedish population-based study. Menopause 22:633-639. de Hullu JA, Pras E, Hollema H, van der Zee AG, Bogchelman DH, Mourits MJ (2005) Presentations of endometrial activity after curative radiotherapy for cervical cancer. Maturitas 51:172-176. Pitkin J, Rees MC, Gray S, Lumsden MA, Marsden J, Stevenson JC, Williamson J (2007) Management of premature menopause. Menopause Int 13:44-45. Shim SH, Lee SJ, Kim SN (2014) Effects of hormone replacement therapy on the rate of recurrence in endometrial cancer survivors: a meta-analysis. Eur J Cancer 50:1628-1637. Barcellini A, Dominoni M, Dal Mas F, Biancuzzi H, Venturini SC, Gardella B, Oramdi E, Bø K (2022) Sexual health dysfunction after radiotherapy for gynecological cancer: role of physical rehabilitation including pelvic floor muscle training. Front Med (Lausanne) 8:813352. Perrone AM, Tesei M, Ferzoli M, De Terlizzi F, Della Gatta AN, Boussedra S, Dondi G, Galuppi A, Morganti AG, De Iaco P (2020) Results of a phase I-II study on laser therapy for vaginal side effects after radiotherapy for cancer of uterine cervix or endometrium. Cancers (Basel) 12:1639. Martins J, Vaz AF, Grion RC, Costa-Paiva L, Baccaro LF (2021) Topical estrogen, testosterone, and vaginal dilator in the prevention of vaginal stenosis after radiotherapy in women with cervical cancer: a randomized clinical trial. BMC Cancer 21:682. Johnson N, Miles TP, Cornes P (2010) Dilating the vagina to prevent damage from radiotherapy: systematic review of the literature. BJOG 117:522-531. . 183. Damast S, Jeffery DD, Son CH et al (2019) Literature review of vaginal stenosis and dilator use in radiation oncology. Pract Radiat Oncol 9(6):479-491. Zhang Y, Noorian F, Abellana R et al (2023) Vaginal dilator use more than 9 months is a main prognostic factor for reducing G2-late vaginal complications in 3D-vaginal-cuff brachytherapy (interventional radiotherapy)? Clin Transl Oncol 25:1748-1755. Cerentini TM, Schlottgen J, Viana da Rosa P, La Rosa VL, Vitale SG, Giampaolino P, Valenti G, Cianci S, Macagnan FE (2019) Clinical and psychological outcomes of the use of vaginal dilators after gynaecological brachytherapy: a randomized clinical trial. Adv Ther 36:1936-1949. Seland M, Skrede K, Lindemann K, Skaali T, Blomhoff R, Bruheim K, Wisloff T, Thorsen L (2022) Distress, problems and unmet rehabilitation needs after treatment for gynecological cancer. Acta Obstet Gynecol Scand 101:313-322. de Boer SM, Nout RA, Jürgenliemk-Schulz IM, Jobsen JJ, Lutgens LC, van der Steen-Banasik EM, Mens JW, Slot A, Stenfert Kroese MC, Oerlemans S, Putter H, Verhoeven-Adema KW, Nijman HW, Creutzberg CL (2015) Long-term impact of endometrial cancer diagnosis and treatment on health-related quality of life and cancer survivorship: results from the randomized PORTEC-2 Trial. Int J Radiat Oncol Biol Phys 93:797-809. Kirchheiner K, Pötter R, Tandertup K, Lindegaard JC, Haie-Meder C, Petrič P, Mahantshetty U, Jürgenliemk-Schulz IM, Rai B, Cooper R, Dörr W, Nout RA (2016) EMBRACE Collaborative GroupHealth-related quality of life in locally advanced cervical cancer patients after definitive chemoradiation therapy including image guided adaptive brachytherapy: an analysis from EMBRACE study. Int J Radiat Oncol Biol Phys 94:1088-1098. Hymel R, Jones GC, Simone CB II (2015) Whole pelvic intensity-modulated radiotherapy for gynaecological malignancies: a review of the literature. Crit Rev Oncol Hematol 94:371-379. Fernandez-Ots A, Crook J (2013) The role of intensity modulated radiotherapy in gynaecological radiotherapy: present and future. Rep Pract Oncol Radiother 18:363-370. Holch P, Henry AM, Davidson S et al (2017) Acute and late adverse events associated with radical radiation therapy prostate cancer treatment: a systematic review of clinician and patient toxicity reporting in randomized controlled trials. Int J Radiat Oncol Biol Phys 97:495-510. Chan M, Olson R, Lapointe V, Hamm J, Bachand F, Holloway C, Parsons C, Lim P (2022) Using a weekly patient reported outcome questionnaire to track acute toxicity in patients undergoing pelvic radiotherapy for gynecologic cancers. Curr Oncol 29:3306-3317. . Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.. # Authors and Affiliations. Elisabetta Perrucci1 . Valeria Epifanivaleria.epifani@ospedale.perugia.it1 Radiation Oncology Section, Perugia General Hospital, Perugia, Italy2 Radiation Oncology Unit, Responsible Research Hospital, Campobasso, Italy3 Radiotherapy Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy4 Radiotherapy Unit, Azienda Ospedaliera San Giovanni Addolorata, Rome, Italy5 UOC di Radioterapia, Dipartimento di Scienze Radiologiche, Radioterapiche ed Ematologiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy6 Radiation Oncology Unit, Clinical Department, CNAO National Center for Oncological Hadrontherapy, Pavia, Italy7 Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy8 Department of Radiotherapy, IFO European Institute of Oncology IRCCS, Milan, Italy9 Radiation Oncology Centre, Santa Maria Hospital, Terni, Italy10 Radiotherapy Oncology, Department of Medicine, Surgery and Translational Medicine, St. Andrea Hospital, Sapienza University of Rome, Rome, Italy11 Dipartimento Di Oncologia P.O. S. Anna - SS Radioterapia, A.O.U "Città Della Salute E Della Scienza", Turin, Italy12 Radiation Oncology Section, University of Perugia, Perugia, Italy13 UO Radioterapia Oncologica, Ospedale S. Chiara, Trento, Italy14 Department of Radiation Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. 15 Department of Radiotherapy, Ospedale Regionale Parini- AUSL Valle d'Aosta, Aosta, Italy16 Department of Translational Medicine, Radiation Oncology Division, University of Pisa, Pisa, Italy17 Department of Radiotherapy, Santa Chiara Hospital, Trento, Italy18 Radiotherapy Department, Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy19 UOC Radioterapia Oncologica, Ospedale Generale Provinciale di Macerata, AST Macerata, Italy20 Radiotherapy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy21 Radiotherapy, A.O.SS. Antonio e Biagio, Alessandria, Italy22 Radiotherapy Unit, Ospedale di Circolo Fondazione Macchi, Varese, Italy23 Radiotherapy Unit, Ospedale Maggiore di Trieste, Trieste, Italy24 Department of Radiation Oncology, General Regional Hospital "F. Miulli", Acquaviva delle Fonti, Bari, Italy25 Radiation Oncology Unit, Department of Oncology, "Santa Maria della Misericordia" University Hospital, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy26 U.O.C. Radiotherapy, Ospedale Isola Tiberina - Gemelli Isola, Rome, Italy27 Department of Radiotherapy, Policlinico Umberto I, Department of Radiological, Oncological and Pathological Sciences, "Sapienza" University of Rome, Rome, Italy28 Radiation Oncology Section, University of Perugia and Perugia General Hospital, Perugia, Italy.	None	None	None
a81ae2a7e46f4208b08f22e652700d85	2024+AIUM实践参数	女性盆腔的超声检查表现	# AIUM Practice Parameter for the Performance of Ultrasound of the Female Pelvis, 2024 Revision. The American Institute of Ultrasound in Medicine (AIUM) is a multidisciplinary association dedicated to advancing the safe and effective use of ultrasound in medicine through professional and public education, research, development of clinical practice parameters, and accreditation of practices performing ultrasound examinations.. The AIUM Practice Parameter for the Performance of Ultrasound of the Female Pelvis was developed and revised by the American Institute of Ultrasound in Medicine (AIUM) in collaboration with other organizations whose members use ultrasound for performing these examinations (see "Acknowledgments"). Recommendations for personnel requirements, the request for the examination, documentation, quality assurance, and safety may vary among the organizations and may be addressed by each separately.. This Practice Parameter is intended to provide the medical ultrasound community with recommendations for the performance and recording of high- quality ultrasound examinations. The parameter reflects what the AIUM considers the appropriate criteria for this type of ultrasound examination but is not intended to establish a legal standard of care. Examinations performed in this specialty area are expected to follow the Parameter with the recognition that deviations may occur depending on the clinical situation.. Indications. Indications for pelvic sonography include, but are not limited to, the following:. 1. Evaluation of pelvic pain 2. Evaluation of pelvic masses 3. Evaluation of dyspareunia 4. Evaluation of pregnancy of unknown location or ectopic pregnancy 5. Evaluation of endocrine abnormalities, including polycystic ovaries 6. Evaluation of dysmenorrhea 7. Evaluation of amenorrhea 8. Evaluation of abnormal uterine bleeding (AUB). # 9. Evaluation of postmenopausal bleeding 10. Evaluation of delayed menses 11. Follow-up of a previously detected abnormality 12. Evaluation, monitoring, and/or treatment of patients with infertility 13. Evaluation when there is limited clinical examination of the pelvis 14. Evaluation for signs or symptoms of pelvic infection 15. Further characterization of a pelvic abnormality noted on another imaging study 16. Evaluation of congenital uterine, gonadal, and lower genital tract anomalies 17. Evaluation of excessive bleeding, pain, or signs of infection after pelvic surgery, delivery, or abortion 18. Localization of an intrauterine device (IUD) 19. Surveillance for malignancy in high-risk patients 20. Evaluation of incontinence or pelvic organ prolapse 21. Guidance for interventional or surgical procedures 22. Preoperative and postoperative evaluation of pelvic structures. Qualifications and Responsibilities of Personnel. Physicians interpreting or performing this type of ultrasound examination should meet the specified AIUM Training Guidelines in accordance with AIUM accreditation policies.. Sonographers performing the ultrasound examination should be appropriately credentialed in the specialty area in accordance with AIUM accreditation policies.. Physicians not personally performing the examination must provide supervision, as defined by the Centers for Medicare and Medicaid Services Code of Federal Regulations 42 CFR §410.32, which is available from the U.S. Government Publishing Office.. Request for the Examination. The written or electronic request for an ultrasound examination must originate from a physician or other . Specification of the Examination. The following section details the examination to be performed for each organ and anatomic region in the female pelvis. All relevant structures should be identified by the transabdominal and/or transvaginal approach. A transrectal or transperineal approach may be useful in patients who are not candidates for introduction of a vaginal transducer and in assessing the patient with pelvic organ prolapse. More than one approach may be necessary.. General Pelvic Preparation. For a transabdominal pelvic sonogram, a full bladder is typically needed to displace the bowel from the field of view and to provide an optimal acoustic window to better visualize the pelvic structures, particularly if a transvaginal examination cannot be performed. Occasionally, overdistention of the bladder may compromise the evaluation. When this occurs, imaging may be repeated after partial bladder emptying. If any abnormalities of the urinary bladder are detected, these findings should be documented in accordance with the AIUM Practice Parameter for the Performance of an Ultrasound Examination of the Abdomen and/or Retroperitoneum.. For a transvaginal sonogram, the urinary bladder is preferably empty. The patient, the sonographer, or the clinician may introduce the vaginal transducer, preferably under real- time monitoring. Consideration of having a chaperone present should be in accordance with local policy. Two- handed technique (one hand on probe and one hand on external lower abdomen) is helpful to assess mobility of structures and may help move bowel away from the adnexa or to stabilize adnexal structures to aid in their visualization. It is recommended that the examiner inform the patient before a dynamic maneuver such as direct. # manual pressure on the lower abdomen or sliding of the probe is performed.. Uterus. The vagina and uterus provide anatomic landmarks that can be used as reference points for the other pelvic structures, whether normal or abnormal. When examining the uterus, the following should be evaluated: 1) the uterine size, shape, and orientation; 2) the endometrium; 3) the myometrium; and 4) the cervix. In children and adolescents, note should be made whether the uterine configuration is prepubertal or postpubertal. The vagina may be imaged while introducing the transducer and can be a landmark for the cervix. Although not part of the standard examination, if evaluation of the vaginal mucosa and rectovaginal septum is desired, instillation of . Overall uterine length is evaluated in sagittal view from the fundus to the cervix (to the external os, if it can be identified). The length can be measured as a straight line from the fundus to the external os using outer- to- outer technique or by measuring from the fundal region along the endometrial lining and endocervical canal (trace method) using outer- to- outer technique. The depth of the uterus (anteroposterior dimension) is measured in the same sagittal view from its anterior to posterior walls, perpendicular to the longitudinal axis of the endometrium. The . Abnormalities of the uterus should be documented. The myometrium and cervix should be evaluated for contour changes, echogenicity, masses, and cysts as well as symmetry between anterior and posterior myometrium. The myometrial echogenicity is reported as either homogenous or heterogeneous. If the myometrium is heterogenous due to shadowing or hyperechogenic islands, that should be specified. Myometrial lesions need to be assessed and described. When an abnormality of the myometrium is noted, the objective finding leading to this conclusion must be documented. For example, simply documenting adenomyosis as a subjective finding is insufficient and has poor reproducibility and reliability. Note should be made when the uterus is not mobile or tenderness is elicited during the examination. Fixed retroflexion of the uterus, particularly in the presence of posterior adenomyosis, or absence of sliding between the uterus and adjacent rectum or adnexa, should be recognized as a possible indicator of pelvic adhesion seen in deep endometriosis (DE) in the posterior cul- de- sac. Size and location of clinically relevant lesions should be documented. Masses that may require follow- up or intervention should be measured in at least two dimensions, acknowledging that it is not usually necessary to measure all uterine fibroids.. The endometrium should be evaluated for thickness, focal abnormality, echogenicity, and echotexture (homogeneous vs heterogeneous), and the presence and characteristics of fluid or masses in the uterine cavity. The thickest part of the endometrium should be measured perpendicular to its longitudinal plane in the anteroposterior diameter from echogenic to echogenic border, using outer- to- outer technique (see Figure 1). When fluid is present in the cavity, the endometrial thickness should be measured on either side of the fluid in the same plane and the measurements added together to report the total thickness; the fluid should. # Figure 2. Measurement of endometrium with fluid in cavity. In the presence of endometrial fluid, the measurement of the two separate layers of the endometrium (calipers), excluding the fluid, are added to determine the endometrial thickness.. be excluded in this measurement (see Figure 2). In reproductive- aged postmenarchal patients, assessment of the endometrium should allow for variations expected with phases of the menstrual cycle and with hormonal supplementation.16,20,21 It must be reported if the endometrium is not adequately seen in its entirety or is ill defined; in this circumstance, measurement may not be included in the report. The endometrium should be evaluated using power Doppler to assess the vascular pattern. The location of any areas of focal hypervascularity or feeding vessels should be documented. Sonohysterography may be useful to further evaluate the patient with AUB, an abnormal appearing endometrium, and to further evaluate or evaluate an incompletely visualized endometrium (see the AIUM Practice Parameter for the Performance of Sonohysterography and Hysterosalpingo- Contrast Sonography22). If the patient has an IUD, its location should be documented.. The addition of 3D ultrasound (transabdominal, transvaginal, transperineal, and/or transrectal) can be helpful in many circumstances, including, but not limited to, evaluating the relationship of masses to the endometrial cavity, identifying uterine congenital anomalies and thickened and/or heterogenous endometrium, identifying uterine synechia, and evaluating the location and orientation of an IUD and the integrity of the pelvic floor.19,23- 30. Performing 3D ultrasound of the uterus may be enhanced if done in the luteal phase because the endometrium is hyperechoic and enables visualization of uterine cavity abnormalities.. Adnexae Including Ovaries and Fallopian Tubes. When evaluating the adnexa, an attempt should be made to identify the ovaries first because they can serve as a major point of reference for assessing the presence of adnexal pathology. Ovarian size may be determined by measuring the ovary in three dimensions (longitudinal, transverse, and anteroposterior diameters) on views obtained in two orthogonal planes31,32 with the calculation of ovarian volume as necessary. Any ovarian abnormalities should be documented.33- 38. The ovaries may not be identifiable in some individuals. This issue occurs most frequently before puberty and after menopause when the ovaries are smaller and/or follicles are not consistently present to serve as a landmark. The adnexal region should be surveyed for abnormalities, particularly masses and dilated tubular structures.. If an adnexal abnormality is noted, its relationship to the ovaries and uterus should be assessed. The size and sonographic characteristics of adnexal masses should be documented. Any ovarian lesion should be fully documented with both gray scale and color; gray scale alone cannot determine solid versus debris- containing cystic mass. The addition of 3D to 2D ultrasound can be helpful to differentiate multilocular ovarian cysts from hydrosalpinges. The use of the sliding organ sign technique can demonstrate the presence or absence of mobility of the adnexal structures.39,40 Abnormal ovarian location, such as in the posterior cul- de- sac with adhesion, particularly to the uterus, pelvic side wall, or contralateral ovary, should be documented because this may indicate endometriosis, other sources of adhesions, or displacement of the ovary in the setting of adnexal torsion (ovarian torsion, isolated tubal torsion, or both ovarian and tubal torsion). Asymmetrical enlargement of the ovary and peripheral location of the follicles are suggestive of ovarian torsion. Identifying the twisted vessel ("whirlpool" sign) is also helpful in making this diagnosis.41 The presence of Doppler signal does not exclude ovarian torsion.. # All ovarian lesions should be documented according to a validated standardized risk stratification system. A lesion is defined as a finding judged to be inconsistent with normal physiologic function. The size of the ovary and the lesion are measured in mm as the largest three diameters in two perpendicular planes. If using the Oviarian- Adnexal Imaging Reporting Data System (O- RADS), lesions are described as unilocular, unilocular- solid, multilocular, multilocular- solid, or solid. Internal contents of cysts should be described as anechoic, low- level internal echoes, ground glass internal echoes, or mixed internal echoes. Papillary projections are solid projections at least . Spectral, color, and/or power Doppler ultrasound may be useful to evaluate the vascular characteristics of pelvic lesions.49- 52. Cul-de-Sac. The cul- de- sac and bowel posterior to the uterus should be evaluated for the presence of free or loculated fluid, or mass. If a mass is detected, its size, position, shape, sonographic characteristics, and relationship to the ovaries and uterus should be documented. Differentiation of normal loops of bowel from a mass may be difficult if only a transabdominal examination is performed. The rectosigmoid colon wall may be imaged from the posterior vaginal fornix.53 Special attention to the posterior cul- de- sac should be made in women with pelvic pain, with fixed retroflexion of the uterus, with sonographic evidence of posterior adenomyosis, and with known or clinically suspected endometriosis.19,53 Hypoechoic masses with tapering ends in the rectosigmoid wall may be seen in DE.53,54 The presence of adhesions in the cul- de- sac may be inferred in the absence of a . Documentation. Accurate and complete documentation is essential for high- quality patient care. Written reports and ultrasound images/video clips that contain diagnostic information should be obtained and archived, with recommendations for follow- up studies if clinically applicable, in accordance with the AIUM Practice Parameter for Documentation of an Ultrasound Examination.56. Adequate documentation is essential for high- quality patient care. There should be a permanent record of the ultrasound examination and its interpretation. Cine clips may be useful. Comparison with prior relevant imaging studies should be made and is helpful when available. Images of all appropriate areas, both normal and abnormal, should be recorded. Variations from normal size should generally be accompanied by measurements. Images should be labeled with the patient identification, facility identification, examination date, anatomic landmarks, and image orientation. An official interpretation (final report) of the ultrasound examination should be included in the patient's medical record. Retention of the ultrasound examination images should be consistent both with clinical need and with relevant legal and local healthcare facility requirements.. Equipment Specifications. Equipment performance monitoring should be in accordance with AIUM Routine Quality Assurance of Clinical Ultrasound Equipment.57. The sonographic examination of the female pelvis should be conducted with a real- time scanner, preferably using sector, curved linear, and/or endocavitary transducers. The transducer should be adjusted to operate at the highest frequency appropriate for clinical circumstances, realizing that there is a trade- off between resolution and beam penetration.. # Quality and Safety. Quality and SafetyPolicies and procedures related to quality assurance and improvement, safety, infection control, and equipment- performance monitoring should be developed and implemented in accordance with the AIUM Standards and Guidelines for the Accreditation of Ultrasound Practices.. ALARA Principle. ALARA PrincipleThe potential benefits and risks of each examination should be considered. The ALARA (As Low As Reasonably Achievable) principle. Infection Control. Infection ControlTransducer preparation, cleaning, and disinfection should follow manufacturer recommendations and be consistent with the AIUM's Guidelines for Cleaning and Preparing External- and Internal- Use Ultrasound Transducers Between Patients, Safe Handling, and Use of Ultrasound Coupling Gel.. Equipment Performance Monitoring. Monitoring protocols for equipment performance should be developed and implemented in accordance with the AIUM Standards and Guidelines for the Accreditation of Ultrasound Practice.2. Acknowledgments. This parameter was developed by the AIUM in collaboration with the American College of Obstetricians and Gynecologists (ACOG), the American College of Radiology (ACR), the Society for Pediatric Radiology (SPR), and the Society of Radiologists in Ultrasound (SRU). We are indebted to the many volunteers who contributed their time, knowledge, and energy to developing this document.. Collaborative Subcommittees. AIUM Laura Detti, MD Yvette Groszmann, MD, MPH Lauri Silver Hochberg, MD Elizabeth E. Puscheck, MBA, MD, MS. ACOG Wendy Brewster, MD, PhD Bethany Skinner, MD. ACR. ACRMarcela Bohm- Velez, MD, ChairHarris L. Cohen, MDMalak Itani, MDArleen Li, MDMichelle Melany, MDRoya Sohaey, MD. SPR Judy Estroff, MDJeffrey Tutman, MD. SRU Rochelle E. Andreotti, MD Nadia J. Khati, MD. AIUM Clinical Standards Committee. Rachel Bo- ming Liu, MD, FACEP, FAIUM, Chair Margarita V. Revzin, MD, MS, FSRU, FAIUM, Vice Chair Tracy Anton, BS, RDMS, RDCS, FAIUM Creagh T. Boulger, MD, FAIUM John R. Eisenbrey, PhD, FAIUM Rob Goodman, MB, BChir, FAIUM Ethan J. Halpern, MD, FAIUM Oliver Daniel Kripfgans, PhD, FAIUM Juliana Gevaerd Martins, MD John Stephen Pellerito, MD, FACK, FAIUM, FSRU James M. Shwayder, MD, JD, FAIUM Jean Lea Spitz, MPH, CAE, RDMS, FAIUM, FSDMS. Original copyright 1995; revised 1999, 2004, 2006, 2009, 2014, 2019, 2024; renamed 2015. # References. 1. American Institute of Ultrasound in Medicine. 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e679156e66de43f28ac061e1a62ff3da	2024+BFS实践指南	卵巢过度刺激综合征的预防	# Prevention of ovarian hyperstimulation syndrome (OHSS): British Fertility Society policy and practice guideline. N. Tsampras, K. Palinska-Rudzka, Y. Alebrahim, L. Craciunas & R. Mathur. To cite this article: N. Tsampras, K. Palinska- Rudzka, Y. Alebrahim, L. Craciunas & R. Mathur (2025) Prevention of ovarian hyperstimulation syndrome (OHSS): British Fertility Society policy and practice guideline, Human Fertility, 28:1, 2441827, DOI: 10.1080/14647273.2024.2441827. To link to this article: . # Prevention of ovarian hyperstimulation syndrome (OHSS): British Fertility Society policy and practice guideline. N. Tsampras<sup>a</sup>, K. Palinska-Rudzka<sup>b</sup>, Y. Alebrahim<sup>b</sup>, L. Caciunas<sup>c</sup> and R. Mathur<sup>a</sup>. <sup>a</sup>Developmental Biology and Medicine, School of Medical Sciences, The University of Manchester, Manchester, United Kingdom; <sup>b</sup>Department of Reproductive Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom; <sup>c</sup>Newcastle Fertility Centre, Biomedicine West Wing, International Centre for Life, Times Square, Newcastle upon Tyne, United Kingdom. ABSTRACT. ABSTRACTThis British Fertility Society (BFS) Policy and Practice guideline aims to support clinicians in preventing ovarian hyperstimulation syndrome (OHSS) in patients undergoing gonadotropin ovarian stimulation. A systematic literature search of the medical databases was performed. The Guideline Development Group (GDG) identified the risk factors of OHSS before and during ovarian stimulation. The relation of different pre- treatment measures and different ovarian stimulation protocols with OHSS was evaluated. The optimal monitoring during treatment was assessed. The current evidence on preventive strategies during and after ovarian stimulation and the available adjuvant preventive agents were examined. Based on this, the GDG developed evidence- based, graded recommendations for clinical practice. The evidence was evaluated within context, considering the effectiveness, cost and practical problems of assisted reproductive technology for patients and healthcare providers. Early identification and application of preventive measures identified in this guideline may reduce the incidence of OHSS or reduce its severity. Suggestions for future research on OHSS prevention are provided.. ARTICLE HISTORY. Received 9 November 2024 Accepted 13 November 2024. KEYWORDS. KEYWORDSOvarian hyperstimulation syndrome; prevention; assisted reproductive technology; gonadotropins; ovarian stimulation. Introduction. Ovarian hyperstimulation syndrome (OHss) is the most important short- term complication of supraphysiologic ovarian stimulation. Salient features of OHSS include ovarian enlargement and increased vascular permeability leading to third space fluid accumulation, intravascular dehydration and an increased risk of thrombo- embolism. OHSS can cause serious morbidity and, rarely, mortality. There is no universally accepted classification of OHSS severity, with the Royal College of Obstetricians and Gynaecologists (RCOG) classification being widely used in the UK Royal College of Obstetricians and Gynaecologists, 2016).. The true incidence of OHSS is not known due to a lack of standardized classification and the absence of mandatory reporting, apart from a requirement of the Human Fertilization and Embryology Authority (HFEA) for UK clinics to report cases of severe or critical OHSS. Observational studies prior to the widespread application of Gonadotropin- Releasing Hormone (GnRH) antagonist found the risk of moderate or . The course of OHSS is more prolonged and severe in the presence of pregnancy or exposure to human Chorionic Gonadotropin (hCG). In UK practice, most cases of severe OHSS are managed as inpatients, sometimes with recourse to intravenous colloids and paracentesis, while mild or moderate cases may be safely managed on an outpatient basis with monitoring and support (Royal College of Obstetricians and Gynaecologists, 2016).. This evidence- based guideline aims to support clinicians in preventing OHSS in women undergoing gonadotropin ovarian stimulation. It represents the views of the Guideline Development Group (GDG) which were reached after careful consideration of the. # scientific evidence available at the time of preparation. It is produced as an aid to good clinical practice and clinical decision- making. The advice expressed herein is not binding on professionals, and the British Fertility Society (BFS) cannot guarantee correctness, completeness or accuracy of the guideline in every respect. The BFS is not liable for damages related to the use of the information contained herein.. Materials and methods. The proposal for this guideline and membership of the GDG were approved by the Executive Committee of the BFS. The GDG applied the Population, Interventions, Comparisons and Outcomes (PICO) model to develop a search strategy for the interventions used in prevention of OHSS and their application in clinical practice.. A systematic literature search of the electronic databases MEDLINE/PubMed, SCOPUS, EMBASE, CENTRAL, DARE and the Cochrane Library was performed to identify systematic reviews and primary studies investigating predictive factors of OHSS and interventions aimed at reducing the risk of OHSS. Additional studies were identified through previous experience of the authors and reference lists of the studies obtained by the search. Where a high- quality systematic review was found, the search continued to identify randomized controlled trials (RCTs) published since the date of the review. The systematic search was conducted in March 2024, and limited to the English language and where full text was available. More recent publications identified by peer- review were also included.. The database search was undertaken using a combination of keywords including OHSS, In Vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), ovarian stimulation, oocyte donation, oocyte cryopreservation, in vitro maturation (IVM), ovarian drilling, progestin- primed ovarian stimulation (PPOS), ovulation trigger, gonadotropins, personalization, coasting, luteal phase support, clomiphene, ketozole, metformin, aspirin, melatonin, inositol, hydroxyethyl starch, calcium, cabergoline, diosmin, ketoconazole, vitamin D, albumin and vascular endothelial growth factor (VEGF) blockade. The list of the included interventions was finalized through consensus between all authors. Studies pertaining to the management of OHSS and interventions for complications associated with OHSS were excluded.. The evidence was assessed by all authors and the recommendations were graded using the RCOG criteria (Royal College of Obstetricians and Gynaecologists, 2020). The study design was appraised, and the quality of the methodology was assessed based on blinding, allocation concealment, appropriate control groups and other risks of bias. The GDG summarized the data in a narrative form to include the characteristics, quality, efficiency and conclusions of the studies included. The format including 'Mechanism of Action', 'Evidence and Classification', 'Recommendation and Grade' and 'Context' was adopted for clarity and uniformity of reporting on the different interventions. Where the quality of the evidence was poor, the grading of the recommendation was downgraded, and this is discussed further in the context.. # Prediction of OHSS. Prediction of OHSSSeveral demographic and clinical factors are associated with an increased risk of developing OHSS. Identifying patients at a high risk of OHSS may allow clinicians to ensure appropriate counselling and targeted preventive measures.. Patient demographic and clinical characteristics. A cohort study using the Society for Assisted Reproductive Technology database found that compared to white women, black women were more likely to suffer from OHSS (Luke et al., 2010). There was no statistically significant difference between white, Asian and Hispanic women in the risk of severe OHSS.. A recent study on patients classed as high responders and treated with GnRH agonist trigger and freezeall found that ethnicity was not a predictive factor in development of mild OHSS in this situation (Fernandez- Sanchez et al., 2023).. A retrospective study of patients with polycystic ovary syndrome (PCOS) undergoing assisted reproduction found BMI to be slightly lower among those who developed OHSS compared to those who did not . An inverse association between age and OHSS risk has been demonstrated in several studies, but without a clinically useful cut- off identified for either an increased or reduced risk of OHSS. Younger age was identified as a risk factor, together with high ovarian reserve and a lower requirement for gonadotropins in a multivariate logistic regression analysis of 33 cases of moderate or severe OHSS in 300 consecutive IVF cycles predominantly using GnRH agonist in a Chinese population (Ma et al., 2020). A UK observational study of 2362 consecutive GnRH agonist cycles found that patients with late- onset OHSS were significantly younger than those without OHSS (median (range) 32 (28- 38) years vs 34 (19- 49) years), but there was no statistically significant difference between patients with early- onset OHSS and those without OHSS (Mathur et al., 2000). In GnRH antagonist cycles with hCG trigger, women who developed OHSS were found to be younger than women who did not develop OHSS (mean . Several studies have identified polycystic ovarian morphology on ultrasound as well as PCOS as risk factors for OHSS Jayaprakasan et al., 2012; Luke et al.,. 2010; MacDougall et al., 1992; Mathur et al., 2000; Swanton et al., 2010). A meta- analysis of 11 studies identified a significantly higher risk of OHSS in women with PCOS compared to women without this diagnosis (OR 4.96, . Pre-stimulation patient characteristics. Serum anti- mullerian hormone (AMH) concentrations and Antral Follicle Count (AFC) are markers of ovarian reserve that have been shown to predict the risk of OHSS.. Several cohort studies on women undergoing ovarian stimulation in GnRH agonist cycles have found elevated AMH to be a marker for the risk of OHSS, with varying thresholds and levels of sensitivity and specificity (Aghssa et al., 2015; Lee et al., 2008; Nakhuda et al., 2006; Ocal et al., 2011; Salmassi et al., 2015).. A cohort study on GnRH antagonist cycles using corifollitropin examined the risk of excessive ovarian response (defined as . The predictive value of ovarian reserve markers to identify the risk of moderate or severe OHSS in GnRH antagonist cycles with daily FSH dosing was studied by Sood et al. (2022) in a cohort of 1492 consecutive cycles. AMH was measured within 6months of the start of stimulation using a Roche Elecsys assay. AMH concentration of . In GnRH agonist cycles, AFC was found to be a predictor of the risk of OHSS by Ocal et al. (2011), Jayaprakasan et al. (2012) and Ashrafi et al. (2015). Jayaprakasan et al. (2012) documented a risk of moderate or severe OHSS of . # 72.2\%. The risk of OHSS is higher in women with a predicted high response to ovarian stimulation as shown by young age, PCO morphology, PCOS, raised AMH and raised AFC. Evidence level . Ovarian response to stimulation. The ovarian response to stimulation has been investigated as a predictor of OHSS using oestradiol concentrations and follicle number at the end of the stimulation period, and the number of oocytes retrieved.. Elevated oestradiol (E2) levels during ovarian stimulation have been found by some investigators to be associated with increased OHSS risk in patients receiving long protocol GnRH agonist treatment (Delvigne & Rozenberg, 2002; Hendriks et al., 2004; Lee et al., 2008), although this has not been found in relation to late OHSS in such cycles (Lyons et al., 1994; Mathur et al., 2000).. E2 levels were found to be a poor predictor of the risk of OHSS in GnRH antagonist cycles by Papanikolaou et al. (2006), especially for late- onset and severe OHSS. Similarly, Sood et al. (2022) found that E2 levels did not distinguish between OHSS and non- OHSS cycles in women receiving GnRH antagonist.. The number of follicles developing in response to stimulation has been found to correlate with the risk of OHSS, for both GnRH agonist and antagonist cycles (Danninger et al., 1996; Griesinger et al., 2016; Ma et al., 2020; Papanikolaou et al., 2006; Tarlatzi et al., 2017). The threshold diameter for inclusion of follicles in this count has varied from . E2 concentration in response to ovarian stimulation is a poor predictor of OHSS risk, especially for late-onset OHSS. Evidence level . Increased number of follicles of greater than . Studies in both GnRH antagonist and agonist cycles have shown an increased risk of OHSS with increased number of oocytes retrieved (Chen et al., 2015; Drakopoulos et al., 2016; Magnusson et al., 2018; Mathur et al., 2000; Sood et al., 2022). Sood et al. (2022) identified an oocyte number of 20 as providing sensitivity of . Retrieval of 20 or more oocytes predicts an increased risk of OHSS. Evidence level . All patients undergoing gonadotropin ovarian stimulation should be advised about the risk of OHSS. Grade GPP. Patients with a predicted high response to gonadotropins based on clinical features or ovarian reserve tests should be counselled about their elevated risk of OHSS and specific preventive measures should be considered (see below). Due to variation between assays, it is not possible to be categorical about a threshold of AMH that constitutes a high risk, however, levels above 22.5 pmol/l have been shown to have an optimum balance of sensitivity and specificity. A higher AMH threshold is associated with greater specificity but lower sensitivity (see text). AFC above 20 has been associated with an increased risk of OHSS. Grade B. E2 concentrations following stimulation should not be used on their own to determine whether. # preventive measures for OHss are indicated. Women with a high ovarian reserve should be considered at increased risk of OHss even in the presence of E2 levels below arbitrary thresholds. Grade D. The number of recruited follicles on the final ultrasound scan prior to trigger should be considered in planning the nature of the trigger. If more than 17- 19 follicles greater than or equal to 11- . If 20 or more oocytes are retrieved, consideration should be given to preventive measures, such as elective freeze- all. Grade B. The GDG considered that several risk factors for OHSS have been identified, but these are not exhaustive, either individually or in combination, due to the significant overlap between the values of various parameters in patients with and without OHSS. As a result, all patients undergoing gonadotropin stimulation should be considered potentially at risk of OHSS. Establishing evidence- based cut- offs is at present difficult. However, the GDG felt that the evidence allows it to propose cut- offs for follicle and oocyte number which clinicians may find useful. Clinical judgement and patient counselling remain key to decision- making in individual cases. Clinicians should bear in mind that severe OHSS has been described in situations that would be considered 'low- risk' by common criteria of ovarian response (DeVigne & Rozenberg, 2002).. Prevention of OHSS prior to ovarian stimulation. Pre-treatment with combined oral contraceptive pill (C0CP). C0CP pre- treatment has been used in clinical practice to aid scheduling of treatment cycles and help synchronize the recruitment of a cohesive cohort of follicles. It is plausible that these actions may affect the risk of OHSS.. A Cochrane meta- analysis identified two RCTs of COCP pre- treatment in women undergoing GnRH antagonist cycles, which included OHSS incidence as an outcome. No difference was identified in the incidence of OHSS between COCP and control groups (OR 0.98, . The risk of OHSS in GnRH antagonist cycles is not altered by COCP pre- treatment. Evidence Level . COCP pre-treatment should not be considered for reducing the risk of OHSS. Grade A. Ovarian drilling. Ovarian drilling has endocrine effects including a reduction in androgen, luteinizing hormone (LH) and AMH levels and restoration of the pituitary- ovarian feedback mechanism in women with PCOS. It is plausible that these effects may alter the incidence of OHSS in subsequent controlled ovarian stimulation.. A Cochrane review in 2020 identified a single trial and found no impact of laparoscopic ovarian drilling prior to IVF on the risk of OHSS in women with PCOS (1 RCT; OR 0.27, . The RCT showing a potential benefit of ovarian drilling in reducing the risk of OHSS included a small number of participants with two previous failed cycles and did not include the use of GnRH agonist trigger and freeze- all. The severity of OHSS and the mode of ascertainment of OHSS are not described. Moreover, ovarian drilling is an invasive procedure and carries associated risks.. There is insufficient evidence to conclude whether laparoscopic drilling prior to controlled ovarian stimulation reduces the risk of OHSS. Evidence Level 1-. Ovarian drilling should not be considered for reducing the risk of OHSS. (Grade C). GnRH agonist vs. GnRH antagonist. Both GnRH agonist and GnRH antagonist protocols suppress the endogenous LH surge, allowing efficient controlled ovarian stimulation. However, the mechanism of action differs - agonists cause down- regulation of pituitary GnRH receptors and desensitization of gonadotrophs, while antagonists act via competitive binding to GnRH receptors. GnRH antagonist use also provides the option to trigger oocyte maturation with a GnRH agonist rather than hCG.. # General IVF population. A meta- analysis of 73 RCTs, 36 of which reported on OHSS, revealed a lower incidence of any grade of OHSS in GnRH antagonist cycles (OR 0.61, . A subsequent systematic review and meta- analysis confirmed that antagonist use resulted in significantly lower OHSS incidence rates than agonist in the general population 22 trials, 5598 couples;RR 0.63, Cl . Another meta- analysis found that the antagonist treatment significantly reduced the OHSS rate compared to the long- acting follicular agonist (RR 1.63; . GnRH antagonist protocols are associated with a lower risk of OHSS compared with GnRH agonist protocols in the general population. Evidence levels . Predicted normal responders. A meta- analysis of 21 RCTs found that the incidence of OHSS was significantly lower with the use of GnRH antagonist compared to agonist protocol (OR 0.69, . GnRH antagonist protocols are associated with a lower risk of OHSS compared with GnRH agonist protocols in predicted normal responders. Evidence level . Predicted high responders. In PCOS patients, a recent meta- analysis revealed that using GnRH antagonist protocol significantly reduced the risk of OHSS compared to long GnRH agonist protocols (9 RCTs; OR 0.65, . GnRH antagonist protocols are associated with a lower risk of OHSS compared with GnRH agonist protocols in predicted high responders even when hCG trigger is used.Evidence level . GnRH antagonist protocols should be considered for the prevention of OHSS in the general IVF population and predicted normal responders. Grade A. GnRH antagonist protocols are recommended for prevention of OHSS for predicted high responders. Grade A. In assessing GnRH antagonist and agonist protocols, the GDG emphasized the importance of considering safety, treatment burden and cost- effectiveness. GnRH antagonist protocols are favoured for their lower risk of OHSS and shorter timelines relative to GnRH agonist protocols.. Progestin-Primed ovarian stimulation (PPOS). Progestins administered during the early follicular phase suppress the LH surge, preventing premature luteinization. This may affect the size of the follicular cohort. Due to effects on the endometrium, PPOS inherently involves cryopreservation of all oocytes/embryos and thus effectively eliminates the risk of late- onset OHSS.. # A meta- analysis found no difference in the incidence of OHSS when comparing PPOS with GnRH antagonist in women with normal ovarian reserve with a relative risk (RR) of 0.55 (95% CI: 0.11- 2.80, . PPOS is associated with a similar risk of OHSS as GnRH antagonist protocols. Evidence Levels: . PPOS could be considered as an alternative to the GnRH- antagonist protocol for the purpose of OHSS prevention where fresh embryo transfer is not anticipated. Grade B. PPOS offers some advantages such as oral administration and potential cost- effectiveness. However, PPOS does not allow the possibility of fresh embryo transfer, and some studies suggest that it may necessitate higher doses of gonadotropins, possibly affecting its overall cost- benefit balance (Deng et al., 2024).. Starting dose of FSH - universal vs personalized. Standard daily FSH doses and individualized dosing based on patients' characteristics have both been used in controlled ovarian stimulation (Yates et al., 2011). Different doses of FSH may result in different degrees of ovarian response and may affect the risk of developing OHSS.. A recent systematic review and meta- analysis assessed the safety and efficacy of individualized gonadotropin dosing, based on ovarian reserve tests (ORT), compared to utilization of a universal dose or a dose not based on ORT. FSH doses based on ORT algorithms were associated with a reduced risk of moderate or severe OHSS compared to standard doses (Peto OR 0.60, 95% CI 0.42 to 0.84; . When direct dose comparison studies were considered, there was no evidence of an impact of starting dose on the risk of OHSS in predicted low or normal responders (very low certainty). In predicted high . Mild ovarian stimulation for IVF is defined as a protocol in which the ovaries are stimulated with a lower dose of gonadotropins, aiming for the development of a few follicles. The definition of mild stimulation in studies and practice is variable. The ESHRE COS Guideline defines the daily dose of FSH of 150- 225 IU as conventional, while mild stimulation is achieved by a lower dose of FSH, or a delayed start (The Eshre Guideline Group On Ovarian Stimulation et al., 2020).. Datta et al. (2021) found a lower incidence of OHSS with mild ovarian stimulation protocols. However, their meta- analysis included some studies where the daily dose of FSH was 150 IU, which would fall under the ESHRE COS guideline definition of conventional stimulation. There was a reduction in the number of oocytes retrieved when mild stimulation was used for poor and normal responders, but the live birth rate was not affected.. ORT-based dose of FSH is associated with a lower incidence of moderate or severe OHSS. Evidence level . FSH dose lower than 150 IU daily may be associated with lower risk of OHSS in GnRH agonist protocols. Evidence level 1-. ORT- based dose of FSH should be considered to reduce the risk of OHSS. Grade A. A reduced gonadotropin dose could be considered in predicted high responders receiving GnRH agonist protocols to decrease the risk of OHSS. Grade B. A conventional gonadotropin dose should be considered for safety and efficacy when a GnRH antagonist protocol is used. Grade B. The GDG considered that the literature on ORT- based starting doses of FSH shows a lower incidence of moderate or severe OHSS, but not severe OHSS alone, compared to standard dosing. The group also acknowledged that in practice ORT have a wider application in counselling patients about their reproductive options and chances of success. FSH daily dose of less than 150 IU may be associated with a lower rate of OHSS in predicted high responders undergoing GnRH agonist cycles, but the GDG cautions that GnRH antagonist is preferable in this group as it carries a lower risk of OHSS. The GDG did not find convincing. # evidence of a benefit from a reduced FSH dose in antagonist cycles. There is consistent evidence indicating a linear association between the number of oocytes retrieved and the cumulative live birth rate per treatment started (Neves et al., 2023; Polyzos et al., 2018), and this should be considered when planning treatment. A conventional daily dose of FSH is associated with an optimal balance of safety and efficacy in GnRH antagonist protocols.. Types of gonadotropins. Different types of gonadotropins include human Menopausal Gonadotropin (hMG), Recombinant FSH (rFSH), Purified FSH (p- FSH), highly purified FSH (hp- FSH) and Recombinant LH (rLH). hMG, p- FSH and hp- FSH are human derived, produced from the urine of postmenopausal women. hMG regimes contain LH in a 1:1 ratio, when p- FSH and hp- FSH contain minimal LH (van Wely et al., 2011). rFSH is produced using recombinant DNA technology. The rFSHs are biochemically pure preparations, free from urinary protein contaminants and provide minimal batch- to- batch discrepancy (Bergh, 1999). It is plausible that the different pharmacokinetic properties of various gonadotropin preparations could affect the risk of OHSS.. A meta- analysis on the efficacy and safety of different gonadotropin preparations identified 42 studies (9606 participants), of which 32 reported the incidence of OHSS. There was no difference in the OHSS rate when using recombinant or human- derived gonadotropins (7740 patients, OR 1.18, . The risk of OHSS is similar between recombinant and urinary gonadotropins. Level of evidence . The GDG agreed that evidence shows a similar risk of OHSS with the use of different gonadotropins. Therefore, the choice of gonadotropin can be made based on availability, cost, ease of administration and patient characteristics.. Long-acting FSH. Corifollitropin alfa is a recombinant, long- acting FSH. A single injection can provide follicle- stimulating activity . A meta- analysis included eight RCTs, comparing corifollitropin alfa and daily recombinant FSH. Two RCTs included poor responders. No difference was observed in the incidence of OHSS (5 RCTs; RR 1.15, . The risk of OHSS is similar between daily and long- acting recombinant FSH in normal responders in GnRH antagonist protocols. Evidence level . Both daily and long- acting recombinant FSH may be considered for normal responders. Grade A. Long- acting FSH with sustained follicle- stimulating activity for the induction of multi- follicular growth is a convenient and safe option for normal responders.. Follitropin Delta. Follitropin delta is an rFSH with a pharmacokinetic profile characterized by slower clearance, inducing a higher ovarian response compared to previous rFSH preparations, when administered at equal doses of biological activity (Nyboe Andersen et al., 2017; Olsson et al., 2014). An individualized dosing algorithm incorporating body weight and AMH levels is used (Olsson et al., 2014).. Several studies have assessed the safety and efficacy of follitropin delta (Ishihara et al., 2021; Nyboe Andersen et al., 2017; Qiao et al., 2021; Yang et al., 2022). The largest, low risk of bias, study by Qiao et al. (2021) compared the outcomes of ovarian stimulation with individualized dose of follitropin delta vs 150IU of follitropin alfa, adjusted after day 5 depending on the response and found no significant difference in the risk of early- onset or late- onset OHSS between the two groups. However, there was a lower incidence of preventive measures for early OHSS in the follitropin delta group (1.2% vs 3.5%, . # p< 0.001. Follitropin delta used in doses according to an algorithm including weight and AMH may be associated with a reduction in risk of OHSS Evidence level . Follitropin delta used in doses according to an algorithm based on weight and AMH may be considered for prevention of OHSS. Grade A. The GDG took into account evidence showing a reduced need for preventive measures and a lower risk of OHSS in patients with . Prevention of OHSS during ovarian stimulation. Monitoring. Monitoring of COS cycles is used to determine the timing of trigger injection for final oocyte maturation and oocyte retrieval. It may allow early detection of hyper- response and consideration of preventive measures prior to trigger.. A Cochrane Review included 6 trials (781 women) undergoing monitoring of COS with transvaginal ultrasound scan (TVUS) alone or combination of TVUS and E2 concentrations (Kwan et al., 2021). All studies included an unselected population, except one which excluded patients with previous history of severe OHSS (Lass & UK Timing of hCG Group, 2003). The risk of OHSS was not affected by the addition of E2 concentrations (OR 1.03; . The addition of E2 or other biomarkers to ultrasound scan monitoring does not reduce the risk of OHSS in unselected patients. Evidence Level . The addition of serum E2, progesterone or LH concentration to ultrasound monitoring should not . be considered in unselected patients from the point of view of OHSS risk. Grade A. Coasting. Coasting refers to discontinuation of gonadotropins while maintaining pituitary down- regulation during COS in women who manifest an 'excessive' response to gonadotropins. It aims to reduce circulating gonadotropin levels, leading to apoptosis of granulosa cells in small- and medium- sized follicles, while larger follicles that are gonadotropin- independent continue to develop. A similar mechanism of action is postulated for reducing the dose of FSH. However, studies on FSH pharmacokinetics show that following discontinuation of recombinant FSH, serum FSH levels remain above the threshold for follicular development for several days (Olsson et al., 2014).. A meta- analysis showed that coasting was associated with a reduced OHSS risk compared to no coasting in GnRH agonist cycles with an excessive response to stimulation (2 RCTs; OR 0.11, . Coasting is associated with a reduced incidence of OHSS in patients receiving GnRH agonist who show an excessive response to stimulation. Evidence level . Coasting could be considered in patients at high risk of OHSS based on ovarian response in GnRH agonist protocols. Grade A. # Coasting should not be considered for prevention of OHSS in GnRH antagonist protocols. Grade GPP. Evidence is lacking to compare coasting to GnRH agonist trigger in GnRH antagonist cycles. Currently the GnRH antagonist protocol is recommended for high and normal responders. However, when a GnRH agonist protocol is used and unexpected over- response occurs, coasting could be considered to reduce the risk of OHSS.. Choice of trigger in GnRH antagonist cycles. Follicular and oocyte maturation prior to oocyte retrieval requires activation of LH receptors and can be achieved in GnRH antagonist cycles through the use of hCG, GnRH agonist or recombinant LH. hCG has a longer half- life than endogenous LH and causes more sustained stimulation of luteal cells. GnRH agonists induce an endogenous LH and FSH surge, the duration of which is shorter than that of a physiological surge.. GnRH agonist vs. Urinary hCG. A Cochrane review of 17 RCTs with 1,847 participants compared GnRH agonists to hCG as the follicular maturation trigger. GnRH agonists significantly reduced OHSS risk OR 0.15 . GnRH agonist trigger is associated with a lower risk of OHSS compared to hCG trigger. Evidence level . Type of hCG. A Cochrane systematic review by Youssef et al. (2016) compared rhCG and rLH with uhCG in IVF cycles, including 18 RCTs with 2,952 participants. The results showed no significant differences in OHSS incidence between the rhCG/rLH and uhCG groups. The quality assessment indicated high quality, though the certainty of evidence of data was low.. The use of urinary or recombinant hCG carries a similar risk of OHSS. Evidence level . Altering uhCG dosage. An RCT of 98 ICSI patients compared uhCG doses of 5000 IU vs. 10,000 IU. The incidence of mild OHSS was . In a study with 164 IVF/ICSI patients, Lin et al. (2011) compared uhCG doses of 4000 IU vs. 6000 IU. The results showed no statistically significant difference in OHSS rates . The use of uhCG doses between 4000 IU and 10,000 IU for trigger carries a similar risk of OHSS in the general IVF population. Evidence level . Dual trigger. Meta- analysis by Hu et al. (2021) focused on the efficacy of dual trigger (GnRH agonist and hCG) vs. hCG alone for follicular maturation in women undergoing IVF, without specifically targeting patients at high risk of OHSS. Dual trigger treatment was associated with a significantly higher live birth rate per started cycle compared to the hCG trigger treatment (Risk Ratio . Dual trigger with GnRH agonist and hCG has a similar risk of OHSS as hCG trigger alone in the general IVF population. Evidence level . GnRH agonist trigger should be considered for OHSS prevention in preference to urinary or recombinant hCG in GnRH antagonist cycles. Grading of Recommendation A. uhCG doses lower than 5000 IU should not be considered for prevention of OHSS. Grading of Recommendation: B. GnRH agonist trigger is effective relative to hCG in preventing OHSS but requires either a freeze- all strategy or provision of enhanced luteal support, if a fresh embryo transfer is performed. hCG use is associated with an increased risk of OHSS compared to GnRH agonist trigger, irrespective of the type of hCG.. Cycle cancellation. Cycle cancellation and withholding the ovulatory trigger eliminates the risk of OHSS, as this is a post- ovulatory. # phenomenon relating to activation of LH receptors on granulosa cells.. There are no identified systematic reviews or experimental studies reporting the efficacy of cycle cancellation in the context of OHSS.. Cycle cancellation could be considered for the prevention of OHSS in the event of excessive ovarian response. Grade: GPP. Cycle cancellation is an effective method in OHSS prevention and could be considered where alternate strategies are not available or are unlikely to be effective. Clinicians should consider the psychological impact and financial burden of cycle cancellation on patients. This includes recognizing previous patient experience and preference.. Prevention of OHSS during luteal phase. Cryopreservation of all embryos. Cryopreservation of all embryos avoids fresh embryo transfer within the stimulated cycle and, by avoiding pregnancy, prevents the endogenous production of hCG, preventing late- onset OHSS (Bourdon et al., 2021).. A Cochrane Systematic Review of fresh versus frozen embryo transfers identified 6 RCTs, 2 using GnRH agonist and 4 using GnRH antagonist protocols. Only 3 studies focused on OHSS prevention as an indication for elective cryopreservation. The incidence of OHSS was significantly lower in the freeze- all group (9 per 100 women) compared to the fresh embryo transfer group (33 per 1000 women) (OR 0.26, 95% CI 0.17- 0.39, 6 RCTs, 4478 women). There was no difference in the cumulative live birth rate (OR 1.08, 95% CI 0.95- 1.22, 8 RCTs, 4712 women) (Zaat et al., 2021).. Cryopreservation of all embryos is associated with a lower incidence of OHSS compared with fresh embryo transfer. Evidence level: 1+. Cryopreservation of all embryos should be considered for the prevention of OHSS in individuals at high risk. Grade A. Cryopreservation of all embryos is an effective risk- reducing strategy that will, by definition, prevent late- onset OHSS, but it may prolong the time to conception. Patients should be counselled regarding 'freeze- all' prior to commencing ovarian stimulation in the presence of a high ovarian reserve or in the event of an unexpected excessive response. Patients should also be advised that studies do not show a difference . Luteal phase support. OHSS is a post- ovulatory phenomenon, and the risk of OHSS may be influenced by medications used in the luteal phase.. Luteal phase support with progesterone vs hCG. A Cochrane Review of luteal phase support in assisted reproduction cycles found no RCTs that reported OHSS incidence when comparing progesterone with a placebo. Other studies reported an increased risk of OHSS with the use of hCG compared with progesterone alone (OR 0.46, 95% CI 0.30- 0.71, 5 RCTs, 1293 women) (van der Linden et al., 2015).. The review also compared the risk of OHSS with the use of progesterone alone or in combination with oestrogen. There was no significant difference in OHSS incidence with addition of oestrogen (OR 0.56, 95% CI 0.2- 1.63, 2 RCTs, 461 women) (van der Linden et al., 2015).. The incidence of OHSS is increased with the use of hCG compared with the use of progesterone alone for luteal support. Evidence level: 1+. Addition of oestrogen to progesterone for luteal phase support does not affect the incidence of OHSS. Evidence level: 1+. Intensified luteal phase support with low-dose hCG. One RCT investigated administration of low- dose hCG with oral oestrogen and vaginal progesterone after a GnRH agonist trigger compared with a freeze- all in hyper- responders. There was a significant increase in moderate- to- severe OHSS in the group receiving low- dose hCG (RD - 8.6%, 95% CI - 13.9% to - 3.2%, p < 0.01, 1 RCT, 209 women) (Santos- Ribeiro et al., 2020).. Intensified luteal phase support with low-dose hCG following GnRH agonist trigger increases the risk of OHSS. Evidence level: 1+. Luteal phase support with GnRH agonist. A systematic review on luteal phase support with GnRH agonist did not find a significant difference in OHSS incidence compared with traditional luteal. # phase support (RR 0.96, . Luteal phase support with GnRH agonist does not affect the incidence of OHSS. Evidence level: . The use of hCG for luteal phase support is not recommended from the point of view of OHSS risk. Grade A. If hCG is used for luteal phase support in women who have a fresh embryo transfer after a GnRH agonist trigger, clinicians and patients should be aware of the increased risk of developing OHSS. Grade A. The use of a GnRH agonist for luteal phase support is not recommended for reducing OHSS incidence. Grade B. The use of hCG in the luteal phase increases the risk of OHSS. The GDG considered that there may be situations when, following a GnRH agonist trigger, fresh embryo transfer is performed with intensified luteal support. In such circumstances, clinicians should bear in mind that even a low dose of hCG may increase the risk of developing OHSS, and this should be included in patient counselling.. Adjuvant treatments for prevention of OHSS. Luteal GnRH antagonist. GnRH antagonist administration following oocyte retrieval has been proposed to prevent and reduce severity of OHSS. A possible mechanism is by suppressing endogenous LH and thus inducing early luteolysis.. There are no RCTs directly reporting incidence of OHSS following luteal GnRH antagonist administration. One prospective cohort study investigated the effect of . Luteal GnRH antagonist may reduce the incidence of OHSS, in women who have cryopreservation of all embryos. Evidence level 2-. GnRH antagonist administration could be considered for prevention of moderate to severe OHSS following elective cryopreservation of all embryos. Grade D. The GDG identified only limited evidence for luteal GnRH antagonist for prevention of OHSS and considered the potential benefit of preventing moderate- to- severe OHSS.. Clomiphene citrate/Letrozole co-treatment. Clomiphene citrate stimulates endogenous FSH and LH secretion by competing for estrogen receptors at the hypothalamic level. Letrozole is an aromatase inhibitor, which inhibits androgen aromatization into oestrogens in granulosa cells leading to an increase in endogenous FSH and LH. The mechanism for a possible reduction in the risk of OHSS is not completely understood.. A Cochrane review assessed the effect of Clomiphene citrate (4 RCTs) and Letrozole (1 RCT) during ovarian hyperstimulation on the risk of OHSS. There was evidence of reduced OHSS incidence in women co- treated with Clomiphene citrate or Letrozole when all 5 RCTs were combined (Peto OR 0.21, . A meta- analysis reported lower OHSS rates following co- treatment with letrozole during ovarian stimulation (RR 0.43, . Letrozole co- treatment during ovarian stimulation may be associated with a lower risk of OHSS in GnRH antagonist cycles. Evidence level 1-. Letrozole co- treatment during ovarian stimulation could be considered to reduce the incidence of OHSS in selected high- risk patients. Grade C. The GDG did not identify trials comparing the use of Clomiphene with GnRH antagonist cycles. The meta- analysis included studies assessing the effect of letrozole in both agonist and antagonist protocols.. # The oestradiol levels were reduced in the letrozole groups when co- administration occurred during ovarian stimulation or during luteal phase, but the number of studies and included patients was overall low to draw definitive conclusions.. Metformin. Metformin has been proposed as a preventive agent for OHSS, through mechanisms involving inhibition of VEGF, which is the chief mediator of increased vascular permeability in OHSS (Elia et al., 2013).. A Cochrane review included 11 randomized controlled trials, 9 of which were in GnRH agonist cycles, assessing the role of Metformin co- treatment during controlled ovarian hyperstimulation in women with PCOS. When all studies were combined, Metformin was associated with a reduced incidence of OHSS compared with placebo/no treatment (RR 0.46, . Metformin administration reduces the risk of OHSS in women with PCOS undergoing GnRH agonist cycles, but not in women receiving GnRH antagonist. Evidence level . Metformin co- treatment could be considered to reduce the risk of OHSS in women with PCOS who are receiving GnRH agonist protocols. Grade A. Metformin co- treatment should not be considered to reduce the risk of OHSS in women with PCOS who are receiving GnRH antagonist protocols. Grade A. Most of the included studies in the Cochrane meta- analysis used a long agonist protocol, which is not recommended in women with PCOS and a high risk of OHSS. One RCT in GnRH antagonist cycles suggested that Metformin may reduce live birth rate compared with placebo/no treatment with low level of evidence (Jacob et al., 2016). The gastrointestinal side effects of Metformin should be considered when counselling about co- treatment.. Aspirin. Aspirin has been proposed as a therapeutic agent for reducing the risk of OHSS through modulating the pathophysiological cascade triggered by elevated VEGF levels.. Three RCTs evaluated the use of aspirin co- treatment during COS with an aim to reduce the incidence of OHSS. Revelli et al. (2008) administered aspirin and prednisolone co- treatment in a GnRH agonist protocol in 97 patients who were compared with a control group of 298 patients to suggest a lower incidence of severe OHSS in the treatment group (1.7% vs 6.5%). Varnagy et al. (2010) randomized 1503 patients to receive co- treatment with low- dose aspirin alongside a long agonist protocol and compared them with a control group of 922 patients to suggest a lower incidence of OHSS in the high- risk patients allocated to aspirin group (0.25% vs 8.4%). Namavar Jahromi et al. (2019) reported a similar risk of OHSS (34.9% vs 30.5%) in PCOS patients undergoing GnRH agonist long protocol treatment randomized to low- dose aspirin (n = 109) or placebo (n = 105).. Aspirin use may be associated with a lower risk of OHSS in women undergoing IVF using GnRH agonist protocols, but evidence is inconsistent. Evidence level 1-. Aspirin should not be considered to prevent OHSS during controlled ovarian hyperstimulation. Grade C. The GDG identified only limited and contradictory evidence, mostly in GnRH agonist cycles.. Melatonin. Melatonin has been proposed as a potential agent for the prevention of OHSS through mechanisms involving reactive oxygen species and regulation of apoptosis (Zheng et al., 2023).. A systematic review and meta- analysis of RCTs identified 5 trials, of which one reported on the need for interventions to reduce the risk of OHSS as a surrogate marker for OHSS. Data were insufficient to draw any conclusions (Seko et al., 2014).. There is no evidence that melatonin co-administration reduces the risk of OHSS. Evidence level 1-. Melatonin should not be considered to prevent OHSS. Grade B. The GDG identified only limited clinical evidence in this area.. Inositol. Inositol, a carbocyclic sugar present in nine iso- forms, has been proposed as a preventive measure for OHSS. # through reduced vascular permeability, VEGF and COX- 2 expression (Turan et al., 2015).. Two RCTs evaluated the use of inositol for the prevention of OHSS. Mendoza et al. (2019) randomized 60 PCOS patients to receive Myo- inositol and a high or low dose of D- chiro- inositol for 3 months prior to the start of controlled ovarian stimulation and reported lower OHSS rates in the high dose group . There is insufficient evidence to support the role of Inositol in decreasing the risk of OHSS. Evidence level 1-. Inositol should not be considered for the prevention of OHSS. Grade C. The GDG did not identify any high- quality RCTs comparing Inositol with placebo for the prevention of OHSS.. Volume expanders. Various volume expanders such as albumin and hydroxyethyl starch (HES) have been investigated for their potential prevention of severe OHSS through mechanisms involving increased intravascular volume and reduction of coagulability due to reduced platelet aggregation (Morris et al., 1995).. A network meta- analysis of RCTs evaluating the role of various adjuvants in the prevention of moderate- to- severe OHSS included 31 studies (4964 women) and reported lower incidence of OHSS following the use of HES (RR 0.25, . The use of albumin is not associated with a reduced incidence of OHSS. Evidence level . Albumin should not be considered for the prevention of OHSS. Grade A. HES is no longer approved for use in the UK since 2013. Albumin use has been associated with reduced pregnancy rates (Wu et al., 2022). The quality of evidence is poor and mostly relates to long protocol GnRH agonist cycles.. Calcium infusion. Calcium may reduce the incidence of OHSS through mechanisms involving reduced VEGF expression in luteinized granulosa cells (Herr et al., 2010).. An RCT involving 200 women compared the use of calcium gluconate infusion versus placebo on the 4 days starting with the day of oocyte collection in GnRH agonist long protocol cycles. The incidence of severe, moderate and all cases of OHSS was lower in the intervention group (El- Khayat & Elsadek, 2015).. The Cochrane review of the use of dopamine agonists for preventing OHSS reported similar OHSS rates following the use of cabergoline and calcium (OR 1.83, . There is insufficient evidence to support the use of calcium infusion for the prevention of OHSS. Evidence level 1-. Calcium infusion should not be considered for the prevention of OHSS. Grade B. The GDG considered the cost and inconvenience of calcium infusions and the lack of superiority over alternative preventive measures.. Dopamine agonists. Dopamine agonists may selectively inhibit VEGF- induced vascular permeability, which is part of the pathophysiology of OHSS (Soares, 2012).. The Cochrane review on the use of dopamine agonists such as cabergoline, quinagolide and bromocriptine, in the context of OHSS concluded that dopamine agonists probably lowered the risk of moderate or severe OHSS compared to placebo or no intervention in long agonist protocols (OR 0.32, . Dopamine agonists may reduce the risk of OHSS in long agonist protocols. Evidence level . Dopamine agonists may reduce the risk of OHSS in antagonist protocols. Evidence level . Dopamine agonists should be considered following trigger or on the day of oocyte retrieval in long agonist protocols to reduce the incidence of OHSS in selected high- risk patients. Grade A. Dopamine agonists could be considered following trigger or on the day of oocyte retrieval in. # antagonist protocols to reduce the incidence of OHSS in selected high-risk patients. Grade B. antagonist protocols to reduce the incidence of OHSS in selected high- risk patients. Grade BThe GDG considered the low cost, availability, ease of use and safety of dopamine agonists. The Cochrane review included studies in which a dopamine agonist was started on either day of hCG trigger or day of oocyte collection. Most of the included studies used a daily dose of . In vitro maturation (IVM). IVM involves the culture of immature oocytes retrieved without exogenous ovarian stimulation or with minimal doses of gonadotropins, avoiding the need for supraphysiological ovarian stimulation (Dahan et al., 2016; Das & Son, 2023).. A Cochrane Systematic Review of the use of IVM in women with PCOS, including two RCTs with high risk of bias, found no cases of OHSS in the IVM or control groups . IVM is associated with a reduction of the risk of OHSS in women at risk of hyper-response to ovarian stimulation.Evidence level:1-. IVM may be considered for the prevention of OHSS in individuals at high risk. Grade B. The use of IVM avoids the need for supraphysiological ovarian stimulation and has not been found to be associated with a risk of OHSS. However, ongoing pregnancy rates may be lower after IVM compared with controlled ovarian stimulation (Vuong et al., 2023). Provision of IVM is dependent on availability of the technology and expertise at fertility clinics.. Research recommendations. The GDG identified the following unanswered questions from the review of the evidence:. 1. Further work is required to determine safe regimes for fresh embryo transfer following GnRH agonist trigger.. 2. The efficacy and safety of oral ovulation induction agents with conventional doses of FSH in GnRH antagonist protocol requires further study. 3. 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Journal of Assisted Reproduction and Genetics, 30(2), 239- 245. 012- 9919- 3Magnusson, A., Källen, K., Thurin- Kjellberg, A., & Bergh, C. (2018). The number of oocytes retrieved during IVF: A balance between efficacy and safety. Human Reproduction (Oxford, England), 33(1), 58- 64. R. S., Akande, A. V., Keay, S. D., Hunt, L. P., & Jenkins, J. M. (2000). Distinction between early and late ovarian hyperstimulation syndrome. Fertility and Sterility, 73(5), 901- 907. 0282(00)00492- 1Mendoza, N., Diaz- Ropero, M. P., Aragon, M., Maldonado, V., Llaneza, P., Lorente, J., Mendoza- Tesarik, R., Maldonado- Lobon, J., Olivares, M., & Fonolla, J. (2019). Comparison of the effect of two combinations of myo- inositol and D- chiro- inositol in women with polycystic ovary syndrome undergoing ICSI: A randomized controlled trial. Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology, 35(8), 695- 700. 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Effect of low- dose aspirin on the development of ovarian hyperstimulation syndrome and outcomes of assisted reproductive techniques in the women with PCOS, a randomized double- blinded clinical trial. Taiwanese Journal of Obstetrics & Gynecology, 58(2), 255- 260. . Nelson, S. M., Shaw, M., Alrashid, K., & Anderson, R. A. (2024). Individualized dosing of follitropin delta affects live birth and safety in in vitro fertilization treatment: An individual participant data meta- analysis of randomized controlled trials. Fertility and Sterility, 122(3), 445- 454. A. R., Montoya- Botero, P., Sachs- Guedj, N., & Polyzos, N. P. (2023). Association between the number of oocytes and cumulative live birth rate: A systematic review. Best Practice & Research. Clinical Obstetrics & Gynaecology, 87, 102307. O., Lensen, S. F., Vail, A., Mol, B. W. J., Broekmans, F. J., & Wilkinson, J. (2024). Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI). The Cochrane Database of Systematic Reviews, 1(1), CD012693. CD012693. pub3Nyboe Andersen, A., Nelson, S. M., Fauser, B. C., Garcia- Velasco, J. A., Klein, B. M., & Arcé, J. C., ESTHER- 1 study group. (2017). Individualized versus conventional ovarian stimulation for in vitro fertilization: A multicenter, randomized, controlled, assessor- blinded, phase 3 noninferiority trial. Fertility and Sterility, 107(2), 387- 396. e4. P., Sahmay, S., Cetin, M., Irez, T., Guralp, O., & Cepni, I. (2011). Serum anti- Mullerian hormone and antral follicle count as predictive markers of CDSS in ART cycles. Journal of Assisted Reproduction and Genetics, 28(12), 1197- 1203. 011- 9627- 4Olsson, H., Sandström, R., & Grundemar, L. (2014). Different pharmacokinetic and pharmacodynamic properties of recombinant follicle- stimulating hormone (rFSH) derived from a human cell line compared with rFSH from a nonhuman cell line. Journal of Clinical Pharmacology, 54(11), 1299- 1307. S. C., van Tilborg, T. C., Eijkemans, M. J. C., Oosterhuis, G. J. E., Friederich, J., van Hooff, M. H. A., van Santbrink, E. J. P., Brinkhuis, E. A., Smeenk, J. M. J., Kwee, J., de Koning, C. H., Groen, H., Lambalk, C. B., Mol, B. W. J., Broekmans, F. J. M., & Torrance, H. L., OPTIMIST study group. (2017). Individualized versus standard FSH dosing in women starting IVF/ICSI: An RCT. Part 2: The predicted hyper responder. Human Reproduction (Oxford, England), 32(12), 2506- 2514. E. G., Pozzobon, C., Kolibanakis, E. M., Camus, M., Tournaye, H., Fatemi, H. M., Van Steirteghem, A., & Devroey, P. (2006). Incidence and prediction of ovarian hyperstimulation syndrome in women undergoing gonadotropin- releasing hormone antagonist in vitro fertilization cycles. Fertility and Sterility, 85(1), 112- 120. M. E., Jahromi, B. N., Rezaee, S., Kooshesh, L., & Alaee, S. (2017). The effect of four different gonadotropin protocols on oocyte and embryo quality and pregnancy outcomes in IVF/ICSI cycles; a randomized controlled trial. Iranian Journal of Medical Sciences, 42(1), 57- 65. Polyzos, N. P., Drakopoulos, P., Parra, J., Pellicer, A., Santos- Ribeiro, S., Tournaye, H., Bosch, E., & Garcia- Velasco, J. (2018). Cumulative live birth rates according to the number of oocytes retrieved after the first ovarian stimulation for in vitro fertilization/intracytoplasmic sperm injection: A. # multicenter multinational analysis including approximately 15,000 women. Fertility and Sterility, 110(4), 661- 670 e661. N. P., Tournaye, H., Guzman, L., Camus, M., & Nelson, S. M. (2013). Predictors of ovarian response in women treated with corifollitropin alfa for in vitro fertilization/intracytoplasmic sperm injection. Fertility and Sterility, 100(2), 430- 437. J., Zhang, Y., Liang, X., Ho, T., Huang, H. Y., Kim, S. H., Goethberg, M., Mannaerts, B., & Arce, J. C. (2021). A randomised controlled trial to clinically validate follitropin delta in its individualised dosing regimen for ovarian stimulation in Asian IVF/CSI patients. Human Reproduction (Oxford, England), 36(9), 2452- 2462. K., Malhotra, N., Mahey, R., Khadgawat, R., & Kalaivani, M. (2022). Myoinositol versus metformin pretreatment in GnRH- antagonist cycle for women with PCOS undergoing IVF: A double- blinded randomized controlled study. Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology, 38(2), 140- 147. A., Dolfin, E., Gennarelli, G., Lantieri, T., Massobrio, M., Holte, J. G., & Tur- Kaspa, I. (2008). Low- dose acetylsalicylic acid plus prednisolone as an adjuvant treatment in IVF: A prospective, randomized study. Fertility and Sterility, 90(5), 1685- 1691. College of Obstetricians and Gynaecologists. (2016). The management of ovarian hyperstimulation syndrome: Green- top guideline no. 5. all- guidance/green- top- guidelines/the- management- of- ovarian- hyperstimulation- syndrome- green- top- guideline- no- 5/Royal College of Obstetricians and Gynaecologists. (2020). Developing a green- top guideline. RCOG. guideline- development- guide.pdfSalama, K. M., Abo Ragab, H. M., El Sherbiny, M. F., Morsi, A. A., & Souidan, I. I. (2017). Sequential E2 levels not ovarian maximal diameter estimates were correlated with outcome of cetrotide therapy for management of women at high- risk of ovarian hyperstimulation syndrome: A randomized controlled study. BMC Women's Health, 17(1), 108. 017- 0466- zSalehpour, S., Nazari, L., Hosseini, S., Azizi, E., Borumandnia, N., & Hashemi, T. (2021). Efficacy of daily GnRH agonist for luteal phase support following GnRH agonist triggered ICSI cycles versus conventional strategy: A Randomized controlled trial. JBRA Assisted Reproduction, 25(3), 368- 372. 0557.20200077Salmassi, A., Mettler, L., Hedderich, J., Jonat, W., Deenadayal, A., von Otte, S., Eckmann- Scholz, C., & Schmutzler, A. G. (2015). Cut- off levels of anti- mullerian hormone for the prediction of ovarian response, in vitro fertilization outcome and ovarian hyperstimulation syndrome. International Journal of Fertility & Sterility, 9(2), 157- 167. Ribeiro, S., Mackens, S., Popovic- Todorovic, B., Racca, A., Polyzos, N. P., Van Landuyt, L., Drakopoulos, P., de Vos, M., Tournaye, H., & Bockeel, C. (2020). The freeze- all strategy versus agonist triggering with low- dose hCG for luteal phase support in IVF/ICSI for high responders: A . # Tang, H., Mourad, S. M., Wang, A., Zhai, S. D., & Hart, R. J. (2021). Dopamine agonists for preventing ovarian hyperstimulation syndrome. The Cochrane Database of Systematic Reviews, 4(4), CD008605. CD008605. pub4 Tarlatzi, T. B., Venetis, C. A., Devreker, F., Englert, Y., & Delbaere, A. (2017). What is the best predictor of severe ovarian hyperstimulation syndrome in IVF? A cohort study. Journal of Assisted Reproduction and Genetics, 34(10), 1341- 1351. 017- 0990- 7 The Eshre Guideline Group On Ovarian Stimulation, Bosch, E., Broer, S., Griesinger, G., Grynberg, M., Humaidan, P., Kolibianakis, E., Kunicki, M., La Marca, A., Lainas, G., Le Ciel, N., Massin, N., Mastenbroek, S., Polyzos, N., Sunkara, S. K., Timeva, T., Toyoi, M., Urbancsek, J., Vermeulen, N., & Broekmans, F. (2020). ESHRE guideline: Ovarian stimulation for IVF/ICSI. Human Reproduction Open, 2020(2), hoaa009. Tso, L. O., Costello, M. F., Albuquerque, L. E. T., Andriolo, R. B., & Macedo, C. R. (2020). Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. The Cochrane Database of Systematic Reviews, 12(12), CD006105. CD006105. pub4 Turan, G. A., Eskicioglu, F., Sivrikoz, O. N., Cengiz, H., Adakan, S., Gur, E. B., Tatar, S., Sahin, N., & Yilmaz, O. (2015). Myoinositol is a promising treatment for the prevention of ovarian hyperstimulation syndrome (OHSS): An animal study. Archives of Gynecology and Obstetrics, 292(5), 1163- 1171. 015- 3747- 5 van der Linden, M., Buckingham, K., Farquhar, C., Kremer, J. A., & Metwally, M. (2015). Luteal phase support for assisted reproduction cycles. The Cochrane Database of Systematic Reviews, 2015(7), CD009154. CD009154. pub3 van Wely, M., Kwan, I., Kurt, A. L., Thomas, J., Vail, A., Van der Veen, F., & Al- Inany, H. G. (2011). Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles. The Cochrane Database of Systematic Reviews, 2011(2), CD005354. CD005354. pub2 Varnagy, A., Bodis, J., Manfai, Z., Wilhelm, F., Busznyak, C., & Koppan, M. (2010). Low- dose aspirin therapy to prevent ovarian hyperstimulation syndrome. Fertility and Sterility, 93(7), 2281- 2284. Vuong, L. N., Pham, T. D., Ho, T. M., & De Vos, M. (2023). Outcomes of clinical in vitro maturation programs for treating infertility in hyper responders: A systematic review. Fertility and Sterility, 119(4), 540- 549. Wang, R., Lin, S., Wang, Y., Qian, W., & Zhou, L. (2017). Comparisons of GnRH antagonist protocol versus GnRH agonist long protocol in patients with normal ovarian reserve: A systematic review and meta- analysis. PLoS One, 12(4), e0175985. Witz, C. A., Daftary, G. S., Doody, K. J., Park, J. K., Seifu, Y., Yankov, V. I., Heiser, P. W., & Menopur in GnRH Antagonist Cycles with Single Embryo Transfer - High Responder (MEGASET- HR) Trial Group. (2020). Randomized, assessor- blinded trial comparing highly purified human .	None	None	None
3394f4d63ab04c6fb4e12f35ab59bedb	2024+BGCS／BMS指南	妇科癌症治疗后更年期症状的管理	# British Gynaecological Cancer Society and British Menopause Society guidelines: Management of menopausal symptoms following treatment of gynaecological cancer. Alexandra Taylor. Abstract. These guidelines have been developed jointly by the British Gynaecological Cancer Society and British Menopause Society to provide information for all healthcare professionals managing women treated for gynaecological cancer. Menopausal symptoms can have a significant impact on quality of life for women. Cancer therapies, including surgery, pelvic radiotherapy, chemotherapy and endocrine therapy, can all affect ovarian function. The benefits and risks of using hormone replacement therapy are considered by cancer type with guidance on the type of HRT and optimal time of commencement after cancer treatment. Vaginal estrogens can be very effective for improving urogenital symptoms and are safe for the majority of women, including those for whom systemic HRT is contraindicated with rare exceptions. Alternative options to HRT are reviewed including pharmacological and non- pharmacological approaches.. # Keywords. KeywordsMenopause, hormone replacement therapy, alternative therapies, gynaecological cancer. Introduction. Menopausal symptoms can have a significant impact on quality of life for women following treatment for gynaecological cancer. Cancer therapies, including surgery, pelvic radiotherapy, chemotherapy and endocrine therapy, can all cause premature ovarian insufficiency (OOr) or iatrogenic menopause. With continued advances in oncology, there are increasing numbers of long- term survivors, and it is therefore essential to consider and manage the consequences of treatment.. Menopause can cause a variety of symptoms including vasomotor symptoms, sleep disturbance, variable mood, sexual dysfunction, musculoskeletal symptoms, fatigue and cognitive symptoms. The health risks from premature ovarian insufficiency include loss of fertility, increased incidence of osteoporosis, mortality from heart disease, bladder dysfunction and dementia or neurocognitive impairment. This impact may be more significant in the context of menopause due to the diagnosis and treatment of gynaecological cancer. Many of the treatments, such as pelvic radiotherapy, can exacerbate and mimic menopausal symptoms including bladder dysfunction, sexual dysfunction and pelvic bone thinning.. Hormone replacement therapy (HRT) is an effective treatment for menopausal symptoms, for primary prevention of the health risks associated with early menopause, and is an effective therapy for osteoporosis prevention in women under 60 years. For the majority of women with premature ovarian insufficiency, the benefits of HRT outweigh the risks. When deciding on management options, consideration of whether the patient had a hormone- sensitive tumour, such as endometrial stromal sarcoma, is required to fully inform decisions. When quality of life is being impacted by menopausal symptoms, women should be counselled regarding the known risks and benefits of HRT and about the alternative options to enable them to make an informed decision about their treatment.. The aim of this guideline is to provide information for healthcare professionals managing women treated for gynaecological cancer who are reporting menopausal symptoms when other causes have been excluded.. For more comprehensive information on general management of the menopause, we refer the reader to British Menopause Society (BMS) guidance and National Institute for Health and Care Excellence (NICE) guidelines:. \Rightarrow. Methods. An expert panel of clinicians, nurses and charity partners was nominated by the British Gynaecological Cancer Society (BGCS) and the British Menopause Society (BMS). The group included healthcare professionals with expertise in management of women with gynaecological cancer and menopause. For each topic, focused literature review was undertaken to develop evidence- led recommendations. The guidance statements were determined by consensus within the group and have been approved by the BMS and BGCS councils.. Recommendations are graded as per the Royal College of Obstetricians and Gynaecologists document Clinical Governance Advice No. 1: Guidance for the Development of RCOG Green- top Guidelines (Table 1).. These guidelines refer to the treatment of all people with, or at risk from, gynaecological malignancies. The majority will define themselves as women and, in line with other RCOG guidelines where the term women is used, this also includes those who have other gender identities.. General recommendations. General recommendations- All women who are likely to go through menopause as a result of surgery, systemic therapy and/or radiotherapy treatment should have a pretreatment discussion of possible menopausal symptoms and potential management options (Grade D).- Women should have access to evidence- based information about menopausal symptoms, HRT and alternative treatment options (Grade D).- Evaluation of symptoms and individual needs should be reassessed on a regular basis, with annual review once stable (Grade D).- All clinicians and clinical nurse specialists managing gynaecological cancer should have appropriate training to support women with menopausal symptoms. Referral to or discussion with a menopause specialist is recommended for complex situations (Grade D).- High- quality research studies are required on management of menopausal symptoms in women treated for gynaecological cancers (Grade D).. Throughout these recommendations, the term hormone replacement therapy (HRT) refers tosystemic HRT and this. # does not include vaginal estrogen which is considered separately.. Many of the recommendations are based on expert opinion. There is a paucity of evidence in many areas and individual patient decision- making is necessary, balancing uncertainties and individual risks and benefits, with input from specialist services for complex patients.. Hormone replacement therapy after treatment for specific gynaecological tumour types. The following sections consider the evidence for HRT after treatment for gynaecological cancer and the recommendations are summarised in Table 2. However, for women with a life- limiting illness, consideration of quality of life is essential and there may be benefits from HRT even with hormone- sensitive tumours on an individualised basis. In addition, vaginal estrogens can have significant benefits for many women and can be considered even when systemic HRT is contraindicated or not required. Where recommendations for HRT are made, the options of estrogen- only HRT versus combined continuous HRT, optimal time of commencement . Ovarian cancer (includes ovarian, fallopian tube and primary peritoneal cancer). HRT is not usually contraindicated following treatment for epithelial ovarian cancer and potential risks and benefits should be discussed with women (Grade B). Although the majority of high- grade serous and endometrioid ovarian cancers express estrogen receptors, the limited randomised controlled trial data do not suggest an increased risk of disease recurrence with systemic HRT. It may be appropriate to offer non- hormonal options in the first instance, particularly for women who do not have the health impacts of an early menopause (Grade B). Non- hormonal options should be offered in the first instance to women with FIGO Stage I low- grade serous ovarian cancers, but HRT is not contraindicated (Grade D). HRT is not recommended for women with FIGO stages II- IV or recurrent low- grade serous ovarian cancers, as the disease is hormone- sensitive and there is an advantage to estrogen- suppressing treatment (Grade D).. # HRT should be offered to women who have menopausal symptoms following treatment for borderline ovarian tumours and actively recommended for those with surgical menopause as a result of treatment for early- stage disease (Grade C).. HRT should be offered to women who have premature ovarian insufficiency following treatment for germ cell tumours (Grade D). Limited evidence does not demonstrate harm with HRT following treatment for stage I granulosa cell. # tumours, but these tumours are hormone-sensitive and women should be counselled regarding the uncertainties (Grade D).. High- grade serous epithelial ovarian carcinoma. The majority of women with epithelial ovarian cancer (EOC) are diagnosed at a late stage and with high- grade serous carcinoma. There is a need to balance quality and quantity of life, and the risk/benefit profiles need to be individualised based on symptoms and cancer risks. Furthermore, many women with early- stage cancer are younger, have a good prognosis and treatment potentially leads to surgical menopause or premature ovarian insufficiency, and so the impact of early menopause in long- term survivors needs to be balanced with the risks of cancer recurrence. HRT may therefore be an important consideration for women with both early- and late- stage disease.. There is a theoretical risk of estrogen use for women with high- grade serous or endometrioid EOC since up to . In contrast, there are specific data that support the use of HRT in women with EOC. In a Swedish observational study of 649 patients previously treated for high- grade epithelial ovarian cancer, there was improved survival in the cohort that received HRT after diagnosis . A Cochrane review assessing HRT after treatment for EOC identified three studies involving 350 women.11 Two studies included pre- and postmenopausal women and one only included premenopausal women. The age range of the women included in the studies was 20 to 89.6 years old. Median follow- up ranged from 31.4 months to 19.1 years. They reported that HRT may slightly improve overall survival (OS) after surgical treatment for EOC (HR 0.71, . A recent systematic review and meta- analysis identified eight publications including 3578 patients of whom 912 received systemic HRT and this did report an impact of HRT on survival. This highlighted a slight benefit in OS and PFS in favour of HRT (HR 0.66 and 0.73) and no difference based on age or stage and grade of tumour.12. Non- serous epithelial ovarian cancer (clear cell, mucinous, endometrioid). The impact of HRT in non- serous tumours is less clear. A retrospective cohort study of 357 women with non- serous cancers demonstrated no harmful effects and no impact on OS or PFS.13. In those with endometrioid ovarian cancer, HRT did not appear to worsen outcomes despite these being potentially estrogen- sensitive tumours. Following treatment for FIGO Stage I disease, non- hormonal options should be considered in the first instance, but HRT is not contraindicated. However, in those with more advanced or residual disease, HRT should be used with caution as the presence of residual disease may promote tumour growth.. For women with clear cell and mucinous cancer, where endocrine treatments are not routinely used, HRT can be considered. However, treatment should be individualised and the uncertainties discussed, especially for patients with advanced disease.. Low- grade serous ovarian cancer (LGsOC). Low- grade serous ovarian tumours are generally ER- positive and commonly hormone- sensitive, with anti- estrogen treatment frequently used in the recurrent setting.14,15 There is a lack of data on the safety of HRT in women treated for low- grade serous carcinoma and so a precautionary principle is advisable. Non- hormonal options should be offered in the first instance to women with Stage I low- grade serous ovarian cancers, but HRT can be considered after a discussion of the individualised potential risks and health benefits. A joint position statement by the European Menopause and Andropause Society (EMAS) and the International Gynecological Society (IGCS) concluded that given the benefits seen with hormone therapy with letrozole, anastrozole, tamoxifen, and leuprolide acetate after primary cytoreductive surgery and platinum- based chemotherapy in women with Stage II to IV low- grade serous carcinoma of the ovary or peritoneum, [sic] estrogen- based therapies are currently not recommended in advanced disease of these types'.16. # Borderline ovarian tumour (BOT). Borderline ovarian tumours (BOTs) more commonly occur in younger women compared to epithelial ovarian cancer. Treatment that involves bilateral salpingo- oophorectomy may therefore cause significant rates of premature menopause. Furthermore, in young women retention of fertility is a common consideration and fertility- sparing surgery is often appropriate. With high overall survival rates, women with surgically induced menopause are likely to live for many years associated with increasing consequences of estrogen deficiency, unless appropriate hormone replacement therapy is provided.. In the Swedish observational study, in addition to epithelial ovarian cancers discussed above, there were 150 women who had been treated for BOT. With a 5- year follow- up, . After examination of the available evidence, the French national guidelines concluded that use of hormonal contraception after serous or mucinous BOT was not contraindicated. Specifically for women aged under 45 years who had a surgical menopause as a result of treatment, given the benefit of HRT on cardiovascular and bone risks, and the lack of hormone- sensitivity of mucinous BOTs, they actively recommended the use of HRT, in the absence of other contraindications. For women over 45 years of age, they found no argument to contraindicate the use of HRT on the basis of the BOT diagnosis alone and recommended that HRT can be prescribed for menopausal symptoms, as part of an individual benefit to risk assessment. However, there should be caution if there is residual disease following surgery, advanced stage or recurrent disease.. Germ cell tumours. Germ cell tumours most commonly occur in young women and account for . Treatment should therefore be aimed at preserving ovarian function for the majority of patients. However, in those who either have bilateral oophorectomy or lose ovarian function due to chemotherapy, HRT use should be encouraged. Due to the rarity, there are no specific . Granulosa cell tumours. Granulosa cell tumours can present at any age, although are most common in postmenopausal women. An important minority of granulosa cell tumours . A study of 454 patients, previously diagnosed with granulosa and theca cell tumours, reviewed the original histology and re- classified the cases based on current diagnostic criteria and methods. Only . Granulosa cell tumours are potentially estrogen- dependent and commonly produce estrogens and inhibin. Treatment of advanced or recurrent disease usually involves endocrine approaches including aromatase inhibitors, leuprolide and tamoxifen. There are no data on the safety of HRT with early- stage disease. HRT use, especially in advanced disease, would depend on treatment regimens, individual symptoms and risk/benefit discussions, but non- hormonal treatment options should be strongly considered initially in advanced and recurrent disease and women counselled about the uncertainties and minimal evidence- base.. Cervical and vaginal cancer. - HRT is not contraindicated after treatment for cervical or vaginal cancer, with the recommended HRT options dependent on the received treatment (Grade B). Estrogen-only HRT should be offered after hysterectomy and bilateral salpingo-oophorectomy for cervical cancer in premenopausal women (Grade B).. # Continuous combined estrogen-progestogen HRT or tibolone is recommended after chemoradiotherapy to the pelvis for premenopausal women (Grade B).. Cervical and vaginal cancers are not hormone dependent, and there is no contraindication to the use of HRT or vaginal estrogens. Although adenocarcinomas of the cervix commonly express estrogen receptors, several studies have found that estrogen and progesterone receptor expression does not correlate with recurrence or survival outcomes, and no detrimental impact has been reported with the use of HRT following treatment.24- 27 Furthermore, there was no correlation of ER or PR expression and prognostic factors, such as stage, age, lymph node status or lymphovascular invasion.25. Treatment- induced menopause is a significant problem after cervical cancer treatment, especially in women diagnosed at a young age and with a good prognosis. A population- based study of 837 women aged under 45 years at the time of cervical cancer diagnosis demonstrated that almost a third had treatmentinduced menopause due to surgery or radiotherapy.28 Fewer than half of the women who had therapy- induced early menopause used HRT at the recommended dose. By 4.5- 5 year follow- up, HRT use decreased further with only . In a randomised clinical trial of HRT use in 120 women aged under 45 at diagnosis (80 HRT; 40 controls) treated with surgery and/or radiotherapy for cervical cancer, there was no difference in disease- free or overall survival between those prescribed HRT and controls.29 This study demonstrated better control of menopausal symptoms and relief of radiationinduced bladder, rectal, and vaginal symptoms in the HRT group. Narrative reviews of the literature have consistently concluded that there is no evidence that HRT- use after a diagnosis of cervical cancer is associated with an increased risk of cervical cancer recurrence or death.30- 32. Following hysterectomy and bilateral salpingooophorectomy, estrogen- only HRT is recommended. Some clinicians would recommend combination HRT instead of estrogen- only HRT following treatment for adenocarcinoma of the cervix, but data are lacking for this approach.. After pelvic radiotherapy, for those who have not had a hysterectomy, continuous combined estrogen and progestogen HRT should be prescribed for premenopausal women. Functional endometrium can persist after pelvic radiotherapy for cervical cancer, and endometrial cancer has been reported in women previously treated with radiotherapy who have an intact uterus.28,32,33 HRT reduces the incidence of vaginal toxicity, sexual dysfunction and pelvic insufficiency fractures following radiotherapy and should ideally be commenced during or within a few weeks of completing radiotherapy.. Endometrial Carcinoma. Premenopausal women with low- risk endometrial cancer can be considered for ovarian- sparing surgery to prevent surgical menopause (Grade D). Women with low- risk and intermediate- risk endometrial cancer, who are premenopausal or have menopausal symptoms, should have discussion about the advantages and disadvantages of HRT after hysterectomy. The limited evidence to date does not identify an increased risk of recurrence with HRT (Grade B). For women with high- intermediate risk, or high- risk endometrial cancer with estrogen- and progesteronereceptor negative tumours, treatment should be individualised following discussion of theoretical risks and benefits as the risk of HRT is unknown (Grade D). HRT is not recommended for women with high risk, advanced or metastatic disease that is expressing hormone receptors (Grade D). Women with advanced disease, where treatment is with palliative intent, should have careful consideration of all treatments to improve quality of life, which may include HRT depending on symptoms (Grade D). Women diagnosed with endometrial cancer whilst on tamoxifen for breast cancer should be discussed with their breast oncology team, with consideration being given to either switching to an aromatase inhibitor or discontinuation of endocrine therapy (Grade D).. Endometrial cancer is the fourth most common cancer in females in the UK, and the numbers are escalating due to increasing rates of obesity. Risk groups have been identified based on tumour histology, stage and molecular profile which can guide management options and help to provide patients with informed advice.34,35 In these recommendations, the risk groups are defined according to the ESGO- ESTRO- ESP 2021 guidelines and BGCS guidelines (Appendix 1).. There is limited evidence in the literature around HRT after treatment for endometrial cancer. A Cochrane review assessed the available evidence with data from one randomised controlled trial that closed early and two low- quality studies, and found no evidence of increased recurrence for use of HRT after endometrial cancer.36 The randomised trial contained 1236 participants who had FIGO stage I- II endometrial cancer and the rate of tumour recurrence was not significantly different during the 36 month follow- up (2.3% in the estrogen arm vs 1.9% receiving placebo [RR 1.17]).37 A meta- analysis by Shim et al based mainly on observational studies showed no significant increase in recurrence with HRT use following endometrial cancer, irrespective of tumour stage or type of HRT.38. # Ovarian conservation is an option in premenopausal women with a low- grade endometrioid endometrial cancer with less than . It is advisable to await final pathology and the potential need for adjuvant treatment before discussing menopausal symptoms and management with the patient. With low- and intermediate- risk endometrial cancer it is reasonable to discuss both systemic and vaginal estrogen.1,39. It should be discussed with women with highintermediate and high- risk endometrioid endometrial cancer that there is no evidence on the harms and benefits of HRT use. There are also no data on the impact of HRT on tumours that do not express hormone receptors. Endocrine therapies are used for treatment of recurrent and metastatic disease, particularly for tumours with strong expression of estrogen and/or progesterone receptors, so there is a theoretical risk associated with HRT use in women at a higher risk of recurrence.. In the palliative situation, HRT can be discussed with women as part of managing symptoms and quality of life. It should be a priority to ensure that all women can access a specialised clinic to discuss the risks and benefits of HRT if they are struggling with menopausal symptoms.. There is evidence that combined HRT can reduce the risk of developing endometrial cancer in women with a uterus. The Women's Health Initiative (WHI) study published in 2016 showed a significant decrease in endometrial cancer from the background population of women with a uterus having continuous combined HRT compared to no HRT.40 This data could be extrapolated to consider prescribing continuous combined HRT to women after treatment for endometrial cancer, particularly in women with highintermediate or high- risk endometrial cancer whose quality of life is severely affected by menopausal symptoms. However, there are no data comparing continuous combined HRT with estrogen- only HRT in women with endometrial cancer and breast cancer risk needs to be taken into consideration.. Tamoxifen is one of a class of agents known as selective estrogen receptor modulators (SERMs). It is used as an adjuvant treatment for breast cancer but has a weakly positive effect on the estrogen receptors in the endometrium. It therefore increases the risk of endometrial cancer two- to three- fold.41 Any woman who has developed endometrial cancer whilst on tamoxifen should be advised to stop the tamoxifen and be referred back to their breast oncology team for consideration of alternative endocrine options.. Uterine sarcomas. Uterine leiomyosarcomas can be hormone- sensitive, and therefore HRT should be avoided (Grade C).. For women with significant menopausal symptoms following treatment for leiomyosarcoma, HRT should only be considered if alternative options have been ineffective (Grade D). Women should be advised to avoid HRT after treatment for endometrial stromal sarcoma, unless the individual benefits outweigh the risk (Grade C).. Leiomyosarcoma. Leiomyosarcomas are rare tumours, making up . Endometrial stromal sarcoma. Endometrial stromal sarcomas are hormone- sensitive tumours which are usually treated with endocrine approaches for advanced and recurrent disease. These cancers often occur in premenopausal women. Oophorectomy as part of surgery improves progression- free survival compared to women with retained ovaries, but not overall survival, so this is an important area to counsel women about when planning surgery.47 There is a paucity of evidence with regards to endometrial stromal sarcoma. There are only two retrospective studies in the literature looking at HRT after treatment for endometrial stromal sarcoma. In these studies, 12 out of 23 patients with recurrence were on HRT, and 6 of 23 were taking tamoxifen.48,49 It is therefore recommended that HRT is avoided in this group, unless quality of life benefits for an individual outweighs the risk. Referral to a healthcare professional with expertise in menopause is recommended if HRT is considered.. Vulval cancer. Following treatment for squamous cell carcinoma of the vulva, there is no contraindication to HRT or local estrogens (Grade D). Evidence from cutaneous melanoma at all sites does not support or contradict HRT use following treatment for melanoma of the vulva (Grade C).. The majority of vulval cancers are squamous cell cancers, adeno- squamous or adenocarcinomas which are not. # hormonally driven and are not hormone- sensitive tumours. These cancers are either HPV- associated or related to inflammatory skin disorders such as lichen sclerosus. Adenocarcinomas can arise in the Bartholin's gland or in Paget's disease of the vulva. Since radical surgery does not affect the menopausal status of women, the quality- of- life discussions related to menopause are less affected by treatment unless pelvic radiotherapy is used. If a postmenopausal woman is on HRT when diagnosed with vulval cancer, there is no contraindication to continuing with this.. Local estrogen can be beneficial to aid healing of the vulva, and also as part of management of inflammatory vulval skin disorders. However, it can increase the risk of candidiasis, particularly in women also on topical steroids, and this should be discussed with women when prescribing.. Melanoma is the fourth most common histological type of vulval cancer. For melanomas at all sites, there have been several studies assessing the association between HRT and melanoma. A meta- analysis including five prospective studies in the literature looking at HRT use and likelihood of developing melanoma does not support or contraindicate the use of HRT in women following treatment for vulval melanoma.50. HRT for women with an increased risk or genetic predisposition to develop breast, ovarian and/or endometrial cancer. Premenopausal women need careful counselling with consideration of HRT options and access to evidencebased patient information prior to decision- making for risk- reducing surgery (Grade D). Access to a specialist service for women with a high risk of gynaecological cancer is strongly recommended (Grade D). Following premenopausal oophorectomy, HRT should be offered until the usual age of the natural menopause, unless there is a personal history of breast cancer Grade C). Continuation beyond this age lacks an evidence base in women with a cancer susceptibility gene associated with an increased risk of breast cancer (such as BRCA carriers) and is not routinely recommended. However, continuation can be considered depending on the individual balance of risks and benefits in women who have had bilateral risk- reducing mastectomy for primary breast cancer prevention (Grade D). Hysterectomy is not indicated at the time of riskreducing salpingo- oophorectomy (RRsO) if there is no increased genetic risk for endometrial cancer or other clinical indication for hysterectomy (Grade D). Women with Lynch syndrome or BRIP1 mutation are not at an increased risk of breast cancer. HRT use . Risk-reducing surgery. Risk- reducing surgery with bilateral salpingooophorectomy (RRsO) is the most effective method of preventing ovarian cancer for those with an increased risk due to inherited pathogenic variants and likely pathogenic variants (henceforth called pathogenic variants or PVs) in cancer susceptibility genes associated with an increased risk of ovarian cancer. This includes the breast cancer genes 1 and 2 (BRCA1 and BRCA2), as well as moderate penetrance genes RAD51C, RAD51D, BRIP1 and PALB2. Women with Lynch syndrome have PVs in mismatch repair genes (MMR) (MLH- 1, PMS- 2, MSH- 2 and MSH- 6) and are at an increased risk of ovarian cancer as well as endometrial cancer. RRsO is cost- effective for women at . With increasing uptake of risk- reducing surgery, more women will be exposed to the long- term consequences of premature surgical menopause.53,54 Risk- reducing early salpingectomy and delayed oophorectomy (RRESDO) as a twostep alternative for ovarian cancer risk reduction should at present only be considered in a research study due to current paucity of long- term outcome data, particularly with respect to reduction in cancer incidence and endocrine function.55- 57. Role of HRT. Women considering risk- reducing surgery should be provided with evidence- based information and multidisciplinary input, with advice on symptom management, use of HRT if appropriate, specialist counselling and sustained support to deal with various physical, emotional and long. # term health consequences of a surgical menopause.58,59 Women at high- risk are best managed in multidisciplinary teams which should include a gynaecologist/ gynaecological oncologist with a special interest, a menopause specialist, a clinical nurse specialist and psychological support. It should be discussed that retaining the uterus impacts on HRT options, as estrogen must be combined with a progestogen (either cyclical or continuous) to protect against endometrial hyperplasia, whereas estrogen alone is required following hysterectomy.. HRT can ameliorate symptoms and reduces the adverse longterm consequences of premature menopause.54,60,61 It should be routinely offered to all women having premenopausal RRSO unless there is a personal history of breast cancer which necessitates a more detailed consultation. Historically, use or compliance with HRT after RRSO has been limited . Short- term HRT use in BRCA mutation carriers below the age of natural menopause does not increase the risk of breast cancer.53,63- 66 The health benefit of HRT is greatest after RRSO at younger ages. One small retrospective cohort study has reported breast cancer risk may rise from use at 45- 50 years.66. Some women at an increased risk of ovarian cancer may not be at an increased risk of breast cancer (e.g. those with BRIP1 mutations or Lynch syndrome), and HRT use beyond the usual age of natural menopause in these women should be governed by the same principles as women at populationbased risk. These principles should also be applied to cancer susceptibility gene carriers associated with an increased risk of breast cancer (such as BRCA or PALB2), but no personal history of breast cancer, following risk- reducing bilateral mastectomy for primary breast cancer prevention.. HRT is usually contraindicated in women with a personal history of breast cancer. It should not be routinely recommended to women with a history of estrogen receptor or progesterone receptor positive breast cancers, although it can be considered on an individualised basis after careful counselling for women with significant symptoms where non- hormonal alternatives are not effective or acceptable.67 Short- term HRT may be considered on a case- by- case basis in women with triple- negative breast cancer. Any such decision should be individualised, and multidisciplinary team involvement is important including the woman, breast oncologist and menopause specialist/gynaecologist experienced in caring for women with a high risk of cancer. Even if HRT is contraindicated, vaginal estrogens can still be considered, especially in women taking tamoxifen.68. Options for hormone replacement therapy. Transdermal administration of estradiol is unlikely to increase the risk of venous thromboembolism. (VTE) or stroke above that of non- users and is associated with a lower risk than oral administration of estradiol. The transdermal route should therefore be considered as the preferred choice for women with related risk factors (Grade A). Oral estradiol is effective and safe in most women unless there are concerns about gut malabsorption, drug interactions or there are risk factors for VTE (Grade A). The lowest effective dose of estrogen that relieves symptoms should be used (Grade B). Serum levels of estrogen should not be routinely measured to titrate HRT dosage, other than in situations to check absorption (Grade C). Continuous combined HRT should be offered to all non- hysterectomised women once clearly postmenopausal if HRT is indicated (Grade A). The dose of progestogen should be proportionate to the dose of estrogen. Women who require high doses of estrogen should consider having their progestogen dose increased to ensure adequate endometrial protection (Grade D). The use of compounded bioidentical hormone replacement therapies from 'Specialist Pharmacies' is not recommended. These products do not follow the same regulatory pathways as prescribed HRT, with potential issues related to their purity, safety and efficacy (Grade D). Due to the potential risk of stimulation or malignant conversion of endometriotic deposits with unopposed estrogens, continuous combined HRT should be prescribed following hysterectomy in women with a history of endometriosis (Grade D).. In women with previous gynaecological cancer, HRT options depend on tumour factors, oncological treatment and the type of drug to be used, always balancing risk and benefit for the individual.69 In addition to the oncology history, other risk factors to consider include history of VTE, cerebrovascular accident (CVA), myocardial infarctions (MI), liver dysfunction, gut malabsorption syndromes and high body mass index (BMI).. Further information is available in the following documents:. \Rrightarrow. # Estrogen. Transdermal estradiol does not increase the risk of VTE or stroke above baseline risk.72- 74 Whilst transdermal estrogen is optimal for most women, oral estrogens are effective and safe in most women without risk factors for VTE or malabsorption. Oral conjugated equine estrogens (CEEs) do have a higher risk of VTE than oral estradiol.72. Women should use the dose of estrogen that relieves their symptoms. The long- term data for higher doses are unknown, and caution is advised for using higher doses when there is the possibility of estrogen stimulation of tumour. Women with premature ovarian insufficiency may need higher doses than women with menopause at an average age. However, high doses of estrogen which exceed the product licenses should not be regularly prescribed as these limits are informed by the results of clinical trials to ensure patient safety. If in exceptional circumstances a higher than licensed dose is deemed necessary for symptom control, informed consent should be obtained according to good medical practice guidance and patients must be made aware that treatment falls outside of currently available safety evidence. In addition, the dose of progestogen should be increased proportionately.75. Progestogens. Progestogen administration is required to protect against endometrial stimulation that can occur with unopposed estrogen. The dose of progestogen should be proportionate to the dose of estrogen.75,76 Observational and case control data suggest that micronised progesterone may reduce the increased risk of VTE conferred by oral estrogen, compared to that noted with synthetic progestins.75. The type of progestogen can also impact on the risk of developing breast cancer. A meta- analysis by Asi et al found that micronised progesterone was associated with a lower risk of breast cancer compared with synthetic progestins although longer- term data are lacking.77 Compared with HRT never- use, there was no increased risk of breast cancer with micronised progesterone (relative risk [RR] 1.00) for up to 5 years use, whereas women using estrogen plus progestins had an RR of 1.16- 1.69.78 Similarly, Cordina- Duverger et al reported no increased risk of breast cancer among users of estrogen with micronised progesterone for any duration (odds ratio [OR] 0.80), whereas among users of combined HRT containing a synthetic progestin, the OR was 1.57- 3.35 (depending on the progestin used).79. Sequential combined HRT given for more than 5 years does slightly increase the risk of endometrial cancer, but there is no increased risk when estrogen is combined with continuous daily progestogen in postmenopausal women using standard dose estrogen.80 Therefore, continuous . The BMS Consensus Statement on Bioidentical HRT highlights concerns related to the efficacy and safety of nonregulated compounded bioidentical products, and the lack of evidence that this route and dosage of progesterone provides sufficient endometrial protection. The use of such compounded products is therefore not recommended.82. Tibolone is an alternative option to estrogen- progestogen combination HRT. It produces metabolites that have estrogenic, progestogenic and androgenic effects, and it does not stimulate the endometrium. Cummings et al not only reported a reduction in risk of fractures and of breast and colon cancer with tibolone but also reported a small increase in the risk of stroke in older women with additional risk factors.83. In women with a history of endometriosis, there is a potential risk of stimulation of quiescent endometriosis or malignant conversion with unopposed estrogens.84 ESHRE guidelines recommend continuous combined HRT at least up to the age of natural menopause following surgical menopause.85 Further information is available in the BMS document: Induced menopause in women with endometriosis - British Menopause Society (thebms.org.uk).86. Vaginal estrogens (alone or in addition to HRT). Always enquire specifically about symptoms of urogenital atrophy and sexual dysfunction. General advice about vaginal lubricants and moisturisers should be provided (Grade D). Vaginal estrogens are safe for the majority of women after treatment for a gynaecological malignancy, including those for whom systemic HRT is contraindicated with rare exceptions (Grade B). For those in whom HRT is not contraindicated, women may need vaginal estrogen in addition to systemic HRT for treatment of urogenital symptoms (Grade D).. Urogenital symptoms including vaginal dryness, itching, discomfort and painful sexual intercourse can be very distressing. Alternative terminology used for these symptoms includes vulvovaginal atrophy (VVA), urogenital atrophy (UGA) and genitourinary syndrome of menopause (GSM). These symptoms are under- reported, often not recognised by healthcare professionals and under- treated. In addition, many of the treatments for cancer can exacerbate these symptoms. Sexual dysfunction is particularly. # common in cancer survivors especially in younger women and in those who have had pelvic radiotherapy.. Vaginal estrogens are very effective at improving urogenital symptoms.1,87 They have also been found to be superior to placebo for urinary symptoms including urgency, urge incontinence, frequency and nocturia. For some women taking HRT, vaginal estrogen may be required in addition to improve urogenital symptoms. Vaginal lubricants and moisturisers can be used as well as vaginal estrogen. Further information is available in the BMS consensus statement on Urogenital Atrophy and the North American Menopause.2020 position statement on genitourinary syndrome.88,89. While the data regarding the use of topical vaginal estrogen after gynaecological cancer are sparse, it should be highlighted that with current low- dose estrogen preparations, the total administered vaginal dose per year is equivalent to just a single dose of systemic oral therapy. Systemic absorption is minimal and vaginal estrogens are therefore not generally contraindicated, even when systemic HRT is not recommended.. Women with a history of breast cancer who have significant symptoms of urogenital atrophy may consider low- dose vaginal estrogens.71,90,91 Although there is a theoretical increased risk of recurrence, this is not borne out in the available data.92 While non- hormonal vulvo- vaginal preparations are preferable in the first instance, for women with severe symptoms there should be joint decision- making between the patient and her oncology team to consider a switch in adjuvant breast therapy and/or vaginal estrogens on an individualised basis.93 Women on aromatase inhibitors who wish to use vaginal estrogen treatment could consider switching their adjuvant therapy to tamoxifen given that the mode of action of tamoxifen is through estrogen receptor antagonism while aromatase inhibitors exert their effect by lowering total estrogen levels.. Vaginal dehydroepiandrosterone (DHEA) is converted intra- cellularly within the vaginal mucosa to estradiol and testosterone and is contraindicated for breast cancer survivors.1 Ospenalfene is an oral selective estrogen receptor modulator (SERM) which can act similarly to estrogen on the vaginal epithelium, and it is licensed for treatment of moderate- to- severe VVA in postmenopausal women who are not candidates for vaginal estrogen therapy.94 It is contraindicated in women undergoing active treatment for breast cancer, but it may be used once adjuvant therapy is complete although data are limited.. Testosterone. Sexual dysfunction is very common in women who have had treatment for a gynaecological cancer and is . Testosterone levels in women decline gradually with age, and there is no sudden change at menopause unless oophorectomy is performed. Sexual dysfunction is very common following treatment for gynaecological cancer. Testosterone levels do not correlate with symptoms. Testosterone supplementation should only be considered in women who complain of low sexual desire after a biopsychosocial approach has excluded other causes, such as relationship, psychological and medication related issues. Testosterone is only indicated for hypoactive sexual desire disorder (HSSD). There is a lack of scientific evidence supporting its use for 'brain fog', cognitive function and tiredness and it should not be prescribed for this indication.95. Testosterone should only be considered after a trial of standard HRT and should be prescribed in conjunction with HRT. Whilst some studies have shown benefit on its own this is not recommended. Testosterone is metabolised to estrogen, so it should not be used if estrogen is contraindicated.. The most common side effects are excess hair growth and acne which are reversible with reduction in dosage. Alopecia, deepening of voice and clitoral enlargement are rare with physiological testosterone replacement. Levels should be monitored to ensure systemic levels stay within the physiological range. There are no licensed testosterone products available, so all prescribing is off- label. More detail on prescribing and monitoring testosterone for menopausal women is available via the BMS tool for clinicians document on Testosterone Therapy in Menopause.96. When to start HRT and duration of usage?. When treatment for gynaecological cancer will result in surgical menopause and the tumour type is not hormone- sensitive, discussion regarding HRT should be made before surgery. If the woman wishes to start HRT and there are no contraindications, this should be commenced as soon as clinically appropriate (Grade D).. # When provision of HRT is complex and/or controversial, the decision to start HRT should wait until the histology is known, full staging has been achieved and a plan for any additional treatment has been made (Grade D). In the context of a potentially hormone- sensitive cancer, such as ER- positive endometrial cancer, the final pathology is required before considering HRT. There may also be an advantage to delaying further in peri- menopausal and older women, to evaluate the need for HRT to treat menopausal symptoms (Grade D). Women who are receiving chemotherapy or radiotherapy can be commenced on HRT during treatment, provided there are no contraindications (Grade D). Maintaining HRT compliance is necessary to minimise the detrimental consequences of premature ovarian insufficiency (Grade D). If HRT is prescribed, the medication should be used for as long as the benefits outweigh the risks for the individual woman (Grade A). HRT in younger women replaces ovarian hormones that would normally be produced at this age and should be continued at least until the age of natural menopause (Grade A). If vaginal estrogen therapy is appropriate, this therapy can be started once the vagina has healed from any surgical intervention and there is no time- limit on its use (Grade B).. The decision whether to take HRT, the dose of HRT and the duration of its use should be made on an individualised basis after discussing the benefits and risks with each patient. NICE guidance recommends that women who are likely to go through menopause as a result of medical or surgical treatment (including women with cancer, at a high risk of hormone- sensitive cancer or having gynaecological surgery) should be offered support and information about menopause and fertility before they have their treatment, and referral to a healthcare professional with expertise in menopause.2. When bilateral oophorectomy results in surgical menopause, symptoms start very soon after surgery and commencing HRT will prevent symptoms from the outset. In cases where the tumour type is not hormone- sensitive, the decision regarding HRT can be made before surgery. If the woman wishes to start HRT and there are no contraindications, this can be started before discharge from hospital and/or a recommendation to the GP should accompany the discharge summary.. When the decision about commencing HRT is complex and/or controversial the decision to start HRT should wait until the histology is known, full staging has been achieved and a plan for any additional treatment has been made.. Duration of treatment. If HRT is prescribed, the medication should be used for as long as the benefits outweigh the risks for the individual women taking into account the tumour prognosis, symptom relief, beneficial long- term effects versus the potential for increased risk of recurrence or a new primary including breast cancer. Arbitrary limits should not be placed on the duration of usage of HRT.. HRT in younger women is thought to simply replace ovarian hormones that would normally be produced at this age, and years of HRT exposure should be counted from age of natural menopause with respect to breast cancer risk. The average age at natural menopause is around 51 years in Caucasian women but may be a bit earlier in women from other ethnic backgrounds.7 The Collaborative Group on Hormonal Factors in Breast Cancer concluded that for women under the age of 40 there was no increased breast cancer risk. In a worldwide meta- analysis of worldwide epidemiological data, there was insufficient evidence in the 40- 45 year group with a reported increase in risk in observational studies, and a slight rise in the age 45- 50 year group, but these were not compared with the appropriate control group of age- matched premenopausal women.98. HRT in the form of estradiol and micronized progesterone or dydrogesterone used for 5 years or less in women aged 50 years old or older with no genetic predisposition to breast cancer appears to have a neutral effect on breast cancer risk.78,99. If vaginal estrogen therapy is appropriate, this can be started once the vagina has healed from any surgical intervention. There is no time- limit to use and no evidence of an increased risk of breast cancer with this treatment.. Non-hormonal options for management of menopausal symptoms. Non- hormonal treatment options should be discussed with women who choose not to use HRT, or for whom HRT is less desirable or is contraindicated. This should be revisited at intervals for women who were premenopausal at the time of treatment and in whom HRT would usually be recommended (Grade D). Women should be informed that several non- hormonal therapies are used to reduce the impact of menopausal symptoms yet none are as effective as estrogen- based therapies (Grade A). Cognitive behavioural therapy (CBT) should be considered to alleviate vasomotor symptoms, low mood, sleep difficulties or anxiety that arise as a result of the menopause (Grade B). Phyto- estrogens should be discouraged for women who had hormone- sensitive tumours if formal HRT is contraindicated (Grade D).. # - St John's Wort should be discouraged due to its drug interactions, especially with chemotherapy or PARP inhibitors (Grade D). Selective serotonin re-uptake inhibitors, such as paroxetine and citalopram, and serotonin noradrenaline re-uptake inhibitor/selective serotonin re-uptake inhibitors (SSRI-SNRI), such as venlafaxine, can be considered to reduce vasomotor symptoms (Grade A). For women on tamoxifen, venlafaxine, escitalopram and citalopram can be offered but paroxetine, sertraline and fluoxetine are contraindicated due to cytochrome P450 interactions (Grade D). Pregabalin and gabapentin are effective alternatives to manage vasomotor symptoms as well as improving sleep and musculoskeletal issues but can be very sedative (Grade A). Oxybutynin may improve generalised sweating and vasomotor symptoms, but caution should be exercised in the older population due to toxicity profile including cognitive impairment (Grade C). Neurokinin 3 receptor antagonists can be considered for treatment of moderate-to-severe vasomotor symptoms (Grade A). Women should be referred to a healthcare professional with expertise in menopause if non-HRT treatments do not improve their symptoms or they have ongoing troublesome side effects (Grade D).. Healthcare professionals within the oncology team should be encouraged to develop skills and knowledge in non- hormonal options to alleviate menopausal symptoms. This is required to help inform and guide women for whom HRT is contraindicated, or who choose not to use it, as to which options are most likely to be beneficial to them. Services for non- hormonal treatment options including cognitive behavioural therapy should be available, and women should be signposted to these.. Further information and guidance are available in:. \Rightarrow. Lifestyle modifications. Cognitive behavioural therapy (CBT). Cognitive behavioural therapy (CBT) can improve both vasomotor symptom . Exercise. Randomised clinical trials have reported that exercise- based interventions including yoga and Pilates had limited impact on vasomotor and psychological symptoms. Whilst some international guidelines recommend exercise as part of lifestyle modification at menopause and there are additional health benefits, the evidence does not support exercise as an effective treatment for vasomotor symptoms.102,104,105. Weight loss. Observational data indicate that higher body mass index and increasing body fat are associated with more frequent and/or severe vasomotor symptoms. These observations have led to recommendations that weight loss may reduce vasomotor symptoms. This should also be encouraged in overweight postmenopausal women to reduce other adverse health outcomes including diabetes, cardiovascular disease, renal impairment and osteoarthritis.104. Avoiding triggers. It is also often recommended that women avoid 'triggers' such as alcohol, spicy foods and hot foods or liquids. No clinical trials have studied the effect of presumed triggers, and the Melbourne Women's Midlife Health Project found no significant association between alcohol intake and vasomotor symptoms.102. Acupuncture. Although acupuncture is superior to no treatment or a wait- list control in randomised clinical trials, systematic reviews concluded that acupuncture was not significantly superior to sham acupuncture.102,106. Herbal options. Many women seek herbal options to manage menopausal symptoms hoping these will be associated with less side effects. However, evidence for efficacy is very limited and no specific preparation can be recommended. Careful counselling regarding indication, side- effect profile and drug interaction is recommended. Patients who choose to take a herbal treatment should be advised to look for the Traditional Herbal Remedy (THR) stamp validating strength and quality.100. Phyto- estrogens should be discouraged for women with hormone- sensitive tumours. In some studies, Black Cohosh has been shown to reduce hot flushes but can be associated with adverse effects such as constipation, arrhythmia, weight gain and abdominal cramps. Additionally, it should be avoided by women taking tamoxifen because it interferes with drug action.100. # Whilst St John's Wort may be of benefit to relief vasomotor symptoms, it should be discouraged due to its drug interactions, especially with chemotherapy and PARP inhibitors. There are also uncertainties about dose, variation in the nature and potency of preparations and interactions with other drugs including tamoxifen, anticoagulants and anticonvulsants. Ginseng does not appear to be effective for vasomotor symptoms and therefore should not be recommended.. Pharmacological alternatives to HRT. There are multiple prescribable non- hormonal therapies that have been tested in randomised placebo- controlled trials and shown benefits in alleviating vasomotor symptoms, although none are as effective as HRT. These can vary in side effect profiles and patient preference, and potential drug interactions should be considered.. Selective serotonin re- uptake inhibitors (SSRIs) are antidepressants that include paroxetine, fluoxetine and citalopram. Women should be counselled about the negative impact these drugs can have on sexual function. Paroxetine . Pregabalin and gabapentin are effective alternatives to manage vasomotor symptoms as well as improving sleep and musculoskeletal issues. They can improve hot flushes by up to about . Clonidine has a lucenced indication for control of hot flushes in the UK. It has been shown to be modestly more beneficial than placebo but less beneficial than SSRIs, SNRIs, pregabalin and gabapentin, and it can cause significant side effects. It must be withdrawn gradually and is not suitable for patients with hypotension at baseline.. Emerging options. Oxybutynin is an anticholinergic, antimuscarinic medication traditionally used for urinary urge . Neurokinin 3 receptor antagonists including fezolinetant and elinzanetant have shown benefit for improving vasomotor symptoms, quality of life and sleep quality. This non- hormonal approach directly targets the neural mechanism underlying vasomotor symptoms. Two randomised clinical trials with fezolinetant have shown significant benefit compared to placebo, and a systematic review concluded that it compared favourably to other non- hormonal options, and it is now licensed in the UK.. Who should manage menopause and HRT?. - All healthcare professionals (HCPs) looking after women with gynaecological malignancies should have an understanding of the menopause and know where to signpost women for advice, support and treatment whenever appropriate (Grade D).- Gynaecologists, oncologists and specialist nurses should initiate discussions about menopausal symptoms and management options including HRT in women who have treatment for gynaecological cancers, including chemotherapy or radiotherapy (Grade D).- Assessment of menopausal symptoms should be conducted at each follow-up review or, if agreed via shared care, with ongoing primary care team (Grade D).- Consider recording indications and/or contraindications for HRT within a treatment summary and recommendations for ongoing review or onward referral to specialist menopause services (Grade D).- All HCPs should have access to specialists with expertise in menopause management for advice, support, onward referral and leadership of multidisciplinary education (Grade D).- Although decisions about HRT are often straightforward and can be made in primary and secondary care, some patients have complex needs and access to specialist multi-disciplinary menopause clinics is necessary (Grade D).. # Healthcare professionals managing women with gynaecological cancer should demonstrate continuing professional development about management of menopause (Grade D).. All women should be able to access advice regarding transition through menopause and can be seen in any area of healthcare. All medical and nursing healthcare professionals dealing with women of menopausal age should be familiar with recognising symptoms and signposting for women. A holistic and individualised approach is required, with an emphasis on the importance of accurate, evidence- based patient education.. NICE guidance recommends review at 3 months after commencing treatment to assess efficacy and tolerability and then annually unless there are clinical indications for earlier review including ineffectiveness, side effects or adverse events. There should be clarity about responsibility for ongoing assessment and management if care transitions between secondary and primary care. A treatment summary should include recommendations regarding menopause care which includes any indications or contraindications for HRT or specialist review.. Healthcare professionals managing women with gynaecological cancer should demonstrate continuing professional development about management of menopause.. Further information is available in the following documents:. \Rightarrow. Levels of practice. The Royal College of Nurses has produced guidance on the levels of clinical practice that are required to manage women with menopausal symptoms.117. Level one: Every healthcare professional should have some understanding of the impact of menopause and know where to signpost women for support and advice.. Level two: Healthcare professionals with a special interest in menopause. National guidelines will be followed, and discussions will include symptoms, medication and non- prescribed therapies. Local pathways should be developed with routes to specialist- level menopause services for further advice or referral.. Level three: The menopause specialist will have additional knowledge and skills for assessing and treating women with complex needs. They are also responsible for provision of local education and engaging with multidisciplinary teams across specialities with development of local pathways and guidelines.. Indications for specialist menopause referral. Criteria for referral to (or seeking advice from) a specialist menopause service include the following:116. \diamond. Bone health and monitoring (whether on HRT or not). Baseline bone mineral density testing with a DEXA scan, or FRAX scoring with DEXA scanning depending on the risks, should be considered for premenopausal women with treatment- induced menopause or women commenced on aromatase inhibitors (Grade B). Baseline 25- OH vitamin D level measurement or blanket vitamin D supplementation of 1000 IU/day should be considered for women at a higher risk of bone loss (Grade B). Weight- bearing exercise, smoking cessation, reduced alcohol intake and adequate dietary calcium intake should be encouraged (Grade C). For women under 50, HRT is recommended for prevention of bone loss, if not contraindicated (Grade D).. Women with gynaecological cancer are at an increased risk of bone loss due to the combined effects of oophorectomy and adjuvant therapies.118- 121 Data on bone loss in women with gynaecological cancer is lacking compared to other cancer populations. Consequently, guidelines for osteoporosis screening in women with cancer are largely based on data generated from non- gynaecological cancer survivors.122. Estrogen deficiency is the major cause of accelerated bone loss. Studies showed that estrogen deprivation in women with breast cancer accelerates bone turnover leading to a decrease in bone mineral density (BMD) and a . It is important to consider bone health at diagnosis of gynaecological cancer and during ongoing care. NICE clinical. # guideline CG146 on assessing the risk of fragility fracture recommends measuring bone mineral density (BMD) with dual- energy X- ray absorptiometry (DEXA) before starting treatments that may have a rapid adverse effect on bone density.. Bone mineral density assessment. Dual- Energy X- ray Absorptiometry (DEXA) is the most reliable assessment for BMD, and the amount of ionising radiation used is very small. While DEXA is considered the 'gold standard' method of BMD measurement, it has limitations, including large size of the equipment, high cost and limited availability. Also when repeat measurements are indicated, intervals of several years are required based on the limitations of DEXA for measuring small changes in BMD.. There is no clear consensus on how often the DEXA scan should be repeated.. Women who are not on HRT and who are prescribed a drug that causes bone loss or whose baseline or subsequent BMD is near the threshold of treatment using FRAX should be offered BMD testing every 2 years, or more frequently if deemed medically necessary. Testing should generally not be conducted more than annually.. Lifestyle modification. There are a number of modifiable risk factors associated with fracture risk that are of potential relevance to women with premature menopause. Cigarette smoking negatively affects bone quality and increases fracture risk.. Data for exercise in survivors of cancer are conflicting as to the preservation of BMD.. Vitamin D and calcium. Vitamin D levels are typically low in patients with cancer. Measurement of plasma 25(OH)D is the best way of estimating vitamin D status, and a baseline level should be considered when starting any cancer therapy that is associated with bone loss including pelvic radiotherapy, premature ovarian insufficiency below 40 years old or when the first DEXA scan shows osteopenia or osteoporosis.. Adequate calcium intake in the presence of adequate vitamin D status has been shown to reduce bone loss in periand postmenopausal women and reduce fractures in postmenopausal women older than age 60 with low calcium intakes.138- 140 Patients should be encouraged to consume a diet with adequate calcium and vitamin D. If intake of calcium (1,000 to . Key messages. Key messages for commissioners. Women with complex menopausal symptoms or decision- making regarding HRT require ready access to specialist menopause services. All healthcare professionals should have access to specialists with expertise in menopause management for advice, support, onward referral and leadership of multidisciplinary education. Although decisions about HRT are often straightforward and can be made in primary and secondary care, some patients have complex needs and access to specialist MDT menopause clinics is necessary.. Key messages for primary care. A gynaecological malignancy is not an automatic contraindication to HRT.. # Women with treatment- induced premature ovarian insufficiency are at an increased risk of osteoporosis and reduced overall survival from other causes; HRT should therefore be considered. Women with a uterus following treatment (e.g. chemoradiotherapy for cervical cancer) will need a continuous combined HRT preparation to reduce the risk of abnormal bleeding and later development of endometrial cancer. Vaginal estrogen is safe for the majority of women after treatment for a gynaecological malignancy. Women should be asked about menopausal symptoms at their follow- up appointments.. Key messages for secondary and tertiary care. Key messages for secondary and tertiary care- All healthcare professionals looking after women with gynaecological cancers should have an awareness of menopause management and the options for HRT, especially in women with premature ovarian insufficiency.- Treatment- induced menopause should be discussed with pre- and peri- menopausal women prior to treatment and options for HRT considered, if recommended or required.- Women should be asked about menopausal symptoms at hospital follow- up appointments. Health services should have access to specialist menopausal clinics for help with management of complex patients.. Key messages for patients. Key messages for patients- A gynaecological malignancy is not an automatic contraindication to HRT, and there are potential benefits for many women.- Premenopausal women should ask about treatment- induced menopause when oncological treatment options are being considered, and about the options for HRT or alternatives after treatment.. Suggested priority topics for research. Suggested priority topics for research- Safety of HRT following endometrial cancer treatment. Is there a survival advantage to continuous combined HRT versus estrogen only and what is the optimal timing to start treatment?- Safety and efficacy of HRT following ovarian cancer treatment.- Inclusion of HRT usage in databases of patients treated for rare tumours.. Further Resources. British Menopause Society National Institute of Care and Excellence NICE.org.uk. Daisy Network . Rock my menopause Menopause Matters Women's Health Concern healthconcern.org. Primary Care Women's Health Forum Menopause education for nurses Faculty of Sexual and Reproductive Healthcare . Acknowledgements. AcknowledgementsThe development and review of these guidelines were supported by the BGCS and BMS councils. Table 2 was developed with Gabriella Yongue.. Declaration of Conflicting Interests. Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RM: Grants from GSK, NHS England, Yorkshire Cancer Research, Barts Charity, Rosetrees Trust outside the submitted work, and honoraria for advisory board membership from AstraZeneca/MSD/GSK/EGL. RM was clinical lead/ topic advisor for NICE Guideline NG241 Ovarian cancer: identifying and managing familial and genetic risk. SG- M: membership of NICE HRT guidelines committee. TH: Consultancy and lecture fees from Astellas. JS: Funding for conference attendance, speaking and advisory board funding from Bayer, Astellas, Gedeon Richter and Theramex.. Funding. FundingThe author(s) received no financial support for the research, authorship, and/or publication of this article.. Contributorship. ContributorshipAll authors contributed to the preparation, discussion and review of the recommendations and supporting text.. ORCID iDs. ORCID iDsAlexandra Taylor 0001- 8100- 5388 Jo Morrison 0003- 0000- 520X. References. References1. Hamoda H, Panay N, Pedder H, et al. The British Menopause Society & Women's Health Concern 2020 recommendations on hormone replacement therapy in menopausal women. Post Reprod Health 2020; 26(4): 181- 209. DOI: 10.1177/2053369120957514.2. Nice Guideline [NG23]. Menopause:diagnosis and management 2019. Available from: Maringe C, Walters S, Fau - Butler J, et al. Stage at diagnosis and ovarian cancer survival: evidence from the International Cancer Benchmarking Partnership. 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ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod 2016; 31(5): 926- 937. DOI: 10.1093/humrep/dew027.128. Gregson C, Armstrong D, Bowden J, et al. UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporosis 2022; 17: 58. DOI: 10.1007/s11657- 022- 01061- 5.129. Kanis JA, McCloskey EV, Johansson H, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2013; 24(1): 23- 57. DOI: 10.1007/s00198- 012- 2074- y.130. Hamoda H. The British Menopause Society and Women's Health Concern recommendations on the management of women with premature ovarian insufficiency. Post Reprod Health 2017; 23(1): 22- 35. DOI: 10.1177/2053369117690058.131. Chaplin S. SIGN on managing osteoporosis and fragility fracture prevention. Prescriber 2021; 32: 29- 32. DOI: 10.1002/psb.1896.132. Bijelic R, Milicevic S and Balaban J. Risk factors for osteoporosis in postmenopausal women. Med Arch 2017; 71: 25. DOI: 10.5455/medarh.2017.71.25- 28.133. Pompe E, Bartstra J, Verhaar HJ, et al. Bone density loss on computed tomography at 3- year follow- up in current compared to former male smokers. Eur J Radiol 2017; 89: 177- 181. DOI: 10.1016/j.ejrad.2017.02.011.134. Mostofsky E, Mukamal KJ, Giovannucci EL, et al. Key findings on alcohol consumption and a variety of health outcomes from the nurses' health study. Am J Publ Health 2016; 106(9): 1586- 1591. DOI: 10.2105/ajph.2016.303336.135. Via J, Daly R and Fraser S. The effect of exercise on bone mineral density in adult cancer survivors: a systematic review and meta- analysis. Osteoporos Int 2017; 29: 287- 303. DOI: 10.1007/s00198- 017- 4237- 3.136. Fornusek CP and Kilbreath SL. Exercise for improving bone health in women treated for stages I- III breast cancer: a systematic review and meta- analyses. Journal of Cancer Survivorship 2017; 11(5): 525- 541. DOI: 10.1007/s11764- 017- 0622- 3.137. Francis R, Aspray T, Bowring C, et al. National Osteoporosis Society practical clinical guideline on vitamin D and bone health. Maturitas 2014; 80: 119- 121. DOI: 10.1016/j.maturitas.2014.11.018.138. The role of calcium in peri- and postmenopausal women: 2006 position statement of the North American Menopause Society. Menopause 2006; 13(6): 862- 877. doi: 10.1097/01.gme.0000243566.25205.0b.. # 139. Bolland MJ, Leung W, Tai V, et al. Calcium intake and risk of fracture: systematic review. BMJ 2015; 351: h4580. DOI: 10.1136/bmj.h4580.. 140. Tai V, Leung W, Grey A, et al. Calcium intake and bone mineral density: systematic review and meta-analysis. BMJ 2015; 351: h4183. DOI: 10.1136/bmj.h4183.. Appendix. Appendix I. Risk groups for endometrial cancer as defined in the ESGO- ESTRO- ESP 2021 guidelines based on FIGO 2009 staging.34.	None	None	None
1e4bc7b7bb754fc59eb222c768af2f04	2024+ESGAR／ESUR／PSOGI／EANM联合建议	卵巢癌和结直肠癌腹膜转移的影像学检查	# Imaging of peritoneal metastases of ovarian and colorectal cancer: joint recommendations of ESGAR, ESUR, PSOGI, and EANM. Vincent Vandecaveye<sup>1,2</sup>, Pascal Rousset<sup>3</sup>, Stephanie Nougaret<sup>4,5</sup>, Artem Stepanyan<sup>6</sup>, Milagros Otero- Garcia<sup>7</sup>, Olivera Nikolic<sup>8</sup>, Maira Hameed<sup>9,10</sup>, Karolien Goffin<sup>11,12</sup>, Ignace H. J. de Hingh<sup>13,14</sup>, Max J. Lahaye<sup>15,16*</sup>, for the European Society of Gastrointestinal and Abdominal Radiology (ESGAR) European Society of Urogenital Radiology (ESUR) Peritoneal Surface Oncology Group International (PSOGI) and European Association of Nuclear Medicine (EANM). Abstract. Objectives Diagnostic imaging of peritoneal metastases in ovarian and colorectal cancer remains pivotal in selecting the most appropriate treatment and balancing clinical benefit with treatment- related morbidity and mortality. To address the challenges related to diagnostic imaging and detecting and reporting peritoneal metastatic spread, a joint guideline was created by the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), European Society of Urogenital Radiology (ESUR), Peritoneal Surface Oncology Group International (PSOGI), and European Association of Nuclear Medicine (EANM).. Methods A targeted literature search was performed and consensus recommendations were proposed using Delphi questionnaires and a five- point Likert scale.. Results A total of three Delphi rounds were performed. Consensus was reached on the position of diagnostic imaging for assessment of operability, treatment response monitoring, and follow- up of peritoneal metastases, optimal imaging modality and their technical imaging requirements depending on the indication and how to optimise communication of imaging results by the report and multidisciplinary board discussion. The complete list of recommendations is provided.. Conclusion These expert consensus statements aim to guide appropriate indications, acquisition, interpretation, and reporting of imaging for operability assessment, treatment response monitoring, and follow- up of peritoneal metastases in ovarian and colorectal cancer patients.. Key Points. Question Staging peritoneal metastases (PM) helps to guide clinical decision- making for colorectal and ovarian cancer patients. How can we optimise the use of imaging techniques to assess PM?. # Findings Imaging plays a crucial role in the detection, operability assessment, treatment response monitoring, and follow- up of peritoneal metastases in colorectal and ovarian cancer patients. Clinical relevance These expert consensus statements aim to guide appropriate indication, acquisition, interpretation, and reporting of imaging for operability assessment, treatment response monitoring, and follow- up of peritoneal metastases in ovarian and colorectal cancer patients.. Keywords MRI, CT, Peritoneal metastases, Colorectal cancer, Ovarian cancer. Main recommendations. - Radiological imaging plays a crucial role in the detection, operability assessment, treatment response monitoring, and follow-up of peritoneal metastases in colorectal and ovarian cancer patients. . - An abdominal CT for peritoneal metastases consists of . # - Preferably, all colorectal and ovarian cancer patients with peritoneal metastases should be discussed in a multidisciplinary tumour board, including a radiologist with experience in imaging of peritoneal metastases. . Introduction. Peritoneal metastases (PM) are common in ovarian and colorectal cancer patients. In colorectal cancer, PM occur in . Unfortunately, imaging of PM poses many challenges for radiologists and nuclear medicine physicians. Depiction of the total spread of PM and surgically critical lesions can be difficult due to the small size of the metastases or obscurement of metastases by ascites, nearby organs, or other structures.. This means that the total extent of PM can be easily underestimated, particularly in mesenteric and serosal bowel disease, requiring additional surgical staging procedures to assess operability [10]. This is an invasive procedure with a small risk of complications. In addition, diagnostic laparoscopies are often challenging and incomplete due to adhesions and confluent tumours obscuring the view of the peritoneal surface [11].. Additionally, communication of imaging findings regarding total disease extent and involvement of critical surgical sites require optimisation to effectively guide clinical and therapeutic decision- making.. Therefore, there is a clinical need to address these challenges of imaging PM. As this issue affects multiple clinical disciplines, representatives from several . Source and scope. These guidelines are recommendations developed by the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), European Society of Urogenital Radiology (ESUR), Peritoneal Surface Oncology Group International (PSOGI), and European Association of Nuclear Medicine (EANM). A targeted literature search was performed to discover recent evidence concerning the imaging of peritoneal metastases in ovarian and colorectal cancer patients. The guidelines were formulated after careful consideration of the available literature by a group of international experts. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was adopted to define the strength of recommendations and the quality of evidence.. Methods. The ESGAR Research Committee appointed a chair (M.J.L.) to supervise guideline development; next to the chair, there were seven committee members. The chair selected three other ESGAR members based on their experience and authorships of prior relevant peer- reviewed indexed publications (V.V., P.R., S.N.). The European Society of Urogenital Radiology delivered two committee members (M.O.- G., O.N.). A representative of the following societies was also added to the guideline committee: Peritoneal Surface Oncology Group International (IdH) and the European Association of Nuclear Medicine (K.G.). The guideline committee complied with the ESGAR recommendations for guideline development principles and of the AGREE II instrument if applicable [12, 13].. A literature search was performed and included all relevant articles published until September 2021. A summary of the search strategy can be found in Appendix A. Two committee members (M.J.L. and V.V.), by consensus, composed a list of relevant articles based on the evaluation of all abstracts. This list was given to the guideline committee for approval. All members could add any additional suitable articles to be used as evidence. In addition, during the development of the guidelines, all relevant articles published until January 2023 could also be used as evidence.. Most literature was found for detecting peritoneal metastases with computed tomography (CT). Recently,. # more and more literature has been published concerning staging peritoneal metastases in colorectal and ovarian cancer using magnetic resonance imaging (MRI).. The chair devised draft Delphi questionnaires, which were further improved and approved by the guideline committee. The questions in the final approved questionnaire were used to formulate the consensus recommendations. All committee members scored their agreement with the recommendations using a five- point scale . The coordinating chairs sent the draft manuscript to all guideline committee members for improvements and approval. All participating societies reviewed the final manuscript for approval prior to submission for publication.. Recommendations and statements. The recommendations are described below, and each point will be discussed separately.. Grades of evidence and agreement level of the group (in percentage) are included in brackets after each statement. Overall, the evidence is of moderate quality at best. This is mainly because the evidence is based primarily on singlecentre prospective and retrospective studies and a lack of studies comparing different imaging techniques in the same patient cohort.. 1. Radiological imaging plays a crucial role in the detection, operability assessment, treatment response monitoring, and follow-up of peritoneal metastases in colorectal and ovarian cancer patients . Imaging aims to correctly identify the primary tumour or recurrence(s), malignant lymph nodes, PM, and other distant metastases. In addition, imaging can detect potential complications related to disease spread, such as hydronephrosis or small bowel obstruction [14]. In both ovarian and colorectal cancer, detecting PM and assessing total disease extent is essential to stage the patients and correctly select the optimal treatment strategy. In addition to surgical staging, imaging can detect disease spread in abdominal sites that are difficult to access by diagnostic laparoscopy, including the retro- hepatic area, the retroperitoneal spaces and the porta hepatis as well as distant metastatic disease sites [11]. Thus, imaging contributes to developing an individualised treatment strategy for patients suspected of PM. Despite the variable performance of different imaging modalities in assessing . 2. Although CT tends to underestimate the extent of peritoneal metastases, CT can be used for the initial assessment at the time of diagnosis, treatment response monitoring, and suspicion of recurrence of PM in colorectal and ovarian cancer patients due to its widespread availability. . Although CT tends to underestimate the extent of disease in the abdomen, it provides a general overview of the disease and its potential complications in the abdomen. In a meta- analysis, CT had a pooled sensitivity of . 3. CT is the most accessible technique in daily clinical routine and can help to identify patients with extraperitoneal or widespread peritoneal disease that could exclude upfront surgery. Due to the low accuracy for detecting small or isodense PM, CT plays a minimal role in selecting patients in which complete cytoreductive surgery is feasible. . As mentioned above, CT will likely underestimate the extent of peritoneal metastases in colon and ovarian cancer.. For colorectal cancer, a meta- analysis showed that CT consistently underestimates the surgical PCI by . # attributable to difficulties in depicting small- sized metastases, particularly over the intestinal serosa and mesentery, but also due to the inability to accurately detect suprarenal or supradiaphragmatic lymphadenopathies or metastases to the liver hilum, coeliac trunk or pancreas.. While the inability to reliably assess occult disease at critical surgical sites and PCI limits its role in selecting patients for cytoreductive surgery, its widespread availability and robustness allow CT to be used for rapid initial assessment of colorectal or ovarian cancer patients. CT can depict potential disease features that would immediately affect treatment, including gross distant or (extra) peritoneal disease that would prohibit upfront surgery.. 4. STIR-DWI-MRI is currently the most accurate imaging modality to assess the extent of PM. It can play a role in selecting colorectal and ovarian cancer patients for cytoreductive surgery at primary diagnosis, after neoadjuvant chemotherapy or tumour recurrence. . In several studies, including two meta- analyses, DWIMRI was demonstrated to be highly sensitive and specific . Similarly, DWI- MRI shows higher accuracy for depicting potentially surgically critical upper abdominal disease involvement behind the portal vein, beyond the left and right main portal branches, involvement of the duodenum, stomach, pancreas and coeliac trunk, mesenteric root, and the main branch of the superior mesenteric artery. Additionally, DWI- MRI- based PCI has been shown to have the strongest correlation with surgical PCI [24]. The high accuracy of DWI- MRI for predicting disease at surgically critical disease sites and accurate prediction of surgical PCI has been shown in the primary diagnosis of PM in ovarian and colorectal cancer, recurrent PM in ovarian cancer and after neoadjuvant chemotherapy in colorectal cancer (see Fig. 1). This means that DWI- MRI can help in initial treatment planning by assessing. # disease load in anatomical locations that correlate with suboptimal cytoreduction or require specific surgical considerations to avoid perioperative morbidity or functional complications in case of potential extensive bowel resection.. 5. FDG PET/CT is not accurate enough for preoperative staging, missing small lesions, as CT, and hypometabolic (e.g., mucinous) metastases. Still, FDG PET/CT can help detect other extraperitoneal metastases missed on prior imaging. Strong recommendation. low-moderate quality evidence. . FDG- PET/CT shows a high specificity of . 6. Whole-body MRI and FDG-PET/CT can be a problem-solver in colorectal and ovarian cancer patients suspected of PM/recurrence. Both modalities can help detect other extraperitoneal metastases missed on prior imaging. . Both PET/CT and WB- DWI/MRI have the advantage of high contrast resolution and have the ability to detect tumours, respectively, based on metabolic and microstructural properties without the need for underlying anatomical distortions facilitating the detection of subcentimeter mediastinal or cervical lymph nodes, pleural metastases and small liver metastases that do not cause parenchymal distortion or are hampered in their detection by underlying steatosis [29]. In ovarian cancer, liver and lung metastases are extremely rare at primary diagnosis, and distant metastatic disease mainly consists of supradiaphragmatic lymphadenopathy and pleural metastases, for both of which FDG- PET/CT and WB- DWI/MRI have been shown to outperform CT for their detection. In colorectal cancer patients with peritoneal metastases and candidates for HIPEC surgery, abdominal MRI with DWI had added value over CT in detecting abdominopelvic extraperitoneal metastases relevant to the treatment planning [24].. 7. An abdominal CT for PM consists of . There is no relevant literature comparing different CT protocols for detecting PM. Therefore, the standard abdominal CT in the portal venous phase is recommended (Table 1). To be able to detect small- volume disease, . 8. An abdominal or whole-body 1.5- or 3-T MRI for PM consists of axial T2 (slice thickness . DWI detects tumours by combining heavy diffusion weighting and background signal suppression of organs and ascites. Applying a sufficiently high b- value (e.g., b1000) allows perceiving small water molecule movements, thereby maximising the information provided by the molecule movements in the extravascular extracellular space and optimising the detection of restricted diffusion in tumours as opposed to benign or background tissue. The DWI sequence can be further optimised for large- volume body imaging and lesion detection by using a short T1 inversion recovery (STIR) instead of the standard spectral. # attenuated inversion recovery (SPAIR) prepulse. The suppressive effect of the STIR prepulse on the bowel wall, having a short T1 value, facilitates the detection of serosal metastases. At the same time, it is more robust to inhomogeneity- induced fat suppression and susceptibility artefacts [30]. T2 and post- contrast T1 weighted sequences primarily act to locate lesions detected by DwI anatomically, correlate physiologically impeded diffusion attributable to T2 shine- through or anatomical structures, and facilitate the detection of lesions below the spatial resolution limit of DwI . Combining a negative peroral contrast and an intravenous antispasmodic can improve the detection of small serosal deposits by reducing physiological bowel wall hyperintensity and susceptibility artefacts caused by intraluminal air, which may obscure or be mistaken for serosal deposits [32]. Therefore, it is recommended that patients drink . 9. FDG PET/CT for PM should be performed according to the 'EANM procedure guidelines for tumour imaging: version 2'. The combination with a CT of diagnostic quality, as described in statement 7, is highly recommended. . The guideline committee refers to 'EANM procedure guidelines for tumour imaging: version . 10. There are no differences in FDG PET/CT, CT, or MR imaging protocols of the abdomen for PM between colorectal and ovarian cancer. . Current literature and expert opinion do not advocate different imaging protocols.. 11. The imaging report of colorectal cancer patients should include the extent of PM using the Peritoneal. # Cancer Index (PCI) combined with a qualitative description of the involvement of surgically critical sites and involved abdominal organs. Tools like PROMISE and PAUSE can be used to optimise and standardise the imaging report. . A descriptive report remains the mainstay in reporting peritoneal metastases. However, a more standardised scoring system is advised for the location and extent of the PM. Especially MRI can accurately predict PCI in colorectal and ovarian cancer patients. In colorectal cancer, the PCI is widely validated and used by clinicians. Therefore, it is logical to adopt this scoring system in the radiological report. However, some multidisciplinary teams might prefer to use PROMISE or PAUSE [34, 35]. The PeRitOneal Mallgancy Stage Evaluation (PROMISE) is an internet application which automatically calculates PCI and other surgically validated scores such as Gilly score, SPCI, Fagotti, and Fagotti- modified scores. The acronym PAUSE is used to emphasise the key imaging features that a radiology report should include like; P, primary tumour and peritoneal carcinomatosis index (PCI) as estimated by imaging; A, ascites and abdominal wall involvement; U, unfavourable sites of involvement; S, small bowel and mesenteric disease; E, extraperitoneal metastases. Radiologists should be in close contact with their clinicians to optimise their reports to local preferences. Structured reporting can be of added value for both radiological and clinicians and should be contemplated if technically feasible.. 12. The imaging report of ovarian cancer patients must include the extent of PM using one quantitative scoring method of local preference in combination with a qualitative description of the involvement of surgically critical sites and involved abdominal organs. Tools like PROMISE and PAUSE can be used to optimise and standardise the imaging report. . Similar to reporting in colorectal cancer, a descriptive report concerning the location and extent of the PM, a more standardised scoring system is recommended. Although MRI can accurately predict the PCI and involvement of surgically critical sites in ovarian cancer patients, it is not yet widely used in ovarian cancer. Therefore, local preferences should dictate which standardised scoring system is to be used by the multidisciplinary team, including the radiologists. Radiologists should be actively involved in the MDT, and their reports should be tailored to local preferences.. Structured reporting can be of added value for both radiological and clinicians and should be contemplated if technically feasible.. 13. Preferably, all colorectal and ovarian cancer patients with PM should be discussed in a multidisciplinary tumour board, including a radiologist with experience in imaging of peritoneal metastases. . Multidisciplinary tumour boards (MDTs) are the cornerstone in the treatment of oncological patients [36, 37].. # MDTs have been shown to improve patient outcomes [38]. Close collaboration of all involved professions and disciplines improves cancer care. The radiologist plays an important role in the MDT and should stage the disease correctly and demonstrate to the clinicians the location and extent of the disease to optimise surgical planning. Potential complex surgical sites like the liver hilum, diaphragm, mesentery, and pelvis should be demonstrated during the MDT. This means that a dedicated radiologist must be present at the MDT to be able to address and demonstrate all important imaging findings.. Limitations. A lack of randomised data concerning the imaging of PM hampers making evidence- based guidelines. However, systematic reviews and large observational studies were used to formulate the recommendations. The guideline committee encourages further research involving both the development and clinical integration of existing and novel imaging techniques. Another limitation is that the preferences of the patients are not addressed in the current guidelines.. Implementation and adherence to guidelines. In the daily clinic, CT can be used for initial screening when the clinical diagnosis of peritoneal metastases is unclear or when an extensive disease load not amenable to surgery is suspected. If upfront operability assessment is required, or when there are equivocal CT findings, DwMRI is the preferred method for peritoneal staging and simultaneously allows for the detection of extraperitoneal disease. FDG- PET/CT can be used to detect lymphadenopathy and extraperitoneal metastases.. The committee aimed to make the guidelines applicable to hospitals throughout Europe. However, the committee is aware that not all hospitals have implemented MRI in the daily diagnostic workup of ovarian and colorectal cancer patients with PM. This entails that large implementation studies must be performed to implement MRI in the diagnostic workup to improve adherence to this guideline further. By doing so, all patients with advanced colorectal and ovarian cancer can receive the most optimal diagnostic workup to guide their tailored treatment.. Updating the guideline. These guidelines should be updated in or before 2028 if new evidence of good quality warrants a significant modification to these recommendations.. Abbreviations. CT Computed tomography DWI Diffusion- weighted imaging EANM European Association of Nuclear Medicine. ESGAR European Society of Gastrointestinal and Abdominal Radiology ESUR European Society of Urogenital Radiology Evaluation FDG Fluorine- 18- deoxyglucose GRADE Grading of Recommendations Assessment, Development and Evaluation HIPEC Hyperthermic intraperitoneal chemotherapy MDT Multidisciplinary tumour boards MAI Magnetic resonance imaging PAUSE P, primary tumour and peritoneal carcinomatosis index (PCI) as estimated by imaging; A, ascites and abdominal wall involvement; U, unfavourable sites of involvement; S, small bowel and mesenteric disease; E, extraperitoneal metastases PCI Peritoneal Cancer Index PET/CT Positron emission tomography/computed tomography PM Peritoneal metastases PROMISE Peritoneal malignancy stage evaluation PSOGI Peritoneal Surface Oncology Group International SPAIR Spectral attenuated inversion recovery STIR Short T1 inversion recovery WB Whole body. Supplementary information. The online version contains supplementary material available at org/10.1007/s00330- 024- 11124- 5.. Acknowledgements. The guidelines were brought to the attention of the relevant Committees of the participating societies. The comments and suggestions from all participating societies are highly appreciated and have been considered for this Guideline. This guideline summarises the views of the participating societies and reflects recommendations for which the societies cannot be held responsible. The recommendations should be considered in the context of good medical practice and do not substitute for national and international legal or regulatory provisions.. Funding. The authors state that this work has not received any funding.. Compliance with ethical standards. Guarantor. The scientific guarantor of this publication is M.J.L.. Conflict of interest. V.V. is a member of the Scientific Editorial Board (section: Oncology) for European Radiology. The remaining authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.. Statistics and biometry. No complex statistical methods were necessary for this paper.. Informed consent. Written informed consent was not required for these recommendations.. Ethical approval. Institutional Review Board approval was not required for these recommendations.. Study subjects or cohorts overlap Not applicable.. Methodology. A joint guideline was created by the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), European Society of Urogenital Radiology (ESUR), Peritoneal Surface Oncology Group International (PSOGI) and European Association of Nuclear Medicine (EANM). # Author details. Author details1Department of Radiology, University Hospitals Leuven, Leuven, Belgium. 2Division of Translational MRI, Department of Imaging and Pathology, KU Leuven, 3000 Leuven, Belgium. 3Department of Radiology, Hospices Civils de Lyon, Lyon Sud University Hospital, Lyon 1 Claude Bernard University, 69495 Pierre Benite, France. 4Department of Radiology, Montpellier Cancer Institute, Montpellier, France. 5PINKCC Lab, U1194, IRCM, Montpellier, France. 6Gynecologic Oncology Service, NMRl Medical Center, 0015 Yerevan, Armenia. 7Department of Radiology, University Hospital Vigo (Hospital Alvaro Cunqueiro), Instituto de Investigacion Sanitaria Galicia Sur (llSGS), 36213 Vigo, Spain. 8University of Novi Sad, Faculty of Medicine, Center for Radiology, University Clinical Center of Ojivodina, 21000 Novi Sad, Serbia. 9University College London Hospitals NHS Foundation Trust, London, UK. 10University College London Centre for Medical Imaging, Charles Bell House, W1W 7TS London, UK. 11Nuclear Medicine, University Hospital Leuven, Leuven, Belgium. 12Nuclear Medicine & Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium. 13Catharina Cancer Institute, Eindhoven, the Netherlands. 14Department of Epidemiology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center . 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Michielsen K, Vergote I, Cip de Beeck K et al (2014) Whole- body MRI with diffusion- weighted sequence for staging of patients with suspected ovarian cancer: a clinical feasibility study in comparison to CT and FDG- PET/CT. Eur Radiol 24:889- 901 33. Boellaard R, Delgado- Bolton R, Oyen WJG et al (2015) FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging 42:328- 354. 014- 2961- x 34. Chandramohan A, Thrower A, Smith SA et al (2017) "PAUSE": a method for communicating radiological extent of peritoneal malignancy. Clin Radiol 72:972- 980 35. Villeneuve L, Thivolet A, Bakrin N et al (2016) A new internet tool to report peritoneal malignancy extent. Peritoneal malignancy stage evaluation (PROMISE) application. Eur J Surg Oncol 42:877- 882. . 36. European Partnership Action Against Cancer consensus group, Borras JM, Albreht T et al (2014) Policy statement on multidisciplinary cancer care. Eur J Cancer 50:475-480. 37. 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b135c2442c534843becb13a7ed6d3d91	2024+ESGE实践建议	肌瘤切除的外科技术—第1部分	# European Society for Gynaecological Endoscopy (ESGE) Good Practice Recommendations on surgical techniques for removal of fibroids: part 1 abdominal (laparoscopic and open) myomectomy. E. SARIDOGAN<sup>1</sup>, L. ANTOUN<sup>2</sup>, E.V.A. BOUWSMA<sup>3</sup>, T.J. CLARK<sup>2</sup>, A. DI SPEZIO SARDO<sup>4</sup>, J. HUIRNE<sup>5</sup>, T.S. WALKER<sup>6</sup>, V. TANOS<sup>7</sup>. ON BEHALF OF THE EUROPEAN SOCIETY FOR GYNAECOLOGICAL ENDOSCOPY UTERINE FIBROIDS WORKING GROUP. Elizabeth Garrett Anderson Institute for Women's Health, University College London and University College London Hospital, United Kingdom; Birmingham Women's & Children's Hospital, University of Birmingham, United Kingdom; Department of Obstetrics & Gynecology, St. Antonius Hospital, The Netherlands; Obstetrics and Gynaecology Department, Universita degli Studi di Napoli Federico II Italy; Department of Obstetrics & Gynaecology, Amsterdam University Medical Center and Amsterdam Reproduction and Development Research Institute, The Netherlands; Gynaecology Department, Royal Cornwall Hospital, United Kingdom; Department of Basic and Clinical Science, University of Nicosia Medical School and Aretaeio Hospital, Cyprus.. Correspondence at: Prof. Ertan Saridogan, PhD, FRCOG, Women's Health Division, University College London Hospital, London NW1 2PG. E- mail: ertan.saridogan@nhs.net. Abstract. Uterine fibroids are the most common benign tumours of the female reproductive tract and can cause a range of symptoms including abnormal uterine bleeding, pain, pressure symptoms and subfertility. Surgery may be required for some symptomatic fibroids via abdominal or transvaginal routes. The European Society for Gynaecological Endoscopy Uterine Fibroids Working Group developed recommendations based on the best available evidence and expert opinion for the surgical treatment of uterine fibroids. In this first part of the recommendations, abdominal approaches to surgical treatment of fibroids including laparoscopic, robot- assisted and open myomectomy are described.. Introduction. Uterine fibroids (also known as myomas or leiomyomas) are the most common benign tumours of the female reproductive tract and can be found by ultrasound in about . Fibroid classification. There are two widely used classification systems for fibroids, one developed by the European Society for Gynaecological Endoscopy (ESGE) and the other adopted by the International Federation of Gynaecology and Obstetrics (FIGO) (Munro et al., 2011; Wamsteker et al., 1993). The FIGO classification is relevant to abdominal. # myomectomy because it adopted and expanded the initial ESGE classification that was restricted to submucosal fibroids. Both FIGO and ESGE classifications of uterine fibroids are shown in (Table I).. The "STEPW" or "Lasmar" hysteroscopic myoma classification was developed in 2005 (Lasmar et al., 2012). This classification not only evaluates the proportion of myometrial involvement as described in the original ESGE submucosal fibroid classification (Wamsteker et al., 1993), but also describes three additional parameters: the size, location in the cavity (topography) and extension of the base. This more detailed classification of submucosal fibroids may further help assess the feasibility of hysteroscopic myomectomy, informing clinical decision- making, patient counselling and surgical preparation (See Part 2 ESGE Good Practice Recommendations on Surgical Techniques for Removal of Fibroids: Part 2 Hysteroscopic Myomectomy, in press).. Clinical assessment. Many fibroids are asymptomatic, but up to . Material and methods. Electronic bibliographic databases (Medline / Embase) and the Cochrane Central Register of Controlled Trials from inception up to January 2024, were searched for randomised controlled trials, observational studies and expert opinions which addressed the surgical treatment of fibroids either in isolation or in comparison to medical and other non- surgical treatments. In addition, the National Institute for Health Research and Clinical Excellence (NICE) guidelines, the American Association of Gynecologic Laparoscopists (AAGL) practice reports, the European Society for Gynaecological Endoscopy (ESGE) guidelines and the British Society of Gynaecological Endoscopy (BSGE) statements that included any reference to the management of fibroids were reviewed.. The suitability and safety of surgery will vary according to patient factors, including patient preferences and the outcomes they desire as well as the characteristics of the fibroid(s) themselves. Management should thus be individualised. Moreover, the feasibility and efficacy of the surgical techniques described here may vary according to several factors that include background factors such as the woman's age and comorbidities, her symptoms (e.g. pain, pressure symptoms, infertility), the primary aim of the treatment (e.g. eliminating/improving bulk symptoms, treating abnormal uterine bleeding, reducing pain or enhancing fertility), the. # # fibroid characteristics (localisation, appearance, number, size(s)), tubal status and history of previous surgery (i.e. recurrence). These factors will need to be taken into consideration when making a decision for surgery and selecting the most appropriate surgical technique.. Defining abdominal myomectomy. Abdominal myomectomy includes both laparoscopic (including robot assisted) and open myomectomy. The first open myomectomy was reported in the 19th century and it remained the main option for fibroid removal until 1970s when the first cases of hysteroscopic and laparoscopic myomectomy were described (Semm, 1979). Hysteroscopic approaches, indicated for submucosal fibroids and fibroids abutting the endometrium (FIGO type 0- 3 fibroids (Munro et al., 2011)) will be covered in "Part 2: Hysteroscopic Myomectomy". An abdominal approach is indicated for some large . Pre-operative planning and preparation. Fibroid mapping is essential to plan the perioperative surgical approach and to determine the required pre- operative work- up (Munro et al., 2011). Pre- operative work- up includes the assessment of the number, size and localisation of the fibroids, their relation to the uterine cavity and tubes and their vascularisation (Munro et al., 2011). This is useful in predicting difficulties during surgery such as fibroids with protrusion towards the broad ligament and close relation to the uterine arteries or ureters, and development of postoperative intra- uterine adhesions. It also helps estimating the fertility prognosis when a myomectomy is performed for reproductive reasons. When the fertility chances are very low because of other reasons, for example poor ovarian reserve, damaged fallopian tubes or male factor issues, it is essential to discuss the likely benefit, if any, of abdominal myomectomy from a fertility perspective with patients before surgery. This includes discussing the potential negative effect of delay in commencing natural or assisted conception imposed by the need for recovery and healing to . Treating pre-operative anaemia. Significant fibroids often cause heavy menstrual bleeding leading to iron deficiency anaemia. Moreover, myomectomy carries a risk of significant blood loss during and after surgery. In a retrospective study comparing surgical outcomes by route of myomectomy in 575 women, it was found that . In addition to the risk of operative blood loss, it is important to treat pre- operative anaemia because pre- operative anaemia increases postoperative morbidity. A large retrospective cohort study among 12,836 patients who underwent gynaecological surgery (Richards et al., 2015) demonstrated that preoperative anaemia was independently associated with an increased odds of 30- day mortality (OR: 2.40, . As preoperative anaemia is easily detectable, it can be considered as a potentially preventable risk factor in patients undergoing elective surgery (Spahn et al., 2012). Therefore, haemoglobin levels of patients should be evaluated some time. # in advance before the planned surgery, in order to allow time for the pre- operative treatment of anaemia. This may involve oral or parenteral iron supplementation, blood transfusion and suppression of uterine bleeding using hormonal treatment with progestogens, GnRH analogues or SPRMs.. Pre-operative reduction in fibroid volume. Agents that are known to reduce fibroid volume are Gonadotrophin releasing hormone agonists (GnRHa), the selective progesterone receptor modulator (SPRM) Ulipristal Acetate (de Milliano et al., 2017), or GnRH antagonists (Huirne et al., 2001). The most studied agents for this indication are GnRH- agonists. There is clear evidence from randomised controlled trials (RCTs) that preoperative GnRHa can reduce both uterine and fibroid volume and improve haemoglobin levels and reduce peri- operative blood loss, although at the expense of increased oestrogen deficient side effects such as hot flushes, before surgery. Rates of more morbid and less cosmetically desirable vertical incisions and blood loss are also reduced in women undergoing an open myomectomy (Lethaby et al., 2017). Reduction in uterine volume may also increase the feasibility of minimally invasive, laparoscopic approaches and reduce the presence of intra- abdominal adhesions. In addition, there is no compelling evidence to support the notion that the use of GnRHa impact adversely on the identification of cleavage planes (de Milliano et al., 2017).. Administration of systematic GnRH antagonists prior to laparoscopic myomectomy appears to reduce peri- operative blood loss (Huirne et al., 2001) although data are mainly from small cohort studies and so there remains insufficient evidence to support the routine use of GnRH antagonist prior to myomectomy (Huirne et al., 2001). Oral GnRH antagonists have recently become available (Al- Hendy et al., 2021; Donnez et al., 2022) and most are combined with HRT to reduce the side effects. So far no clinically meaningful volume reductions have been found with GnRH antagonist combination preparations (de Lange et al., 2024).. Another pre- treatment agent is Ulipristal acetate. This oral drug is effective in the reduction of menstrual blood loss and in increasing pre- operative haemoglobin levels. However, in a double- blind randomised controlled trial comparing Ulipristal with GnRHa pre- treatment, GnRHa was in favour in terms of stronger volume reduction, reduction in fibroid vascularity, less peri- operative blood loss and surgical ease including better cleavage plane (de Milliano et al., 2017). Very recently, the risk- efficacy balance of Ulipristal has been investigated by the European Medicine Agency because it . Patient selection. The location, number and size of the fibroids are essential in determining the procedure type and technique. Fibroid mapping using high- quality transvaginal ultrasound scan or MRI can help to assess the feasibility of performing the procedure laparoscopically or via laparotomy (Saridogan, 2016). The position of the fibroids in relation to the uterine arteries and fallopian tubes is also important, as well as the depth of penetration within the myometrium. Laparoscopic removal of fibroids deeply embedded in the myometrium may be associated with more blood loss than removal of more superficial fibroids and closing the uterine defect adequately requires better technical skills. Removing fibroids that impinge on the fallopian tubes or uterine vessels requires meticulous dissection and suturing (Guo and Segars, 2012; Parker and Rodi, 1994).. Myomectomy, either open or laparoscopic, is a surgical treatment particularly suited for those women who wish for future fertility or want to preserve their uterus for other reasons (Saridogan, 2016). It seems clear that, in well- trained and experienced hands, well- selected patients can have myomectomy performed via laparoscopy. Large, multiple or cervical fibroids may not be as suitable for a laparoscopic approach but are still amenable to a uterine conserving procedure via laparotomy that is facilitated by a number of preoperative and intraoperative measures aimed to minimise or replace operative blood loss (Parker and Rodi, 1994). In the past years experienced endoscopists are also able to take the pre- and intra- operative measures during laparoscopy or robotic surgery. Laparoscopic techniques should provide appropriately selected women with a safe and effective uterine- conserving procedure with possibly reduced post- operative morbidity and enhanced recovery.. Evidence from randomised control trials suggest similar cumulative pregnancy and live birth rates in women with otherwise unexplained infertility. # following laparoscopic versus open myomectomy (Palomba et al., 2007).. Informed consent. Obtaining appropriate consent is essential before surgery. The patient should be fully informed of all possible risks associated with the surgical procedure, including general risks of laparoscopic and open surgery, risks of intra- uterine/ abdominal adhesion formation, damage to the Fallopian tubes and potential risks during subsequent pregnancy and delivery (Orlando et al., 2021). Alternatives should be discussed. Surgery should only be performed when sufficient expertise is available in the centre by a surgeon and team with sufficient expertise and otherwise the woman should be referred to a centre with the required expertise (Johnson et al., 2013).. Pre-operative Antibiotics. Broad- spectrum antibiotics are indicated to reduce infective morbidity prior to laparotomy (World Health Organization, 2018). Antibiotics are widely used for major gynaecological procedures, but there is no significant evidence to say that their use specifically reduces myomectomy related infections (Spahn et al., 2013). There has been some evidence demonstrating lower surgical site infections in open myomectomies, but this was not translated across for the laparoscopic approach (Lethaby et al., 2017; Kim et al., 2019; Van Eyk et al., 2012; Banerjee et al., 2020).. Interventions to reduce blood loss. Injection of synthetic vasopressin into the myometrium and/or broad ligament is effective in reducing blood loss during myomectomy (Kongnyuy and Wiysonge, 2014; Takeuchi et al., 2003) but can result in intraoperative hypertension and vasoconstriction. Whilst it is widely used during laparoscopic and open myomectomy in many countries, it is not available in some countries due to safety concerns. There is moderate evidence to support the use of vaginal misoprostol to reduce blood loss during laparoscopic and/or open myomectomy (Kongnyuy and Wiysonge, 2014) and the use of peri- cervical tourniquet by Foley catheter at open myomectomy in combination with temporary occlusion on the ovarian vessels (Alptekin and Efe, 2014). Only low- quality evidence supports interventions such as bupivacaine plus epinephrine, tranexamic acid, gelatin- thrombin matrix, ascorbic acid, dinoprostone, loop ligation and a fibrin sealant patch to reduce intra- operative blood loss (Hickman et al., 2016; Kumakiri et al., 2012; Opoku- Anane et al., 2020). There is no clear evidence to support the routine use of oxytocin or . Cell Salvage / Saver should be considered in patients who are anaemic . Interventions to reduce adhesion formation. The development of adhesions can be considered as a physiological reaction following surgical exposure (Torres- de la Roche et al., 2023). In a systematic review with statistical pooling the formation rate, distribution and severity of postoperative adhesions in patients undergoing abdominal surgery was estimated using 25 studies in which the formation of adhesions was confirmed by "second- look" laparoscopy or laparotomy (Okabayashi et al., 2014). In patients who underwent gynaecological laparoscopic myomectomy, the weighted mean adhesion formation rates were . The consequences of adhesion formation include chronic abdominal pain, dyspareunia and impaired fertility, small bowel obstruction and complications in further surgery, which can cause significant morbidity (Herrmann et al., 2020; Takeuchi et al., 2008). The Adhesions Research Special Interest Group of the European Society for Gynaecological Endoscopy (Torres- de la Roche et al., 2023; De Wilde et al., 2012) provided a list of anti- adhesion strategies, including shortening of operating time, meticulous haemostasis and improving intraabdominal environment by humidifying the CO2 and using lactated ringer's solution for irrigation (De Wilde et al., 2012). In recent years, a number of barrier agents with different characteristics became commercially available such as oxidized regenerated cellulose, polytetrafluoroethylene surgical membrane, hyaluronic acid products, dual- sided hydrophilic film and fibrin sheet. Other strategies include the use of fluid and gel agents as well as pharmacological methods, aimed at modifying aspects of the healing process (Ahmad et al., 2020).. There are two recently updated Cochrane reviews on the effect of barrier agents and fluid and pharmacological agents for adhesion prevention in gynaecological surgery (de Milliano et al., 2017; Ahmad et al., 2020). Remarkably, in the review. # on barrier agents, none of the 19 included studies reported the outcomes of pelvic pain or live birth rate. The review on fluid and pharmacological agents included 32 included studies, of which one study reported on pelvic pain and three on live birth rate. Due to the lack of evidence and low quality of the studies sound conclusions could not be drawn. However, there is some limited evidence that suggests that using anti- adhesion measures such as oxidized regenerated cellulose, polytetrafluoroethylene surgical membrane, and hyaluronic acid products, may be beneficial in reducing postoperative adhesion formation. In a recent systematic review including eight RCTs focusing on the effectiveness of different adhesion barriers in the prevention of de novo adhesion development after laparoscopic myomectomy, adhesion barrier methods showing the most promising results were oxidized regenerated cellulose, hyaluronic acid products and, polyethylene glycol amine plus dextran aldehyde polymers (Borghese et al., 2021). In addition, hydroflotation and gel agents appear to reduce adhesion formation after gynaecological surgery, compared with no treatment (Kahnickx et al., 2023; Torres- de la Roche et al., 2023). It should be mentioned that there is a large gap in evidence regarding actual effects on clinical outcomes, which are more important to women than the extent of their adhesions.. Open myomectomy. Open myomectomy refers to the surgical removal of fibroids via a laparotomy. The procedure was first performed in 1840 and was the only uterus- preserving surgical option for the treatment of symptomatic fibroids until the late 20th century when laparoscopic and hysteroscopic techniques were developed (Saridogan., 2016). It is still a commonly performed procedure when there are multiple symptomatic fibroids that are less suitable for laparoscopic approaches. An open approach may also be considered, depending upon experience of the surgeon, where fibroids are located within more challenging locations such as the cervix or broad ligament.. Abdominal and uterine incision(s) and enucleation of fibroids. The abdomen is usually opened via a low transverse incision such as Pfannenstiel incision even for large uteri, because a mobile uterus can usually be mobilised and exteriorised through the abdominal incision. However, when the uterus is unusually enlarged (i.e. reaching the epigastrium), or the presence of significant adhesions posteriorly is . Once the abdomen is opened, the pelvic and abdominal structures should be assessed. This may initially be difficult in the presence of fibroids as access to the pelvic cavity and visualisation may be compromised. In such cases the pelvic assessment can be carried out after removal of the fibroids. The uterus should be carefully examined, and the nature and location of the fibroids determined as well as their position in relation to the fallopian tubes and ovaries. Adhesions, if present, should be divided to restore normal anatomy. Exteriorising a large, mobile uterus through the laparotomy incision can help access to the fibroids, however this is not always immediately possible in case of large fibroids located at the level of the cervix or in the broad ligament. The choice of uterine incisions depends on the location of fibroids. In general, uterine incision sites are chosen to minimise the final number of incisions by giving access to maximum number of fibroids through each incision and avoiding the fallopian tubes, uterine and ovarian vessels and the bladder (Gehlbach et al., 1993). Although number of incisions may be less relevant that the total size and depth of the incisions.. It is important to expose the fibroid pseudocapsule, the plane between the fibroid and the myometrium, to facilitate smooth, atraumatic enucleation of the fibroids. Enucleation is achieved by a combination of traction and countertraction on the fibroid and myometrium as well as blunt and sharp dissection of the pseudocapsule. A number of instruments such as myomectomy screws and other clamps/forceps are frequently used to aid enucleation. Fibroids do not have a single vascular pedicle and the surrounding pseudocapsule houses the 'vascular layer'. Hence remaining within the pseudocapsule tends to reduce the blood loss during enucleation. Where fibroids have undergone degeneration or infarction after UAE, the plane within the pseudocapsule can be less easy to delineate, resulting in piecemeal removal of tissue and increased risks of bleeding and myometrial trauma.. Smaller fibroids should be identified by meticulous palpation of the entire uterus/myometrium and removed using an appropriate incision to reduce the risk of 'residual fibroids' (Gehlbach et al., 1993). Gentle manipulation and dissection during fibroid enucleation is important in fibroids abutting or protruding into the uterine cavity to minimise the risk of breaching the cavity.. Broad ligament and cervical fibroids are not only in close proximity to the uterine vessels but also to. # the ureters or may have altered their course. For this reason, the ureter should be carefully identified and dissected laterally, away from the fibroid for it to be removed from these locations (Saridogan, 2016). Identification of the ureter in this way minimises the risk of injury especially if bleeding ensues during fibroid removal because the uterine and other blood vessels within the broad ligament can be safely ligated.. Repair of the myometrial defect. Haemostasis is primarily achieved by effective closure of the myometrial defect, but targeted use of diathermy or vessel ligation may also be used in the presence of obvious bleeding vessels. Extensive coagulation of the myometrium should be prevented. Myometrial closure should ensure obliteration of all potential 'dead space' in the fibroid bed(s), but passing sutures through the endometrial cavity should be avoided to reduce the risk of intrauterine adhesions (Saridogan, 2016). Closing the defect in this way and avoiding excessive and indiscriminate application of diathermy allows for better healing of the myometrium and may minimise the risk of post- operative infection. Depending on the depth of incision, the myometrium may need to be repaired in multiple layers.. The serosa is then closed to achieve good approximation of the edges, covering exposed myometrium and giving additional haemostasis (Zhang et al., 2016). These measures may potentially reduce the adhesion formation around the uterus postoperatively. At the end of the procedure a thorough peritoneal lavage is carried out to remove any remaining blood to minimise risk of adhesion formation (Arung et al., 2011). Appropriate types of suture material for uterine closure are discussed in the laparoscopic myomectomy section below.. Laparoscopic myomectomy. Positioning of patient and port placement. As in most gynaecological laparoscopic procedures, the patient is placed in a modified lithotomy position, with hands placed along the body, legs slightly flexed and abducted, and the pelvic floor protruding a few centimetres from the end of the operating table to allow easy mobilisation of the uterus, with an intrauterine manipulator (Tuandi and Einarsson, 2014). It is crucial to take measures such as anti- slip mats to prevent the patient sliding down towards the direction of the head when shifting in Trendelenburg position or during the course of surgery (Mattei et al., 2011; Sadashivaiah et al., 2018).. Three or four ports would usually be required for laparoscopic myomectomy, one of these would be . To perform successful robot- assisted surgery, an experienced team is required to execute essential steps in preparing a patient for surgery; these are patient positioning, robotic port placement, and docking (Quaas et al., 2010). Four or five ports would be required depending on the number of robotics arms that would be used. The layout of port placement and size of the ports vary significantly depending on the robotic platform that is in use, as well as the surgeon's preference. Similar to laparoscopic myomectomy, the camera port is usually placed either at or above the umbilicus depending on the size of the uterus and surgeon preference. This port accommodates the laparoscope which provides the three- dimensional imaging. Similar to laparoscopic myomectomy, with robotics as a general rule, at least a hands- breadth distance or approximately . # irrigation (Senapati et al., 2015; Takmaz et al., 2018). An alternative placement for this accessory port is in either the left or right lower quadrant.. Uterine incision(s) and enucleation of fibroids. Uterine incisions to remove fibroids are tailored according to the location of fibroid(s) and the surgeon's preference for suturing. As a general rule, incisions should be designed to avoid extending onto the Fallopian tubes, ovarian ligaments and main uterine arteries. Incisions can be made using ultrasonic instruments, monopolar needles, hooks or scissors, or laser. The incision should penetrate deep into the fibroid to identify the plane between the fibroid and the myometrium (Figures 1A and 1B). There is a tendency to remain too superficial avulsing the adherent endometrium, although opening the cavity may sometimes be inevitable when the fibroid has substantial protrusion into the cavity. Smaller fibroids should be placed in a preloaded endobag, in the Pouch of Douglas or sutured onto a string to avoid losing them amongst the loops of small bowel or beneath the omentum. Larger fibroids can be placed above the pelvic brim into the iliac fossae as they would be relatively easy to locate at a later stage (Moawad et al., 2019) (Figures 1C and 1D).. Excessive haemostasis using diathermy should be avoided during and after enucleation of the fibroids, as this may increase the risk of uterine rupture in future pregnancies (Parker et al., 2010). Targeted diathermy for haemostasis can be performed for obviously bleeding vessels, but the dominant . When approaching the base of the fibroid, dissection should be carefully performed to avoid pushing instruments into the uterine cavity, or method of haemostasis remains suturing to repair the myometrium (see later).. Identification of the endometrial cavity. Abdominal myomectomy may cause intra- uterine adhesion formation that may compromise fertility outcomes and increase the potential risk of abnormal placentation and related complications (Bhandari et al., 2016). The risk of intrauterine adhesion development is substantially higher when the uterine cavity is opened during myomectomy (Sukur and Saridogan, 2021). Careful dissection of the fibroid to reduce likelihood of opening the endometrial cavity and avoiding unnecessary coagulation are highly relevant to preserve endometrial function. Intrauterine blue dye application in the uterus may facilitate early identification of the endometrium. # during a myomectomy (Bhandari et al., 2016). This is useful during both enucleation of the fibroid(s) and suturing the incision(s). An additional advantage of instilling blue dye into the uterus is that during the procedure the patency of the tubes can be tested if indicated. More recently the use of indocyanine green (ICG) has been described for this purpose (Ferreira et al., 2019).. Repair of the myometrial defect and choice of suture. The type and size of suture material and needles vary between the teams. The commonly used materials for both open and laparoscopic/robotic myomectomy include braided sutures such as polyglactin 910 or polyglycolide (Vicryl™, Velosorb™), monofilament sutures such as polypropylene, polydioxanone, poliglecaprone or the key principle to close the layers and reduce the dead space.. One concern is that conventional suturing can add additional time to the procedure and this in turn can mean potentially more blood loss. Barbed sutures appear to be quicker than conventional suturing, therefore reducing the operative time, this in turn may also reduce blood loss (Zhang et al., 2016). The use of knotless sutures may also allow an easier technique of tissue approximation and suturing and be advantageous for the surgeon (Tulandi and Einarsson, 2014).. However, it should be remembered when using barbed sutures that there have been case reports of bowel becoming adherent to the barbed suture extending from the wound and causing intestinal . The aim is to close the uterine defect created by the removal of the fibroid, in as many layers as is required without leaving 'dead space' as much as possible, whilst avoiding the uterine cavity (Fernandes et al., 2021) (Figures 1E, 1F and 1G). Leaving as little suture material exposed on the serosal surface may reduce the formation of adhesions, techniques such as a 'baseball suture' have been described to facilitate this (Fernandes et al., 2021). There is, however, no one technique and obstruction. These complications can potentially be reduced by reducing the amount of suture that is exposed, ensuring the 'end' of the suture is cut short and covering the suture line with one separate knotted suture and with an adhesion barrier (Alessandri et al., 2010; Stabile et al., 2021) (Figure 1H).. Fibroid removal and morcellation. With the introduction of laparoscopic myomectomy, new techniques were developed to remove the specimen from the abdominal cavity. Morcellation is a procedure during which larger specimens are broken into smaller pieces, in order to remove them from the abdominal cavity (van der Meij et al., 2018). For this purpose, reusable and single use electromechanical morcellators were developed.. # These usually involve a motor that powers a rotating blade which is housed in a hollow cylinder. The fibroid is pulled towards the blade with a heavy grasper or tenaculum and the morcellator is activated. The rotational action of the blade cuts a fibroid strip that is pulled into the hollow cylinder and then extracted out of the abdominal cavity. Presence of a lip' at the tip of the cylinder keeps the blade on the surface of the fibroid and allows peeling' style fibroid morcellation, enabling longer strips to be removed.. In 2014 possibility of spread of malignancy during the morcellation process was raised (Brohmann et al., 2015) and this led to significant changes in clinical practice including detailed preoperative assessment and counselling, in- bag morcellation (where the surgical specimen is inserted into the containment bag, the bag inflated with CO2 and tissue morcellation performed inside the bag) and abandoning electromechanical morcellation altogether in favour of manual morcellation by small incisions using the so called Chinese "paper roll" (Wong et al., 2010) or open surgery in the following years. These diverse approaches are still in practice to date.. In 2015, the ESGE carried out a systematic literature review in order to evaluate the risk of malignancy in presumed benign fibroids, potential risk factors and investigation methods (Brohmann et al., 2015). The overall risk of sarcomatous changes in the uterus from all published articles was 0.14 . Limited data from relatively small randomised controlled trials does not show significant differences in safety and duration of morcellation between uncontained, in- bag electromechanical and in- bag manual morcellation approaches (Frasca et al., 2018; Venturella et al., 2016). However, . Complications of abdominal myomectomy. Intraoperative complications include bleeding, transfusion, damage to visceral organs or structures and hysterectomy. The latter is rare and is more likely to occur in the presence of multiple large fibroids or in cases of repeat myomectomy (Tanos et al., 2023; Kikuchi et al., 2008). High temperature and febrile illness on postoperative day 1 or 2 is quite common due to pyrogenic substances being released from the myometrium (Saridogan., 2016). This does not always require antibiotic treatment, but the possibility of infection should be considered and broad spectrum antibiotics started, especially if multiple uterine incisions were made, there was significant blood loss, the patient is unwell or the temperature remains high beyond the second postoperative day.. Other postoperative risks include pelvic abscess formation, development of a paralytic ileus, bowel obstruction and thrombosis. Adhesion formation in the long term is a common occurrence after myomectomy that may cause chronic pain, bowel dysfunction and subfertility, (Tanos et al., 2023; Kikuchi et al., 2008). The prevalence of complications depends on the complexity of cases included in the published literature. In a case series of 200 patients requiring open myomectomy with uterine size of 16 weeks or larger the overall major complication rate was . The larger case series of laparoscopic myomectomy report major complication rates of . # Thromboprophylaxis for all major abdominal surgery needs to be considered. The measures include early mobilisation, graduated compression stockings, intermittent pneumatic compression and pharmacological agents such as low molecular weight heparins (LMWH). Pharmacological agents need to be weighed against risk of bleeding, if high risk for postoperative bleeding, mechanical prophylaxis should be continued until it is safe to switch to pharmacological agents. Scoring systems such as Caprini risk assessment tool or other similar formula to calculate risk and duration of treatment can be useful (Cronin et al., 2019). These tools take a number of factors into account including the patient's age, body mass index, duration of surgery, smoking status and additional morbidity. A proportion of the cases with significant fibroids will need 7- 10 days of prophylactic anticoagulation.. Postoperative management. Postoperative recovery and convalescence advice. The rationale of minimally invasive techniques is that the use of small incisions is beneficial over conventional open surgery, as it results in less tissue trauma and inflammation, leading to reduced pain, faster mobilisation, shorter hospital stay and postoperative recovery time, translating into speedier return to normal activities and work (Bhave Chittawar et al., 2014; Aarts et al., 2015). With the adoption of enhanced recovery programmes, same day discharge appears to be feasible and safe in a significant proportion of patients after minimally invasive myomectomy (American College of Obstetricians and Gynecologists, 2018; Applebaum et al., 2023). The Cochrane review comparing minimal invasive techniques versus open myomectomy demonstrated that myomectomy by laparoscopy was a less painful procedure compared with open surgery with lower pain scores at 6 and 48 hours after surgery. In addition, patients in the laparoscopic group had a shorter median length of stay compared to women in the open surgery group (Bhave Chittawar et al., 2014). The review did not report on duration until return to normal activities or work but a prospective nationwide registry (COMPARE- UF) (Laughlin- Tommaso et al., 2020) has assessed the differences in recovery times between myomectomy routes. In a total of 1206 women who underwent a myomectomy (338 hysteroscopic, 519 laparoscopic, and 349 abdominal) in the United States (Laughlin- Tommaso et al., 2020). Return to usual activities averaged 0 days (IQR 0- 14) for hysteroscopic myomectomy, 21 days (IQR 14- 28) for laparoscopic myomectomy, and 28 days (IQR 14- 35) for abdominal myomectomy.. Return to work averaged 4 days (IQR 3- 10) for hysteroscopic myomectomy, 21 days (IQR 14- 39) for laparoscopic myomectomy, and 42 days (IQR 28- 56 days) for abdominal myomectomy.. Two smaller studies assessed recovery times in laparoscopic myomectomy. In a sample of 194 Canadian women the mean duration until return to office work was 12.5 days (11.4- 13.7) and to physical work was 16 days (13.7- 18.3) (Liu et al., 2010). In a study performed in the United Kingdom in a sample of 71 women who underwent laparoscopic myomectomy . These studies demonstrate that there is substantial variation in recovery times in women recovering from myomectomy, even within the same type of approach. Moreover, in some of these studies actual recovery times exceeded the recovery time considered appropriate by specialists. One explanation for the differences in recovery times between populations might be geographical differences in attitudes towards health and work as well as differences in the organisation of social and healthcare systems. Secondly, because of increasing experience in the technique, the complexity of cases being carried out laparoscopically has probably increased over time, with a resultant increase in the necessary convalescence time (Huff et al., 2018).. In another field of benign gynaecologic surgery, it has been demonstrated that evidence- based convalescence advice plays a crucial role in determining the length of recovery of patients (Hollenbeck et al., 2008). Managing recovery expectations might be equally important in reducing recovery times as the degree of invasiveness of the surgery itself (Vonk Noordegraaf et al., 2014; Bouwsma et al., 2017; van der Meij et al., 2018). Therefore, to obtain full potential of minimal invasive techniques, it is recommended to invest in perioperative guidance and education of women undergoing myomectomy.. Second look hysteroscopy. The incidence of intrauterine adhesions following myomectomy varies widely from . # .	None	None	None
6e93c96cae504e28af1564f10c60809e	2024+ESGE实践建议	肌瘤切除的外科技术—第2部分	# European Society for Gynaecological Endoscopy (ESGE) Good Practice Recommendations on surgical techniques for Removal of Fibroids: Part 2 Hysteroscopic Myomectomy. T.J. CLARK<sup>1</sup>, L. ANTOUN<sup>1</sup>, A. Di SPIEZIO SARDO<sup>2</sup>, V. TANOS<sup>3</sup>, J. HUIRNE<sup>4</sup>, E.W. BOUSMA<sup>5</sup>, T.SMITH-WALKER<sup>6</sup>, E. SARIDOGAN<sup>7</sup> ON BEHALF OF THE EUROPEAN SOCIETY FOR GYNAECOLOGICAL ENDOSCOPY UTERINE FIBROIDS WORKING GROUP. <sup>1</sup>Birmingham Women's & Children's Hospital, University of Birmingham, United Kingdom; <sup>2</sup>Obstetrics and Gynaecology Department, Università degli Studi di Napoli "Federico II", Italy; <sup>3</sup>Department of Basic and Clinical Science, University of Nicosia Medical School and Aretaeo Hospital, Cyprus; <sup>4</sup>Department of Obstetrics & Gynecology, St. Antonius Hospital, The Netherlands; <sup>5</sup>Department of Obstetrics & Gynaecology, Amsterdam University Medical Center and Amsterdam Reproduction and Development Research Institute, The Netherlands; <sup>6</sup>Gynaecology Department, Royal Cornwall Hospital, United Kingdom; <sup>7</sup>Elizabeth Garrett Anderson Institute for Women's Health, University College London and University College London Hospital, United Kingdom.. Correspondence at: Professor T Justin Clark, MB ChB, MD (Hons), FRCOG, Consultant Gynaecologist, Birmingham Women's and Children's Hospital, Edgbaston, Birmingham, UK B15 2TG. E- mail: t.j.clark@doctors.org.uk. Abstract. Submucosal uterine fibroids are the rarest type of fibroids. They can lead to abnormal uterine bleeding and may play a role in infertility and miscarriage. Hysteroscopic myomectomy is the preferred treatment to relieve bleeding caused by these fibroids and to restore the normal structure of the uterine cavity. The European Society for Gynaecological Endoscopy Uterine Fibroids Working Group developed recommendations based on the best available evidence and expert opinion for the surgical treatment of uterine fibroids. In this second part of the recommendations, hysteroscopic approaches are described. This review explores the techniques related to hysteroscopic myomectomy, focusing on narrower scopes, fluid management and advances in tissue removal systems and electrosurgery.. Introduction. Hysteroscopic myomectomy is considered the first- line treatment option in the surgical management of submucosal fibroids because it is the least invasive approach to myomectomy, avoiding surgical incisions and preserving the integrity of the outer uterine wall. Hysteroscopic myomectomy is safe and effective in treating heavy menstrual bleeding (HMB) with a success rate of between . Several authors have assessed the impact of hysteroscopic myomectomy on reproductive outcomes in infertile women although the limitations of research designs limit clinical inferences. The data we have from one small randomised controlled trial (RCT) (Casini et al., 2006; Bosteels et al., 2015) and observational data (Pritts et al., 2009) seems consistent with a doubling of the clinical pregnancy rate with removal of fibroids but any effect on live birth or miscarriage rates remains uncertain. This lack of certainty may in part be attributed to the difficulty. # of controlling the many confounding factors that may account for infertility, as well as inadequate study sample sizes, limited duration and completeness of follow- up, and variation in the characteristics of the fibroids treated (i.e. number, size, intramural extension and the coexistence of multiple intramural fibroids).. Whilst we need higher quality data regarding the effectiveness of hysteroscopic removal of submucosal fibroids on abnormal uterine bleeding and fertility, the focus of this guideline is on describing the surgical techniques. Pre- operative and post- operative care and fluid management are briefly described because successful surgery cannot be achieved without attention to these aspects of care. However, this guidance concentrates on informing the reader about the surgical approaches to conducting successful hysteroscopic myomectomy. The definitions of treatment setting; office, outpatient and operating room (inpatient/ day- case/ambulatory) are described according to the International Consensus Statement for recommended terminology describing hysteroscopic procedures (Carugno et al., 2021).. Material and methods. In this guideline, we will refer to the 2013 revision of the FIGO classification, which to date . # The main surgical technologies and techniques used in contemporary gynaecological practice to undertake hysteroscopic myomectomy are described below. Less commonly performed methods such as the use of Nd:Ag or diode lasers are not described.. Fluid management. A detailed discussion on fluid management is beyond the scope of this guideline. There are two detailed guidelines covering the management of fluid distension media in hysteroscopic surgery (Unruinkar et al., 2016; AAGL., 2013) which we would draw the attention of the reader to. Whilst the use of gravity and pressure cuffs can be used to instil fluid into the uterine cavity, these methods are only appropriate for diagnostic and simple, short operative procedures such as targeted biopsy and polypectomy. Successful, and importantly safe, removal of submucosal fibroids by hysteroscopic means necessitates good visualisation. This can only be achieved reliably by the use of automated fluid management systems (e.g. Aquilex, Fluent, Hysterobalance, Hysterolux and Hysteromat systems) that provide constant irrigation to remove blood / debris and consistent intrauterine pressures. It is important to keep the intrauterine pressure below mean arterial pressure to minimise systemic absorption of fluid; the lowest irrigation pressure that allows adequate visualisation should be chosen typically starting at . The other main reason for using automated fluid management systems for hysteroscopic myomectomy is because the procedure can be associated with serious complications arising from excessive intravasation of fluid. This results in fluid overload within the systemic vascular circulation and electrolyte disturbances. These fluid complications are more likely when large or multiple fibroids with significant intramural involvement. Thus, meticulous peri- operative monitoring of fluid deficit is mandatory to avoid potentially life- threatening complications from systemic absorption of fluid. Automated fluid management systems are the only way of reliably measuring fluid deficit in real time. Physiological (Normal) saline is less likely to induce hyponatraemia and should be used with mechanical or bipolar electrosurgical methods. Monopolar electrosurgery necessitates the use of a non- conducting fluid medium such as sorbitol or glycine. Greater care is needed with hypo- osmolar solutions such as these. For healthy patients the maximum, acceptable fluid deficit thresholds at which the hysteroscopic myomectomy procedure . Pre-operative planning and preparation. Pre-operative planning. The aim of hysteroscopic myomectomy, regardless of the surgical modality used, is complete enucleation of the submucosal fibroid, leaving behind no residual fibroid tissue. Diagnostic work- up is important to counsel women as well as plan their hysteroscopic treatment with the aim of optimising both procedural and clinical outcomes. Radiological imaging and hysteroscopy should be considered complimentary tests, although they will provide some overlapping information.. Imaging. Imaging in the form of 2D and 3D pelvic ultrasound with or without contrast is important to assess the number, size (dimensions) and location of fibroids. The FIGO type of submucosal fibroid can be estimated, assessing the relative degree of intramural involvement and for FIGO type 2 fibroids, the distance from the serosal surface. The greater this "myometrial free margin" the more feasible complete fibroid removal is likely to be. Magnetic Resonance Imaging (MRI) can also be used but is more expensive and should be considered second line (Namkung et al., 2001).. Hysteroscopy. Direct endoscopic visualisation of a submucosal fibroid is considered the gold standard diagnostic test (Farquhar et al., 2003; van Dongen et al., 2007). However, it should be noted that type 2 fibroids may be pushed into the myometrium with the pressure of distension fluid during hysteroscopy and may be overlooked. Therefore, the entire cavity should be assessed carefully when the distension fluid is turned off to see if any fibroids protrude into the cavity, after the initial assessment with fluid distension. Hysteroscopy allows key characteristics of the submucosal fibroid to be recorded such as estimates of its size, the intramural proportion of the fibroid (based upon the angle between the intracavity fibroid and endometrial surface; acute angle . # allows counselling of women about the potential need for multi- step procedures. Hysteroscopy in the context of planning fibroid treatment should be performed in an outpatient / office setting where possible (De Silva et al., 2024).. Pre-operative preparation. Medical preparation. The decision to employ pre- operative hormonal treatment should be left to the surgeon's discretion, as existing data on surgical feasibility. # (e.g., duration, completeness), safety (e.g., fluid absorption, uterine trauma), and prognosis (clinical outcomes) remains inconsistent when comparing hormonal preparation with the absence of preoperative medical intervention (Gulmann et al., 2005; Campo et al., 2005; Mavrelos et al., 2010; Muzli et al., 2010). Regarding endometrial or fibroid preparation, practice varies among surgeons; some never employ pre- surgical treatment, while others utilize it routinely or selectively, depending on the anticipated surgical complexity and fibroid size. Some surgeons also strategically schedule procedures to coincide with the thinnest endometrial phase during the proliferative stage of the menstrual cycle.. Where medical treatment is deemed appropriate, a 2- 3- month regimen prior to surgery is recommended to achieve endometrial downregulation. Hormonal treatments available include progestogens, danazol, gonadotropin- releasing hormone analogues (GnRH- a), and gonadotropin- releasing hormone antagonists (GnRH- ant), each inducing amenorrhea. This preoperative amenorrheic state offers the benefit of allowing patients to take iron supplements and optimize iron stores, potentially lowering surgical morbidity. Additionally, surgical visibility is improved in the absence of blood, endometrial debris, and congestion. GnRH- a treatments are particularly effective in thinning the endometrium and reducing both the volume and vascularity of submucosal fibroids by inducing a hypoestrogenic state.. Conversely, GnRH antagonists, such as relugolix, elagolix, and linzagolix, achieve adequate haemoglobin levels and reduce both myoma and uterine size by suppressing the hypothalamic- pituitary- ovarian axis and decreasing sex steroid levels without the flare- up effect (Muzii et al., 2024). These agents, with the additional benefit of oral administration, have been shown to reduce heavy menstrual bleeding and induce amenorrhea within a month (Neblett et al., 2023; Di Spiezio Sardo et al., 2023). Furthermore, an additional advantage of using GnRH antagonists is the possibility of combining them with add- back therapy (e.g., relugolix with low- dose oestrogen and progestin). This solution enables the mitigation of hypoestrogenic side effects, enhancing both tolerability and patient comfort, thereby promoting adherence to the pre- operative treatment regimen. Although data on surgical outcomes remains limited, preliminary findings indicate that GnRH antagonists offer promising alternatives to traditional treatment options.. Surgical preparation. Surgical preparation in the outpatient / office hysteroscopy clinic has been described and uses a 5Fr bipolar electrode to incise over the endometrial mucosa covering the fibroid, proceeding along the reflection line on the uterine wall, up to the cleavage plane between the fibroid and its pseudocapsule (Bettocchi et al., 2009; Haimovich et al., 2013). The hope is that subsequent myometrial contractions will partially or wholly expel the intramural component of the fibroid rendering them more accessible and amenable to removal. However, efficacy data are lacking to recommend the routine use of this approach.. Vasopressin induces a vasoconstrictive effect on tissues and is used liberally in abdominal approaches to myomectomy (Kongnyuy et al., 2008; Kongnyuy et al., 2014). Its use is encouraged in the European Guidelines as well (Umranikar et al., 2016). However, studies on the use of vasopressin in hysteroscopic myomectomy are limited. Some studies have shown that the intracervical administration of vasopressin reduces the amount of blood loss and distension fluid absorbed due to its vasoconstrictive effect (Goldenberg et al., 1996; Philips et al., 1996). Some clinicians have investigated the direct hysteroscopic injection of diluted vasopressin into the submucosal fibroid using a 5Fr hysteroscopic needle (Holloran- Schwartz et al., 2014; Rouholamin et al., 2021; Philips et al., 1996). Data are limited, but a small randomised controlled trial showed that that the injection of vasopressin during hysteroscopic myomectomy reduced surgical time, fluid deficit and improved visualisation (Phillips et al., 1996; Rouholamin et al., 2021). More research regarding the effectiveness of this intervention is needed to guide practice.. Radiological preparation. The use of immediate pre- operative uterine artery embolisation has been described to devascularise large submucosal fibroids, typically greater than . Cervical preparation. There is no compelling evidence to support the routine use of cervical preparation with oestrogen (post- menopausal women), prostaglandins (e.g. misoprostol), osmotic dilators (e.g. laminaria tents) to enhance the feasibility, safety or patient experience of hysteroscopic myomectomy (AAGL, 2012; Al Fozan et al., 2015; Phillips et al., 1997).. # Clinicians may decide to selectively use such measures where cervical dilatation beyond Hegar 6 (6mm) is anticipated (Cooper et al., 2011).. Antibiotics. Antibiotics should not be routinely prescribed prior to hysteroscopic procedures, including hysteroscopic myomectomy. Whilst endometritis following resectoscopic myomectomy has been reported to effect 1 in 200 women (Agostini et al., 2002), there is no evidence to support the routine use of antibiotics to prevent genital tract or systemic infection (Agostini et al., 2002; Bhattacharya et al., 1995).. Fibroids without intramural involvement (FIGO type 0). Hysteroscopic removal of fibroids without an intramural component are the least technically challenging procedures because the whole fibroid is visible within the uterine cavity and so more easily accessible. However, they can be more mobile than FIGO type 1 and 2 fibroids which can create some challenges, especially when adopting the technique of resectoscopic slicing. The risks of inadvertent uterine trauma and fluid overload are lower because operating within the deeper myometrium, where larger diameter blood vessels are present.. Several surgical techniques and technologies have been proposed for the removal of fibroids without an intra- myometrial component. These techniques are described in the three sections below.. Resectoscopic slicing of fibroid. The slicing technique, generally referred to as transcervical resection of fibroid (TCRF) (Hart et al., 1999; Vercellini et al., 1999; AAGL, 2012; Di Spiezio Sardo et al., 2008) is performed with a standard . The "slicing" technique involves repeated passes of the cutting loop to gradually remove slices of fibroid tissue until it has all been removed. The cutting loop is placed beyond the distal border of the fibroid and repeated, systematic, retrograde electrosurgical cutting movements, facilitated by movement of the hysteroscope or withdrawal of the cutting loop or a combination of both methods, are . The resected slices or 'chips' are most commonly removed using blind polyp forceps and 7 or by trapping them onto the end of the hysteroscope by retracting the inactivated cutting loop and removing the resectoscope. Care should be taken during blind removal as this may potentially increase risk of uterine perforation. Repeated instrument insertions are usually required. In the case of small lesions, retrieval of the resected tissue can be done at the end of the procedure. For larger fibroids, removal of free- flowing 'chips' of tissue will be required on one or more occasions during the procedure to maintain an adequate view. Some surgeons avoid the formation of free flowing 'chips' of tissue by removing each resected strip of tissue by immediate removal of the resectoscope followed by re- insertions. Whilst this approach maintains a view, it can be laborious, and repeated loss of uterine distension and tamponade can temporarily lose view, contains a risk of air embolism (Conner and Clark, 2020; Brooks et al., 1997) and prolongs the procedure. Another option for removing resected fibroid tissue from the uterine cavity is by aspiration. An evacuator (e.g. the Urovac bladder evacuator) is attached to the outer sheath of the resectoscope after removal of the working element, and pieces of detached fibroid tissue are aspirated in a manner similar to that used by urologists when undertaking transurethral resection of prostate (TURP).. On completion of detachment of the fibroid and removal of all tissue retained within the cavity, the final step is to inspect the base where the fibroid was attached, to ensure complete enucleation (Figure 2). Myometrial tissue is identified as pinker, softer tissue and muscular fascicles should be visible. The inactivated cutting loop can be used to help judge the tissue density and delineate the myometrial base (fibroid capsule). The activated electrode is used to remove any residual fibroid tissue from the base. During this final step, the hysteroscopist must be particularly careful and meticulous in adjusting the depth of each cut making sure that iatrogenic thermal injury to healthy myometrium or surrounding endometrium is prevented.. # Resectoscopic slicing of FIGO type 0 fibroids can be performed in both outpatient/office and operating room settings but in general smaller fibroids are amenable to outpatient/office removal with smaller diameter . 5Fr electrode slicing of fibroid. This method utilises a straight 5Fr electrode passed down the working channel of a continuous flow operating hysteroscope of . 5Fr electrode slicing can be used for FIGO type 0 fibroids, typically no more than . Electrosurgical en-bloc removal of fibroid. The electrode (5Fr straight, or resectoscopic cutting loop/knife) is placed at the level of attachment of the fibroid to the myometrium and beyond its distal border (Clark et al., 2002; Varma et al., 2009; Bettocchi et al., 2002). Retrograde electrosurgical cutting is then performed by movement of the hysteroscope or withdrawal of the electrode or a combination of both methods. Repeated anterograde, or preferably retrograde (to minimise the risk of thermal uterine perforation), cutting motions are continued in a systematic way until the fibroid is detached (these may proceed in one direction or may be done alternatively from each free border until they meet centrally). The inactivated electrode can be used periodically to probe the fibroid to help identify the basal attachment to the myometrium.. # The electrode can be used to slice the fully or partially detached fibroid into smaller pieces to aid removal from the cavity (Bettocchi et al., 2002) using hysteroscopic or blind instruments like polyp forceps. In practice, it is difficult to morcellate a fibroid that has been partially or fully detached from the myometrium due to its mobility. Alternatively, the fibroid can be retrieved from the uterine cavity in one piece. This usually necessitates variable degrees of cervical dilatation and blind insertion of instruments such as polyp forceps. Wherever possible, blind instrumentation of the uterus should be avoided to minimise the risk of genital tract trauma. Another option for blind removal, or when blind removal is not easily achieved, is to leave the detached fibroid in situ to degenerate and pass spontaneously postoperatively and often during the first menstruation after surgery (Varma et al., 2009; Haimovich et al., 2015). An outpatient hysteroscopy 6- 8 weeks later can be considered to see if there is any residual necrotic fibroid tissue, which can be removed using hysteroscopic instruments on a mHTR. Finally, a 'hybrid' procedure can be performed where a mHTR is used to remove under direct vision after complete or partial detachment of the fibroid (Munro, 2016).. Electrosurgical en- bloc removal of FIGO type 0 fibroids can be performed in both outpatient/office and operating room settings but in general smaller fibroids are amenable to outpatient/office removal with smaller diameter . Vaporisation of the fibroid. Vaporisation of the fibroid is performed using ballshaped (spherical) or barrel- shaped (cylindrical) electrodes, which are passed in a retrograde fashion slowly along the surface of the fibroid (Brooks, 1995), inducing its complete disintegration. The depth of vaporisation depends on the duration of contact, as well as the resistance and power of the generator. It is important to move the electrode slowly along the tissue, applying current only when the electrode is being retracted toward the operator. Any pressure exerted too long on a single spot may result in uterine perforation. High power outputs are required, which produce gas bubbles that can enter the vascular system although they generally dissipate rapidly in the blood. A constant monitoring of the patient's end- tidal CO2 together with close cooperation between the surgeon and anaesthetist is recommended to avoid serious complications from gas emboli. The advantage of this technique is the avoidance of chip formation.. However, the main drawback of using vaporising electrodes is that no tissue is left for histological examination.. Ablation by retrograde passage of an Nd:yAG laser over the surface of a submucosal fibroid . Mechanical Hysteroscopic Tissue Removal (mHTR) of fibroid. mHTR systems provide a means of mechanical cutting of fibroid tissue with simultaneous aspiration of this tissue, allowing a clear surgical view and a specimen for histological examination. The available mHTR systems vary between 5mm and . The technique requires firm contact of the instrument tip with the submucous fibroid prior to activation. The cutting window is placed within the central portion of the fibroid to create a 'bite' (likened to eating an apple), followed by lateral rotations of the cutting window (likened to spreading butter on toast) (Emanuel and Wamsteker, 2005; van Dongen et al., 2008). These manoeuvres are repeated until the fibroid removed. Minimal anterograde or retrograde movements of the HTRS are required and these are only to ensure that the cutting window is placed within fibroid tissue at all times to ensure efficient removal.. Mechanical hysteroscopic tissue removal of FIGO type 0 fibroids can be performed in both outpatient/office and operating room settings but in general smaller fibroids are amenable to outpatient/ office removal using mHTR systems . Fibroids with intramural component (FIGO Type 1 & 2). Hysteroscopic treatment of fibroids with an intramural component is technically more challenging and associated with a higher risk of complications, especially uterine trauma and fluid overload. When planning hysteroscopic myomectomy, the size of FIGO type 1 and 2 fibroids is the most important characteristic to appreciate as regards feasibility and safety. As a general rule, FIGO type 1 and 2 fibroids that are planned to be removed hysteroscopically should not exceed . # Several surgical techniques have been proposed for the removal of fibroids with a myometrial component that cannot be seen. All techniques have the common objective of trying to produce an intracavitary projection of the previously intramural component, facilitating direct and safe cutting and removal. These techniques are described in the following sections "Resectoscopic slicing of fibroid, 'Cold loop' myomectomy, 5Fr electrode en- bloc removal of fibroid and Mechanical Hysteroscopic Tissue Removal of fibroid". In addition, non- surgical measures can be considered to induce myometrial contractions, facilitating the migration of the 'hidden' intramural component of a fibroid into the uterine cavity, thus making hysteroscopic resection safer and more feasible. Myometrial contractions may be induced manually, hydrostatically and pharmacologically and are applicable to all surgical methods described in the sections below. Hydro- massage involves inducing changes in intrauterine pressure by intentionally interrupting and restarting the instillation of distension fluid repeated times. Manual massage can also be used to compress and stimulate the uterus. Reported pharmacologically aided techniques include transabdominal injection of prostaglandin F (PGF)- 2a under laparoscopic monitoring and intracervical injection of carboprost, a methyl analogue of PGF- 2a. These techniques are generally not practised in isolation but in conjunction with the previously described techniques (Di Spiezio Sardo et al., 2008; Istre et al., 2009).. Resectoscopic slicing of fibroid. Removal of the intracavity component of the fibroid by resectoscopic slicing is described in the Fibroids without intramural component (FIGO type O) section. Removal of the fibroid is continued with slicing of the portion enveloped within the muscle of the uterine wall, until it is completely removed. The technique is described below.. As soon as the visible intracavity portion of the fibroid has been removed, the inactivated cutting loop is gently used, exerting care to avoid damaging the fragile loop, to undermine the myometrial component of the fibroid in order to separate it from the underlying capsular attachment (Hart et al., 1999; Vercellini et al., 1999; AAGL., 2012; Di Spiezio Sardo et al., 2008; Istre et al., 2009). Whilst mechanical separation may not be possible with the relatively delicate loop, such manoeuvres help distinguish fibroid tissue, which appears as smooth, white and compact, from the underlying, softer and pinker myometrium. The capsule within the myometrium from where the . The careful use of the activated and inactivated electrosurgical loop is continued in this manner along the cleavage plane until the fibroid has been enucleated (Figure 3). Attempts may be made to coagulate specific bleeding points during the procedure using the loop if the bleeding persists and is compromising visualisation. However, deeper myometrial vessels are of larger diameter such that bleeding may only be limited using greater fluid distension to tamponade vessels. Meticulous fluid balance (see 'Fluid Management' section above) must be kept as rapid intravasation of fluid can occur the deeper into myometrial tissue the fibroid extends (Umranikar et al., 2016; AAGL, 2013). Removal is as described in the section for FIGO type 0 fibroids.. Techniques to preserve endometrium during resection of fibroids with a significant intramural component (FIGO Type II and III) fibroids have been described in women with an intention of future pregnancy to reduce the potential risk of intrauterine adhesion and thin endometrium (Di Spiezio Sardo et al., 2016). This technique comprises either making an endometrial incision or making a small opening in the overlying endometrium to expose the cleavage plane between the fibroid and myometrium. Subsequent steps of resection are then performed through this small opening without resecting the overlying endometrium (Vorona and Saridogan, 2022).. 'Cold loop' myomectomy. This technique, developed by Mazzon et al. (2015) is an adaptation of conventional electrosurgical loop resection. Electrosurgical resection continues in the described fashion until the level of the plane of the endometrial surface. The cleavage. # plane is then identified. Subsequent enucleation of the intramural component of the fibroid is then undertaken using more robust, bespoke 'cold' loops designed for mechanical blunt dissection. Hard rectangular and single- toothed loops can be used to separate, hook and lacerate the slender connective bridges of myometrial tissue which join the fibroid and the adjacent myometrium. Once the intramural part of the fibroid is totally separated within the uterine cavity, standard electrosurgical resection using an angled cutting loop completes the procedure as described in the previous section (Mazzon et al., 2015).. Resectoscopic slicing of FIGO type 1 and 2 fibroids is generally performed in an operating room setting under regional or general anaesthesia due to the longer duration of procedures and the need to manipulate within the myometrium.. 5Fr electrode en-bloc removal offibroid. The activated 5Fr straight electrode is used to wholly, or partially, to circumscribe the endometrium overlying the visible margins of the fibroid, where possible moving the activated electrode in a retrograde direction. Complete circumcision can usually be achieved with more sessile fibroids as . # # until the fibroid is completely enucleated. Removal is as described in section for FIGO type 0 fibroids. Electrosurgical en- bloc removal of FIGO type 1 and 2 fibroids is generally performed in an operating room setting under regional or general anaesthesia due to the longer duration of procedures and the need to manipulate within the myometrium.. Fibroids with intramural development (FIGO Type 3). To date, the surgical technique for treatment of FIGO type 3 fibroids has not been well- defined. A recent study has demonstrated the potential efficacy of operative hysteroscopy as a treatment option for this type of fibroid (Capmas et al., 2016). Hysteroscopic removal of FIGO type 3 fibroids should only be attempted by experienced surgeons because of the increased complexity of the procedure. The technique requires thorough exploratory mapping to elicit their precise location and topographic- anatomical relationships with regard to the uterine cavity. Resectoscopic removal of FIGO type 3 fibroids potentially offers several advantages over conventional laparotomic or laparoscopic approaches. These include less intraoperative and postoperative blood loss, shorter length of stay and rapid recovery with reduced postoperative pain, although the need for a further procedure to complete the resection is more likely.. Resectoscopic slicing of FIGO type 3 fibroids is performed in an operating room setting under regional or general anaesthesia due to the longer duration of procedures and the need to manipulate within the myometrium.. Multi-step procedures. All women undergoing hysteroscopic myomectomy should be aware of the chance of incomplete resection and the need for further procedures. This is more likely where there are adverse features, namely maximum diameter above . It is important that the surgeon and the patient do not consider the inability to complete the procedure . Post-operative care. Control of post-operative bleeding and pain. The origin of bleeding should be assessed. If arising from cervical trauma then mechanical compression, topical haemostatic agents (e.g. Monsel's ferric subsulphate solution) or surgical sutures may be used. Intrauterine bleeding is more common following the removal of larger or multiple, FIGO type 1 and 2 fibroids. Emptying the bladder and bimanual compression will normally suffice, but if bleeding persists then uterine tamponade with a balloon catheter (e.g. Foley catheter) for a few hours can be used. If continued bleeding despite these measures, particularly if the procedure was complex, should alert the operator to the possibility of unrecognised uterine trauma requiring further exploratory intervention such as laparoscopy / laparotomy. Similarly, if the patient has excessive post- operative pain that is not controllable with routine opiate and non- opiate analgesics, the risk of uterine perforation and intra- abdominal bleeding or visceral injury should be suspected (Istre et al., 2009).. Fluid overload. Fluid deficit thresholds are . # removed. Oxygen saturation and respiratory rate should be monitored and the patient observed for a productive cough. Where intravasation of excessive fluid ("fluid overload") is suspected, then specific, evidence- based management protocols produced by the British Society of Gynaecological Endoscopy (BSGE) and the European Society for Gynaecological Endoscopy (ESGE) (Umranikar et al., 2016) and the American Association of Gynaecological Laparoscopists (AAGL) (AAGL., 2013), should be adhered to. The basic approach is to fluid restrict, use diuretics judiciously and observe (including urinary catheterisation to measure output, and measurement of serum urea, electrolytes and O2 saturation) and obtain help from anaesthetic and medical colleagues if required.. Adhesion prevention. The de novo formation of intrauterine adhesions (IUAs) can be associated with hysteroscopic myomectomy especially if the fibroid(s) removed covers a relatively large surface area or fibroids on opposing uterine surfaces are removed. Careful, precise and atraumatic surgery is likely to minimise the risk of IUAs. The overall incidence of clinically significant IUAs is thought to be low (Di Spiezio Sardo et al., 2008; Yang et al., 2008). For women requiring future fertility, the formation of intrauterine adhesions (IUAs) may impact adversely on reproductive potential. Thus, preventative strategies should be considered such as the use of hormones to stimulate the endometrium, intrauterine anti- adhesive barriers (e.g. Hyaluronic acid gel) and second look outpatient/office hysteroscopies to detect and lyse newly formed IUAs (Yang et al., 2016). However, in the absence of clear evidence of benefit (Di Spiezio Sardo et al., 2016) on reproductive outcomes, the use of post- operative IUA preventative strategies should be left to the discretion of the operator.. Assessing completeness of treatment. Ultrasound examination and second- look hysteroscopy should be considered where complete removal of fibroid tissue is not achieved or is uncertain as a result of suboptimal visualisation, patient tolerance factors (outpatient/office) or curtailment of the procedure due to fluid deficit thresholds being reached. If a small amount of residual fibroid tissue is suspected at most, then an outpatient/office setting is suitable and more convenient to inspect the cavity and remove any residual tissue if feasible or schedule an operating room repeat procedure. Ideally, second- look procedures should be undertaken within 6- 8 weeks of the index procedure.. Conclusion. These ESGE Good Practice recommendations provide guidance to help optimise the care of women undergoing surgical removal of submucosal uterine fibroids using a hysteroscopic approach. Optimal clinical outcomes necessitate an understanding of the indications for hysteroscopic myomectomy, diagnostic workup and treatment planning as well as the importance of good surgical technique, appropriate use of available technologies and fluid management.. Recommendations. 1. Women should be counselled about medical and hysteroscopic surgical management and submucosal fibroids, including their relative risks and benefits. 2. Pre-operative assessment using imaging and/or hysteroscopy is of key importance to characterise the submucosal fibroid(s) to help plan hysteroscopic myomectomy, including patient counselling, the likelihood of multistage procedures, the need for medical/surgical preparation, selection of viable technologies and appropriate treatment setting(s). 3. Understanding fluid management is essential to optimise the safety and feasibility of hysteroscopic myomectomy. Automated fluid management systems should be used to maintain intrauterine pressures and visualisation and monitor fluid deficit. 4. Identification and delineation of the plane between the fibroid and myometrium (pseudocapsule) are important to ensure complete enucleation (removal) of the fibroid. 5. The size and intramural penetration of the submucosal fibroid(s) are the main factors to consider when deciding about the best surgical approach, technologies (mechanical, electrosurgical and mHTR), techniques (slicing, en- bloc removal, cold loop, vaporisation, mHTR) and setting. 6. Where possible, smaller diameter operative hysteroscopes should be used to minimize the risk of cervical trauma and increase the feasibility of the office/outpatient setting. 7. Consider post-operative imaging / outpatient hysteroscopy to assess the completeness of treatment and intrauterine adhesions.. What does this mean for patients?. These recommendations have been produced by the European Society for Gynaecological Endoscopy. # (ESGE) Uterine Fibroids Working Group. The objective of the Working Group was to develop guidance based on the best available evidence and expert opinion for the surgical treatment of uterine fibroids. The recommendations are intended to provide information for clinicians involved in the care of women where surgical treatment of fibroids is indicated because of their interference with fertility and pregnancy or because of ongoing pressure, pain or bleeding symptoms.. The working group has produced two documents describing procedures to perform myomectomy utilising both abdominal (part 1) and hysteroscopic (part 2) routes. This second document (part 2) focuses on hysteroscopic myomectomy and considers preoperative work- up, and intraoperative techniques including fluid management, the available technologies and treatment settings. Postoperative management and follow up is also covered.. 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GnRH analogue treatment before hysteroscopic resection of submucous myomas: a prospective, randomized, multicenter study. Fertil Steril. 2010;94:1496- 9. Muzii L, Galati G, Mercurio A et al. Presurgical treatment of uterine myomas with the GnRH- antagonist relugolix in combination therapy: an observational study. Sci Rep. 2024;14:22481. Namkung J, Kang SY, Chung YJ et al. Multidisciplinary Approach in Large- sized Submucosal Myoma: Hysteroscopic Myomectomy after Uterine Artery Embolization. J Minim Invasive Gynecol. 2019;26:643- 7. Neblett 2nd MF, Stewart EA. Oral Gonadotropin- Releasing Hormone Antagonists for the Treatment of Uterine Leiomyomas. Obstet Gynecol. 2023;141:901- 10. Phillips DR, Nathanson HG, Milim SJ et al. The effect of dilute vasopressin solution on blood loss during operative hysteroscopy: a randomized controlled trial. Obstet Gynecol. 1996;88:761- 6. Phillips DR, Nathanson HG, Milim SJ et al. The effect of dilute vasopressin solution on the force needed for cervical dilatation: a randomized controlled trial. Obstet Gynecol. 1997;89:507- 11. Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence Fertil Steril. 2009;91:1215- 23. Rouholamin S, Hashemi M, Haghshenas S. The Effect of Vasopressin during Hysteroscopic Myomectomy in Patients with Submucosal Myoma: A Randomized Controlled Trial. Adv Biomed Res. 2021;10:22.. Saridogan E, Antoun L, Bousma EVA et al. European Society for Gynaecological Endoscopy (ESGE) Good Practice Recommendations on surgical techniques for removal of fibroids: part 1 abdominal (laparoscopic and open) myomectomy. Facts Views Vis Obgyn. 2024;16:263- 80. Umranikar S, Clark TJ, Saridogan E et al. BSGE/ESGE guideline on management of fluid distension media in operative hysteroscopy. British Society for Gynaecological Endoscopy /European Society for Gynaecological Endoscopy Guideline Development Group for Management of Fluid Distension Media in Operative Hysteroscopy. Gynecol Surg. 2016;13:289- 303. van Dongen H, de Kroon CD, Jacobi CE et al. Diagnostic hysteroscopy in abnormal uterine bleeding: a systematic review and meta- analysis. BJOG. 2007;114:664- 75. van Dongen H, Emanuel MH, Smeets MJ et al. Follow- up after incomplete hysteroscopic removal of uterine fibroids. Acta Obstet Gynecol Scand. 2006;85:1463- 7. van Dongen H, Emanuel MH, Wolterbeek R, Trimbos JB, Jansen FW. Hysteroscopic morcellator for removal of intrauterine polyps and myomas: a randomized controlled pilot study among residents in training. J Minim Invasive Gynecol. 2008;15:466- 71. Varma R, Soneja H, Clark TJ et al. Hysteroscopic myomectomy for menorrhagia using VersascopeTM bipolar system: Efficacy and prognostic factors at a minimum of one year follow up. Eur J Obstet Gynecol Reprod Biol. 2009;142:154- 9. Vercellini P, Zaina B, Yaylayan L et al. Hysteroscopic myomectomy: long- term effects on menstrual pattern and fertility. Obstet Gynecol. 1999;94:341- 7. Vorona G, Saridogan E. Endometrial preservation during resection of type II and type III submucosal fibroids. Facts Views Vis Obgyn. 2022;14:283- 5. Wamsteker K, Emanuel MH, de Kruif JH. Transcervical hysteroscopic resection of submucous fibroids for abnormal uterine bleeding: results regarding the degree of intramural extension. Obstet Gynecol. 1993;82:736- 40. Yang JH, Chen CD, Chen SU et al. The influence of the location and extent of intrauterine adhesions on recurrence after hysteroscopic adhesiolysis. BJOG. 2016;123:618- 23. Yang JH, Chen MJ, Wu MY et al. Office hysteroscopic early lysis of intrauterine adhesion after transcervical resection of multiple apposing submucous myomas. Fertil Steril. 2008;89:1254- 9..	None	None	None
204f5e1b194846a1935d8f050d6caabe	2024+FIGO实践建议	膀胱阴道瘘手术后疗效评估标准	# FIGO good practice recommendations to standardize the assessment of outcomes following vesicovaginal fistula surgery. Andrew Browning12 \| Lilli Trautvetter3 \| Gillian Slinger3 \| Sayeba Akhter4,5 \| Fekade Ayenachew6 \| James Chapa7 \| Yeshineh Demrew8 \| Hillary Mabeya9 \| Peter Majinge7 \| Vindhya Pathirana10 \| Thomas Raassen11. ^{1}. Correspondence. Andrew Browning, Maternity Africa, Arusha 16464, Tanzania. Email: andrew_browning@hotmail.com. Funding information. Anonymous Foundation; Texas Children's Hospital.. 1 BACKGROUND. Obstetric fistula- although prevalent in more than 60 countries with approximately two million women affected worldwide- remains a neglected public health and human rights issue.1,2 This leads to an array of medical repercussions, including: a high patient burden with . Abstract. KEYWORDS. dye test, fistula surgeon, obstetric fistula, ongoing incontinence, pad test, postvoid residual volume, surgical outcome assessment, vesicovaginal fistula surgery. a relatively small number of trained competent surgeons; inconsistent approaches to surgical treatment as well as pre- and postoperative management; and few resources to innovate and standardize practice.. Assessing outcomes following vesicovaginal fistula surgery is part of a fistula surgeon's routine work and determining these. # BOX 1 Step-by-step protocol on how to assess the surgical outcomes following vesicovaginal fistula surgery.. 1. Carry out dye test: This should be done 10-14 days postoperatively, before removing the Foley catheter. Place the patient in the lithotomy position, introduce a Sims speculum and put dye in the catheter, then ask the patient to cough. Document the results.. If the dye test is positive, check if the Foley catheter is protruding through the fistula; if it is, the catheter should be removed. If not, leave the Foley catheter in place for a further 7 days. During this time, observe if the patient is leaking any urine while waking, sitting, and/or lying in bed. Consider nursing the patient in a prone position when in bed.. If, after longer catheterization, the wetness becomes absent, leave the Foley catheter in place until the patient has been dry for 7 days. If wetness is decreasing, consider leaving the Foley catheter in place for up to 4 weeks until the patient is dry, then keep it in situ for 7 additional days. After the patient has been dry for 7 days with the Foley catheter in place, repeat the dye test.. If wetness is increasing or staying the same and the amount of urine in the drainage bag/bucket is increasing or staying the same, then the fistula is unlikely to close with further bladder catheterization. Remove the Foley catheter.. Outcome: Conclude that the fistula is not closed/repair broken and the patient is incontinent of urine. As the repair has not been successful, a repeat operation should be scheduled, usually in 3 months' time. An unsuccessful repair can be very disappointing for the patient. Patients should therefore be carefully counseled, with appropriate hygiene and ongoing emotional support.. If the dye test is negative, remove the Foley catheter, measure the voided volume and measure the postvoid residual volume of urine.. 2. Measure postvoid residual volume by asking the patient to drink sufficient fluids to ensure that her urine is clear. Throughout the next 24-48h, measure and record the patient's voided volume and postvoid residual volume of urine 3 times (even if the patient is wet). Measure postvoid residual urine volume with either an in-out catheter or, if available, a bladder scanner or ultrasound that can measure bladder volume.. If the residual volume is borderline and does not fit into the categories below, the patient should continue measuring residual volume a few more times.. If postvoid residual volume is greater than . Outcome: Conclude that the fistula is closed but that the patient has urinary retention. Teach clean intermittent self- catheterization 3- 4 times a day until the patient is emptying her bladder completely or the residual volume is less than . If postvoid residual volume is less than . The day after the Foley catheter is removed, carry out a pad test.. 3. Carry out pad test. This is a useful standardized technique to obtain an objective assessment and measurement of urinary leakage. Ask the patient to drink . If the pad is wet:. Outcome: Conclude that the fistula is closed but the patient has ongoing urinary incontinence. Investigate and plan appropriate management.. If the pad is dry:. Outcome: Conclude that the fistula is closed and the patient is continent of urine (cured). A few days after removal of the Foley catheter, arrange for discharge and usual follow- up, as long as there are no medical contraindications.. Following the above steps, a successful fistula repair closure (i.e. fistula closed and patient continent) can be determined by applying the following criteria:. The dye test is negative prior to removal of the Foley catheter (normally, between 10 and 14 days postoperatively). After the Foley catheter has been removed, the postvoid residual volume of urine is less than . accurately is critical, as the assessment will inform the surgeon's decisions regarding subsequent treatment, possibly necessitating further surgery and conservative management, including physiotherapy.. In general, postoperative clinical outcomes of vesicovaginal fistula repair surgery can be categorized as follows:. Fistula closed and patient continent of urine (cured). Fistula closed but patient has ongoing urinary incontinence.. # The dye test is negative prior to removal of the Foleycatheter (normally between 10 and 14 days postoperatively). After the Foleycatheter has been removed, the postvoid residual volume of urine is less than 100 mL and less than . FIGURE 1 Assessing outcomes following vesicovaginal fistula repair (updated flowchart originally published in FIGO Fistula Surgery Training Manual 2022).. Fistula closed but patient has chronic urinary retention. Fistula not closed/repair broken down and patient incontinent of urine.. Existing evidence suggests that ongoing urinary incontinence after fistula closure is not uncommon, with studies reporting a wide- ranging incident rate of between . Additionally, relying on patients to accurately report postoperative clinical outcomes has proven unreliable, as patients may feel obliged to give positive feedback to please the surgeon even though they may be experiencing little or no improvement after surgery.. Therefore, if postoperative clinical surgical outcomes are not correctly assessed, surgeons inevitably run the risk of discharging their patients with ongoing urinary incontinence or other associated problems and with no management plan in place. This will most likely have a devastating impact on the patients who, as a result, will continue to experience poor quality of life, which can lead to renewed and persistent marginalization from their communities, increasing . 2 \| UTILIZING ESTABLISHED PROTOCOLS TO OBJECTIVELY ASSESS SURGICAL OUTCOMES. Assessment protocols on how to objectively measure the level of urinary incontinence have been developed and published, including freely accessible publications by prominent fistula surgeons as well as limited research reinforcing the effectiveness of such tools and their validity. However, the level of awareness about these resources and their use by the fistula community is unknown.. As approaches regarding how to determine surgical outcomes continue to be inconsistent, the aim of these good practice recommendations is to provide a detailed protocol with the objective of standardizing:. (1) Assessment of surgical outcomes following vesicovaginal fistula repair;. # (2) Interpretation of results; and. (3) Ongoing management of patients.. 3 KEY RECOMMENDATIONS. The recommendations listed in Box 1, based on the expert opinions of practicing fistula surgeons, including the Fistula Surgery Training Initiative's Expert Advisory Group,16 show a step- by- step protocol on how to assess the surgical outcomes following vesicovaginal fistula surgery.. The key recommendations are shown in flowchart format in Figure 1.. 4 IMPLEMENTATION AND COST-EFFECTIVENESS. Although a variety of materials are required to carry out a complete postoperative assessment following vesicovaginal fistula repair, most of these resources are relatively low cost and should be widely available, including Foley catheters, dye, Sims vaginal specula, different types of pads, and locally available scales to weigh the pad. Procuring any missing materials can also be explored in the treatment facility or with supporting partners.. Utilizing these good practice recommendations will give clear direction to any fistula surgeon and care teams assessing patients after vesicovaginal fistula repair. As the protocol explains the different steps in terms of actions, time periods, and materials needed, the costs per patient/ assessment can easily be calculated and budgeted accordingly. Free print versions of the flowchart in A4 and A3 format in English, French, and Portuguese are also available on the FIGO Fistula Resource Hub.17. It is hoped that use of this expert- recommended tool will enhance cost- effectiveness and treatment outcomes as it will reduce the risk of the surgeon inadvertently missing something critical during the assessment, which could lead to premature discharge of the patient and subsequent return visits in future- if this is even possible- to undergo further investigations.. 5 CONCLUSION. These good practice recommendations detail the steps required for an accurate assessment of surgical outcomes following vesicovaginal fistula repair and outline the options available for correct management of a variety of different outcomes. Based on expert opinion, it is anticipated that this protocol will lead to greater uptake and standardization for fistula surgeons and their care teams, as well as contributing to the further development of a common language to facilitate discussion of fistula patients and their treatment outcomes by the fistula community. Finally, and most importantly, it is hoped that these recommendations will result in more women being discharged following . 6 EVOLVING EFFORTS TO ADDRESS ONGOING URINARY INCONTINENCE FOLLOWING VESICOVAGINAL FISTULA REPAIR SURGERY. Ongoing urinary incontinence as one of the potential surgical outcomes following vesicovaginal fistula repair poses a great challenge for fistula surgeons and patients alike. To bring this pressing issue to the forefront, FIGO, together with Hamlin Fistula Ethiopia, convened expert fistula surgeons from around the world in the Addis Ababa Fistula Hospital in early 2024 to share the latest surgical and conservative techniques for treatment and start the development of a set of good practice recommendations to specifically address the management of ongoing urinary incontinence in postrepair fistula patients. The presentations made at the workshop are available for download18 and a freely accessible position paper and detailed flowchart are currently being developed by the workshop participants for future publication.. AUTHOR CONTRIBUTIONS. Development of this article was conducted by L.T., using the FIGO Fistula Surgery Training Manual as the basis for the key recommendations. Guidance, contributions, and amendments were made by A.B. and G.S. All co- authors were invited to provide feedback. An overall review of the final draft was carried out in the presence of most co- authors.. ACKNOWLEDGMENTS. We extend our sincere thanks and appreciation to all FIGO fellows, trainers, and partners for their support of the Fistula Surgery Training Initiative.. FUNDING INFORMATION. Open Access funding for this article was financially supported by the Texas Children's Hospital and an anonymous foundation.. CONFLICT OF INTEREST STATEMENT. The authors declare no conflicts of interest.. DATA AVAILABILITY STATEMENT. Data sharing is not applicable to this article as no new data were created or analyzed in this study.. REFERENCES. 1. Adler AJ, Ronsmans C, Calvert C, Filippi V. Estimating the prevalence of obstetric fistula: a systematic review and MetaAnalysis. BMC Pregnancy. 2013;13:246. 2. Waaldijk K, Armiya'u YD. The obstetric fistula: a major public health problem still unsolved. Int Urogynecol J. 1993;4:126-128.. # 3. International Incontinence Society. ICS Glossary. Chronic (urinary) retention. Accessed May 23, 2024. Nembunzu D, Mayemba N, Sidibe S, et al. Factors associated with persistent urinary incontinence among women undergoing female genital fistula surgery in the Democratic Republic of Congo from 2017 to 2019. Front Glob Womens Health. 2022;3:896991.5. Bengtson AM, Kopp D, Tang JH, Chipungu E, Moyo M, Wilkinson J. Identifying patients with vesicovaginal fistula at high risk of urinary incontinence after surgery. Obstet Gynecol. 2016;128:945-953.6. Tadesse S, Mekete D, Negoro S, Belachew DZ, Namara GT. Urinary incontinence following successful closure of obstetric vesicovaginal fistula repair in Southern Ethiopia. BMC Womens Health. 2024;24:164.7. Goh JT, Krause H. Urinary incontinence following obstetric fistula repair. World J Obstet Gynecol. 2016;5:182-186.8. Nardos R, Jacobson L, Garg B, Wall LL, Emasu A, Ruder B. Characterizing persistent urinary incontinence after successful fistula closure: the Uganda experience. Am J Obstet Gynecol. 2022;227(70):e1-e9.9. Browning A, Menber B. Women with obstetric fistula in Ethiopia: a 6-month follow up after surgical treatment. BJOG. 2008;115:1564-1569.10. Nardos R, Phoutrides EK, Jacobson L, et al. Characteristics of persistent urinary incontinence after successful fistula closure in Ethiopian women. Int Urogynecol J. 2020;31:2277-2283.11. Kruht J, Zachoval R, Smith PP, et al. Pad weight testing in the evaluation of urinary incontinence. Neurourol Urodyn. 2014;33:507-510.12. Borazjani A, Tadesse H, Kemter A, Ayenachew F, et al. Application of the 1-hour pad-test and a novel pictorial questionnaire in the assessment of urinary incontinence following successful closure of obstetric vesicovaginal fistula. Conference abstract. ICS 2014, October 20-24, Rio de Janeiro, Brazil, Urinary incontinence following successful closure of obstetric vesicovaginal fistula repair in Southern Ethiopia, 24. 2014.. 13. Breen M. Manual of obstetric fistula surgery. The Foundation for the Global Library of Women's Medicine; 2019.14. Browning A, Hancock B. Practical Obstetric Fistula Surgery. Second ed. Halstead Press; 2022.15. Kopp D, Bengtson A, Tang J, Chipungu E, Moyo M, Wilkinson J. Use of a postoperative pad test to identify continence status in women after obstetric vesicovaginal fistula repair: a prospective cohort study. BJOG. 2017;124:966-972.16. FIGO. Fistula expert advisory group. FIGO Fistula Surgery Training Manual. Accessed May 23, 2024. FIGO. Fistula Resource Hub. Accessed May 23, 2024. FIGO. FIGO-HFE Expert Surgical Workshop in Addis Ababa. Accessed May 23, 2024. . How to cite this article: Browning A, Trautvetter L, Slinger G, et al. FIGO good practice recommendations to standardize the assessment of outcomes following vesicovaginal fistula surgery. Int J Gynecol Obstet. 2024;00:1- 5. doi:10.1002/ijgo.16017.	None	None	None
7882a087ed1b45f2b6b511a89b076e8b	2024+FIGO立场声明	机会性输卵管切除术作为卵巢癌预防策略	# FIGO position statement on opportunistic salpingectomy as an ovarian cancer prevention strategy. Danielle Mor- Hadar<sup>1</sup> \| Sarikapan Wilailak<sup>2</sup> \| Jonathan Berek<sup>3,4</sup> \| Orla M. McNally<sup>1,5</sup> \| on behalf of the FIGO Committee on Women's Cancer. <sup>1</sup>Royal Women's Hospital, Melbourne, Australia <sup>2</sup>Department of Obstetrics and Gynecology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand <sup>3</sup>Stanford University School of Medicine, Palo Alto, California, USA <sup>4</sup>Stanford Women's Cancer Center, Palo Alto, California, USA <sup>5</sup>Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Australia. Correspondence. Orla M. McNally, Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Australia. Email: orla.mcnally@thewomens.org.au. Abstract. Epithelial ovarian cancer, with the highest mortality rate among gynecologic malignancies, often goes undetected until advanced stages due to non- specific symptoms. Traditional prevention strategies such as bilateral salpingo- oophorectomy (BSO) are limited to high- risk women and induce surgical menopause, often leading to significant health concerns. Recent findings suggest that many serous epithelial ovarian cancers originate in the fallopian tubes rather than the ovaries. This has led to the hypothesis that salpingectomy, with preservation of the ovaries, may reduce the risk of ovarian cancer while avoiding the adverse effects of early menopause. Studies show that bilateral salpingectomy (BS) significantly reduces ovarian cancer incidence even in average- risk women. Bilateral salpingectomy has been demonstrated to be safe with minimal added operative time, no adverse effects on ovarian function and is also cost effective. Opportunistic salpingectomy (OS), at the time of non- gynecologic surgeries, is a promising strategy for reducing ovarian cancer risk, especially among average- risk women who have completed childbearing. It offers a safe and cost- effective alternative to traditional methods. Emerging data supports incorporating OS into standard surgical practices for benign gynecologic conditions and considering it during unrelated abdominal/pelvic surgeries after adequate patient counseling and informed consent. Further training of non- gynecologic surgeons in OS is recommended to expand its preventive benefits.. KEYWORDS. cancer prevention, opportunistic, salpingectomy. 1 \| INTRODUCTION. Epithelial ovarian cancer has the highest mortality rate of all gynecologic malignancies, with an overall five- year survival rate of . # who are diagnosed with ovarian cancer are over 60 years of age. The onset of ovarian cancer is known to be earlier for those with a genetic predisposition with an average age of 51 years for BRCA1 carriers and 61 years for BRCA2 carriers.3. When studying the ovarian cancer population overall, the majority of cases still arise in the average- risk population.4. Prevention measures that are both safe and effective are urgently needed. Currently, the only option for prevention of ovarian carcinoma is bilateral salpingo- oophorectomy (BSO), which is only recommended for high- risk women at a certain age according to their calculated risk of developing ovarian cancer and it is known to reduce the risk to about . Over the past two decades, it has become apparent and more commonly accepted that serous epithelial ovarian cancer, the most common histologic subtype of ovarian cancer, probably arises from the epithelium of the fallopian tube rather than from the ovary itself.9. Serous tubal intraepithelial carcinoma (STIC) is thought to be the precursor lesion within the fallopian tube for many high- grade serous carcinomas, carcinosarcoma and undifferentiated carcinomas.10 STIC is defined as dysplastic changes located in the fimbrial portion of the fallopian tube and has a reported incidence of . The fact that serous precursor lesions often arise in the fallopian tube has given rise to the hypothesis that salpingectomy with ovarian preservation, after the completion of childbearing, may reduce the risk of ovarian cancer, allowing longer health benefit from endogenous ovarian hormones before menopause.14,15. 2 EMERGING DATA. A growing body of published evidence supports the effect of bilateral salpingectomy on reducing ovarian cancer incidence.16- 21 While tubal ligation (TL) alone appears to reduce ovarian cancer risk by about . A recent population- based retrospective cohort study by Hanley et al. included all individuals in British Columbia, Canada, who underwent hysterectomy with bilateral salpingectomy or hysterectomy . 3 BILATERAL SALPINGECTOMY. Bilateral salpingectomy is defined as the surgical excision of both fallopian tubes, up to the tubal corner of the uterus. This procedure is often performed at the time of hysterectomy for both benign and malignant gynecologic conditions. In the absence of a diseased fallopian tube this is called an opportunistic salpingectomy (OS). OS may also be performed at the time of cesarean section; as a standalone procedure for sterilization; replacing the traditional tubal ligation (TL); or at the time of vaginal hysterectomy.. A few studies have addressed the question of safety of OS and concluded that both peri- and postoperative outcomes with or without the addition of OS were similar with rare adverse events.24 McAlpine et al. showed that the added operative time was minimal, with a mean of 16min when added to hysterectomy and 10min additional time when compared to TL.25 Moreover, there was no difference in estimated blood loss in the rate of conversion from laparoscopy to open, or in length of hospitalization.25. Another concern is that salpingectomy could affect the ovarian reserve since the ovaries and the fallopian tubes partially share the same blood supply.24 When examining hormonal status after hysterectomy with or without OS, no clinically relevant differences were found.26 A meta- analysis of studies among women opting for assisted reproductive technologies investigated the effect of salpingectomy on ovarian reserve and (for reasons other than ectopic pregnancy) found no differences.27 When looking at AMH levels, it was found that the postoperative change in AMH can vary from a substantial decrease to even a slight increase.28. In relation to cost- effectiveness, up- front risk- reducing SO carries the lowest cost and highest life expectancy; however, the value of quality of life is challenging to measure. Few studies have demonstrated the cost- effectiveness of OS over hysterectomy alone or in comparison to TL. Subramaniam et al. conducted a cost- effectiveness analysis using decision modeling to compare opportunistic salpingectomy to TL at the time of cesarean section using probabilities of procedure completion, and concluded that in women undergoing cesarean section with sterilization, OS is likely cost- effective and may be cost- effective in comparison to TL for ovarian cancer risk reduction.29 Kwon et al. examined a Markov Monte Carlo simulation model and estimated the costs and benefits of OS in a hypothetical cohort of women undergoing hysterectomy for benign gynecologic conditions or surgical sterilization. Salpingectomy with hysterectomy was less costly than. # hysterectomy alone or with BSO but more effective. For surgical sterilization, salpingectomy was more costly than TL but more effective.. 4 \| CURRENT LANDSCAPE. With the accumulating data, the two- stage approach, early salpingectomy with delayed oophorectomy as an alternative to risk- reducing BSO, is gaining popularity among high- risk women. In a study conducted on 293 BRCA carriers, more than half of the women who had yet to undergo risk- reducing surgery reported interest in having salpingectomy with delayed oophorectomy.. Hysterectomy and TL are two common gynecologic surgeries in which the fallopian tubes have usually been left in place in premenopausal women. Currently, it is well accepted to offer OS to all women undergoing hysterectomy for benign indications or seeking sterilization. The addition/change to OS is discussed with the provision of a clear overview of current evidence of benefits and risks and this approach has become the standard of care. Another consideration given the emerging evidence on the potential benefit of OS, is whether women undergoing unrelated abdominal or pelvic surgery should also be offered prophylactic OS once fertility is not pursued.. In a pilot study conducted in Austria, women over 45 who were scheduled for laparoscopic cholecystectomy were interviewed to understand potential concerns and acceptance of concomitant salpingectomy. The results suggest that most of the enrolled women were open to the possibility of concomitant salpingectomy.. 5 \| IMPLEMENTATION CHALLENGES. Clearly, removing reproductive organs in women undergoing other surgical procedures will require careful and comprehensive counseling . With the guidance of the gynecology team, surgeons in other disciplines will need to be trained to perform salpingectomy and understand the implications and the risks involved in order to obtain valid consent from the patient, bearing in mind this is a significant cost- effective strategy to prevent ovarian cancer among average- risk women.. Although salpingectomy at the time of gynecologic surgeries carries low risk, the risks may be greater when OS is performed with upper abdomen laparoscopies. Careful judgment would be required regarding when not to pursue salpingectomy; for example, in a woman with previous extensive/multiple pelvic surgeries, background of severe endometriosis, diverticulitis, or if intraoperative evaluations suggest pelvic adhesions and poor visualization or approach to the fallopian tubes.. To conclude, as BSO remains the standard of care to reduce ovarian cancer incidence in high- risk patients, FIGO (the International Federation of Gynecology & Obstetrics) firmly supports opportunistic salpingectomy. This has become an important cancer- risk- reducing strategy for average- risk women who have completed their families and are undergoing abdominal or pelvic surgery. Nongynecologic surgical subspecialties have an opportunity to contribute to the decrease in incidence of such a lethal disease and save lives by introducing OS in surgical practice where appropriate, in collaboration with gynecologic specialists for the purpose of training and patient counseling.. AUTHOR CONTRIBUTIONS. Concept: Jonathan Berek, Orla M McNally, Sarikapan Wilailak and Danielle Mor- Hadar. Draft and revision of the manuscript: Danielle Mor- Hadar and Orla M. McNally. Review: Orla M McNally, Jonathan Berek and Sarikapan Wilailak.. ACKNOWLEDGMENTS. FIGO Committee on Women's Cancer members: Professor Sarikapan Wilailak - Chair; Dr Jonathan Berek- Past- Chair; Dr Christina Fotopoulou; Dr Joanna Cain; Dr Rene Pareja; Ms Barbara Schmalfeldt; Professor Giovanni Scambia; Professor Rose Anorlu; Dr Anna Marshall; Dr Nestor Garello; Dr Kenneth Ruzindana; Dr Yolanda Ramirez; Associate Professor Orla McNally; Professor Xavier Matias- Guiu; Dr Nozomu Yanaihara and Professor Nicole Concin.. CONFLICT OF INTEREST STATEMENT. All co- authors are members of the FIGO Committee on Women's Cancer, with the exception of Danielle Mor- Hadar. The authors declare no conflict of interest.. # DATA AVAILABILITY STATEMENT. No new data were created or analyzed in this study. Data sharing is not applicable to this article.. REFERENCES. 1. Siegel RL, Miller KD, Jenial A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30. doi:10.3322/CAAC.213872. Mathis J, Jellouli MA, Sabiani L, Fest J, Blache G, Mathevet P. Ovarian cancer screening in the general population. Horm Mol Biol Clin Invest. 2020;41(3):20190038 doi:10.1515/HMBCI-2019-0038/MACHINEREADABLECITATION/RIS3. Kotsopoulos J, Gronwald J, Karlan B, et al. Age-specific ovarian cancer risks among women with a BRCA1 or BRCA2 mutation. Gynecol Oncol. 2018;150(1):85-91. doi:10.1016/J.GYNO.2018.05.0114. Swanson CL, Bakkum-Gomez JN. Options in prophylactic surgery to prevent ovarian cancer in high-risk women: how new hypotheses of fallopian tube origin influence recommendations. Curr Treat Options Oncol. 2016;17(5):20. doi:10.1007/S11864-016-0396-25. Jervis S, Song H, Lee A, et al. Ovarian cancer familial relative risks by tumour subtypes and by known ovarian cancer genetic susceptibility variants. J Med Genet. 2014;51(2):108-113. doi:10.1136/JMEDGENET-2013-1020156. Dowdy SC, Stefanek M, Hartmann LC. Surgical risk reduction: prophylactic salpingo-oophorectomy and prophylactic mastectomy. Am J Obstet Gynecol. 2004;191(4):1113. doi:10.1016/j.ajog.2004.04.0287. Mytton J, Evison F, Chilton PJ, Lilford RJ. Removal of all ovarian tissue versus conserving ovarian tissue at time of hysterectomy in premenopausal patients with benign disease: study using routine data and data linkage. BMJ. 2017;356:356. doi:10.1136/BMJ.J3728. Shuster LT, Rhodes DJ, Gostout BS, Grossardt BR, Rocca WA. Premature menopause for early menopause: long-term health consequences. Maturitas. 2010;65(2):161-166. doi:10.1016/J.MATURITAS.2009.08.0039. Chen F, Gaitskell K, Garcia MJ, Albukhari A, Tsaltas J, Ahmed AA. Serous tubal intraepithelial carcinomas associated with high-grade serous ovarian carcinomas: a systematic review. BJOG. 2017;124(6):872-878. doi:10.1111/1471-0528.1454310. Kurman RJ, Shih IM. The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded. Am J Pathol. 2016;186(4):733-747. doi:10.1016/J.AJPATH.2015.11.01111. Weinberger V, Bednarikova M, Cibula D, Zikan M. Serous tubal intraepithelial carcinoma (STIC)-clinical impact and management. Expert Rev Anticancer Ther. 2016;16(12):1311-1321. doi:10.1080/14737140.2016.124769912. Saccardi C, Zovato S, Spagnol G, et al. Efficacy of risk-reducing salpingo-oophorectomy in BRCA1-2 variants and clinical outcomes of follow-up in patients with isolated serous tubal intraepithelial carcinoma (STIC). Gynecol Oncol. 2021;163(2):364-370. doi:10.1016/J.GYNO.2021.08.02113. Przybycin CG, Kurman RJ, Ronnett BM, Shih IM, Vang R. Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am J Surg Pathol. 2010;34(10):1407-1416. doi:10.1097/PAS.0B013E3181EF7B1614. Perez-Lopez FR, Ceausu I, Depypere H, et al. Interventions to reduce the risk of ovarian and fallopian tube cancer: a European menopause and Andropause society Position statement. Maturitas. 2017;100:86-91. doi:10.1016/J.MATURITAS.2017.03.00315. Holman LL, Friedman S, Daniels MS, Sun CC, Lu KH. Acceptability of prophylactic salpingectomy with delayed oophorectomy as risk-reducing surgery among BRCA mutation carriers. Gynecol Oncol. 2014;133(2):283-286. doi:10.1016/J.GYNO.2014.02.03016. Madsen C, Baandrup L, Dehlendorff C, Kjaer SK. Tubal ligation and salpingectomy and the risk of epithelial ovarian cancer and borderline ovarian tumors: a nationwide case-control study. Acta Obstet Gynecol Scand. 2015;94(1):86-94. doi:10.1111/AOGS.1251617. Lessard-Anderson CR, Handlogten KS, Molitor RJ, et al. Effect of tubal sterilization technique on risk of serous ovarian and primary peritoneal carcinoma. Gynecol Oncol. 2014;135(3):423-427. doi:10.1016/J.GYNO.2014.10.00518. Silver AL. Tubal ligation, hysterectomy, and risk of ovarian cancer. JAMA. 1994;271(16):1235b. doi:10.1001/JAMA.271.16.1235B19. Cibula D, Widschwendter M, Majek O, Dusek L. Tubal ligation and the risk of ovarian cancer: review and meta-analysis. Hum Reprod Update. 2011;17(1):55-67. doi:10.1093/humupd/DMQ03020. Rice MS, Murphy MA, Tworoger SS. Tubal ligation, hysterectomy and ovarian cancer: a meta-analysis. J Ovarian Res. 2012;5(1):13. doi:10.1186/1757-2215-5-1321. Rice MS, Hankinson SE, Tworoger SS. Tubal ligation, hysterectomy, unilateral oophorectomy, and risk of ovarian cancer in the Nurses' health studies. Fertil Steril. 2014;102(1):192-198.e3. doi:10.1016/J.FERTNSTERT.2014.03.04122. Yoon SH, Kim SN, Shim SH, Kang SB, Lee SJ. Bilateral salpingectomy can reduce the risk of ovarian cancer in the general population: a meta-analysis. Eur J Cancer. 2016;55:38-46. doi:10.1016/J.EJCA.2015.12.00323. Hanley GE, Pearce CL, Talhouk A, et al. Outcomes from opportunistic salpingectomy for ovarian cancer prevention. JAMA Netw Open. 2022;5(2):e2147343. doi:10.1001/JAMANETWORKOPEN.2021.4734324. van Lieshout LAM, Steenbeek MP, De Hullu JA, et al. Hysterectomy with opportunistic salpingectomy versus hysterectomy alone. Cochrane Database Syst Rev. 2019;8(8):CD012858. doi:10.1002/14651858.CD012858.PUB225. McAlpine JN, Hanley GE, Woo MMN, et al. Opportunistic salpingectomy: uptake, risks, and complications of a regional initiative for ovarian cancer prevention. Am J Obstet Gynecol. 2014;210(5):471.e1-471.e11. doi:10.1016/J.AJOG.2014.01.00326. Mohamed AA, Yosef AH, James C, Al-Hussaini TK, Bedaiwy MA, Amer SAKS. Ovarian reserve after salpingectomy: a systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2017;96(7):795-803. doi:10.1111/AOGS.1313327. Kotlyar A, Gingold J, Shue S, Falcone T. The effect of salpingectomy on ovarian function. J Minim Invasive Gynecol. 2017;24(4):563-578. doi:10.1016/J.JMIG.2017.02.01428. Van Lieshout LAM, Pijlman B, Vos MC, et al. Opportunistic salpingectomy in women undergoing hysterectomy: results from the HYSTUB randomised controlled trial. Maturitas. 2018;107:1-6. doi:10.1016/J.MATURITAS.2017.09.01229. Subramaniam A, Einerson BD, Blanchard CT, et al. The cost-effectiveness of opportunistic salpingectomy versus standard tubal ligation at the time of cesarean delivery for ovarian cancer risk reduction. Gynecol Oncol. 2019;152(1):127-132. doi:10.1016/J.GYNO.2018.11.00930. Kwon JS, Mcalpine JN, Hanley GE, et al. Costs and benefits of opportunistic salpingectomy as an ovarian cancer prevention strategy. Obstet Gynecol. 2015;125(2):338-345. doi:10.1097/AOG.000000000000063031. Mohr-Sasson A, Dadon T, Perri T, Rosenblat O, Friedman E, Korach J. Prophylactic salpingectomy with delayed oophorectomy as a two-staged alternative for primary prevention of ovarian cancer in BRCA1/2 mutation carriers: women's point of view. Menopause. 2023;30(5):476-479. doi:10.1097/GME.0000000000000216832. The Role of the Fallopian Tube in Ovarian Cancer-Hematology & Oncology. Accessed November 29, 2023. Tomasch G, Bliem B, Lemmerer M, et al. Would women accept opportunistic (prophylactic) salpingectomy at the time of nongynecologic surgery to prevent development of ovarian cancer? Surgery. 2018;164(5):931-934. doi:10.1016/J.SURG.2018.03.024. borderline ovarian tumors: a nationwide case- control study. Acta Obstet Gynecol Scand. 2015;94(1):86- 94. doi:10.1111/AOGS.1251617. Lessard- Anderson CR, Handlogten KS, Molitor RJ, et al. Effect of tubal sterilization technique on risk of serous ovarian and primary peritoneal carcinoma. Gynecol Oncol. 2014;135(3):423- 427. doi:10.1016/J.GYNO.2014.10.00518. Silver AL. Tubal ligation, hysterectomy, and risk of ovarian cancer. JAMA. 1994;271(16):1235b. doi:10.1001/JAMA.271.16.1235B19. Cibal D, Widschwendter M, Majek O, Dusek L. Tubal ligation and the risk of ovarian cancer: review and meta- analysis. Hum Reprod Update. 2011;17(1):55- 67. doi:10.1093/humupd/DMQ03020. Rice MS, Murphy MA, Tworoger SS. Tubal ligation, hysterectomy and ovarian cancer: a meta- analysis. J Ovarian Res. 2012;5(1):13. doi:10.1186/1757- 2215- 5- 1321. Rice MS, Hankinson SE, Tworoger SS. Tubal ligation, hysterectomy, unilateral oophorectomy, and risk of ovarian cancer in the Nurses' health studies. Fertil Steril. 2014;102(1):192- 198. e3. doi:10.1016/J.FERTNSTERT.2014.03.04122. Yoon SH, Kim SN, Shim SH, Kang SB, Lee SJ. Bilateral salpingectomy can reduce the risk of ovarian cancer in the general population: a meta- analysis. Eur J Cancer. 2016;55:38- 46. doi:10.1016/J.EJCA.2015.12.00323. Hanley GE, Pearce CL, Talhouk A, et al. Outcomes from opportunistic salpingectomy for ovarian cancer prevention. JAMA Netw Open. 2022;5(2):e2147343. doi:10.1001/JAMANETWORKOPEN.ZO21.4734324. van Lieshout LAM, Steenbeek MP, De Hullu JA, et al. Hysterectomy with opportunistic salpingectomy versus hysterectomy alone. Cochrane Database Syst Rev. 2019;8(8):CD012858. doi:10.1002/14651858.CD012858.Pub225. McAlpine JN, Hanley GE, Woo MMN, et al. Opportunistic salpingectomy: uptake, risks, and complications of a regional initiative for ovarian cancer prevention. Am J Obstet Gynecol. 2014;210(5):471. e1- 471. e11. doi:10.1016/J.AJOG.2014.01.00326. Mohamed AA, Yosef AH, James C, Al- Hussaini TK, Bedaiwy MA, Amer SAKS. Ovarian reserve after salpingectomy: a systematic review and meta- analysis. Acta Obstet Gynecol Scand. 2017;96(7):795- 803. doi:10.1111/AOGS.1313327. Kotlyar A, Gingold J, Shue S, Falcone T. The effect of salpingectomy on ovarian function. J Minim Invasive Gynecol. 2017;24(4):563- 578. doi:10.1016/J.JMIG.2017.02.01428. Van Lieshout LAM, Pijlman B, Vos MC, et al. Opportunistic salpingectomy in women undergoing hysterectomy: results from the HYSTUB randomised controlled trial. Maturitas. 2018;107:1- 6. doi:10.1016/J.MATURITAS.2017.09.01229. Subramaniam A, Einerson BD, Blanchard CT, et al. The cost- effectiveness of opportunistic salpingectomy versus standard tubal ligation at the time of cesarean delivery for ovarian cancer risk reduction. Gynecol Oncol. 2019;152(1):127- 132. doi:10.1016/J.GYNO.2018.11.00930. Kwon JS, Mcalpine JN, Hanley GE, et al. Costs and benefits of opportunistic salpingectomy as an ovarian cancer prevention strategy. Obstet Gynecol. 2015;125(2):338- 345. doi:10.1097/AOG.000000000000063031. Mohr- Sasson A, Dadon T, Perri T, Rosenblat O, Friedman E, Korach J. Prophylactic salpingectomy with delayed oophorectomy as a two- staged alternative for primary prevention of ovarian cancer in BRCA1/2 mutation carriers: women's point of view. Menopause. 2023;30(5):476- 479. doi:10.1097/GME.0000000000000216832. The Role of the Fallopian Tube in Ovarian Cancer- Hematology & Oncology. Accessed November 29, 2023. 2012/the- role- of- the- fallopian- tube- in- ovarian- cancer/33. Tomasch G, Bliem B, Lemmerer M, et al. Would women accept opportunistic (prophylactic) salpingectomy at the time of nongynecologic surgery to prevent development of ovarian cancer? Surgery. 2018;164(5):931- 934. doi:10.1016/J.SURG.2018.03.024. # 34. Tomasch G, Lemmerer M, Oswald S, et al. Prophylactic salpingectomy for prevention of ovarian cancer at the time of elective laparoscopic cholecystectomy. Br J Surg. 2020;107(5):519-524. doi:10.1002/BJS.1141935. Matsuo K, Chen L, Matsuzaki S, et al. Opportunistic salpingectomy at the time of laparoscopic cholecystectomy for ovarian cancer prevention: a cost-effectiveness analysis. Ann Surg. 2023;277(5):E1116 -E1123. doi:10.1097/SLA.0000000000005374. How to cite this article: Mor- Hadar D, Wilailak S, Berek J, McNally OM. FIGO position statement on opportunistic salpingectomy as an ovarian cancer prevention strategy. Int J Gynecol Obstet. 2024;00:1- 5. doi:10.1002/ijgo.15884.	None	None	None
cdeb41cd89b148d78fb78e141363c2ac	2024+KSE指南	子宫内膜异位症的临床评估和管理	# Clinical evaluation and management of endometriosis: 2024 guideline for Korean patients from the Korean Society of Endometriosis. Hyun Joo Lee, MD, PhD<sup>1</sup>, Sang- Hee Yoon, MD, PhD<sup>2</sup>, Jae Hoon Lee, MD<sup>3</sup>, Youn- Jee Chung, MD, PhD<sup>4</sup>, So Yun Park, MD, PhD<sup>5</sup>, Sung Woo Kim, MD<sup>6</sup>, Yeon Hee Hong, MD<sup>6,7</sup>, Sung Eun Kim, MD<sup>8</sup>, Youjin Kim, MD, PhD<sup>9</sup>, Sungwook Chun, MD, PhD<sup>10</sup>, Yong Jin Na, MD, PhD<sup>11</sup>. Drt f t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t h t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t s t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t u t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t e t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t c t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t o t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t b t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t w t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t a t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t n t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t i t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t r t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t d t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t f t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t. Endometriosis, a prevalent but debilitating condition affecting women, poses significant challenges in diagnosis and management. The current 2024 guideline, developed by the Korean Society of Endometriosis (KSE), builds upon the 2018 KSE guideline. This guideline aims to provide customized recommendations tailored to Korea's unique clinical aspects and medical environment, and addresses key areas such as diagnosis, medical and surgical management, considerations for special populations, and its complex relationship with cancer.. Keywords: Endometriosis; Guideline; Diagnosis; Disease management; Cancer. Introduction. Endometriosis, a prevalent but debilitating condition affecting women, poses significant challenges in diagnosis and management. Although international guidelines exist, the unique clinical presentations and healthcare landscape in Korea necessitate tailored recommendations. The current 2024 guideline, developed by the Korean Society of Endometriosis (KSE), builds upon the 2018 KSE guideline and incorporates the latest evidence- based research and expert consensus to provide clinicians with comprehensive, up- to- date guidance [1]. This guideline addresses key areas such as diagnosis, medical and surgical management, considerations for special populations, and its complex relationship with cancer. The recommendations are categorized based on the strength of evidence using the grading of recommendations, assessment, development, and evaluations framework, and the details are described in Table 1.. Received: 2024.09.01. Revised: 2024.11.11. Accepted: 2024.11.24. Corresponding author: Sungwook Chun, MD, PhD Department of Obstetrics and Gynecology, Inje University Haeundae Paik Hospital, Inje University College of Medicine, 875 Haeun- daero, Haeundae- gu, Busan 48108, Korea E- mail: wooki1974@empal.com 0002- 9948- 0360. Corresponding author: Yong Jin Na, MD, PhD Department of Obstetrics and Gynecology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, 20 Geumo- ro, Mulgeum- eup, Yangsan 50612, Korea E- mail: yjna@pusan.ac.kr 0001- 6842- 3139. *These authors contributed equally and share first authorship. Articles published in Obstet Gynecol Sci are open- access, distributed under the terms of the Creative Commons Attribution Non- Commercial License ( org/licenses/by- nc/3.0/) which permits unrestricted non- commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.. Copyright © 2025 Korean Society of Obstetrics and Gynecology. # Obstetrics & Gynecology Science. Vol.68, No.1,2025. Diagnosis. Detailed history taking and physical examination are crucial to prevent delayed diagnosis, as patients may endure the disease for years before diagnosis [2,3]. Imaging studies, such as pelvic ultrasound and magnetic resonance imaging (MRI), are also notably accurate for endometriosis diagnosis. Therefore, international societies, including the European Society for Reproductive Medicine, have recommended that ovarian endometrioma and deep endometriosis (DE) be diagnosed solely upon imaging findings, excluding diagnostic laparoscopy [4].. 1. Symptoms and signs. Endometriosis should be suspected in women of childbearing age presenting with gynecological symptoms, including menstrual pain, pelvic pain, dyspareunia, fatigue, and infertility (grade D) [5]. Endometriosis should be considered in women of childbearing age with dyschezia, dysuria, painful rectal bleeding or hematuria, periodic swelling/pain at the surgical site, and cough/hemoptysis/chest pain/shoulder pain/ catamenial pneumothorax (grade D) [5].. 2. Diagnostic tools. 1) Physical examination. Pelvic and abdominal examinations should be performed in all patients with suspected endometriosis. This examination can be conducted at any point during the menstrual cycle (grade D) [6]. Painful nodules near the rectum, vagina, or fornix during a physical examination may indicate DE (grade C). Palpation of an ovarian mass during pelvic examination in women with suspected endometriosis suggests an ovarian endometrioma (grade C). Endometriosis cannot be excluded in women with suspected endometriosis, even with normal physical examination results. Additional tests, mostly based on imaging, should be considered (grade B) [7].. 2) Biomarkers. There is insufficient evidence regarding the use of biomarkers from endometrial tissue, blood, menstrual blood, and uterine fluids for diagnosing endometriosis (grade A) [8]. Further research is needed on biomarkers for endometriosis recurrence (grade C).. 3) Imaging studies and approaches thereafter. For suspected endometriosis, transvaginal or transrectal ultrasound is recommended as the initial step to confirm or exclude ovarian endometrioma (grade A) [9]. For signs or symptoms of endometriosis, transvaginal or transrectal ultrasound may help confirm or exclude DE involving the sigmoid colon and rectum (grade A) [10]. if DE is suspected, especially involving the ureters, bladder, or intestines, additional imaging such as MRI should be considered (grade D). Even if imaging studies, such as pelvic ultrasound and MRI, appear normal, endometriosis cannot be excluded (grade D). In women with suspected endometriosis, empirical medical treatment, such as gonadotropin- releasing hormone (GnRH) agonists, progestins, and combined oral contraceptives (COC), may be initiated following imaging, regardless of imaging confirmation of endometriosis (grade D) [10]. After imaging studies are conducted on women with suspected endometriosis, diagnostic laparoscopy can be performed for lesion removal and pathological confirmation. Both empirical medical therapy and diagnostic laparoscopy are viable options for managing the condition. Currently, no evidence indicates which approach is more effective, and decisions can be made through patient discussion (grade D) [1].. 3. Follow-up monitoring. Women with endometriosis, especially deep or ovarian cases, require close follow- up care (grade D). Cancer antigen- 125 (CA- 125) exhibits low sensitivity but a high positive predictive value, making it a potential option for follow- up monitoring during treatment (grade D) [8].. # Obstetrics & Gynecology Science. Hyun Joo Lee, et al. Clinical guideline for endometriosis 2024. Pelvic pain - medical treatment. 1.Nonsteroidal anti-inflammatory drugs (NSAIDs) and other analgesics. Women may be offered NSAIDs or other analgesics, alone or with other treatments, to reduce endometriosis- associated pain (grade C).. 2.Hormone treatments. Hormone therapy is based on evidence that endometriosis is 'estrogen- dependent'. The most commonly prescribed drugs for endometriosis modify the hormonal environment by suppressing ovarian activity or acting directly on steroid receptors and enzymes in lesions [11]. These include progestogens, anti- progestogens, COC, GnRH agonists, GnRH antagonists, the levonorgestrel intrauterine system (LNG- IUS), and aromatase inhibitors such as letrozole [4]. Danazol and gestrinone are no longer recommended for endometriosis- associated pain owing to their severe side effects. In the clinical setting, the magnitude of the analgesic effect has been shown to be similar for all types of medical treatments, but inevitable side effects still exist [11]. Thus, the efficacy and side effect profiles of these therapies should be individualized.. 1)COC. COCs are recommended to reduce endometriosis- associated dyspareunia, dysmenorrhea, and non- menstrual pain (grade A) [12]. Women with endometriosis- associated dysmenorrhea can be offered the continuous use of COC (grade A) [13].. 2) Progestogens (including progestogen-only contraceptives), anti-progestogens and danazol. Progestogens are recommended to reduce endometriosisassociated pain (grade A) [14]. Clinicians should take the different side- effect profiles of progestogens into account when prescribing them (grade D).LNG- IUS system or an etonogestrel- releasing subdermal implant is recommended to reduce endometriosis- associated pain (grade A) [15,16]. Danazol and gestrinone are no longer recommended as medical treatments for endometriosis- associated pain (grade C). Long- term treatment with dienogest should be individualized depending on the woman's pregnancy plan, disease recurrence, and side effects, without limiting the treatment period (grade D) [11,15,17- 19]. When receiving long- term . 3) GnRH agonist. 3) GnRH agonistGnRH agonists are recommended to reduce endometriosis-associated pain, although evidence is limited regarding dosage or treatment duration (grade A) [23]. GnRH agonists are prescribed as second-line treatment (i.e., if COC or progestogens have been ineffective) due to their side-effect profile (grade B) [21]. Clinicians should consider prescribing add-back therapy alongside GnRH agonists to prevent bone loss and hypoestrogenic symptoms (grade A) [24].. 4) GnRH antagonist. 4) GnRH antagonistGnRH antagonists can be considered for reducing endometriosis-associated pain, although evidence is limited regarding the dosage or treatment duration (grade C) [25-27]. GnRH antagonists are prescribed as second-line treatment (i.e., if COC or progestogens have been ineffective) owing to their side-effect profile (grade D) [5].. 5) Aromatase inhibitor. 5) Aromatase inhibitorFor endometriosis-associated pain refractory to other medical or surgical treatments, aromatase inhibitors are recommended. Aromatase inhibitors may be prescribed along with COC, progestogens, GnRH agonists, or GnRH antagonists (grade B) [28].. 3.Other treatment options. 3. Other treatment optionsExperts recommend that clinicians discuss non-medical strategies, such as acupuncture, physiotherapy, electrotherapy, psychological interventions, dietary interventions, and Chinese medicine, to address the quality of life and psychological well-being of women with endometriotic symptoms. However, clinicians should acknowledge that no recommendations can be made for any specific non-medical intervention to reduce pain or improve quality-of-life measures in women with endometriosis, since the potential benefits and harms are unclear (grade D) [29].. # Obstetrics & Gynecology Science. Vol.68, No.1,2025. Pelvic pain - surgical treatment. Surgical intervention may be considered for the reduction of endometriosis- associated pain (grade A). Excising endometriotic lesions is more effective than draining or ablating them in terms of pain and symptom reduction, as well as recurrence prevention (grade B).. Laparoscopy is recommended as the standard surgical method [30]. Compared to laparotomy, laparoscopic surgery has advantages, such as reduced pain, shorter hospitalization, and cosmetic aspects [31]. Compared to laparotomy, it also has the same effect on endometriosis pain [32]. Regarding robotic surgery, there was no difference in surgical results, but the robotic approach showed longer operation time compared to conventional laparoscopic surgery in certain situations [33]. Further studies are required to evaluate the cost- effectiveness of various surgical techniques.. 1.Ovarian endometrioma. Cystectomy is more effective than drainage or ablation in reducing recurrence rates and endometriosis- associated pain during the surgical treatment of ovarian endometriomas (grade B). Minimizing ovarian damage is crucial during surgical intervention for ovarian endometriomas (grade A). Preoperative assessment of Anti- Mullerian hormone levels should be considered in cases of large, recurrent, or bilateral endometriomas in women who desire future pregnancy due to the increased risk of ovarian damage (grade D).. Surgical removal of large ovarian endometriomas . 2.DE. Surgical excision of DE can reduce endometriosis- associated pain and improve the quality of life (grade B) [37,38]. Clinicians should consider referrals to tertiary care institutions to minimize complications during surgery, which often requires multidisciplinary expertise (grade D).. 3.Hysterectomy. Considering hysterectomy for severe, treatment- resistant endometriosis pain in women who do not wish to conceive or if other uterine pathologies exist is a viable treatment option . The decision to perform bilateral oophorectomy with hysterectomy should be carefully considered. Thorough patient discussions should be held before surgery, explaining that the probability of pain persisting after hysterectomy is about . 4.Adjuvant medication before and after surgery. Preoperative hormonal treatment, compared to surgery alone, is not recommended for pain management in women with endometriosis, as it does not provide significant benefits on the pain and/or recurrence reduction rate in the postoperative period (grade A) [40]. Postoperative hormonal treatment includes short- term (less than 6 months) and long- term (6 months or more) treatment, and long- term treatment aims to prevent recurrence (grade D). In women who are not planning to become pregnant, postoperative hormonal treatment may be considered for the management of endometriosisassociated pain (grade C) [40].. Infertility: assisted-reproductive techniques (ART). 1. Intrauterine insemination (IUI) after superovulation. In women with minimal or mild endometriosis- related infertility, IUI with superovulation can be performed (grade B) [1, 41]. IUI with superovulation could be considered in severe endometriosis- related infertility, although its effectiveness is unproven (grade B) [42].. 2.ART. ART can be performed in women with endometriosis- related infertility, especially when fallopian tube function is poor, male factor infertility exists, or other infertility treatments fail (grade B) [43]. Surgery is not recommended to increase the live birth rate before ART in patients with minimal or mild en. # Obstetrics & Gynecology Science. Hyun Joo Lee, et al. Clinical guideline for endometriosis 2024. dometriosis (grade A) [44,45]. Performing surgery before ART in women with ovarian endometrioma may negatively affect the ovarian reserve. However, surgery to relieve endometriosis- related pain or increase access to follicles should be considered (grade A). Surgery to remove DE before ART should be decided based on pain and patient preference, as research on whether surgery improves fertility is lacking (grade B) [46]. There is insufficient evidence to support the long- term use of gonadotropin- releasing hormone agonists to increase live birth rates before ART (grade A) [47,48]. There is insufficient evidence regarding whether long- term use of COCs or progesterone before ART increases the live birth rate (grade B) [49]. Since there is no difference in live birth rates depending on the type of gonadotropin- releasing hormone analog used during superovulation for ART, the choice of gonadotropin- releasing hormone analog can be determined based on patient and physician preference (grade B) [50,51]. ART does not worsen symptoms or cause recurrence of endometriosis (grade A) [52]. In women with endometriomas in the ovaries, the risk of ovarian abscesses after oocyte retrieval is very low; however, antibiotics can be used for prevention (grade B) [53].. 3.Preservation of fertility in patients with endometriosis. There is insufficient evidence regarding the indications, benefits, and safety of fertility preservation in women with moderate- to- severe endometriosis. However, healthcare professionals should provide thorough counseling to patients regarding fertility preservation (grade B) [54]. Women with bilateral endometriomas or those with recurrent endometriomas after surgery may consider fertility preservation before surgery for endometriomas (grade C) [55- 57]. Women who do not wish to or cannot undergo ovarian stimulation for oocyte retrieval or those who require the removal of ovaries may consider ovarian tissue cryopreservation (grade C) [56,57].. Infertility: surgical, medical, and non-medical treatments. Endometriosis can induce infertility through various mechanisms, and studies on treatments for endometriosis- associated infertility, including medical, surgical, and non- medical therapies, have been conducted to enhance natural concep . 1.Surgical treatment. For mild- revised American Society for Reproductive Medicine (IASRM) stage I/II- endometriosis- associated infertility, surgery may be considered to increase natural conception rates. Concerning pregnancy rates, laparoscopic surgery is superior to diagnostic laparoscopy (grade A) [58- 60]. In severe- IASRM stage II/IV- endometriosis, laparoscopic surgery demonstrates higher natural conception rates than expectant management (grade A) [61,62]. There is no definitive evidence that laparoscopic surgery improves fertility in DE. However, among patients experiencing clinical symptoms such as dyschezia who desire pregnancy, it can be considered a treatment option (grade D) [58- 62]. When deciding on surgery, factors such as the presence of pain, patient's age, surgical history, presence of other infertility factors, and ovarian reserve should be considered (grade D). To increase natural conception rates, ovarian cystectomy may be considered over other surgical methods, such as drainage or ablation (grade A) [63- 65]. It is important to be cautious, as ovarian reserve may diminish during surgery, potentially impacting future pregnancy rates (grade B) [66]. The endometriosis fertility index can be used to counsel patients regarding the possibility of natural conception without the need for ART after surgery for endometriosis (grade D) [67].. 2.Medical treatment. In women with endometriosis- related infertility, the use of ovarian suppression therapy, such as GnRH agonists, progesterone, or COCs, is not recommended for improving fertility (grade A) [68- 70]. Hormonal suppression therapy following surgery for endometriosis is not recommended for increasing pregnancy rates (grade A) [68]. Women who do not immediately attempt pregnancy after surgery or those who seek pain relief or aim to prevent recurrence may consider hormonal therapy following surgery for endometriosis (grade B) [69]. Using letrozole for purposes other than ovulation induction, as well as other anti- inflammatory medications, is not recommended for improving natural pregnancy rates in infertile women with endometriosis (grade A) [70]. The provision of specific nutrients or the application of non- medical alternative therapies is not recommended for infertile women with endometriosis (grade D).. # Obstetrics & Gynecology Science. Vol.68, No.1,2025. 3.Non-medical treatment. 3. Non-medical treatmentThere is no reliable evidence supporting the efficacy of nonmedical methods, such as diet, Chinese medicine, electrotherapy, acupuncture, physiotherapy, exercise, and psychological interventions, to increase the likelihood of pregnancy in women with endometriosis; therefore, they are not recommended.. Endometriosis in specific age-groups. 1.Endometriosis in pregnancy. Endometriosis in specific age- groups1. Endometriosis in pregnancyPregnancy does not always suppress the progression of endometriosis, and it is not recommended to encourage pregnancy for the treatment of endometriosis (grade C) [71,72]. Surgery should be considered if endometriosis is suspected to be atypical or if malignancy cannot be excluded (grade B). Women with endometriosis may experience an increased risk of miscarriage and ectopic pregnancy during the first trimester (grade B) [73- 75]. Complications related to endometriosis in the second and third trimesters include gestational diabetes, gestational hypertension, small for gestational age, premature rupture of membranes, preterm labor, placenta previa, placental abruption, cesarean section, and miscarriage (grade B) [73- 75]. Women with endometriosis before pregnancy can be managed with regular prenatal care unless they have high- risk endometriosis (adenomyosis, ART pregnancies, and DE). However, clinicians should be aware of potential complications (grade D). Close observation is necessary even after childbirth (grade C).. 2.Endometriosis in adolescence. 1)Diagnosis. Detailed history- taking, including age at menarche, menstrual cycle, family history, and presence of reproductive tract anomalies, is necessary for diagnosing endometriosis during adolescence (grade B) [76- 78]. Endometriosis during adolescence should be considered if chronic or acyclic pelvic pain is accompanied by nausea, dysmenorrhea, gastrointestinal disturbances, dysuria, or dyspareunia (grade B) [79]. Transvaginal ultrasonography is effective for diagnosing endometriosis, but if not feasible, transabdominal, transrectal, or transperineal ultrasonography or pelvic MRI may be considered (grade B) [79].Diagnosing endometriosis in adolescents . 2) Treatment. 2) TreatmentIf endometriosis is suspected, NSAIDs can be considered as the first-line treatment to control pain (grade B) [82]. If there is no response to NSAIDs for pain associated with endometriosis, COCs or progestins should be prescribed. However, it is important to note that some progestins may cause BMD loss (grade B) [83,84]. If COCs or progestin therapy fails, GnRH agonists with add-back therapy may be considered (grade C) [85]. Treatment may be considered to control related symptoms in adolescents with endometriosis, but high recurrence rates should be taken into account (grade C) [86,87]. If surgery is necessary, it should be performed by a skilled specialist using laparoscopy, and all lesions should be removed if possible (grade D) [88,89].. 3)Fertility preservation. 3) Fertility preservationAdolescents with endometriosis should be informed that endometriomas and the impact of surgery can decrease ovarian reserve, which may affect future fertility (grade D).. 3.Endometriosis after menopause. 3. Endometriosis after menopauseEndometriosis is steroid-dependent; therefore, its progression decreases after menopause [90]. However, some of these women continue to experience endometriosis-related symptoms even after menopause [91]. Understanding whether endometriosis remains active after menopause and its association with health issues is crucial for making careful decisions regarding treatment.. 1) Treatment. 1) TreatmentEndometriotic symptoms may persist even after menopause (grade C) [90,91]. Treatment for endometriosis may still be necessary after menopause if needed (grade B). Any pelvic masses should be carefully evaluated and addressed, as they may be cancerous (grade C).. 2) Menopausal symptom management in women with a history of endometriosis. In menopausal women who have undergone hysterectomy for endometriosis and experience vasomotor symptoms, pro. # Obstetrics & Gynecology Science. Hyun Joo Lee, et al. Clinical guideline for endometriosis 2024. gestogens should be combined with estrogen therapy, considering the higher risk of malignant transformation (grade C) [92,93]. Tibolone may be considered a second- line agent for patients who find it difficult to continue with combined estrogen- progestogen continuous HT (grade D) [92- 94]. For women with a history of endometriosis who have undergone surgical menopause at a young age, continuous combined estrogen- progestogen HT is recommended until the natural age of menopause (grade D) [95,96].. Endometriosis in special situations. 1. Asymptomatic endometriosis. No electrocauterization is required for endometriosis discovered incidentally during surgery (grade B). It is not necessary to administer medication to patients with incidentally diagnosed endometriosis (grade C) [97]. Surgical removal of a . 2. Recurrent endometriosis. When operating on patients with endometrioma, ovarian cystectomy should be performed instead of drainage or electrocauterization to prevent endometriosis- related dysmenorrhea, dyspareunia, or pelvic pain. However, the possibility of decreased ovarian reserve during surgery must be considered (grade B) [101]. For secondary prevention of endometriosis- related dysmenorrhea after surgery, LNG- IUS . 3. Primary prevention of endometriosis. The intake of vitamin D, omega- 3, dairy products, and alcohol abstinence may help reduce the risk of endometriosis (grade C) [51,107- 110]. The usefulness of COCs for the primary prevention of endometriosis is still uncertain (grade C) [111].. 4. Extrapelvic endometriosis. Endometriosis primarily affects the pelvic organs, yet approximately . 1) Diagnosis of extrapelvic endometriosis. Endometriosis should be considered in women of childbearing age who have dyschezia, dysuria, painful rectal bleeding or hematuria, periodic swelling/pain at the surgical site, and cough/hemoptysis/chest pain/shoulder pain/catamenial pneumothorax (grade D). A multidisciplinary approach is recommended for diagnosing and treating suspected extrapelvic endometriosis (grade D).. # Obstetrics & Gynecology Science. Vol.68, No.1,2025. 2) Management of extrapelvic endometriosis. Surgical resection is preferred for endometriosis in the abdominal wall, umbilicus, perineum, and inguinal region. In cases where surgery is difficult, medical treatment can be considered, such as in pelvic endometriosis (grade D) [119,120].. For thoracic endometriosis, surgical and medical treatments such as GnRH agonists, COCs, and progestins can be considered, and a multidisciplinary approach is necessary (grade D) [121]. Owing to the high recurrence rate of thoracic endometriosis, medical treatment is frequently initiated after surgical resection (grade D) [118,122].. Endometriosis and cancer. Endometriosis shares characteristics with cancer, including chronic inflammation, resistance to cell death, tissue invasion, and the presence of local and distant lesions [123,124]. Research is ongoing to understand its association with can . 1. Malignant tumors associated with endometriosis. Endometriosis does not have a high overall cancer risk but is linked to ovarian, breast, and thyroid cancers, although the absolute increase in risk compared to the general population is minimal (grade A). Clinicians should inform women that endometriosis does not significantly increase the risk of ovarian, breast, or thyroid cancers (grade D). More data are needed to predict if endometriosis will progress to cancer. Until clear risk factors for ovarian cancer in patients with endometriosis are identified, proactive measures, such as surgical oophorectomy, are not recommended (grade D).. 1) Risk assessment by cancer type. Endometriosis is associated with a relatively increased ovarian cancer risk, particularly clear- cell and endometrioid carcino. # Obstetrics & Gynecology Science. Hyun Joo Lee, et al. Clinical guideline for endometriosis 2024. mas [125- 127]. Two meta- analyses reported that the relative risk of cervical cancer is low in women with endometriosis (Table 2) [127,128]. Recent meta- analyses report that endometriosis increases the relative risk of breast cancer [128,129], particularly among individuals aged over 50 [130,131]. In a meta- analysis of five studies, endometriosis was reported to increase the thyroid cancer risk [128]. A meta- analysis of seven studies explored the link between endometriosis and melanoma and found no association, although only two studies concerning basal cell carcinoma were included, with an increased risk reported [128]. Additional research is required to fully understand these associations.. 2) Comparison with the cancer incidence rate in the general population. Risk estimates derived from recent meta- analytic data indicating elevated risks for ovarian cancer (summary relative risks [SRR], 1.93), breast cancer (SRR, 1.04), and thyroid cancer (SRR, 1.39) among women with endometriosis demonstrate that while these relative risks are higher, the absolute risks remain notably low compared to the general population (Table 3) [128,132]. Clinicians are advised to reassure women with endometriosis that despite the association with certain cancers, such as ovarian, breast, and thyroid cancer, their absolute cancer risk is minimal and akin to that of women without endometriosis [132].. 3) Factors predicting progression to ovarian cancer. Factors predicting progression to ovarian cancer include the association of endometrioma with an increased risk, whereas superficial and DE show no such correlation [133]. Studies of- . fer limited evidence regarding the predictive value of somatic mutations in DE in ovarian cancer [128]. Serum CA- 125 testing or imaging, commonly used for ovarian malignancy . 2. Cancer risk linked to the treatment of endometriosis. Clinicians should inform and reassure women with endometriosis regarding the risk of malignant tumors when using oral contraceptives for pain management or preventing recurrence (grade D) [3,137,138]. Complete removal of endometriosis and endometrioma- containing ovaries can reduce ovarian cancer risk. However, the treatment method must be decided considering the disadvantages of surgery (surgeryrelated complications, pain, decreased ovarian function, etc.) (grade D) [139,140].. 3. Monitoring to detect malignant tumors. Women with endometriosis should not undergo additional testing beyond the current cancer screening protocols (grade D). For individuals with additional risk factors, such as specific gene mutations or family history, cancer screening may be warranted following individualized guidelines (grade D).. Conclusion. ConclusionThe current 2024 guideline represents a significant advancement in the clinical evaluation and management of endometriosis for Korean patients. By integrating the latest research findings and expert consensus, this guideline offers comprehensive recommendations tailored to the specific needs of the Korean population. 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Cromer BA, Blair JM, Mahan JD, Zibners L, Naumovski Z. A prospective comparison of bone density in adolescent girls receiving depot medroxyprogesterone acetate (Depo- Provena), levonorgestrel (Norplant), or oral contraceptives. J Pediatr 1996;129:671- 6. 85. DiVasta AD, Feldman HA, Sadler Gallagher J, Stokes NA, Laufer MR, Hornstein MD, et al. Hormonal add- back therapy for females treated with gonadotropin- releasing hormone agonist for endometriosis: a randomized controlled trial. Obstet Gynecol 2015;126:617- 27. 86. Tandoi I, Somigliana E, Riparini J, Ronzoni S, Vigano' P, Candiani M. High rate of endometriosis recurrence in young women. J Pediatr Adolesc Gynecol 2011; 24:376- 9. 87. Seo JW, Lee DY, Yoon BK, Choi D. The efficacy of postoperative cyclic oral contraceptives after gonadotropin- releasing hormone agonist therapy to prevent endometrioma recurrence in adolescents. J Pediatr Adolesc Gynecol 2017;30:223- 7. 88. Stavroulis AI, Saridogan E, Creighton SM, Cutner AS. Laparoscopic treatment of endometriosis in teenagers. Eur J Obstet Gynecol Reprod Biol 2006;125:248- 50. 89. Yeung P Jr, Sinervo K, Winer W, Albee RB Jr. Complete laparoscopic excision of endometriosis in teenagers: is postoperative hormonal suppression necessary? Fertil Steril 2011;95:1909- 12 e1. 90. Bendon CL, Becker CM. Potential mechanisms of postmenopausal endometriosis. Maturitas 2012;72:214- 9. 91. Streuli I, Galtzsch H, Wenger JM, Petignat P. Endometriosis after menopause: physiopathology and management of an uncommon condition. Climacteric 2017; 20:138- 43. 92. Moen MH, Rees M, Brincat M, Erel T, Gambacciani M, Lambrinoudaki I, et al. EMAS position statement: managing the menopause in women with a past history of endometriosis. Maturitas 2010;67:94- 7. 93. Gemmell LC, Webster KE, Kirtley S, Vincent K, Zondervan KT, Becker CM. The management of menopause . # Obstetrics & Gynecology Science. Hyun Joo Lee, et al. Clinical guideline for endometriosis 2024. dent and fellow. 2nd ed. Gunja: Gunja Publishing; 2022. 106. Ota I, Taniguchi F, Ota Y, Nagata H, Wada I, Nakaso T, et al. A controlled clinical trial comparing potent progestins, LNG- IUS and dienogest, for the treatment of women with adenomyosis. Reprod Med Biol 2021;20;427- 34. 107. Parazzini F, Vigano P, Candiani M, Fedele L. Diet and endometriosis risk: a literature review. Reprod Biomed Online 2013;26:323- 36. 108. Harris HR, Eke AC, Chavarro JE, Missmer SA. Fruit and vegetable consumption and risk of endometriosis. Hum Reprod 2018;33:715- 27. 109. Nodler JL, Harris HR, Chavarro JE, Frazier AL, Missmer SA. Dairy consumption during adolescence and endometriosis risk. Am J Obstet Gynecol 2020;222:257. e1- 16. 110. Hansen SO, Knudsen UB. Endometriosis, dysmenorrhoea and diet. Eur J Obstet Gynecol Reprod Biol 2013; 169:162- 71. 111. Vercellini P, Eskenazi B, Consonni D, Somigliana E, Parazzini F, Abbiati A, et al. Oral contraceptives and risk of endometriosis: a systematic review and meta- analysis. Hum Reprod Update 2011;17:159- 70. 112. Andres MP, Arcoverde FVL, Souza CCC, Fernandes LFC, Abrão MS, Kho RM. Extrapelvic endometriosis: a systematic review. J Minim Invasive Gynecol 2020;27:373- 89. 113. Hirata T, Koga K, Kitade M, Fukuda S, Neriishi K, Taniguchi F, et al. A national survey of umbilical endometriosis in Japan. J Minim Invasive Gynecol 2020;27:80- 7. 114. Chamié LP, Ribeiro DMFR, Tiferes DA, Macedo Neto AC, Serafini PC. Atypical sites of deeply infiltrative endometriosis: clinical characteristics and imaging findings. Radiographics 2018;38:309- 28. 115. Song H, Lee S, Kim MJ, Shin JE, Lee DW, Lee HH. Abdominal wall mass suspected of endometriosis: clinical and pathologic features. Obstet Gynecol Sci 2020;63:357- 62. 116. Jang HI, Kim SE, Kim TJ, Lee YY, Choi CH, Lee JW, et al. Catamenial hemoptysis accompanied by subcutaneous endometriosis treated with combination therapy. Obstet Gynecol Sci 2017;60:236- 9. 117. Vigueras Smith A, Cabrera R, Kondo W, Ferreira H. Diaphragmatic endometriosis minimally invasive treat. ment: a feasible and effective approach. J Obstet Gynaecol 2021;41:176- 86. 118. Gil Y, Tulandi T. Diagnosis and treatment of catamenial pneumothorax: a systematic review. J Minim Invasive Gynecol 2020;27:48- 53. 119. Boesgaard- Kjer D, Boesgaard- Kjer D, Kjer JJ. Primary umbilical endometriosis (PUE). Eur J Obstet Gynecol Reprod Biol 2017;209:44- 5. 120. Saito A, Koga K, Osuga Y, Harada M, Takemura Y, Yoshimura K, et al. Individualized management of umbilical endometriosis: a report of seven cases. J Obstet Gynaecol Res 2014;40:40- 5. 121. Nezhat C, Main J, Paka C, Nezhat A, Beygui RE. Multidisciplinary treatment for thoracic and abdominopelvic endometriosis. JSLS 2014;18:e2014.00312. 122. Ciriaco P, Muriana P, Lembo R, Carretta A, Negri G. Treatment of thoracic endometriosis syndrome: a meta- analysis and review. Ann Thorac Surg 2022;113:324- 36. 123. Bulun SE. Endometriosis. N Engl J Med 2009;360:268- 79. 124. Giudice LC. Clinical practice. Endometriosis. N Engl J Med 2010;362:2389- 98. 125. Kim HS, Kim TH, Chung HH, Song YS. Risk and prognosis of ovarian cancer in women with endometriosis: a meta- analysis. Br J Cancer 2014;110:1878- 90. 126. Wang C, Liang Z, Liu X, Zhang Q, Li S. The association between endometriosis, tubal ligation, hysterectomy and epithelial ovarian cancer: meta- analyses. Int J Environ Res Public Health 2016;13:1138. 127. Li J, Liu R, Tang S, Feng F, Liu C, Wang L, et al. Impact of endometriosis on risk of ovarian, endometrial and cervical cancers: a meta- analysis. Arch Gynecol Obstet 2019;299:35- 46. 128. Kvaskoff M, Mahamat- Saleh Y, Farland LV, Shigesi N, Terry KL, Harris HR, et al. Endometriosis and cancer: a systematic review and meta- analysis. Hum Reprod Update 2021;27:393- 420. 129. Saavalainen L, Lassus H, But A, Tiitinen A, Härkki P, Gissler M, et al. Risk of gynecologic cancer according to the type of endometriosis. Obstet Gynecol 2018;131:1095- 102. 130. Ye J, Peng H, Huang X, Qi X. The association between endometriosis and risk of endometrial cancer and breast cancer: a meta- analysis. BMC Womens Health 2022;22:455. 131. Mogensen JB, Kjaer SK, Mellekmjaer L, Jensen A. Endo-. # Obstetrics & Gynecology Science. Vol.68, No.1,2025. metriosis and risks for ovarian, endometrial and breast cancers: a nationwide cohort study. Gynecol Oncol 2016;143:87- 92. 132. Bertelsen L, Mellemkjaer L, Frederiksen K, Kjaer SK, Brinton LA, Sakoda LC, et al. Risk for breast cancer among women with endometriosis. Int J Cancer 2007; 120:1372- 5. 133. Moseson M, Koenig KL, Shore RE, Pasternack BS. The influence of medical conditions associated with hormones on the risk of breast cancer. Int J Epidemiol 1993;22:1000- 9. 134. Weiss HA, Brinton LA, Potischman NA, Brogan D, Coates RJ, Gammon MD, et al. Breast cancer risk in young women and history of selected medical conditions. Int J Epidemiol 1999;28:816- 23. 135. Yu EH, Joo JK. Commentary on the new 2022 European Society of Human Reproduction and Embryology (ESHRE) endometriosis guidelines. Clin Exp Reprod Med 2022;49:219- 24. 136. Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, et al. Effect of screening on ovarian cancer mortality: the prostate, lung, colorectal and ovarian. PLCO) cancer screening randomized controlled trial. JAMA 2011;305:2295- 303. 137. Haraguchi H, Koga K, Takamura M, Makabe T, Sue F, Miyashita M, et al. Development of ovarian cancer after excision of endometrioma. Fertil Steril 2016; 106:1432- 7. e2. 138. Berlanda N, Somigliana E, Viganò P, Vercellini P. Safety of medical treatments for endometriosis. Expert Opin Drug Saf 2016;15:21- 30. 139. Melin AS, Lundholm C, Malki N, Swahn ML, Sparèn P, Bergqvist A. Hormonal and surgical treatments for endometriosis and risk of epithelial ovarian cancer. Acta Obstet Gynecol Scand 2013;92:546- 54. 140. Green A, Purdie D, Bain C, Siskind V, Russell P, Quinn M, et al. Tubal sterilisation, hysterectomy and decreased risk of ovarian cancer. Survey of Women's Health Study Group. Int J Cancer 1997;71:948- 51. 141. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck- Ytter Y, Alonso- Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924- 6..	None	None	None
ae65f64cf4fe468494464e9e2f5f1b88	2024+RCOG指南	门诊宫腔镜检查（No.59）	# Outpatient Hysteroscopy. (Green- top Guideline no. 59). Prathiba M. De Silva \| Paul P. Smith \| Natalie A. M. Cooper \| T. Justin Clark \| on behalf of the Royal College of Obstetricians and Gynaecologists. Correspondence. Royal College of Obstetricians and Gynaecologists, 10- 18 Union Street, London SE1 1SZ. Email: clinicaffectiveness@rcog.org.uk. This is the second edition of this guideline. The first edition of the guideline was published under the Best Practice in Outpatient Hysteroscopy title in 2011.. Key recommendations. All gynaecology departments should provide a dedicated outpatient hysteroscopy service to aid care of women and people with abnormal uterine bleeding, reproductive problems, and insertion/retrieval of intrauterine devices. [Grade A] Written information should be provided to the woman prior to their appointment. This should include details about the procedure, the benefits and risks, advice regarding pre- operative analgesia, as well as alternative options for care and contact details for the hysteroscopy unit. [Good Practice Point] Women should be made aware of other settings and modes of anaesthesia for hysteroscopy (e.g. under general or regional anaesthesia or intravenous sedation). [GPP] The woman should be advised that if they find the procedure too painful or distressing at any point, they must alert the clinical team who will stop the procedure immediately. The clinical team should alert the hysteroscopist if the woman appears to be in too much pain or is experiencing a vasovagal episode and therefore unable to voice the concerns so that the procedure can be stopped. [GPP] Women should be advised to take standard doses of oral non- steroidal anti- inflammatory agents (NSAIDs) one hour before their scheduled appointment. Vaginoscopy should be the standard technique for outpatient hysteroscopy unless the use of a vaginal speculum is required (e.g. for administering local cervical anaesthesia or dilating the cervix). [Grade A] When performing operative hysteroscopy, the smallest diameter hysteroscope should be used, with consideration given to the use of hysteroscopes with expandable outer working channels because they are associated with less pain. [Grade B] Mechanical hysteroscopic tissue removal systems should be preferred over miniature bipolar electrodes to remove endometrial polyps. [Grade A] Local anaesthesia should not be routinely administered prior to outpatient hysteroscopy where a vaginoscopic approach is used. It should be considered where use of a vaginal speculum is planned e.g. for cervical dilatation if anticipated, due to either cervical stenosis and/or the utilisation of larger diameter hysteroscopes . # 1 PURPOSE AND SCOPE. The aim of this guideline is to provide clinicians with up to date, evidence- based information regarding outpatient hysteroscopy, with particular reference to minimising pain and optimising the experience of the woman or person. The scope has been widened since the first edition to cover operative outpatient hysteroscopy, prevention of infection, training, and documentation. This guideline should be read in conjunction with the RCOG Good Practice Paper No. 16 Pain Relief and Informed Decision Making for Outpatient Hysteroscopy.. It is important to acknowledge that it is not only women for whom it is necessary to access women's health and reproductive services in order to maintain their gynaecological health and reproductive wellbeing. Gynaecological and obstetric services and delivery of care must therefore be appropriate, inclusive and sensitive to the needs of those individuals whose gender identity does not align with the sex recorded at birth.. 2 INTRODUCTION AND BACKGROUND EPIDEMIOLOGY. Outpatient hysteroscopy is an established diagnostic and therapeutic procedure,2- 4 widely used across the UK.5- 7 The procedure involves the use of miniaturised endoscopic equipment to directly visualise the uterine cavity, without the need for intravenous sedation or regional/general anaesthesia necessitating the use of formal theatre facilities. However, women or people should be made aware of other settings and modes of anaesthesia for hysteroscopy (e.g. procedure under general or regional anaesthesia, intravenous sedation) as an alternative to outpatient hysteroscopy. Outpatient hysteroscopy is indicated primarily in the assessment of women or people with abnormal uterine bleeding2- 4 but is also employed in the diagnostic work up of reproductive problems. Advances in endoscopic technology and ancillary instrumentation have facilitated the development of operative hysteroscopic procedures in an outpatient setting with or without the use of local anaesthesia. Common procedures include endometrial polypectomy,7,9,10 removal of submucous fibroids,11 endometrial ablation,12- 15 removal of chronic retained products of conception16 and retrieval of lost intrauterine devices.17. Outpatient hysteroscopy, whether diagnostic2,18 or operative7,9- 17 is successful, safe and well tolerated by most women. However, as with any procedure requiring instrumentation of the uterus, outpatient hysteroscopy can be associated with significant pain,19,20 anxiety and embarrassment.21,22. This not only impacts upon the satisfaction of women with their experience, but also limits the feasibility and possibly the safety, accuracy and effectiveness of the procedure. In order to minimise pain and discomfort, variations in hysteroscopic equipment, adaptations in technique and use of pharmacological agents have been advocated. This guideline assesses these components along with issues relating to optimal service provision.. 3 IDENTIFICATION AND ASSESSMENT OF EVIDENCE. Four databases (MEDLINE, EMBASE, CINAHL, Cochrane) were systematically searched from inception to March 2023. No restrictions were placed on the searches in an attempt to reduce selection bias. The databases were searched using relevant MeSH terms and keywords. The main keywords used were 'hysteroscopy', outpatient', office' and ambulatory' which were combined with the following words depending upon the area of hysteroscopy being examined; analgesia,analgesic,local anestheticlocal anesthesia, local anaesthetic, local anaesthesia, local infiltration, tetracaine,procaine,prilocaine, lidocaine,ethyl chloride, emla cream, cocaine,bupivacaine, benzocaine, sedation, sedative, hypnotic,tranquilizing agents, 'cervical ripening,prostaglandin,estrogen, oestrogen,progestin, laminaria, mifepristone, dilapan,progesterone, gestagen, cervical dilatation, cervical ripening, cervical preparation, cervix dilatation and effacement, no touch', vaginoscopy, 'vaginoscopic, sodium chloride, carbon dioxide, glycine, mannitol, sorbitol, saline, dextrans, glucose, distension media, distension medium, hysteroscope, endometrial ablation, flexible, rigid, diameter, size, angle, infection,sepsis, endometritis, antibiotic, and pyometra. The results of the searches were systematically reviewed to include randomised controlled trials or systematic reviews of randomised controlled trials only, in order to capture the highest level of evidence for the basis of this guideline. The definitions of the types of evidence used in this guideline originate from the Scottish Intercollegiate Guideline Network (SIGN) methodology and developed in accordance with the standard methodology for producing RCOG Green- top Guidelines.23. Where possible, recommendations are based on, and explicitly linked to, the evidence that supports them. Areas lacking evidence are highlighted and annotated as good practice points' (GPP), which were agreed upon by consensus at the British Society for Gynaecological Endoscopy (BSGE) Ambulatory Care Network (ACN) Meeting, held virtually on Friday 18th June 2021.24. # 4 SERVICE PROVISION. 4.1 What are the requirements for running an effective outpatient hysteroscopy service?. An outpatient hysteroscopy service offers a safe, convenient and cost- effective means of diagnosing and treating abnormal uterine bleeding, as well as aiding the management of reproductive problems and insertion/retrieval of intrauterine devices.26 A randomised controlled trial reported rapid mobilisation post- operatively (0 minutes [0- 5] versus 105 minutes [80- 120], . Outpatient hysteroscopy should be performed in an appropriately sized and fully equipped treatment room. This may be a dedicated hysteroscopy suite or a multipurpose facility. Outpatient hysteroscopy can be associated with substantial anxiety21 and so the treatment room should be private and patient friendly, with a separate, and ideally . Appropriate staffing levels are required and these will vary according to local circumstances (patient populations, numbers seen per clinic) and the type of service offered (concomitant pelvic ultrasound, pure diagnostic service or diagnostic and therapeutic service). In general, there will be a complement of ideally three, but a minimum of two, support staff, consisting of at least one registered nurse and one healthcare assistant. One of the staff members should act as an advocate for the women during the procedure to provide reassurance, explanation and support. Communication with the woman in this way may help alleviate anxiety. If the woman wishes for a partner or friend to be present during their appointment, this wish should be accommodated, unless infection control precautions prevent this. [Evidence level 4]. 4.2 What information should be provided prior to outpatient hysteroscopy?. Adequate, clear and simple, written information should be provided to the woman with the appointment letter, in. # the preferred language for the woman where possible. This information should include the recommendation to take oral pain relief (see section 5) one hour before their scheduled appointment. It should also provide details about what the procedure entails, benefits and risks (including pain), and alternative options for care (e.g. alternatives to undergoing an outpatient hysteroscopic procedure) and pain- relief (e.g. inhaled analgesia, local anaesthesia etc.). Where simultaneous treatments are offered ('see and treat' services), it is important that this fact is reflected in the patient information to facilitate informed choice. In addition, the provided information should make women aware that there are alternative types of pain management (e.g. intravenous sedation, regional or general anaesthesia) that they can choose if they have concerns about undergoing hysteroscopy in the outpatient setting or if the procedure needs to be abandoned at the woman's request. Women and people should be aware that these alternative options can be discussed at their clinic appointment and that their hysteroscopy can be rescheduled to accommodate their preferred model of care and pain management as necessary.8. It is important to recognise that hysteroscopy can cause more pain and trauma for some women, but predicting such adverse experiences can be difficult. However, women should be made aware that an outpatient procedure may be more painful and traumatic for them if they have experienced:. - Faintness during their menstrual period because of pain- Severe pain or anxiety during previous vaginal examinations, including undergoing cervical smears- Traumatic events especially sexual violence.. Women should also be provided with up to date local contact details, should they have any questions or concerns before their procedure.. If a woman attending her appointment is unaware that she has been referred for an OPH, then she should be given the opportunity to reschedule the hysteroscopy after being given written and verbal information, once she has had time to consider her options. Similarly, any woman who is unsure whether she wants to proceed with an OPH should be allowed more time to make a decision and offered a further appointment.. Units are advised to access the joint Royal College of Obstetricians and Gynaecologists (RCOG) and British Society for Gynaecological Endoscopy (BSGE) standards for further guidance, however, the information may vary according to local circumstances and the type of service offered. Women should be directed to, or provided with, the joint Royal College of Obstetricians and Gynaecologists (RCOG) and British Society for Gynaecological Endoscopy (BSGE) patient information on outpatient hysteroscopy, in the absence of adequate, contemporary local patient information based on the RCOG patient information or to supplement the local resources.31. 4.3 \| How should consent be obtained prior to outpatient hysteroscopy?. The clinical team should be mindful of the fact that arrival of the woman or person at the clinic does not imply consent has been given for the procedure. The hysteroscopist is the responsible clinician and must be certain that the woman has had sufficient information and enough time for consideration to give informed verbal and written consent on the day of their procedure. Units should consider providing women with a pre- prepared written or electronic consent form for them to review before attending their appointment. Their appointment should be rescheduled if the women feels that they need more time to consider their decision, especially if they have not received or read the pre- procedural patient information prior to attending.1. The hysteroscopist must inform the woman that they are likely to experience period- like cramping and lower abdominal pain during and/or after the procedure. However, the woman or person should be advised that if they find the procedure too painful or distressing at any point, then they must alert the clinical team who will stop the procedure immediately. The clinical team should alert the hysteroscopist if the woman appears to be in too much pain or is experiencing a vasovagal episode and therefore is unable to voice their concerns so that the procedure can be stopped. The team should then make subsequent arrangements for the hysteroscopy to be rescheduled and to involve an alternative type of pain management (e.g. intravenous sedation, regional and general anaesthesia) or consider alternative options for ongoing management in agreement with the woman.1. The RCOG and BSGE, in conjunction with NHS England and NHS Improvement "Getting it Right First Time. # (GIRFT)" programme, have recently developed relevant standardised consent documents for outpatient hysteroscopy, operative hysteroscopy and endometrial ablation.32- 34. This should include the indication for the procedure, what it involves, any additional procedures that may be necessary, possible adverse effects, and the benefits and risks when compared to other alternative options for care, which should encompass other settings and modes of anaesthesia for hysteroscopy. [Evidence level 4]. 4.4 Should a pre-procedural safety checklist be performed prior to outpatient hysteroscopy?. Units should consider using a checklist (e.g. a specifically adapted World Health Organisation [WHO] surgical safety checklist35 or a locally developed outpatient procedure safety standard checklist) to make sure essential elements such as patient identity checks, allergy status and exclusion of pregnancy are recorded where appropriate. If the woman or person declines to provide a pregnancy test and states that they are definitely not pregnant, their wishes should be respected should they want to proceed with hysteroscopy. While involving women in a checklist can be empowering, for others, it may make the outpatient setting feel more like an operating theatre and induce anxiety. Units should therefore consider how and when they complete the safety checklist prior to the outpatient hysteroscopy. In self- contained, enclosed clinical areas with adjoining procedure rooms and changing areas, safety checks can be completed with the woman during the pre- procedural consultation. If safety checks are undertaken in the procedure room, women should not be unnecessarily exposed during the process.. A urinary pregnancy test should either be undertaken routinely in women who are premenopausal and sexually active, or based upon the timing of their last menstrual period and history of unprotected sexual intercourse. If unable to exclude a pregnancy, based upon recent unprotected sexual intercourse and the fact that it may be too early for a urinary pregnancy test to provide a reliable result, then the woman . A checklist which captures the following information is suitable for use in outpatient hysteroscopy:. Date Confirmation of identification (3 identifiers; e.g. name, date of birth, address) Discussion of alternative pain management and settings in which these will be offered (e.g. intravenous sedation, regional/general anaesthesia in a day- case theatre setting) Consent performed (verbal and / or written) Allergy status Exclusion of pregnancy (with urinary pregnancy test if applicable) Details of whether and what pre- procedural analgesia has been taken (including timing and dose). [Evidence level 4]. 4.5 How should care after outpatient hysteroscopy be provided?. Following the procedure, the woman or person should be given time to change back into their clothes for a post- procedure consultation, which should ideally take place away from the procedure area. The hysteroscopist should. # explain the clinical findings and explain when and how histological/cytological/microbiological results will be communicated, if appropriate. If further care is required, it should be discussed in light of the clinical findings, and the woman should be informed when and how this will take place. This information should be summarised and written copies given to both the woman and their general practitioner (GP).1 [Evidence level 4]. The woman should be given post- procedural information, ideally both verbally and written. This should include contact numbers (e.g. a direct line to the clinic and an out of hours contact number) should the woman have any problems or concerns over the next two weeks. In particular, women should be told to make contact if they experience abdominal pain not controlled with simple analgesia, bleeding heavier than a period, or symptoms/signs of sepsis (fever, rigors and/ or malodourous vaginal discharge). [Evidence level 4]. Women or people may prefer to leave after their postprocedure consultation without staying for a period of observation. However, recuperation and refreshments should be offered to all women in a dedicated recovery area with comfortable chairs/recliners and privacy (e.g. curtained off areas with bed(s)/trolley(s)). The woman's condition, comfort and pain control should be assessed, monitored and analgesia be provided when necessary. Access should be available to a longer duration recovery area when pain cannot be easily managed or complications have arisen during the procedure.1 [Evidence level 4]. 4.6 How should training and standards in outpatient hysteroscopy be provided and assessed?. The RCOG offers a Special Interest Training Module in "Therapeutic Hysteroscopy" which requires competence in hysteroscopy.36 The European Society for Gynaecological. Endoscopy (ESGE) has developed a diploma programme for laparoscopic and hysteroscopic skills training, known as the Gynaecological Endoscopic Surgical Education and Assessment Minimally Invasive Gynaecological Surgery (GESEA MIGS) Diploma, of which there are two hysteroscopy modules of different levels of difficulty (Hysteroscopic Skills Training and Testing method [HYSTT 1 and 2]).37 These curricula not only cover hysteroscopic procedures but also pre- operative planning, case selection and service development. [Evidence level 4]. Achievement of competency in outpatient hysteroscopy requires having the opportunity to undertake training in the clinical setting on women while they are awake. It is important to consider, however, that this may lead to a prolonged procedure time and in turn impact upon the woman or person's experience. Training packages have tried to address this by using various models and simulators in order to improve psychomotor skills and performance. As illustrated by a systematic review on training and assessment of hysteroscopic skills, vegetables (e.g. potatoes, pears, butternut squash etc.), animal organs (e.g. porcine hearts, pig bladders, cattle uteri, etc.) and synthetic models (e.g. HYSTT box trainer [European Academy of Gynecological Surgery, Leuven, Belgium]) have been used to simulate intrauterine pathology, allowing for the development of a variety of different hysteroscopic skills (e.g. fibroid resection, septoplasty, etc.).38 Virtual reality simulators (e.g. HystSimTM [VirtaMed AG, Zurich, Switzerland]) have a variety of pathologies and cases that the user can access, allowing for a standardised environment where data can be collected to allow an objective assessment of the trainee's performance.. Clinicians undertaking outpatient hysteroscopy clinics should have sufficient workload in the job plan to maintain competencies and enhance their skills. Clinicians are expected to review their clinical outcomes and participate in audits for quality assurance purposes (refer to Auditable Topics).. 5 Analgesia. 5.1 What analgesia should be recommended prior to outpatient hysteroscopy and how should it be given in order to reduce the pain felt by women during and after their procedure?. # A systematic review and meta- analysis39 identified twenty- two randomised controlled trials (RCTs)41- 62 examining the use of analgesics against a control prior to outpatient hysteroscopy for the reduction of pain.. Meta- analysis showed a statistically significant reduction in intra- procedural (standardized mean difference [SMD] . There was a statistically significant reduction in intra- procedural (SMD . A statistically significant reduction in intra- procedural (SMD . Meta- analysis showed a statistically significant reduction in intra- procedural (SMD . Three trials40,63,64 have been published since the aforementioned systematic review39 was performed. The first trial64 randomised postmenopausal women undergoing diagnostic hysteroscopy to tramadol or placebo, and was in keeping with the conclusions of the aforementioned systematic review. The second trial63 randomised women undergoing diagnostic hysteroscopy and directed biopsy or operative hysteroscopy to either oral diclofenac, oral diclofenac and hyoscine, or placebo. Their findings contrasted slightly with the systematic review because a significant reduction in intra- procedural pain with oral diclofenac was restricted to women with a prior history of chronic pelvic pain . There has been recent interest in using another inhalational agent called Penthrox® (methoxyflurane) as an easily administered, short acting, pain control solution for ambulatory procedures like hysteroscopy. Penthrox® is anaesthetic agent which is self- administered through a custom- built handheld inhaler and is currently used for the relief of moderate to severe trauma- associated pain in emergency. # settings.. 6 \| CERVICAL PREPARATION. 6.1 \| Should cervical preparation be used in order to facilitate outpatient hysteroscopy?. Uterine trauma (lacerations to the cervix or uterine perforation) is recognised with blind and endoscopic instrumentation of the uterus,. A systematic review and meta- analysis. Prostaglandins are associated with gastrointestinal side- effects and are contraindicated in severe uncontrolled asthma, chronic adrenal failure, acute porphyria and renal or hepatic impairment.. # vomiting, diarrhoea, pyrexia/fever and vasovagal episodes. The incidence of complications were too small and balanced between groups for meta- analysis, and were only reported in studies randomising women to either misoprostol or placebo/nil.46,49,76,78,81,84,86- 89,91- 94 These included cervical trauma . One of the main reasons for failure to successfully perform an outpatient hysteroscopy is the inability to access the uterine cavity due to cervical stenosis, and this is most commonly encountered in a postmenopausal population. The previously mentioned systematic review,68 showed that administration of cervical preparation was associated with significantly greater cervical dilatation prior to hysteroscopy (gauged by the size of Heggardilator the cervical canal could accommodate), when compared with placebo (SMD 0.81, . No comparative studies were identified for other methods of cervical dilatation prior to outpatient hysteroscopy (e.g. local / systemic administration of oestrogens or osmotic agents).. 7 TYPE OF HYSTEROSCOPE. 7.1 What size and angle of hysteroscope should be used in the outpatient setting?. A systematic review and meta- analysis97 identified seven RCTs99- 105 examining how the diameter of the outer sheath of the hysteroscope affected pain during outpatient hysteroscopy. Women randomised to mini- hysteroscopes (outer diameter . A systematic review106 identifying the operative devices used in outpatient hysteroscopy to determine which technologies confer the least pain, found one randomised controlled trial98 comparing hysteroscope diameters for operative hysteroscopy in the outpatient setting. Women randomised to the use of a semi- rigid hysteroscopic system (AlphascopeTM [Gynecare, division of Ethicon, NJ, USA]) with a collapsible sheath . # of adverse events minimal and balanced between groups . There were no studies comparing the outer diameters of mechanical hysteroscopic tissue removal (mHTR) systems for the reduction of pain in operative hysteroscopy, however, these are generally between 5 and . No studies were identified that compared . 7.2 \| Should rigid or flexible hysteroscopes be used routinely in the outpatient setting?. Two, small randomised controlled trials compared the pain experienced during outpatient hysteroscopy with the use of a flexible hysteroscope versus a rigid hysteroscope. [108,109] Both found that the use of the flexible hysteroscope significantly reduced pain during the procedure . 7.3 \| What devices should be used for operative procedures in the outpatient setting?. A systematic review [106] identifying the operative devices used in outpatient hysteroscopy to determine which technologies confer the least pain, found seven randomised controlled trials [10,112- 116] investigating technologies for endometrial polypectomy, two trials [17,118] investigating endometrial ablation devices, and one trial [111] for uterine septoplasty.. Two trials [10,113] compared the use of a bipolar electrode (using a 5Fr Versapoint [Gynecare, division of Ethicon, NJ, USA] mini- electrode) for polypectomy, against a mHTR system (TruclearTM 5mm system [Medtronic, MN, USA]) that allows for simultaneous cutting and aspiration of polyp tissue. While the earlier study, which was larger and of higher quality, found a significant reduction in pain during polypectomy when using a mHTR system . # serious complications (e.g. uterine perforation), reported in either group. When patient satisfaction was reported, there was a statistically significant preference for the use of the mHTR system . In the two trials, comparing endometrial ablation devices, women were randomised to either bipolar radiofrequency impedance- controlled ablation (Novasure [Hologic, MA, USA]), thermal balloon ablation (Thermachoice III [Gynecare, division of Ethicon, NJ, USA] or Thermablate [Idoman Teoranta, Toronto, Canada]). Pain scores were not significantly different with the use of either device type, however, these older devices have been replaced by smaller- diameter and more rapid ablative technologies (e.g. Novasure ADVANCED [Hologic, MA, USA], LiNA LibrataTM [LiNA Medical, Glostrup, Denmark], MinitouchTM [MicroCube, Fremont, CA, USA] etc.). [Evidence level 4]. One small randomised controlled trial compared the use of inactivated 7Fr mini- scissors against a bipolar electrode (using a 5Fr VersapointTM [Gynecare, division of Ethicon, NJ, USA] mini- electrode) through an expandable . 8 DISTENSION MEDIUM. 8.1 Which uterine distension medium should be used during outpatient hysteroscopy?. A systematic review and meta- analysis investigating the optimal distension media for outpatient hysteroscopy identified . Meta- analysis showed no significant difference in intra- procedural pain102,120- 126 (SMD - 0.12; 95% CI - 0.36 to 0.13) or post- procedural pain (immediately after,122 1 minute after127 and 15 minutes102 after hysteroscopy) (SMD 5.54; 95% CI - 2.34 to 13.43) between saline and carbon dioxide, however, after excluding the lower quality study,127 a statistically significant reduction in post- procedural pain was demonstrated with the use of saline102,122 (SMD - 0.65; 95% CI - 1.14 to - 0.16). There was a statistically significant reduction in hysteroscopies with an unsatisfactory view with saline (Peto OR, 0.38; 95% CI 0.22- 0.66).102,120,122,124,125 Women randomised to saline had significantly fewer side- effects compared to women randomised to carbon dioxide (Peto OR, 0.29; 95% CI 0.20- 0.40).102,120- 127 Vasovagal symptoms (e.g. nausea, vomiting, dizziness, and fainting) . Saline allows for the efficient practice of "see and treat" services, where diagnosis is immediately followed by treatment, in the same outpatient hysteroscopy appointment. Furthermore, it is isotonic, which minimises risks associated with fluid overload and conducts electricity to allow for the operation of miniature bipolar electrosurgical electrodes.136 Finally, saline is the distension medium of choice when using hysteroscopic tissue retrieval systems, as the use of carbon dioxide with these devices has not been evaluated. [Evidence level 3]. 8.2 How should uterine distension media be delivered during outpatient hysteroscopy?. # Fluid instillation methods and the effect on pain, acceptability and feasibility have not been compared for outpatient hysteroscopy, however, current approaches include:25,107. Use of automated fluid management systems, e.g. setting initial intrauterine pressures at . Fluid instillation methods and the effect on pain, acceptability and feasibility have not been compared for outpatient hysteroscopy, however, current approaches include:25,107- Use of automated fluid management systems, e.g. setting initial intrauterine pressures at . that the flow rate of distension media through the hysteroscope and subsequent uterine pressure will depend on the hysteroscope diameter, fluid reservoir height and dynamic losses.Four randomised controlled trials132- 135 allowed for the meta- analysis of pain scores of women randomised to either saline at room temperature or warmed saline in the previously mentioned systematic review,119 of which three132- 134 reported intra- procedural pain and all four reported post- procedural pain (recorded immediately after,135 and at 1,132 . 9 LOCAL ANAESTHESIA AND CERVICAL DILATATION. 9.1 Should routine dilatation of the cervical canal be performed prior to insertion of the hysteroscope in the outpatient setting?. Blind dilatation of the cervix in order to instrument the uterine cavity is commonly performed under general anaesthesia and is associated with cervical and uterine trauma.2,71- 74 However, in the outpatient setting, dilatation of the cervix causes pain and discomfort and generally requires the use of local anaesthesia.1 No RCTs examining the routine or selective use of blind cervical dilatation prior to outpatient hysteroscopy were identified.68. # 9.2 Should local anaesthesia be administered prior to outpatient hysteroscopy?. A systematic review and meta- analysis138 identified 37 RCTs42,47,51,55,58,82,105,124,139- 167 examining pain in women undergoing outpatient hysteroscopy randomised to receive either a local anaesthetic or a control. Meta- analysis showed that administering local anaesthesia significantly reduced pain during outpatient hysteroscopy (SMD . The clinical significance for the demonstrated reduction in average pain scores remains unclear, especially when considering that few studies commented on the impact of the reduction in pain on satisfaction and acceptability of administration of local anaesthesia when compared to their control. In studies where a placebo was administered, instead of a local anaesthetic, a lower than expected difference in mean pain was likely observed because instillation of placebo into the cervix/uterus still causes pain. A systematic review168 investigating the impact of the vaginoscopic approach on pain in outpatient hysteroscopy identified one RCT randomising women to either hysteroscopy with intracervical mepivacaine or to hysteroscopy using the vaginoscopic approach.169 This found a significant reduction in pain both during . 9.3 Which local anaesthesia should be administered and how should it be given prior to outpatient hysteroscopy?. # In the previously mentioned systematic review and meta- analysis,138 subgroup analyses were performed in order to identify the specific local anaesthetic agents that were effective in reducing pain during and after outpatient hysteroscopy, when compared to nil or placebo. Bupivacaine, a long- acting local anaesthetic, produced the greatest reduction in intraprocedural pain (SMD - 4.27, . The same systematic review and meta- analysis138 also performed subgroup analyses to identify which specific routes of local anaesthesia administration led to a reduction in pain during and after outpatient hysteroscopy. Topical (application of local anaesthesia directly onto the ectocervix), transcervical (instillation of local anaesthesia through the cervix via either a cannula or within the distension medium), intracervical (injection of local anaesthesia directly into the ectocervix) and paracervical (injection of local anaesthesia into the cervicovaginal junction) routes were investigated when given in an outpatient setting. All routes of administration were associated with a significant reduction in pain during outpatient hysteroscopy when compared against placebo or nil; this encompassed the topical (SMD - 0.36, . A randomised controlled trial found that giving intrauterine fundal anaesthesia, using a combination of mepivacaine and bupivacaine, during outpatient hysteroscopy three minutes prior to outpatient endometrial ablation, showed a statistically significant reduction in intra- procedural (SMD - 0.49, . Unless given within the distension media,124 local anaesthesia in the aforementioned systematic review and meta- analysis138 was given two minutes (lidocaine),147,152 . 10 \| CONSCIOUS SEDATION. 10.1 \| Should conscious sedation be used to reduce pain associated with outpatient hysteroscopic procedures?. Sedation induces a depression in consciousness, which ranges from minimal sedation and anxiolysis, through to moderate or 'conscious' sedation, deep sedation, and finally ending with general anaesthesia. While responsiveness is always suppressed, as the level of sedation becomes deeper, so does the potential ability of the woman to maintain their airway, ventilation and cardiovascular function.173 Conscious sedation is therefore defined as a drug- induced depression of consciousness during which women respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation" (i.e. not a painful stimulus) where "no interventions are required to maintain a patent airway when. # spontaneous ventilation is adequate" and "cardiovascular function is usually maintained".174. spontaneous ventilation is adequate" and "cardiovascular function is usually maintained".<sup>174</sup>A systematic review and meta- analysis<sup>171</sup> investigating the role of conscious sedation against suitable controls for the control of pain for outpatient hysteroscopy, included seven RCTs.<sup>44,55,56,60,151,175,176</sup> Intravenous conscious sedation, when compared with local anaesthesia, reduced pain during (SMD . Inhaled conscious sedation (in the form of . Because sedative drugs depress the central nervous system and have the potential to impair respiration, circulation or both, close monitoring of the woman or person must be undertaken by a designated staff member, separate to the hysteroscopist, to ensure maintenance of vital observations (heart rate, blood pressure, respiratory rate, pulse oximetry, with electrocardiography and capnography performed where appropriate) peri- and post- procedurally, in accordance with guidance produced by the Academy of Medical Royal Colleges.<sup>172</sup> This individual must be able to identify a woman who becomes over sedated and ensure the appropriate response is taken such as requiring the administration of a reversal agent, airway maintenance, and, rarely, full cardiopulmonary resuscitation. Patient selection is of paramount importance, in order to minimise the risks associated with conscious sedation, where obese, elderly and/or comorbid women may either not be suitable or require different sedating regimes. Many centres do not have the equipment, clinic space and staff necessary to deliver conscious sedation safely in the outpatient setting, which require facilities to convert to a general anaesthetic in the event of cardiorespiratory compromise. In those that do, it is performed in an endoscopy suite, and does not confer the benefits of being in an "office setting"; women still need to arrive at the start of the session to be seen by an anaesthetist, be fasted prior to their procedure, and cannot be discharged until the effects of the conscious sedative wear away, often necessitating . 11 VAGINOSCOPY. 11.1 Does a vaginoscopic approach to outpatient hysteroscopy reduce pain and increase the feasibility of the procedure?. Vaginoscopy or the 'no touch' approach to hysteroscopy refers to a technique where the hysteroscope is introduced into the vagina, through the cervical canal and into the uterine cavity without the need for a vaginal speculum or cervical instrumentation. By performing hysteroscopy without a vaginal speculum, which causes lower genital tract pain, manoeuvrability of the hysteroscope within the uterine cavity is improved because there is no vaginal speculum restricting movement. This is particularly advantageous in women and people who cannot lie supine due to medical comorbidities (e.g. heart failure, respiratory disease etc.), are obese, who have acutely flexed uteri and in those who have restricted hip movement. Women who are nulliparous, suffer from vaginismus, are virgo intact and/or suffer from genital tract atrophy may also benefit from vaginoscopy, where distension of the vagina is minimised. A systematic review and meta- analysis<sup>168</sup> identified seven RCTs comparing vaginoscopic versus traditional outpatient hysteroscopy, which. # employed the use of a vaginal speculum as a minimum.. In women who require a vaginal speculum for administration of local anaesthesia, many clinicians remove the speculum before performing hysteroscopy to invoke the aforementioned benefits of the vaginoscopic approach.. 12 \| PREVENTION OF INFECTION. 12.1 \| Should routine antibiotic prophylaxis be employed in outpatient hysteroscopic procedures to reduce the incidence of procedural-related infection?. Only one RCT examined the incidence of post- procedural infection in women undergoing outpatient hysteroscopy randomised to receive either antibiotic prophylaxis (in the form of . Despite the low incidence of pelvic infection following hysteroscopy. 13 \| DOCUMENTATION. 13.1 \| How should procedural technique and findings at hysteroscopy be recorded?. # The majority of units use either a written or digital/computerised standardised proforma to record procedural technique and findings. [Evidence level 4]. Items that should be recorded pertaining to technique include:. Operator / surgeon Hysteroscope/operative device used, including instrument diameter as a minimum Approach (vaginoscopy or speculum) Distension medium used Local anaesthesia (agent, volume, route) Cervical instrumentation (tenaculum, cervical dilatation) Biopsy performed (and if so, method used e.g.directed/ blind and device used i.e. Pipelle or other device) Operative procedure performed, if applicable (e.g. polypectomy, myomectomy, septoplasty, coil removal, removal of retained pregnancy tissue etc.) Use of oral or inhalational medications with an analgesic or sedative effect (e.g. Entonox, Penthrox) Procedural success (yes/no) and reasons for abandonment (e.g. intolerable pain, poor visualisation etc.), if applicable Complications (e.g. vasovagal reaction, uterine perforation, heavy bleeding etc.) [Evidence level 4]. Items that should be recorded regarding findings include:. Impression and description of vulva, vagina, cervix and endometrium (functional or pathological) Visualisation of both ostia Details of any congenital (hypoplastic T' or Y' shaped uterus, septum, other structural anomalies) or acquired uterine pathology (adhesions, cervical niches, fibroids FIGO Type 0- 3, polyps, retained products of conception) The uterocervical length should be recorded when a global biopsy is taken or an intrauterine device fitted. [Evidence level 4]. Pictures and/or diagrams may also be helpful in recording findings at hysteroscopy. Where possible, digital images of the uterine cavity and/or cervix (e.g. panoramic view of the cavity, magnified views of the tubal ostia/connual regions, fundus, uterine walls, cervical canal etc.) should be captured, especially where there is any intrauterine pathology (e.g. global endometrial appearances such as vascularity, thickening, irregularity, necrosis; focal endometrial lesions such as polyps, fibroids, adhesions, congenital uterine anomalies, embedded coils etc.). [Evidence level 4]. 14 RECOMMENDATIONS FOR RESEARCH. Effect of cervical preparation with prostaglandins on pain relief and feasibility in outpatient hysteroscopy.. 14 RECOMMENDATIONS FOR RESEARCH- Effect of cervical preparation with prostaglandins on pain relief and feasibility in outpatient hysteroscopy.- Safety, acceptability and feasibility of hysteroscopy according to angle of distal optical lens.- Effectiveness of the vaginoscopic approach to outpatient hysteroscopy in relieving pain compared with traditional approaches with local anaesthesia.- Relative effectiveness of different types, routes, doses and timings of local anaesthesia on pain and incidence of vasovagal reactions.- Effectiveness of warming fluid distension media on pain relief and satisfaction.- Effectiveness of methoxyflurane (Penthrox) on pain relief and satisfaction.- Assessment of specific operative hysteroscopic technologies including endometrial ablative devices, regarding pain, acceptability, feasibility and effectiveness.- Evaluation of technical, analgesic, anaesthetic and sedative interventions for specific operative outpatient hysteroscopic procedures.- Qualitative research exploring patient experience and preferences.- Qualitative research exploring patient recovery and return to daily activity following outpatient hysteroscopy.. 15 AUDITABLE TOPICS. Units should consider collecting data for quality assurance purposes. The lower estimate of the confidence intervals have been used to define the minimum audit standard or where data are lacking or considered inappropriate, expert opinion has been relied upon (BSGE Ambulatory Care Network). However, the data sources have been provided to allow units / practitioners to set and aim for higher standards as appropriate where units / practitioners should strive for continual improvement.. # 16 USEFUL LINKS. The following British Society for Gynaecological Endoscopy (BSGE) quality assurance tools for outpatient hysteroscopy are recommended:. BSGE outpatient hysteroscopy patient satisfaction survey, allowing for local data to compared with national standards.22 A template of the survey be accessed from:. content/uploads/2019/09/ Outpatient- hysteroscopy- patient- survey- FINAL- 010919. pdf. BSGE Surgical Information Collection System (BSGE SICS) to collect data on demographic, technologies, feasibility and complications of outpatient hysteroscopic procedures (diagnostic outpatient hysteroscopy, polypectomy, myomectomy, septoplasty, removal retained products of conception, tubal cannulation / sterilisation, endometrial ablation). This can be accessed from: ics.com/. ACKNOWLEDGEMENTS. The authors acknowledge the contributions of Dr A Mahmud PhD MRCOG PGDip (MedEd), Dr H Stevenson MRCOG MSc MED, Dr A Carnegy BMedSc (Hons) MBChB, Dr L Wilson BSc, MBChB (Hons), Dr CS Graham BSc (Hons) FRCA and Ms L Davies.. FUNDING INFORMATION. All those involved in the development of the Green- top Guidelines, including the Guidelines Committee, Guidelines Committee co- chairs, guideline developers, peer reviewers and other reviewers, are unpaid volunteers and receive no direct funding for their work in producing the guideline. The exception to this are the RCOG staff involved who are salaried employees of the College and Guidelines Committee members who receive reimbursement for expenses for attending Guidelines Committee meetings. Please see more information on travel expense rules on the RCOG website.. CONFLICT OF INTEREST STATEMENT. PMD has received part funding for a PhD stipend from Tommys and the Birmingham Women's Hospital Ambulatory Gynaecology Fund and travel and accommodation funding for attending a meeting from Hologic (Smith & Nephew). PPS has received an honorarium for speaking from Medtronic (Smith & Nephew). NAMC has received an honorarium for attending an advisory meeting from Hologic. TJC has received research grants, honoraria for speaking and running courses, and honoraria for attending advisory board meetings from Hologic (Cytye) and Medtronic (Smith & Nephew); he is also a former president of the British Society for Gynaecology and Endoscopy (BSGE).. REFERENCES. 1. 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GPP Recommended best practice based on the clinical experience of the guideline development group.\*. # This guideline was produced on behalf of the British Society of Gynaecological Endoscopists and the Royal College of Obstetricians and Gynaecologists by:. Dr PM De Silva PhD MRCOG PGCert(MedEd), Birmingham; Mr PP Smith PhD MRCOG, Birmingham; Dr NAM Cooper PhD MRCOG, London; Professor TJ Clark MD(Hons) FRCOG, Birmingham. The authors acknowledge the contributions of: Dr A Mahmud PhD MRCOG PGDip(MedEd), Dr H Stevenson MRCOG MSc MED, Dr A Carnegy BMedSc(Hons) MBChB, Dr L Wilson BSc, MBChB (Hons), Dr CS Graham BSc(Hons) FRCA and Ms L Davies.. Peer reviewers: Ms L Shilcock Patient, Leicester; Royal College of Anaesthetist; Mrs J Bushell, Didcot; P Howe, Patient; Dr J Lord FRCOG, London; Ms G Connor, Patient; Dr J Harrington, Patient; FEmISA; Campaign Against Painful Hysteroscopy; Ms C Mardon, Patient; MG Munro FRCSC FACOG, Los Angeles; Ms G Johnson Patient, Newcastle Upon Tyne; A Wright, Newcastle; S Knights BSc, Colchester; Ms T Parsons Patient, Suffolk; Patient Safety Learning; Ms C Wood Patient, Colchester; Dr J K Gupta FRCOG, Birmingham; Dr M Shahin MRCOG, Stoke on Trent; Mr J Nicholls FRCOG, Oxford; Dr S Mabbutt MRCOG, Northampton.. Committee lead reviewers were: Dr A Macleod FRCOG, Edinburgh; Dr M Madhra MRCOG, Edinburgh; Dr G Ahmad FRCOG, Manchester; Mr K Jayaprakasan FRCOG, Nottingham.. until May 2020; until May 2022; from June 2020; from June 2022.. The co- Chairs of the Guidelines Committee were: Dr MA Ledingham MRCOG, Glasgow; Dr B Magowan FRCOG, Melrose; Ms N Potdar FRCOG, Leicester; Mr A McKelvey MRCOG, Norwich.. until December 2020; until June 2020; from January 2021.. All RCOG guidance developers are asked to declare any conflicts of interest. A statement summarising any conflicts of interest for this guideline is available from: research- services/guidelines/gtg59.. The final version is the responsibility of the Guidelines Committee of the RCOG.. The guideline will be considered for update 3 years after publication, with an intermediate assessment of the need to update 2 years after publication.. DISCLAIMER. The Royal College of Obstetricians and Gynaecologists produces guidelines as an educational aid to good clinical practice. They present recognised methods and techniques of clinical practice, based on published evidence, for consideration by obstetricians and gynaecologists and other relevant health professionals. The ultimate judgement regarding a particular clinical procedure or treatment plan must be made by the doctor or other attendant in the light of clinical data presented by the patient and the diagnostic and treatment options available.. This means that RCOG Guidelines are unlike protocols or guidelines issued by employers, as they are not intended to be prescriptive directions defining a single course of management. Departure from the local prescriptive protocols or guidelines should be fully documented in the patient's case notes at the time the relevant decision is taken..	None	None	None
c4df55f751384311975a259d11efdc7e	2024+SIGO专家共识意见	乳腺癌和妇科癌症后的全身激素治疗	# Systemic hormone therapy after breast and gynecological cancers: an Italian expert group consensus opinion. Angelo Cagnacci. ^{a}. ABSTRACT. The specific Italian Group of Study of the Menopause formulated a consensus opinion on the use of estrogen therapy (ET) or combined estro- progestin hormone therapy (HT) after breast and gynecological cancers. This consensus is based on the risk of recurrence of the specific cancer during ET/HT, the presence of steroid receptors in cancer cells, the use of adjuvant hormone therapies and data on the use of ET/HT after cancer. The following positions were reached. ET/HT can be used after vulvar cancers and melanoma, but with great caution after the rare adenocarcinomas. ET/HT can be used after cervical cancer, but ET should be used with caution after adenocarcinomas. ET/HT can be used after International Federation of Obstetrics and Gynecology (FIGO) stage I- II estrogen- dependent endometrial cancers, except in Black women, and can probably be used after estrogen- independent endometrial cancers. ET/HT cannot be administered or should be used with great caution after most uterine sarcomas. ET/HT can probably be used after ovarian neoplasms except for granulosa cell tumors, and with great caution after low- grade serous ovarian carcinoma and serous borderline ovarian tumors. ET/HT can be used with great caution in women after estrogen receptor (ER)/progesterone receptor (PR)- positive breast cancer and is probably allowed after ER/PR- negative breast cancer.. ARTICLE HISTORY. Received 13 June 2024 Revised 10 September 2024 Accepted 9 October 2024. KEYWORDS. Hormone therapy; cervical uterine cancer; ovarian neoplasms; endometrial cancer; vulvar neoplasms; breast carcinoma; uterine sarcoma. Introduction. Methods. The consequences of surgery and antitumoral therapies can markedly impact quality of life of survivors of breast and gynecological cancers. Systemic estrogen therapy (ET) or combined hormone therapy (HT), when allowed, may be a possible tool to improve climacteric and genitourinary symptoms, to prevent postmenopausal osteoporosis and to decrease the risk of cognitive decline and cardiovascular diseases [1]. To clarify the possible use of ET/HT in cancer survivors, the Italian Society of Gynecology and Obstetrics (SIGO) endorsed the two national societies on menopause - the Italian Society for Menopause (SIM) and the Italian Society of Gynecology for the Third Age (SIGITE) - to select a group of expert clinicians to produce an integrated consensus opinion on the possible use of ET/HT after breast and gynecological cancers.. The members of the group selected the relevant articles for any type of cancer. Articles were identified through a comprehensive search of medical databases, including Medline, PubMed, Scopus and the Cochrane Central Register of Controlled Trials. The search terms used were 'hormone therapy,' 'hormone replacement therapy,' 'menopausal hormone therapy,' 'estrogen,' 'progesterin,' 'cervical uterine cancer,' 'ovarian cancer and neoplasms,' 'endometrial cancer,' 'uterine sarcomas,' 'vulvar neoplasms and cancer,' 'breast cancer,' 'steroid receptors,' 'estrogen receptors' (ERs), 'progesterone receptors' (PRs), 'adjuvant therapy,' 'tamoxifen' and 'aromatase inhibitors'. The search was limited to full articles, published in English from 1987 onwards. Randomized controlled trials, cohort and case- control studies, systematic reviews and meta- analyses were considered. When. # necessary, cited older manuscripts were manually selected and analyzed. The conclusive opinion was based on a shared integrated analysis of the available evidence, and was condensed as follows: ET/HT allowed - the available data are sufficient to indicate that cancer recurrence or mortality is not increased by ET/HT; ET/HT probably allowed - there are insufficient data on cancer recurrence or mortality during ET/HT, but the few available reports or the integrated evaluation of evidence (no indication to adjuvant endocrine therapy, ET/HT not being a risk factor for that cancer, absence of ERs) do not indicate possible harm; ET/HT prescribed with great caution - there is no direct evidence that ET/HT can be detrimental, but integrated evaluation of evidence may indicate a possible harm; and ET/HT not allowed - there is direct evidence that ET/HT can increase recurrence or mortality. In some articles, HT was also performed with tibolone, a synthetic molecule degraded in molecules with estrogenic and progestin/androgenic properties [2]. When appropriate, we mention whether data with tibolone differ from those with HT.. Vulvar neoplasia. Vulvar neoplasms mostly include vulvar squamous cell carcinomas . Squamous cell carcinoma can be human papilloma virus (HPV) or non- HPV related, the latter being predominantly associated with lichen sclerosus, squamous cell hyperplasia or differentiated intraepithelial neoplasia [4].. Basal cell carcinoma originates from the basal cells of the epidermis and hair follicles [5]. Rare adenocarcinomas are represented by invasive Paget's disease, originating from a pluripotent epidermal cell of the interfollicular epidermis or apocrine- sebaceous unit, and adenocarcinoma of the Bartholin's gland, of sweat glands, breast- like and apocrine [5]. Among skin neoplasia, malignant melanoma is the most aggressive [5].. ET/HT and risk of neoplasia. ERa staining is completely lost in vulvar squamous cell carcinomas, while ERβ shifts from nuclear to mainly cytoplasmic staining, with a currently unknown functional role [6]. Prevalence of this carcinoma is not influenced by ET/HT use [7].. The extra- mammary Paget's disease is rich in androgen receptors (ARs) and has a low expression of ERs and PRs [8]. For this reason, anti- androgens were proposed as an adjuvant therapy. Except for apocrine cancer, adenocarcinomas, particularly Bartholin's gland adenocarcinoma, express ERs and PRs [8,9]. The quality of life of affected individuals can be improved by adjuvant therapy with anti- estrogens [9]. Malignant melanoma and basal cell carcinoma are not hormone- related, and their prevalence is not associated with the use of ET/HT [10].. ET/HT in women with previous vulvar neoplasia. Due to the rarity of the disease, there are no data on the use of ET/HT after vulvar neoplasia. HT users had a prolonged survival in an observational prospective study performed on 206 women with cutaneous malignant melanoma [11] (Table 1).. Conclusive opinion. There is no reason to contraindicate ET/HT after squamous cell and basal cell carcinoma. ET/HT is allowed after localized malignant melanoma. There is no direct evidence, but ET/HT should be used with great caution after adenocarcinomas rich in ERs, particularly Bartholin's gland adenocarcinoma. Cervical uterine cancer. Squamous cell carcinoma and adenocarcinoma are the most frequent cancers; uncommon types are adenoma- squamous carcinoma and neuroendocrine cervical cancers. Squamous cell and adenocarcinomas find their pathogenesis in the infection and persistence of oncogenic types of HPV [12]. Hormonal contraceptives are among the risk factors for HPV infection and persistence [13]. ERs are expressed by metaplastic cells and cells of the squamous epithelium and endocervical glandular [14].. ET/HT and risk of cervical cancer. In the HPV- infected cervix, estradiol induces DNA instability via ER- independent mechanisms [12].. A case- control study reported that the risk of cervical cancer was reduced in 645 HT users versus non- users regardless of time of use (hazard ratio [HR] 0.5, 95% confidence interval [CI] 0.3- 0.8) [16]. In a cohort study with 308,036 women, ever use of an unspecified HT for >1 year was associated with a reduction of cervical cancer (HR 0.3, 95% CI 0.1- 0.7) [17]. In another cohort study performed with 22,579 women with a 13- year follow- up, the use of HT (any type) was associated with a decreased cancer- related mortality (HR 0.3, 95% CI 0.2- 0.6) [18]. In a case- control study with 124 women with adenocarcinoma and 139 women with squamous cell carcinoma, ever use of HT was not associated with an increased risk of overall cervical cancer, but with a time- related increase of adenocarcinoma (HR 2.7, 95% CI 1.1- 6.8) [19]. In a large cohort study with 243,857 postmenopausal women with a 5- year follow- up, estradiol administered by different routes and in association with various progestins decreased the risk of squamous cell carcinoma (HR 0.41, 95% CI 0.28- 0.58). The risk of adenocarcinoma increased but only when ET was associated every 3 months with a progestin (HR 1.31, 95% CI 1.01- 1.67). This risk further increased after 5 years of exposure (HR 1.83, 95% CI 1.24- 2.59) [20]. In the Woman's Health Initiative (WHI), a placebo- controlled clinical trial performed with 15,733 women, the use of continuous combined conjugated estrogens (CEE) plus medroxyprogesterone acetate (MPA) . # increased the risk of cytologic abnormalities (HR 1.4, . # ET/HT in women with previous cervical cancer. Cervical cancer tends to lose ERs and PRs in the epithelium but not in the stroma [14,24], and the presence of ERs and PRs is associated with a better prognosis [25,26].. In one retrospective study with a 5- year follow- up, progression- free survival and death from stage 1 adenocarcinomas were not increased in 38 users of tibolone versus 32 non- users [27]; and in another retrospective study, unspecified HT (25 treated vs. 13 untreated and 25 women with conserved ovaries) was not detrimental for the 6- year progression- free survival of International Federation of Obstetrics and Gynecology (FIGO) stage I- II adenocarcinomas [28]. In one randomized controlled study of HT versus no HT performed in 80 FIGO stage I- II cervical cancer survivors, HT (estradiol and norethisterone or dienestrol and chlormadinone) did not affect the 5- year disease- free survival and cancer- specific survival [29] (Table 1).. Conclusive opinion. ET/HT is allowed after FIGO stage I- II squamous cell carcinoma. Limited evidence indicates that HT may be allowed with caution after stage I- II adenocarcinoma. In this case, the use of combined HT rather than ET appears more appropriate, as in a normal population ET increases the risk of adenocarcinoma.. Endometrial cancer. Endometrial cancer can be estrogen- dependent or estrogen- independent. Therapy of endometrial cancer is surgical, combined, if needed, with chemo- radiotherapy [30]. Ovaries can be preserved in women younger than 45 years of age and with FIGO stage I cancer, at low or intermediate risk. In all the other cases, the ovaries are removed at the time of hysterectomy.. ET/HT and risk of cancer. ERs and PRs are present in normal endometrial cells and in estrogen- dependent endometrial cancer [31].. Meta- analysis of randomized studies shows that the risk of endometrial hyperplasia develops after 1 year of low- dose ET. The risk is magnified by the dose and length of ET use, with the odds ratio OR) increasing from 1.1 to 13.1 [32]. Hyperplasia does not increase when ET is sequentially or continuously associated with a progestin (mainly MPA), norgestimate (NGM) or nerethisterone (NETA) [32]. A meta- analysis of observational and clinical trials indicates that hyperplasia does not increase with ET sequentially (12 days/month) or continuously associated with either oral (200 mg/day) or vaginal (100 mg/day) progesterone [33].. In a large observational study, the Million Women Study, the risk of endometrial cancer was increased by ET (relative risk [RR] 1.45, . HT (RR 1.05, . ET/HT in women with previous endometrial carcinoma. ERs and PRs are present in estrogen- dependent endometrial cancer [31,40], and ARs in estrogen- independent endometrial cancer [41]. The decreased expression of ERs and PRs is associated with a worse cancer prognosis [31,42,43]. In a retrospective study including 110 Black and 1049 White patients with stage I and II endometrial cancer, ET increased the risk of tumor recurrence in Black but not in White women (RR 11.2, . A Cochrane meta- analysis concluded that, despite limited evidence, HT is probably not contraindicated in women with FIGO stage I- II endometrial cancer [47]. A more recent meta- analysis including one clinical trial and eight observational studies, totaling 1867 ET/HT users and 6077 non- users, shows that ET/HT does not increase the risk of cancer (OR 1.17, . Conclusive opinion. ET or HT (not tibolone, which was not tested) is allowed after FIGO stage I- II endometrial cancer. There are no data on women with an advanced stage of endometrial cancer. In Black women, ET is not allowed for a higher risk of recurrence, and HT was not tested. ET/HT is probably allowed after ER- negative endometrial carcinoma. The data are too limited to reach a strong conclusion, but a negative impact cannot be anticipated.. # Uterine sarcoma. Uterine sarcomaUterine leiomyosarcoma, endometrial stromal sarcoma and undifferentiated uterine sarcoma are the most frequent sarcomas [49,50]. The high- grade endometrial stromal sarcoma is highly aggressive, while low- grade endometrial stromal sarcoma has a 5- year survival rate of . ET/HT and uterine sarcoma risk. ET/HT and uterine sarcoma riskIn a Finnish national study, 243,857 postmenopausal women having used an estradiol- based sequential or continuous HT (oral/transdermal) for at least 6 months did not show an increased risk of sarcomas in the first 5 years of use, but the standardized incidence ratio of sarcomas (events in users/event in background population) increased to 2.0 (95% 1.4- 2.9) after 5- 10 years and to 3.0 (95% CI 1.3- 5.9) after 10 years of HT use [61].. ET/HT in women with previous uterine sarcomas. ET/HT in women with previous uterine sarcomasA review of observational studies reported that in some patients affected by low- grade endometrial stromal sarcoma, the elimination of HT or tamoxifen, stabilizes the disease [57]. Likely, these data cannot be extended to sarcomas with no ERs and PRs, such as high- grade endometrial stromal sarcoma or some uterine leiomyosarcoma.. Conclusive opinion. Conclusive opinionET/HT is not allowed after low- grade endometrial stromal sarcoma and ER- positive uterine leiomyosarcoma. No data are available on ER- negative uterine leiomyosarcoma, high- grade endometrial stromal sarcoma and undifferentiated uterine sarcoma. After these tumors, ET/HT could be administered with great caution, and probably for a period of time . Ovarian neoplasia. Ovarian neoplasia represents . More than . ET/HT and the risk of ovarian neoplasia. ET/HT and the risk of ovarian neoplasiaIn a meta- analysis of 52 epidemiological studies, the use of ET or HT was associated with a similar increase of ovarian cancer risk (RR 1.37, 95% CI 1.29- 1.46), mainly of serous and endometrioid cancer [74]. Women on combined HT may have previously used ET. A subsequent pooled analysis of five population- based case- control studies, including 1509 cases and 2295 postmenopausal controls, did not show an increased risk of ovarian cancer in users of continuous combined HT (OR 0.85, 95% CI 0.72- 1.0). Subgroup analysis indicated a decreased risk of mucinous ovarian cancer (OR 0.40, 95% CI 0.18- 0.91) [75]. In another meta- analysis, with no distinction between ET, HT and HT regimens, the risk of ovarian cancer. # was increased by therapy (RR 1.16, . As regards BOTs, observational studies indicate that the risk of serous or mucinous BOT is either not increased in HT users (unspecified regimen) [78] or increased after any type of HT used for a period . ET/HT in women with a previous ovarian neoplasia. A review of two randomized and six cohort studies, including 419 HT users and 1029 HT non- users, indicated that at follow- up of 48 months, the administration for a median time of 28 months of CEE or estradiol alone, estradiol plus progesterone or estradiol plus tibolone had a favorable impact on overall survival after epithelial ovarian cancer (HR 0.69, . Conclusive opinion. After epithelial ovarian cancers, HT is more indicated that ET, as in healthy individuals ET increases the risk of these cancers and most of the evidence after cancers were obtained with HT. HT is allowed after high- grade serous ovarian carcinoma, endometroid carcinoma, mucinous ovarian cancer and, . HT should be prescribed with great caution after low- grade serous ovarian carcinoma. There are no specific data indicating that HT increases tumor recurrence, but its disease- free survival (not mortality) is increased by adjuvant HT.. HT is allowed after mucinous BOTs, and probably allowed after endometroid, clear cell and Brenner's BOTs.. HT can be prescribed with great caution after serous BOTs. There are no specific data in cancer survivors, but in healthy individuals HT increases the risk of serous BOTs.. ET/HT is allowed after non- epithelial ovarian cancers with the exclusion of granulosa cell tumor.. Breast cancer. Breast cancer is the most common tumor in women, with subtypes characterized by the expression of ERs and PRs, of human epidermal growth factor receptor 2 (HER2+) or of none of them (basal- like or triple- negative tumors) [86]. Adjuvant HT is indicated after ER/PR- positive [87,88], but not negative tumors [89].. ET/HT and breast cancer risk. Exogenous hormones are considered among the risk factors for breast cancer [86]. In a meta- analysis of 58 observational studies were included 108,647 women who developed breast cancer. After 1- 4 years the risk of breast cancer was slightly higher with HT than with ET (OR 1.60, . Meta- analyses of randomized placebo- controlled studies were published in the same manuscript, as a supplement [90]. The risk of breast cancers was decreased by ET (HR 0.77, . ET/HT in women with previous breast cancer. Three randomized, placebo- controlled trials were performed to evaluate the risk of breast cancer recurrence during HT. # [98- 100], and they were prematurely stopped due to an increased recurrence rate. A Swedish study, initiated in 1997, randomized 188 cancer survivors to HT and 190 to no HT [98]. Breast cancer recurrence was not increased after 4 and 10.8 years of follow- up (HR 1.3, . Conclusive opinion. Data in healthy women indicate that the risk of breast cancer is higher with HT than ET, but this does not emerge in breast cancer survivors. ET/HT increases breast cancer recurrence but decreases cancer- specific and overall survival. ET/HT can probably be used with great caution after breast cancer. ET/HT is probably allowed after ER/PR- negative breast cancers. HT represents a risk factor for these cancers, but the limited data in cancer survivors do not show an increased recurrence rate with ET/HT.. Discussion. The present analysis was focused on the effect that systemic ET/HT can exert in survivors from breast and gynecological malignancies. Different to previous positions regarding this issue, we placed considerable effort to evaluate the differences among different types of tumors, also of the same specific organ and to differentiate between the use of ET and HT. In addition, when the data on ET/HT were scanty, we used a combination of indirect evidence to reach a sufficiently reliable indication. For example, the post- cancer need for an adjuvant hormonal therapy was considered one of the parameters possibly contraindicating ET/HT use. Yet after epithelial ovarian cancers [65], adjuvant HT was performed also with the administration of a potent estrogen (ethynyl- estradiol) combined with a progestin [65], and this led us to conclude that HT is not contraindicated after epithelial ovarian cancer.. Cancer expression of ERs and PRs was also considered among the other parameters possibly contraindicating the use of ET/HT. Vulvar squamous cell carcinomas express ERs but they . # HT represent risk factors for low- grade serous ovarian cancer. Accordingly, we left the option that ET/HT can be used with great caution after this tumor. ET/HT could be a potential risk factor for ER/PR- negative breast cancers [87], because the risk of these tumors is increased by HT [87]. Yet recurrence is presumably not increased by ET/HT [93- 95].. Overall, we used a combination of information to reach a consensus on the effect of ET/HT use after different types of breast and gynecological cancers. There are several limitations to our analysis due to the lack of specific data on different types of cancer, and on different ET/HT molecules, regimens and routes of administration. Yet the analysis details and balances the available evidence of the literature as much as possible, and may be useful in counseling, in indicating practical guidelines and in stimulating clinical studies aimed to implement the scanty evidence available for many types of cancers.. Acknowledgements. The authors thank Dr Valentina Cugusi for the revision of the English language and dedicate the work to Mario Gallo and Nicoletta Biglia, who passed away prematurely. The work was promoted by the Italian Group of study of the Menopause (IGS- Menopause) of the Italian Society of Gynecology and Obstetrics (SGO) (President: Vito Trojano; past . Disclosure statement. No potential conflict of interest was reported by the authors.. Funding. This research did not receive any specific grant from funding agencies in the public, commercial or not- for- profit sectors.. ORCID. Angelo Cagnacci . References. [1] Santen RJ, Allred DC, Ardoin SP, et al. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2010;95(7 Suppl 1):s1- s66. doi: 10.1210/jc.2009- 2509. [2] Del Rio JP, Molina S, Hidalgo- Lanussa O, et al. Tibolone as Hormonal Therapy and Neuroprotective Agent. Trends Endocrinol Metab. 2020;31(10):742- 759. doi: 10.1016/j.tem.2020.04.007. 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cf0087ef79b9443f93d535eb7372b173	2024+SOGC临床实践指南	子宫内膜切除治疗异常子宫出血（No.453）	# SOGC CLINICAL PRACTICE GUIDELINE. It is the Society of Obstetricians and Gynaecologists of Canada (SOGC) policy to review the content 5 years after publication, at which time the document may be revised to reflect new evidence, or the document may be archived.. No. 453, September 2024 (Replaces No. 322, April 2015). Guideline No. 453: Endometrial Ablation in the Management of Abnormal Uterine Bleeding. (En français : Ablation de I'endometre dans la prise en charge des saignements uterins anormaux). The English document is the original version; translation may introduce small differences in the French version.. This clinical practice guideline was prepared by the authors and overseen by the SOGC Clinical Gynaecology Committee (2024). It was approved by the SOGC Guideline Management and Oversight Committee (2024). This clinical practice guideline supersedes No. 322, published in April 2015.. Authors. Nicholas Leyland, MD, MHCM, Hamilton, ON Philippe Laberge, MD, Quebec, QC Devon Evans, MD, MPH, Winnipeg, MB Emilie Gorak Savard, MD, Montreal, QC David Rittenberg, MD, Halifax, NS. SOGC Clinical Gynaecology Committee (2024): Gregg Nelson (Chair), Angela Vintunache, Susan Thorne, Kiel Luhning, Olga Bougie, Frank Potestro, David Rittenberg, Brent Jim, Marie- Hélène Mayrand, Chelsea Elwood, Sari Kives, Paul Yong, Devon Evans, Sarah McQuillan, Philippa Brain, Rachel Spitzer, Andréanne Jodoin, Bryden Magee, Roland Antaki, Tarek Motan, Aisling Clancy, Baharak Amir, Jane Schulz. Disclosures: Statements were received from all authors. Relationships or activities that could involve a conflict of interest were declared. NL reports no disclosures. PL reports research grant funding from Réponi, fellowship grant funding from Hologic, AbbVie, and Pfizer, and speaker honoraria from Hologic and AbbVie. DE reports advisory meeting honoraria from Pfizer and speaker honoraria from Olympus, Baxter, and AbbVie. EG reports no disclosures. DR reports no disclosures. All authors have indicated that they meet the journal's requirements for authorship.. Subject Categories: gynaecological surgery; gynaecology. Keywords: endometrial ablation techniques; uterine hemorrhage; endometrium; electrosurgery; cryosurgery; ablation. Corresponding Author: Nicholas Leyland, leylann@mcmaster.ca. J Obstet Gynaecol Can 2024;46(9):102641. . \widehat{\Xi}. This docmet reects emergin clical and scitific advancs as of the pubication date and is subject to change. The infomation is not meant to dictate an exclusive course of treatment or procedure. Institutions are free to amend the recommendations. The SOGC suggests, however, that they adequately document any such amendments.. Inomed consent: Patients have the right and responsibilit to make informed decisions about their care, in partnership with their health care provider. To facilitat inomed choice, patiens should be provided with inomation and support that is evidence- based, culturally appropriate, and personalized. The values, beliefs, and individual needs of each patient in the context of their personal circumstances should be considered and the final decision about care and treatment options chosen by the patient should be respected.. Language and inclusivity: The SOGC recognizes the importance to be fully inclusive and when context is appropriate, gender- neutral language will be used. In other circumstances, we continue to use gendered language because of our mission to advance women's health. The SOGC recognizes and respects the rights of all people for whom the information in this document may apply, including but not limited to transgender, nonbinary, and intersex people. The SOGC encourages health care providers to engage in respectful conversation with their patients about their gender identity and preferred gender pronouns and to apply these guidelines in a way that is sensitive to each person's needs.. # RECOMMENDED CHANGES IN PRACTICE. 1. Regarding the use of distension media, when the fluid deficit reaches . KEY MESSAGES. 1. Endometrial ablation techniques are safe and effective minimally invasive alternatives to hysterectomy for benign abnormal uterine bleeding. 2. Medically complex patients . ABSTRACT. Objective: To provide an update of the current evidence- based guideline on the techniques and technologies used in endometrial ablation, a minimally invasive technique for the management of abnormal uterine bleeding of benign origin.. Target Population: Women of reproductive age with abnormal uterine bleeding and benign pathology with or without structural abnormalities.. Benefits, Harms, and Costs: Implementation of the guideline recommendations will improve the provision of endometrial ablation as an effective treatment for abnormal uterine bleeding. Following these recommendations would allow the surgical procedure to be performed safely and maximize success for patients.. Evidence: The guideline was updated with published literature retrieved through searches of Medline and the Cochrane Library from January 2014 to April 2023, using appropriate controlled vocabulary and keywords (endometrial ablation, hysteroscopy, menorrhagia, heavy menstrual bleeding, abnormal uterine bleeding, hysterectomy). Results were . Grey (unpublished) literature was retrieved from the Association of Obstetricians and Gynecologists of Quebec (AOGQ) in 2023.. Validation Methods: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional [weak] recommendations).. Intended Audience: Obstetricians, gynaecologists, and primary care providers.. Social Media Abstract: This is an updated version of the 2015 SOGC Endometrial Ablation guideline. The authors discuss special considerations, update evidence, and make new fluid deficit recommendations.. SUMMARY STATEMENTS:. 1. Endometrial ablation is a safe and effective minimally invasive surgical procedure that has become a well-established alternative to medical treatment or hysterectomy for abnormal uterine bleeding in select cases (high). 2. Medical preparation to thin the endometrium can be used to facilitate resectoscopic endometrial ablation and can be considered for some non-resectoscopic techniques. For resectoscopic endometrial ablation, preoperative endometrial thinning results in higher short-term rates of amenorrhea, decreased distension media fluid absorption, and shorter operative time when compared with no treatment (high). 3. Non-resectoscopic techniques are technically easier to perform than resectoscopic techniques, have shorter operative times, and can be done in procedure rooms rather than formal operating rooms. Both techniques have comparable results with respect to patient satisfaction and reduction of heavy menstrual bleeding (high). 4. Both resectoscopic and non-resectoscopic endometrial ablation have low complication rates. Uterine perforation, fluid overload, hematometra, and cervical lacerations are more common with resectoscopic endometrial ablation; perioperative nausea/vomiting, uterine cramping, and pain are more common with non-resectoscopic endometrial ablation (high). 5. All non-resectoscopic endometrial ablation devices available in Canada have demonstrated effectiveness in decreasing menstrual flow and result in high patient satisfaction. Device selection depends primarily on surgical judgement and the availability of resources. In general, non-resectoscopic endometrial ablation devices require the confirmation of a relatively normal endometrial cavity before device selection (high). 6. The use of local anaesthetic and blocks, oral analgesia, and conscious sedation allows for the provision of non-resectoscopic endometrial ablation in less resource-intensive environments, including regulated non-hospital settings (moderate). 7. Low-risk patients with satisfactory pain tolerance are good candidates to undergo endometrial ablation in settings outside the operating room or in free-standing surgical centres (moderate). 8. Endometrial ablation procedures do not increase the risk of cancer, do not cause delayed diagnosis of endometrial cancer, and may decrease the overall risk of endometrial cancer (high).. RECOMMENDATIONS:. 1. Preoperative assessment should be comprehensive to rule out any contraindications to endometrial ablation or to plan for. # concurrent management of fibroids, cavitary anomalies, or polyps (good practice point). 2. Patients should be counselled about the need for effective contraception following endometrial ablation (good practice point). 3. Recommended evaluations for abnormal uterine bleeding, including but not limited to endometrial sampling and an assessment of the uterine cavity, are necessary components of the preoperative assessment (good practice point). 4. Clinicians should be knowledgeable about complications specific to resectoscopic endometrial ablation, such as those related to fluid distension media and electrosurgical injury (good practice point). 5. For resectoscopic endometrial ablation, a strict protocol should be followed for fluid monitoring and management to minimize the risks associated with distension medium overload. The maximum threshold for hypotonic solution, such as glycine, is . # INTRODUCTION. E abnormal uterine bleeding (AUB), defined as changes in the frequency of menses, duration of flow, or amount of blood loss. Endometrial ablation consists of targeted destruction or removal of the endometrial surface of the uterine cavity in select women who have no desire for future pregnancy. The procedure was initially designed to treat heavy menstrual bleeding refractory to medical therapy and not caused by structural uterine pathology. It is a less invasive alternative to hysterectomy.. Although endometrial destruction through the endocervical canal dates back to 1937, this technique became more widely adopted in 1981 with the advent of laser endometrial ablation, followed by rollerball and loop resection in the late 1980s. Subsequent to these techniques, various non- resectoscopic ablation techniques have become available. They use different energy sources to achieve destruction of the endometrium, including heated liquid (either free circulating or confined within a balloon), radiofrequency electricity, and tissue freezing. Currently, a number of these systems are available in Canada.. According to the Association of Obstetricians and Gynecologists of Quebec (AOGQ), 6623 endometrial ablations were performed in Quebec in 2020/21, compared with 3646 in 2012/13, an increase of more than . ABBREVIATIONS. AUB Abnormal uterine bleeding GnRH Gonadotropin- releasing hormone LNG- IUS Levonorgestrel intrauterine system NaCl Sodium chloride PASD Placenta accreta spectrum disorder. In the past 20 years alone, there have been more than 1100 publications on endometrial ablation. This guideline reviews the indications and contraindications for performing endometrial ablation (Table 1) and compares resectoscopic and non- resectoscopic techniques. The document also includes discussions of operative set- up, anaesthesia, preoperative and postoperative care, and some special considerations in clinical practice.. COMPARISON OF ENDOMETRIAL ABLATION WITH OTHER THERAPIES. Endometrial Ablation Versus a Levonorgestrel Intrauterine System. A levonorgestrel intrauterine system (LNG- IUS) is a simple treatment option for women with AUB and is more cost- effective than any surgical technique, including endometrial ablation. In a recent meta- analysis, LNG- IUS and endometrial ablation had similar outcomes for up to 3 years after treatment in terms of subsequent hysterectomy, patient satisfaction, quality of life, amenorrhea, and treatment failure. A Cochrane review concluded that endometrial ablation and LNG- IUS had similar patient satisfaction outcomes, though endometrial ablation was associated with a greater reduction in menstrual bleeding. During the first 6 months of use, the LNG- IUS may be associated with a number of progestogenic side effects, including but not limited to irregular bleeding, breast tenderness, and headache.. Clinical Tip. LNG- IUS should be discussed prior to any surgical option for women with AUB and a relatively normal uterine cavity.. Endometrial Ablation Versus Hysterectomy. In a review of 9 prospective randomized clinical trials, hysterectomy was associated with improved pain control and reduced bleeding. In another study, at 4- year follow- up. # 98% of women post hysterectomy versus 85% of women post endometrial ablation were satisfied with their results. However, hysterectomy was associated with higher risks of adverse events, severe complications, and a longer hospital stay. In a large retrospective study with 11 years of follow- up data, risk of surgery for subsequent pelvic floor repair and stress urinary incontinence was lower with endometrial ablation than with hysterectomy. Although the direct costs of endometrial ablation are about half those of hysterectomy, it appears that the costs of the 2 procedures become equivalent at 4 years, because some women with endometrial ablation will need additional treatment. Age . Summary Statement 1. PREOPERATIVE AND POSTOPERATIVE CARE. Preoperative Care. The work- up of patients with AUB and the algorithm for decision- making have been previously described. Patients must not have any contraindication to hysteroscopy and must not desire future pregnancy, as serious maternal- fetal complications have been reported in pregnancies following endometrial ablation (i.e., uterine rupture causing maternal death, limb defects, premature labour). Therefore, women must be counselled that endometrial ablation is not considered a sterilization method. Women must also be appropriately counselled about realistic expectations of ablation outcomes. The goal of endometrial ablation is to sufficiently reduce bleeding symptoms from the patient's perspective; amenorrhea, although possible, cannot be guaranteed. Management of patient expectations is an important consideration.. Endometrial preparation can be considered preoperatively, as a thin endometrium can improve visualization for the resectoscopic techniques and improve patient outcomes. A thin endometrium may be achieved by scheduling the procedure in the immediate postmenstrual phase, performing curettage prior to the procedure, or administering preoperative hormonal therapy. A systematic review suggested that preoperative endometrial thinning with gonadotropin- releasing hormone (GnRH) agonists or danazol resulted in higher rates of amenorrhea at 12 and 24 months than placebo or no treatment. Whether or not this difference is maintained beyond 24 months is uncertain. Both GnRH agonists and danazol also had a beneficial effect on the intrauterine operating environment with respect to shorter . The use of endometrial preparation prior to non- resectoscopic endometrial ablation will depend on the product monograph for each individual device. Meta- analysis of a few randomized trials on second- generation devices (radiofrequency ablation and balloon devices) suggest that preoperative endometrial thinning does not improve postoperative rates of amenorrhea.. No randomized controlled trials with sufficient numbers and power have supported or refuted the role of antibiotic prophylaxis before endometrial ablation by any technique.. Postoperative Care. Patients can usually be discharged within 1- 3 hours of endometrial ablation depending on the type of anaesthesia used. They can resume their normal activities progressively but are advised to abstain from sexual intercourse for 1 week. Pain can be managed with non- steroidal anti- inflammatory drugs or analgesics and will usually resolve within 24 hours. Light vaginal bleeding or pinkish discharge is usual and can last up to several weeks following the procedure. Patients are counselled to seek medical care if they have fever, intense pain, or profuse vaginal bleeding.. Summary Statement 2 & Recommendations 1, 2, and 3. Clinical Tip. Required investigations prior to endometrial ablation include:. - Pregnancy test- Up-to-date Pap test- Cervical cultures, if clinically appropriate- Endometrial sampling- Assessment of uterine cavity for Müllerian anomalies or intracavitary pathology using transvaginal ultrasound, saline infusion sonography, or diagnostic hysteroscopy.. # (See also SOGC Clinical Practice Guideline No. 292, Abnormal Uterine Bleeding in Pre- Menopausal Women.. Because it is often difficult to interpret residual menstrual discharge post procedure, the efficacy of the endometrial ablation should be assessed no earlier than 12 weeks postoperatively.. COMPARISON OF RESECTOSCOPIC AND NON-RESECTOSCOPIC ENDOMETRIAL ABLATION TECHNIQUES. First- generation techniques introduced in the 1980s consisted of targeted endometrial destruction under direct hysteroscopic visualization. These techniques included laser ablation and electrosurgical endometrial resection or ablation. Despite their efficacy, the first- generation methods had certain disadvantages. They required a skilled hysteroscopic surgeon and an operating room environment. Their uncommon but serious complications of fluid overload and uterine perforation led to the advent of simpler, less user- dependent alternatives.. These second- generation techniques, also known as non- resectoscopic ablation, use a variety of energy sources to non- selectively destroy the endometrial lining. The advantage of these newer technologies is that they require shorter surgical time, less specialized training, and they can be performed in an outpatient setting. They also help to avert complications associated with the use of fluid distension media while achieving similar clinical outcomes.. Resectoscopic Endometrial Ablation. Resectoscopic endometrial resection/ablation is an attempt to destroy the basal endometrial layer to prevent further endometrial proliferation. Patients are placed in supported dorsal lithotomy position and the cervix dilated to at least . The rollerball is used at the fundus and ostial regions with a touch technique applying no pressure. The treatment endpoint is a visual change in the endometrium to a yellow- brown honeycomb appearance indicating myometrial tissue has been reached. Tissue destruction to a depth of . Endometrial polyps and small submucosal fibroids can be resected using the resectoscope, larger myoma (. Use of a fluid management system is recommended. Bipolar resectoscopic systems require the use of normal saline as a distension medium, thereby eliminating concerns about hyponatremia; however, large quantities of normal saline can still result in fluid overload complications. Therefore, fluid monitoring is required with the use of any distension medium.. Efficacy of Resectoscopic Endometrial Ablation. Early studies reported high rates of improvement in heavy menstrual bleeding and high rates of patient satisfaction. O'Connor and Magos reported a . A meta- analysis of 21 randomized trials comparing different resectoscopic techniques of endometrial destruction showed. # no difference in rates of amenorrhea and subsequent hysterectomy.. Advantages and Disadvantages of Resectoscopic Endometrial Ablation. Compared with the non- resectoscopic techniques, resectoscopic endometrial ablation offers certain advantages. It allows for accurate assessment of uterine pathology with directed biopsies, documentation with photography, and concurrent treatment of intracavitary pathology. It can also be used in patients who have had previous endometrial ablation or trans- myometrial surgery. However, resectoscopic endometrial ablation is a skill- dependent procedure that generally requires a hospital operating room environment and has a higher complication rate than non- resectoscopic methods.. Fluid Management During Endometrial Resection. Resectoscopic endometrial ablation has potential complications specific to this surgical modality. Careful fluid management is critical to the safe use of hysteroscopic endometrial ablation. Fluid overload leading to pulmonary edema and cardiovascular compromise can occur with hypotonic solutions, such as glycine . Normal sodium concentration in a healthy individual varies between 135 and . Isotonic solutions such as . Association of Gynecologic Laparoscopists (AAGL). For hypotonic solutions:. At a fluid deficit of . Ensure the anesthesiologist and surgeon are aware of the deficit in return of uterine distension fluid.. At a fluid deficit of . Stop the procedure and reassess accuracy of fluid loss; if confirmed, discontinue surgery immediately.. Serum electrolyte values should be obtained, and abnormalities managed appropriately.. Observe the patient for signs of fluid overload and encephalopathy, changes in level of consciousness, seizure activity, pulmonary fluid management, and tachypnea.. Consider admitting the patient for observation and management of complications.. For isotonic solutions:. When the fluid deficit reaches . For older women and/or those with cardiopulmonary compromise. Use . Use . # patients undergoing type 1 and type 2 myoma resection using monopolar electrodes had an incomplete removal, which required a second surgery owing to excessive fluid absorption, whereas patients who were operated on using bipolar electrodes had a complete surgery on the first attempt.30 Although calculation of fluid deficit has become more accurate using dedicated irrigation- pump systems, there is still an approximation of actual fluid intravasation because of spillage onto the floor, absorption by pads and drapes, intraperitoneal absorption through the fallopian tubes, bag overfill, and blood loss.24,31. Table 2 provides an approach to prudent management of hysteroscopic distension fluid issues.. Excessive fluid absorption may be prevented by pretreatment of the endometrium, intracervical injection of pressor agents (vasopressin, epinephrine), and the use of a distension pressure that is less than that of the patient's mean arterial pressure. Electronic fluid monitoring systems, which allow regulation of the flow rate, infusion pressure, outflow suction, and fluid deficit are more accurate in calculating fluid deficits than traditional gravity infusion systems and manual estimation of fluid deficit.. Non-Resectoscopic Endometrial Ablation. Currently various energy sources are used in 6 non- resectoscopic endometrial ablation devices approved by Health Canada, including bipolar radiofrequency ablation (NovaSure), heated fluid freely circulated in the uterine cavity (Genesys HTA), and fluid contained in a balloon (Thermablate EAS, Cavaterm, LiNA Librata). Specifications of each of these devices are compared in Table 3. It is important to note that some of these devices are approved but not commercially sold in Canada at this time. Others are approved in the United States only (PlasmaSense, Cerene cryotherapy, Mara Water Vapor System). Future technologies like these have promising preliminary results.32. In the absence of large differences in effectiveness and with low complication rates for each of the devices, the choice of which to use depends primarily on the following practical issues and patient factors:. - Availability of scientific evidence- Local availability and cost effectiveness- Surgeon preference- Ease of use in outpatient/clinic setting- Requirement of endometrial preparation- Uterine cavity characteristics (size, cavitary pathology). Clinical Tip. For safety and appropriate intracavitary device placement, pre- and postprocedural diagnostic hysteroscopy or intraprocedural ultrasound guidance may be considered.. The balloon technologies involve coagulation of the endometrium that eventually leads to fibrosis. The maximum effect of this process is seen at 6 months post procedure rather than at 2- 4 weeks, as seen with other technologies.. Comparing the Efficacy of Non-Resectoscopic Devices. Patient satisfaction and re- intervention rates may be more clinically meaningful than absolute amenorrhea rates in comparing outcomes of procedures using non- resectoscopic devices. All of these devices work well and are associated with high levels of patient satisfaction, as demonstrated by the pivotal trials conducted by the US Food and Drug Administration (FDA) that showed satisfaction rates of . Direct comparisons of non- resectoscopic devices are scarce, and differences between trials with respect to outcome measures, preoperative endometrial preparation, practice settings, and follow- up times make it challenging to compare outcomes accurately. NovaSure radiofrequency ablation has been the most studied in randomized trials, which compare the device with the Hydro ThermAblator hot liquid balloon and Cavaterm.. NovaSure versus Hydro ThermAblator. At 12 months of follow- up, NovaSure had significantly higher rates of patient satisfaction (87% vs. 68%) and amenorrhea (47% vs. 24%) than the Hydro ThermAblator.34 This benefit persisted at 5 years, with NovaSure having significantly higher satisfaction rates (81% vs. 48%), higher amenorrhea rates (55% vs. 37%), and fewer surgical re- interventions (15% vs. 35%).35. NovaSure versus Cavaterm. In a small, randomized trial of 57 patients, there was no difference in patient satisfaction (92% vs. 83%) or reintervention rates between groups at 1- year follow- up. Amenorrhea rates, however, were significantly higher with NovaSure (42% vs. 12%).36. A network meta- analysis reported that bipolar radio frequency endometrial ablation resulted in higher rates of amenorrhea than thermal balloon at 12 months,37 which was confirmed by another systematic review.38 However, there was no difference between techniques in patient satisfaction or number of women still experiencing heavy bleeding.. # # EFFECTIVENESS OF RESECTOSCOPIC VERSUS NON-RESECTOSCOPIC TECHNIQUES. Primary outcome measures when evaluating endometrial ablation procedures include rates of amenorrhea, patient satisfaction, and surgical re- intervention. A Cochrane Database review compared resectoscopic and nonresectoscopic techniques and reported similar amenorrhea rates at 1 year . Although clinical outcomes between techniques were comparable, non- resectoscopic procedures required shorter surgical time, were more likely to be performed under local anaesthesia, and resulted in patients' quicker return to normal activity.39,40 The overall perioperative complication rate was low with both techniques . Summary Statements 3, 4, and 5. ANAESTHESIA AND OPERATIVE SET-UP. Resectoscopic ablation is frequently performed under general or regional anaesthesia in the operating room. However, in the appropriate setting, it can also be safely and effectively performed using a local paracervical block with intravenous sedation. Local, regional, or general anaesthesia can be used . In addition to local anaesthesia by paracervical block, oral or intravenous conscious sedation may be used depending on patient pain tolerance and surgeon preference. Nonsteroidal anti- inflammatory drugs can be given preoperatively and are moderately effective in diminishing uterine contractions during and after the procedure.41. Procedure Room Versus Operating Room Setting. In the United States, non- resectoscopic endometrial ablation is frequently an office- based procedure, and provider payment processes promote use of these less resourceintensive environments.42 In the Canadian setting, although there is less funding available for this practice, an estimated savings of CAD 562\(per patient undergoing endometrial ablation has been attributed to the introduction of balloon devices in the outpatient setting.38 Endometrial ablation performed in a hospital - based procedure room or a free - standing day surgery centre rather than an operating room offers the advantages of a patient - centred environment, easier scheduling, and lower case costs. Appropriate low - risk patient selection and a satisfactory pain management strategy are critical in this environment. Procedure rooms must have appropriate emergency equipment readily accessible, and all personnel must be trained in appropriate adverse event protocols. A systematic review comparing non - resectoscopic endometrial ablation performed in the outpatient setting with resectoscopic endometrial ablation in the operating room showed varying amounts of significant cost - savings.38. Summary Statements 6 and 7. COMPLICATIONS OF ENDOMETRIAL ABLATION. The most common adverse events following endometrial ablation are pelvic pain, cramping, and nausea/vomiting. These will generally resolve within 12- 24 hours of the procedure. Other problems that can develop post procedure are hematometrium, pyometrium, and endometritis. More severe complications are rare with both techniques of endometrial ablation but may include injury to contiguous pelvic structures, such as pelvic blood vessels, bowel, and urinary tract anatomic components.. # Procedural complications, such as severe pain, bleeding, uterine perforation, and infection may require emergent surgical management.. The FDA has a reporting system for non- resectoscopic ablation complications, and bowel injury is the most common complication reported to its Manufacturer and User Facility Device (MAUDE) database.. Long- term recurrent AUB after endometrial ablation may be caused by endometrial proliferation, adenomyosis, or (rarely) a pre- malignant or malignant condition of the uterus. Investigation should include an endometrial biopsy if more than 1 year has passed since the procedure. Because dense intrauterine synechiae sometimes result from endometrial ablation, endometrial biopsy and even dilatation and curettage, may often be impossible.. Serious Complications of Endometrial Ablation Immediate complications. Uterine perforation has been reported in . Perioperative hemorrhage has been reported in . Pelvic infections and fever occur in the immediate postoperative period in approximately . Delayed complications. Hematometra has been reported in . Post- ablation tubal sterilization syndrome has been reported to occur at a rate as high as . Clinical Tip. For acute hemorrhage in resectoscopic endometrial ablation, if uterine perforation has been ruled out, bleeding may be managed with one or more of these techniques: intrauterine Foley balloon tamponade, intracervical injection of vasopressors, rectal misoprostol administration, and systemic tranexamic acid administration.. Hematometra should be suspected in a patient with a history of an endometrial ablation who presents with amenorrhea and cyclic pain, even when remote from the procedure.. Tips for administering paracervical block. - Infiltration of the cervix carries risks of intravascular injection and toxicity of the local anaesthetic. These. # risks can be minimized by infiltrating slowly, using lower concentrations of local anaesthetic, frequently aspirating, and monitoring for symptoms of intravasation (tinnitus, blurring of vision, perioral/facial numbness). If the local anaesthetic contains epinephrine, patients may experience palpitations, tachycardia, or feelings of anxiety. Basic resuscitative equipment should be available.. - Allow the block to take effect by waiting . Complications Specific to Resectoscopic Endometrial Ablation. Resectoscopic endometrial ablation has potential complications specific to this surgical modality. Careful fluid management is critical to the safe use of hysteroscopic endometrial ablation. In addition, surgeons must possess a comprehensive understanding of potential electrosurgical injuries during hysteroscopic endometrial ablation.. Safe hysteroscopic surgery requires careful fluid management to avoid excessive intravasation of hysteroscopic distension media. Adherence to a strict protocol for fluid monitoring and management criteria will minimize the risk of complications of distension medium overload such as cardiovascular compromise and pulmonary edema, electrolyte abnormalities, and encephalopathy. Table 2 provides an approach to prudent management of hysteroscopic distension fluid issues.. Electrosurgical injuries with monopolar operative hysteroscopy can occur due to capacitive coupling and defective insulation and result in cervical, vaginal, or perineal burns. There is an increased risk of this occurring when the tip of the resectoscope is in the cervical canal, when the cervix is over- dilatated, or when there are electrode insulation defects. There is a greater degree of capacitive coupling injury with higher voltage outputs, which may occur with use of a dampened coagulation mode, long uninterrupted periods of electrode activation, and non- contact with tissue.4 Risks of capacitive coupling can be reduced by preventing cervical over- dilatation, using the lower voltage "cut" current, avoiding prolonged and uninterrupted activation, checking for insulation defects, ensuring contact with tissue during activation, and using a metallic speculum (weighted or Sims speculums) during the procedure to disperse any stray currents.. Recommendations 4, 5, 6, and 7. SPECIAL CONSIDERATIONS. Repeat Ablation. Irrespective of technique, endometrial ablation has a success rate of . If repeat endometrial ablation is considered, a hysteroscopic approach using the resectoscope is recommended. A non- resectoscopic blind procedure is contraindicated in this clinical scenario. Complication rates of repeat endometrial ablation are statistically higher than those of primary procedures, with risks of perforation, more fluid absorption, and bleeding occurring at rates of . Recommendation 8. Previous Cesarean Delivery. The literature regarding endometrial ablation in patients with a history of cesarean delivery consists primarily of small retrospective cohort studies. For resectoscopic endometrial ablation, there are generally no restrictions following cesarean delivery. However, caution should be exercised over the cesarean delivery seat, as myometrial thinning may predispose it to perforation or thermal injury. For a patient with previous transmural myomectomy, obtaining adequate visualization of the cavity using a pressure pump should allow for safe treatment. Evaluation of the isthmocele and, in particular, the minimum residual myometrium associated with this defect is an important consideration to prevent potential electrosurgical bladder injury.. For the available non- resectoscopic technologies, no restriction on the minimum myometrial thickness has been mentioned. However, caution is recommended with patients who have had . # Non- resectoscopic endometrial ablation is contraindicated in patients who have undergone classical cesarean delivery or transmural myomectomy. Five- year data on satisfaction, treatment failure, and operative complications of non- resectoscopic endometrial ablation in patients with a history of cesarean delivery are similar to those in patients who have not undergone cesarean delivery.. Recommendation 9. Adenomyosis. Endometrial ablation may be a safe and effective strategy to reduce both AUB and dysmenorrhea associated with adenomyosis in appropriately selected patients when medical therapy has failed. However, there are no randomized controlled trials involving endometrial ablation that compare interventions for adenomyosis- related AUB or dysmenorrhea. In the most recently published Cochrane systematic review and meta- analysis of interventions for heavy menstrual bleeding,. The largest prospective study published to date evaluating endometrial ablation in the setting of adenomyosis was a single- site cohort study in France.. One concern during preoperative counselling is that adenomyosis- associated dysmenorrhea may worsen following endometrial ablation and lead to hysterectomy. A large retrospective cohort study of 5818 women in the United States who underwent non- resectoscopic endometrial ablation between 2003 and 2015 identified preoperative pelvic pain as an independent risk factor for . Especially in patients with adenomyosis and comorbid dysmenorrhea, concomitant insertion of an LNG- IUS at the time of endometrial ablation may be helpful in reducing postoperative failure due to recurrent bleeding or new or recurrent pain. This question is being investigated in a multicentre randomized controlled trial in 35 hospitals in the Netherlands, and patients with adenomyosis will be included.. Recommendations 10 and 11. Intracavitary Pathology and Non-Resectoscopic Endometrial Ablation. Intracavitary fibroids and polyps were excluded from the original randomized controlled trials evaluating non- resectoscopic endometrial ablation techniques. These procedures were originally designed to treat normal uterine cavities. Subsequently, various attempts have been made to examine the utility of these technologies in distorted cavities with submucosal fibroids. The Genesys HTA, which relies on freely circulating heated fluid under direct visualization, may be suited to treat distorted cavities, as it does not rely on the fixed shape of a mesh. # or balloon. Women with types 1 and 2 submucosal fibroids . Similarly, there are limited data on sequential resection of intracavitary pathology followed by non- resectoscopic endometrial ablation. The NovaSure radiofrequency ablation device monograph lists as a contraindication "a patient with any anatomic condition [...] or pathologic condition that could lead to weakening of the myometrium.". Despite encouraging results showing that non- resectoscopic endometrial ablation may be beneficial in treating AUB in women with small submucosal fibroids . Recommendation 12 and 13. Endometrial Ablation and Diagnosis of Subsequent Endometrial Cancer. Endometrial ablation or resection often leads to severe synechiae (i.e., partial or complete Asherman syndrome), . In summary, endometrial ablation procedures do not increase the risk of cancer, do not delay the diagnosis of endometrial cancer, and may decrease the overall risk of the disease. However, the presence of persistent AUB or uterine pain following this intervention warrants a thorough investigation; if endometrial sampling cannot be performed, ultrasound endometrial thickness evaluation should be performed, and hysterectomy considered.. Summary Statement 8 and Recommendation 14. Pregnancy After Endometrial Ablation. Scar tissue formation such as dense synechiae and altered vascularization after endometrial ablation reduce the probability of pregnancy significantly. However, endometrial ablation is not a sterilization procedure. Pregnancies that occur after endometrial ablation are often complicated and can even lead to maternal death.. # ablation is 1.5 years, and . In summary, preoperative discussion on contraception method is paramount before planning surgery. In some cases, concomitant sterilization can be offered at the time of endometrial ablation, but the method of sterilization should attempt to minimize the risk of post- ablation tubal ligation syndrome. Women who do become pregnant after endometrial ablation should obtain information from their care provider regarding the risks and benefits of continuing the pregnancy. Pregnancy termination complications as well as third- trimester complications are not infrequent, and care should be provided in a safe environment by medical staff equipped with the skills and experience to manage obstetrical complications like unanticipated PASD.. CONCLUSION. Endometrial ablation is an established and effective procedure to manage AUB. In well- selected patients, success rates and rates of patient satisfaction are high, and the procedure provides a viable alternative to other more invasive and higher risk procedures, such as hysterectomy.. Cavity assessment and endometrial sampling prior to endometrial ablation is vital and imperative.. Choice of technique for endometrial ablation should be dictated by both patient and anatomical factors. Resectoscopic endometrial ablation techniques continue to be a valuable skill set and should remain a critical element to residency training programs. Use of fluid management systems and bipolar resectoscopes aid in reducing the risks associated with this technique.. Adenomyosis is not a contraindication to endometrial ablation, although failure rates may be higher in this patient . Concerns regarding endometrial ablation leading to delayed diagnosis of endometrial cancer are currently unfounded. Endometrial ablation may in fact reduce the risk of developing endometrial cancer. Endometrial ablation should therefore be considered a reasonable option for managing AUB after negative endometrial sampling. Combined medical therapy and endometrial ablation should continue to be studied to provide evidence for these questions.. REFERENCES. 1. Tremblay D. Personal Communication between Philippe Laberge and Dominique Tremblay of AOGQ. In: Laberge P, editor. Email Communication2023. 2. 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Cochrane Database Syst Rev 2010:CD007710. Available at: 42. Glasser MH. Practical tips for office hysteroscopy and second-generation "global" endometrial ablation. J Minim Invasive Gynecol 2009;16:384-99. Available at: 43. Gardner S, Schultz DG. Complications associated with global endometrial ablation: the utility of the MAUDE database. Obstet Gynecol 2004;103:995-6. Available at: pubmed/15121577. 44. Gadzinski JA, Sheran J, Garbe G, et al. The Postendometrial Ablation Endometrium: Reassessment With Biopsy and Ultrasonography. Obstetrics & Gynecology 2014;123:124S. 45. McCausland AM, McCausland VM. Frequency of symptomatic cornual hematometra and postablation tubal sterilization syndrome after total rollerball endometrial ablation: a 10-year follow-up. Am J Obstet Gynecol. # 2002;186:1274- 80; discussion 80- 3. Available at: 46. McCausland AM, McCausland VM. Long- term complications of endometrial ablation: cause, diagnosis, treatment, and prevention. J Minim Invasive Gynecol 2007;14:399- 406. Available at: 47. Glasser MH, Heinlein PK, Hung YY. Office endometrial ablation with local anesthesia using the HydroThermAblator system: Comparison of outcomes in patients with submucous myomas with those with normal cavities in 246 cases performed over . Health 2022;22:257. Available at: 59. Lou J, Huang X, Zhang L, et al. [The second generation endometrial ablation (NovaSure) improves efficacy of levonorgestrel- releasing intrauterine system in management of adenomyosis]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2019;48:136- 41. Available at: 9292- 2019- 48- 2- 136. pdf. 60. Sabbah R, Desaulniers G. Use of the NovaSure Impedance Controlled Endometrial Ablation System in patients with intracavitary disease: 12- month follow- up results of a prospective, single- arm clinical study. J Minim Invasive Gynecol 2006;13:46- 71. Available at: 61. Soysal ME, Soysal SK, Vicdan K. Thermal balloon ablation in myoma- induced menorrhagia under local anesthesia. Gynecol Obstet Invest 2001;51:128- 33. Available at: 62. NovaSure Instructions for Use and Controller Operator's Manual. Hologic Inc.; 2019. p. 32. Available at: 07/AW- 09898- 000_012_02%20%281%29_RFC10%20controller%20IFU_Rev%2012. pdf. 63. Rubino RJ, Roy KH, Presthus J, et al. Abnormal Uterine Bleeding Control by Sequential Application of Hysteroscopic Lesion Morcellation and Endometrial Ablation. J Reprod Med 2017;62:102- 10. 64. Oderkerk TJ, van de Kar MRD, Cornel KMC, et al. Endometrial cancer after endometrial ablation: a systematic review. International journal of gynecological cancer 2022;32:1555- 60. 65. Gimpelson RJ. Not so benign endometrial hyperplasia: Endometrial cancer after endometrial ablation. The Journal of the American Association of Gynecologic Laparoscopists 1997;4:507- 11. 66. Singh M, Hosni MM, Jones SE. Is endometrial ablation protective against endometrial cancer? A retrospective observational study. Archives of gynecology and obstetrics 2016;293:1033- 7. 67. Dion L, Agostini A, Collier F, et al. In which cases should endometrial destruction be performed during an operative hysteroscopy? Clinical practice guidelines from the French College of Gynaecologists and Obstetricians (CNGOIC). Journal of gynecology obstetrics and human reproduction 2021;50:102188. 68. Dood RLMDM, Gracia CRMDM, Sammel MDS, et al. Endometrial Cancer After Endometrial Ablation vs Medical Management of Abnormal Uterine Bleeding. Journal of minimally invasive gynecology 2014;21:744- 52. 69. Bauer AM, Hackney LN, El- Nashar S, et al. Pregnancy outcomes after endometrial ablation in a multi- institutional cohort. American Journal of Perinatology 2018;35:931- 5. 70. Ibiebele I, Nippita TA, Baber R, et al. A study of pregnancy after endometrial ablation using linked population data. Acta Obstetricia et Gynecologica Scandinavica 2021;100:286- 93. Available at: 71. Kohn J, Shamshirsaz A, Popek E, et al. Pregnancy after endometrial ablation: a systematic review. BJOG: An International Journal of Obstetrics & Gynaecology 2018;125:43- 53. Available at: 0528.14854. 72. Townsend DE, Duleb AJ, Wilkes MM. Durability of treatment effects after endometrial cryoablation versus rollerball electroablation for abnormal uterine bleeding: Two- year results of a multicenter randomized trial. American journal of obstetrics and gynecology 2003;188:699- 701.. # APPENDIX A.	None	None	None
35340f71b98d499fb0133d4b04483b58	2024+SOGC临床实践指南	子宫内膜息肉的诊断和管理	# SOGC CLINICAL PRACTICE GUIDELINE. It is the Society of Obstetrician and Gynaecologists of Canada (SOGC) policy to review the content 5 years after publication, at which time the document may be revised to reflect new evidence, or the document may be archived.. No. 447, March 2024. Guideline No. 447: Diagnosis and Management of Endometrial Polyps. (En français : Diagnostic et prise en charge duvasa pravia). The English document is the original version; translation may introduce small differences in the French version.. This clinical practice guideline was prepared by the authors and overseen by the SOGC Clinical Practice Gynaecology. It was reviewed by the SOGC Guideline Management and Oversight Committee.. Authors. Olga Bougie, MD, MPH, Kingston, ON Elizabeth Randle, MD, Halifax, NS Jackie Thurston, MD, Calgary, AB Bryden Magee, MD, Ottawa, ON Chelsie Warshafsky, MD, Ottawa, ON David Rittenberg, MD, Halifax, NS. SOGC Clinical Practice Gynaecology Committee (2023): Olga Bougie, Innie Chen, Anisha Dubey, Devon Evans, Joann James, Marie Jones, Sari Kives, Ally Murji, Jessica Papillon- Smith, Leslie Po, Elizabeth Randle, David Rittenberg (co- chair), Jackie Thurston, Paul Yong (co- chair). Disclosures: Statements were received from all authors. Twelve relationships or activities that could involve a conflict of interest were declared. All authors have indicated that they meet the journal's requirements for authorship. Olga Bougie declared that she received consulting fees from AbbVie and Pfizer, payment for a presentation from AbbVie, support for meeting attendance from Pfizer, is on the Data Safety Monitor Board of Organon, is on the Advisory board of Pfizer, and is an executive board member of CanSAGE. Elizabeth Randle declared that she received consulting fees from Pfizer, honoraria for a presentation from AbbVie, and is on the Advisory board of Pfizer. Jackie Thurston declared that she was a CPSA expert witness in 2023. Bryden Magee declared that she was on the advisory board of Biosyent. Chelsie Warshafsky and David Rittenberg had nothing to declare.. Subject Categories: gynaecology, diagnostic imaging, reproductive endocrinology and infertility. Keywords: endometrium; polyps; endometrial neoplasms; metrorrhagia; hysteroscopy. Corresponding Author: Olga Bougie, olga.bougie@kingstomsc.ca. Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.. This document reflects emerging clinical and scientific advances as of the publication date and is subject to change. The information is not meant to dictate an exclusive course of treatment or procedure. Institutions are free to amend the recommendations. The SOGC suggests, however, that they adequately document any such amendments.. Informed consent: Everyone has the right and responsibility to make informed decisions about their care together with their health care providers. To facilitate this, the SOGC recommends that health care providers provide patients with information and support that is evidence- based, culturally appropriate, and personalized.. Language and inclusivity: This document uses gendered language in order to facilitate plain language writing but is meant to be inclusive of all individuals, including those who do not identify as a woman/female. The SOGC recognizes and respects the rights of all people for whom the information in this document may apply, including but not limited to transgender, non- binary, and intersex people. The SOGC encourages healthcare providers to engage in respectful conversation with their patients about their gender identity and preferred gender pronouns and to apply these guidelines in a way that is sensitive to each person's needs.. # KEY MESSAGES. KEY MESSAGES1. Endometrial polyps are common and can present with abnormal uterine bleeding, postmenopausal bleeding, infertility, or may be asymptomatic. 2. Transvaginal ultrasound should be first- line investigation in patients suspected to have endometrial polyps. 3. Risk of malignancy in an endometrial polyp is estimated to be between . ABSTRACT. Objective: The primary objective of this clinical practice guideline is to provide gynaecologists with an algorithm and evidence to guide the diagnosis and management of endometrial polyps.. Target population: All patients with symptomatic or asymptomatic endometrial polyps.. Options: Options for management of endometrial polyps include expectant, medical, and surgical management. These will depend on symptoms, risks for malignancy, and patient choice.. Outcomes: Outcomes include resolution of symptoms, histopathological diagnosis, and complete removal of the polyp.. Benefits, harms, and costs: The implementation of this guideline aims to benefit patients with symptomatic or asymptomatic endometrial polyps and provide physicians with an evidence- based approach toward diagnosis and management (including expectant, medical, and surgical management) of polyps.. Evidence: The following search terms were entered into PubMed/ Medline and Cochrane: endometrial polyps, polyps, endometrial thickening, abnormal uterine bleeding, postmenopausal bleeding, endometrial hyperplasia, endometrial cancer, hormonal therapy, female infertility. All articles were included in the literature search up to 2021 and the following study types were included: randomized controlled trials, meta- analyses, systematic reviews, observational studies, and case reports. Additional publications were identified from the bibliographies of these articles. Only English- language articles were reviewed.. Validation methods: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations).. Intended audience: Gynaecologists, family physicians, registered nurses, nurse practitioners, medical students, and residents and fellows.. Tweetable Abstract: Uterine polyps are common and can cause abnormal bleeding, infertility, or bleeding after menopause. If patients don't experience symptoms, treatment is often not necessary. Polyps can be treated with medication but often a surgery will be necessary.. SUMMARY STATEMENTS:. SUMMARY STATEMENTS:1. Endometrial polyps are a common diagnosis in both pre- and postmenopausal patients (high). 2. Patients with endometrial polyps may present with abnormal uterine bleeding, postmenopausal bleeding, infertility, or may be asymptomatic (high). 3. Transvaginal ultrasound is associated with a wide range of accuracy in diagnosing endometrial polyps; however, it remains a good first- line investigation because of safety, availability, and patient acceptance (high). 4. In situations where the diagnosis of polyp on transvaginal ultrasound remains in question, consideration of saline- infused sonohysterography or 3D ultrasound, if available, can be considered as alternative diagnostic imaging techniques (moderate). 5. Hysterosalpingography, CT scanning, and MRI are not useful in the diagnosis of endometrial polyps (high). 6. Hysteroscopy with guided biopsy remains the gold standard for diagnosis of endometrial polyps (high). 7. Patients at highest risk for premalignant or malignant endometrial polyps are older (. # RECOMMENDATIONS:. 1. Transvaginal ultrasound should be used as initial investigation in patients suspected to have endometrial polyps (strong, high). 2. Patients who present with features suspicious for endometrial polyps and who would benefit from subsequent polypectomy should be directed toward hysteroscopy, with a plan for operative management should a polyp be diagnosed (strong, moderate). 3. Blind sampling to diagnose endometrial polyps via endometrial biopsy or dilation and curettage should not be performed (strong, high). 4. Patients with endometrial polyps who are older . an endometrial polyp, particularly in cases of uterine preservation (strong, low). 7. Expectant management can be considered for asymptomatic patients and those with a low risk of malignancy (conditional, moderate). 8. Polypectomy should be performed via direct hysteroscopic visualization, as this approach decreases the risk of complications, incomplete removal, and recurrence (strong, high). 9. Bipolar energy should be used preferentially over monopolar energy, as it reduces the risk of electrosurgical burns and fluid overload. Tissue removal systems also reduce the risk of fluid overload and avoid the risk of electrosurgical burns altogether but have functional and cost limitations (strong, high). 10. Patients diagnosed with an endometrial polyp should be offered hysteroscopic resection to improve their fertility potential if they are experiencing infertility, regardless of polyp size (strong, high). 11. When a new endometrial polyp is diagnosed during in vitro fertilization stimulation, the following options should be discussed with the patient: 1) cycle cancellation, 2) freeze- all, and 3) transfer. There is no evidence to support need to cancel the cycle (conditional, low).. # INTRODUCTION. ndometrial polyps are a common gynecological pre- . sentation, both in pre and postmenopausal patients. They may be identified incidentally on imaging, or patients may present with abnormal uterine bleeding, postmenopausal bleeding, or infertility. The risk of malignancy in an endometrial polyp is generally low, but each patient should be individually evaluated. Treatment options include expectant, medical and surgical options. Surgical excision of a polyp is often favoured to ensure symptom resolution and obtain histological assessment. The objective of this guideline is to summarize the available evidence on the diagnosis and management of endometrial polyps for obstetrician gynaecologists in Canada. The scope of this guideline is limited to patients presenting with endometrial polyps. This guideline does not address the management of malignant endometrial polyps.. EPIDEMIOLOGY. Endometrial polyps, defined as a localized intrauterine lesion consisting of endometrial glands, stroma, and blood vessels covered by epithelium, are common. Although the exact pathophysiology of polyp development is still under investigation, evidence suggests that their growth is stimulated by estrogen.23 Endometrial polyps contain both estrogen and progesterone receptors at higher concentrations than found in normal endometrium.4,5. The prevalence of endometrial polyps varies by the demographic characteristics of the population studied, as well as by patient's clinical presentation and diagnostic investigations performed. Approximately . ABBREVIATIONS. menopausal status, obesity, hypertension, polycystic ovary syndrome, and use of tamoxifen.6,15- 18 Estrogen and progesterone therapy use post menopause has been demonstrated to increase the risk of polyps in some studies,4,6,19 but not others.15,20,21. Endometrial polyps may be asymptomatic and incidentally identified either on imaging or on histologic or hysteroscopic assessment of the endometrial cavity.6,11- 14 When symptomatic, they most commonly present with abnormal uterine bleeding or postmenopausal bleeding, but can also be present in the context of infertility.10. Summary Statements 1 and 2. DIAGNOSIS. Endometrial polyps can be diagnosed via imaging studies or direct visualization, typically with pathologic confirmation following tissue sampling. Transvaginal ultrasound is commonly used as an initial investigation. Ultrasonographic features in keeping with a diagnosis of endometrial polyps are nonspecific and include hyperechoic focal endometrial mass with or without vascularity and distortion of the endometrial contour (interrupted mucosa sign).22- 24 Less commonly, cystic spaces corresponding to dilated glands filled with proteinaceous fluid may be seen within the polyp, or the polyp may appear as a nonspecific endometrial thickening within the endometrial cavity. The accuracy of transvaginal ultrasound in diagnosing endometrial polyps varies widely in the literature, with sensitivity and specificity reported from . To improve the accuracy of transvaginal ultrasound in diagnosing endometrial polyps, 3D and power Doppler applications have been studied. 3D ultrasound can provide additional information regarding endometrial contour and thickness, which can be particularly helpful in cases of intrauterine anomalies.27 These 3D measurements have been demonstrated to increase the sensitivity and specificity of transvaginal ultrasound to . # patterns that can differentiate an endometrial polyp from leiomyoma or hyperplasia.29 In the case of endometrial polyp, a single feeding "sentinel" vessel is considered characteristic.30 The inclusion of power Doppler at the time of transvaginal ultrasound has been shown to increase the sensitivity and specificity of transvaginal ultrasound to . Saline- infused sonohysterography (SIS), which defines the polyp as an echogenic mass outlined in fluid,22 has a sensitivity of . Hysterosalpingography can identify polyps as nonspecific filling defects within the endometrial cavity with a sensitivity of . Blind sampling, either through endometrial biopsy or dilation and curettage, is ineffective at diagnosing endometrial polyps, with a sensitivity of . Hysteroscopy with guided biopsy remains the gold standard for the diagnosis of endometrial polyps. In addition to allowing direct visualization of endometrial polyps for diagnostic purposes, hysteroscopy facilitates the appraisal of size, number, location, consistency, characteristics of the base, and vascularity of polyps.41 This information is valuable when considering therapeutic approaches. Hysteroscopy has traditionally been performed in operative settings; however, several studies suggest that in- office hysteroscopy is a feasible alternative, associated with reduced need for anaesthesia and its associated risks, improved recovery, and better time- and cost- effectiveness.22,23,25. Summary Statements 3, 4, 5, 6 and Recommendations 1, 2, 3. RISK OF MALIGNANCY. While most endometrial polyps are benign, premalignant and malignant lesions can be found in . 53,55 are consistently associated with higher prevalence of premalignant or malignant pathology within endometrial polyps. Other risk factors that are less reliably correlated with increased rates of premalignant or malignant pathology include polyp size,44,49,55,56 obesity,43,47,49 systemic arterial hypertension,43,47- 49 and diabetes mellitus.43,47 While some studies suggest that menopausal hormonal therapy may be associated with the development of endometrial polyps in postmenopausal women,6,57 menopausal hormonal therapy does not increase the risk of malignancy in polyps.43,44,47,49- 52. # Tamoxifen therapy is linked to an increased risk of endometrial polyp malignancy regardless of years of use.. The highest risk group for premalignant or malignant endometrial polyps are older patients, postmenopausal patients, and those experiencing postmenopausal bleeding. These patients should be referred to a gynaecologist for further assessment. Patients on tamoxifen should also be given special consideration as an at- risk group, and polyp resection should be planned regardless of menopausal status. Premenopausal patients with endometrial polyps are at higher risk for premalignant or malignant lesions if symptoms of abnormal uterine bleeding are present, and referral to a gynaecologist should be considered. Patients who have additional risk factors for endometrial cancer or are seeking treatment for infertility should also be referred to a gynaecologist. In the studies that found that polyp size correlated with premalignant or malignant pathology, malignancy risk was increased with lesions greater than 10 mm.. Endometrial polyps can be associated with an increased risk of malignancy within subgroups of patients. However, polyps are not generally considered a precursor to cancer.. In a situation where a polyp cannot be resected in a patient deemed to be at higher risk for malignancy, a hysterectomy may be considered for definitive treatment. The surgical risk of hysterectomy must be weighed against the risk of malignancy.. Summary Statements 7, 8, 9, 10 and Recommendations 4, 5, 6. TREATMENT. Treatment options for endometrial polyps include expectant and medical management, as well as surgical excision. The choice of treatment should be guided by the patient's symptomatology (or lack thereof) as well as the risk of malignancy.. If a patient meets criteria for endometrial biopsy sampling (e.g., experiencing postmenopausal bleeding), it should be performed without delay for hysteroscopic assessment of a polyp.. Expectant. The natural history of endometrial polyps can be difficult to predict. Approximately . There is currently a paucity of evidence to guide expectant management, with respect to the need for further repeat imaging or assessment. Patient characteristics and risk of malignancy must be considered. Repeat imaging in . Medical. Primary Treatment. Several studies testing progesterone treatment of polyps have shown promising results. Administration of . # dydrogesterone . Prevention. Like polyp regression, LNG- IUS can be considered for prevention of endometrial polyps in select, high- risk populations.66 A Cochrane review reported that in tamoxifen users the LNG- IUS reduced the incidence of polyps in both short- . Surgical. Surgical management is the most effective treatment for endometrial polyps. This can be divided into conservative and radical management. Conservative management can be subdivided into blind and hysteroscopic methods.. Conservative. Blind Resection. The sensitivity of blind dilation and curettage to detect endometrial polyps is only . Hysteroscopic Polypectomy. Hysteroscopic polypectomy is the most effective option for both diagnosis and treatment. The goals of hysteroscopy are three- fold: 1) complete resection (to the level of the endometrial basalis), 2) minimize recurrence, and 3) obtain a pathology specimen.72 Depending on the pathology results and patient characteristics, polyp visualization, excision, and removal can be achieved using either mechanical or electrosurgical . Mechanical Instruments. Classic polyp removal involves reusable scissors and graspers.73 This low- cost intervention can be used in any procedural setting but is limited by the fragility of the instruments and inability to control bleeding. Its use should be limited to smaller, glandular polyps 66,71. The use of polyp forceps followed by immediate repeat hysteroscopy has also been used. In a study by Gebauer and colleagues, blind dilation and curettage was performed.71 After repeat hysteroscopy, a second curettage and forceps resulted in complete polyp extraction in . Tissue Removal Systems. Tissue removal systems (TRSs) consist of a bespoke . Resectoscope. The larger diameter resectoscope allows for removal of large, more fibrous polyps under general anaesthesia or conscious sedation.66 Polyps can be removed in strips or by cutting at the polyp base, then removed by grasping it with the loop. The standard. # resectoscope is composed of a hysteroscope, an inner and outer sheath, and a loop electrode, connected to a radiofrequency electrosurgical generator.74 Resectoscopic instruments are traditionally 24 and . Choice of Technique. Mechanical methods have been shown to be faster than resectoscopic removal.74 TRSs have a shorter operating time, lower fluid deficits, faster learning curves, and better visualization than the resectoscope.75,76 However, the cost of polypectomy is significantly higher when using disposable equipment. The cost- effectiveness of the chosen approach should be balanced against the technical expertise required to perform this procedure.77 Table 3 reviews common considerations in choosing a surgical approach.. Setting. Diagnostic and operative hysteroscopy may be performed in the operating room or outpatient/clinic setting. The safety and feasibility of ambulatory hysteroscopy has been consistently demonstrated in large- scale studies.78,79 A review and summary of anaesthetic options for hysteroscopy is available in other literature.80 Analgesia options for patients include oral acetaminophen, non- steroidal antiinflammatory drugs, nitrous oxide, and opioids if necessary.81 Local anaesthetic (paracervical block) as well as intravenous sedation may be administered as well.81 Several other non- pharmacologic practices can help . Office or outpatient hysteroscopy offers a safe, effective, and cost- saving alternative to traditional hysteroscopy performed in the operating room.83 A 2019 systematic review suggested a potential increase in postoperative pain following office/outpatient hysteroscopy compared with hysteroscopy performed under general anaesthesia;. # however, the authors cautioned the interpretation of this finding given the limited number of studies examining this outcome, as well as the noted study variability.. Complications. Complications associated with hysteroscopic surgery can be classified as intraoperative or postoperative in nature. Intraoperative complications include uterine perforation, fluid overload and subsequent sequelae, hemorrhage, and intraabdominal visceral injury. Some patients experience a vasovagal reaction with cervical dilation. Anaesthetic complications may occur, including local anaesthetic toxicity. Overall, studies suggest that intraoperative complications related to hysteroscopy are low . Postoperative complications may include infection and hemorrhage, which typically present in the early recovery period. Later complications can include development of intrauterine adhesions.. Summary Statements 10, 11, 12 and Recommendations 7, 8, 9. SPECIAL CONSIDERATION - FERTILITY. Prevalence. In the infertile population, the reported prevalence of endometrial polyps varies widely, ranging from . Polyps may impact fertility by hindering movement of sperm through the tubal ostia or by physically or chemically impairing embryo implantation.. Clinical Scenarios Natural Conception. Studies generally demonstrate an improvement in pregnancy rate following hysteroscopic removal of polyps,. Intrauterine Insemination. A randomized controlled study of 215 patients with infertility who were candidates for intrauterine insemination (IUI) had a 2- fold higher pregnancy rate . A prospective comparative study of 110 patients undergoing IUI demonstrated a cumulative pregnancy rate of . In Vitro Fertilization. The removal of polyps identified during the infertility workup has become accepted practice in patients planning in vitro fertilization (IVF), likely because of extrapolation from data in the IUI population, as well as the low risk of surgical complications or postoperative adhesion formation with hysteroscopic polypectomy. The time interval between hysteroscopic polypectomy and subsequent embryo transfer does not appear to impact implantation, clinical pregnancy, miscarriage, or live birth rates, so IVF could be initiated as soon as the next menstrual cycle after polypectomy.. However, the appropriate management of newly discovered suspected polyps during the follicular phase of ovarian stimulation for IVF remains uncertain. Management options include. 1) Cancelling the cycle and performing hysteroscopic polypectomy; 2) Continuing ovarian stimulation and egg retrieval, but delaying frozen embryo transfer until after hysteroscopic polypectomy; or 3) Proceed with fresh embryo transfer as planned.. Although studies examining this question have significant limitations due to small sample sizes and potential confounders, they do not suggest that cycle cancellation followed by hysteroscopic polypectomy (option 1) is associated with higher pregnancy and live birth rates.. In 1999, Lass and colleagues compared pregnancy rates of those who elected for option 2 over option 3, listed above. There were no statistical differences in pregnancy rates, but the results are limited by the age of the study (and. # embryo freezing techniques at the time) as well as by the fact that histological diagnosis of endometrial polyp was only confirmed in . Recurrent Pregnancy Loss. The reported prevalence of acquired uterine anomalies, including endometrial polyps, among patients with recurrent pregnancy loss varies between . Summary Statements 13, 14, 15, 16 and Recommendations 10, 11. Conclusion. Endometrial polyps are common, and can present with abnormal uterine bleeding, infertility, or postmenopausal bleeding. Many are found incidentally on imaging. Investigations for endometrial polyps typically start with transvaginal ultrasound, but diagnostic capability may be improved with SIS or 3D ultrasound. Hysteroscopy can offer diagnosis and treatment or removal of polyps.. Treatment or removal of polyps may be indicated for symptom management or if there is a high risk of malignancy. In general, the risk of malignancy in endometrial polyps is estimated at . Treatment options for endometrial polyps include expectant, medical and surgical management. Hysteroscopic polypectomy is the standard of surgical management and offers the benefit of polyp removal for histopathologic assessment. There are several polypectomy techniques available, including variations in instruments, settings, and analgesia/anaesthesia used. Choice of polypectomy technique should consider the following: patient factors, local access to instruments and operating room time, setting, fluid management, cost, and surgeon preference.. REFERENCES. 1. Sant'Ana de Almeida EC, Nogueira AA, Candido dos Reis FJ, et al. Immunohistochemical expression of estrogen and progesterone receptors in endometrial polyps and adjacent endometrium in postmenopausal women. Maturitas 2004;49:229-33. Available at 2. Peng X, Li T, Xia E, et al. A comparison of oestrogen receptor and progesterone receptor expression in endometrial polyps and endometrium of premenopausal women. J Obstet Gynaecol 2009;29:340-6. Available at 3. Mittal K, Schwartz L, Goswami S, Demopoulos R. 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84effe2a6d254a30ac9d66c29ffc6abd	2024+SRU共识	子宫内膜异位症盆腔常规超声检查	# Society of Radiologists in Ultrasound Consensus on Routine Pelvic US for Endometriosis. Scott W. Young, MD* • Priyanka Jha, MBBS* • Luciana Chamié, MD, PhD • Shuchi Rodgers, MD • Rosanne M. Kho, MD • Mindy M. Horrow, MD • Phyllis Glanc, MD • Myra Feldman, MD • Yvette Groszmann, MD • Zaraq Khan, MBBS • Steven L. Young, MD, PhD • Liina Poder, MD • Tatnai L. Burnett, MD • Eric M. Hu, MD • Susan Egan, RDMS • Wendaline VanBuren, MD. From the Department of Radiology, Mayo Clinic Arizona, 5777 E Mayo Blvd, Phoenix, AZ 85054 (S.W.Y.); Department of Radiology, Stanford University School of Medicine, Stanford, Calif (P.J.); Department of Radiology, Chamié Imagem da Mulher, São Paulo, Brazil (L.C.); Department of Radiology, Albert Einstein Medical Center, Philadelphia, Pa (S.R., M.M.H.); Department of Obstetrics and Gynecology, Banner Health System, Phoenix, Ariz (R.M.K.); Department of Medical Imaging, University of Toronto, Toronto, Canada (D.G.); Imaging Institute, Cleveland Clinic Foundation, Cleveland, Ohio (M.F.); Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Mass (Y.G.); Department of Obstetrics and Gynecology (Z.K. T.L.); Department of Radiology (W.V.B.); Mayo Clinic, Rochester, Minn; Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC (S.L.Y.); Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, Calif (L.P.); Department of Radiology, Intermountain Healthcare, Salt Lake City, Utah (E.M.H.); and Department of Radiology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ (S.E.). Received August 24, 2023; revision requested October 31; revision received November 21; accepted December 22. Address correspondence to S.W.Y. (email: Young.Scott@mayo.edu).. * S.W.Y. and P.J. contributed equally to this work. Conflicts of interest are listed at the end of this article.. Radiology 2024; 311(1):e232191 • • Content codes: OB US. Endometriosis is a prevalent and potentially debilitating condition that mostly affects individuals of reproductive age, and often has a substantial diagnostic delay. US is usually the first- line imaging modality used when patients report chronic pelvic pain or have issues of infertility, both common symptoms of endometriosis. Other than the visualization of an endometrioma, sonologists frequently do not appreciate endometriosis on routine transvaginal US images. Given a substantial body of literature describing techniques to depict endometriosis at US, the Society of Radiologists in Ultrasound convened a multidisciplinary panel of experts to make recommendations aimed at improving the screening process for endometriosis. The panel was composed of experts in the imaging and management of endometriosis, including radiologists, sonographers, gynecologists, reproductive endocrinologists, and minimally invasive gynecologic surgeons. A comprehensive literature review combined with a modified Delphi technique achieved a consensus. This statement defines the targeted screening population, describes techniques for augmenting pelvic US, establishes direct and indirect observations for endometriosis at US, creates an observational grading and reporting system, and makes recommendations for additional imaging and patient management. The panel recommends transvaginal US of the posterior compartment, observation of the relative positioning of the uterus and ovaries, and the uterine sliding sign maneuver to improve the detection of endometriosis. These additional techniques can be performed in 5 minutes or less and could ultimately decrease the delay of an endometriosis diagnosis in at- risk patients.. \widehat{\mathbb{C}}. Supplemental material is available for this article.. Endometriosis, defined as the presence of endometrium- like tissue outside the uterus, is a common condition estimated to affect . Transvaginal sonography is used worldwide as a first- line modality for pelvic pain and infertility evaluation. It has also been advocated as a second- line modality for preoperative mapping of endometriomas and DE observations, after an initial diagnosis of DE has been established (4- 7). Yet, in the United States, there is a delay longer than 7 years between the onset of symptoms and diagnosis of endometriosis (8,9). Although transvaginal US is commonly interpreted by sonologists (radiologists and gynecologists) in the United States, few centers use US as a screening modality for DE . DE manifests in the posterior compartment of . # Abbreviations. AbbreviationsDE = deep endometriosis, O- RADS = Ovarian- Adnexal Reporting and Data System, USL = uterosacral ligament. Summary. SummaryThe Society of Radiologists in Ultrasound expert consensus provides recommendations for augmenting routine pelvic US examinations through additional maneuvers and imaging to improve diagnosis of deep endometriosis.. Essentials. Essentials- The Society of Radiologists in Ultrasound expert panel recommends performing augmented pelvic US in premenopausal or early postmenopausal individuals (<5 years since the cessation of menses) who are symptomatic for or have a history of endometriosis or infertility.- Additional techniques to augment pelvic US examinations include transvaginal US of the posterior compartment, observation of the relative positioning of the uterus and ovaries, and the uterine sliding sign maneuver.- Direct and indirect observations of deep endometriosis should be assessed during the examination and results should be reported using four categories: Incomplete (augmented pelvic US, or APU- 0), normal (APU- 1), equivocal (APU- 2), and positive (APU- 3) with associated management recommendations.. (USLs) . Most of these studies have been performed in patient populations at high risk for DE, often by experienced physician sonologists. The sensitivity and specificity for the detection of DE in a symptomatic patient by sonographers and subsequently interpreted by sonologists are not well known. However, in one study of average- risk patients (high- risk, tertiary care patients underwent endometriosis protocol MRI [32] or physician- acquired US- based DE mapping after bowel preparation [6]), the introduction of uterine sliding sign and static imaging of the posterior compartment with a review of cervicouterine cine clips performed solely by nonphysician sonographers and interpreted remotely by radiologists increased the detection of posterior compartment DE by three- fold and yielded sensitivity and specificity of . The purpose of this consensus panel is to recommend methods that increase the diagnostic sensitivity for endometriosis at pelvic US by increasing awareness, improving interpretation, adding simple techniques that are high yield for DE, and improving protocols to triage patients. The recommendations are expected to add minimal time to the current recommended protocols. This statement defines the targeted screening population, describes techniques for augmenting pelvic US, establishes direct and indirect observations for endometriosis at US, creates an observational grading and . Materials and Methods. Note on Terminology. Materials and MethodsNote on TerminologyThe Society of Radiologists in Ultrasound panel recognizes that there are individuals who may be affected by endometriosis who are transgender, who do not identify with the term female, who do not menstruate, or who have undergone hysterectomy. The terms female and reproductive age are used in this statement to maintain consistency with the existing literature and their use is not intended to exclude or marginalize any individual affected by this debilitating disease.. Expert Panel. Expert PanelIn June 2022, the Society of Radiologists in Ultrasound convened a panel of 16 experts in imaging and management of endometriosis. The panel included gynecologic US experts from both radiology and gynecology; a community radiologist; a registered diagnostic medical sonographer; board members or practice guideline chairs from key stakeholder societies such as the Society for Reproductive Endocrinology and Infertility (2), the American Society for Reproductive Medicine (1), the Society of Gynecologic Surgeons (1), the American Association of Gynecologic Laparoscopists (1), the Society of Reproductive Surgeons (1), the American Institute of Ultrasound in Medicine (1), and the Society for Assisted Reproductive Technology (1); minimally invasive gynecologic surgeons with expertise in the resection of advanced- stage DE (3); and cochairs or members of Society of Abdominal Radiology disease- focused panel on endometriosis (8). All the solicited experts agreed to join the panel.. Literature Search. Literature SearchA literature review was conducted to obtain the following information regarding the use of pelvic US in detecting endometriosis: sensitivities and specificities for detection in various locations, technique descriptions, and examples of direct observations (ie, the presence of ectopic endometrial tissue) and indirect observations (ie, a fibrotic reaction induced by endometriosis). A librarian performed a comprehensive English- language search in PubMed for literature published from January 1994 to December 2022. The following search strategy was used: (((“deep infiltrating endometriosis”) OR (“deep infiltrating”) AND (“Endometriosis”[Mesh])) AND (English[Filter])) OR (“deep* infiltrat* endometriosis” AND (English[Filter])) OR (“deep* endometriosis” AND (English[Filter])) AND (English[Filter])) AND ultrasound AND (English[Filter])) ± Filters: Meta- Analysis, Systematic Review, English. The results yielded 637 general literature articles and 21 meta- analyses. Of the 637 articles, 205 were excluded because they were older than 10 years or were case reports. Two authors (S.W.Y. and R.M.K.) reviewed the abstracts of the remaining 432 articles and excluded an additional 289 publications and four meta- analyses because they did not directly study US of DE. Seventy- five articles described site- specific or multisite direct. # observations. These articles were categorized into six groups based on endometriosis site (Table 1; structured literature flow diagram, Fig S1). Each of the site- specific groups was assigned to one panel member who reviewed the full article. Those panel members also reviewed the full articles reporting on multisite direct observations. Meta- analyses reporting the sensitivity and specificity of direct transvaginal US observations were identified (Table 2). The remaining studies included 14 learning curve articles, 16 mobility and indirect observations articles, and 55 other articles that were deemed relevant to US- based DE. One panel member reviewed these articles. All panel members reviewed the meta- analyses.. Expert Consensus. Simultaneously with the structured literature review, panel members completed a survey to gather expert opinions to augment the literature review. Panelists answered 35 multiple- choice questions based on the following topics: general goals of the recommendations for pelvic US examinations, patient inclusion criteria for augmented pelvic US, imaging techniques for endometriosis, time constraints for image acquisition, and direct and indirect observations of endometriosis at US and. # when to recommend advanced endometriosis imaging or gynecologic referral. The panel achieved consensus utilizing the modified Delphi method, which included up to seven rating rounds of multiple- choice questions with two to 10 options each and free text answers (Appendix S1). Panel- wide discussion of the survey created agreement regarding terminology and narrowed the options until consensus was achieved. Virtual discussions were recorded for those not able to attend in real time, with an opportunity to comment on the final consensus results. After consensus was reached regarding the relevant observational categories, the imagers (ie, radiologists and gynecologists) created diagnostic categories to stratify risk and need for follow- up based on expert opinion. Subsequently, the clinicians (gynecologists and gynecologic surgeons) achieved consensus regarding the appropriate management recommendations for the diagnostic categories.. Consensus Summary and Recommendations. For the purposes of the consensus, definitions for routine pelvic US, augmented pelvic US, advanced endometriosis imaging, and direct and indirect signs of DE were developed (Table 3) (34- 39).. The consensus panel unanimously agreed that routine pelvic US techniques have not been optimized for the depiction of endometriosis and can thus exacerbate diagnostic delay in symptomatic patients. The panel agreed to raise awareness of the signs of endometriosis on all pelvic US images and list additional sonographic maneuvers that can augment the examination to depict DE. Table 4 lists a summary of consensus panel recommendations. Management recommendations should be guidance rather than requirements and are based on patients with average risk (nontertiary care) and typical symptoms.. Identifying the Screening Population. Recommendation: Perform augmented pelvic US only in premenopausal or early postmenopausal patients (<5 years since the cessation of menses). Patients should be symptomatic or have a history of infertility based on imaging indication or patient- provided history (40).. The panel identified patient history and symptoms that met the criteria for screening for DE at augmented pelvic US in premenopausal or early postmenopausal patients based on literature search and expert consensus (Table 5) (40- 42). Although the predictive value of the listed endometriosis symptoms is low (41), current. # guidelines do not recommend surgical or medical treatment for asymptomatic endometriosis (15). In clinical practice, patients meeting the criteria for screening can be identified by the clinical providers at the time of ordering the examination, by the sonographer during patient intake and scanning, and, ultimately, by the sonologist, who will be interpreting the examination. The sonologist should serve as the final checkpoint to identify if a patient who met the inclusion criteria for screening received the augmented maneuvers and include their observations and grading in the report. The panel acknowledged that there may be observations of DE at routine pelvic US in a patient who did not report any of the eligible history or symptoms. In this scenario, the recommendation is to report the observations with a suspicion of DE. Patients with a long history of contraceptive use may also have DE with minor or no symptoms (41,43,44). Augmented pelvic US may be indicated by other symptoms or history and may be performed at the discretion of the ordering or reading clinician.. Additional Imaging Techniques for Augmented Pelvic US. Recommendation: The panel unanimously agreed that an augmented pelvic US examination would have the greatest feasibility, acceptance, and impact in general US- based screening for DE.. Augmented pelvic US should include additional imaging focusing on the posterior compartment, the relative positioning of the uterus and ovaries, and the uterine sliding sign (transducer pressure or bimanual demonstration of uterine mobility).. Transvaginal evaluation is essential for screening detection of DE and transabdominal examination alone is insufficient. The panel recommends MRI when transvaginal imaging is not feasible and there is high clinical suspicion of endometriosis.. The panel recommended no bowel preparation for augmented pelvic US.. Routine pelvic US examinations are conventionally performed for all conditions requiring imaging of the pelvis. Minimum standard US views are mandated by multisociety practice guidelines but make no specific DE- focused imaging . Two- dimensional images may be obtained with a two- or three- dimensional transducer. Cine sweeps are preferred in addition to routine transverse and longitudinal static images of the uterus in routine pelvic US. If a cine sweep cannot be recorded or stored for review, representative static images should be stored and the sonographer should make a note of the uterine sliding sign as normal, abnormal, equivocal, technically inadequate, or not performed.. # # A modest learning curve exists for the technical aspects of sliding maneuver and posterior compartment image acquisition and adequate imaging can be obtained by education and training (46,47). Attention to probe placement (Fig 2) and suggested imaging techniques can lead to high- yield imaging (Table 6).. Augmented pelvic US- based evaluation of uterine serosa.- The panel recommends focusing special attention on the posterior uterine serosa during augmented pelvic US on static and cine images, which is a common site for endometriosis. Evaluation includes assessment for serosal implants that may mimic adenomyosis but extend inward from the uterine serosa toward the endometrium. This is in contradistinction to typical adenomyosis, which begins at the endometrial- myometrial junction and extends toward the uterine serosa.. Augmented pelvic US- based evaluation of retrocervical space.- Acquire static or preferably cine images focusing on the retrocervical region to assess for USL DE. There was a . USL position varies depending on the uterine version. When feasible, reposition the transducer from the anterior vaginal fornix to the posterior vaginal fornix for optimal evaluation (37). In anteverted uteri, the retrocervical space may be imaged from both the anterior and posterior fornices (Table 6). The retrocervical space of interest is posterior and inferior to the cervicouterine junction in the anterior fornix view (Fig 1). On the posterior fornix view, the retrocervical space is in the near field and is immediately underneath the vaginal wall. The torus uterus is an anatomic landmark located posterior to the cervicouterine junction where the uterine ends of the two USLs insert in the midline. Most retrocervical DE involves the area near the torus uterus. Normal USLs appear as smoothly echogenic, homogeneous band- like structures angling laterally from just inferior to the cervicouterine junction (torus uterus) (Fig 3) (48). If there is difficulty entering the posterior vaginal fornix, the area of the retrocervical space may also be. # assessed by scanning transversely through the cervix from the anterior fornix. In this scenario, an echogenic band extending from the posterior cervical serosa and coursing laterally can be observed (Movie 7). Although confident identification of the USLs as a distinct echogenic band is possible on US, simply imaging through the retrocervical space is sufficient to observe DE, which frequently involves the USLs in this area.. In retroverted and most retroflexed uteri, longitudinal and axial sweeps are acquired from the posterior vaginal fornix only as the probe slides and naturally comes to lie in the posterior fornix with the retroverted uterus anatomy (Table 6, Movie 5). The retrocervical space will lie in the near field beneath the vaginal musculature in such individuals. Occasionally, in the setting of DE, the cervix will be anteverted and the uterus steeply retroflexed (question mark or horseshoe- shaped uterus) (Fig 4). In such individuals, the transducer may be positioned in the anterior fornix and findings of retrocervical DE may be observed adhering the posterior cervix to the uterus and may involve the adjacent wall of the posterior vaginal fornix.. Uterine and ovarian relative positioning.- Two- and three- dimensional static and cine images may be acquired to help assess the relative positioning of the uterus and ovaries (Movies 4, 5). The panel advocated for but did not mandate the acquisition and review of cine clips to evaluate the pelvic anatomy whenever possible. Alternatively, when available, one may use a three- dimensional transducer to obtain rapid, standardized views, storing them as cine clips (Movie 6). Normally, ovaries are located at the sides of the uterus along the pelvic side walls. Evaluation for DE should include assessing the ovarian position and noting a location posterior to the uterus, adjacent to each other (ie, kissing ovaries configuration), near the cervix, or low in the posterior compartment. When a kissing ovaries configuration or abnormal ovarian position is noted, optional dynamic imaging can be performed by applying direct probe pressure with the intent to separate the ovaries and record the tethering of the ovaries to each other, the pelvic side wall, or the uterus (Movie 8).. When the ipsilateral ovary is retropositional close to the cervix or cervicouterine junction, the retrocervical space should be assessed for DE. This is because adhesion of the ovary to DE in the USL in the retrocervical space is a common cause of retropositioned ovary, especially in the presence of an endometrioma. Careful interrogation of the edge of the malpositioned ovary or endometrioma may reveal adjacent solid tissue outside the ovary, which is typically DE on the USL. Bilateral retrocervical DE is common when both ovaries are retropositioned and in contact with each other (kissing ovaries) (Fig 5). In such individuals, the anterior rectal wall should be carefully reviewed for serosal or muscularis DE observations, preferably identified on cine clips (29). Adhesions present as hypoechoic bands and lines between DE implants and adjacent structures. Adhesions to the rectosigmoid wall, even in the absence of an invasive bowel observation, are often recognized by tenting of the bowel wall toward the torus uterus with or without a retrocervical DE observation (Movie 9).. # Evaluation of uterine sliding sign.- The sliding maneuver should be performed to evaluate adhesions in the posterior cul- de- sac and represents an integral component of augmented pelvic US. The uterine sliding maneuver increases the detection of DE- related pouch of Douglas obliteration on US (49,50). The sonographer should explain to the patient the pushing technique and its clinical importance in diagnosing endometriosis before proceeding and remain cognizant of and responsive to patient discomfort. In anteverted uteri, preferably obtain the sliding maneuver from the posterior fornix view with the transducer pressure technique (Movies 1, 2). If there is difficulty placing the transducer in the posterior fornix, it is possible to obtain a cone of the sliding maneuver from the anterior fornix (Movie 3). In this situation, it is important to place enough pressure inferiorly on the cervix to create a clear slide between the uterus and posterior compartment structures. Avoid merely compressing the posterior compartment structures through the uterus. Always focus attention on the posterior cervicouterine junction. If the transducer push is equivocal, consider using the illustrated bimanual technique (Fig 6). In retroflexed and retroverted uteri, the sliding cine is best obtained by pressing with steep posterior angulation in the posterior fornix and then quickly releasing transducer pressure, looking for mobility between the cervix and retrocervical perirectal adipose or physiologic fluid pooling in the retrocervical area (Movie 2) (37). An absence of sliding is an indicator of posterior cul- de- sac adhesions (49).. Sonologists can apply the sliding maneuver to the anterior and middle compartments, including the vesicouterine space and ovaries (Movies 8, 10). The panel does not mandate these optional views because of the time constraints of augmented pelvic US. Immobility of the ovary relative to the uterus, pelvic sidewall, bowel, or contralateral ovary can be demonstrated, which is a useful indirect observation of endometriosis (35,51,52). Focused evaluation on the areas of tethering may. # depict direct DE observations. Similarly, the panel encourages but does not mandate ovarian mobility assessment, especially when other endometriosis features are observed. The panel notes that ovarian tethering and fixation is sometimes incidentally observed during the uterine sliding maneuver and should be reported when present.. The role of color Doppler.- Color Doppler imaging of the adnexa is routinely performed and should be done so in compliance with societal guidelines. The panel made no specific recommendations regarding color Doppler imaging for DE and deferred to previously published guidelines (19). Color Doppler imaging can help assess solid- appearing elements in suspected endometriomas. Color Doppler is not necessary for identifying or categorizing DE observations, which are typically hypovascular.. Evaluation of the anterior compartment and urinary bladder.- The panel did not make any specific recommendations about imaging the anterior compartment and urinary bladder. The anterior compartment is the least common site of pelvic DE involvement. Therefore, the panel recommended that the augmented maneuvers focus on the posterior compartment where DE most frequently occurs. Images of the urinary bladder can either be acquired transabdominally or transvaginally as a part of the routine pelvic US and reviewed for the presence of nodularity, particularly at the vesicouterine space and posterior bladder wall. Although uncommon, US has been reported to distinguish bladder endometriosis with high accuracy (18,26,53).. US-based Observations and Interpretation for Endometriosis: Direct and Indirect Observations. Recommendation: Assess direct and indirect observations during augmented pelvic US.. The panel considered the results from the literature search, including published sensitivity and specificity data (Table 6), along with expert opinion, and reached a consensus on direct and indirect imaging observations of DE (Table 7).. Endometriosis implants are typically hypoechoic with punctate echogenic foci. These may have regular, irregular, lobulated, or stellate margins. Linear hypoechoic bands of tissue may be observed extending peripherally from the implants secondary to surrounding fibrosis. Vascularity at color Doppler imaging is variable, and DE implants are usually hypovascular. Specific imaging observations vary by location.. We organized endometriosis observations into categories based on the highest association with DE (Table 7).. Category A: Direct endometriosis observations.- Direct observations result from the presence of ectopic endometrial glands and/or stroma outside the uterus. These include ovarian endometriomas and DE observations in characteristic, commonly encountered locations on pelvic US, such as posterior uterine serosa, retrocervical space and USLs, rectovaginal space, rectosigmoid colon, posterior bladder, or uterovesical space.. Ovarian endometriomas: Ovarian endometriomas are typically benign, cystic ovarian lesions with low- level, homogeneous (ground glass) internal echoes and no internal vascularity (Fig 7). Any solid- appearing areas should be evaluated with color Doppler,. # optimizing color scale and gain. Vascularized solid components should be noted owing to the risk of clear cell and endometrioid carcinomas (54). The risk of ovarian cancer in patients with endometriosis is . Uterine serosal DE: The posterior uterine serosa is commonly involved with posterior compartment DE, where uterine implants manifest as ill- defined hypoechoic observations, with . Retrocervical DE (including USLs): Retrocervical DE typically occurs near the posterior aspect of the cervix, where USLs insert, extending laterally and posteriorly within the posterior compartment. Retrocervical DE usually manifests as hypoechoic observations that may be smooth, irregular, or spiculated. Punctate echogenic foci are common. Cystic foci are less common. The midline retrocervical USL insertion site, the torus uterus, is frequently involved (Fig 9). Adhesions to one or both ovaries may be assessed and adhesions to the adjacent rectum are frequently observed, often with distortion of the rectal wall toward the retrocervical observation (Fig 10) (48,51).. Bladder and vesicouterine space endometriosis: Bladder endometriosis manifests as an isoechoic or hypoechoic, smooth or irregular, elongated or spherical mass invading the detrusor muscle, often at the base or dome (Fig 11). Such observations may or may not protrude into the bladder lumen and may be cystoscopically occult (61,62). These observations can be contiguous with DE in the vesicouterine space.. Rectosigmoid endometriosis: Bowel endometriosis manifests as solid and markedly hypoechoic elliptical, C- shaped, or. Rectosigmoid endometriosis: Bowel endometriosis manifests as solid and markedly hypoechoic elliptical, C- shaped, or . # are common. Whereas sonography is excellent for the full depiction of bowel implants, such depiction is beyond the scope of augmented pelvic US. The consensus panel recommends advanced endometriosis imaging (expert US or expert MRI) for bowel endometriosis mapping (4,6,13).. Vaginal DE: Vaginal DE usually manifests in the posterior apex with moderately hypoechoic echotexture similar to retrocervical or USL DE. Vaginal DE is commonly confluent with USL . Category B: Indirect endometriosis observations.- Indirect observations are associated findings or sequelae of endometriosis present at imaging without direct visualization of DE implants. These include observations commonly encountered with DE, such as fixed uterine retroversion, abnormal ovarian location or mobility, and tethering of bowel loops to the. # posterior uterus but without an observation of DE. The existing literature regarding the sensitivity and specificity of these observations is sparse. The identification and recommendations are, therefore, based on expert consensus.. Fixed uterine retroversion: A retroflexed uterus that remains in this position even with direct transducer pressure may be associated . Bowel tethering to the posterior uterus: Scarring from DE can cause tethering of bowel loops to the posterior uterus. However,. # when there is no observation of DE, it is essential to exclude other causes of fibrosis and adhesions such as pelvic inflammatory disease, inflammatory bowel disease, and prior pelvic surgery. One may optionally perform a dynamic evaluation with probe pressure to separate the areas of potential tethering.. Abnormalities of ovarian position and mobility: Retropositioned or kissing ovaries, in which the ovaries are posteriorly and medially located behind the uterus, can occur in DE, even in the absence of endometrioma. The likelihood of advanced- stage endometriosis is eight times higher with kissing ovaries than with normally positioned ovaries, regardless of the presence of an endometrioma at MRI (64). Abnormal ovarian location may be further evaluated for immobility with direct probe pressure or may be observed during the performance of the uterine sliding maneuver.. Category C: Endometriosis- associated observations.- These observations are associated with endometriosis but are not always a direct result of DE or are observed infrequently in isolation, and include adenomyosis, hydrosalpinx, and hematosalpinx.. Adenomyosis: Historically, features of adenomyosis have been found at transvaginal US in . The Morphological Uterus Sonographic Assessment group has recently classified direct and indirect imaging features of adenomyosis (67). Direct features are myometrial cysts, hyperechoic islands, and echogenic subendometrial lines and buds. Indirect features are a globular uterus, asymmetric myometrial thickening, fan- shaped shadowing, translesional vascularity, irregular junctional zone, and interrupted junctional zone. Adenomyomas are recognized as focal observations with characteristics of adenomyosis that create myometrial asymmetry, have ill- defined borders, and translesional vascularity without a mass effect . Hydrosalpinx and hematosalpinx: Hydrosalpinges may be observed in endometriosis either by direct involvement or adhesions. Hydrosalpinges are tubular, cystic areas separate from the ovary. Incomplete septations, waist- sign, endosalpingal folds or ridges, and chains of cysts are common features (58,69). The presence of low- level internal echoes is suggestive of hematosalpinx. In the absence of clinical signs of infection or ectopic pregnancy, hematosalpinx may be an indicator of endometriosis in the fallopian tube. In the panel's expert opinion, the multifactorial etiology of hydrosalpinx makes this observation too nonspecific to warrant further evaluation for endometriosis when seen in isolation. Because of the difficulty distinguishing pyosalpinx from hematosalpinx at imaging and the infrequent isolated finding of hematosalpinx in patients with endometriosis, isolated hematosalpinx was deemed too infrequent to prompt advanced endometriosis imaging in the absence of high clinical concern.. # Reporting Augmented Pelvic US for Endometriosis and Follow-up Recommendations. The panel recommendations for reporting and follow- up of endometriosis (Table 8) are based on the literature review and expert consensus in the instance of limited or no data, which pertains predominantly to indirect observations (category B) and endometriosis- associated observations (category C). Appropriate follow- up imaging and clinical recommendations are provided for each category. The purpose is to capture a greater spectrum of disease presentations at US, but future research validation is needed.. Recommendation: Reporting for augmented pelvic US examinations should include the following four categories: Incomplete (APU- 0), normal (APU- 1), equivocal (APU- 2), and positive (APU- 3), where APU indicates augmented pelvic US (Table 8).. Any single direct imaging observation (category A) of endometriosis should lead to endometriosis diagnosis, a recommendation for advanced endometriosis imaging, and referral to a reproductive endocrinologist or gynecologic surgeon familiar with DE, as appropriate. In the absence of category A observations, findings are suggestive of endometriosis when two or more indirect observations (category B) or one category B and one . Advanced endometriosis imaging consists of either expert US- based mapping of endometriosis following a prescribed pattern of search (4,6,7,13) and/or endometriosis- specific MRI with expert interpretation (32,59). The International Deep Endometriosis Analysis protocol or a similar protocol can be adopted for expert advanced US (13). Given large regional differences in training and credentialling criteria, like the Ovarian- Adnexal Reporting and Data System (O- RADS), emphasis is placed on the importance of experience in the accurate assessment of endometriosis (70). Examples include involvement in quality assurance activities and specialty conferences (ie, multidisciplinary and quality assurance conferences, gynecology and minimally invasive surgery correlation conferences, and gynecologic- oncology tumor boards) which typically denote a higher level of investment in the radiology- pathology correlation, a noteworthy aspect of specialization as it relates to endometriosis. The Society of Abdominal Radiology or European Society of Urogenital Radiology guidelines are suggested templates that can be followed for expert MRI review (32,70).. Structured reporting improves clarity, completeness, and compliance (71,72). Reporting adnexal lesions using the American College of Radiology O- RADS US Risk Stratification Lexicon and Management System is recommended. Endometriomas smaller than . Features of adenomyosis should be reported as present or absent using the descriptors from the Morphological Uterus Sonographic Assessment group (67). A summary opinion regarding the likelihood of adenomyosis should be given based on the observations, either absent/unlikely, possible, or very likely/definite. The location and approximate size of adenomyomas should be described, including the presence of serosal involvement.. When indicated, the uterine sliding sign should be reported as normal, abnormal, equivocal, technically inadequate, or not performed. The quality and confidence assessments are subjective, and confidence is expected to increase over time. The learning curve for performance and offline interpretation of uterine sliding, as well as most aspects of DE assessment, is around 40 cases (47,73,74). Patient obesity and inadequate or improperly directed compression of the tissues may impair sliding sign assessment. One may observe normal sliding in cases of incomplete posterior compartment obliteration (75). An example of structured reporting for augmented pelvic US is provided in Appendix S2 and Movie 12.. Conclusion. Endometriosis is a common condition with substantial diagnostic delay, leading patients to experience pain, infertility, lost wages, and interrupted relationships. US is the. # first- line imaging modality to evaluate pelvic pain. The Society of Radiologists in Ultrasound consensus regarding routine pelvic US for endometriosis aims to enhance deep endometriosis (DE) detection even at an initial US and with minimal additional time during imaging and no special patient preparation. Focusing imaging on anatomic regions where DE is common can increase detection of DE and decrease diagnostic delay.. These guidelines are meant for symptomatic patients (ie, pain and infertility) at typical risk for endometriosis. Patients at high risk for endometriosis because of prior diagnostic or therapeutic laparoscopy for endometriosis or strong clinical indications may benefit from proceeding directly to advanced endometriosis imaging, particularly if they are likely to undergo surgery or if monitoring is needed in the setting of infertility and medical treatment.. # This consensus is based on expert opinion and review of the literature. Therefore, validation studies will be necessary to prove the accuracy of augmented pelvic US in widespread clinical application. Additionally, continuing education for sonographers, gynecologists, and radiologists regarding recognition of common observations of deep endometriosis (DE) and the applicability of augmented pelvic US with additional maneuvers and advanced endometriosis imaging will be paramount. The quality of advanced imaging protocols and equipment as well as the expertise of interpreting physicians for advanced endometriosis imaging and laparoscopy is also important for confirming the diagnosis of endometriosis. Accurate diagnosis requires recognition of tissue distortion and an intense, prescribed search pattern that leverages knowledge of common DE sites and associated observations. Laparoscopic surgery alone is recognized as an insufficient . Acknowledgment: The Society of Radiologists in Ultrasound panel acknowledges the valuable contributions to the consensus panel of Beryl Benacerraf, MD, prior to her death in October 2022. She was a professor of obstetrics, gynecology, and reproductive biology and radiology at Harvard Medical School and Brigham and Women's Hospital.. Author contributions: Guarantors of integrity of entire study, S.W.Y., P.J., L.C., M.M.H., Y.G., E.M.H., S.E., W.V.B.; study concepts/study design or data. # acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, S.W.Y., P.J., L.C., S.R., R.M.K., M.M.H., P.G., M.F., Y.G., S.L.Y., L.P.; clinical studies, P.J., M.M.H.; experimental studies, E.M.H.; statistical analysis, P.J.; and manuscript editing, all authors. Disclosures of conflicts of interest: S.W.Y. No relevant relationships. P.J. Payment for lectures from World Class CME. L.C. No relevant relationships. S.R. Royalties from Elsevier. R.M.K. Payment for lectures from Sumitomo Pharmacy (formerly Myovant/Pfizer). M.M.H. Payment for lectures from Clinical Educational Symposia—Ultrasound Course, leadership or fiduciary role of Ultrasound for RadioGraphics; spouse is employee of Bristol Meyers Squibb. P.G. Payment for chapter on fetal musculoskeletal disorder from UpToDate. M.F. No relevant relationships. Y.G. Book royalties from Elsevier; consultant for Femasys; honoraria from World Class CME; vice- president of the AIUM and chair of the Gynecology section. Z.K. No relevant relationships. S.L.Y. Grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health (P01HD106485, R01HD100329, R44 HD097750); royalties from Cicero Diagnostics; patent issued (Methods And Compositions For Sirt1 Expression As A Marker For Endometriosis And Subfertility. Steven L Young, Bruce A Lessey, Jae- Wook Jeong, U.S. Patent No. 11,474,105; Issued October 18, 2022. UNC Ref. 16- 0123; MB Ref. 5470.810); president, Society for Reproductive Endocrinology and Infertility (SREI); board member, American Society for Reproductive Medicine (ASRM); board member, Society for Assisted Reproductive Technology (SART). L.P. No relevant relationships. T.L.B. No relevant relationships. E.M.H. Patents planned, issued, or pending from IHC. S.E. Patents planned, issued, or pending from Rutgers/RWJ Medical School. W.V.B. Travel and hotel covered to speak at the World Endometriosis Congress, American Association of Gynecological Laparoscopists, and the Society for Women's Health Research; member and cofounder of the Society of Abdominal Radiology Endometriosis Disease- Focused Panel.. References. 1. Mowers EL, Lim CS, Skinner B, et al. Prevalence of Endometriosis During Abdominal or Laparoscopic Hysterectomy for Chronic Pelvic Pain. 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Uterine sliding sign: a simple sonographic predictor for presence of deep infiltrating endometriosis of the rectum. Ultrasound Obstet Gynecol 2013;41(6):692-695. 35. Rao T, Condous G, Reid S. Ovarian Immobility at Transvaginal Ultrasound: An Important Sonographic Marker for Prediction of Need for Pelvic Sidewall Surgery in Women With Suspected Endometriosis. J Ultrasound Med 2022;41(5):1109-1113.. # 36. Alborzi S, Poordast T, Askary E, et al. Evaluation and comparison of the accuracy of transvaginal ultrasound and MRI for the diagnosis of deep rectal endometriosis: A cross-sectional study. Int J Gynaecol Obstet 2023;161(2):586-593. 37. Aas-Eng MK, Montanari E, Lieng M, Keckstein J, Hudelist G. Transvaginal Sonographic Imaging and Associated Techniques for Diagnosis of Ovarian, Deep Endometriosis, and Adenomyosis: A Comprehensive Review. Semin Reprod Med 2020;38(2-03):216-226. 38. Exacoustos C, De Felice G, Pizzo A, et al. Isolated Ovarian Endometrioma: A History Between Myth and Reality. J Minim Invasive Gynecol 2018;25(5):884-891. 39. Ferrero S, Barra F, Scala C, Condonous G. Ultrasonography for bowel endometriosis. Best Pract Res Clin Obstet Gynaecol 2021;71:38-50. 40. Levine D, Patel MD, Suh-Burgmann EJ, et al. Simple Adnexal Cysts: SRU Consensus Conference Update on Follow-up and Reporting. Radiology 2019;293(2):359-371. 41. Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod 2014;29(3):400-412. 42. Ballard KD, Seaman HE, de Vries CS, Wright JT. Can symptomatology help in the diagnosis of endometriosis? Findings from a national case-control study--Part 1. BJOG 2008;115(11):1382-1391. 43. Chapron C, Souza C, Borghese B, et al. Oral contraceptives and endometriosis: the past use of oral contraceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis. Hum Reprod 2011;26(8):2028-2035. 44. Vercellini P, Eskenazi B, Consonni D, et al. Oral contraceptives and risk of endometriosis: a systematic review and meta-analysis. Hum Reprod Update 2011;17(2):159-170. 45. American Institute of Ultrasound in Medicine (AIUM); American College of Radiology (ACR); American College of Obstetricians and Gynecologists (ACOG); Society for Pediatric Radiology (SPR); Society of Radiologists in Ultrasound (SRU). AIUM practice guideline for the performance of ultrasound of the female pelvis. J Ultrasound Med 2014;33(6):1122-1130. 46. Tammaa A, Fritzner N, Strunk G, Krell A, Salzer H, Hudelist G. Learning curve for the detection of pouch of Douglas obliteration and deep infiltrating endometriosis of the rectum. Hum Reprod 2014;29(6):1199-1204. 47. Indrielle-Kelly T, Fischerova D, Hanus P, et al. Early Learning Curve in the Assessment of Deep Pelvic Endometriosis for Ultrasound and Magnetic Resonance Imaging. Biomed Res Int 2020;2020:8757281. 48. Maple S, Chalmers KJ, Bezak E, Henry K, Parange N. Ultrasound Characteristics and Scanning Techniques of Uterosacral Ligaments for the Diagnosis of Endometriosis: A Systematic Review. J Ultrasound Med 2023;42(6):1193-1209. 49. Reid S, Lu C, Casikar I, et al. Prediction of pouch of Douglas obliteration in women with suspected endometriosis using a new real-time dynamic transvaginal ultrasound technique: the sliding sign. Ultrasound Obstet Gynecol 2013;41(6):685-691. 50. Arion K, Aksoy T, Allaire C, et al. Prediction of Pouch of Douglas Obliteration: Point-of-care Ultrasound Versus Pelvic Examination. J Minim Invasive Gynecol 2019;26(5):928-934. 51. Gerges B, Lu C, Reid S, Chou D, Chang T, Condonous G. Sonographic evaluation of immobility of normal and endometriotic ovary in detection of deep endometriosis. Ultrasound Obstet Gynecol 2017;49(6):793-798. 52. Reid S, Leonardi M, Lu C, Condonous G. The association between ultrasound-based 'soft markers' and endometriosis type/location: A prospective observational study. Eur J Obstet Gynecol Reprod Biol 2019;234:171-178. 53. Exacoustos C, Malzoni M, Di Giovanni A, et al. Ultrasound mapping system for the surgical management of deep infiltrating endometriosis. Fertil Steril 2014;102(1):143-150.e2. 54. Orlando MS, Cadish LA, Shepherd JP, Falcone T, Chang OH, Kho RM. Salpingo-oophorectomy or surveillance for ovarian endometrioma in asymptomatic premenopausal women: a cost-effectiveness analysis. Am J Obstet Gynecol 2022;227(2):311.e1-311.e7. 55. Pearce CL, Templeman C, Rossing MA, et al. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol 2012;13(4):385-394. 56. Saavalainen L, Lassus H, But A, et al. Risk of Gynecologic Cancer According to the Type of Endometriosis. Obstet Gynecol 2018;131(6):1095-1102. 57. Vercellini P, Viganò P, Buggio L, et al. Perimenopausal management of ovarian endometriosis and associated cancer risk: When is medical or surgical treatment indicated? Best Pract Res Clin Obstet Gynaecol 2018;51:151-168.. 58. Andreotti RF, Timmerman D, Benacerraf BR, et al. Ovarian-Adnexal Reporting Lexicon for Ultrasound: A White Paper of the ACR Ovarian-Adnexal Reporting and Data System Committee. J Am Coll Radiol 2018;15(10):1415-1429. [Published correction appears in J AM Coll Radiol 2019;16(3):403-406.] 59. Strachowski LM, Jha P, Phillips CH, et al. O-RADS US v2022: An Update from the American College of Radiology's Ovarian-Adnexal Reporting and Data System US Committee. Radiology 2023;308(3):e230685. 60. Malzoni M, Casarella L, Coppola M, et al. Preoperative Ultrasound Indications Determine Excision Technique for Bowel Surgery for Deep Infiltrating Endometriosis: A Single, High-Volume Center. J Minim Invasive Gynecol 2020;27(5):1141-1147. 61. Ros C, de Guirior C, Rius M, et al. Accuracy of Transvaginal Ultrasound Compared to Cystoscopy in the Diagnosis of Bladder Endometriosis Nodules. J Ultrasound Med 2021;40(8):1571-1578. 62. Noventa M, Saccardi C, Litta P, et al. Ultrasound techniques in the diagnosis of deep pelvic endometriosis: algorithm based on a systematic review and meta-analysis. Fertil Steril 2015;104(2):366-382. 63. Benacerraf BR, Groszmann Y, Hornstein MD, Bromley B. Deep infiltrating endometriosis of the bowel wall: the comet sign. J Ultrasound Med 2015;34(3):537-542. 64. Ghezzi F, Raio L, Cromi A, et al. "Kissing ovaries": a sonographic sign of moderate to severe endometriosis. Fertil Steril 2005;83(1):143-147. 65. Di Donato N, Montanari G, Benfanti A, et al. Prevalence of adenomyosis in women undergoing surgery for endometriosis. Eur J Obstet Gynecol Reprod Biol 2014;181:289-293. 66. Olgan S, Dirican EK, Ozsipahi AC, Salinci M. Uterine involvement by endometriosis: Sonographic features from elusive findings to apparent adenomyosis. Eur J Obstet Gynecol Reprod Biol 2021;262:93-98. 67. Harmsen MJ, Van den Bosch T, de Leeuw RA, et al. Consensus on revised definitions of Morphological Uterus Sonographic Assessment (MUSA) features of adenomyosis: results of modified Delphi procedure. Ultrasound Obstet Gynecol 2022;60(1):118-131. 68. Van den Bosch T, Dueholm M, Leone FP, et al. Terms, definitions and measurements to describe sonographic features of myometrium and uterine masses: a consensus opinion from the Morphological Uterus Sonographic Assessment (MUSA) group. Ultrasound Obstet Gynecol 2015;46(3):284-298. 69. Patel MD, Acord DL, Young SW. Likelihood ratio of sonographic findings in discriminating hydrosalpinx from other adnexal masses. AJR Am J Roentgenol 2006;186(4):1033-1038. 70. Bazot M, Bharwani N, Huchon C, et al. European society of urogenital radiology (ESUR) guidelines: MR imaging of pelvic endometriosis. Eur Radiol 2017;27(7):2765-2775. 71. Goncalves MO, Siufi Neto J, Andres MP, Siufi D, de Mattos LA, Abrao MS. Systematic evaluation of endometriosis by transvaginal ultrasound can accurately replace diagnostic laparoscopy, mainly for deep and ovarian endometriosis. Hum Reprod 2021;36(6):1492-1500. 72. Mattos LA, Goncalves MO, Andres MP, et al. Structured Ultrasound and Magnetic Resonance Imaging Reports for Patients with Suspected Endometriosis: Guide for Imagers and Clinicians. J Minim Invasive Gynecol 2019;26(6):1016-1025. 73. Guevriero S, Pascual MA, Ajossa S, et al. Learning curve for ultrasonographic diagnosis of deep infiltrating endometriosis using structured offline training program. Ultrasound Obstet Gynecol 2019;54(2):262-269. 74. Young SW, Dahiya N, Patel MD, et al. Initial Accuracy of and Learning Curve for Transvaginal Ultrasound with Bowel Preparation for Deep Endometriosis in a US Tertiary Care Center. J Minim Invasive Gynecol 2017;24(7):1170-1176. 75. Leonardi M, Reid S, Lu C, et al. Diagnostic Accuracy and Reproducibility of Predicting Cul-de-Sac Obliteration by General Gynaecologists and Minimally Invasive Gynaecologic Surgeons. J Obstet Gynaecol Can 2019;41(4):443-449.e2. 76. Nisenblat V, Prentice L, Bossuyt PM, Farquhar C, Hull ML, Johnson N. Combination of the non-invasive tests for the diagnosis of endometriosis. Cochrane Libr 2016;7(7):CD012281. 77. Chapron C, Tosti C, Marcellin L, et al. Relationship between the magnetic resonance imaging appearance of adenomyosis and endometriosis phenotypes. Hum Reprod 2017;32(7):1393-1401. 78. Reid S, Condous G. Update on the ultrasound diagnosis of deep pelvic endometriosis. Eur J Obstet Gynecol Reprod Biol 2017;209:50-54. 79. Indrielle-Kelly T, Frilhauf F, Burgetova A, Fanta M, Fischerova D. Diagnosis of endometriosis 2nd part - Ultrasound diagnosis of endometriosis. # (adenomyosis, endometriomas, adhesions) in the community. Ceska Gynekol 2019;84(4):260- 268. 80. Zannoni L, Ambrosio M, Raimondo D, et al. Question Mark Sign and Transvaginal Ultrasound Uterine Tenderness for the Diagnosis of Adenomyosis: A Prospective Validation. J Ultrasound Med 2020;39(7):1405- 1412. 81. Reid S, Lu C, Condous G. Can we improve the prediction of pouch of Douglas obliteration in women with suspected endometriosis using ultrasound- based models? A multicenter prospective observational study. Acta Obstet Gynecol Scand 2015;94(12):1297- 1306. 82. Manieri Rocha R, Leonardi M, Eathorne A, Armour M, Condous G. Anatomical distribution of endometriosis: A cross- sectional analysis of .	None	None	None
58f254436bf44540836c760d089e1cb0	2024+昆士兰临床指南	原发性产后出血（V11）	# Queensland Clinical GuidelinesTranslating evidence into best clinical practice. Primary postpartum haemorrhage (PPH). # Document title: Publication date: Document number:. Document supplement:. Amendments: Amendment date: Replaces document: Author:. Audience:. Review date:. Endered by:. Contact:. Primary postpartum haemorrhage (PPH). August 2024. MN24.1- V11- R29. The document supplement details development processes and implementation activities, and is integral to and should be read in conjunction with this guideline Full version history is supplied in the document supplement. Full version history is supplied in the document supplement. MN18.1- V10- R23. Queensland Clinical Guidelines. Health professionals in Queensland public and private maternity and neonatal services. August 2029. Queensland Clinical Guidelines Steering Committee. Queensland Maternity and Neonatal Clinical Network. Email: Guidelines@health.qld.gov.au. URL: www.health.qld.gov.au/qcg. Acknowledgement. AcknowledgementThe Department of Health acknowledges the Traditional Custodians of the lands, waters and seas across the State of Queensland on which we work and live. We also acknowledge First Nations peoples in Queensland are both Aboriginal Peoples and Torres Strait Islander Peoples and pay respect to the Aboriginal and Torres Strait Islander Elders past, present and emerging.. Disclaimer. This guideline is intended as a guide and provided for information purposes only. The information has been prepared using a multidisciplinary approach with reference to the best information and evidence available at the time of preparation. No assurance is given that the information is entirely complete, current, or accurate in every respect.. The guideline is not a substitute for clinical judgement, knowledge and expertise, or medical advice. Variation from the guideline, taking into account individual circumstances, may be appropriate.. This guideline does not address all elements of standard practice and accepts that individual clinicians are responsible for:. Providing care within the context of locally available resources, expertise, and scope of practice Supporting consumer rights and informed decision making, including the right to decline intervention or ongoing management Advising consumers of their choices in an environment that is culturally appropriate and which enables comfortable and confidential discussion. This includes the use of interpreter services where necessary Ensuring informed consent is obtained prior to delivering care Meeting all legislative requirements and professional standards Applying standard precautions, and additional precautions as necessary, when delivering care Documenting all care in accordance with mandatory and local requirements. Queensland Health disclaims, to the maximum extent permitted by law, all responsibility and all liability (including without limitation, liability in negligence) for all expenses, losses, damages and costs incurred for any reason associated with the use of this guideline, including the materials within or referred to throughout this document being in any way inaccurate, out of context, incomplete or unavailable.. Recommended citation: Queensland Clinical Guidelines. Primary postpartum haemorrhage (PPH) Guideline No. MN24.1- V11- R29 Queensland Health. 2024. Available from: . ⑤. This work is licensed under a Creative Commons Attribution- Non- commercial- NoDerivatives V4.0 International licence. In essence, you are free to copy and communicate the work in its current form for non- commercial purposes, as long as you attribute Queensland Clinical Guidelines, Queensland Health and abide by the license terms. You may not alter or adapt the work in any way. To view a copy of this licence, visit nc- nd/4.0/deed.en For further information, contact Queensland Clinical Guidelines, RBWH Post Office, Herston Qld 4029, email Guidelines@health.qld.gov.au, phone (07) 3131 6777. For permissions beyond the scope of this licence, contact: Intellectual Property Officer, Queensland Health, GPO Box 48, Brisbane Qld 4001, email ip_officer@health.qld.gov.au. # Flowchart: Initial response to postpartum haemorrhage (PPH). Flowchart: F24.1-1-V6-R29. # Flowchart: Major haemorrhage protocol (MHP). Flowchart: F24.1- 2- V5- R29. # Table of ContentsDefinitions 71 Introduction 81.1 PPH Definition 81.2 Incidence of PPH in Queensland 81.3 Aetiology 91.4 Clinical standards 92 Risk factors 103 Antenatal risk management 114 Intrapartum risk management 124.1 Third stage 134.2 Prophylactic uterotonics 144.2.1 Oxytocin 144.2.2 Syntometrine 144.2.3 Carbetocin 154.2.4 Misoprostol 155 Fourth stage 166 Recognition of PPH 176.1 Assessment of blood loss 176.2 Haemodynamic compromise 177 Responding to PPH 187.1 Resuscitation 187.2 Tranexamic acid 197.3 Point of care blood clotting analysers 197.4 Support during PPH 208 Management of Four Ts 208.1 Tone 208.1.1 First line pharmacological therapy for uterine atony 208.1.2 Second line pharmacological therapy for uterine atony 218.2 Trauma 228.2.1 Genital trauma 228.2.2 Cervical trauma 238.2.3 Uterine rupture 248.2.4 Uterine inversion 258.3 Tissue 268.4 Thrombin 278.4.1 Coagulopathy principles 278.4.2 Correction of coagulopathy 288.4.3 Laboratory values 298.4.4 Cross matched RBC not available 299 Intractable bleeding 309.1 Mechanical treatment of intractable bleeding 309.2 Surgical treatment of intractable bleeding 3110 Major haemorrhage 3110.1 Major haemorrhage protocol considerations 3211 Women who cannot receive a blood transfusion 3312 Postnatal care after PPH 34References 35Appendix A: Uterine atonia interventions 41Appendix B: Surgical ligation procedures 42Appendix C: Prophylactic uterotonics 43Appendix D: Drugs and blood products for PPH treatment 44Appendix E: PoC testing obstetric specific reference ranges 45Acknowledgements 46. # List of Tables. Table 1. Postpartum haemorrhage definitions 8 Table 2. Incidence of PPH in Queensland 8 Table 3. Aetiology of PPH 9 Table 4. Clinical standards 9 Table 5. Risk factors for PPH 10 Table 6. Antenatal risk management 11 Table 7. Intrapartum risk management 12 Table 8. Third stage risk management 13 Table 9. Oxytocin 14 Table 10. Syntometrine® 14 Table 11. Carbetocin 15 Table 12. Misoprostol 15 Table 13. Fourth stage management 16 Table 14. Assessment of blood loss 17 Table 15. Clinical signs and symptoms of blood loss 17 Table 16. Resuscitation 18 Table 17. Tranexamic acid 19 Table 18. Point of care blood clotting analysers 19 Table 19. Support during PPH 20 Table 20. Oxytocin 20 Table 21. Ergometrine 21 Table 22. Misoprostol 21 Table 23. 15- methyl prostaglandin F2 alpha (carboprost) 21 Table 24. Genital trauma 22 Table 25. Cervical trauma 23 Table 26. Uterine rupture 24 Table 27. Uterine inversion 25 Table 28. Tissue 26 Table 29. Coagulopathy principles 27 Table 30. Correction of coagulopathy 28 Table 31. Laboratory values 29 Table 32. Blood cell replacement 29 Table 33. Intractable bleeding 30 Table 34. Mechanical procedures 30 Table 35. Surgical procedures 31 Table 36. MHP considerations 32 Table 37. Blood products declined 33 Table 38. Postnatal care 34. # Abbreviations. Definitions. # 1 Introduction. 1 IntroductionPrimary postpartum haemorrhage (PPH) is the most common form of obstetric haemorrhage and is a leading cause of maternal morbidity and mortality in Australia<sup>7</sup> and worldwide.<sup>8,9</sup> In developed countries there is a trend of increasing PPH that has not been completely explained by the changing risk profile of women.<sup>10,11</sup> Obstetric haemorrhage (which includes antepartum and postpartum haemorrhage) was responsible for 11 Australian maternal deaths between 2012- 2021 (a maternal mortality ratio of 0.4 per 100,000).<sup>12</sup>. 1.1 PPH Definition. 1.1 PPH DefinitionAlthough there is no single definition, primary postpartum haemorrhage is termed as excessive bleeding in the first 24 hours post birth. PPH can be classified using definitions in Table 1. Postpartum haemorrhage definitions. In an emergent situation, recognition most commonly occurs through estimation of blood loss volume and changes in the haemodynamic state.. 1.2 Incidence of PPH in Queensland. # 1.3 Aetiology. 1.3 AetiologyThe common causes of PPH are referred to as the 'Four Ts'. More than one cause may be present (e.g. tone and tissue).. 1.4 Clinical standards. # 2 Risk factors. 2 Risk factorsWherever possible, identify PPH risk factors in advance. The magnitude of risk attributable to each factor varies across reports. # 3 Antenatal risk management. # 4 Intrapartum risk management. # 4.1 Third stage. Refer to Queensland Clinical Guideline: Normal birth53 for routine management of third stage.. # 4.2 Prophylactic uterotonics. Refer to Appendix C: Prophylactic uterotonics. 4.2.1 Oxytocin. 4.2.2 Syntometrine. Ampoule contains oxytocin 5 International units and ergometrine maleate 500 micrograms per mL.68. # 4.2.3 Carbetocin. 4.2.4 Misoprostol. # 5 Fourth stage. This guideline defines fourth stage as the first six hours immediately following the birth.. # 6 Recognition of PPH. 6 Recognition of PPHBlood loss can occur rapidly around the time of birth, with or without haemodynamic compromise. As soon as PPH recognised, call for assistance including the immediate attendance of an experienced/senior obstetrician.. 6.1 Assessment of blood loss. 6.2 Haemodynamic compromise. Signs of haemodynamic compromise are a late indicator of PPH and may not be evident until large volumes of blood are lost (e.g. up to . Refer to Table 15. Clinical signs and symptoms of blood loss as a guide- - many women will present without these direct correlations.5 Conversely, compromise may occur earlier in women with41,69:. Gestational hypertension with proteinuria Anaemia Dehydration Small stature Cardiac disease. # 7 Responding to PPH. 7.1 Resuscitation. Initial response to PPH requires a multidisciplinary team approach3,16 to restore the woman's haemodynamic state whilst simultaneously identifying and treating the cause of bleeding.1. # 7.2 Tranexamic acid Give tranexamic acid (TXA) as soon as possible after onset of . 7.3 Point of care blood clotting analysers. # 7.4 Support during PPH. 8 Management of Four Ts. 8.1 Tone. The incidence of PPH caused by uterine atony is rising.79 The uterine cavity must be empty of tissue for effective uterine contraction.. Initial clinical and mechanical measures include:. - Massage uterine fundus to stimulate contractions2,16- Assess the need for bimanual compression10,13 [refer to Appendix A: Uterine atonia interventions]- Consider early, can be a lifesaving measure- Expel blood clots from uterus—fundal stimulation by repetitive massage or squeezing- Check placenta and membranes are complete- Insert indwelling catheter to maintain empty bladder16- Timely administration of first line uterotonics if preventative uterotonics ineffective79,101. If bleeding persists, consider mechanical or surgical options [refer to Section 9 Intractable bleeding]. 8.1.1 First line pharmacological therapy for uterine atony. The following uterotonics are useful in treatment of PPH due to atonia.13 Drugs differ in effectiveness and side effects and should be chosen based on individual circumstances and in the absence of contraindications.13,101 Generally drugs are administered in the order presented below and may be used in combination.13,102 [refer to Appendix D: Drugs and blood products for PPH treatment].. # 8.1.2 Second line pharmacological therapy for uterine atony. # 8.2 Trauma. 8.2.1 Genital trauma. # 8.2.2 Cervical trauma. # 8.2.3 Uterine rupture. 8.2.3 Uterine ruptureUterine rupture can occur spontaneously or be associated with previous uterine trauma. The severity of the haemorrhage depends upon the extent of the rupture and may be a life- threatening obstetric emergency.. # 8.2.4 Uterine inversion Requires immediate treatment due to possibility of life- threatening haemorrhage and shock.. # 8.3 Tissue. # 8.4 Thrombin. 8.4 ThrombinCoagulopathy risk assessment should include consideration of obstetric conditions and aetiology of PPH, not just estimation of blood loss.. 8.4.1 Coagulopathy principles. Remain cognisant that coagulopathy can occur at any stage of a PPH, and often co- occurs with other causes.1,10. # 8.4.2 Correction of coagulopathy. # 8.4.3 Laboratory values. 8.4.3 Laboratory valuesMeasure the following parameters early and frequently. With successful treatment, values should trend toward normal.. 8.4.4 Cross matched RBC not available. Take blood for cross matching prior to giving O negative RBC- - do not wait for results.16. # 9 Intractable bleeding. Uterine atony is a leading cause of intractable bleeding that does not respond to first line interventions, first and second line uterotonics, and requires mechanical or surgical interventions to control.102,141,142. Initiate life- saving mechanical and/or surgical interventions early13:. Selection of procedure is best determined based on cause of bleeding, clinical expertise, service capabilities and individual clinical circumstances13 Treat coagulopathy concurrently [refer to Section 8.4.2 Correction of coagulopathy]. 9.1 Mechanical treatment of intractable bleeding. # 9.2 Surgical treatment of intractable bleeding. 10 Major haemorrhage. Reduction of morbidity and mortality associated with critical bleeding can be achieved through1:. Early detection and a rapid, coordinated multidisciplinary approach to control the haemorrhage, correct coagulopathy and normalise physiological parameters Implementation of a major haemorrhage protocol (MHP) that is reviewed annually by local key stakeholders A structured approach that includes laboratory escalation procedures for timely delivery and administration of blood components For further considerations, refer to Table 36. MHP considerations. # 10.1 Major haemorrhage protocol considerations. # 11 Women who cannot receive a blood transfusion. Blood transfusion may not be a management option in some situations. This may be due to personal choice, religious and/or cultural beliefs, the presence of rare blood groups or complex antibodies, or the unavailability of blood products.. # 12 Postnatal care after PPH. # References. 1. National Blood Authority (NBA). Patient blood management guideline for adults with critical bleeding [Internet]. 2023 [cited 2024 January 29]. Available from: . 2. Munoz M, Stensballe J, Ducloy-Bouthors AS, Bonnet MP, De Robertis E, Fornel I, et al. Patient blood management in obstetrics: prevention and treatment of postpartum haemorrhage. A NATA consensus statement. Blood Transfus 2019;17(2):112-36. doi:10.2450/2019.0245-18.. 3. Bienstock JL, Eke AC, Hueppchen NA. Postpartum hemorrhage. N Engl J Med 2021;384(17):1635-45. doi:10.1056/NEJMra1513247.. 4. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Placenta accreta spectrum (PAS) C-Obs 20. [Internet]. 2023. [cited 2024 March 28]. Available from: Australian College of Midwives. Aims and scope [Internet]. 2024 [cited 2024 March 03]. Available from: . 6. Australian Government Department of Health and Aged Care. First evaluation report: national stillbirth action and implementation plan. [Internet]. 2023 [cited 2024 March 4]. Available from: Australian Institute of Health and Welfare. National maternity data development project: primary postpartum haemorrhage: research brief no 8. Cat. no. PER 82 [Internet]. 2016 [cited 2024 January 31]. Available from: . 8. Begley CM, Gyte GM, Devane D, McGuire W, Weeks A, Biesty LM. Active versus expectant management for women in the third stage of labour. Cochrane Database of Systematic Reviews. [Internet]. 2019, [cited 2024 January 31]. Issue 2. Art No.: CD007412. DOI:10.1002/14651858.CD007412.pub5.. 9. World Health Organization. WHO recommendations: uterotonics for the prevention of postpartum haemorrhage. 2018. [cited 2024 January 29]. Available from: . 10. Escobar MF, Nassar AH, Theron G, Barnea ER, Nicholson W, Ramasauskaite D, et al. FIGO recommendations on the management of postpartum hemorrhage 2022. Int J Gynaecol Obstet 2022;157(1):3-50. doi:10.1002/ijog.14116.. 11. van Stralen G, von Schmidt Auf Altenstadt JF, Bloemenkamp KW, van Roosmalen J, Hukkelhoven CW. 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Rotational thromboelastometry reference range during pregnancy, labor and postpartum period: A systematic review with meta-analysis. Journal of Obstetric Anaesthesia and Critical Care 2022;12(2):105-15. doi:10.4103/JOACC.JOACC_21_22.146. Lee J, Eley VA, Wyssusek KH, Kimble RMN, Way M, van Zundert AA. Rotational thromboelastometry (ROTEM®) in gestational diabetes mellitus and coagulation in healthy term pregnancy: A prospective observational study in Australia. Aust N Z J Obstet Gynaecol 2022;62(3):389-94. doi:10.1111/ajo.13474.147. Lee J, Eley VA, Wyssusek KH, Kimble RMN, Way M, Cohen J, et al. The influence of obesity on coagulation in healthy term pregnancy as assessed by rotational thromboelastometry. Aust N Z J Obstet Gynaecol 2020;60(5):714-9. doi:10.1111/ajo.13141.148. Shreeve NE, Barry JA, Deutsch LR, Gomez K, Kadir RA. Changes in thromboelastography parameters in pregnancy, labor, and the immediate postpartum period. 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BMC Res Notes 2018;11(1):686. doi:10.1186/s13104-018-3800-0.157. Crossland E WD, Bamber J, Tassell R, Besser M, Symington E, Robinson M, Thomas W, MacDonald S. Validation of clinical reference ranges for viscoelastometric assessment of haemostasis (TEG® 6S) and standard laboratory tests in obstetric patients [abstract]. [Internet]. 2022 [cited 2024 May 1]. Available from: . # Appendix A: Uterine atonia interventions. Bimanual compression. Consider early if Bimanual compression of the uterus vaginally and abdominally Vaginally- Keep fingers straight and thumb tucked across palm, insert hand into vagina with palm facing the woman's thigh Once fingers meet resistance roll the hand so that palm is upward and curl fingers into a fist placing thumb on top of index finger Place the fist into the anterior fornix of the vagina and apply upward pressure Abdominally- Identify the uterine fundus Deeply palpate to stuate fingers behind the fundus Cupping the fundus compress it firmly around the intravaginal fist. Maintain compression until uterotonics take effect or surgical intervention initiated. Intrauterine balloon tamponade. Empty uterine cavity of clots and insert balloon portion of catheter through the cervix into uterine cavity. Balloon must be completely inside uterus Inflate the balloon with sufficient volume of warm sterile saline (approximately . B-Lynch compression suture. Image reproduced with permission from Wiley. B- Lynch C, Coker A, Lawal A, et al. The B- Lynch surgical technique for the control of massive postpartum haemorrhage: an alternative to hysterectomy? Five cases reported. BJOG 1997; 104:372- 375. # Appendix B: Surgical ligation procedures. Ligation of the uterine arteries. HL: high ligation of the uterine arteries; LL: a second low ligation 2- 3 cm below the first; o: ovary; bl: bladder; ut: uterus; ur: ureter Image reproduced with permission from Elsevier Ltd. Bouchghoul. Uterine- sparing surgical procedures. Am J Obstet Gynecol 2024. Uterine and ovarian artery ligation. - Progressive uterine devascularisation, involving a stepwise ligation approach- Ligate the ascending branch of one of the uterine arteries- Follow with ligation of the contralateral artery- Then ligate the uterine branch of one of the ovarian arteries- Follow with ligation of the contralateral branch- The sequence stops as soon as haemorrhage is controlledUterine blood flow is maintained through anastomoses from the vesical and rectal arteries. Internal iliac artery ligation. - Ligation of the anterior branch of the internal iliac artery- Demonstrates the vulnerability of the internal iliac vein and obturator nerve in proximity. # Appendix C: Prophylactic uterotonics. Consult a pharmacopeia for full details of indications, cautions, contraindications and interactions. # Appendix D: Drugs and blood products for PPH treatment. Consult a pharmacopeia for full details of indications, cautions, contraindications and interactions. # Appendix E: PoC testing obstetric specific reference ranges. Reference ranges for ROTEM parameters. # Acknowledgements. AcknowledgementsQueensland Clinical Guidelines gratefully acknowledge the contribution of Queensland clinicians and other stakeholders who participated throughout the guideline development process particularly:. Working Party Clinical Leads. Working Party Clinical LeadsProfessor Rebecca Kimble, Pre- Eminent Staff Specialist Obstetrics and Gynaecology, Royal Brisbane and Women's HospitalDr Julie Lee, Staff Specialist Anaesthetics, Royal Brisbane and Women's Hospital. QCG Program Officer. Ms Leah Vekve, Clinical Midwife Consultant. Working Party Members. Working Party MembersMs Noor Al- Adhami, Pharmacist, Royal Brisbane and Women's HospitalDr Gareth Ansell, Staff specialist Anaesthetist, Mater Health ServicesDr Elize Bolton, Obstetrician and Gynaecologist, BundabergMrs Anne Bousfield, Clinical Midwife Consultant, Roma HospitalDr Yogesh Chadha, Obstetrician and Gynaecologist, Royal Brisbane and Women's HospitalDr Lindsay Cochrane, Obstetrician and Gynaecologist, Caboolture HospitalMs Allison Corcoran, Clinical Nurse, Royal Brisbane and Women's HospitalMrs Victoria De Araujo, Clinical Midwife Consultant, Logan HospitalMs Ashleigh Eastment, Registered Nurse/Midwife, Sunshine Coast University HospitalProfessor Victoria Eley, Senior Staff Specialist, Royal Brisbane and Women's HospitalMs Leah Hardiman, Consumer Representative, Mothers and Babies AustraliaDr Natalie Kiesey- Calding, Obstetrician and Gynaecologist, Mount Isa HospitalMs Eleanor Kitcatt, Clinical Director, Retrieval Services QueenslandMr Karl Kizur, Pharmacist, Townsville HospitalMs Janelle Laws, Assistant Nursing and Midwifery Director - Education and Workforce, Metro North Hospital and Health ServiceDr Nigel Lee, Midwifery Lecturer/Researcher, University of QueenslandDr Michelle Spanevello, Senior Staff Specialist/Deputy Director Haematology, Royal Brisbane and Women's HospitalDr Makarla Stead, Director, Anaesthesia and Perioperative Medicine, Royal Brisbane and Women's HospitalMs Meghan Wischusen, Practice Development Midwife, Gold Coast University Hospital. Queensland Clinical Guidelines Team. Professor Rebecca Kimble, Director Ms Jacinta Lee, Manager Ms Stephanie Sutherns, Clinical Nurse Consultant Ms Cara Cox, Clinical Nurse Consultant Ms Emily Holmes, Clinical Nurse Consultant Ms Jacqueline Plazina, Clinical Nurse Consultant Ms Leah Vekve, Clinical Midwife Consultant Ms Jillian Clarke, Clinical Midwife Consultant Steering Committee. Funding: This clinical guideline was funded by Healthcare Improvement Unit, Queensland Health.	None	None	None
dc544f5310a8441ea159891d20a7c724	2024+昆士兰临床指南	早期妊娠丢失（V7）	# Queensland Clinical GuidelinesTranslating evidence into best clinical practice. Early pregnancy loss. # Acknowledgement. We acknowledge the Traditional Custodians of the land on which we work and pay our respect to the Aboriginal and Torres Strait Islander Elders past, present and emerging.. Disclaimer. This guideline is intended as a guide and provided for information purposes only. The information has been prepared using a multidisciplinary approach with reference to the best information and evidence available at the time of preparation. No assurance is given that the information is entirely complete, current, or accurate in every respect.. The guideline is not a substitute for clinical judgement, knowledge and expertise, or medical advice. Variation from the guideline, taking into account individual circumstances, may be appropriate.. This guideline does not address all elements of standard practice and accepts that individual clinicians are responsible for:. Providing care within the context of locally available resources, expertise, and scope of practice Supporting consumer rights and informed decision making, including the right to decline intervention or ongoing management Advising consumers of their choices in an environment that is culturally appropriate and which enables comfortable and confidential discussion. This includes the use of interpreter services where necessary Ensuring informed consent is obtained prior to delivering care Meeting all legislative requirements and professional standards Applying standard precautions, and additional precautions as necessary, when delivering care Documenting all care in accordance with mandatory and local requirements. Queensland Health disclaims, to the maximum extent permitted by law, all responsibility and all liability (including without limitation, liability in negligence) for all expenses, losses, damages and costs incurred for any reason associated with the use of this guideline, including the materials within or referred to throughout this document being in any way inaccurate, out of context, incomplete or unavailable.. Recommended citation: Queensland Clinical Guidelines. Early pregnancy loss. Guideline No. MN22.29- V7- R27 Queensland Health. 2022. Available from: . \circledcirc. This work is licensed under a Creative Commons Attribution- NonCommercial- NoDerivatives V4.0 International licence. In essence, you are free to copy and communicate the work in its current form for non- commercial purposes, as long as you attribute Queensland Clinical Guidelines, Queensland Health and abide by the licence terms. You may not alter or adapt the work in any way. To view a copy of this licence, visit nc- nd/4.0/deed.en. For further information, contact Queensland Clinical Guidelines, RBWH Post Office, Herston Qld 4029, email Guidelines@health.qld.gov.au. For permissions beyond the scope of this licence, contact: Intellectual Property Officer, Queensland Health, GFO Box 48, Brisbane Qld 4001, email ip_officer@health.qld.gov.au. # Flowchart: Assessment of suspected early pregnancy loss. Flowchart: F22.29- 2- V5- R27. # Flowchart: Assessment of location and viability in suspected early pregnancy loss. Use clinical judgement and consider the woman's individual circumstances when recommending management and the need for specialist referral. \beta. Flowchart: F22.29- 4- V3- R27. # Flowchart: Ectopic pregnancy. \beta. Flowchart: F22.29- 3- V6- R27. # Flowchart: Stable intrauterine non-viable pregnancy. # Table of Contents. 1 Introduction 9 1.1 Clinical standards 9 1.2 Emergency presentation 9 1.3 Haemodynamic instability 10 2 Principles of EPL care 11 2.1 Psychological support 12 2.2 Psychological morbidity 13 3 Assessment 14 3.1 Determining viability and location of pregnancy 15 3.2 Diagnosis of non- viable intrauterine pregnancy 16 3.3 Pregnancy of unknown location 17 3.3.1 Frequency of outcome after classification of PUL 17 3.4 Other pregnancy outcomes 18 4 Ectopic pregnancy 19 4.1 Risk factors for ectopic pregnancy 19 4.2 Expectant management of ectopic pregnancy 20 4.3 Medical management of ectopic pregnancy 21 4.3.1 Advice for women treated with methotrexate 22 4.4 Surgical management of ectopic pregnancy 22 5 Non- viable intrauterine pregnancy 23 5.1 Risk factors 23 5.2 Expectant management of non- viable intrauterine pregnancy 24 5.3 Medical management of first trimester non- viable intrauterine pregnancy 25 5.4 Surgical management of first trimester non- viable IUP 26 6 Second trimester pregnancy loss 27 7 Gestational trophoblastic disease (GTD) 28 7.1 Management of GTD 28 7.2 Follow- up 29 8 Recurrent early pregnancy loss 30 9 Sensitive management of fetal tissue/remains 31 References 32 Appendix A: Early pregnancy assessment service 35 Appendix B: Sonographic anatomy, landmarks and documentation 36 Appendix C: Methotrexate regimens for ectopic pregnancy 37 Acknowledgements 38. List of Tables. Table 1. Clinical standards 9 Table 2. Presentation at emergency department 9 Table 3. Haemodynamic instability 10 Table 4. General care principles for EPL 11 Table 5. Context and experience of early pregnancy loss 12 Table 6. Psychological morbidity 13 Table 7. Confirmation of pregnancy and assessment 14 Table 8. Determining viability and location of pregnancy 15 Table 9. Diagnosis of non- viable IUP 16 Table 10. Pregnancy of unknown location 17 Table 11. Frequency of outcome following PUL 17 Table 12. Other pregnancy outcomes 18 Table 13. Ectopic pregnancy 19 Table 14. Risk factors associated with ectopic pregnancy 19 Table 15. Expectant management of ectopic pregnancy 20 Table 16. Medical management of ectopic pregnancy 21 Table 17. Advice for women post- methotrexate 22 Table 18. Surgical management of ectopic pregnancy 22 Table 19. Risk factors associated with non- viable intrauterine pregnancy loss 23 Table 20. Expectant management for stable non- viable IUP 24 Table 21. Indications for medical management for the stable non- viable IUP 25 Table 22. Surgical management of the stable non- viable IUP 26 Table 23. Second trimester loss 27 Table 24. Classification of GTD 28 Table 25. Gestational Trophoblastic Disease 28 Table 26. Follow- up after GTD 29 Table 27. Recurrent early pregnancy loss 30 Table 28. Sensitive management of fetal remains 31. # Abbreviations. Definitions. # 1 Introduction. Early pregnancy loss (EPL) is estimated to occur in approximately . Little can be done to prevent a threatened pregnancy loss from progressing. However, high quality care can increase levels of satisfaction with care, minimise negative outcomes, and support women and their families to navigate their way through an emotional and highly stressful time.4. 1.1 Clinical standards. 1.2 Emergency presentation. # 1.3 Haemodynamic instability. 1.3 Haemodynamic instabilityWomen who are believed to be pregnant, with haemodynamic instability and vaginal bleeding and/or pain (abdominal, diaphragmatic or shoulder tip pain) require urgent intervention. Presume ruptured ectopic pregnancy or incomplete miscarriage with cervical shock or massive haemorrhage.. # 2 Principles of EPL care. The following care is common to women experiencing EPL irrespective of pregnancy location or management option. Consider in conjunction with other care recommendations.. # 2.1 Psychological support. 2.1 Psychological supportEarly pregnancy loss is an experience common to many women, and yet it is simultaneously an intensely personal, private, intimate and individual experience. It is important for longer term health and wellbeing, that a woman's psychological needs are not overlooked, and that any symptoms of grief, depression and anxiety are recognised and acknowledged by health professionals.. # 2.2 Psychological morbidity. # 3 Assessment. 3 AssessmentAssessment and diagnosis are made through a combination of a physical examination, history and clinical investigations.. # 3.1 Determining viability and location of pregnancy. # 3.2 Diagnosis of non-viable intrauterine pregnancy. # 3.3 Pregnancy of unknown location. 3.3 Pregnancy of unknown locationPUL is a classification not a final diagnosis. Following a classification of PUL, a final diagnosis of ectopic pregnancy places women at the most risk of clinical complications and harm.38 Therefore, it is the most important outcome to predict or exclude.38. 3.3.1 Frequency of outcome after classification of PUL. Outcomes reported from an evaluation of various cut off levels following a TVS and an initial classification of PUL, among women who were clinically stable.34. # 3.4 Other pregnancy outcomes. # 4 Ectopic pregnancy. 4.1 Risk factors for ectopic pregnancy. One half of women diagnosed with an ectopic pregnancy will have no known risk factors53. # 4.2 Expectant management of ectopic pregnancy. Expectant management is an option for selected women. Clear criteria for selection are not well defined.50. # 4.3 Medical management of ectopic pregnancy. Methotrexate is the drug of choice for medical management, although regimens vary.58,59 If no local protocols exist, refer to Appendix C: Methotrexate regimens for ectopic pregnancy.. # 4.3.1 Advice for women treated with methotrexate. 4.4 Surgical management of ectopic pregnancy. # 5 Non-viable intrauterine pregnancy. 5 Non- viable intrauterine pregnancyThere are no significant differences between expectant, medical and surgical management for a non- viable IUP. Surgical management has the timeliest resolution (defined in most studies as complete emptying of the uterus and lack of need for unplanned surgery). The individual preferences and values of the woman as well as the clinical situation determine the choice of management.. 5.1 Risk factors. # 5.2 Expectant management of non-viable intrauterine pregnancy. # 5.3 Medical management of first trimester non-viable intrauterine pregnancy. # 5.4 Surgical management of first trimester non-viable IUP. # 6 Second trimester pregnancy loss. 6 Second trimester pregnancy lossSecond trimester pregnancy loss represents . # 7 Gestational trophoblastic disease (GTD). 7.1 Management of GTD. # 7.2 Follow- up Post- evacuation weekly surveillance of . # 8 Recurrent early pregnancy loss. 8 Recurrent early pregnancy lossRecurrent early pregnancy loss is variously defined as either two or more, or three or more miscarriages. The definition is further complicated by whether previous pregnancy losses need to be consecutive or not.. # 9 Sensitive management of fetal tissue/remains. 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Traditional and molecular chromosomal abnormality analysis of products of conception in spontaneous and recurrent miscarriage. British Journal of Obstetrics and Gynaecology: An International Journal of Obstetrics & Gynaecology 2018;125(4):414-20. doi:. 66. Ghosh J, Papadopoulou A, Devai AJ, Jeffery H, Beeson L, Do V, et al. Methods for managing miscarriage: a network meta-analysis (review). Cochrane Database of Systematic Reviews. [Internet]. 2021, [cited 22 April 08]. Issue 6. Art No.: CD012602. DOI:10.1002/14651858.0000000000000644.. # 67. Fernlund A, Jokubkiene L, Sladkevicius P, Valentin L. Predictors of complete miscarriage after expectant management or misoprostol treatment of non-viable early pregnancy in women with vaginal bleeding. Archives of Gynecology and Obstetrics 2020;302(5):1279-96. doi:10.1007/s00404-020-05672-6.68. Fernlund A, Jokubkiene L, Sladkevicius P, Valentin L. Reproductive outcome after early miscarriage: comparing vaginal misoprostol treatment with expectant management in a planned secondary analysis of a randomized controlled trial. Ultrasound in Obstetrics & Gynecology 2022;59(1):100-6. doi:10.1002/uog.24769.69. B HAW, Murugesu N, Tobias A, Zamora J, Khan KS. Management of first-trimester miscarriage: a systematic review and network meta-analysis. Human Reproduction Update 2019;25(3):362-74. doi:10.1093/humupd/dmz002.70. Fernlund A, Jokubkiene L, Sladkevicius P, Valentin L, Sjöström K. Psychological impact of early miscarriage and client satisfaction with treatment: comparison between expectant management and misoprostol treatment in a randomized controlled trial. Ultrasound in Obstetrics & Gynecology 2021;58(5):757-65. doi: Petersen SG, Perkins AR, Gibbons KS, Bertolone JI, Mahomed K. Utility of betahCG monitoring in the follow-up of medical management of miscarriage. Australian and New Zealand Journal of Obstetrics and Gynecology 2017. doi:10.1111/ajo.12607.72. Kim C, Barnard S, Neilson JP, Hickey M, Vazquez C, Dou L. Medical treatments for incomplete miscarriage [Internet]. 2017 [cited 2017 March 31]; Issue 1. Art No.: CD007223.73. Chu JJ, Devall AJ, Beeson LE, Hardy P, Cheed V, Sun Y, et al. Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial. The Lancet 2020;396(10253):770-8. doi:10.1016/S0140-6736(20)31788-8.74. Ehrnstén L, Altman D, Ljungblad A, Kopp Kallner H. Efficacy of mifepristone and misoprostol for medical treatment of missed miscarriage in clinical practice—A cohort study. Acta Obstetricia et Gynecologica Scandinavica 2020;99(4):488-93. doi:10.1111/acogs.13780.75. Tuncalp O, Gulmezoglu AM, Souza JP. Surgical procedures for evacuating incomplete miscarriage. Cochrane Database of Systematic Reviews 2010;Issue 9. Art. No.:CD001993. 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Reproductive Biomedicine Online 2021;42(6):1146-71. doi:10.1016/j.rbmo.2021.02.014.94. Hong Li Y, Marren A. Recurrent pregnancy loss: A summary of international evidence-based guidelines and practice. Australian Journal for General Practitioners 2018;47:432-6.95. Haas D, Hathaway T, Ramsey P. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology (Review). Cochrane Database of Systematic Reviews. [Internet]. 2019. [cited 2022 August 05]. Issue 11. Art No.: CD003511. DOI:10.1002/14651858.CD003511.pub5.96. Rasmark Roepke E, Hellgren M, Hjertberg R, Blomqvist L, Matthiesen L, Henic E, et al. Treatment efficacy for idiopathic recurrent pregnancy loss – a systematic review and meta-analyses. Acta Obstetricia et Gynecologica Scandinavica 2018;97(8):921-41. doi:10.1111/aogs.13352.97. Royal College of Nursing. Sensitive disposal of all fetal remains [Internet]. 2007 [cited 2016 October 10]. Available from: Queensland Government. Public Health Act 2005: current as at July 1 2016 [Internet]. 2005 [cited 2016 October 14]. Available from: Human Tissue Authority. Guidance on the disposal of pregnancy remains following pregnancy loss or termination [Internet]. 2015 [cited 2016 October 10]. Available from: . # Appendix A: Early pregnancy assessment service. # Appendix B: Sonographic anatomy, landmarks and documentation. Sonographic landmarks: TVS is recommended for the accurate assessment of early pregnancy. Standard ultrasound documentation. # Appendix C: Methotrexate regimens for ectopic pregnancy. Follow local protocols for the safe administration/disposal of cytotoxic medications and equipment. Refer to an Australian pharmacopeia for complete drug information.. # Acknowledgements. AcknowledgementsQueensland Clinical Guidelines gratefully acknowledge the contribution of Queensland clinicians and other stakeholders who participated throughout the guideline development process particularly:. Working Party Clinical Lead. Working Party Clinical LeadDr David Baartz, Senior Staff Specialist Obstetrics and Gynaecology, Royal Brisbane and Women's HospitalMs Julia Brownlie, Nurse Practitioner, Department of Emergency Medicine, Royal Brisbane and Women's HospitalDr Scott Petersen, Maternal Fetal Medicine Specialist, Mater Mothers' Hospital Brisbane. QCG Program Officer. Ms Jacinta Lee, Manager Queensland Clinical Guidelines. Working Party Members. Working Party MembersMs Noor Al- Adhami, Advanced Pharmacist, Royal Brisbane and Women's HospitalDr Amy Arnold, Staff Specialist, Obstetrics and Gynaecology, Royal Brisbane and Women's HospitalDr Bob Baade, Staff Specialist, Obstetrics and Gynaecology, Cairns HospitalDr Lindsay Cochrane, Director, Obstetrics and Gynaecology, Caboolture HospitalMs Tracey Davies, Registered Midwife, Clinical Coach, Sunshine Coast University HospitalDr Natasha Frost, Staff Specialist, Obstetrics and Gynaecology, Townsville HospitalDr Lauren Kearney, Conjoint Professor of Midwifery, Royal Brisbane and Women's HospitalMs Melanie McKenzie, Consumer Representative, Harrison's Little WingsMs Shona Morrison, Clinical Nurse Consultant, Queensland Trophoblast Centre, Royal Brisbane and Women's HospitalMs Ashleigh Rousseaux, Consumer Representative, Red NoseDr Renuka Sekar, Staff Specialist, Centre for Advanced Prenatal Care, Royal Brisbane and Women's Hospital. Queensland Clinical Guidelines Team. Queensland Clinical Guidelines TeamProfessor Rebecca Kimble, DirectorMs Jacinta Lee, ManagerMs Stephanie Sutherns, Clinical Nurse ConsultantMs Cara Cox, Clinical Nurse ConsultantMs Emily Holmes, Clinical Nurse ConsultantMs Janene Rattray, Clinical Nurse ConsultantSteering Committee. Funding. FundingThis clinical guideline was funded by Healthcare Improvement Unit, Queensland Health.	None	None	None
12cc5b14798948d3a3cf1fc2644d0be8	2025+BSCCP／ESGO共识声明	宫颈上皮内瘤变2级的主动监测	# Active surveillance of cervical intraepithelial neoplasia grade 2: 2025 British Society of Colposcopy and Cervical Pathology and European Society of Gynaecologic Oncology consensus statement. Maria Kyrgiou, Sarah J Bowden, Laura Burney Ellis, Anne Hammer, Deirdre Lyons, Theresa Freeman- Wang, Konstaantinos S Kechagias, Ilkka Kalliala, Mario Preti, Vesna Kesic, Ignacio Zapardiel, Margaret Cruickshank, Murat Gultekin, Pierre Martin- Hirsch. Histological diagnosis of cervical intraepithelial neoplasia grade 2 (CIN2) has traditionally been the cutoff for local surgical treatment, due to a substantial risk of cancer development. However, evidence from the past decade suggests . Introduction. The introduction of systematic call and recall screening programmes over the past 20 years has resulted in substantial reductions to the incidence and mortality of invasive cervical cancer, as its precursors, cervical preinvasive lesions, can be detected and treated.12. Persistent infection by high- risk oncogenic human papillomavirus (HPV) subtypes is a necessary condition for the development of invasive cervical cancer, although only a small number of infections develop into cancer. More than . Traditionally, the diagnosis of CIN2 with histological biopsy has been considered the cutoff for local excision . Lancet Oncol 2025; 26: e140-51. *Contributed equally. Institute of Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK. Prof M Kyrgiou PhD, S J Bowden PhD, L B Ellis MBChB, K S Kechagias MD, I Kalliala PhD; Department of Surgery and Cancer, Imperial College London, London, UK. Prof M Kyrgiou, S J Bowden, L B Ellis, K S Kechagias, I Kalliala; Imperial College NHS Trust, London, UK (Prof M Kyrgiou, S J Bowden, L B Ellis, D Lyons MRCOG); Department of Obstetrics and Gynecology, Gadsdruh Hospital, Henning,. D Lyons MRCOG); Department of Obstetrics and Gynecology, Gadsdruh Hospital, Henning, Denmark (Prof A Hammer PhD);. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. Prof A Hammer); Department of Obstetrics & Gynaecology, Whittington Hospital, London,. UK (T Freeman- Wang FRCOG); Department of Obstetrics & Gynaecology, University of Helsinki and Helsinki. Helsinki and Helsinki University Hospital, Helsinki, Finland (I Kalliala); Department of Surgical Sciences, University . University Hospital, Madrid, Spain (Prof I Zapardiel PhD); Aberdeen Centre for Women's Health Research, University of Aberdeen, Aberdeen, UK (Prof M Cruickshank MD);. Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, Hacettepe University Faculty of Medicine, Ankara, Turkey. Prof M Gultekin MD; NIHR Clinical Research Facility, Lancashire Teaching Hospitals,. # Preston, UK (Prof P Martin-Hirsch MD). Correspondence to: Maria Kyrgiou, Institute of Reproductive and Developmental Biology, Department of Metabolism, Division and Reproduction, Imperial College London, London W12 0NN, UK m.kyrgiou@imperial.ac.uk See Online for appendix. The histological classification of CIN2 as a high- grade lesion might induce a tendency towards overtreatment, in our opinion. The current US national guidelines, the 2019 American Society of Colposcopy and Cervical Pathology (ASCCP) risk- based management consensus guidelines, developed through a consensus effort of 19 national organisations, recommended that histological high- grade lesions be classified as CIN2 or CIN3 to allow for the option of active surveillance of CIN2.13 The ASCCP additionally proposed . Although active surveillance of CIN2 lesions is sometimes practised in the UK and in other European countries, such as Finland and Denmark, clear and detailed guidelines on who to recommend for active surveillance and the exact management and follow- up protocol are either insufficient or unavailable, depending on the country. Eligibility for active surveillance, frequency of surveillance, threshold of treatment, and criteria for return to routine recall have not been previously adequately described. National screening guidelines (including UK Government guidance from National Health Service [NHS] England)15 aim to outline best practice and can improve standardisation while allowing personalised treatment. This Policy Review aims to summarise existing evidence and present a consensus statement on the clinical course of CIN2, management and treatment options (panel), and an algorithm to support clinician decision making (figure 1). The consensus statement is based on a literature review and critical appraisal of the evidence by a group of experts from the British Society of Colposcopy and Cervical Pathology (BSCCP) and the European Society of Gynaecologic Oncology (ESGO) prevention committee.. Methods. BSCCP and ESGO prevention committee executive councils nominated specialists from their membership . We conducted a systematic literature review of MEDLINE for studies published between database inception and May 3, 2024. Search indexing terms and criteria are listed in the appendix (p 1). The literature search was limited to publications in English. Case reports, letters, and in vitro studies were excluded.. Data extraction and preparation was done by SJB and LBE for all particles dealing with active surveillance. Discrepancies were resolved with the involvement of MK.. Evidence- based consensus statements were developed on active surveillance of CIN2 and prepared into tabular format by SJB and LBE. The chair (MK) was responsible for drafting corresponding preliminary statements based on the review of the relevant literature. These preliminary statements were then sent to the group of selected specialists. After discussion, specialists were asked to vote for, vote against, or abstain from agreement on 28 statements. The chair then discussed the results of this first round of voting and revised the statements if necessary. The revised version of the statements was distributed again to all experts, who were given the opportunity to evaluate and revise the next version of the statements. The statements were finalised on the basis of the results of this second round of voting. The group reached consensus on all 28 statements.. Epidemiology and evidence on natural history of CIN2. Given that CIN2 preinvasive cervical lesions are not recorded in cancer registries, the true incidence of CIN2 is difficult to establish. Approximately . Accurate data from longitudinal studies on the clinical course of CIN2 lesions have been limited by both the equivocal histological diagnosis and the ethical dilemma of conservatively managing possible precancer, with most data coming from studies in adolescents and women younger than 25 years. Furthermore, the definition of regression varies between studies. The first report on the clinical course of CIN, published in 1984 by McIndoe and colleagues,20 reported CIN3 progression to invasive cancer to be as high as . # Panel: Recommendations for the active surveillance of women with cervical intraepithelial neoplasia grade 2. Case selection. - Active surveillance of cervical intraepithelial neoplasia (CIN) grade 2 lesions is an option for carefully selected patients.- In women younger than 25 years with CIN grade 2 (CIN2), active surveillance is preferred, although treatment is acceptable.- In women aged 25 years and older, active surveillance is an acceptable management option. There is no upper age limit for active surveillance if other criteria as described in this panel are met, although the risks and benefits should be discussed in the context of the low, long-term risk of invasion that is associated with active surveillance, particularly in women older than 30 years.- Active surveillance of CIN2 lesions should only be offered to women who are willing and likely to comply with intensive monitoring visits.- All women considered for active surveillance should have histological confirmation at baseline and additional histological confirmation in case of worsening or persistent lesions or at least once every 12 months, until negative for high-risk HPV (human papillomavirus) or the decision to treat is made.- All cases of CIN2 that are proposed for active surveillance should be discussed in multidisciplinary meetings or equivalent panels, with expert review of the cytology, colposcopic impression, and biopsy.- The squamocolumnar junction and the upper limit of the lesion or lesions should be visible in order to consider active surveillance of CIN.- Women with immunosuppression should not be offered active surveillance and should instead be treated.- Women with previous treatment should not be offered active surveillance and should instead be treated.- The screening history, age, HPV vaccination history, likelihood of compliance with intense surveillance, and patient's fertility wishes should be carefully considered during decision making.- Factors such as large lesion size, the number of involved quadrants being more than 2, presence of expansile CIN, cytocomplement, HPV-16 or HPV-18 genotypes (if available), and high-grade index cytology might increase the risk of progression and should be carefully considered during decision making.- No evidence supports recommending endovisceral curettage in women with CIN2.- Women of reproductive age should be counselled that their risk of preterm birth is lower if the lesion regresses but higher if the lesion progresses and treatment is performed at a later date.- Patients with cytological or histological abnormalities in the glandular epithelium are excluded from this algorithm and should be managed as per existing guidelines.. Active surveillance and management. - Active surveillance should include co-testing or repeat testing for high-risk HPV with reflex cytology if positive, and colposcopic assessment at least once every 6 months. Histological biopsy should be done at least every 6 months if presumed persistent or progressive disease is suspected on the basis of colposcopy and cytology. In the presence of high-risk HPV positivity and evidence of regression on cytology and colposcopy (to low-grade or healthy status), histological biopsy should be done at least every 12 months.- If there is evidence of a progressive lesion, it should be treated with local excision of the tran-formation zone.- Local excisional treatment should be offered at 24 months of active surveillance if CIN2 persists, unless there is histological confirmation of regressive disease to CIN grade 1 (CIN1) or normal grade cytology. . Follow-up after active surveillance. - Two consecutive high-risk HPV negative tests 12 months apart are required to discharge a woman back to a 3-year recall. If high-risk HPV testing is negative at 3 years after discharge, the woman can return to routine recall which could include extended 5-yearly screening intervals until the usual exit screening round.- If a high-risk HPV screening test is positive at any stage in women who were previously managed with active surveillance and regressed without local treatment, immediate referral to colposcopy is recommended irrespective of triage cytology.. Use of biomarkers. - Genotyping for HPV-16 and HPV-18, DNA methylation testing, or a combination of these are not practised in all settings and cannot be routinely used to triage women for treatment during follow-up or at the end of 2 years of surveillance, but might support clinical decision making where available. HPV-16 positivity is associated with risk in terms of persistence and progression of CIN compared with other HPV genotypes.. - . (Continues on next page). # (Panel continued from previous page). staining could be useful as a negative predictor of high- grade disease in equivocal cases.. Risk of developing invasion. The risk of invasive disease (3 in 1000) and the risk of glandular disease (5 in 1000) during follow- up are low but not absent.10,12 Counselling women on the importance of attending their follow- up is important. The absolute cumulative risk for invasion at 20 years after either immediate surgical excision or successful active surveillance of CIN2 is low overall, but higher in the active surveillance group (2- 65% [95% CI 2- 07- 3- 23]) in comparison with the immediate surgical excision group (0- 76% [0- 58- 0- 95]).13 This risk is also higher in women who had histological regression during active surveillance (3- 83% [3- 24- 4- 42]) than in the immediate treatment group. (0- 69% [0- 45- 0- 91]),12 which emphasises the importance of follow- up and the low threshold for future colposcopy or treatment in those managed with active surveillance.. Administration. A patient information sheet should be provided that emphasises the importance of compliance with intensive active surveillance. The discussion on risks and benefits and mutual agreement of the plan for active surveillance and importance of compliance with follow- up should be clearly documented in the medical notes. Patients under active CIN2 surveillance should be regularly audited for outcomes and ideally recorded on prospective national screening databases.. # CIN2 was not studied. The most- cited report by Ostoril documents a . Tainio and colleagues included 36 studies of more than 3160 women with histologically confirmed, untreated CIN2 managed with active surveillance in their systematic review and meta- analysis and reported that after 2 years, . Denmark is one of the first countries to have introduced guidelines regarding active surveillance of CIN2, with active surveillance being practised in regions of Denmark from as early as 1995 based on local guidelines. National guidance introduced in 2012 recommended consideration of active surveillance of CIN2 in women of reproductive age, with monitoring every 6 months up to 2 years.26 A nationwide, register- based cohort study of women aged 18- 44 years comparing outcomes in those who had active surveillance for histologically confirmed CIN2 (6721 in 2008- 11 and 6399 in 2014- 17) showed that the implementation of the Danish national guidance in 2012 led to an increase in active surveillance from . Eligibility criteria for active surveillance vary substantially globally. Although English guidelines suggest active surveillance should be an option only for small lesions (ie, involving no more than two quadrants of the cervix),28 Denmark currently has no restrictions on what makes a CIN2 lesion eligible for active surveillance, except that the patient should be of reproductive age.26 13 . Risk factors. Risk factors proposed to affect chances of progression or regression during the 2- year surveillance period include age, immunosuppression, HPV- 16 or HPV- 18 positivity, HPV vaccination (received before age 15 years),29 high- grade index cytology, crypt involvement, expansile CIN at histology, and possibly DNA methylation positivity. One of the most important predictors of progression or regression appears to be age. Although Tainio and colleagues found a higher rate of regression over 2 years since diagnosis in women 30 years or younger . Subgroup analysis by Tainio and colleagues30 revealed that across three studies, the risk of progression was lower in women who tested negative for any high- risk HPV type . # was higher in women with HPV persistence of any type or with hormonal contraceptive use, and marginally higher in women who tested positive for HPV- 16 or HPV- 18. In a study based in New Zealand and Australia of 201 women aged younger than 25 years who had active surveillance of CIN2, regression was observed in 146 . In a prospective cohort study of 149 women with CIN2 managed with active surveillance, 88 . In a similar way to HPV genotyping and DNA methylation, a high- grade index cytology might confer a high risk of progression during the 2- year active surveillance period. The 2023 Danish cohort study of 11056 women reported that 5125 women . In addition to a high- grade cytology at baseline, the presence of expansile CIN at histology (a feature of CIN that involves the endocervical crypts and is associated with high- grade CIN) and a greater number of involved cervical quadrants at colposcopic examination could be associated with a reduced chance of CIN2 regression. In a 2011 study of 42 women with CIN2, lesions involving only one quadrant were 6.5 times more likely to regress than those extending beyond one quadrant in the first 3 months of follow- up, although by 12 months, no statistically significant difference in regression was observed according to number of affected quadrants (odds ratio 2.40 . Given that many countries have transitioned to primary HPV screening (with most using cytology triage), the importance of using HPV assays that enable partial or extended genotyping could be useful in stratifying the risk of disease progression. For example, information on HPV genotype, particularly the presence of HPV- 16 in combination with associated cytology and lesion size, could be useful for shared decision making in people diagnosed with CIN2.. CIN is difficult to diagnose and treat in patients with previous local excision and in patients without a fully visible squamous columnar junction; therefore, active surveillance cannot be recommended in these groups. Immunosuppression from HIV or systemic immunosuppressive treatments increases HPV persistence and risk of CIN, cervical cancer and treatment failure. Although treatment of HIV with antiretroviral treatment might increase likelihood of regression of CIN, the safety in these groups is unknown, and active surveillance therefore cannot be recommended at present.. Adherence with follow-up. Likelihood of compliance with surveillance is important in deciding management. Tainio and colleagues found the rate of non- compliance at 6- 24 months of follow- up in prospective studies was approximately . # Missing invasive and glandular disease. One of the major concerns in the management of CIN2 is the risk of missing prevalent invasive disease. Tainio and colleagues reported a total of 15 . In the Danish cohort study, 33 . Tainio and colleagues also reported a high incidence of invasive disease in women older than 40 years. Lycke and colleagues reported that . Although glandular disease is excluded from most active surveillance protocols, among 3160 patients, Tainio and colleagues found 15 cases of cervical glandular intraepithelial neoplasia or adenocarcinoma in situ during the follow- up period. These findings highlight the value of histological confirmation of CIN2 at baseline, including evaluation for cervical glandular intraepithelial neoplasia or adenocarcinoma in situ, and the need for local excision if CIN2 persists after 24 months.. Recurrence, reproduction, and long-term risk of cancer. When managing CIN2, the harms of immediate local excision should be balanced against the potential harms . of the number of repeat visits, delayed treatment, the risk of non- compliance, rates of recurrence, and the possible increased long- term risk of cancer associated with active surveillance. Although local surgical excision increases the risk of preterm birth, especially when repeated, a 2024 cohort of 10 537 women with CIN2 and a subsequent singleton birth found that the risk of preterm birth was similar between active surveillance and immediate LLETZ (RR 1- 03; . # untreated CIN1. The study was not powered to assess for risk of invasive disease. Lycke and colleagues reported an increase in the 15- year cumulative risk of cervical cancer from . Histological assessment and p16 immunostaining. Integral to a successful active surveillance programme is the quality of colposcopy practice and histopathology reporting. Even in the best performing screening programmes and research studies, interobserver variability in histological classification is well . # several molecular markers are under investigation (eg, E6 and E7 proteins, HPV mRNA, and methylation), p16 protein immunostaining is the only marker with current use in clinical practice worldwide. High- grade histology samples were shown to be more likely to stain positive for p16 protein in a meta- analysis and have been suggested as a useful adjunct to prevent misclassification between CIN1 and CIN2 in cases where morphology is uncertain. The 2019 ASCCP guidelines recommend p16 immunohistochemistry to support the diagnosis of histological CIN2 or worse if morphological assessment on the haematoxylin and eosin slide is consistent with CIN2 or CIN3, with the caveat that p16 should not be . # should not be used as a triage for active surveillance, particularly in women younger than 30 years.60 The performance of E4 and p16 is currently under investigation in a historical cohort study of 500 women with CIN2 who had active surveillance.61 The British Association of Gynaecological Pathologists guidance from 2022 on interpretation of p16 immunohistochemistry reports that up to . 2025 BSCCP ESGO recommendations. The 2019 ASCCP1 risk- based management consensus guidelines outline options for active surveillance of CIN2 lesions in women younger than 25 years and in women 25 years or older (appendix p 2). In the UK, screening does not commence until the age of 25 years. In other European countries, the age of initiation of screening varies; primary high- risk HPV testing is commonly offered after the age of 30 years and cytology is the screening test of choice in younger women.64 The BSCCP ESGO 2025 recommendations, made after assessment of the existing evidence, are summarised in the panel.. Conclusion. This Policy Review adds to an increasing body of evidence that active surveillance of CIN2, rather than immediate treatment, might be reasonable for a carefully selected cohort of patients. When considering active surveillance, the risk of missed or future invasive disease should be balanced against the benefits of awaiting regression, age, fertility wishes, the impact and cost of repeat visits, and the possibility of only delaying treatment. Patients should be informed that the cumulative risk of invasion within 20 years is low overall, but substantially higher when compared with immediate excision. Prospective databases are required to monitor long- term outcomes and safety in those who are managed with active surveillance, for future appropriate risk stratification. Continued research into biomarkers that could differentiate those at higher risk of progression from those likely to regress will also be highly valuable.. Contributors. This Policy Review was conceived by PM- H and MK. MK and SJB wrote the first draft. All authors contributed to regular consensus statement meeting and proposed recommendations. All authors reviewed the manuscript.. Declaration of interests. MK received funding from the European Society of Gynaecological Oncology for this work. MK received honoraria from Hologic unrelated to this work. SJB has received funding from the National Institute of. Health and Care Research and a Wellcome Trust Clinician Scientist 4i Fellowship, unrelated to this work. AH has received an honorarium from Exeltis and equipment from Roche Diagnostics, unrelated to this work. DL is the president of the British Society of Colposcopy and Cervical Pathology. TF- W has received travel funding from the Chinese Colposcopy Society, unrelated to this work, and she is the past president of the British Society of Colposcopy and Cervical Pathology and president elect of the International Federation for Colposcopy and Cervical Pathology. IK has received funding from the Finnish Research Council, Finnish Medical Foundation, Sigrid Juselius Foundation, and Finnish State Research Funding, unrelated to this work. All other authors declare no competing interests.. Acknowledgments. This work was supported by the European Society of Gynaecological Oncology. We thank Katherine Lycke for assistance in the production of the figures.. References. 1 Saslow D, Solomon D, Lawson HW, et al. 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The p16/ki- 67 assay is a safe, effective and rapid approach to triage women with mild cervical lesions. PLoS One 2021; 16: e0253045. 59 Wentzensen N, Fetterman B, Castle PE, et al. p16/Ki- 67 dual stain cytology for detection of cervical precancer in HPV- positive women. J Natl Cancer Inst 2019; 107: djv257. 60 Castle PE, Adcock R, Cuzick J, et al. Relationships of p16 immunohistochemistry and other biomarkers with diagnoses of cervical abnormalities: implications for LAST terminology. Arch Pathol Lab Med 2020; 144: 725- 34.. 61 Damgaard RK, Jenkins D, de Koning MN, et al. Performance of HPV E4 and p16INK4a biomarkers in predicting regression of cervical intraepithelial neoplasia grade 2 (CIN2): protocol for a historical cohort study. BMJ Open 2022; 12: e059593. 62 Singh N, Giks BC, Wing- Cheuk Wong R, et al. Interpretation of p16 immunohistochemistry in lower anogenital tract neoplasia. August 12, 2022. of- p16- immunohistochemistry- in- lower- anogenital- tract- neoplasia/ (accessed March 4, 2023). 63 Maniar KP, Sanchez B, Paintal A, Gursel DB, Nayar R. Role of the biomarker p16 in downgrading - IN 2 diagnoses and predicting higher- grade lesion. Am J Surg Pathol 2015; 39: 1708- 18. 64 Kyrgiou M, Arbyn M, Bergeron C, et al. Cervical screening: ESGO- EFC position paper of the European Society of Gynaecologic Oncology (ESGO) and the European Federation of Colposcopy (EFC). Br J Cancer 2020; 123: 510- 17. Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.. Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies..	None	None	None
e196d5068b55486a8ef322699abca087	2025+CAR／CSAR实践声明	子宫内膜异位症的盆腔MRI检查	# CAR/CSAR Practice Statement on Pelvic MRI for Endometriosis. Emily Pang<sup>1</sup>, Arvind Shergill<sup>1</sup>, Silvia Chang<sup>1</sup>, Priscila Crivellaro<sup>2</sup>, Shauna Duigenan<sup>3</sup>, Ania Kielar<sup>4</sup>, Signy Holmes<sup>5</sup>, Iffat Rehman<sup>1</sup>, Caroline Reinhold<sup>6</sup>, and Basma Al- Arnawoot<sup>7</sup>. Abstract. The Canadian Association of Radiologists (CAR) Endometriosis Working Group was tasked with providing guidance and benchmarks to ensure the quality of technique and interpretation for advanced imaging modalities associated with diagnosing endometriosis. Advanced pelvic ultrasound is essential in diagnosing and mapping pelvic endometriosis, but pelvic MRI serves as an excellent imaging tool in instances where access to advanced ultrasound is limited, or an alternative imaging modality is required. Despite the known utility of MRI for endometriosis, there is no consensus on imaging protocol and patient preparation in Canada. To improve patient care and support excellence in imaging, the Working Group has developed recommendations for the use of pelvic MRI to assess for endometriosis with an aim to standardize MRI technique for use in both community and academic practices across Canada. The guidelines provide recommendations regarding imaging technique and patient preparation for pelvic MRI, along with suggestions for structured reporting of pelvic MRI for endometriosis.. Resume. Le groupe de travail sur l'endometriose de l'Association canadienne des radiologistes (CAR) a récu la tâche de fournir une orientation et des répères pour garantir la qualité de la technique et de l'interprétation des modalités d'imagerie avancées associées au diagnostic d'endometriose. L'échographie pelvienne avancée est essentielle en vue de diagnostiquer et de cartographier l'endometriose pelvienne, mais l'IRM pelvienne constitue un excellent outil d'imagerie dans les cas où l'accès à l'échographie avancée est limité ou lorsqu'une modalité d'imagerie subsidiale est nécessaire. Malgré l'utilité reconnue de l'IRM pour l'endometriose, il n'existe au Canada aucun consensus sur les protocoles d'imagerie et la préparation des patientes. Afin d'améliorer les soins aux patientes et de promouvoir l'excelence en matière d'imagerie, le groupe de travail a rédigé des recommandations au sujet du recours à l'IRM pelvienne lors de l'évaluation de l'endometriose, dans le but de normaliser la technique d'IRM dans les milieux communautaires et universitaires à travers le pays. Les lignes directrices offrent des recommandations concernant la technique d'imagerie et la préparation des patientes pour l'IRM pelvienne, ainsi que des suggestions concernant un rapport structuré des examens d'IRM visant à observer l'endometriose.. Keywords. endometriosis, MRI, guidelines, advanced pelvic MRI, protocols. Introduction and Background. Endometriosis is a common condition, affecting approximately . Advanced pelvic ultrasound (US) plays an essential role in diagnosing and mapping pelvic endometriosis. In regions where the availability of specially- trained professionals to perform advanced pelvic ultrasound is lacking, in cases where the use of ultrasound is limited (e.g. inability to perform transvaginal ultrasounds), the area being investigated is outside the field of view of ultrasound, or an alternative modality is required to. # work up an ultrasound finding (e.g., there is negative/abnormal sliding sign but a full advanced pelvic ultrasound could not be performed, et cetera), pelvic MRI serves as an excellent alternative imaging tool for diagnosis and mapping of pelvic endometriosis.6 It can address the varying clinical presentations, as well as provide the benefits of reproducibility, non- invasiveness, and observer independence.. In the last few years, many societies have developed recommendations and guidelines relevant to the role of imaging in endometriosis.7 For example, the Society of Obstetrics and Gynecologists in Canada Endometriosis Guideline published in 2024 recommends that healthcare providers order a pelvic MRI if advanced ultrasound is not possible or unavailable and when there is a high degree of suspicion for ovarian endometriomas and deep endometriosis.8 The American College of Radiology (ACR) Appropriateness Criteria deem MRI appropriate for initial diagnosis, characterization/treatment planning (particularly if ultrasound is negative or indeterminate), suspected rectosigmoid disease, and follow- up for endometriosis.9 The European Society of Human Reproduction and Embryology Endometriosis Guidelines published in 2022 recommend imaging (US or MRI) for suspected endometriosis while cautioning professionals that a negative result does not exclude the diagnosis.10 The National Institute for Health and Care Excellence11 and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists Endometriosis Guidelines recommend MRI to assess the extent of deep endometriosis involving the bowel, bladder, or ureter.12. Despite the known utility of MRI for endometriosis, there is no consensus on imaging protocol and patient preparation across Canada. This lack of uniform technique can lead to suboptimal evaluation and reduced inter- reader agreement. To improve patient care and support excellence in imaging, the Canadian Association of Radiologists (CAR) Endometriosis Working Group has developed recommendations for the use of pelvic MRI to assess for endometriosis with an aim to standardize MRI technique for use in both community and academic practices across Canada. The guidelines were developed by the Working Group based on an extensive scoping review of existing literature, followed by a Delphi process to achieve consensus on imaging technique and patient preparation recommendations for pelvic MRI. The final practice guidelines detail these recommendations and include suggestions for endometriosis MRI structured reporting.. Methods. A comprehensive scoping review was conducted by 2 of the authors (EP and AS) to determine the current state of evidence for pelvic MRI protocolling and patient preparation in cases of endometriosis. A literature search was conducted in Pubmed using the search strategy ((endometriosis[MeSH Terms]) OR (endometriosis)) AND (mr imaging[MeSH Terms] OR (MRI)) to October 2023. Two reviewers (EP and AS) independently screened the title/abstracts and any conflicts were resolved by consensus opinion. The full text of records identified as potentially relevant were further reviewed by the 2 reviewers with data extracted for the purposes of the scoping review. Studies that described an MRI protocol for endometriosis in detail were included in the review. Results from the literature search are summarized in the PRISMA diagram (Figure 1).. This evidence was used to inform the recommendations where possible, with expert consensus applied when the published evidence was insufficient. A cut- off of . The Working Group, composed of 10 abdominal radiologists who are experts in endometriosis imaging, were asked to complete 2 survey rounds to rate the proposed recommendations using the online survey tool SurveyMonkey. Cut- offs for agreement and disagreement were previously established and communicated to all Working Group members before beginning the Delphi process. Recommendations were rated on a 7- point Likert scale, such that (1) Strongly Disagree; (2) Disagree; (3) Somewhat Disagree; (4) Neither Agree nor Disagree; (5) Somewhat Agree; (6) Agree; and (7) Strongly Agree.. Working Group members provided anonymous responses and feedback that was reviewed and evaluated at the end of Round 1. Statements rated 6.0 to 7.0 by . # insufficient evidence to make a recommendation for or against the proposed sequence or preparation. Statements rated 3.0 to 5.9 were included in Round 2 of the Delphi and incorporated suggestions for rewording or rephrasing, as indicated by the anonymous comments submitted by the Working Group members in Round 1. Working Group members were again asked to rate the revised statements in Round 2. The same cut- offs for agreement and disagreement were applied to Round 2 of the Delphi. The data was compiled, and the working group met to discuss the full set of recommendations to ensure broad consensus on the possible practical and policy- related implications. The final recommendations are presented in this practice guideline (Table 1).. Image Acquisition. For a summary of image acquisition parameters see Appendix A; for selected imaging examples, see Appendix B.. 1.5 T Versus 3 T Scanners. Recommendation: When assessing for endometriosis with pelvic MRI, either a 1.5 T or 3 T magnet strength scanner can be used.. MRI for the evaluation of pelvic endometriosis can be performed using either a . 3 T scanners have improved signal- to- noise (SNR) compared to . 1.5\mathrm{T}. Coil. Recommendation: When assessing for endometriosis with pelvic MRI, the use of a phased array body coil placed over the pelvis is essential.. The use of a phased array coil placed over the pelvis with the patient supine is the current standard for pelvic MRI and is also specifically recommended for endometriosis evaluation to increase the SNR and improve spatial resolution. Flexible coils are preferred to rigid coils for their improved SNR and adaptability to a variety of body habitus types.17 In the scoping review, most studies . Standard Orthogonal T2 Sequences. Recommendation: When assessing for endometriosis with pelvic MRI, axial and sagittal T2 sequences are essential. A coronal T2- weighted sequence is not essential but is recommended.. Orthogonal sagittal and axial T2 sequences without fat saturation are essential for evaluating pelvic endometriosis. Most deep endometriosis nodules are characterized by their typical T2 hypointense fibrotic signal and are best identified when contrasted against the hyperintense signal of visceral fat. Previous consensus guidelines have also recommended at least 2 T2- weighted orthogonal planes, including axial and sagittal, with mixed opinions on inclusion of a coronal T2 plane.21,22 In the scoping review, axial T2- weighted images were included in . The sagittal T2- weighted sequence is the optimal plane for visualizing the pelvis as it is divided into the 3 compartments (anterior, middle, posterior) used for systematically localizing. # Table I. Summary of the Recommendations Based on . Image acquisition. When assessing for endometriosis with pelvic MRI, either a 1.5T or 3T magnet strength scanner can be used.\* When assessing for endometriosis with pelvic MRI, the use of a phased array body coil placed over the pelvis is essential.\* When assessing for endometriosis with pelvic MRI, axial and sagittal T2 sequences are essential. A coronal T2- weighted sequence is not essential but is recommended.\* When assessing for endometriosis with pelvic MRI, an oblique axial T2- weighted sequence (oblique axial along the uterosacral ligaments or oblique perpendicular to the long axis of the uterine body) is optional. When assessing for endometriosis with pelvic MRI, a 3D T2- weighted sequence (ie, CUBE/SPACE/VISTA) is optional but should not replace conventional T2 sequences if the resolution is not comparable. When assessing for endometriosis with pelvic MRI, an axial T1 FS sequence is essential. If available, we recommend the routine use of an axial T1- weighted DIXON sequence as this can replace the conventional axial T1 FS and T1 non- FS sequences. If DIXON is unavailable, an axial T1 non- FS sequence can be acquired separately as an option (ie, in addition to the recommended axial T1 FS sequence). A sagittal T1 FS sequence is optional to assess for haemorrhagic foci in the anterior and posterior cul- de- sac.\* When assessing for endometriosis with pelvic MRI, axial diffusion- weighted imaging is not essential but is recommended, particularly if gadolinium is not used or if there is a risk of malignant degeneration. When assessing for endometriosis with pelvic MRI, the use of intravenous gadolinium contrast is optional and can be considered if there is an increased risk for malignant degeneration or if there is a known adnexal lesion.. Patient preparation. When assessing for endometriosis with pelvic MRI, routine use of an antiperistaltic agent is recommended.\* When assessing for endometriosis with pelvic MRI, timing the study according to the menstrual cycle is not recommended.\* When assessing for endometriosis with pelvic MRI, scans are generally performed in the supine position.\* When assessing for endometriosis with pelvic MRI, voiding I h prior to the scan to ensure optimal bladder re- distension is recommended.\* When assessing for endometriosis with pelvic MRI, if there is a specific concern for a vaginal or rectal nodule, the use of endoluminal gel (ie, vaginal or rectal) is optional but not essential. When assessing for endometriosis with pelvic MRI, abdominal strapping is optional.\* When assessing for endometriosis with pelvic MRI, the use of bowel preparation (ie, NPO, fleet enema) is optional.. \Recommendations based on scoping review. \\Recommendations following Round I of the Delphi process; all other recommendations were determined following Round 2 of the Delphi process. \Recommendation based on both the scoping review and from the Delphi process.. sites of endometriosis involvement, as recommended by the Society of Abdominal Radiology and based on the 2016 International Deep Endometriosis Analysis consensus guidelines.23,24 It is also essential for assessing uterine position, endometrial and junctional zone thickness, the anterior and posterior cul- de- sacs, and rectosigmoid and vaginal nodules due to the craniocaudal orientation of these structures. The axial plane is useful for evaluating the ureters, round ligaments, and often the uterosacral ligaments, as they are usually oriented perpendicular to the transverse plane.. A coronal T2- weighted sequence is not essential but is recommended. It provides a useful cross reference when evaluating the uterine junctional zone (particularly if the uterine long axis is horizontal), sciatic nerves, pelvic sidewall, uterosacral ligaments, pelvic small bowel/appendix, and depth of invasion of high rectosigmoid nodules. Kissing ovaries- in which both ovaries are medialized by adhesions- are a characteristic feature of advanced endometriosis and are also more readily appreciated in the coronal plane. It is also helpful when assessing the tubular configuration of hemato/hydrosalpinges to distinguish them from endometriomas.. Oblique T2. Recommendation: When assessing for endometriosis with pelvic MRI, an oblique T2- weighted sequence (oblique- axial . The uterosacral ligaments support the uterus in the pelvis, extending from the cervix to the anterior sacrum, and are commonly involved in deep endometriosis. The European Society of Urogenital Radiology guidelines recommend a thin slice axial oblique T2 sequence oriented in a cross- sectional plane through the uterosacral ligaments (USL) that was based on a 2011 study by Bazot et al.23,25 In practice, the quality of the images acquired usually allows identification of the USLs on T2 axial sequences (approximating the mesorectal fascia) and acquiring a separate oblique- axial plane is generally not required). However, it could be optionally included if the USLs are difficult to visualize, such as in patients with reduced visceral fat, obscuration by distended bowel, or significant distortion from fibrosis. Rectosigmoid/midrectal deep endometriosis nodules may also be better assessed in cross- section in this plane.. The standard coronal plane can be sufficient to assess the uterine body in cross- section (for junctional zone evaluation or for distal sigmoid nodules which are often oriented parallel to the uterine body) in cases where the uterus has a predominantly transverse lie. However, if the uterine body position is more axially oriented, there may be value in obtaining an oblique coronal plane oriented perpendicular to the long axis of the uterus. The SAR guidelines consider this as optional but could potentially replace the conventional coronal plane.22 As it may be difficult to. # know the uterine orientation in advance and whether an oblique plane would simply just replicate an existing axial or coronal sequence, we share the opinion that this is an optional sequence, and its inclusion would depend on local practice.. In the scoping review, an oblique T2- weighted (oriented either to the USLs or uterus) was acquired in only . 3D T2. Recommendation: When assessing for endometriosis with pelvic MRI, a 3D T2- weighted sequence (ie, CUBE/SPACE/ VISTA) is optional but should not replace conventional T2 sequences if the resolution is not comparable.. Given the number of T2 planes that are potentially acquired in most endometriosis protocols, it has been proposed that a single volumetric 3D T2 sequence (such as CUBE, VISTA, SPACE) could be acquired and reformatted in multiple planes, replacing conventional T2 sequences. In theory, this could reduce overall scan time and allow for thinner slice reconstructions. However, optimizing the 3D sequence to have comparable image quality and spatial resolution to conventional T2 sequences, without an overly lengthy acquisition time, remains a challenge in clinical practice.26. Bazot et al found that 3D CUBE resulted in significantly reduced image quality and worsened motion artifact compared to conventional T2 sequences, although diagnostic accuracy for deep endometriosis was similar.25 Other studies have found comparable image quality between 3D and 2D T2 for deep endometriosis or female pelvic imaging in general.26,27 In our scoping review, 3D T2 was utilized in . In the consensus group's experience, the image quality of 3D T2 is highly variable and scanner- dependent; in many cases not comparable to conventional T2. We thus consider this optional and should not replace conventional T2 sequences if the image quality is not comparable.. T1/T1 Fat-Saturated Sequences. Recommendation: When assessing for endometriosis with pelvic MRI, an axial T1 fat- saturated (FS) sequence is essential. If available, we recommend the routine use of an axial T1- weighted DIXON sequence as this can replace the conventional axial T1 FS and T1 non- FS sequences. If DIXON is unavailable, an axial T1 non- FS sequence can be acquired separately as an option (i.e. in addition to the recommended axial T1 FS sequence). A sagittal T1 FS sequence is optional for assessing haemorrhagic foci in the anterior and posterior cul- de- sac.. The use of a T1 fat- saturated/suppressed sequence is essential for endometriosis assessment. This sequence is used to increase the conspicuity of T1 hyperintense haemorrhagic foci that are often seen with deep endometriosis lesions, adenomyosis, and to identify hematosalpinx.28- 31 The sequence can also differentiate T1 hyperintense ovarian endometriomas from macroscopic fat within dermoid cysts. An axial T1 FS plane is . The Dixon method is a technique of fat suppression using chemical shift and mathematically combines the acquired in and out of phase T1 sequences to obtain post- processed fat and water maps, the latter equivalent to a conventional T1 fat- saturated sequence with often more uniform fat suppression.32,33 All 4 sets of images (T1 in- phase, T1 out- of- phase, fat map, water map) can be generated with a single breath hold. The Dixon method has been gaining popularity in the past decade, with all the major MRI vendors now offering some variation of a Dixon sequence. If available, the Dixon water map can replace the conventional axial T1 FS sequence as alluded to above. This is also in agreement with the ESUR guidelines.21. A sagittal T1 FS sequence is not essential but recommended, as it can be useful for cross- referencing the axial plane and more confidently localizing haemorrhagic foci in the anterior and posterior cul- de- sac. The SAR guidelines recommend T1 FS imaging in at least 2 planes, although they do not specify which planes.22 This consensus group's opinion is that a sagittal sequence can be omitted if reducing scan time and protocol complexity is a priority, as a single axial plane will suffice in most cases.. A T1 non fat- saturated axial sequence is included in many routine pelvic MRI protocols to characterize macroscopic fat in dermoid cysts. This sequence is also included as part of the Dixon set of sequences as the T1 in- phase component. If Dixon is unavailable, this can be acquired optionally as it is not specifically useful for endometriosis assessment but is beneficial for other gynaecologic indications such as the characterization of dermoid cysts.. In the scoping review, axial T1 FS was included in the protocol of . Diffusion-Weighted Imaging. Recommendation: When assessing for endometriosis with pelvic MRI, axial diffusion- weighted imaging is not essential but is recommended, particularly if gadolinium is not used or if there is a risk of malignant degeneration.. Diffusion- weighted imaging (DWI) sequences are also included in most routine pelvic protocols, typically acquired in the axial plane with 2 to 4 b- values and a generated apparent diffusion coefficient (ADC) map. In the scoping review, a DWI sequence was acquired in . It is well known that benign endometriomas can demonstrate diffusion restriction,31,34,35 while there is little literature on how deep endometriosis nodules behave on DWI. From what has been published, and from our own experience, deep endometriosis nodules will often demonstrate low ADC values due to the T2- "blackout" effect. This effect arises from an intrinsically low T2 signal due to the predominantly fibrotic composition and no significant hyperintensity on high b- value. # DWI (ie, only mild or no true restricted diffusion). An exception to this may be the presence of true diffusion restriction localized to intralesional haemorrhagic components.22,36,37. While DWI is not useful for the detection of deep endometriosis itself, it can be helpful for detecting diffusion restriction associated with malignant degeneration, a rare complication of both ovarian endometriomas and extraovarian endometriosis.39- 41 While assessment may be confounded by benign endometriomas that can also restrict diffusion (as noted earlier), a localized DWI abnormality correlating to suspicious nodularity that is detected on other sequences should raise concern for malignant transformation.42 DWI may also be useful for differentiating deep endometriosis from other malignancies or detecting incidental malignancy, for example, Busard et al found that bowel deep endometriosis nodules demonstrated lower signal intensity on high b- value DWI compared to colorectal carcinoma.43. DWI is also helpful for lymph node detection and localizing the ovaries, which are usually hyperintense on high b- value DWI and can be challenging to find when they are smaller in volume (such as in patients on oral contraceptives) or obscured by the anatomic distortion that can co- occur with deep endometriosis.. The consensus group recommends the use of an axial DWI sequence, though not essential, as part of an endometriosis protocol, particularly when gadolinium is not used. The axial DWI sequence can compensate for the otherwise reduced sensitivity for alternative diagnoses or malignant degeneration on a non- contrast study.. Gadolinium. Recommendation: When assessing for endometriosis with pelvic MRI, the use of intravenous gadolinium contrast is optional and can be considered if there is an increased risk for malignant degeneration or if there is a known adnexal lesion.. Like DWI, the primary reason for including gadolinium would be to detect malignant degeneration either in relation to or incidental to endometriosis. However, the population most impacted by endometriosis- namely premenopausal females- are, in general, at lower risk of malignancy compared to older demographic groups.44 False positives can also occur with polypoid forms of endometriosis and endometrioma decidualization, both of which enhance and can mimic malignancy.31,45. Contrast has otherwise limited utility in endometriosisspecific imaging as most deep endometriosis nodules progressively enhance similarly to fibrotic tissue and it has not been shown to improve the detection of nodules compared to the routine non- contrast sequences.46,47 Occasionally, contrast may improve confidence when a rectosigmoid endometriosis nodule is difficult to distinguish from stool content.. The benefits of omitting gadolinium include reduced cost and scan time, no risk of allergic reaction or sensitivity, the ability to perform studies during "off hours (i.e. does not . Given the risk- benefit considerations, the consensus group agrees that the use of contrast is optional. Contrast was included in the protocols of . Patients over 40 years of age (as ovarian cancer risk increases more steeply in this demographic48). Patients with a known adnexal mass/endometrioma requiring characterization. If a finding on a non- contrast study is felt to require contrast for characterization, the patient could be recalled for a limited follow- up study.. When contrast is used, pre and post gadolinium subtracted images are useful in detecting areas of true enhancement within endometriomas and in other areas of concern.. Susceptibility Weighted Imaging. Susceptibility- weighted imaging (SWI) increases the sensitivity for the detection of chronic haemorrhagic foci and can theoretically be used to improve the characterization of deep pelvic endometriosis. Most studies evaluating the use of SWI sequences have been in the context of differentiating endometriomas from other ovarian cysts.49- 51 There is very limited evidence that SWI may improve sensitivity for extra- ovarian endometriosis.52,53 However, there can be several other causes of increased susceptibility in the pelvis such as bowel gas, foreign bodies (such as IUD), and calcifications that can confound interpretation.22 Only . Patient Preparation. For a summary of patient preparation recommendations, see Appendix C.. Use of Antiperistaltic Agents. Recommendation: When assessing for endometriosis with pelvic MRI, routine use of an antiperistaltic agent is recommended.. Small bowel peristalsis causes motion artifact which can degrade image quality and limit the detection of subtle endometriosis lesions.22 It is also important to decrease uterine peristalsis, which can result in apparent thickening of the junctional zone. This can be falsely misinterpreted as adenomyosis, a common coexisting condition.54 . # MRI exam to maximize the effective duration. IV HBB acts rapidly and is more reliable than the IM route, which can take longer to act, with both routes comparable in duration of effect.. Menstrual Cycle Timing. Recommendation: When assessing for endometriosis with pelvic MRI, timing the study according to the menstrual cycle is not recommended.. As endometriosis is hormonally sensitive, it is theoretically possible that it may change in conspicuity depending on the menstrual cycle timing. Previously published protocol recommendations have explicitly not timed the MRI study based on the menstrual cycle phase, as there is no strong evidence to support this practice and it would be logistically challenging as many patients may have irregular or unpredictable menstrual cycles.. Patient Position. Recommendation: When assessing for endometriosis with pelvic MRI, scans are generally performed in the supine position.. Pelvic MRI is generally performed with patients in the supine position. Although only . Bladder Distension. Recommendation: When assessing for endometriosis with pelvic MRI, voiding 1 hour prior to the scan to ensure optimal bladder distension is recommended.. In . The Use of Endoluminal Gel. Recommendation: When assessing for endometriosis with pelvic MRI, if there is a specific concern for a vaginal or rectal nodule, the use of endoluminal gel (ie, vaginal or rectal) is optional but not essential.. Opacification of the rectum and vaginal canal with ultrasound gel (sterile or non- sterile) has been recommended by some studies. Luminal distension with aqueous gel separates the normally closely opposed walls of these structures and its T2 hyperintensity contrasts with the low T2 signal of endometriosis nodules, improving conspicuity.. Other studies did not find significant improvement in endometriosis detection with the use of endoluminal gel.. Abdominal Strapping. Recommendation: When assessing for endometriosis with pelvic MRI, abdominal strapping is optional.. Abdominal strapping uses a broad belt tied over the abdomen and pelvis to decrease the artifact caused by respiratory motion.. # Bowel Preparation. Recommendation: When assessing for endometriosis with pelvic MRI, the use of bowel preparation (ie, NPO, fleet enema) is optional.. Fasting for 4 hours prior to the pelvic MRI scan can decrease bowel peristalsis which can theoretically improve visibility of endometriosis lesions. However, there is limited evidence for fasting leading to improved detection of endometriosis on pelvic MRI as antiperistaltic agents are usually sufficient for reducing bowel motility.22,70 Similarly, bowel preparation using. enemas has limited evidence at this time.57 Although . Structured Reporting. For complex diseases such as endometriosis, preoperative imaging plays a crucial role in presurgical planning and patient counselling.71,72 This requires effective communication between the radiologist and the clinical team, primarily via the radiology report. Traditional narrative reports can lack clarity and depend on the radiologist's experience and training, while structured reports are proven to enhance accuracy and reduce errors.73 This ensures comprehensive mapping of the disease and standardized description using a universally accepted lexicon.5,71. Various societies and working groups have published structured report templates for ultrasound and MRI reporting of pelvic endometriosis.71,72 Most published templates use a compartmental model to divide the pelvis, with some variations, such as keeping the uterus and ovary separate instead of grouping them under the "middle compartment"71 or dividing the pelvis into more than 3 compartments.74 Each variation has its merits, but the format and order of compartments are less important than ensuring a complete anatomical review and reporting findings that may change management using a standard lexicon.. To maintain consistency with the CAR ultrasound reporting template for endometriosis, the MRI template for standardized reporting also employs a 3- compartment model (anterior, middle, and posterior), grouping the ovary and uterus under the middle compartment (see Table 2). The compartments are listed in order of location of most frequent disease (middle, posterior, and anterior). A fourth subheading specifically for endometriosis is added, titled "Additional sites of endometriosis," to accommodate other sites not covered by the 3- compartment model.. For each of these subheadings, the specific structures to evaluate and report on are listed. While the detailed imaging characteristics of deep endometriosis are not listed within the template as it is beyond the scope of this paper, a summary of key descriptors using a standard lexicon within the template is provided. For each rectal lesion, the template includes integral descriptors that should be reported by the radiologist and can modify the surgical approach or type of resection. For bowel lesions, the size and number of lesions, distance of the most caudal lesion from the anal verge, depth of invasion, and percent circumference of bowel involved . When visualization of a structure is suboptimal, we suggest labelling it as "not visualized" or "suboptimally visualized" to ensure transparency and completeness. We also acknowledge that in instances of multiorgan involvement, radiologists may need to combine sections of the structured report. For instance, if a retrocervical lesion extends into the vaginal fornix/vagina, forming one lesion, combining these 2 sections may be appropriate or if the hematosalpinx is inseparable from the ovarian endometrioma, the radiologist may choose to group both structures under "adnexa." In the case of non- endometriosis related pathology, it is recommended to adhere to existing classification systems, such as ACR O- RADSTM for ovarian lesions75,76 and FIGO77 classification for fibroids. Finally, it is recommended that this template is adjusted as per institutional preference and discussion between radiologists and clinical stakeholders.. Conclusion. MRI has become an integral modality in the non- invasive assessment of endometriosis, providing excellent soft tissue contrast for detection of endometriosis nodules and a comprehensive view of the pelvis to inform management decisions including surgical planning. The guidelines described in this paper were developed by a panel of expert radiologists with the aim of providing a standardized pelvic endometriosis MRI protocol which balances the need for optimal diagnostic image quality with efficient resource utilization and patient experience in the Canadian context.. Additionally, the group developed a suggested reporting template to facilitate radiologist evaluation, which emphasizes the common sites of involvement and aims to make communication between healthcare providers more uniform.. # Use this section to describe other findings in the scan [Lymph nodes, osseous findings, free fluid, soft tissues etc.]. IMPRESSION:. 1. Uterine adenomyosis: Absent/present 2. Other uterine findings: eg, endometrial polyp(s), IUD, Fibroids etc. 3. Ovarian endometriosis: Absent/present 4. Deep endometriosis: Absent/present 5. Cul-de-sac [rectouterine pouch] obliteration: favoured present/favoured absent 6. Other findings:. # Appendix A. Appendix B. Images. # # # # Appendix C. Appendix D. Acknowledgments. AcknowledgmentsThe authors acknowledge the assistance and contributions of the other members of the CAR Endometriosis Working Group: Dr. Mathew Leonardi. The authors would also like to thank the members of the Canadian Association of Radiologists who took the time to provide their feedback and peer review during the drafting of these guidelines.. Declaration of Conflicting Interests. Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Unrelated to the recommendations contained herein: Dr. Basma Al- Arnawoot has delivered talks for Bayer; Dr. Caroline Reinhold is the VP of Oncology for Spire Sciences Inc.; Dr. Ania Kielar is President of the Canadian Association of Radiologists.. Funding. FundingThe author(s) received no financial support for the research, authorship, and/or publication of this article.. ORCID iDs. ORCID iDsSilvia Chang 0002- 9201- 8114 Priscila Crivellaro 0003- 1600- 034X Ania Kielar 0001- 6887- 5266 Iffat Rehman 0009- 1070- 3491 Caroline Reinhold 0002- 8852- 3273. References. References1. 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J Am Assoc Gynecol Laparosc. 2002;9(1):15-23. doi:10.1016/S1074-3804(05)60099-021. Bazot M, Bharwani N, Huchon C, et al. European society of urogenital radiology (ESUR) guidelines: MR imaging of pelvic endometriosis. Eur Radiol. 2017;27(7):2765-2775. doi:10.1007/s00330-016-4673-z22. Tong A, VanBuren WM, Chamié L, et al. Recommendations for MRI technique in the evaluation of pelvic endometriosis: consensus statement from the Society of Abdominal Radiology: endometriosis disease-focused panel. Abdom Radiol (NY). 2020;45(6):1569-1586. doi:10.1007/s00261-020-02483-w. 23. Guerriero S, Condous G, van den Bosch T, et al. Systematic approach to sonographic evaluation of the pelvis in women with suspected endometriosis, including terms, definitions and measurements: a consensus opinion from the International Deep Endometriosis Analysis (IDEA) group. Ultrasound Obstet Gynecol. 2016;48(3):318-332. doi:10.1002/uog.1595524. Jha P, Sakala M, Chamié LP, et al. Endometriosis MRI lexicon: consensus statement from the society of abdominal radiology endometriosis disease-focused panel. Abdom Radiol (NY). 2020;45(6):1552-1568. doi:10.1007/s00261-019-02291-x25. Bazot M, Gasner A, Ballester M, Darai E. Value of thin-section oblique axial T2-weighted magnetic resonance images to assess uterosacral ligament endometriosis. Hum Reprod. 2011;26(2):346-353. doi:10.1093/humrep/deq33626. Florin M, Vaussy A, Macron L, et al. Evaluation of iterative denoising 3-dimensional T2-weighted turbo spin echo for the diagnosis of deep infiltrating endometriosis. Invest Radiol. 2021;56(10):637-644. doi:10.1097/RLI.000000000000078627. Proscia N, Jaffe TA, Neville AM, Wang CL, Dale BM, Merkle EM. MRI of the pelvis in women: 3D versus 2D T2-weighted technique. Am J Roentgenol. 2010;195(1):254-259. doi:10.2214/AJR.09.322628. Takahashi K, Okada S, Ozaki T, Kitao M, Sugimura K. Diagnosis of pelvic endometriosis by magnetic resonance imaging using "fat-saturation" technique. Fertil Steril. 1994;62(5):973-977. doi:10.1016/S0015-0282(16)57060-529. Tanaka YO, Itai Y, Anno I, Matsumoto K, Ebihara R, Nishida M. MR staging of pelvic endometriosis: role of fat-suppression T1-weighted images. Radiat Med. 1996;14(3):111-116.30. Ha HK, Lim YT, Kim HS, Suh TS, Song HH, Kim SJ. Diagnosis of pelvic endometriosis: fat-suppressed T1-weighted vs conventional MR images. AJR Am J Roentgenol. 1994;163(1):127-131. doi:10.2214/ajr.163.1.801019831. Siegelman ES, Oliver ER. MR imaging of endometriosis: ten imaging pearls. Radiographics. 2012;32(6):1675-1691. doi:10.1148/rg.32612551832. Ma J. Dixon techniques for water and fat imaging. J Magn Reson Imaging. 2008;28(3):543-558. doi:10.1002/jmri.2149233. Cornfeld DM, Israel G, McCarthy SM, Weinreb JC. Pelvic imaging using a T1W fat-suppressed three-dimensional dual echo Dixon technique at 3T. J Magn Reson Imaging. 2008;28(1):121-127. doi:10.1002/jmri.2140234. Balaban M, Idilman IS, Toprak H, Unal O, Ipek A, Kocakoc E. The utility of diffusion-weighted magnetic resonance imaging in differentiation of endometriomas from hemorrhagic ovarian cysts. Clin Imaging. 2015;39(5):830-833. doi:10.1016/j.clinimag.2015.05.00335. Bonde A, Andreazza Dal Lago E, Foster B, Javadi S, Palmquist S, Bhosale P. Utility of the diffusion weighted sequence in gynecological imaging: review article. Cancers. 2022;14(18):4468. doi:10.3390/cancers1418446836. Busard MPH, Mijatovic V, van Kuijk C, Pieters-van den Bos IC, Hompes PGA, van Waesberghe JHTM. Magnetic resonance imaging in the evaluation of (deep infiltrating) endometriosis: the value of diffusion-weighted imaging. J Magn Reson Imaging. 2010;32(4):1003-1009. doi:10.1002/jmri.2231037. Raafat M, Talaat SH, Abdelghaffar SM, Ali EA. Can diffusion and T2 star-weighted magnetic resonance imaging aid in the diagnosis of ectopic endometrium? Egypt J Radiol Nucl Med. 2021;52(1):137. doi:10.1186/s43055-021-00513-1. # 38. McDermott S, Oei TN, Iyer VR, Lee SI. MR Imaging of malignancies arising in endometriomas and extraovarian endometriosis. Radiographics. 2012;32(3):845-863. doi:10.1148/rg.32311573639. Radzynski L, Boyer L, Kossai M, Mouraire A, Montoriol PF. Pictorial essay: MRI evaluation of endometriosis-associated neoplasms. Insights Imaging. 2023;14:144. doi:10.1186/s13244-023-01485-840. Benoit L, Arnould L, Choytel N, et al. Malignant extraovarian endometriosis: a review. Eur J Surg Oncol. 2006;32(1):6-11. doi:10.1016/j.ejso.2005.08.01141. Van Gorp T, Amant F, Neven P, Vergote I, Moerman P. Endometriosis and the development of malignant tumours of the pelvis. A review of literature. Best Pract Res Clin Obstet Gynaecol. 2004;18(2):349-371. doi:10.1016/j.bpob-gyn.2003.03.00142. Robinson KA, Menias CO, Chen L, et al. Understanding malignant transformation of endometriosis: imaging features with pathologic correlation. Abdom Radiol (NY). 2020;45(6):1762-1775. doi:10.1007/s00261-019-01914-743. Busard MPH, Pieters-van den Bos IC, Mijatovic V, Van Kuijk C, Bleeker MCG, van Waesberghe JHTM. Evaluation of MR diffusion-weighted imaging in differentiating endometriosis infiltrating the bowel from colorectal carcinoma. Eur J Radiol. 2012;81(6):1376-1380. doi:10.1016/j.ejrad.2011.03.03844. Navaneelan T. Trends in the incidence and mortality of female reproductive system cancers. 2015. Accessed July 11, 2024. Takeuchi M, Matsuzaki K, Bando Y, Harada M. Magnetic resonance imaging characteristics of polypoid endometriosis and review of the literature. J Obstet Gynaecol Res. 2022;48(10):2583-2593. doi:10.1111/jog.1536746. Bazot M, Gasner A, Lafont C, Ballester M, Darai E. Deep pelvic endometriosis: limited additional diagnostic value of postcontrast in comparison with conventional MR images. Eur J Radiol. 2011;80(3):e331-339. doi:10.1016/j.ejrad.2010.12.00647. Hausmann D, Perignon V, Grabherr R, et al. Can dynamic contrast-enhanced MRI contribute to improved assessment of rectosigmoid involvement in deep infiltrating endometriosis? In Vivo. 2021;35(4):2217-2226. doi:10.21873/invivo.1249448. Cancer Research UK. Ovarian cancer incidence statistics. May 15, 2015. Accessed July 11, 2024. Li Y, Song QW, Sun MV, et al. Use of enhanced T2 star-weighted angiography (ESWAN) and . 53. Takeuchi M, Matsuzaki K, Harada M. Susceptibility-weighted MRI of extra-ovarian endometriosis: preliminary results. Abdom Imaging. 2015;40(7):2512-2516. doi:10.1007/s00261-015-0378-z54. Zhang M, Bazot M, Tsatoumas M, Munro MG, Reinhold C. MRI of adenomyosis: where are we today? Can Assoc Radiol J. 2023;74(1):58-68. doi:10.1177/0846537122111419755. Gutzeit A, Binkert CA, Koh DM, et al. Evaluation of the anti-peristaltic effect of glucagon and hyoscine on the small bowel: comparison of intravenous and intramuscular drug administration. Eur Radiol. 2012;22(6):1186-1194. doi:10.1007/s00330-011-2366-156. Coutinho A, Bittencourt LK, Pires CE, et al. MR imaging in deep pelvic endometriosis: a pictorial essay. Radiographics. 2011;31(2):549-567. doi:10.1148/rg.31210514457. Schneider C, Oehmke F, Tinneberg HR, Krombach GA. MRI technique for the preoperative evaluation of deep infiltrating endometriosis: current status and protocol recommendation. Clin Radiol. 2016;71(3):179-194. doi:10.1016/j.crad.2015.09.01458. Botterill EM, Esler SJ, McIlwaine KT, et al. Endometriosis: does the menstrual cycle affect magnetic resonance (MR) imaging evaluation? Eur J Radiol. 2015;84(11):2071-2079. doi:10.1016/j.ejrad.2015.08.00359. Foti PV, Farina R, Palmucci S, et al. Endometriosis: clinical features, MR imaging findings and pathologic correlation. Insights Imaging. 2018;9(2):149-172. doi:10.1007/s13244-017-0591-060. Munn Z, Jordan Z. Interventions to reduce anxiety, distress and the need for sedation in adult patients undergoing magnetic resonance imaging: a systematic review. Int J Evid Based Healthc. 2013;11(4):265-274. doi:10.1111/1744-1609.1204561. Enders J, Zimmermann E, Rief M, et al. Reduction of claustrophobia during magnetic resonance imaging: methods and design of the “CLAUSTRO” randomized controlled trial. BMC Med Imaging. 2011;11:4. doi:10.1186/1471-2342-11-462. Wild M, Pandhi S, Rendle J, Swift J, Ofuasia E. MRI for the diagnosis and staging of deeply infiltrating endometriosis: a national survey of BSGE accredited endometriosis centres and review of the literature. Br J Radiol. 2020;93(1114):20200690. doi:10.1259/bjr.2020069063. Sheikh-Sarraf M, Nougaret S, Forstner R, Kubik-Huch RA. Patient preparation and image quality in female pelvic MRI: recommendations revisited. Eur Radiol. 2020;30(10):5374-5383. doi:10.1007/s00330-020-06869-864. Rousset P, Bischoff E, Charlot M, et al. Bladder endometriosis: preoperative MRI analysis with assessment of extension to ureteral orifices. Diagn Interv Imaging. 2021;102(4):255-263. doi:10.1016/j.diii.2020.11.01165. Fiaschetti V, Crusco S, Meschini A, et al. Deeply infiltrating endometriosis: evaluation of retro-cervical space on MRI after vaginal opacification. Eur J Radiol. 2012;81(11):3638-3645. doi:10.1016/j.ejrad.2011.06.05866. Unlu E, Virarkar M, Rao S, Sun J, Bhosale P. Assessment of the effectiveness of the vaginal contrast media in magnetic resonance imaging for detection of pelvic pathologies: a meta-analysis. J Comput Assist Tomogr. 2020;44(3):436-442. doi:10.1097/RCT.000000000000101267. Chassang M, Novellas S, Bloch-Marcotte C, et al. Utility of vaginal and rectal contrast medium in MRI for the detection of deep pelvic endometriosis. Eur Radiol. 2010;20(4):1003-1010. doi:10.1007/s00330-009-1627-868. Hughes NJ, Kalkur S, Zhang J, Liyanage SH. Patient acceptability and quality of self-administered intravaginal gel for. # pelvic MRI. J Endometr Pelvic Pain Disord. 2022;14(1):6- 13. doi:10.1177/2284026521106522369. Engelacre C, Poncelet E, Durot C, Dohan A, Rousset P, Hoeffel C. Pelvic MRI: is endovaginal or rectal filling needed? Korean J Radiol. 2018;19(3):397- 409. doi:10.3348/kjr.2018.19.3.39770. Ciggaar IA, Henneman ODF, Oei SA, Vanhooymissen IJSML, Blikkendaal MD, Bipat S. Bowel preparation in MRI for detection of endometriosis: comparison of the effect of an enema, no additional medication and intravenous butylscopolamine on image quality. Eur J Radiol. 2022;149:110222. doi:10.1016/j.ejrad.2022.11022271. Mattes LA, Goncalves MO, Andres MP, et al. Structured ultrasound and magnetic resonance imaging reports for patients with suspected endometriosis: guide for imagers and clinicians. J Minim Invasive Gynecol. 2019;26(6):1016- 1025. doi:10.1016/j.jmig.2019.02.01772. Feldman MK, VanBuren WM, Barnard H, Taffel MT, Kho RM. Systematic interpretation and structured reporting for pelvic magnetic resonance imaging studies in patients with endometriosis: value added for improved patient care. Abdom Radiol (NY). 2020;45(6):1608- 1622. doi:10.1007/s00261- 019- 02182- 173. Tuncyurek O, Garces- Descovich A, Jaramillo- Cardoso A, et al. Structured versus narrative reporting of pelvic MRI in .	None	None	None
22c1bad6266145e69ea286161db70c88	2025+ISUOG／ESGO共识声明	超声引导下妇科肿瘤活检	# ISUOG/ESGO Consensus Statement on ultrasound-guided biopsy in gynecological oncology\. D. Fischerova1,\, F. Planchamp2, J.L. Alcazar3,20, P. Dundr4, E. Epstein5, A. Felix6,7, F. Fruhauf1, G. Garganese8,9, I. Salvesen Haldorsen10,21, D. Jurkovic11, R. Kocian1, D. Lengyel12,22, F. Masticilini8, A. Stepanyan13, M. Stukan14,15, S. Timmerman16, T. Vanassche17, Z. Yuan Ng18, U. Scovazzi19. Available online xxx. ABSTRACT. The Inttio f ound in d g wth th f g g 16 xpers who t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t. The objective of this Consensus Statement is to assist clinicians, including gynecological sonographers, gynecological oncologists and radiologists, to achieve the best standards of practice in ultrasound- guided biopsy procedures. ISUOG/ESGO nominated a multidisciplinary international group of 16 experts who have demonstrated leadership in the use of ultrasound- guided biopsy in the clinical management of patients with gynecological cancer. In addition, two early- career gynecological fellows were nominated to participate from the European Network of Young Gynae Oncologists (ENyG) within ESGO and from ISUOG. The group also included a patient representative from the European Network of Gynaecological Cancer Advocacy Groups. The document is divided into six sections: (1) general recommendations; (2) image- guided biopsy (imaging guidance, sampling methods); (3) indications and contraindications; (4) technique; (5) reporting; and (6) training and quality assurance. To ensure that the statements are evidence- based, the current literature was reviewed and critically appraised. Preliminary statements were drafted based on this review of the literature. During a conference call, the whole group discussed each preliminary statement, and a first round of voting was carried out. The group achieved consensus on all 46 preliminary statements without the need for revision.. These ISUOG/ESGO statements on ultrasound- guided biopsy in gynecological oncology, together with a summary of the evidence supporting each statement, are presented herein. This Consensus Statement is supplemented by detailed narrated videoclips presenting different approaches and indications for ultrasound- guided biopsy, a patient leaflet, and an extended version which includes a detailed review of the evidence.. Keywords:. Ultrasound- guided biopsy; Gynecologic oncology; Consensus Statement. INTRODUCTION. There has been increasing use of minimally invasive diagnostic procedures in gynecological oncology in recent years, which confers the advantage of accurate diagnosis while minimizing procedure- associated morbidity.1- 3 These diagnostic procedures are often indispensable to inform patient management in situations such as unresectable advanced gynecological cancer or suspected disease recurrence. There are no specific guidelines available to assist gynecologists in performing ultrasound- guided biopsies. Real- time biopsy guidance using a transvaginal or transrectal . In parallel with the introduction and improvement of ultrasound diagnosis in gynecological oncology, a broad spectrum of minimally invasive ultrasound- guided diagnostic and therapeutic procedures. # has been developed (Table 1). Ultrasound- guided diagnostic procedures include core- needle (tru- cut) biopsy and fine- needle aspiration. Any ultrasound- guided intervention changes the ultrasound modality from a risk- free method to an intervention that carries risk and therefore needs its own clear standard operating procedure. Given an appropriate indication and careful execution, these procedures are well- tolerated by patients and less risky and costly than surgical procedures.4- 11 Until recently, common practice has been for ultrasound- guided procedures to be performed mainly by interventional radiologists. There have been many useful guidelines published on the topic of interventional ultrasound using the percutaneous ultrasound- guided approach. However, these guidelines focusing on intra- abdominal interventions (including biopsies of, for example, liver, kidney, pancreas, spleen) do not address the pelvic organs full.12- 16 Moreover, the transvaginal approach is rarely included in the armamentarium of radiologists. Scientific data from radiologic departments suggest underestimation of the applicability of transvaginal ultrasoundguided biopsy in a gynecological oncology setting, with limited case numbers over a long period of time.17. The lack of information on best practice in ultrasound- guided biopsy in gynecology and the growing need for this service in every gynecological oncology center led to the initiation of the process that produced this Consensus Statement. The objective of this work is to assist clinicians, including gynecological sonographers, gynecological oncologists and radiologists, to achieve the best standards of practice in diagnostic (biopsy) procedures. It includes the following sections:. 1. General recommendations 2. Image-guided biopsy (imaging guidance modalities, adequacy, accuracy, diagnostic yield and complications of sampling methods) 3. Indications and contraindications 4. Technique 5. Reporting 6. Training and quality assurance. A comprehensive summary of published data for all six sections is provided in the extended version of this Consensus Statement (Appendix S1). The technique is demonstrated in Videoclips S1- S3 and the indications for biopsy in Videoclip S4. A sample patient leaflet is also provided to aid counseling and communication with patients (Appendix S2).. Supplementary video related to this article can be found at . RESPONSIBILITIES. The present series of statements represent a consensus of the authors regarding their currently accepted approaches for ultrasound- guided biopsy, based on the available literature and evidence. Any clinician applying or consulting these statements is expected to use independent medical judgment in the context of individual clinical circumstances to determine all patients' care and treatment. These statements are presented without any warranty regarding their content, use or application and the authors disclaim any responsibility for their application or use in any way.. METHODS. These consensus statements on ultrasound- guided biopsy in gynecological oncology were developed using an eight- step process, chaired by Professor Daniela Fischerova (Figure S1 in Appendix S1).. Aiming to assemble a multidisciplinary international group, the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) and the European Society of Gynaecological Oncology (ESGO) nominated 16 experts who have demonstrated leadership in the use of ultrasound- guided biopsy in the clinical management of patients through research, administrative responsibilities and/or committee membership. Altogether, six gynecologists with special interest in ultrasonography, one radiologist, two pathologists, one cardiologist and six gynecological oncologists were included. In addition, two early- career gynecological fellows with special interest in ultrasound- guided biopsy were nominated to participate from the European Network of Young Gynae Oncologists (ENYGO) within ESGO and from ISUOG, to form the final working group of 18 participants. The participants did not represent the societies from which they were elected but were asked to base their decisions on their own experience and expertise. A patient representative from the European Network of Gynaecological Cancer Advocacy Groups (ENGAGE Co- Chair) was also included in the group.. An initial conference call including the whole group was held to facilitate introductions, as well as to review the purpose and scope of the Consensus Statement. The proposed document was divided into six sections, each with a lead author and a working group according to previously expressed interests and expertise. To ensure that the statements were evidence- based, the current literature was reviewed and critically appraised. A systematic literature review of relevant studies published between technique inception and 2023 was carried out using the MEDLINE database (Appendix S3). The literature search was limited to publications in the English language. Priority was given to high- quality systematic reviews, meta- analyses and validating cohort studies, although studies with lower levels of evidence were also evaluated. The search strategy excluded editorials, letters and case reports. The reference list of each identified article was reviewed for other potentially relevant articles. The results of the literature search were distributed to the whole group, including electronic full- text versions of each article. One of the authors (F.P.) provided methodology support throughout the process, but did not participate in the voting on the consensus statements. Thus, there were 18 voting participants.. Each lead author, following discussion with their working group, was responsible for drafting preliminary statements after a review. # of the relevant literature. These were then circulated to the entire group prior to a second conference call. During the second conference call, the whole group discussed each preliminary statement, and a first round of binary voting (agree/disagree) was carried out for each potential statement. All 18 participants took part in each vote, but they were permitted to abstain from voting if they felt they had insufficient expertise to agree/disagree with the statement or if they had a conflict of interest that could influence their vote. Statements would be removed if a consensus among group members was not reached. The voters had the opportunity to provide comments or suggestions together with their votes, which would require revision of the statement and a second round of voting. The group achieved consensus on all 46 preliminary statements without the need for revision and another round of voting. Thus, based on the results of the first round of voting, the statements were finalized. In the main text of this Consensus Statement, we present a summary of the supporting evidence, the finalized series of statements, and their levels of evidence and grades as described in Appendix S4. The extended version of this Consensus Statement, including a detailed evidence review, is provided in Appendix S1.. RESULTS. General recommendations. The purpose of performing minimally invasive biopsy procedures in gynecology is to obtain a representative tissue sample from suspected pathological processes to enable a morphological examination.11,17- 20 These biopsy procedures are particularly useful for patients not eligible for more invasive interventions or to accelerate the process from diagnosis to therapy without the need for a period of recovery.7,18 In addition, in the era of personalized medicine, obtaining biopsy samples from gynecological cancers, either primary or recurrent disease, has become increasingly important to obtain material for predictive testing and to plan subsequent targeted therapy.5,11,21,22 Evidence indicates that repeated biopsies at different times are well tolerated by patients.4,5,23 The indication for biopsy, performance and reporting of biopsy, and final interpretation of results according to the clinical and imaging findings require multidisciplinary team expertise. This was recently highlighted by a National Cancer Institute panel, which reported that improving the communication between radiologists, oncologists and pathologists increases the probability of obtaining fit- for- purpose samples for pathological diagnosis and/or genomic analysis.24 Multidisciplinary team discussion is also required if procedure- related risk is deemed to be high or in the event of inconclusive biopsy results, to discuss possible alternative diagnostic options.25. Statement 1: Image- guided tumor biopsy forms an integral component of the individualized treatment of gynecological cancers, especially in the context of disseminated disease, recurrence or the presence of surgical contraindications.. Level of evidence:3b Grade of statement: C Consensus: yes, . Statement 2: Expertise and effective communication within a multidisciplinary team are essential to determine a proper indication and technical execution of an ultrasound- guided biopsy, to . Level of evidence:3b Grade of statement: C Consensus: yes, . Image-guided biopsy (image-guidance modalities, adequacy, accuracy, diagnostic yield and complications of sampling methods). Image- guided biopsy aims to sample a target tissue using a guided approach, by ultrasound or other imaging technology. Real- time biopsy guidance is essential to optimize tissue sample acquisition. Obtaining biopsy specimens which are suitable for histopathological and molecular analysis should be quick and minimally invasive, and should pose a low risk of procedure- related complications. Ideally, the procedure should be performed in the outpatient setting, to avoid delays in initiating appropriate treatment, while also ensuring diagnostic accuracy and safety.18,19,26. Image-guidance modalities. Ultrasound offers many benefits, including a low rate of false- negative biopsies and low rate of complications, wide availability, short procedure time, lack of ionizing radiation, portability and relatively low cost (Table S1 in Appendix S1).27 Crucially, it allows real- time intraprocedural visualization of the biopsy needle and target lesion, dynamic multiplanar vision (i.e. the ability to guide the procedure in almost any anatomical plane), high soft- tissue resolution (especially in the pelvis in the case of endovaginal/endocardial probe insertion) and the use of power or color Doppler, which are essential to achieve safe access to target lesions.18,26- 30 Doppler examination helps to visualize blood vessels and define the most suitable part of the tumor for biopsy. Alternatively, contrast- enhanced ultrasound can be used to evaluate the presence of vascularity as a sign of tumor tissue viability, especially in large intra- abdominal tumors with areas of necrosis.21,31,32 Ultrasound- guided procedures can be done utilizing a variety of transducers (endocavitary, convex array, linear array and sector, among others), allowing different approaches for biopsy- needle insertion (percutaneous, transvaginal, transcervical, transrectal) (Figure 1, Videoclips S1- S3).18,26,29 The safest path to the target lesion should be selected by avoiding non- target organs and blood vessels. For biopsy of pelvic lesions, the transvaginal approach is preferred for its good diagnostic yield and safety profile, and should be considered the first choice, even when other approaches are feasible.17,18. Within the pelvis, the transrectal biopsy approach offers a short distance to the target and visualization similar to that of the transvaginal approach, but is less comfortable for patients and carries the potential risk of bacterial contamination.33- 35 It is crucial to explain carefully the reasons for recommending a transrectal biopsy approach and to obtain the patient's explicit consent before this approach is used. In the transcervical biopsy approach, for ultrasound guidance, the probe is placed in the rectum or on the abdomen, while the biopsy needle is inserted transcervically through the endocervical canal and advanced through the uterine cavity (transcavitaly) to reach suspected uterine tumors without passing through the uterine serosa. This provides. # the advantage of an 'in- organ' biopsy, which is important to minimize the risk of spread of malignant tumor cells along the needle- biopsy tract. The adequacy of biopsy using a percutaneous approach, with or without a needle guide, is highly dependent on adequate acoustic conditions and the location of the target lesion. The main limitations of percutaneous ultrasound guidance are related to the possible difficulty in visualizing the tumor target or needle tip. This may occur when the distance between the target and the ultrasound probe is large, such as: in obese subjects or in the presence of high- volume ascites; when there is acoustic shadowing due to intestinal air or solid tissue, such as bone or calcified areas; or when the lesion is inaccessible due to critical or vulnerable anatomical structures.. When visualization at ultrasound examination is problematic, contrast- enhanced ultrasound, or coregistration (fusion imaging) of real- time ultrasound with acquired images from computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET), may be considered, although these require specialized software and equipment and are less widely used.. The next most commonly used imaging method after ultrasound is CT. It is a safe procedure with good diagnostic performance (accuracy estimates: 82–100%) but with major limitations related to the low tissue contrast, the need for patient fasting, the exposure to radiation and the risk of contrast- agent- related toxicity. MRI guidance, despite providing good soft- tissue resolution and having no risks associated with radiation exposure, is still used only rarely, as it requires special non- magnetic equipment and experienced operators. PET in combination with CT or MRI has also been proposed as guidance for biopsy; however, this is rarely used in gynecological practice.. Biopsy methods. Two main sampling techniques are commonly used in gynecological oncology practice, applied to different cases according to the . The use of biopsy specimens can also be extended to other clinical and research applications, such as molecular testing (e.g. complex genomic profiling by next- generation sequencing) and other analyses (e.g. assessment of stromal microenvironment) (Table 2).. Diagnostic performance of image- guided biopsy is evaluated using the following parameters: adequacy (sufficient material for diagnosis), accuracy (concordance with final pathology), safety (low risk of complications (Table S2 in Appendix S1)) and grading of diagnostic yield (detection rate and impact on management). The literature shows no substantial differences between core- needle biopsy and fine- needle aspiration with respect to the adequacy of specimens obtainable (tissue block from core- needle biopsy vs cytological smear from fine- needle aspiration, 84–100% vs 74–100% of procedures provide adequate material) and their accuracy for distinguishing between benign and malignant tumors (73–100% vs 73–99% accuracy) (Tables S3 and S4 in Appendix S1).. Core- needle biopsy is preferred, because it allows a tissue sample to be obtained and thus more accurate assessment of the histological type of the tumor (Figure 3, and Figures S3 and S4 in Appendix S1). This is due in particular to the fact that core- needle biopsy allows assessment of tumor architecture and the relationship between tumor and stroma, which is essential for correct. # diagnosis in some tumors.. Both techniques appear to be acceptable with regard to safety, with an overall rate of major complications of . It has been reported that increasing the biopsy core length (greater penetration depth), needle size (wider needles) and number of cores obtained (higher number of passes) directly influences the cancer detection rate, but may also lead to a greater risk of trauma and bleeding.. # of tissue is also likely to be sufficient for any other diagnostic purpose. For uterine mesenchymal tumors, the diagnostic yield reaches a plateau at three samples and does not appear to be improved by increasing the needle width greater than 18 G (Figure S3 in Appendix S1).72- 74 Effort should be made to target the most heterogeneous area within the mesenchymal tumor tissue to increase diagnostic yield. When lymphoma is suspected, core- needle biopsy may be considered as an alternative to the reference standard which is complete excision of the lymph node.26,75,76 In these cases, a similar strategy, using an 18- G needle with at least three passes through different regions of the lymph node or different lymph nodes, is recommended (Figure S4 in Appendix S1).77. Given the advantages of core- needle biopsy in gynecological oncology, the main emphasis in the following sections will be on this technique, although the indications, contraindications, biopsy technique, reporting and training are very similar to those for fine- needle aspiration.4,11,18- 21. Statement 3: Image- guided biopsy is a minimally invasive technique, which provides a safer alternative to surgery. It is effective in obtaining an adequate tissue sample for an actionable pathological result which can be used to guide treatment.. Level of evidence: 3a Grade of statement: B Consensus: yes, . Statement 4: Among all imaging methods, ultrasound should be considered the first choice for guidance of biopsy, because it provides real- time imaging, is versatile and allows a multiplanar view.. Level of evidence: 3b Grade of statement: B Consensus: yes, . Statement 5: Ultrasound- guided biopsy can be performed with different approaches (transvaginal, transcervical, transrectal and percutaneous), using different transducers (endocavitary, convex array and linear array) according to the safest path to the target and its best visualization.. Level of evidence: 4 Grade of statement: B Consensus: yes, . # Statement 6: Doppler examination may help to define the most suitable viable part of the tumor for biopsy. Alternatively, contrast- enhanced ultrasound can be used.. Level of evidence:4 Grade of statement: C Consensus: yes, . Statement 7: In poorly visualized targets or when there are inconclusive findings with B- mode ultrasound, alternative imaging techniques to guide the biopsy, such as contrast- enhanced ultrasound or novel image fusion methods, can be employed.. Level of evidence:3a Grade of statement: C Consensus: yes, . Statement 8: Other imaging guidance (CT, MRI or PET/CT) may be chosen according to lesion accessibility and/or to overcome suboptimal acoustic conditions.. Level of evidence:4 Grade of statement: C Consensus: yes, . Statement 9: Two sampling techniques can be used for imageguided biopsy: core- needle biopsy and fine- needle aspiration.. Level of evidence:3a Grade of statement: B Consensus: yes, . Statement 10: The choice between core- needle biopsy and fine- needle aspiration depends on the specific clinical situation. However, core- needle biopsy is preferable to fine- needle aspiration, as it allows tumor tissue to be obtained for biopsy examination, including ancillary methods, and it provides a larger volume of tumor tissue for multiple analyses, including molecular methods.. Level of evidence:4 Grade of statement: C Consensus: yes, . Statement 11: In order to ensure adequacy, high accuracy, diagnostic yield and safety of core- needle biopsy, it is recommended to obtain at least two 10- mm- long cylinders using a needle that is . Level of evidence:3b Grade of statement: C Consensus: yes, . Indications and contraindications. It is essential to ensure proper patient selection and valid clinical indication prior to image- guided biopsy. The main indications and contraindications of core- needle biopsy are shown in Table 3 and. Figure S6 in Appendix S1.13,15,78,79 The indications for core- needle biopsy are demonstrated in different clinical cases in Videoclip S4.. The risk of the diagnostic procedure should not outweigh the potential benefits.13,15 Studies investigating core- needle biopsy in gynecology demonstrated a low rate of major bleeding complications . For patients on anticoagulation and/or antiplatelet therapy, the decision whether to withhold the therapeutic agents prior to biopsy and, if so, for what length of time depend on the patient's overall clinical status and thromboembolic and bleeding risks and on the procedure- associated bleeding risk.78,81 If the procedural bleeding risk is low, most anticoagulant/antiplatelet drugs can be continued. In such a situation, the patient's thromboembolic risk does not influence the clinical decision.82 Conversely, for patients at elevated risk of bleeding and for procedures with high risk of bleeding, additional factors need to be considered, including the type of anticoagulant and antiplatelet agents used (Table 5).80,83- 86 The final decision regarding the periprocedural management of anticoagulation, including the use of bridging therapy with low- molecular- weight heparin, should take into account and balance all the above risks.87 High procedural risk, elevated bleeding risk, difficulty of access to the target lesion and other situations which increase biopsy- related risk should be noted prior to the procedure. Such procedures should be performed by the most experienced operators, and the use of a thin core needle (18 G) should be considered to minimize tissue trauma.. Statement 12: Core- needle biopsy should be performed if it is clinically meaningful for the patient's management. Indications include: (1) to determine primary origin in patients with inoperable/ non- resectable disease or unknown primary cancer; (2) to stage disease; (3) to identify residual or suspicious recurrent disease; (4) to establish the nature and histological diagnosis of suspicious uterine mesenchymal tumors; (5) to investigate suspicious cervical, vaginal or endometrial lesions and others; and (6) for targeted treatment including research purposes.. Level of evidence:2b Grade of statement: B Consensus: yes, . # Statement 13: There are no specific absolute contraindications to core- needle biopsy in gynecology/gynecological oncology. However, risks and benefits should be balanced, considering the patient's comorbidities and medications, difficulty of access to the target lesion and risk of tumor spillage.. Level of evidence:4 Grade of statement: C Consensus: yes, . Statement 14: Any decision about periprocedural management should be based on a thorough assessment of the patient's overall clinical status, including thromboembolic and bleeding risks and the procedure- associated risks.. Level of evidence:3b Grade of statement: C Consensus: yes, . Statement 15: Clinicians performing a biopsy should be aware of potential complications and routinely implement strategies to avoid or minimize them.. Level of evidence:2b Grade of statement: B Consensus: yes, . Statement 16: Regarding procedure- related risk of major bleeding, core- needle biopsies in gynecology/gynecological. # oncology are considered to be low risk (risk of major bleeding complication . Level of evidence: 4 Grade of statement: C Consensus: yes, . # Statement 17: Regarding patient- related bleeding risk, women with coagulative disorders or on anticoagulative therapy and those with thrombocytopenia or on antiplatelet therapy are considered at elevated risk of major bleeding.. Level of evidence:4 Grade of statement: C Consensus: yes, . Statement 18: Withholding and restarting anticoagulant and/or antiplatelet drugs should be carried out according to recommendations of relevant specialists. The patient's individual thromboembolic risk should also be taken into consideration.. Level of evidence:4 Grade of statement: C Consensus: yes, . Statement 19: For procedures with low risk of bleeding planned in patients with no or minimal bleeding risk factors, a screening coagulation panel is not required. These procedures can be performed by adequately trained sonographers (level II minimum).. Level of evidence:3a Grade of statement: C Consensus: yes, . Statement 20: For procedures with high risk of bleeding or in patients at elevated risk of bleeding, a screening coagulation panel (platelet count, hemoglobin, INR/PT and aPTT) is routinely recommended. These procedures should be performed by expert sonographers (level III).. Level of evidence:4 Grade of statement: C Consensus: yes, . Statement 21: For all procedures with high risk of bleeding, recommended laboratory thresholds to minimize the risk of major bleeding complications are . Level of evidence:4 Grade of statement: C Consensus: yes, . Statement 22: For patients at elevated risk of bleeding undergoing procedures with low risk of major bleeding complications, laboratory thresholds are . Level of evidence:4 Grade of statement: C Consensus: yes, . Technique. Ultrasound- guided biopsy should be performed only by a physician familiar with the indications, contraindications, limitations, typical findings and possible side effects of the procedure. The physician should be trained in gynecological oncology sonography as well as ultrasound- guided core- needle biopsy and related safety issues, and should undertake quality assurance and control measures routinely. The choice of approach to guide the needle's path, caliber of the needle and penetration depth are dependent on the specific purpose and the safety of the procedure. The necessary instruments for core- needle biopsy are shown in Figure 4. The steps for performing ultrasound- guided biopsy are described in Table 6 and Videoclips S1- S3. The characteristics and an illustration of different approaches are presented in Table S5 and Figures S7 and S8 in Appendix S1.. Statement 23: Before the procedure, the indication should be verified and the biopsy deemed to be clinically relevant.. Level of evidence:3b Grade of statement: C. # # Table 6 (continued). - Patient identifiers- Clinical data, radiological data and patient history- Details of requesting doctor- Biopsy site, type of specimen and fixative used- Clinical impression and differential diagnosis- Previous histopathological findings (if any)- Specific requests to the pathologist according to clinical need (immunohistochemistry, molecular analysis or other processing) Attach pathology request form to specimen container.. This table was formulated using both data from the literature and by consensus of the study authors.108- 113 TC, transcervical; TR, transrectal; TV, transvaginal.. Consensus: yes, . Statement 24: An ultrasound examination should be performed to select the safest path to the target lesion and subsequent approach.. Level of evidence:4 Grade of statement: C Consensus: yes, . Statement 25: Core- needle biopsy in gynecology does not require specific preparation such as fasting, or use of laxatives or antiflattulent medication.. Level of evidence:4 Grade of statement: C Consensus: yes, . Statement 26: The preparation should include providing the patient with procedure- related information, obtaining informed consent and identifying relevant medical history.. Level of evidence:3b Grade of statement: C Consensus: yes, . Statement 27: Bleeding risk assessment should be performed according to the procedure- related and patient- related risks of bleeding.. Level of evidence:4 Grade of statement: C Consensus: yes, . Statement 28: Antibiotic prophylaxis is not recommended routinely, as the risk of infectious complications is low . Level of evidence:4 Grade of statement: C Consensus: yes, . Statement 29: Maximum attention should be paid to minimize patient discomfort, pain and anxiety throughout the procedure.. Level of evidence:2b Grade of statement: B Consensus: yes, . Statement 30: Basic disinfection procedures are sufficient. It is important to perform hand antisepsis. Clean handling of sterile instruments (needles) is recommended. All instruments should be laid out on a sterile trolley. The disinfected ultrasound probe should be covered with a sterile, disposable protective cover.. Level of evidence:4 Grade of statement: C Consensus: yes, . Statement 31: The biopsy device, type of single- use disposable needles, needle gauge, needle length and penetration depth should be based on the planned biopsy route.. Level of evidence:3b Grade of statement: B Consensus: yes, . Statement 32: The puncture site should be cleansed with an antiseptic solution for transvaginal and percutaneous approaches.. Level of evidence:4 Grade of statement: C Consensus: yes, . Statement 33: Local anesthetic reduces discomfort caused by larger needle size and should be administered for all percutaneous biopsies. It can be administered optionally for transvaginal, transcervical and transrectal approaches.. Level of evidence:2b Grade of statement: B Consensus: yes, . Statement 34: While performing the biopsy, the tip of the needle must be visible under continuous ultrasound control. If not, the procedure should be abandoned.. Level of evidence:5 Grade of statement: D Consensus: yes, . # Statement 35: Specimen fixation is critical for proper assessment of the tissue. Core- needle biopsy specimen should be placed immediately in a formalin fixative solution and sent to the pathology laboratory. Optimal fixation is essential for immunohistochemical and molecular analysis. A minimum fixation time of . Level of evidence:3b Grade of statement: B Consensus: yes, . Statement 36: Ultrasound should be used at the end of the procedure to detect any signs of bleeding. Mild internal bleeding usually resolves spontaneously.. Level of evidence:5 Grade of statement: D Consensus: yes, . Statement 37: Following uncomplicated procedures, there is no need for prolonged monitoring. The patient should be informed about the symptoms of potential complications and provided with a written information sheet.. Level of evidence:4 Grade of statement: C Consensus: yes, . Reporting. Biopsy documentation. A detailed report regarding the procedure must be given to the patient and to her healthcare provider. The following data should be included: indication(s) for biopsy, preprocedural ultrasound findings, procedure description including biopsy device used, collection guidance (ultrasound) and approach (transvaginal/transrectal/transcervical/percutaneous), biopsy site, number of samples, adequacy of the sample, difficulty of the procedure, patient tolerance, any complications and when the results are expected to be communicated. Biopsy results may be available between . Specimen and biopsy data sheet. The request form for pathological examination should contain the patient's history and clinical and radiological information in detail, including clinical diagnosis and differential diagnosis. In some situations, the biopsy is taken from multiple sites, thus all specimens must be sent separately, clearly labeled, and documented in the request form. The patient details on the specimen container and request form must be correct and match. Data on the request form and specimen containers are checked in the pathology laboratory before handling the specimen and when reporting. A detailed pathological report will then be discussed by the multidisciplinary team, taking into consideration all relevant patient data (Table S6 in Appendix S1).. Statement 38: The request form for pathological examinations should contain:. - Patient identifiers, including age, gender and unique ID of the patient, which can differ among countries. - All relevant clinical, radiological and patient history data. - Details of the requesting doctor and contact details in case of emergency. - The biopsy site(s), clinical impression and differential diagnosis. - Previous histopathological findings (if any). - The type of specimen and type of fixative used. - The patient details on the request form and specimen container must be correct and match. - Level of evidence: 4 - Grade of statement: C - Consensus: yes, . Statement 39: The pathology report form should contain:. - Identification of the patient. - Type of specimen and sample description. - Type of processing (for fine-needle aspiration). - Evaluation of the sample adequacy. - Limitations. - Diagnosis. - Optional: microscopic description, immunohistochemical/immunocytochemical findings, molecular testing findings, differential diagnosis, recommendation. - Level of evidence: 3a - Grade of statement: B - Consensus: yes, . Statement 40: Analytic turnaround time of 2 days (business days counted only) after receipt of the sample at the pathology laboratory is required. If ancillary techniques such as immunohistochemistry are needed, the turnaround time is longer.. Level of evidence:3b Grade of statement: B Consensus: yes, . Training and quality assurance. To maintain high quality and safety of image- guided biopsies, competent operators who are skilled in invasive diagnostic techniques and anatomy are required. This is crucial when accessing deep lesions in the female pelvis, which can be challenging due to the proximity of the major vessels, urinary bladder, ureters and bowel. The operator should possess a high- level understanding of both the theoretical and practical aspects of the imaging modality used for guidance and the interventional procedures. Developing the necessary skills and techniques involves a steep learning curve, and sufficient volume is required to maintain operator confidence. Similarly, competent pathologists and cytopathologists are essential for accurate reading of the biopsy samples.. For gynecologists/radiologists. Learning interventional ultrasound should always be built upon the knowledge of diagnostic (non- interventional) ultrasound imaging of the area of interest. It is advisable that core- needle biopsy is performed by examiners who already have an intermediate (European Federation of Societies for Ultrasound in Medicine and Biology level II) or advanced (level III) level of competence in gynecological ultrasound imaging. For radiologists, training in interventional radiology is recommended. Studies indicate that the learning. # curve can be shortened by adding simulator- based or phantombased training to clinical practice.98 Web- based teaching resources are also available.9 Clinical training should begin under supervision by an experienced operator and with 'simple' core- needle biopsy or fine- needle aspiration procedures. When performing percutaneous biopsy, commercially available sonographic guides attached to the transabdominal probe may provide more confidence regarding the needle position inside the body and are recommended for less experienced operators.100,101 There is a lack of large studies assessing the impact of examiner experience and training on complication rate when performing pelvic core- needle biopsy. We recommend carrying out at least 20 core- needle biopsy procedures, supervised by an experienced operator, before embarking on the procedure unsupervised.. After achieving competence, operators are recommended to continue to perform these procedures on a regular basis. It is therefore reasonable to adopt the same recommended minimal number, i.e. 20 core- needle biopsies annually per operator.. There should be regular audits of sampling accuracy for malignant tissue and the rate of inadequate specimens submitted within each practice providing biopsy services.95,102 Similarly, reviews of complications and patient experience should be conducted, to identify and address the need for improvement and additional training of staff. Preprocedural provision of patient information, periprocedural psychosocial support, provision of a comfortable environment and postprocedural monitoring of patientreported complications may improve patients' experience.. For pathologists. Pathologists reporting biopsy samples should have completed their postgraduate training in pathology, according to the national authority rules.103,104. Training competencies that pathologists should demonstrate include: (1) the ability to produce clear, concise, comprehensive and timely written reports for surgical pathology and cytopathology; (2) the ability to incorporate the diagnostic, prognostic or predictive implications of molecular pathology tests into an integrated pathology report; (3) promotion of health informatics to improve the quality of patient care and optimize patient safety; (4) participation in quality control, quality assurance and quality improvement initiatives; (5) utilization of genetic testing resources effectively to balance costs with potential utility of result; (6) alerting of the treating physician when inheritable conditions are identified (e.g. genetic disease that may affect the patient's family members).. To maintain competence in pathological reporting, pathologists or cytopathologists should be part of a gynecological oncology multidisciplinary team in a high- volume center. As part of quality assurance, participation in accredited programs for all aspects of tissue diagnostics, for both clinical and non- clinical laboratories and organizations, is recommended.105- 107. Statement 41: Training for operators:. - Training to at least intermediate (level II) or advanced (level III) level in gynecological ultrasound imaging is essential before commencing training in interventional ultrasound. - Training in ultrasound-guided biopsy using phantoms and/or computer simulation improves skills and is useful prior to clinical training. - Targeted training using directly supervised procedures is essential to reduce the risk of complications and increase sample adequacy.. - The needle-guiding system should be used by trainees for all approaches. At least 20 directly supervised core-needle biopsies using a needle guide should be performed before starting unsupervised work. Level of evidence:4 Grade of statement: B Consensus:yes, . Statement 42: Maintaining competence for operators:. Maintain competency by completing or supervising a minimum of 20 core- needle biopsy procedures annually. Seek support from a more experienced operator when difficulties are anticipated or encountered. Level of evidence:3b Grade of statement:C Consensus:yes, . Statement 43: Audit for operators:. Regular audits should be undertaken within each practice providing biopsy services to ensure sampling adequacy and diagnostic yield, and to record complications and patient experience. Level of evidence:3b Grade of statement:C Consensus:yes, . Statement 44: Training for pathologists/cytopathologists:. Biopsies should be read by a pathologist or cytopathologist who has completed his/her postgraduate training in pathology/cytopathology. The rules are defined by national authorities and can differ among countries.. Level of evidence:5 Grade of statement:C Consensus:yes, . Statement 45: Maintaining competence for pathologists/ cytopathologists:. Ultrasound- guided biopsies should be performed in a specialized center with access to a pathologist or cytopathologist with experience in gynecological oncology as part of a multidisciplinary team. Level of evidence:5 Grade of statement:C Consensus:yes, . Statement 46: Audit for pathologists/cytopathologists:. Accreditation of laboratories should be in accordance with national or international standards (such as ISO15189). The rules of accreditation are defined by national authorities in each country and can differ. Level of evidence:5 Grade of statement:C Consensus:yes, . CONCLUSION. Core- needle biopsy under ultrasound guidance is an emerging, minimally invasive outpatient procedure. It allows collection of. # high- quality specimens for histopathological diagnosis, immunohistochemical analysis and molecular testing, enabling the timely commencement of appropriate treatment within a specialized cancer center. Performing core- needle biopsy and interpreting its results requires appropriate expertise and should be conducted within a multidisciplinary team. Under these circumstances, it is simple, quick, effective and safe. To ensure patient- centered care, standard operational procedures, including measures to minimize patient anxiety, pain and risk, are essential. This Consensus Statement aims to facilitate the implementation of this technique in gynecological oncology practice and improve patient outcomes.. Author Affiliations. 1Department of Gynecology, Obstetrics and Neonatology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic 2Institut Bergonie, Bordeaux, France 3University of Navarra, Pamplona, Spain 4Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic 5Department of Clinical Science and Education, Karolinska Institutet, Sodersjukhuset, Stockholm, Sweden 6iNOVA4Health, NOVA Medical School, Faculdade de Ciencias Medicas, NMS, FCM, Universidade NOVA de Lisboa, Lisbon, Portugal 7Instituto Portugues de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal 8Unita Operativa di Chirurgia dei Organi Genitali Esterni Femminili, Divisione di Ginecologia Oncologica, Dipartimento o Scienze della Salute della Donna, del Bambino e di Sanita Pubblica, Fondazione Politecnico Universitario A. Gemelli IRCCS, Rome, Italy 9Gemelli Women Health Center for Digital and Personalized Medicine, Dipartimento Scienze della Vita e Sanita Pubblica, Universita Cattolica del Sacro Cuore, Rome, Italy 10Mohn Medical Imaging and Visualization Centre (MMV), Department of Radiology, Haukeland University Hospital, Bergen, Norway 11EGA Institute for Women's Health University College London, London, UK 12Department of Gynaecology, National Institute of Oncology, Budapest, Hungary 13Gynecologic Oncology Service, Nmri Medical Center, National Institute of Health, Yerevan, Armenia 14Department of Gynecological Oncology, Pomeranian Hospitals (Szpitale Pomorskie), Gdynia, Poland 15Clinic of Surgical Oncology, Faculty of Health Sciences with the Institute of Maritime and Tropical Medicine, Medical University of Gdansk, Gdansk, Poland 16Department of Development and Regeneration, KU Leuven, Leuven, Belgium 17Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium 18Department of Gynaecological Oncology, KK Women's and Children's Hospital, Singapore 19Academic Unit of Obstetrics and Gynecology, Hospital Polyclinic San Martino and University of Genoa, Genoa, Italy 20Hospital QuirónSalud, Málaga, Spain 21Section for Radiology, Department of Clinical Medicine, University of Bergen, Bergen, Norway 22Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary. Disclosure P.D. is a member of advisory boards for AstraZeneca, Merck, MSD, GlaxoSmithKline, Amgen, Janssen, Cilag and Roche, and has received grants for travelling from AstraZeneca. A.F. has participated as a member of the speakers bureau for GlaxoSmithKline. T.V. is a member of advisory boards for Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Sanofi Aventis, and Leo Pharma. D.F., F.P., J.L.A., E.E., F.F., G.G., I.S.H., D.J., R.K., D.L., F.M., A.S., M.S., S.T., Z.Y.N. and U.S. report no conflicts of interest.. Acknowledgments This article has been simultaneously co- published in Ultrasound in Obstetrics & Gynecology and International Journal of Gynecological Cancer. The articles are identical except for minor stylistic and spelling differences in keeping with each journal's style. Any citation can be used when citing this article. We thank Lucia Zanchi (MD, University of Pavia, Pavia, Italy),. Natacha Sousa (MD, Hospital de Braga, Braga, Portugal) and Kim Hulscher (ENGAGE Co- Chair, European Network of Gynaecological Cancer Advocacy Groups) for intellectual contribution and suggestions during proofreading, Adam Preisler (Polygoniq Studio, Prague, Czech Republic) for providing the illustrations and Tomas Herrmann (Institute of Scientific Information, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic) for videoclip editing. We thank ISUOG and ESGO for their support, especially Kamila Macku and Lenka Trestrova, who provided invaluable logistical and administrative support throughout the process. We wish also to express sincere gratitude to Maciej Malecki (University Hospital Leuven, Leuven, Belgium) for providing technical support during the voting process. All costs relating to the development process were covered by ISUOG and ESGO. There was no external funding for the development process or manuscript production.. 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f0503c818b8844d4ae5dad7a018c2716	2025+意大利指南	多囊卵巢综合征患者不孕症的诊断和管理	# Diagnosis and management of infertility in patients with polycystic ovary syndrome (PCOS): guidelines from the Italian Society of Human Reproduction (SIRU) and the Italian Centers for the Study and Conservation of Eggs and Sperm (CECOS Italy). Stefano Palomba<sup>1*</sup>, Giuseppe Seminara<sup>2</sup>, Francesco Tomei<sup>3</sup>, Angelo Marino<sup>4</sup>, Giuseppe Morgante<sup>5</sup>, Domenico Baldini<sup>6</sup>, Enrico Papaleo<sup>7</sup>, Guglielmo Ragusa<sup>8</sup>, Antonio Aversa<sup>2</sup>, Adolfo Allegra<sup>4</sup>, Antonino Guglielmino<sup>9</sup>, Edgardo Somigliana<sup>10</sup> and the SIRU- CECOS Working Group on Italian Guideline for Infertility in PCOS. Abstract. The polycystic ovary syndrome (PCOS) is a multifaceted disease of the reproductive age associated with several comorbidities including infertility. Very few documents regarding the management of the infertility in women with PCOS, including guidelines, position papers and consensus conferences, are available in the literature. The Italian Law indicates that health professionals must comply with the recommendations set out in the guidelines developed by public and private bodies and institutions, as well as scientific societies and technical- scientific associations of the health professions, except for specific cases. Unfortunately, no guideline for the diagnosis and the management of infertility in women with PCOS is currently available in Italy. In 2024, the Italian Society of Human Reproduction (SIRU) and the Italian Centers for the Study and Conservation of Eggs and Sperm (CECOS Italy) pointed out the need to produce Italian guidelines on this topic and established a specific working group to develop those guidelines. The working group chose to adapt the guideline with highest quality to the Italian context rather than developing a de novo document. The International Evidence- Based Guideline for the Assessment and Management of PCOS guidelines were selected. All recommendations regarding the diagnosis and the management of women with PCOS and infertility extracted, adapted to the Italian context and improved incorporating new recommendations or practical comments and suggestions where needed.. Keywords Guidelines, Infertility, Management, Polycystic ovary syndrome, PCOS. # Introduction. Polycystic ovary syndrome (PCOS) is a multifaced disease of the reproductive age associated with several comorbidities, including infertility [1]. Patients with PCOS frequently undergo diagnostic and therapeutic procedures for reproductive problems [2]. Ovulatory dysfunction, one of the criteria for PCOS diagnosis [3], is frequently associated with menstrual irregularities, especially oligo- amenorrhea, and is considered the main cause of infertility in women with PCOS [4]. However, several experimental and clinical findings underline that the fertility in women with PCOS may be also affected for abnormalities in endometrial [5] and oocyte [6] competence, irrespectively from ovulatory dysfunction.. Recent data seem to confirm that a correct therapeutic flow- chart, as suggested by available recommendations, can optimize the reproductive chances in women with PCOS allowing to reach a long- term fecundability like or slightly higher in comparison with women without the disease [7, 8].. In Italy, the Law n. 24 2017, indicates that health professionals must comply, except for specific cases, with the recommendations set out in the guidelines developed by public and private bodies and institutions as well as scientific societies and technical- scientific associations of the health professions. These guidelines must be developed following a scientific methodology [9] and approved by the National Center for the Clinical Excellence, Quality and Safety of the Care (CNEC, Centro Nazionale per l'Eccellenza Clinica, la Qualita e la Sicurezza delle Cure), an institutional organism directly referring to the Ministry of Health.. No specific guideline for the diagnosis and management of infertility in PCOS is currently available in Italy [10]. In 2015, an endocrinological and gynecological consensus statement of the Italian Society of Endocrinology was published [11]. That consensus statement reported in a narrative fashion few generic recommendations about the treatment of infertility in women with PCOS. In addition, the two main therapeutical innovations in the treatment of infertile women with PCOS, i.e. letrozole administration as ovulation inductor and GnRH antagonist use in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI), were not contemplated [12].. Based on these considerations, the Italian Society of Human Reproduction (SIRU, Societa Italiana di Riproduzione Umana) and the Italian Centers for the Study and Conservation of Eggs and Sperm (CECOS Italy, Centri Conservazione Ovociti e Spermatozoi - Italia) decided to produce an official document for the diagnosis and management of infertility in women with PCOS to be adopted in Italy. This report aims to detail the methodological process followed and the results obtained.. Methods. The methodology used agreed with the provisions of the National System Guidelines System (SNLG, Sistema Nazionale Linee- Guida) and all the steps were carried out in accordance with the specific Manual of CNEC (https:// www.iss.it/documents/20126/7949296/Manuale+Metod ologico+- +marzo+2023. pdf/01f4bc8e- f3e6- 66ec- bbe1- e80186908c6c?t=1679921943422).. The initial idea to develop the guidelines was spread and shared among the members of the Society during the VII National Congress of the SIRU (Bari, 11th- 13th April 2024) and was approved. A formal proposal for sharing and participation was made to CECOS Italy that approved the collaboration. In consideration of the experience previously acquired [10], no specific funding was defined and the SIRU and the CECOS Italy themselves participated to cover the expenditures.. SIRU and CECOS Italy steering committees defined an integrated Working Group on Italian Guideline for Infertility in PCOS. That working group was defined according to principles of professional and specialist representation and excluding components that declared any potential important conflict of interest. It included citizens' and patients' associations, different professions (including lawyer, biologist, doctor, and midwife), and medical specialties (including medical genetics, obstetrics and gynecology).. The complete methodological process of elaboration of the guideline followed the "GRADE- ADOLOPMENT approach" based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence to Decision (EtD) frameworks [13]. It was performed through meetings conducted in teleconferences for reducing the expenses/costs. Any disagreements were resolved by consensus methods.. According to the methodology already followed and previous experience [10], the Working Group chose to adapt, rather than to develop, available guideline of high methodological quality to the Italian context. Thus, the Working Group systematically searched recent available guidelines on the diagnosis and management of infertility in women with PCOS, assessed their quality, and selected the guidelines with the highest quality to use as reference. The search was conducted using key terms such as "polycystic ovary syndrome" or "PCOS" matched with "guideline", "consensus conference", "position paper", "position statement", "scientific statement" or "recommendation" on main websites, including PubMed, Web of Science, Google Scholar, Cochrane Library. All articles that referred to guidelines for the diagnosis and management of infertility in women with PCOS were screened without language restriction reading the full text. The. # guidelines intercepted were then rated for quality using the Italian version [14] of the Appraisal of Guidelines for Research and Evaluation II (AGREE II) scoring system [15, 16], and the item with the highest AGREE II score was chosen as the reference document. That reference document was adapted ( pagine/569/it/agree- ii) deleting or changing recommendations considered not relevant, repetitive, debatable, or not/poorly applicable to the Italian context, and reporting the specific reason for each change (deletion or change). No specific attempt was planned and made to update the reference document.. The revised document was analyzed to identify new issues not assessed in the reference guideline, not previously addressed in the SIRU- guidelines for the diagnosis and management of infertility in Italy [10], and potentially relevant for the Italian context and from a clinical point of view. New clinical issues were defined using specific clinical questions and developed according to the Population, Intervention, Comparison and Outcomes (PICO) model [17]. Specifically, the "Population" comprised of infertile patients with PCOS, the "Intervention" encompassed each strategy, procedure, or treatment employed to diagnose or treat infertility in women with PCOS, the "Comparison" involved neither intervention (diagnostic and/or therapeutic) nor a placebo/sham arm or another potentially active intervention, and the "Outcomes" were ranked by importance in evaluating intervention effects case- by- case using three main categories, i.e. critical, important but not critical, and of limited importance.. Using the same websites mentioned above, a further extensive search of published studies was performed for each item using the hierarchy of evidence starting from systematic reviews and meta- analyses, randomized controlled trials (RCTs) up to experimental data or expert opinion, and the highest evidence was used. Each study was analyzed, and the certainty of evidence and the study quality was defined using specific tools. Data published up to August 19, 2024, were collected, analyzed, interpreted, and integrated into the referral guideline.. Each new item of the document was reported according to the GRADE system ( to rate the quality of evidence and the strength of recommendations using a direct and standardized language and graphical descriptions to improve simplicity and transparency. The methodology used was optimized after the selection of the available guideline to harmonize the document (Table 1).. The text including specific recommendations for infertile patients with PCOS was summarized integrating the different items in operative and integrated document for its largest diffusion and applicability.. The document was subsequently subjected to a public consultation with the aim of collecting feedback on the preliminary version of the recommendations, as well as to evaluate their applicability and feasibility. Specifically, the document was announced by email to SIRU and CECOS Italy members and potential stakeholders. Then, it was published for two weeks on the SIRU's website ( to receive further comments and additional suggestions. The participants to public consultation included bioethicists, biologists, endocrinologists, gynecologists, oncologists, immunologists, midwives, psychologists, citizens and patient representatives, and pharmaceutical and biomedical industry representatives. It was asked to provide personal, professional, and contact data, and to list any changes suggested to the clinical recommendations, indicating the related reasons, including possible obstacles to their application, and any useful reference. The Working Group analyzed the suggested changes and integrated those deemed appropriate in the final document.. After the public consultation, the document was submitted to an external review to improve the quality of the document and to collect feedback on the draft version of the recommendations. Two well- recognized international experts were identified, contacted and asked to revise the final document. The Working Group assessed the suggestions and comments received and included those considered relevant in the final version of the document.. The SIRU decided to update the guidelines every two years to integrate new scientific evidence to support modifying pre- existing recommendations or to draft novel recommendations, and to submit the final document to Reproductive Biology and Endocrinology for the normal process of international peer reviewing.. Results. The Fig. 1 details the entire methodological process followed to produce an official document for the diagnosis and management of infertility in women with PCOS in Italy.. After online search and evaluation of the available guidelines, the Recommendations from the 2023 International Evidence- based Guideline for the Assessment and Management of PCOS [3] resulted to have the highest AGREE II score and were selected as the guiding reference for this project. The full details on the methodological aspects, the technical evidence and administrative reports of those recommendations are available online on the following website: www.monash.edu/medicine/mchri/pcos.. These recommendations [3] are international guidelines involving all aspects of the PCOS, organized in sections, and covering five specific areas of interest,. # # including screening, diagnostic and risk assessment and life stage; psychological features and models of care; lifestyle management; management of nonfertility features; and assessment and management of infertility.. Initially, the Working Group extrapolated section number five titled "Assessment and management of infertility". This section was used as the initial document. Other recommendations originally reported in the other sections [3] were selected if considered relevant for making more complete the new document. The total items initially included in the analysis were 116. Specifically, 60 and 56 items for Sect. 5 and for all other sections, respectively, were extracted.. All original recommendations extracted were analyzed for relevance and applicability to the Italian context, contextualized to adult infertile women and accordingly modified. Redundant/repetitive items were also deleted. After the revision process, a total of 93 items remains in the document (Supplementary Table 1). These items resulted modified from the original version in 24 . Secondly, the Working Group identifies new issues not assessed in the reference guideline [3] and considered potentially relevant from a clinical point of view. Table 2 reports these new critical topics as questions and their answers. As already mentioned in the Methods section, . The public consultation of the SIRU- CECOS Italy guideline was attended by external reviewers, including biologists, medical doctors (endocrinologists and gynecologists), midwives, psychologists, representatives of citizens, patients, and pharmaceutical and biomedical industries. During this phase, the items previously defined have been subject to minor revisions; however, their total number and content were unchanged.. After revisions following the public consultation, the document underwent further revision by two international experts. Specifically, dr. Raoul Orvieto (Sheba Institute of Tel Aviv, Israel) and dr. Didier Dewailly (University of Lille, France) were invited to revise the recommendations/suggestions adapted from reference document (Supplementary Table 1) and the new recommendations/ suggestions (Table 2). The Working Group prepared a comprehensive response to the Reviewers' comments. The Reviewers' suggestions were included when considered relevant. Specifically, a total of 38 suggested revisions were addressed, of which 24 were accepted and 14 rejected. After international experts' revisions, 5 and 3 items were modified and deleted, respectively, from the adapted items of the referral document [3], while 3. # Table 2 New issues not specifically assessed in the reference guideline [3] and considered potentially relevant from a clinical point of view. These new topics are presented as clinical questions. 1.How to diagnose PCOS?. 1a.EBR - The diagnosis of PCOS should be based on the presence of at least two of the following three criteria: (a) clinical and/or biochemical hyperandrogenism, (b) polycystic ovarian morphology, and (c) irregular menstrual cycles, after exclusion of other causes of hyperandrogenism and/or irregular menses.. 2.Is hysteroscopic assessment needed in infertile patients with PCOS?. 2a.CR - Hysteroscopic assessment should not be considered as routinary evaluation for diagnostic work- up in infertile patients with PCOS. 2b.CR - Hysteroscopic assessment should be considered in infertile women with PCOS according to clinical data and ultrasonographic findings in consideration of the higher risk of endometrial premalignant/malignant diseases.. 3.Which are the protocols for administering CC, letrozole, and metformin?. 3a.CR - CC should be administrated using an escalation regimen, starting from lowest up to highest doses (from 50 mg to 150 mg daily) for five days, starting in the early proliferative phase . 3c.CR - Metformin is available as immediate- and extended- release formulation: - immediate- release metformin could be taken at meals, beginning with 500 mg at dinner for 3- 4 days, and then increasing by 500 mg every 3- 4 days up to a maximal dosage of 2000 mg daily. - extended- release metformin (1000 mg) could be taken with the evening meal and a second dose could be added after one week with breakfast up to a maximal dosage of 2000 mg daily.. 4.How to define CC and letrozole resistance?. 4a.PP - CC resistance should be diagnosed when 150 mg daily of CC for 5 days is ineffective to induce ovulation. 4b.PP - Letrozole resistance should be diagnosed when 7.5 mg daily of letrozole for 5 days is ineffective to induce ovulation.. 5.How to define CC and letrozole failure?. 5a.EBR - CC failure should be diagnosed in case of reproductive failure after 6 ovulatory cycles. 5b.PP - Letrozole failure should be diagnosed when reproductive failure occurs after 6 ovulatory cycles.. 6. Should oral ovulation induction treatments be started after progesterone withdrawal bleeding?. 6a.EBR - After pregnancy exclusion, oral ovulation inductors could be administered without progesterone- induced uterine bleeding.. 7. Should oral ovulation induction treatments be monitored in women with PCOS?. 7a.PP - Ovulation induction treatments with CC with or without metformin should be monitored to minimize the risk of multiple pregnancy. 7b.CR - Ovulation induction with gonadotropin for non- IVF cycles should be strictly monitored to cancel cycles with a multiple follicular growth (more than two follicles) and minimize the risk of multiple pregnancy.. 8. How many ovulatory cycles should be performed before moving onto the next therapeutic step?. 8a.PP - Before considering an IUI or IVF program, a total of 6- 12 ovulatory cycles should be completed according to clinical context, risks, benefits, costs, timing and patient's individual preferences. Consider a period of 6 ovulatory cycles for women older than 35 years.. 9. How to treat the infertile PCOS patient after failure of the ovulation induction?. 9a.PP - Women with PCOS who did not achieve a pregnancy after 12 ovulatory cycles should be considered as patients with unexplained infertility, considering treatment options in relation to clinical context, risks, benefits, costs, timing and patient's individual preferences.. 10. Is it necessary to perform male and tubal factor assessments before ovulation induction in anovulatory women with PCOS?. 10a.CR - Semen analysis should be considered before starting ovulation induction treatment in infertile patients with PCOS and anovulation. 10b.CR - Tubal patency testing should be considered on an individual basis before starting ovulation induction treatment in infertile patients with PCOS and anovulation.. 11. Are there add-on treatments to improve oocyte and endometrial quality in infertile women with PCOS?. 11a.EBR - No specific add- on treatments should be considered to improve oocyte and endometrial quality in infertile women with PCOS.. 12. Could letrozole be administrated in combination with metformin?. 12a.EBR - Letrozole could be considered in women with PCOS under metformin administration.. 13. Should all the PCOS diagnostic criteria be assessed in the PCOS infertile patient?. 13a.PP - The assessment of all the diagnostic criteria of PCOS could be beneficial for optimizing counselling and management in fertile patients with PCOS. AMH could be useful in infertility setting for driving specific strategies of treatment.. 14. Are progestins administration useful for inhibiting the LH surge in women with PCOS undergoing IVF cycles? 14a.EBR - In IVF cycles, where freeze-all protocol (also called "cycle segmentation") is planned, the administration of progestins could be considered to inhibit the LH surge, potentially reducing the costs.. # further new items were included and extrapolated from the same publication [3]. Eleven and 2 items were modified and deleted, respectively, from new recommendations included by the Working Group.. Following the revisions, a total of 93 recommendations were adapted from the PCOS International Guidelines [3]. A total of 14 new topics were analyzed, leading to the definition of 21 new clinically relevant recommendations (Table 2).. Finally, the Working Group sub- grouped all recommendations (integrating the new items to the main document) in specific sections (Table 3): 1. PCOS diagnosis, 2. preconception risk factors in PCOS (including the screening/diagnosis of PCOS- related comorbidities), 3. interventions for improving general and reproductive health in infertile women with PCOS, 4. general principles of infertility management in women with PCOS (including infertility assessment, drugs administration, complementary interventions/drugs), 5. treatment of PCOS- related anovulatory infertility (first- , second- , and third- line treatments), and 6. IVF in women with PCOS. An algorithm (Algorithm 1) for the management and treatment of infertile patients with PCOS has been implemented (Fig. 2).. The final document and Algorithm 1 are reported in Italian to prevent potential inaccuracies in translation, respectively in Supplementary Table 2 and Supplementary Fig. 1.. Discussion. Clinical guidelines are considered a valuable tool for enhancing the quality of care provided to patients. By consolidating evidence on specific topics, these guidelines facilitate clinicians in making timely, evidence- based decisions for their patients. They support the adoption of effective interventions while discouraging those that are ineffective or potentially harmful. Moreover, guidelines can enhance patient empowerment, shape public policy, standardize care practices, and inform the creation of performance measures and evaluations for diseases [18]. Additionally, clinical guidelines contribute to reducing healthcare costs by streamlining decision- making processes, minimizing unnecessary interventions, and promoting the efficient use of resources while maintaining high standards of care [18]. Evidence- based guidelines are indispensable for assisting physicians, policymakers, and patients across all medical fields, with particular significance in reproductive medicine. These general concepts on the need of clinical guidelines are particularly important for PCOS. In fact, PCOS is a condition with a considerable economic impact, in relation to the therapies needed to promote fertility in these patients [19]. Indeed, in about . Despite these premises, few specific documents have been produced about the management of PCOS- related infertility [11, 12, 20], whereas many others focused on PCOS management included only brief sections on ovulation induction in this clinical context [21- 24]. In 2019, the International PCOS Network produced a specific document of evidence- based recommendations regarding the assessment and treatment of infertility in patients with PCOS [25]. More recently, an updated document on all clinical aspects of PCOS was published [3]. A specific section was dedicated to the management of infertility in women with PCOS [3]. The critical analysis of these documents suggests that, over the last few years, evidence- based medicine has driven new approaches for treating infertility in patients with PCOS, changing rapidly and deeply the clinical practice [12].. The need to translate and adapt international guidelines to each regional context has already been expressed by the authors themselves, to close the knowledge- practice gap, guide future research and enhance positive impact on the health of women with PCOS [26]. However, this wish has not always been fulfilled and national scientific societies have simply adopted these guidelines by providing a summary of them from a local perspective [27, 28]. Considering the absence of guidelines adapted to the Italian context for infertility in PCOS [10], SIRU and CECOS Italy decided to produce an official document for the diagnosis and management of infertility in women with PCOS following a methodology already adopted for the realization of the "2024 SIRU NICE- adapted guidelines" [10]. Simply providing a lay summary or referring to the original guideline is in our opinion a lost opportunity. A formal adaptation of the guidelines to the local context is a stronger and wiser approach.. Current paper provides a detailed account of the process involved in adapting to the Italian context the recommendations included in the "2023 International Evidence- based Guideline for the Assessment and Management of PCOS" related to infertility diagnosis and management (section number five of the original document [3]), which resulted to have the highest AGREE II score after our research and evaluation. A methodological process clinically important to produce the Italian Guidelines was to define other recommendations not reported in the section dedicated to the clinical management of infertile patients with PCOS if considered relevant for making complete the new document. After the first phase of adaptation of international recommendations and drafting of new ones, they were subjected to another two phases of revision. The first regarded the inclusion of new recommendations considered clinically. # Table 3 Final document from the SIRU and the CECOS Italy on the diagnosis and management of infertility in patients with PCOS in Italy including published/adapted and new recommendations after integration of the comments/suggestions from public consultation and international experts. 1.PCOS diagnosis. 1.1 General principles. 1.1.1 EBR - The diagnosis of polycystic ovary syndrome (PCOS) should be based on the presence of at least two of the following three criteria: (a) clinical and/or biochemical hyperandrogenism, (b) polycystic ovarian morphology (PCOM), and (c) irregular menstrual cycles, after exclusion of other causes of hyperandrogenism and/or irregular menses.. 1.1.2 PP - The assessment of all the diagnostic criteria of PCOS could be beneficial for optimizing counselling and management infertile patients with PCOS. Anti- Mullerian hormone (AMH) could be useful in infertility setting for driving specific strategies of treatment.. 1.2 Irregular cycles and ovulatory dysfunction. 1.2.1 CR - Irregular menstrual cycles are defined as 3- year post menarche to perimenopause less than 21 or more than 35 days or less than 8 cycles per year. 1.2.2 CR - Ovulatory dysfunction should be confirmed by measuring serum progesterone levels 7 days before expected menses in the cycle in infertile patients with PCOS, even if menstrual cycles appear normal. A cut- off value of . 1.3 Biochemical hyperandrogenism. 1.3.1.1 EBR - Healthcare professionals should use total testosterone and sex hormone binding globulin (SHBG) to assess biochemical hyperandrogenism as free androgen index (FAI, total testosterone . 1.3.1.2 CR - In obese patients, free testosterone measurement should be preferred to FAI to assess biochemical hyperandrogenism.. 1.3.2 EBR - If FAI is not elevated, healthcare professionals could consider measuring androstenedione and dehydroepiandrosterone sulfate (DHEAS), recognizing their lower specificity and age- related decline in DHEAS levels.. 1.3.3 EBR - Laboratories should use validated, highly accurate tandem mass spectrometry (LC- MS/MS) assays for measuring total testosterone and if needed, for androstenedione and DHEAS. Free testosterone should be assessed by calculation, equilibrium dialysis, or ammonium sulfate precipitation.. 1.3.4 EBR - Direct immunoassays (eg, radiometric and enzyme linked) for assessing total or free testosterone have limited accuracy and demonstrate poor sensitivity and precision for diagnosing hyperandrogenism in PCOS.. 1.3.5.5. PP - Other causes of hyperandrogenemia, including ovarian and adrenal neoplastic growth, congenital adrenal hyperplasia, Cushing's syndrome, ovarian hyperthecosis, latrogenic causes, and syndromes associated with severe insulin resistance, should be excluded.. 1.4 Clinical hyperandrogenism. 1.4.1 EBR - The presence of hirsutism should be considered predictive of biochemical hyperandrogenism and PCOS in adults.. 1.4.2 EBR - Healthcare professionals could recognize that female pattern hair loss and acne in isolation (without hirsutism) are relatively weak predictors of biochemical hyperandrogenism.. 1.4.3 CR - A modified Ferriman Gallwey score (mFG) should be used to detect hirsutism, depending on ethnicity, acknowledging that self- treatment is common and can limit clinical assessment.. 1.4.4 PP - Healthcare professionals should:. - Consider the Ludwig or Olsen visual scales for assessing female pattern hair loss. - Note that there are no universally accepted visual instruments for assessing the presence of acne. - Recognize that women commonly treat clinical hyperandrogenism cosmetically, diminishing their apparent clinical severity. - Note that only terminal hairs need to be considered in defining hirsutism, and these can reach . 1.5 Ultrasound and PCOM. 1.5.1 EBR - Follicle number per ovary (FNPO) should be considered the most effective ultrasound marker to detect PCOM in adults.. 1.5.3 CR - PCOM criteria should be based on follicle excess (FNPO) and/or ovarian enlargement.. 1.5.4 CR - FNPO . 1.5.5 CR - OV . # Table 3 (continued). 1.5.7 PP - There is a need for training in careful and meticulous follicle counting per ovary and clear standardized protocols are recommended for PCOM reporting on ultrasound including at a minimum: - Last menstrual period (or stage of cycle). - Transducer band width frequency. - Approach / route assessed. - Total number of . 2.Preconception risk factors in PCOS. 2.1 Cardiovascular disease risk. 2.1.1 EBR - Women with PCOS should be considered at increased risk of cardiovascular disease and potentially of cardiovascular mortality.. . 2.1.2 EBR - All infertile women with PCOS should be assessed for cardiovascular disease risk factors.. 2.1.3 CR - All infertile women with PCOS, regardless of age and body mass index (BMI), should have a lipid profile (cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol and triglyceride level) at diagnosis.. 2.1.4 CR - All infertile women with PCOS should have blood pressure measured. 2.2 Impaired glucose tolerance and type 2 diabetes risk. 2.2.1 EBR - Women with PCOS, regardless of age and BMI, have an increased risk of impaired fasting glucose, impaired glucose tolerance and type 2 diabetes.. 2.2.2 EBR - Glycemic status should be assessed at diagnosis in all infertile patients with PCOS.. 2.2.3 EBR - All infertile women with PCOS should undergo a 75- g oral glucose tolerance test (OGTT).. 2.3 Endometrial hyperplasia and cancer. 2.3.1 EBR - Health care professionals should be aware of the increased risk of endometrial hyperplasia and cancer in premenopausal women with PCOS.. 2.3.2 FP - When excessive endometrial thickness is detected, consideration of a biopsy with histological analysis and withdrawal bleed is indicated.. 2.3.3 CR - Hysteroscopic assessment should not be considered as routinary evaluation for diagnostic work- up in infertile patients with PCOS.. 2.3.4 CR - Hysteroscopic assessment should be considered in infertile women with PCOS according to clinical data and ultrasonographic findings in consideration of the higher risk of endometrial premalignant/malignant diseases.. 2.4 Depression and anxiety. 2.4.1 EBR - Healthcare professionals should be aware of the high prevalence of moderate to severe depressive symptoms and infertile women with PCOS should be screened for depression during psychological counselling for infertility work- up.. 2.4.2 EBR - Infertile women with PCOS should be screened for anxiety during psychological counselling for infertility work- up.. 2.4.3 CR - If moderate or severe depressive or anxiety symptoms are detected, practitioners should further assess, refer appropriately, or offer treatment.. . 2.5 Psychosexual function. 2.5.1 CR - Healthcare professionals could consider the multiple factors that can influence psychosexual function in PCOS including higher weight, hirsutism, mood disorders, infertility and PCOS medications.. 2.6 Eating disorders. 2.6.1 EBR - Eating disorders and disordered eating should be considered, regardless of weight, in all infertile patients with PCOS.. 3. Interventions for improving general and reproductive health in infertile women with PCOS. 3.1 Lifestyle management. 2.1.1 EBR - Lifestyle intervention (exercise alone or multiscomponent diet combined with exercise and behavioral strategies) should be recommended for all women with PCOS, especially for infertile patients, for improving metabolic health including central adiposity and lipid profile.. 3.1.2 CR - Healthy lifestyle behaviors encompassing healthy eating and/or physical activity should be recommended in all infertile patients with PCOS to optimize general health, quality of life, body composition and weight management (maintaining weight, preventing weight gain and/or modest weight loss).. 3.2 Behavioral strategies. 3.2.1 CR - Lifestyle interventions could include behavioral strategies such as goal- setting, self- monitoring, problem solving, assertiveness training, reinforcing changes, and relapse prevention, to optimize weight management, healthy lifestyle and emotional wellbeing in all infertile patients with PCOS.. # Table 3 (continued). 3.3 Dietary intervention. 3.3.1 EBR - There is no evidence to support anyone type of diet composition over another for anthropometric, metabolic, hormonal, reproductive or psychological outcomes. . 3.3.2 CR - Any diet composition consistent with population guidelines for healthy eating will have health benefits and, within this, healthcare professionals should advise sustainably healthy eating tailored to individual preferences and goals. . 3.4 Exercise intervention. 3.4.1 EBR - There is a lack of evidence supporting any one type and intensity of exercise being better than another for anthropometric, metabolic, hormonal, reproductive or psychological outcomes. . 3.5 Anti-obesity pharmacological agents. 3.5.1 CR - Anti- obesity medications including liraglutide, semaglutide, tirzepatide, both glucagon- like peptide- 1 (GLP- 1) receptor agonists and orlistat, could be considered, in addition to active lifestyle intervention, for the management of obesity in infertile patients with PCOS before starting a reproductive program. . 3.5.2 CR - We recommend using anti- obesity agents in PCOS only before starting a reproductive program. 3.5.3 PP - Effective contraception is needed in women with PCOS under GLP- 1 receptor agonists administration until their discontinuation and before infertility treatment, as pregnancy safety data are lacking.. 3.6 Anti-androgen pharmacological agents. 3.6.1 PP - All infertile patients with PCOS should stop anti- androgen agents before starting a reproductive program.. 3.7 Inositol. 3.7.1 EBR - Inositol exerts limited clinical benefits including ovulation and body weight loss in infertile patients with PCOS. . 3.7.2 EBR - Inositol in any form alone, or in combination with other therapies, should be considered experimental in women with PCOS- related infertility. The benefits and risks remain too uncertain to recommend inositol as a fertility treatment. . 3.7.3 PP - There is limited evidence with uncertain results, on the effect of inositol on ovulation, clinical pregnancy, and live birth rates.. 3.7.4 PP - The side effects and safety profile of inositol are currently unknown.. 3.7.5 PP - Women should be informed that these agents can have limited regulation with variable dose, quality, consistency, and possible combination with other agents.. 3.8 Bariatric/metabolic surgery. 3.8.1 CR - Bariatric/metabolic surgery could be considered to improve weight loss, hypertension, diabetes (prevention and treatment), hirsutism, irregular menstrual cycles, ovulation, and pregnancy rates in severely obese patients with PCOS before to start a reproductive program. . 3.8.2 CR - Infertile patients with PCOS who underwent a bariatric/metabolic surgery can start a reproductive program only after achieving stable weight, usually one- year post- surgery, to minimize significantly increased risk of growth restriction, prematurity, small for gestational age, pregnancy complications, and prolonged hospitalization of the infant. . 3.9 Pregnancy outcomes. 3.9.1 EBR - Women with PCOS are at higher risk for pregnancy complications, and an appropriate counselling should be provided to all infertile patients with PCOS. . 3.9.2 EBR - Pregnant women with PCOS have an increased risk of gestational weight gain, miscarriage, gestational diabetes, hypertension in pregnancy and preeclampsia, intrauterine growth restriction, small for gestational age babies and low- birth weight, preterm delivery, and Caesarean section. . 4. General principles of infertility management in women with PCOS. 4.1 Premises. 4.1.1 PP - The strategy for the management and treatment of infertile patients with PCOS should be guided by the reported algorithm (Algorithm 1).. 4.1.2 PP - Those with PCOS should be reassured that pregnancy can often be successfully achieved either naturally or with assistance.. 4.1.3 PP - Prenatal vitamin supplementation should be commenced with ovulation induction therapy aligned to routine preconception care.. 4.1.4 PP - Pregnancy should be ruled out before initiating ovulation induction therapy.. 4.1.5 PP - The use of lactazol and metformin is off- label in Italy. However, these medications may be considered after discussing the evidence, potential concerns, and side effects with the patient.. 4.1.6 PP - Any potential congenital anomalies should be reported to the Italian Drug Agency.. 4.2 Preconception risk factors. 4.2.1 EBR - Women with PCOS should be counselled on the adverse impact of excess weight on clinical pregnancy, miscarriage, and live birth rates, following infertility treatment. . 4.2.2 CR - Consistent with routine preconception care, in women with PCOS planning pregnancy, weight, blood pressure, smoking, alcohol, diet and nutritional status, folate supplementation (higher dose in those with BMI . 4.2.3 PP - A healthy lifestyle, the prevention of excess weight gain, and the optimization of the preconception risk factors are needed before starting a reproductive program.. # Table 3 (continued). 4.2.4 PP - The body weight and the height should be measured, and BMI calculated for all infertile patients with PCOS at initial visit. 4.2.5 PP - Comorbidities, such as diabetes, high blood pressure, anxiety, depression, and other mental health conditions, should be screened and opti mally managed. All infertile patients with PCOS should be counselled regarding the risk of adverse pregnancy outcomes. 4.2.6 EBR - No specific add- on treatments should be considered to improve oocyte and endometrial quality in infertile women with PCOS.. 4.3 Preliminary analyses. 4.3.1 CR - Semen analysis should be considered before starting ovulation induction treatment in infertile patients with PCOS and anovulation. 4.3.2 CR - Tubal patency testing should be considered on an individual basis before starting ovulation induction treatment in infertile patients with PCOS and anovulation.. 5. Treatment of PCOS-related anovulatory infertility. 5.1 Ovulation induction treatment. 5.1.1 PP - Before considering an intrauterine insemination (IUI) or in vitro fertilization (IVF) program, a total of 6- 12 ovulatory cycles should be completed according to clinical context, risks, benefits, costs, timing and patient's individual preferences. Consider a period of 6 ovulatory cycles for women older than 35 years.. 5.1.2 PP - Women with PCOS who did not achieve a pregnancy after 12 ovulatory cycles should be considered as patients with unexplained infertilit considering treatment options in relation to clinical context, risks, benefits, costs, timing and patient's individual preferences.. 5.1.3 EBR - After pregnancy exclusion, oral ovulation inductors could be administered without progesterone- induced uterine bleeding.. 5.2 Letrozole. 5.2.1 EBR - Letrozole should be the first- line pharmacological treatment for ovulation induction in infertile anovulatory women with PCOS, with no other infertility factors.. 5.2.2 EBR - Letrozole should be used rather than clomiphene citrate (CC) in women with PCOS with anovulatory infertility.. 5.2.3 CR - Letrozole should be administered in an escalation regimen, starting from lowest to the highest doses (from 2.5 mg to 7.5 mg daily) for five days, starting in the early proliferative phase . 5.2.4 PP - Letrozole resistance should be diagnosed when 7.5 mg daily of letrozole for 5 days is ineffective to induce ovulation.. 5.2.5 PP - Letrozole failure should be diagnosed when reproductive failure occurs after 6 ovulatory cycles.. 5.2.6 EBR - Letrozole could be considered in women with PCOS under metformin administration.. 5.2.7 PP - The use of letrozole for ovulation induction is off- label in Italy and other ovulation induction agents could be used.. 5.3 CC. 5.3.1 CR - CC should be administrated using an escalation regimen, starting from lowest up to highest doses (from 50 mg to 150 mg daily) for five days, starting in the early proliferative phase . 5.3.2 PP - CC resistance should be diagnosed when 150 mg daily of CC for 5 days is ineffective to induce ovulation.. 5.3.3 EBR - CC failure should be diagnosed in case of reproductive failure after 6 ovulatory cycles.. 5.3.4 PP - Ovulation induction treatments with CC with or without metformin should be monitored to minimize the risk of multiple pregnancy.. 5.4 Metformin. 5.4.1 EBR - Metformin could be used alone in young (less than 30 years) women with PCOS with anovulatory infertility.. 5.4.2 CR - Metformin is available as immediate- and extended- release formulation: - immediate- release metformin could be taken at meals, beginning with 500 mg at dinner for 3- 4 days, and then increasing by 500 mg every 3- 4 days up to a maximal dosage of 2000 mg daily. - extended- release metformin (1000 mg) could be taken with the evening meal and a second dose could be added after one week with breakfast up to a maximal dosage of 2000 mg daily.. 5.4.3.1 PP - Women should be counselled as to potential mild gastrointestinal side- effects with metformin.. 5.4.3.2 PP - Healthcare and resource burden including monitoring, travel, and costs are lower with metformin.. 5.5 CC and metformin. 5.5.1.1 EBR - CC could be used in preference to metformin in women with PCOS with anovulatory infertility.. 5.5.1.2 PP - The risk of multiple pregnancies is increased with CC use (alone or in combination with metformin), and therefore, CC should require ultra- sound monitoring.. 5.5.2 EBR - CC combined with metformin could be used rather than CC alone in women with PCOS with anovulatory infertility.. 5.6 Gonadotropins. 5.6.1 EBR - Gonadotropins could be considered rather than the combination of CC and metformin in women with PCOS who are anovulatory and infertile with CC resistance and no other infertility factors.. 5.6.2 EBR - Gonadotropins could be used in women with PCOS who are anovulatory and infertile, with CC and/or letrozole resistance and no other infertility factors.. # Table 3 (continued). 5.6.3 EBR - Gonadotropins could be second- line pharmacological therapy for women with PCOS who are anovulatory and infertile, with no other infertility factors and who have failed first line oral ovulation induction.. 5.6.4 PP - Where gonadotropins are to be prescribed, the following should be considered:. - Cost of the intervention for ovulation induction.- Expertise required for the use of the intervention for ovulation induction.- The degree of intensive ultrasound monitoring that is required.- A low-dose step-up gonadotropin protocol should be used to optimize the chance of monofollicular development.- Implications of potential multiple pregnancy.. 5.6.5 PP - There appears to be no difference in the clinical efficacy of the available gonadotropin preparations.. 5.6.6 CR - Ovulation induction with gonadotropin for non- IVF cycles should be strictly monitored to cancel cycles with a multiple follicular growth (more than two follicles) and minimize the risk of multiple pregnancy.. 5.6.7 PP - When using gonadotropins, cycles should be canceled if there are more than a total of 2 follicles greater than . 5.7 Laparoscopic ovarian surgery. 5.7.1 EBR - Laparoscopic ovarian surgery could be second- line therapy for women with PCOS who are anovulatory and infertile, with CC resistance and other potential infertility factors (such as endometriosis, fibroids, and so on).. 5.7.2 PP When using laparoscopic ovarian surgery, the following should be considered:. - Comparative cost of the intervention for ovulation induction.- Expertise required for the safe use of the intervention for ovulation induction.- Both intraoperative and postoperative risks, which are higher in women who are above healthy weight.. 6.IVF in women with PCOS. 6.1 General considerations. 6.1.1 CR - IVF could be offered in women with PCOS and anovulatory infertility, if first- or second- line ovulation induction therapies have failed.. 6.1.2 PP - Women with PCOS undergoing IVF treatment should be counselled prior to starting treatment about the increased risk of ovarian hyperstimulation syndrome (OHSS) and strategies to reduce the risk should be offered.. 6.2 Strategies for inhibiting luteinizing hormone (LH) surge. 6.2.1 PP - The use of a gonadotropin releasing hormone (GnRH) antagonist protocol for women with PCOS undergoing IVF is recommended as it enables the use of GnRH agonist trigger, with the freezing of all embryos generated if required, reducing the risk of significant OHSS without compromising the cumulative live birth rate.. 6.2.2 EBR - In IVF cycles, where freeze- all protocol (also called "cycle segmentation") is planned, the administration of progestins could be considered to inhibit the LH surge, potentially reducing the costs.. 6.3 Trigger type. 6.3.1 CR - Triggering final oocyte maturation with a GnRH agonist and freezing all suitable embryos are recommended, in an IVF cycle with a GnRH antagonist protocol, where a fresh embryo transfer is not intended or where there is an increased risk of OHSS.. 6.4 Choice of gonadotropin. 6.4.1 CR - Either urinary or recombinant gonadotropin could be used in women with PCOS undergoing ovarian stimulation for IVF, with insufficient evidence to recommend a particular type of preparation.. 6.5 Exogenous LH. 6.5.1 CR - Exogenous recombinant LH treatment should not be routinely used in combination with FSH therapy in women with PCOS undergoing controlled ovarian hyperstimulation for IVF.. 6.6 Adjunct metformin. 6.6.1 EBR - Adjunct metformin therapy could be used before and/or during FSH ovarian stimulation in women with PCOS undergoing IVF treatment with GnRH agonist long protocol, to reduce the risk of developing OHSS and miscarriage.. 6.6.2 PP - If using metformin, the following could be considered:. - Commence metformin at the start of GnRH agonist treatment or before.- Gradually titrate metformin up to a dose of between 1000 and 2500 mg daily in order to minimize side effects.- Stopping metformin therapy at the time of the pregnancy test or period, unless the metformin therapy is otherwise indicated.. 6.7 In vitro maturation (IVM). 6.7.1 EBR - IVM and intracytoplasmic sperm injection (ICSI) is associated with no risk of OHSS, but it has a lower cumulative live birth rate. 6.7.2 PP - IVM should only be considered in centers with adequate expertise. Advocacy is needed for regional or national centers specialized in this technique.. 6.7.3 PP - IVM could be offered as an option in women with prior severe OHSS and where the risk of severe OHSS is deemed unacceptably high, provided that the center has expertise in IVM techniques.. 6.7.4 PP - Evidence suggests that IVM/ICSI is less effective than standard IVF/ICSI in terms of clinical pregnancy per patient and live birth rate per patient.. The leged for the graphical description and the teminology used is extensivl reported in Table 1. E: evidence- based recommendations, evidence suffcient to inform a recommendation made by the quideline development group. CR: consensus recommendations, in the absence of adequate evidence, a consensus recommendation has been made by the quideline development group, also informed by evidence from the general population. PP: practice points, evidence not sought; a practice point has been made by the quideline development group where important issues arose from discussion of evidence- based or consensus recommendations. # useful and lacking in the main referral document. The latter regarded external revisions using public consultation and international Referees. A public consultation was performed by external reviewers, including biologists, medical doctors (endocrinologists and gynecologists), midwives, psychologists, representatives of citizens, patients, and pharmaceutical and biomedical industries. On the other hand, two international Referees, experts in female infertility and in PCOS, revised all recommendations by making several suggestions and revisions, which were discussed by the SIRU- CECOS Working Group and integrated when considered relevant. After the revision process, the final document integrated adapted recommendations from the PCOS International Guidelines [3] and 21 new clinically relevant recommendations, subgrouped in specific sections (Table 3).. These guidelines present recommendations adapted from the 2023 International Guidelines for PCOS but differ in several key aspects. Firstly, the new . # hyperstimulation syndrome (OHSS), treatment failure or multiple pregnancy. This assessment is particularly crucial prior to initiating a cycle of ovarian stimulation.. The assessment of OHSS risk is critical in determining the appropriate therapeutic strategy [12]. Emerging evidence suggests, for instance, that the use of follitropin delta may offer advantages for patients with elevated AMH levels, who are more likely to be high responders [29, 30]. However, the clinical trials conducted in this area primarily involved highly selected populations with favorable prognoses and high ovarian responses, limiting the generalizability of the findings to broader, unselected infertile populations [31]. Consequently, the Working Group did not reach a consensus to deviate from the recommendations of the International Guidelines [3]. Instead, it opted to maintain the guidance of not endorsing a specific gonadotropin for infertile patients with PCOS, leaving the decision to the clinician's discretion.. The recommendations of the PCOS International Guidelines left some unresolved issues and gaps that we tried to fill. For example, current guidelines tried to make clearer is the opportunity to assess the seminal and tubal factor before starting the therapy to induce ovulation in PCOS. It is now explicitly recommended that the seminal factor should always be assessed. We also recommend executing a tubal patency testing on an individual basis when the tube patency is not clear (i.e. in absence of previous pregnancies). In the referral document [3], the flowchart on which was based the management of infertility in the PCOS patient included a central pathway following best practice evidence, but also side indications that left wide discretion to the clinician. In particular, International Guidelines lacked clear directives on the number of therapeutic cycles to perform before declaring pharmacological failure, as well as criteria for deciding when to repeat the same treatment or to start an IVF program. To address these shortcomings, the Working Group synthesized widely accepted notions from clinical practice and formally incorporated them into these updated guidelines. We have therefore clearly indicated the protocols for letrozole, clomiphene citrate (CC) and metformin administration and detailed the definitions of CC- and letrozole- resistance and CC- and letrozole- failure. At the same time, we have chosen to advise how long to continue a treatment before moving on to the next one, while leaving the clinician the freedom to adapt this choice to the individual clinical context. The most recent evidence suggests a repeat of CC administration in relation to the anti- estrogenic effects of CC itself [32]. Endometrial thickness . Another controversial issue raised during the formal reviewing process was the use of AMH for infertile women with PCOS. Although AMH is considered by international guidelines as a biomarker of PCOM in adults, no cut- off level or commercial kit is recommended or suggested [3]. In addition, serum AMH levels have a large variability closely dependent on the patient's BMI and age [33]. Therefore, the decision to exclude AMH from the diagnostic criteria, as reflected in current guidelines, is a cautious approach due to the variability of AMH values, and lack of standardized values and kits. On the other hand, the evaluation of AMH levels may be crucial to personalize the treatment strategy of patients with PCOS in an infertility setting [34].. The strengths of these guidelines lie not only in the practical recommendations but also in the methodology employed. The adaptive framework of the International Guidelines enabled the development of updated, tailored, and high- quality recommendations without requiring substantial financial or human resource investments. The work was further enhanced by contributions from a specialized expert group on PCOS and fertility, supplemented by a transparent public consultation that engaged a diverse range of professionals and the input of two independent international experts. Nonetheless, we recognize certain limitations that remain. Overall, the quality of evidence in PCOS research is frequently low to moderate. Further studies are required to provide more definitive and clear guidance for the clinical management of infertile patients with PCOS, addressing the gaps currently left to clinician discretion. Secondly, the adaptability of these guidelines to the Italian healthcare context is constrained by significant regional disparities. Assisted reproductive technologies (ART) procedures are currently covered only in specific infertility centers within certain regions, limiting the uniform application of these guidelines across the country. While the SIRUCECOS Italy guidelines may be relevant in regions that provide ART services, they may not be applicable in regions where such services are unavailable. Additionally, Italy has more private ART centers than public ones, and most of these facilities lack cryopreservation capabilities ( iss.it/site/RegistroPMA/PUB/Centri/CentriPma.aspx). However, the Italian government recently recognized ART as an essential healthcare service, mandating all regions to provide access to it for citizens starting January 1, 2024. This policy change will likely enhance the applicability of these guidelines. Nevertheless, a significant challenge. # that remains to be addressed at the politic level is the prolonged waiting times for accessing ART services through the national healthcare system.. In conclusion, the current document now represents for SIRU and CECOS Italy the formal Italian guidelines for diagnosis and treatment of infertility in women with PCOS, and it replaces the section about the ovulatory dysfunctions included in the NICE- adapted guidelines from the SIRU for the diagnosis and management of infertility in Italy [10].. Abbreviations. AGREE II Appraisal of Guidelines for Research and Evaluation II AIOM Italian Association of Medical Oncology AMH Anti- mullerian hormone ARTs Assisted reproductive technologies ASRM American Society of Reproductive Medicine CCC Clomiphene citrate C CECOS Centers for the Study CNEC National Center for the Clinical Excellence, Quality and Safety of the Care EtD Evidence to Decision GIMBE Italian Team for the Evidence- Based Medicine GRADE Grading of Recommendations Assessment, Development and Evaluation ICSI Intracytoplasmic sperm injection IUI Intrauterine insemination IVF In vitro fertilization MMWG Multidisciplinary and Multiprofessional Working Group NICE National Institute of Clinical Excellence PCOS Polycystic ovary syndrome PDTA Diagnostic- Therapeutic- Care Pathways PICO Population, Intervention, Comparison and Outcomes SIRU Italian Society of Human Reproduction SNLG National System Guidelines System. Supplementary Information. The online version contains supplementary material available at org/10.1186/s12958- 025- 01372- 5.. Supplementary Material 1: Table 1. [All items selected and extracted by the SIRU- CECOS Italy Working Group from the 2023 International Evidencebased Guideline for the Assessment and Management of PCOS [3]. All original items were analyzed by the SIRU- CECOS Italy Working Group for relevance and applicability to the Italian context and contextualized to adult infertile women. In the table are reported the words/statements deleted and those changed in articles.]. Supplementary Material 2: Table 2. [SIRU- CECOS Italy guidelines for the diagnosis and treatment of infertility in women with PCOS - Italian version.]. Supplementary Material 3: Figure 1. [Strategy for the management and treatment of infertile patients with PCOS according to SIRU and CECOS Italy guidelines - Italian version.]. Acknowledgements. The authors would like to express their gratitude to all the external reviewers for their constructive criticism and improvement of the final document. SIRU - CECOS Working Group on Italian Guideline for Diagnosis and Treatment of Infertility in Women with PCOS Adolfo Allegra, Antonio Aversa, Domenico Baldini, Tiziana Bartolotti, Domenico Carone, Maria Paola Costantini, Giacomo D'Amico, Antonino Guglielmino, Annalisa Liprino, Roberto Lagantara, Roberto Marcio, Angelo Marino, Giuseppe Morgante, Stefano Palomba, Mariangela Palmieri, Enrico Papaleo, Guglielmo. Ragusa, Maria Santo, Giuseppe Seminara, Edgardo Somigliana, Laura Sosa Fernandez, Francesco Tomei, Maria Vitale, Aldo Volpes 1Department of Medical- Surgical Science and Translational Medicine, Sapienza University of Rome, Rome, Italy; Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy; Center of Medicine, S. Dona di Piave, VE, Italy; ANDROS Day Surgery Clinic, Palermo, Italy; Department of Molecular and Developmental Medicine, University of Siena, Siena, and Unit of Medically Assisted Reproduction, Siena University Hospital, Siena, Italy; Momcò Fertilife, Bisceglie, BT, Italy; Obstetrics and Gynecology Department, IRCCS San Raffaele Scientific Institute, Milan, Italy; Unit of Reproductive Medicine, Hospital Borgo Trento, Verona, Italy; HERA Center, Unit of Reproductive Medicine (U.M.R), Sant'Agata li Battiati, CT, Italy; Infertility Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy; Demetra Artebios, Lugo, RA, Italy; Eugin, Taranto, Italy; Italian Society for Human Reproduction, SIRU, Rome, Italy; 14University of Messina, Messina, Italy; 15Biotech, PMA, Padua, Italy; 16Department of Translational Medicine University of Ferrara, Ferrara, Italy; 17Centro Hera, Giugliano in Campania, NA, Italy; 18Paparotto Hospital, Messina, Italy; 19Embryos, Battipaglia, SA, Italy; 20Cittadinanzativa Association, Rome, Italy.. Authors' contributions. S.P., A.G., and E.S. conceptualized and designed the study. S.P., G.S. and E.S. drafted the article. All authors (S.P., G.S., F.T., A.M., G.M., D.B., E.P., G.R., A.A., A.A., A.G., E.S.) interpreted the data, critically revised the article, provided their final approval of the version to be published, and agreed to be accountable for all aspects of the work, especially regarding its accuracy and integrity.. Funding. The preparation of the current guidelines was self- funded. Specifically, all costs were covered by SIRU.. Data availability. No datasets were generated or analysed during the current study.. Declarations. Ethics approval and consent to participate Not applicable.. Consent for publication Not applicable.. Competing interests. The authors declare no competing interests.. Author details. 1Department of Medical- Surgical Science and Translational Medicine, Obstetrics & Gynecology, Sapienza University of Rome, Via Di Grottarossa 1039, Rome, Italy. 2Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy. 3Center of Medicine, San Dona di Piave, VE, Italy. 4ANDROS Day Surgery Clinic, Palermo, Italy. 5Unit of Medically Assisted Reproduction and Department of Molecular and Developmental Medicine, Siena University Hospital and University of Siena, Siena, Italy. 6Momò Fertilife, Bisceglie, BT, Italy. 7Obstetrics and Gynecology Department, IRCCS San Raffaele Scientific Institute, Milan, Italy. 8Unit of Reproductive Medicine, Hospital Borgo Trento, Verona, Italy. 9Unit of Reproductive Medicine (U.M.R), HERA Center, Sant'Agata li Battiati, CT, Italy. 10Infertility Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy.. 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A list of authors and their affiliations appears at the end of the paper..	None	None	None
c6d235470ff6466f91baf795824171dc	MSD	乳腺癌非妇科癌症转移	# Breast Cancer. By Lydia Choi, MD, Karmanos Cancer Center Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Jul 2023 \| Modified Apr 2025. Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis is made by biopsy. Treatment usually includes surgical excision, often with radiation therapy, and with or without adjuvant chemotherapy, endocrine therapy, or both.. Risk Factors \| Pathology \| Pathophysiology \| Symptoms and Signs \| Diagnosis \| Treatment \| Prognosis \| Key Points \| More Information. In the United States, breast cancer is the most common cancer in women, except for skin cancers (1). Breast cancer is the 2nd leading cause of cancer death (the most common is lung cancer) in the overall female population but is the leading cause of cancer death in Black women. Black women are more likely to die from breast cancer than any other race or ethnicity; Asian and Pacific Islander women have the lowest death rate from breast cancer.. In 2023, in women in the United States, it is estimated there will be . In 2023, in men in the United States, it is estimated there will be 2800 new cases of invasive breast cancer and 530 deaths from it (2). Manifestations, diagnosis, and management are the same in men and women, although men tend to present at a later stage.. General references. 1. American Cancer Society: Key Statistics for Breast Cancer. Accessed May 4, 2023. 2. American Cancer Society: Key Statistics for Breast Cancer in Men. Accessed May 4, 2023.. Risk Factors for Breast Cancer. For women in the United States, cumulative lifetime risk of developing breast cancer is about . # Factors that may affect breast cancer risk include the following:. - Age: The incidence is highest among women ages 65 to 74 years. Median age at diagnosis is 63 years (1).. - Race and ethnicity: The median age at diagnosis is slightly younger for Black women (60 years old) compared to White women 63 years old) (1). Black women have the highest death rate from breast cancer compared with other races or ethnicities; this may be in part because they have a higher rate of triple-negative breast cancer (negative for estrogen and progesterone receptors and human epidermal growth factor receptor [HER2] oncogene), which has a poorer prognosis than other types. White, Asian, and Pacific Islander women are more likely to be diagnosed with localized breast cancer than Black, Hispanic, American Indian, and Alaska Native women.. - Family history: Having a 1st-degree relative (mother, sister, daughter) with breast cancer doubles risk of developing the cancer, but breast cancer in more distant relatives increases risk only slightly (3). When ≥ 2 1st-degree relatives have breast cancer, risk may be 3 to 4 times higher.. - Breast cancer gene mutations: About 5 to 10% of women with breast cancer carry a mutation in one of the two known breast cancer genes, BRCA1 or BRCA2. The risk of developing breast cancer by age 80 is about 72% with a BRCA1 mutation and about 69% with a BRCA2 mutation. Women with BRCA1 mutations also have an approximate 44% lifetime risk of developing ovarian cancer; risk among women with BRCA2 mutations is about 17% (4, 5). Men who carry a BRCA mutation have a 1 to 2% lifetime risk of developing. # breast cancer. The mutations are more common among people with Ashkenazi Jewish ancestry. Women with BRCA1 or BRCA2 mutations require closer surveillance or preventive measures, such as screening with both mammography and MRI, taking tamoxifen, or undergoing risk- reducing mastectomy.. - Personal history of breast cancer: Having had in situ or invasive breast cancer increases risk. Risk of developing cancer in the contralateral breast after mastectomy is about . - Lobular carcinoma in situ (LCIS): Having LCIS increases the risk of developing invasive carcinoma in either breast by about 7 to 12 times (Z); invasive carcinoma develops in about 1 to . - Gynecologic history: Early menarche or late menopause increases risk. Risk increases with increasing age at first pregnancy (3).. - Benign breast disease: History of a lesion that required a biopsy is associated with a slightly increased risk. Women with multiple breast masses but no histologic confirmation of a high-risk histology should not be considered at high risk. Benign lesions associated with a slightly increased risk of developing invasive breast cancer include complex fibroadenoma, moderate or florid hyperplasia (without atypia), sclerosing adenosis, and papilloma. Risk is about 3 to 5 times higher than average in patients with atypical ductal or lobular hyperplasia (8).. - Dense breast tissue: Dense breast tissue seen on screening mammography is associated with a 1-2- to 2.1-fold increased risk of breast cancer (9).. - Use of oral contraceptives: Study results vary regarding the use of oral contraceptives and risk of breast cancer. Some studies have found a small increased risk in current or recent users (10).. - Hormone therapy: In the Women's Health Initiative randomized trial, menopausal hormone therapy (estrogen plus a progestin) increased risk modestly after only 3 years of use (11). After 5 years of use, the increased risk is about 3 additional cases per 1000 women for each year of use (approximately a . - Radiation therapy: Exposure to radiation therapy of the chest up through 45 years old increases risk, with the highest increase for those exposed between ages 10 to 14 years (12). Mantle-field radiation therapy for Hodgkin lymphoma about quadruples risk of breast cancer over the next 20 to 30 years.. - Diet: Diet may contribute to development, growth, or prognosis of breast cancers, but conclusive evidence about the effect of a particular diet (eg, one high in fats) is lacking.. - Obesity: Postmenopausal women with obesity are at increased risk of breast cancer; studies show a . - Smoking and alcohol: Smoking and alcohol use appear to be associated with an increase in breast cancer risk; the increase with alcohol intake is dose-dependent (14, 15).. # The Breast Cancer Risk Assessment Tool (BCRAT), or Gail model, can be used to calculate a women's 5- year and lifetime risk of developing breast cancer.. Risk factor references. 1. American Cancer Society: Key Statistics for Breast Cancer. Accessed May 4, 2023. 2. American Cancer Society: Survival Rates for Breast Cancer. Accessed March 29, 2023. 3. Collaborative Group on Hormonal Factors in Breast Cancer: Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet 358(9291):1389-1399, 2001. doi:10.1016/S0140-6736(01)06524-2 4. Kuchenbaecker KB, Hopper JL, Barnes DR, et al: Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317 (23):2402-2416, 2017. doi: 10.1001/jama.2017.7112 5. Breast Cancer Association Consortium; Dorling L, Carvalho S, Allen J, et al: Breast cancer risk genes — Association analysis in more than 113,000 women. N Engl J Med 4;384 (5):428-439, 2021. doi: 10.1056/NEJMoa1913948 6. Giannakeas V, Lim DW, Narod SA: The risk of contralateral breast cancer: a SEER-based analysis. Br J Cancer 125(4):601-610, 2021. doi:10.1038/s41416-021-01417-7 7. American Cancer Society (ACOG): Lobular Carcinoma in Situ (LCIS). Accessed May 4, 2023. 8. Collins LC, Baer HJ, Tamimi RM, et al: Magnitude and laterality of breast cancer risk according to histologic type of atypical hyperplasia: results from the Nurses' Health Study. Cancer 109(2):180-187, 2007. doi:10.1002/cncr.22408 9. American College of Obstetricians and Gynecologists (ACOG): Committee opinion no. 625: Management of women with dense breasts diagnosed by mammography. Obstet Gynecol 125 (3):750-751, 2015. Reaffirmed 2020. doi: 10.1097/01.AOG.0000461763.77781.79 Accessed May 4, 2023. 10. American College of Obstetricians and Gynecologists (ACOG): Hormonal contraception and risk of breast cancer: Practice advisory. Published 2018, reaffirmed 2022. Accessed May 4, 2023. 11. Rossouw JE, Anderson GL, Prentice RL, et al.: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 288 (3):321-333, 2002. doi:10.1001/jama.288.3.321 12. John EM, Kelsey JL: Radiation and other environmental exposures and breast cancer. Epidemiol Rev 15(1):157-162, 1993. doi:10.1093/oxfordjournals.epirev.a036099 13. Lauby-Secretan B, Scoccianti C, Loomis D, et al: Body Fatness and Cancer--Viewpoint of the IARC Working Group. N Engl J Med 375(8):794-798, 2016. doi:10.1056/NEJMsr1606602 14. Gram IT, Park SY, Kolonel LN, et al: Smoking and Risk of Breast Cancer in a Racially/Ethnically Diverse Population of Mainly Women Who Do Not Drink Alcohol: The MEC Study. Am J Epidemiol 182(11):917-925, 2015. doi:10.1093/aje/kwv092 15. Zhang SM, Lee IM, Manson JE, et al: Alcohol consumption and breast cancer risk in the Women's Health Study. Am J Epidemiol 165(6):667-676, 2007. doi:10.1093/aje/kwk054. Pathology of Breast Cancer. # Most breast cancers are epithelial tumors (carcinomas) that develop from cells lining ducts or lobules; nonepithelial cancers of the supporting stroma (eg, angiosarcoma, primary stromal sarcomas, phyllodes tumor) are less common.. Anatomy of the Breast (Front and Side Views). IMAGE. GWEN SHOCKEY/SCIENCE PHOTO LIBRARY. Anatomy of the Breast (Side View). IMAGE. GWEN SHOCKEY/SCIENCE PHOTO LIBRARY. Epithelial cancers are divided into carcinoma in situ and invasive cancer.. Carcinoma in situ is proliferation of cancer cells within ducts or lobules but without invasion of stromal tissue. There are 2 types:. # Ductal carcinoma in situ (DCiS): DCiS refers to neoplastic epithelial lesions that are confined to the breast ducts; lesions may have varying histology and malignant potential. It is usually detected only by mammography. It may involve a small or wide area of the breast; if a wide area is involved, microscopic invasive foci may develop over time. DCiS accounts for approximately . Lobular carcinoma in situ (LCiS): LCIS is often multifocal and is bilateral in approximately 20 to . Paget disease of the nipple (not to be confused with the metabolic bone disease also called Paget disease) is a form of ductal carcinoma in situ that extends into the skin over the nipple and areola, manifesting with a skin lesion (eg, an eczematous or a psoriaform lesion). Characteristic malignant cells called Paget cells are present in the epidermis. Women with Paget disease of the nipple often have underlying invasive or in situ cancer.. Invasive carcinoma is primarily adenocarcinoma. Approximately . Epithelial cancers may express hormone receptors (stromal tumors do not express hormone receptors, eg, phyllodes tumors). Approximately . Rare histologic types that are usually associated with a favorable prognosis include medullary, mucinous, cribriform, and tubular carcinomas (4). Mucinous carcinoma tends to develop in older women and be slow growing.. # "CREATIVE COMMONS PATIENT WITH INFLAMMATORY BREAST CANCER" BY EPIDEMIOLOGY AND SURGICAL MANAGEMENT OF BREAST CANCER IN GYNECOLOGICAL DEPARTMENT OF DOUALA GENERAL HOSPITAL (SCIENTIFIC FIGURE ON RESEARCHGATE) IS LICENSED UNDER CREATIVE COMMONS 2.0. AVAILABLE FROM: HTTPS://www.researchgate.net/FIGURE/PATIENT- WITHINFLAMMATORY- BREAST- CANCER_FIG2_234162338 [ACCESSED 3 OCT, 2019].. Rare types that typically have a poor prognosis include metaplastic and inflammatory breast cancer. Inflammatory breast cancer is a fast- growing, particularly aggressive, and often fatal cancer. Cancer cells block the lymphatic vessels in breast skin; as a result, the breast appears inflamed, and the skin appears thickened, resembling orange peel (peau d'orange). Usually, inflammatory breast cancer spreads to the lymph nodes in the armpit. The lymph nodes feel like hard lumps. However, often no mass is felt in the breast itself because this cancer is dispersed throughout the breast.. Paget Disease of the Nipple. IMAGE. References. # 1. Giaquinto AN, Sung H, Miller KD, et al: Breast Cancer Statistics, 2022. CA Cancer J Clin 72(6):524-541, 2022. doi:10.3322/caac.217542. Wapnir IL, Dignam JJ, Fisher B, et al: Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst 103(6):478-488, 2011. doi:10.1093/jnci/djr0273. Wen HY, Brogi E: Lobular Carcinoma In Situ. Surg Pathol Clin 11(1):123-145, 2018. doi:10.1016/j.path.2017.09.0094. American Cancer Society: Breast Cancer Facts & Figures. Accessed May 4, 20235. Anderson WF, Chatterjee N, Ershler WB, et al: Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast Cancer Res Treat. 2002;76(1):27-36. doi:10.1023/a:10202997075106. Li Y, Yang D, Yin X, et al: Clinicopathological Characteristics and Breast Cancer-Specific Survival of Patients With Single Hormone Receptor-Positive Breast Cancer. JAMA Netw Open 3(1):e1918160, 2020. doi:10.1001/jamanetworkopen.2019.181607. Howlader N, Altekruse SF, Li CI, et al: US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst 106(5):dju055, 2014. Published 2014 Apr 28. doi:10.1093/jnci/dju0558. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program.: Cancer Stat Facts: Female Breast Cancer Subtypes. Accessed May 4, 2023. Pathophysiology of Breast Cancer. Breast cancer invades locally and spreads through the regional lymph nodes, bloodstream, or both. Metastatic breast cancer may affect almost any organ in the body—most commonly, lungs, liver, bone, brain, and skin. Most skin metastases occur near the site of breast surgery; scalp metastases are uncommon.. Breast Lymph Nodes. # Some breast cancers may recur sooner than others; recurrence can often be predicted based on tumor markers. For example, metastatic breast cancer may occur within 3 years in patients who are negative for tumor markers or occur . Hormone receptors. Estrogen and progesterone receptors are nuclear hormone receptors that promote DNA replication and cell division when the appropriate hormones bind to them. Thus, medications that block these receptors are useful in treating and preventing tumors with the receptors.. For tumors in which HER2 receptors are overexpressed, medications that block these receptors are part of standard treatment. HER2 overexpressing tumors respond well to these medications because HER2 is a significant driver of cancer cell progression.. Breast cancer genes. BRCA1 and BRCA2 gene mutations increase the risk of developing breast cancer to . Pathophysiology references. 1. Kuchenbaecker KB, Hopper JL, Barnes DR, et al: Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317 (23):2402-2416, 2017. doi: 10.1001/jama.2017.7112 2. Breast Cancer Association Consortium; Dorling L, Carvalho S, Allen J, et al: Breast cancer risk genes — Association analysis in more than 113,000 women. N Engl J Med 4;384 (5):428-439, 2021. doi: 10.1056/NEJMoa1913948. Symptoms and Signs of Breast Cancer. Many breast cancers are discovered as a mass by the patient or during routine physical examination or mammography. Infrequently, the presenting symptom is overall breast enlargement or a nondescript thickening of the breast. Breast pain may be present but is almost never the sole presenting symptom of breast cancer.. A few patients with breast cancer present with signs of metastatic disease (eg, pathologic fracture, abdominal pain, jaundice, dyspnea).. A common finding during physical examination is asymmetry or a dominant mass—a mass distinctly different from the surrounding breast tissue. Diffuse fibrotic changes in a quadrant of the breast,. # usually the upper outer quadrant, are more characteristic of benign disorders; a slightly firmer thickening in one breast but not the other may be a sign of cancer.. Some types of breast cancer manifest with notable skin changes:. - Paget disease of the nipple is associated with an underlying in situ or invasive carcinoma and manifests as skin changes, including erythema, crusting, scaling, and discharge; these changes usually appear so benign that the patient ignores them, delaying diagnosis for a year or more. About . More advanced breast cancers are characterized by one or more of the following examination findings:. - Fixation of the mass to the chest wall or to overlying skin- Satellite nodules or ulcers in the skin. Matted or fixed axillary lymph nodes suggest tumor spread, as does supraclavicular or infraclavicular lymphadenopathy.. Breast Mass. IMAGE. Inflammatory Breast Cancer. # Diagnosis of Breast Cancer. - Initial detection with mammography and/or other imaging (breast tomosynthesis, ultrasonography, MRI) or clinical breast examination- Biopsy, including analysis for estrogen and progesterone receptors and HER2 protein. Symptoms, clinical breast examination, or imaging test results may prompt a diagnostic evaluation for breast cancer.. Patients who present with breast symptoms (eg, pain, nipple discharge) or a palpable breast mass or other abnormality on clinical breast examination are typically evaluated initially with breast ultrasonography. If ultrasound results are abnormal or indeterminate, mammography is done. If imaging findings suggest cancer, biopsy is done.. Even if imaging tests are negative, a biopsy should be performed if a palpable breast mass or other physical findings suggest cancer. If advanced cancer is suspected based on physical examination, biopsy is often done before imaging; however, a prebiopsy bilateral mammogram may help delineate other areas that should be biopsied and provides a baseline for future reference.. For patients with an abnormal screening mammogram, image- guided biopsy is performed. An abnormal breast MRI is typically evaluated with ultrasonography to determine whether biopsy should be performed under guidance with ultrasonography or MRI.. Pearls & Pitfalls. - Biopsy should be done if physical findings (eg, palpable mass) suggest breast cancer, even if mammogram results are negative.. # Biopsy. Percutaneous core needle biopsy is preferred to surgical biopsy. Core biopsy can be done guided by imaging or palpation (freehand). Stereotactic biopsy (needle biopsy guided by mammography done in 2 planes and analyzed by computer to produce a 3- dimensional image) or ultrasound- guided biopsy is commonly used to improve accuracy. Clips are placed at the biopsy site so it can be identified with mammography.. If core biopsy is not possible (eg, the lesion is too posterior), surgical biopsy can be done; a guidewire or localizing metal seed is inserted, using imaging for guidance, to help identify the biopsy site.. Any skin taken with the biopsy specimen should be examined because it may show cancer cells in dermal lymphatic vessels.. The excised specimen should be x- rayed, and the x- ray should be compared with the prebiopsy mammogram to determine whether all of the lesion has been removed. If the original lesion contained microcalcifications, mammography is repeated when the breast is no longer tender, usually 6 to 12 weeks after biopsy, to check for residual microcalcifications. If radiation therapy is planned, mammography should be repeated before radiation therapy begins.. Evaluation after cancer diagnosis. After cancer is diagnosed, a multidisciplinary evaluation is usually done to plan further testing and treatment. The core multidisciplinary team typically includes a breast surgical oncologist, medical oncologist, and radiation oncologist.. A positive biopsy specimen should be analyzed for estrogen and progesterone receptors and for HER2 protein.. Genetic testing. The National Comprehensive Cancer Network (NCCN) recommends that patients with current or a personal history of breast cancer should be tested for inherited gene mutations that predispose to breast cancer, if they meet any of the following criteria (1):. Breast cancer diagnosed at age . # or metastatic or high- risk prostate cancer. Family history with . For these tests, the best approach is to refer patients to a genetic counselor, who can document a detailed family history, counsel the patient about the risks and benefits of genetic testing, choose the most appropriate tests, and help interpret the results.. Evaluation for metastatic disease. A complete blood count (CBC) and liver function tests can be done to check for metastatic disease.. An oncologist should determine whether to measure serum carcinoembryonic antigen (CEA), cancer antigen (CA) 15- 3, or CA 27- 29 and whether bone scanning should be done.. For bone scanning, common indications include the following:. - Bone pain- Elevated serum alkaline phosphatase- Stage III or IV cancer. Abdominal CT is done if patients have any of the following:. - Abnormal liver test results- Abnormal abdominal or pelvic examination- Stage III or IV cancer. Chest CT is done if patients have either of the following:. - Pulmonary symptoms such as shortness of breath- Stage III or IV cancer. MRI is often used by surgeons for preoperative planning; it can accurately determine tumor size, chest wall involvement, and number of tumors.. Grading and staging. Grading is based on histologic examination of the tissue taken during biopsy. Tumor grade describes how abnormal tumor cells and tissue look under a microscope.. Staging follows the TNM (tumor, node, metastasis) classification (see table Anatomic Staging of Breast Cancer). Because clinical examination and imaging have poor sensitivity for nodal involvement, staging is refined during surgery, when regional lymph nodes can be evaluated. However, if patients have palpably abnormal axillary nodes, preoperative ultrasonography- guided fine needle aspiration or core biopsy may be done:. - If biopsy results are positive, axillary lymph node dissection is typically done during the definitive surgical procedure. However, use of neoadjuvant chemotherapy may make sentinel lymph node biopsy possible if chemotherapy changes node status from N1 to N0.. # (Results of intraoperative frozen section analysis determine whether axillary lymph node dissection will be needed.)- If results are negative, a sentinel lymph node biopsy, a less aggressive procedure, may be done instead.. Staging classification follows these models:. - The anatomic staging model, which is based on anatomy of the tumor and which is used in regions of the world where biomarkers cannot be routinely obtained (see table Anatomic Staging of Breast Cancer)- The prognostic staging model, which is based on anatomy of the tumor as well as status of biomarkers and which is predominantly used in the United States. # TABLE. Anatomic Staging of Breast Cancer. Adapted from: Hortobagyi GN, Connolly JL, D'Orsi CJ, Edge SB, Mittendorf EA, et al: Breast. In: Amin MB, Edge S, Greene F, et al, eds; American Joint Committee on Cancer. AJCC cancer staging manual. 8th ed. New York, NY: Springer. 2017. Version 9 changes, when available, can be found on the American Joint Committee on Cancer (AJCC) site AJCC Version 9 Cancer Staging System.. † Classification of regional lymph nodes (N) is divided into clinical (cN) and pathologic (pN), which have slightly different descriptions.. # § Here, N1 excludes N1mi.. Tis . \mathsf{N}\mathsf{X} =. Spread to ipsilateral low or midaxillary nodes that are fixed or matted, detected by clinical examination (cN2) Spread to 4- 9 axillary lymph nodes, detected by testing (pN2) Spread to internal mammary nodes but not axillary nodes as detected by clinical examination or imaging. \mathsf{N}3 =. Spread to ipsilateral internal mammary nodes plus axillary nodes as detected by clinical examination or imaging Spread to infraclavicular nodes Spread to supraclavicular nodes Spread to . \mathsf{M}0 =. Adapted from the American Joint Committee on Cancer, AJCC Cancer Staging Manual, Eighth Edition (2017). Springer New York, Inc.. Fertility preservation. Patients with breast cancer should not become pregnant while being treated for breast cancer. However, all patients who wish to preserve fertility should be referred to a reproductive endocrinologist. # to discuss fertility preservation before systemic therapy is initiated.. Options for fertility preservation include. Assisted reproductive techniques (ART) with ovarian stimulation and oocyte or embryo cryopreservation Ovarian or testicular tissue cryopreservation. Type of breast cancer, anticipated treatment, and patient preferences affect the type of fertility preservation that can be used. Ovarian suppression (eg, with leuprolide) has been used to minimize the destruction of ova by chemotherapy.. Diagnosis references. 1. National Comprehensive Cancer Network (NCCN): Guidelines, Breast Cancer Version 4.2023. 2. Manahan ER, Kuerer HM, Sebastian M, et al. Consensus Guidelines on Genetic Testing for Hereditary Breast Cancer from the American Society of Breast Surgeons. Ann Surg Oncol 26(10):3025-3031, 2019. doi:10.1245/s10434-019-07549-8. Treatment of Breast Cancer. Surgery Radiation therapy Systemic chemotherapy Adjuvant endocrine therapy. For more detailed information about treatment, see National Comprehensive Cancer Network (NCCN) Clinical Practice Guideline: Breast Cancer.. For most types of breast cancer, treatment involves surgery and radiation therapy; systemic therapy is given for lymph node involvement or metastatic disease. Choice of treatment depends on tumor and patient characteristics (see table Treatment by Type of Breast Cancer). Recommendations for surgery are evolving and include early referral to a plastic or reconstruction surgeon for oncoplastic surgery (which combines cancer removal with reconstruction of the breast).. # # Surgery. Surgery involves mastectomy or breast- conserving surgery.. Mastectomy is removal of the entire breast and includes the following types:. - Skin-sparing mastectomy: Spares the pectoral muscles and enough skin to cover the wound, making breast reconstruction much easier, and spares axillary lymph nodes- Nipple-sparing mastectomy: Same as skin-sparing mastectomy plus spares the nipple and areola- Simple mastectomy: Spares the pectoral muscles and axillary lymph nodes. # - Modified radical mastectomy: Spares the pectoral muscles and removes some axillary lymph nodes. - Radical mastectomy: Removes axillary lymph nodes and the pectoral muscles Radical mastectomy is rarely done unless the cancer has invaded the pectoral muscle.. Breast- conserving surgery involves determining the size of the tumor and the required margins (based on the tumor's size relative to the volume of the breast), then surgically removing the tumor with its margins. Various terms (eg, lumpectomy, wide excision, quadrantectomy) are used to describe how much breast tissue is removed.. For patients with invasive cancer, survival and recurrence rates with mastectomy do not differ significantly from those with breast- conserving surgery plus radiation therapy as long as the entire tumor can be removed (1).. Thus, patient preference is part of shared decision- making. The main advantage of breast- conserving surgery plus radiation therapy is less extensive surgery and opportunity to keep the breasts. The need for total removal of the tumor with a tumor- free margin overrides any cosmetic considerations. Consulting a plastic surgeon about oncoplastic surgery may help if patients have ptotic (sagging) breasts, while also achieving good resection margins.. Some oncologists treat with neoadjuvant chemotherapy to shrink the tumor before removing it and applying radiation therapy; thus, some patients who might otherwise have required mastectomy can have breast- conserving surgery.. Lymph node evaluation. During both mastectomy and breast- conserving surgery, axillary lymph nodes are typically evaluated. Methods include. - Axillary lymph node dissection (ALND)- Sentinel lymph node biopsy (SLNB). ALND is a fairly extensive procedure that involves removal of as many axillary nodes as possible; adverse effects, particularly lymphedema, are common. Risk of lymphedema is increased for patients with a high preoperative body mass index (BMI ≥ 30) and for those with significant weight gain during and after breast cancer treatment (2).. Most surgeons now first do SLNB unless biopsy of clinically suspect nodes detected cancer; risk of lymphedema is less with SLNB. Routine use of ALND is not justified because the main value of lymph node removal is diagnostic, not therapeutic, and SLNB has ≥ 95% sensitivity for axillary node involvement.. Lymphedema. # SCIENCE PHOTO LIBRARY. For SLNB, blue dye and/or radioactive colloid is injected around the breast, and a gamma probe (and when dye is used, direct inspection) is used to locate the nodes the tracer drains into. Because these nodes are the first to receive the tracers, they are considered the most likely to receive any metastatic cells and are thus called sentinel nodes.. If any of the sentinel nodes contain cancer cells, ALND may be necessary, based on numerous factors such as. - Tumor stage- Hormone receptor status- Number of involved nodes- Extranodal extension- Patient characteristics (3). Some surgeons do frozen section analysis during mastectomy with SLNB and get prior agreement for ALND in case nodes are positive; others await standard pathology results and do ALND as a 2nd procedure if needed. Frozen section analysis is not routinely done with lumpectomy.. Impaired lymphatic drainage of the ipsilateral arm often occurs after axillary node removal (ALND or SLNB) or radiation therapy, sometimes resulting in substantial swelling due to lymphedema. Magnitude of the effect is roughly proportional to the number of nodes removed; thus, SLNB causes less lymphedema than ALND. The lifetime risk of lymphedema after ALND is about . If lymphedema develops, a specially trained therapist must treat it. Special massage techniques used once or twice a day may help drain fluid from congested areas toward functioning lymph basins; low-. # stretch bandaging is applied immediately after manual drainage, and patients should exercise daily as prescribed. After the lymphedema lessens, typically in 1 to 4 weeks, patients continue daily exercise and overnight bandaging of the affected limb indefinitely.. Reconstructive procedures. Reconstructive procedures include the following:. - Prosthetic reconstruction: Placement of a silicone or saline implant, sometimes after a tissue expander is used- Autologous reconstruction: Muscle flap transfer (using the latissimus dorsi, gluteus maximus, or the lower rectus abdominis) or muscle-free flap transfer. Breast Reconstruction Using the Transverse Rectus Abdominis Muscle (.... IMAGE. Breast reconstruction can be done during the initial mastectomy or breast- conserving surgery or later as a separate procedure. Timing of surgery depends on patient preference as well as the need for adjuvant therapy such as radiation therapy. However, doing radiation therapy first limits the types of reconstructive surgery that can be done. Thus, consulting a plastic surgeon early during treatment planning is recommended.. Advantages of breast reconstruction include improved mental health in patients who have a mastectomy. Disadvantages include surgical complications and possible long- term adverse effects of implants.. Contralateral prophylactic mastectomy. Contralateral prophylactic mastectomy is an option for some women with breast cancer (eg, those with a genetic mutation conferring a high risk of breast cancer).. In women with lobular carcinoma in situ in one breast, invasive cancer is equally likely to develop in either breast. Thus, the only way to eliminate the risk of breast cancer for these women is bilateral. # mastectomy. Some women, particularly those who are at high risk of developing invasive breast cancer, choose this option.. Advantages of contralateral prophylactic mastectomy include. Decreased risk of contralateral breast cancer (especially in women in a family history of breast or ovarian cancer) Improvement in survival in breast cancer patients with an inherited genetic mutation (eg, BRCA1 or BRCA2 mutation) and possibly in women diagnosed at age . Disadvantages of contralateral prophylactic mastectomy include. An almost two- fold increase in surgical complication rates. Contralateral prophylactic mastectomy is not mandatory for patients with the highest risk of developing cancer in the contralateral breast. Close surveillance is a reasonable alternative.. Radiation therapy. Radiation therapy after breast- conserving surgery significantly reduces incidence of local recurrence in the breast and in regional lymph nodes and may improve overall survival. However, if patients are . Radiation therapy is indicated after mastectomy if any of the following is present:. The primary tumor is . In such cases, radiation therapy after mastectomy significantly reduces incidence of local recurrence on the chest wall and in regional lymph nodes and improves overall survival.. Adverse effects of radiation therapy (eg, fatigue, skin changes) are usually transient and mild. Late adverse effects (eg, lymphedema, brachial plexopathy, radiation pneumonitis, rib damage, secondary cancers, cardiac toxicity) are less common.. To improve radiation therapy, researchers are studying several new procedures. Many of these procedures aim to target radiation to the cancer more precisely and spare the rest of the breast from the effects of radiation.. Adjuvant systemic therapy. (See also National Comprehensive Cancer Network (NCCN) Clinical Practice Guideline: Breast Cancer.). # Endocrine therapy, chemotherapy, or HER2- directed therapy delays or prevents recurrence in almost all patients and prolongs survival in some. Hormone positive cancer can be evaluated with Oncotype Dx, which allows targeting chemotherapy and endocrine therapy to the populations most likely to benefit. Hormone negative cancer and HER2 positive cancer are treated with chemotherapy and targeted therapy.. Decisions about the type of adjuvant therapy are made based on tumor characteristics, including estrogen receptor (ER) and progesterone receptor (PR) status, presence of human epidermal growth factor 2 (HER2) protein, grade and stage (including lymph node involvement), and genomic risk stratification. Some patients are treated with a combination of endocrine therapy and chemotherapy.. Chemotherapy is usually begun soon after surgery. If systemic chemotherapy is not required, endocrine therapy is usually begun soon after surgery and is continued for 5 to 10 years.. In higher stage disease, neoadjuvant chemotherapy may be started before surgery.. # Endocrine therapy. In patients with . # The 21- gene recurrence score assay (based on Oncotype Dx) The Amsterdam 70- gene profile (MammaPrint) The 50- gene risk of recurrence score (PAM50 assay). In the United States, most women with breast cancer have ER+/PR+/HER2- breast cancer with negative axillary nodes. In these women, a low or intermediate score on the 21- gene recurrence score assay predicts similar survival rates with chemotherapy plus endocrine therapy and with endocrine therapy alone. Therefore, in this subset of women with breast cancer, chemotherapy may not be necessary.. With endocrine therapy (eg, tamoxifen, aromatase inhibitors), benefit depends on estrogen and progesterone receptor expression; benefit is greatest with the strongest level of hormone receptor expression (7). Medications used for endocrine therapy include tamoxifen and aromatase inhibitors.. Tamoxifen is a selective estrogen receptor modulator that competitively binds with estrogen receptors. Adjuvant tamoxifen reduces breast cancer mortality for women with tumors that have estrogen receptors. Tamoxifen therapy for 5 years reduces annual odds of death by about . Aromatase inhibitors (anaastrozole, exemestane, letrozole) block peripheral production of estrogen in postmenopausal women. More effective than tamoxifen, these medications are becoming the preferred treatment for early- stage hormone receptor- positive cancer in postmenopausal patients. Letrozole may be used in postmenopausal women who have completed tamoxifen treatment. Optimal duration of aromatase inhibitor therapy is uncertain. A recent trial showed that extending treatment to 10 years resulted in a lower rate of breast cancer recurrence and higher rate of disease- free survival. There was no change in overall survival and a higher rate of fractures and osteoporosis in patients treated for an extended time.. Patients with DCIS are often treated with daily oral tamoxifen.. Preferred therapy for premenopausal women with . Adjuvant chemotherapy. # Usual indications for chemotherapy are one or more of the following:. Estrogen receptor (ER) and progesterone receptor (PR)- negative Human epidermal growth factor 2 (HER2) oncogene- positive (chemotherapy and HER2- directed therapy is given) . However, studies have shown that chemotherapy is not necessary for many small . Postmenopausal patients with ER- tumors benefit the most from adjuvant chemotherapy (see table Preferred Breast Cancer Adjuvant Systemic Therapy).. Combination chemotherapy regimens are more effective than a single medication. Dose- dense regimens given for 4 to 6 months are preferred; in dose- dense regimens, the time between doses is shorter than that in standard- dose regimens. There are many regimens; a commonly used one is ACT (doxorubicin plus cyclophosphamide followed by paclitaxel). Acute adverse effects depend on the regimen but usually include nausea, vomiting, mucositis, fatigue, alopecia, myelosuppression, cardiotoxicity, and thrombocytopenia. Growth factors that stimulate bone marrow (eg, filgrastim, pegfilgrastim) are commonly used to reduce risk of fever and infection due to chemotherapy. Long- term adverse effects are infrequent with most regimens; death due to infection or bleeding is rare . HER2-directed therapy. If the tumor overexpresses HER2 (HER2+), anti- HER2 monoclonal antibodies (trastuzumab, pertuzumab) may be used. Adding the humanized monoclonal antibody trastuzumab to chemotherapy provides substantial benefit. Trastuzumab is usually continued for a year, although the optimal duration of therapy is unknown. If lymph nodes are involved, adding pertuzumab to trastuzumab improves disease- free survival. A serious potential adverse effect of both these anti- HER2 medications is a decreased cardiac ejection fraction.. Metastatic disease. Any indication of metastases should prompt immediate evaluation. Treatment of metastases increases median survival by 6 months or longer. These treatments (eg, chemotherapy), although relatively toxic, may palliate symptoms and improve quality of life. Thus, the decision to be treated may be highly personal.. Choice of therapy depends on the following:. - Hormone-receptor status of the tumor- Length of the disease-free interval (from remission to manifestation of metastases)- Number of metastatic sites and organs affected- Patient's menopausal status. # Systemic endocrine therapy or chemotherapy is usually used to treat symptomatic metastatic disease. Initially, patients with multiple metastatic sites outside the central nervous system (CNS) should be given systemic therapy. If metastases are asymptomatic, there is no proof that treatment substantially increases survival, and it may reduce quality of life.. Endocrine therapy is preferred over chemotherapy for patients with any of the following:. - ER+ tumors- A disease-free interval of . In premenopausal women, tamoxifen is often used first. Reasonable alternatives include ovarian ablation by surgery, radiation therapy, and use of a luteinizing- releasing hormone agonist (eg, buserelin, goserelin, leuprolide). Some experts combine ovarian ablation with tamoxifen or an aromatase inhibitor. In postmenopausal women, aromatase inhibitors are being increasingly used as primary endocrine therapy. If the cancer initially responds to endocrine therapy but progresses months or years later, additional forms of endocrine therapy (eg, progestins, the antiestrogen fulvestrant) may be used sequentially until no further response occurs.. The most effective chemotherapy agents are capecitabine, doxorubicin (including its liposomal formulation), gemcitabine, the taxolites paclitaxel and docetaxel, and vinorelbine. Response rate to a combination of agents is higher than that to a single agent, but survival is not improved and toxicity is increased. Thus, some oncologists use single agents sequentially.. Anti- HER2 monoclonal antibodies (eg, trastuzumab, pertuzumab) are used to treat tumors that overexpress HER2. These are effective in treating and controlling visceral metastatic sites. Trastuzumab is used alone or with endocrine therapy, chemotherapy, or pertuzumab. Trastuzumab plus chemotherapy plus pertuzumab slows the growth of HER2+ metastatic breast cancer and increases survival more than trastuzumab plus chemotherapy (11).. Tyrosine kinase inhibitors (eg, lapatinib, neratinib) are being increasingly used in women with HER2+ tumors.. Radiation therapy alone may be used to treat isolated, symptomatic bone lesions or local skin recurrences not amenable to surgical resection. Radiation therapy is the most effective treatment for brain metastases, occasionally providing long- term control.. Palliative mastectomy is sometimes an option for patients with stable metastatic breast cancer.. IV bisphosphonates (eg, pamidronate, zoledronate) decrease bone pain and bone loss and prevent or delay skeletal complications due to bone metastases. About . Treatment references. 1. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast. # cancer. N Engl J Med 347(15):1233- 1241, 2002. doi:10.1056/NEJMoa022152. 2. Jammallo LS, Miller CL, Singer M, et al: Impact of body mass index and weight fluctuation on lymphedema risk in patients treated for breast cancer. Breast Cancer Res Treat 142 (1):59-67, 2013. doi: 10.1007/s10549-013-2715-7. 3. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A randomized clinical trial. JAMA 305 (6):569-575, 2011. doi: 10.1001/jama.2011.90. 4. Krag DN, Anderson SJ, Julian TB, et al: Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol 11(10):927-933, 2010. doi:10.1016/S1470-2045(10)70207-2. 5. National Lymphedema Network Medical Advisory Committee: Position Statement Paper: Lymphedema Risk Reduction Practices. May 2010. Accessed May 8, 2023.. 6. Hughes KS, Schnaper LA, Berry D, et al: Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 351 (10):971-977, 2004. doi:10.1056/NEJMoa040587. 7. Fisher B, Anderson S, Tan-Chiu E, et al: Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 19(4):931-942, 2001. doi:10.1200/JCO.2001.19.4.931. 8. Early Breast Cancer Trialists: Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365(9472):1687-1717, 2005. doi:10.1016/S0140-6736(05)66544-0. 9. Davies C, Pan H, Godwin J, et al: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial [published correction appears in Lancet. 2013 Mar 9;381(9869):804] [published correction appears in Lancet. 2017 May 13;389(10082):1884]. Lancet 381(9869):805-816, 2013. doi:10.1016/S0140-6736(12)61963-1. 10. Rosen PP, Saigo PE, Braun DW Jr, et al: Predictors of recurrence in stage I (T1N0M0) breast carcinoma. Ann Surg 193(1):15-25, 1981. doi:10.1097/00000658-198101000-00003. 11. Swain SM, Baselga J, Kim SB, et al: Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372 (8):724-734, 2015. doi: 10.1056/NEJMoa1413513. Prognosis for Breast Cancer. Long- term prognosis depends on tumor stage. Nodal status (including number and location of nodes) correlates with disease- free and overall survival better than any other prognostic factor.. The 5- year survival rate (from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program) depends on cancer stage:. - Localized (confined to primary site): 99.0%- Regional (confined to regional lymph nodes): 85.8%- Distant (metastasized): 29.0%. # Unknown: . Poorer prognosis is associated with the following other factors:. Young age: Prognosis appears worse for patients diagnosed with breast cancer during their 20s and 30s than for patients diagnosed during middle age.. Race: Breast cancer death rates from 2015 to 2019 were higher in the United States in non- Hispanic Black females (28 per 100,000) than in non- Hispanic White females (19.9 per 100,000 [1]). Black women are diagnosed at a younger age compared with White women (median 60 versus 63 years) and are more likely to have triple negative disease (2).. Larger primary tumor: Larger tumors are more likely to be node- positive, but they also confer a worse prognosis independent of nodal status.. High- grade tumor: Patients with poorly differentiated tumors have a worse prognosis.. Absence of estrogen and progesterone receptors: Patients with . Presence of HER2 protein: When the HER2 gene (HER2/neu [erb- b2]) is amplified, HER2 is overexpressed, increasing cell growth and reproduction and often resulting in more aggressive tumor cells. Overexpression of HER2 is an independent risk factor for a poor prognosis; it may also be associated with high histologic grade, ER- tumors, greater proliferation, and larger tumor size, which are all poor prognostic factors.. Presence of BRCA gene mutations: For any given stage, patients with the BRCA1 gene mutation appear to have a worse prognosis than those with sporadic tumors, perhaps because they have a higher proportion of high- grade, hormone receptor- negative cancers. Patients with the BRCA2 gene mutation probably have the same prognosis as those without the mutation if the tumors have similar characteristics. With either gene mutation, risk of a 2nd cancer in remaining breast tissue is increased (to perhaps as high as . End-of-life issues. For patients with metastatic breast cancer, quality of life may deteriorate, and the chances that further treatment will prolong life may be small. Palliation may eventually become more important than prolongation of life.. Cancer pain can be adequately controlled with appropriate medications, including opioid analgesics. Other symptoms (eg, constipation, difficulty breathing, nausea) should also be treated.. Psychologic and spiritual counseling should be offered.. Patients with metastatic breast cancer should be encouraged to prepare advance directives, indicating the type of care they desire in case they are no longer able to make such decisions.. Prognosis references. # 1. American Cancer Society: Cancer Facts & Figures or African American/Black People 2022-2024. Accessed May 4, 2023. 2. American Cancer Society: Key Statistics for Breast Cancer. Accessed May 4, 2023.. Key Points. Breast cancer is the second leading cause of cancer death in women; cumulative risk of developing breast cancer by age 95 is . More Information. The following English- language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.. NCCN Clinical Practice Guideline: Breast Cancer: The National Comprehensive Cancer Network provides guidelines for the diagnosis, staging, and treatment of breast cancer (and other cancers). U. S. Preventive Services Task Force: Breast Cancer: Medication Use to Reduce Risk: This web site provides the rationale of using medications to reduce the risk of breast cancer in women at high risk and describes the risks of using these medications.. National Cancer Institute: Breast Cancer: This web site discusses the genetics of breast and gynecologic cancers and the screening for and prevention and treatment of breast cancer. It also includes evidence- based information about supportive and palliative care..	None	None	None
1144711fc127475197c3adc16a56ba15	MSD	催乳素瘤	# Prolactinoma. By John D. Carmichael, MD, Keck School of Medicine of the University of Southern California Glenn D. Braunstein, MD, Cedars- Sinai Medical Center Reviewed/Revised Jun 2025. Prolactinomas are noncancerous tumors made up from lactotrophs in the pituitary gland. The most common symptom of a prolactinoma is galactorrhea. Diagnosis is by measurement of prolactin levels and imaging tests. Treatment involves tumor inhibition with dopamine agonists and sometimes removal or destruction of the adenoma.. Etiology \| Symptoms and Signs \| Diagnosis \| Treatment \| Key Points. Galactorrhea involves secretion of breast milk. A discussion of nipple discharge in general is provided elsewhere.. Etiology of Prolactinoma. Prolactinomas are noncancerous pituitary tumors composed of lactotrophs, which are prolactin- secreting adenomas. Prolactin is produced in cells called lactotrophs that constitute approximately . Galactorrhea is generally due to a prolactin- secreting pituitary adenoma (prolactinoma) but may result from any cause of hyperprolactinemia (see table Causes of Hyperprolactinemia). Most tumors in adult females are microadenomas ( . Hyperprolactinemia and galactorrhea also may be caused by ingestion of certain medications, including phenothiazines and some other antipsychotics, certain antihypertensives (especially methyldopa and verapamil), and opioids. Primary hypothyroidism can cause hyperprolactinemia and galactorrhea. # because increased levels of thyroid- releasing hormone increase secretion of prolactin as well as thyroid- stimulating hormone (TSH). Prolactin levels may rise in circulation as a consequence of renal insufficiency due to impaired renal clearance of prolactin. Nipple stimulation and pregnancy are physiologic causes of increased prolactin secretion. Hyperprolactinemia may be associated with low gonadotropins and hypogonadism probably through inhibition of gonadotropin- releasing hormone (GnRH) release or action on the pituitary gonadotropes (see table Causes of Hyperprolactinemia).. # # Symptoms and Signs of Prolactinoma. Abnormal lactation is not defined quantitatively; it is milk release that is inappropriate, persistent, or worrisome to the patient. Spontaneous lactation is more unusual than milk released in response to manual expression. The milk is white, and fat globules can be seen when a sample is examined with a microscope. Adult females with galactorrhea commonly also have amenorrhea or oligomenorrhea. Adult females with galactorrhea and amenorrhea may also have symptoms and signs of estrogen deficiency, including dyspareunia and reduced libido, due to inhibition of pulsatile luteinizing hormone and follicle- stimulating hormone release by high prolactin levels. However, estrogen production may be normal, and signs of androgen excess, including hirsutism, have been observed in some adult females with hyperprolactinemia. Hyperprolactinemia may occur with other menstrual cycle disturbances besides amenorrhea, including infrequent ovulation and corpus luteum dysfunction.. Adult males with prolactin- secreting pituitary tumors typically have headaches or visual difficulties. Approximately two- thirds of affected adult males have loss of libido and erectile dysfunction.. Diagnosis of Prolactinoma. - Prolactin levels. # - Thyroxine (T4) and thyroid-stimulating hormone (TSH) levels- CT or MRI. Diagnosis of galactorrhea due to a prolactin- secreting pituitary adenoma is based on elevated prolactin levels (typically . A trial of dopamine agonist therapy can help distinguish between prolactin- secreting and nonfunctioning lesions; in both types of lesion, prolactin levels decrease after treatment, but prolactin- secreting lesions decrease in size, whereas nonfunctioning lesions do not.. Serum gonadotropin and estradiol levels are either low or in the normal range in adult females with hyperprolactinemia, and testosterone levels may be low in adult males. Primary hypothyroidism is easily excluded by absence of elevated TSH. In patients with a known pituitary tumor, TSH and free thyroxine levels should be measured to evaluate for possible central hypothyroidism.. MRI with contrast is the method of choice in identifying microadenomas. High- resolution CT may be used when MRI is contraindicated or unavailable.. Visual field examination is indicated in all patients with macroadenomas and in any patient who elects surveillance only.. Treatment of Prolactinoma. - Depends on sex, cause, symptoms, and other factors- When indicated, initial treatment is usually with a dopamine agonist. Microadenomas. Microprolactinomas can be treated in multiple ways. Patients with no symptoms who have prolactin levels . Patients with hyperprolactinemia should be monitored with quarterly measurement of prolactin levels and undergo sellar MRI or CT annually for at least an additional 2 years. The frequency of sellar imaging can then be reduced if prolactin levels do not increase.. In adult females, indications for treatment include:. - Desire for pregnancy- Amenorrhea or significant oligomenorrhea (because of the risk of osteoporosis)- Hirsutism- Low libido. # Troublesome galactorrhea. In adult males, galactorrhea itself is rare and rarely troublesome enough to require treatment; indications for treatment include:. Hypogonadism (because of the risk of osteoporosis) Erectile dysfunction Low libido Troublesome infertility. The initial treatment for both sexes is usually a dopamine agonist such as bromocriptine or the longer- acting cabergoline, which lower prolactin levels. Cabergoline is the treatment of choice because it is more easily tolerated (has a lower frequency of adverse effects) and more potent than bromocriptine. Adult females who are trying to become pregnant should stop cabergoline or bromocriptine use at the time of a positive pregnancy test result.. While medical therapy has been considered the initial treatment of choice for microadenomas for decades, there is evidence supporting surgical treatment as first- line treatment in selected patients with microadenomas or noninvasive, encapsulated macroadenomas. This approach, performed by an experienced neurosurgeon, offers the advantage of a cost- effective, one- time treatment with a high chance for remission, thus avoiding long- term medical therapy.. Quinagolide, a nonergot- derived dopamine agonist, is also an option for hyperprolactinemia. It is started at 25 mcg orally once a day and titrated over 7 days up to the usual maintenance dose of 75 mcg once a day (can increase weekly in 75- to 150- mcg increments to maximum dose 600 mcg once a day). Quinagolide should not be used by adult females contemplating pregnancy.. Patients with concomitant hypogonadism who elect to not use dopamine agonist therapy can be treated with estrogen (with or without a progestin, as indicated) or testosterone. Adult females with a microadenoma who are clinically hypoestrogenic or have low estradiol levels, can be given exogenous estrogen. Exogenous estrogen is unlikely to cause tumor expansion.. Macroadenomas. Patients with macroadenomas generally should be treated initially with dopamine agonists even in cases of large tumors invading and compressing the optic chiasm. Dopamine agonists usually shrink a prolactin- secreting tumor. Dopamine agonists will not shrink a nonfunctioning tumor that is causing pituitary stalk compression, although prolactin levels will decrease. If prolactin levels fall and symptoms and signs of compression by the tumor abate, no other therapy may be necessary. Once the prolactin has normalized, surveillance imaging can be done as needed based on clinical judgement, as tumor growth during treatment is rare without recurring hyperprolactinemia.. Typically, larger, nonfunctioning lesions need additional treatment, usually surgery. Although dopamine agonist treatment usually needs to be continued long- term, prolactin- secreting tumors sometimes remit, either spontaneously or perhaps aided by pharmacotherapy. Sometimes, therefore, dopamine agonists can be stopped without a recurrence of the tumor or a rise in prolactin levels; remission is more likely with microadenomas than macroadenomas. Remission is also more likely after pregnancy.. # High doses of dopamine agonists, particularly cabergoline, are thought to have caused valvular heart disease in some patients with Parkinson disease. Studies evaluating the lower doses of dopamine agonists used for hyperprolactinemia have not demonstrated an increased risk of valvular heart disease, but the possibility should be discussed with patients, and echocardiographic surveillance should be considered, especially when doses . For patients with macroadenomas, surgery is second- line therapy. It is typically considered in patients whose tumor is resistant to dopamine agonists or in patients who are intolerant of medical therapy. There may be a benefit of dopamine agonist dose reduction after a debulking surgery.. Radiation therapy should be used only in patients with progressive disease who do not respond to other forms of therapy. With irradiation, hypopituitarism often develops several years after therapy. Monitoring endocrine function and sellar imaging are indicated yearly for life.. Treating pregnant patients. Adult females should stop dopamine agonists (cabergoline or bromocriptine) at the time of a positive pregnancy test result because reduction in prolactin levels is no longer required, and there is little risk of clinically significant pituitary tumor growth. Stopping medication allows prolactin levels to naturally rise during pregnancy. However, if the tumor is invasive or abutting the optic chiasm, it may be prudent to continue dopamine agonist therapy throughout pregnancy. During pregnancy, approximately . Treatment reference. 1. Petersenn S, Fleseriu M, Casanueva FF, et al. Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement [published correction appears in Nat Rev Endocrinol. 2024 Jan;20(1):62. doi: 10.1038/s41574-023-00916-2]. Nat Rev Endocrinol. 2023;19(12):722-740. doi:10.1038/s41574-023-00886-5. Key Points. - Galactorrhea is the most common sign of a prolactinoma.- The most common cause of galactorrhea is a pituitary adenoma, but many medications and endocrine, hypothalamic, or other disorders may be responsible.. # - Measure prolactin levels and do central nervous system imaging to detect a causative tumor.- For microprolactinomas, give a dopamine agonist if certain troublesome symptoms are present.- For macroadenomas, give a dopamine agonist and consider surgical ablation or sometimes radiation therapy when medications fail to achieve treatment goals..	None	None	None
a69e4d0c165d41079977b04b4bf793fa	MSD	多囊卵巢综合征pcos月经周期改变（初潮、月经不规则、怀孕）	# Polycystic Ovary Syndrome (PCOS). (Hyperandrogenic Chronic Anovulation; Stein- Leventhal Syndrome). By JoAnn V. Pinkerton, MD, University of Virginia Health System Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Jan 2023 \| Modified Mar 2024. Polycystic ovary syndrome is a clinical syndrome typically characterized by anovulation or oligo- ovulation, signs of androgen excess (eg, hirsutism, acne), and multiple ovarian cysts in the ovaries. Insulin resistance and obesity are often present. Diagnosis is by clinical criteria, hormone measurement, and imaging to exclude a virilizing tumor. Treatment is symptomatic.. Symptoms and Signs \| Diagnosis \| Treatment \| Key Points \| More Information. Polycystic ovary syndrome (PCOS) occurs in 5 to . PCOS is usually defined as a clinical syndrome, not by the presence of ovarian cysts. But typically, ovaries contain many 2- to 6- mm follicular cysts and sometimes larger cysts containing atretic cells. Ovaries may be enlarged with smooth, thickened capsules or may be normal in size.. Polycystic Ovary Syndrome (PCOS). This syndrome involves anovulation or ovulatory dysfunction and androgen excess of unclear etiology. However, some evidence suggests that patients have a functional abnormality of cytochrome P450c17. # affecting 17- hydroxylase (the rate- limiting enzyme in androgen production); as a result, androgen production increases. Pathogenesis appears to involve environmental and hereditary factors.. General reference. 1. Dumesic DA, Oberfield SE, Stener-Victorin E, et al: Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev 36 (5):487-525, 2015. doi: 10.1210/er.2015-1018. Complications. Polycystic ovary syndrome has several significant potential complications.. Infertility is related to ovulatory dysfunction.. Estrogen levels are elevated, increasing risk of endometrial hyperplasia and, potentially, endometrial cancer.. Androgen levels are often elevated, increasing the risk of metabolic syndrome and obesity and causing hirsutism. Hyperinsulinemia due to insulin resistance may be present and may contribute to increased ovarian production of androgens. Over the long term, androgen excess increases the risk of cardiovascular disorders, including hypertension and hyperlipidemia. Risk of androgen excess and its complications may be just as high in women who are not overweight as in those who are.. Calcification of coronary arteries and thickening of the carotid intima media is more common among women with PCOS, suggesting possible subclinical atherosclerosis.. Type 2 diabetes mellitus and impaired glucose tolerance are more common, and risk of obstructive sleep apnea is increased.. Studies indicate that PCOS is associated with low- grade chronic inflammation and that women with PCOS are at increased risk of nonalcoholic fatty liver disease (1).. Complications reference. 1. Rocha AL, Oliveira FR, Azevedo RC, et al: Recent advances in the understanding and management of polycystic ovary syndrome. F1000Res 26;8, 2019. pii: F1000 Faculty Rev-565. doi: 10.12688/f1000research.15318.1 eCollection 2019.. Symptoms and Signs of PCOS. Symptoms of polycystic ovary syndrome typically begin during puberty and worsen with time. Ovulatory dysfunction is usually present at puberty, resulting in primary amenorrhea; thus, polycystic ovary syndrome is unlikely if regular menses occurred for a time after menarche. Premature adrenarche is common, caused by excess dehydroepiandrosterone sulfate (DHEAS) and often characterized by early growth of axillary hair, body odor, and microcomedonal acne.. # Typical symptoms include irregular menses, usually oligomenorrhea, amenorrhea, mild obesity, and mild hirsutism. However, in up to half of women with PCOS, weight is normal, and some women are underweight. Body hair may grow in a male pattern (eg, on the upper lip, chin, back, thumbs, and toes; around the nipples; and along the linea alba of the lower abdomen). Some women have acne, and some have signs of virilization, such as temporal hair thinning.. Other symptoms may include weight gain (sometimes seemingly hard to control), fatigue, low energy, sleep- related problems (including sleep apnea), mood swings, depression, anxiety, and headaches. In some women, fertility is impaired. Symptoms vary from woman to woman.. Areas of thickened, darkened skin (acanthosis nigricans) may appear in the axillae, on the nape of the neck, in skinfolds, and on knuckles and/or elbows; the cause is high insulin levels due to insulin resistance.. Acanthosis Nigricans in Polycystic Ovary Syndrome. If women with PCOS become pregnant and if obesity is present, risk of pregnancy complications is increased. These complications include gestational diabetes, preterm delivery, and preeclampsia.. Diagnosis of PCOS. - Clinical criteria- Pelvic ultrasonography- Tests to exclude other endocrinologic disorders, such as measurement of serum testosterone, follicle-stimulating hormone (FSH), prolactin, and thyroid-stimulating hormone (TSH) levels. PCOS is suspected if women have at least two typical symptoms (eg, irregular menses, hirsutism).. # The diagnosis requires at least 2 of the following 3 criteria:. Ovulatory dysfunction causing menstrual irregularity Clinical or biochemical evidence of hyperandrogenism . Testing includes pregnancy testing and measurement of FSH, prolactin, and TSH to exclude other possible causes of symptoms.. Transvaginal ultrasonography is done to detect polycystic ovaries and exclude other possible causes of symptoms. However, transvaginal ultrasonography is not done in adolescent girls (see below).. The diagnosis is not based on measurement of serum androgens. For patients who meet diagnostic criteria, other causes of hirsutism or virilization (eg, androgen- secreting tumors) should be excluded by measuring serum androgens including. Total testosterone Early- morning serum 17- hydroxyprogesterone is measured to exclude adrenal virilism DHEAS, if abnormal, women are evaluated as for amenorrhea. Serum free testosterone is more sensitive than total testosterone but is technically more difficult to measure (see algorithm Diagnosis of primary and secondary hypogonadism). Normal to mildly increased testosterone and normal to mildly decreased FSH levels suggest PCOS.. Also, serum cortisol is measured to exclude Cushing syndrome.. Pearls & Pitfalls. Polycystic ovary syndrome is unlikely if regular menses occurred for a time after menarche. In adolescents with symptoms of PCOS, measure testosterone levels.. Diagnosing PCOS in adolescent girls. Diagnosing PCOS in adolescent girlsDiagnosing PCOS in adolescents is complicated because physiologic changes during puberty (eg, hyperandrogenism, menstrual irregularity) are similar to features of PCOS. Thus, separate criteria for diagnosis of PCOS in adolescents (1) have been suggested: however, no consensus has been reached. These criteria require that both of the following conditions be present:. Abnormal uterine bleeding pattern (abnormal for age or gynecologic age or symptoms that persist for 1 to 2 years) Evidence of hyperandrogenism (based on persistently elevated testosterone levels above adult norms [the best evidence], moderate- to- severe hirsutism, or moderate- to- severe inflammatory acne vulgaris as an indication to test for hyperandrogenemia). # Often, a 17- hydroxyprogesterone test is also done to screen adolescents for nonclassic congenital adrenal hyperplasia.. Pelvic ultrasonography is usually indicated only if serum androgen levels or degree of virilization suggests an ovarian tumor. Transvaginal ultrasonography is usually not used to diagnose PCOS in adolescent girls because it detects polycystic morphology in . Diagnosis reference. 1. Tehrani FR, Amiri M: Polycystic ovary syndrome in adolescents: Challenges in diagnosis and treatment. Int J Endocrinol Metab 17 (3): e91554, 2019. doi: 10.5812/ijem.91554. Treatment of PCOS. - Usually estrogen/progestin contraceptives or progestins- Sometimes metformin or other insulin sensitizers- Management of hirsutism and, in adult women, long-term risks of hormonal abnormalities- Infertility treatments in women who desire pregnancy. Treatment of polycystic ovary syndrome aims to. - Manage hormonal and metabolic abnormalities and thus reduce risks of estrogen excess (eg, endometrial hyperplasia) and androgen excess (eg, diabetes, cardiovascular disorders)- Relieve symptoms- Treat infertility. Hormonal medications are used to cause regular shedding of the endometrium and reduce the risk of endometrial hyperplasia and cancer. Women are usually given an intermittent progestin (eg, medroxyprogesterone 5 to . Lifestyle changes and pharmacologic approaches are used to manage insulin insensitivity.. If obesity is present, weight loss and regular exercise are encouraged. These measures may help induce ovulation, make menstrual cycles more regular, increase insulin sensitivity, and reduce acanthosis nigricans and hirsutism. Weight loss may also help improve fertility. Bariatric surgery may be an option for some women with PCOS (1). However, weight loss is unlikely to benefit normal- weight women with PCOS.. Metformin 500 to . # should be done periodically. Because metformin may induce ovulation, contraception is needed if pregnancy is not desired. Metformin helps correct metabolic and glycemic abnormalities and makes menstrual cycles more regular, but it has little or no beneficial effect on hirsutism, acne, or infertility.. Insulin sensitizers (eg, glucagon- like peptide- 1 receptor agonists or thiazolidinediones) combined with metformin are being studied (2). Other studies are evaluating the role of microbiota treatments for PCOS (3).. Many patients with PCOS have infertility, and those who desire pregnancy should be referred to infertility specialists. Infertility treatments (eg, clomiphene) are used. Clomiphene is currently the first- line therapy for infertility. Weight loss may also be helpful. Hormone therapy that may have contraceptive effects is avoided. The aromatase inhibitor letrozole can also be used to stimulate ovulation. Other fertility medications may also be tried. They include follicle- stimulating hormone (FSH) to stimulate the ovaries, a gonadotropin- releasing hormone (GnRH) agonist to stimulate the release of FSH, and human chorionic gonadotropin (hCG) to trigger ovulation.. If clomiphene and other medications are unsuccessful or if there are other indications for laparoscopy, laparoscopic ovarian drilling may be considered; however possible long- term complications of drilling (eg, adhesions, ovarian insufficiency) must be considered. Ovarian drilling involves using electrocautery or a laser to drill holes in small areas of the ovaries that produce androgens. Ovarian wedge resection is not recommended.. Because women with PCOS- associated obesity have a higher risk of pregnancy complications (including gestational diabetes, preterm delivery, and preeclampsia), preconception assessment of body mass index, blood pressure, and oral glucose tolerance is recommended.. For hirsutism, physical measures (eg, bleaching, electrolysis, plucking, waxing, depilation) can be used (4). Eflornithine cream . In adult women who do not desire pregnancy, hormone therapy that decreases androgen levels or spironolactone can be tried. Spironolactone 50 to . GnRH agonists and antagonists are being studied as treatment for unwanted body hair. Both types of medications inhibit the production of sex hormones by the ovaries. But both can cause bone loss and lead to osteoporosis.. Acne can be treated with the usual medications (eg, benzoyl peroxide, tretinoin cream, topical and oral antibiotics). Systemic isotretinoin is used only for severe cases.. Management of comorbidities. # Because risk of depression and anxiety is increased in PCOS, women and adolescents with PCOS should be screened for these problems based on history, and if a problem is identified, they should be referred to a mental health care practitioner and/or treated as needed.. Adolescents and women who have PCOS and overweight or obesity should be screened for symptoms of obstructive sleep apnea using polysomnography and treated as needed.. Because PCOS can increase the risk of cardiovascular disorders, referral to a cardiovascular specialist for prevention of cardiovascular disorders is necessary if women with PCOS have any of the following:. A family history of early- onset cardiovascular disorders Cigarette smoking Diabetes mellitus Hypertension Dyslipidemia Sleep apnea Abdominal obesity (as for metabolic syndrome). Clinicians should evaluate cardiovascular risk by determining body mass index (BMI), measuring fasting lipid and lipoprotein levels, and identifying risk factors for metabolic syndrome.. Adult women with PCOS are evaluated for metabolic syndrome by measuring blood pressure and usually serum glucose and lipids (lipid profile).. Tests for coronary artery calcification and thickened carotid intima media should be done to check for subclinical atherosclerosis.. Women with abnormal vaginal bleeding should be screened for endometrial hyperplasia or carcinoma using endometrial biopsy and/or transvaginal ultrasonography or office hysteroscopy.. Treatment references. 1. Yue W, Huang X, Zhang W, et al: Metabolic surgery on patients with polycystic ovary syndrome: A systematic review and meta-analysis. Front Endocrinol (Lausanne) 13:848947, 2022. doi: 10.3389/fendo.2022.8489472. Xing C, Li C, He B: Insulin sensitizers for improving the endocrine and metabolic profile in overweight women with PCOS. J Clin Endocrinol Metab 10 5(9):2950-2963, 2020.3. Batra M, Bhatnager R, Kumar A, et al: Interplay between PCOS and microbiome: The road less travelled. Am J Reprod Immunol 88 (2):e13580, 2022. doi: 10.1111/aji.13580 Epub 2022 May 29.4. Martin KA, Chang RJ, Ehrmann DA, et al: Evaluation and treatment of hirsutism in premenopausal women: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 93 (4):1105-1120, 2008. doi: 10.1210/jc.2007-2437 Epub 2008 Feb 5.. Key Points. # Polycystic ovary syndrome (PCOS) is a common cause of ovulatory dysfunction. Suspect PCOS in women who have irregular menses, are mildly obese, and are slightly hirsute, but be aware that weight is normal or low in many women with PCOS. Test for serious disorders (eg, Cushing syndrome, tumors) that can cause similar symptoms and for complications (eg, metabolic syndrome) If pregnancy is not desired, treat women with hormonal contraceptives and recommend lifestyle modifications; if lifestyle modifications are ineffective, add metformin or other insulin sensitizers. If women with PCOS are infertile and desire pregnancy, refer them to reproductive infertility specialists. Screen for comorbidities, such as endometrial cancer, mood and anxiety disorders, obstructive sleep apnea, diabetes, and cardiovascular risk factors (including hypertension and hyperlipidemia).. More Information. The following English- language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.. Legro RS, Arslanian SA, Ehrmann DA, et al: Diagnosis and treatment of polycystic ovary syndrome: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 98(12):4565- 4592, 2013. doi: 10.1210/jc.2013- 2350. This evidence- based guideline uses the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence.. Goodman NF, Cobin RH, Futterweit W, et al: American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society Disease State Clinical Review: Guide to the best practices in the evaluation and treatment of polycystic ovary syndrome- - Part 1. Endocr Pract 21(11):1291- 300, 2015. doi: 10.4158/EP15748. DSC: This article summarizes the best practices of 2015.. Hoeger KM, Dokras A, Piltonen T: Update on PCOS: Consequences, challenges and guiding treatment. J Clin Endocrinol Metab 106(3):e1071- e1083, 2021. doi: 10.1210/clinem/dgaa839: This review summarizes key points for diagnosis and treatment of PCOS from an evidence- based guidelines published in 2018 and updates the information based on recent developments. The diagnostic criteria for PCOS are reviewed, and the remaining controversies and challenges for making a clear diagnosis are discussed..	None	None	None
8a47419967a24971b89723f1d1fc2535	MSD	妊娠期子宫肌瘤	# Fibroids in Pregnancy. By Charles Kilpatrick, MD, MEd, Baylor College of Medicine Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Feb 2025. Fibroids in pregnancy usually remain asymptomatic, but may present with pain from fibroid degeneration. Fibroids may increase risk of (1). Preterm labor Abnormal fetal presentation. Placenta previa and placental abruption Early.pregnancy loss or miscarriage Postpartum hemorrhage. Rarely, fibroids partially obstruct the vagina.. Preconception evaluation is recommended for women who have very large fibroids or who have fibroids and have had a spontaneous abortion.. Reference. 1. Coutinho LM, Assis WA, Spagnuolo-Souza A, Reis FM. Uterine Fibroids and Pregnancy: How Do They Affect Each Other?. Reprod Sci. 2022;29(8):2145-2151. doi:10.1007/s43032-021-00656-6.	None	None	None
47d240be698e44e387b25b44115d0881	MSD	妊娠期用药安全	# Drug Safety in Pregnancy. By Ravindu Gunatilake, MD, Valley Perinatal Services; Avinash S. Patil, MD, University of Arizona College of Medicine Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Oct 2023 \| Modified Apr 2025. Regulatory Information about Drug Safety During Pregnancy \| Drug Transfer and Metabolism During Pregnancy \| Vaccines During Pregnancy \| Antivirals During Pregnancy \| Antidepressants During Pregnancy \| References \| More Information. Regulatory Information about Drug Safety During Pregnancy \| Drug Transfer and Metabolism During Pregnancy \| Vaccines During Pregnancy \| Antivirals During Pregnancy \| Antidepressants During Pregnancy \| References \| More InformationMedications may be required for various indications during pregnancy. The most commonly used medications include antiemetics, antacids, antihistamines, analgesics, antimicrobials, diuretics, antidepressants, and tranquilizers. Substance use and misuse is also common. Despite this trend, firm evidence- based guidelines for safe use of medications during pregnancy are still lacking.. Regulatory Information about Drug Safety During Pregnancy. Until the 2010s, the U.S. Food and Drug Administration (FDA) classified over- the- counter (OTC) and prescription drugs into 5 categories of safety for use during pregnancy (A, B, C, D, X). However, few well- controlled studies of therapeutic drugs have been done in pregnant women. Most information about drug safety during pregnancy is derived from animal studies, uncontrolled studies, and postmarketing surveillance. Consequently, the FDA classification system led to confusion and difficulty applying available information to clinical decisions. In December 2014, the FDA responded by requiring that the pregnancy categories A, B, C, D, and X be removed from the labeling of all drugs.. Instead of categories, the FDA now requires that drug labels provide information about the specific drug in a consistent format (called the final rule, or Pregnancy and Lactation Labeling.(Drugs) Final Rule [PLLR]).. The information required by the FDA has 3 subsections:. Pregnancy: Information relevant to the use of the drug in pregnant women (eg, dosing, fetal risks) and information about whether there is a registry that collects and maintains data on how pregnant women are affected by the drug- Lactation: Information about using the drug while breastfeeding (eg, the amount of drug in breast milk, potential effects on the breastfed child)- Females and males of reproductive potential: Information about pregnancy testing, contraception, and infertility as it relates to the drug. # The pregnancy and lactation subsections each include 3 subheadings (risk summary, clinical considerations, and data) that provide more detail. The final rule does not apply to nonprescription (over- the- counter) drugs.. Drug Transfer and Metabolism During Pregnancy. During pregnancy, medications are often required to treat certain disorders. In general, when potential benefit outweighs known risks, medications may be considered for treatment of disorders during pregnancy.. Not all medications or other substances in the maternal circulation cross the placenta (transfer) to the fetus. Some drugs that cross the placenta may have a direct toxic effect or a teratogenic effect. Drugs that do not cross the placenta may still harm the fetus by. - Constricting placental vessels and thus impairing gas and nutrient exchange- Producing severe uterine hypertonia that results in anoxic injury- Altering maternal physiology (eg, causing hypotension). For a list of some medications with adverse effects during pregnancy, see table Safety of Selected Drugs in Pregnancy.. Drugs diffuse across the placenta similarly to the way they cross other epithelial barriers (see Absorption). Whether and how quickly a drug crosses the placenta depend on the drug's molecular weight, extent of its binding to another substance (eg, carrier protein), area available for exchange across the placental villi, and amount of drug metabolized by the placenta. Most drugs with a molecular weight of . A drug's effect on the fetus is determined largely by fetal age at exposure, placental permeability, maternal factors, drug potency, and drug dosage.. Fetal age affects the type of drug effect:. - Before the 20th day after fertilization: Drugs given at this time typically have an all-or-nothing effect, killing the embryo or not affecting it at all. Teratogenesis is unlikely during this stage.- During organogenesis (between 20 and 56 days after fertilization): Teratogenesis is most likely at this stage. Drugs reaching the embryo during this stage may result in spontaneous abortion, a sublethal gross anatomic defect (true teratogenic effect), covert embryopathy (a permanent subtle metabolic or functional defect that may manifest later in. # life), or an increased risk of childhood cancer (eg, when the mother is given radioactive iodine to treat thyroid cancer); or the drugs may have no measurable effect.. - After organogenesis (in the second and third trimesters): Teratogenesis is unlikely, but drugs may alter growth and function of normally formed fetal organs and tissues. As placental metabolism increases, doses must be higher for adverse fetal effects to occur.. Maternal factors include those that affect drug absorption, distribution, metabolism, and excretion. For example, nausea and vomiting may decrease absorption of an oral drug.. The overall rate of major structural birth defects in the United States is approximately . # # # # # # # # newborn may include. # # # # # # * The American College of Obstetricians and Gynecologists (ACOG) recommends avoiding paroxetine use during pregnancy (see ACOG Committee Opinion No. 354: Treatment with selective serotonin reuptake inhibitors during pregnancy).. † The antiseizure drugs brivaracetam and eslicarbazepine are available; there is little to no information about their effects during pregnancy.. ‡ The European Society for Medical Oncology (ESMO) guidelines for diagnosis, treatment, and follow- up of cancer during pregnancy advised that, generally, if chemotherapy is indicated, it should not be given during the first trimester but may begin during the second trimester; the last chemotherapy dose should be given ≥ 3 weeks before anticipated delivery, and chemotherapy should not be given after week 33 of gestation. Peccatori FA, Azim HA Jr, Orecchia R, et al. Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow- up. Ann Oncol 24 Suppl 6:vi160- vi170, 2013. doi:10.1093/annonc/mdt199. 1. Hoeltzenbein M, Slimi S, Pietz AK, et al. Increasing use of newer antiseizure medication during pregnancy: an observational study with special focus on lacosamide. Seizure 107:107-113, 2023. doi:10.1016/j.seizure.2023.02.015. 2. Sun L, Xi Y, Wen X, Zou W. Use of metoclopramide in the first trimester and risk of major congenital malformations: a systematic review and meta-analysis. PLoS One 16(9):e0257584, 2021. Published 2021 Sep 20. doi:10.1371/journal.pone.0257584. 3. Easterling T, Mundle S, Bracken H, et al: Oral antihypertensive regimens (nifedipine retard, labetalol, and methyldopa) for management of severe hypertension in pregnancy: an open-label, randomised controlled trial. Lancet 394(10203):1011-1021, 2019. doi:10.1016/S0140-6736(19)31282-6. 4. Bellos I, Pergialiotis V, Papapanagiotou A, et al: Comparative efficacy and safety of oral antihypertensive agents in pregnant women with chronic hypertension: a network metaanalysis. Am J Obstet Gynecol 223(4):525-537, 2020. doi:10.1016/j.ajog.2020.03.016. # 5. Sridharan K, Sequeira RP: Drugs for treating severe hypertension in pregnancy: a network meta-analysis and trial sequential analysis of randomized clinical trials. Br J Clin Pharmacol 84(9):1906-1916, 2018. doi:10.1111/bcp.13649. 6. Indraratna PL, Virk S, Gurram D, Day RO: Use of colchicine in pregnancy: a systematic review and meta-analysis. Rheumatology (Oxford) 57(2):382-387, 2018. doi:10.1093/rheumatology/lex353. 7. Larsen ER, Damkier P, Pedersen LH, et al: Use of psychotropic drugs during pregnancy and breast-feeding. Acta Psychiatr Scand Suppl 445:1-28, 2015. doi:10.1111/acps.12479. 8. Charlton BM, Molgaard-Nielsen D, Svanstrom H, et al: Maternal use of oral contraceptives and risk of birth defects in Denmark: prospective, nationwide cohort study. BMJ 352:h6712, 2016. Published 2016 Jan 6. doi:10.1136/bmj.h6712. 9. Waller DK, Gallaway MS, Taylor LG, et al: Use of oral contraceptives in pregnancy and major structural birth defects in offspring. Epidemiology 21(2):232-239, 2010. doi:10.1097/EDE.0b013e3181c9fbb3. 10. Yovich JL, Turner SR, Draper R: Medroxyprogesterone acetate therapy in early pregnancy has no apparent fetal effects. Teratology 38(2):135-144, 1988. doi:10.1002/tera.1420380206. 11. Carmichael SL, Shaw GM, Laurent C, et al: Maternal progestin intake and risk of hypospadias. Arch Pediatr Adolesc Med 159(10):957-962, 2005. doi:10.1001/archpedi.159.10.957. 12. Pergialiotis V, Bellos I, Hatziagelaki E, et al: Progestogens for the prevention of preterm birth and risk of developing gestational diabetes mellitus: a meta-analysis. Am J Obstet Gynecol 221(5):429-436.e5, 2019. doi:10.1016/j.ajog.2019.05.033. 13. O'Brien JM, Steichen JJ, Phillips JA, et al: 490: Two year infant outcomes for children exposed to supplemental intravaginal progesterone gel in utero: secondary analysis of a multicenter, randomized, double-blind, placebo-controlled trial, American journal of Obstetrics and Gynecology, Volume 206, Issue 1, Supplement, 2012, Page S223, ISSN 0002-9378, . 14. The American College of Obstetricians and Gynecologists (ACOG): Practice Advisory: Maternal immunization, October 2022. Accessed August 29, 2023.. 15. ACOG: Practice Advisory: Vaccinating pregnant and lactating patients against COVID-19. December 2020. Accessed August 29, 2023.. 16. ACOG: Committee Opinion No. 732: Influenza vaccination during pregnancy. Obstet Gynecol 131(4):e109-e114, 2018. doi:10.1097/AOG.0000000000002588. 17. ACOG: Committee Opinion No. 718: Update on immunization and pregnancy: tetanus, diphtheria, and pertussis vaccination. Obstet Gynecol 130(3):e153-e157, 2017.. # doi:10.1097/AOG.0000000000002301. ACE = angiotensin- converting enzyme; ACIP = Advisory Committee on Immunization Practices; CDC = Centers for Disease Control and Prevention; CNS = central nervous system; G6PD = glucose- 6- phosphate dehydrogenase; OB/GYN = obstetrics and gynecology.. Vaccines During Pregnancy. Immunization is as effective in women who are pregnant as in those who are not.. Influenza vaccine is recommended for all pregnant women during influenza season.. The tetanus- diphtheria- pertussis (Tdap) vaccine is recommended for all pregnant women during the third trimester.. The CDC recommends COVID- 19 vaccination for all people 5 years and older, including people who are pregnant, breastfeeding, trying to get pregnant, or might become pregnant in the future. Evidence about the safety and effectiveness of COVID- 19 vaccination during pregnancy has been growing. These data suggest that the benefits of receiving a COVID- 19 vaccine outweigh any known or potential risks of vaccination during pregnancy. (See also CDC: COVID- 19 Vaccines While Pregnant or Breastfeeding.). In August 2023, the US Food and Drug Administration approved use of a respiratory syncytial virus (RSV) vaccine in pregnant individuals between 32 to 36 weeks of gestation, with a warning to avoid use prior to 32 weeks. Clinical trials have found increased rates of preterm birth, preeclampsia in pregnant patients, and low birth weight and jaundice in infants following prenatal administration of RSV vaccine versus placebo; further study is needed to evaluate these potential risks (3).. Other vaccines should be reserved for situations in which the woman or fetus is at significant risk of exposure to a hazardous infection and risk of adverse effects from the vaccine is low. Vaccinations for cholera, hepatitis A, hepatitis B, measles, mumps, plague, poliomyelitis, rabies, typhoid, and yellow fever may be given during pregnancy if risk of infection is substantial.. Live- virus vaccines should not be given to women who are or may be pregnant. Rubella vaccine, an attenuated live- virus vaccine, may cause subclinical placental and fetal infection. However, no defects in neonates have been attributed to rubella vaccine, and women vaccinated inadvertently during early pregnancy need not be advised to terminate pregnancy based solely on theoretical risk from the vaccine. Varicella vaccine is another attenuated live- virus vaccine that can potentially infect the fetus; risk is highest between 13 weeks and 22 weeks gestation. This vaccine is contraindicated during pregnancy.. Antivirals During Pregnancy. # Some antivirals (eg, zidovudine and ritonavir for HIV infection) have been safely used during pregnancy for many years. However, some antivirals may have significant risks for the fetus.. Pregnancy is associated with an increased risk of severe COVID- 19. For pregnant patients with early mild to moderate COVID- 19, the United States National Institutes of Health (NIH) recommends use of either nirmatrelvir- ritonavir (4) or remdesivir (5), if indicated. The American College of Obstetricians and Gynecologists advises that use of nirmatrelvir- ritonavir may be considered, particularly for patients with at least one additional risk factor for severe disease. For pregnant patients hospitalized for COVID- 19, the NIH recommends use of baricitinib or tocilizumab, if indicated.. Antivirals for influenza should be started as soon as possible, without waiting for test results to confirm the diagnosis, because treatment within 48 hours of illness onset is most effective. However, treatment at any point during the infection reduces risk of severe complications. Controlled clinical studies of zanamivir and oseltamivir have not been done in pregnant women; however, many observational studies indicate that their use during pregnancy does not increase risk of adverse effects. There are fewer data about the safety of peramivir during pregnancy and no data about baloxavir in pregnant women. Health care professionals should tell pregnant women what the symptoms and signs of influenza are and advise them to seek treatment as soon as symptoms begin.. Acyclovir (oral and topical) appears to be safe during pregnancy.. Antidepressants During Pregnancy. Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are commonly used during pregnancy because the prevalence of clinical depression during pregnancy is high (7 to . Pregnant women who are taking antidepressants should be asked about depressive symptoms at each prenatal visit, and appropriate fetal testing should be done. It may include the following:. - A detailed evaluation of fetal anatomy during the second trimester- If a pregnant woman takes paroxetine, echocardiography to evaluate the fetus's heart because in some studies, paroxetine appeared to increase the risk of congenital cardiac anomalies. To reduce the risk of withdrawal symptoms in the neonate, clinicians should consider tapering the dose of all antidepressants to the lowest effective dose during the third trimester. However, the benefits of tapering must be carefully balanced against the risk of symptom recurrence and postpartum depression. Postpartum depression is common, often unrecognized, and should be treated promptly. Periodic visits with a psychiatrist and/or social workers may be helpful.. References. # 1. Centers for Disease Control and Prevention (CDC): Update on overall prevalence of major birth defects--Atlanta, Georgia, 1978-2005. MMWR Morb Mortal Wkly Rep 57(1):1-5, 2008. 2. Feldkamp ML, Carey JC, Byrne JLB, Krikov S, Botto LD: Etiology and clinical presentation of birth defects: population based study. BMJ 357:j2249, 2017. Published 2017 May 30. doi:10.1136/bmj.j2249 3. U.S. Food and Drug Administration (FDA): FDA Approves First Vaccine for Pregnant Individuals to Prevent RSV in Infants. FDA News Release, August 21, 2023. 4. Garneau WM, Jones-Beatty S, Ufua MO, et al: Analysis of clinical outcomes of pregnant patients treated with nirmatrelvir and ritonavir for acute SARS-CoV-2 infection. JAMA Netw Open 5(11):e2244141, 2022. Published 2022 Nov 1. doi:10.1001/jamanetworkopen.2022.44141 5. Liggins GC, Howie RN: A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 50(4):515-525, 1972. 6. Bennett HA, Einarson A, Taddio A, et al: Prevalence of depression during pregnancy: systematic review [published correction appears in Obstet Gynecol 103(6):1344, 2004]. Obstet Gynecol 103(4):698-709, 2004. doi:10.1097/01.AOG.0000116689.75396.5f. More Information. The FDA's Content and Forms of Labeling for Human Prescription Drugs and Biological Products; Requirements for Pregnancy and Lactation Labeling: This document discusses the change in labeling for pregnancy, which eliminates the pregnancy categories (A, B, C, D, X) and replaces them with more helpful and detailed information. The new labeling requires a summary of the risks of drug use during pregnancy and lactation, data to support that summary, and relevant information to help health care professionals make prescribing decisions and advise women about drug use during pregnancy and lactation.. Teratogen Information System: This web site provides resources to help clinicians determine the risks of drugs (and of environmental exposures [eg, vaccines, infections]) during pregnancy. It provides expert information about .	None	None	None
91a1913b134d447f94a2e5e532a44619	MSD	子宫内膜异位症慢性子宫内膜炎	# Endometriosis. By James H. Liu, MD, Case Western Reserve University School of Medicine Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Apr 2024. In endometriosis, functioning endometrial cells are implanted in the pelvis outside the uterine cavity. Symptoms depend on location of the implants. The classic triad of symptoms is dysmenorrhea, dyspareunia, and infertility, but symptoms may also include dysuria and dyschezia. Severity of symptoms is not related to disease stage. Diagnosis is by direct visualization and sometimes biopsy, usually via laparoscopy. Imaging studies (transvaginal ultrasound, MRI) are useful in diagnosing more advanced cases (eg, endometriosis involving the ovary [endometrioma]). Treatments include nonsteroidal anti- inflammatory drugs, medications to suppress ovarian function and endometrial tissue growth, surgical ablation and excision of endometriotic implants, and, if disease is severe and no childbearing is planned, hysterectomy alone or hysterectomy with bilateral salpingo- oophorectomy.. Etiology and Pathophysiology \| Symptoms and Signs \| Diagnosis \| Treatment \| Key Points. Endometriosis is usually confined to the peritoneal or serosal surfaces of pelvic organs, commonly the ovaries, broad ligaments, posterior cul- de- sac, uterosacral ligaments, and peritoneum.. Less common sites include the fallopian tubes, rectovaginal septum, and serosal surfaces of the small and large intestines, ureters, bladder, vagina, cervix, surgical scars, and, more rarely, the lung, pleura, and pericardium.. Bleeding from peritoneal implants is thought to initiate sterile inflammation, followed by fibrin deposition, adhesion formation, and, eventually, scarring.. Prevalences of endometriosis in a meta- analysis of 17 studies were (1). - . Diagnosis of endometriosis may be delayed. The time from onset of symptoms to diagnosis varies from 4 to 11 years (2), with the average age at diagnosis being 28 years (3). Endometriosis also occurs in. # adolescents and, rarely, in premenarchal girls.. References. 1. Moradi Y, Shams-Beyranvand M, Khateri S, et al: A systematic review on the prevalence of endometriosis in women. Indian J Med Res. 2021;154(3):446-454. doi:10.4103/ijmr.IJMR_817_18 2. Arruda MS, Petta CA, Abraño MS, Benetti-Pinto CL: Time elapsed from onset of symptoms to diagnosis of endometriosis in a cohort study of Brazilian women. Hum Reprod. 2003;18(4):756-759. doi:10.1093/humrep/deg136 3. Singh S, Soliman AM, Rahal Y, et al: Prevalence, Symptomatic Burden, and Diagnosis of Endometriosis in Canada: Cross-Sectional Survey of 30 000 Women. J Obstet Gynaecol Can. 2020;42(7):829-838. doi:10.1016/j.jogc.2019.10.038. Etiology and Pathophysiology of Endometriosis. The most widely accepted hypothesis for the pathogenesis of endometriosis is that endometrial cells are transported from the uterine cavity during menstruation and subsequently become implanted at ectopic sites. Retrograde menstruation through the fallopian tubes is common and could transport endometrial cells intra- abdominally.. Other hypotheses for the pathogenesis of endometriosis include coelomic metaplasia (transformation of peritoneal mesothelium into endometrium- like glands); Mullerian rests (endometrium- like cells develop from residual embryologic Mullerian cells); transport of endometrial cells through the lymphatic or circulatory systems (1).. The increased incidence in first- degree relatives of women with endometriosis and in large twin studies (2) suggests that heredity is a factor.. Potential risk factors for endometriosis are. Family history of first- degree relatives with endometriosis Delayed childbearing or nulliparity Early menarche Late menopause Shortened menstrual cycles (< 27 days) with menses that are heavy and prolonged (> 8 days) Mullerian duct defects (eg, noncommunicating uterine horn remnant, cervical hypoplasia with obstruction of the uterine outflow tract) Exposure to diethylstilbestrol in utero. Potential protective factors seem to be. Multiple births Prolonged lactation. # Late menarche Long- term use of low- dose oral contraceptives (continuous or cyclic) Regular exercise (especially if begun before age 15, if done for . Microscopically, endometriotic implants consist of glands and stroma histologically identical to intrauterine endometrium. These tissues contain estrogen and progesterone receptors and thus usually grow, differentiate, and bleed in response to changes in hormone levels during the menstrual cycle; also, some endometriotic implants produce estrogen and prostaglandins. Implants may become self- sustaining or regress, as may occur during pregnancy (probably because progesterone levels are high). Ultimately, the implants cause inflammation and increase the number of activated macrophages and the production of proinflammatory cytokines.. In patients with severe endometriosis and distorted pelvic anatomy, the infertility. rate is high, possibly because the distorted anatomy and inflammation interfere with mechanisms of ovum pickup, oocyte fertilization, and tubal transport. Reasons for impaired fertility are unclear but may include:. Increased incidence of luteinized unruptured ovarian follicle syndrome (trapped oocyte) Increased peritoneal prostaglandin production or peritoneal macrophage activity that may affect fertilization, sperm, and oocyte function Nonreceptive endometrium (because of luteal phase dysfunction or other abnormalities). Etiology and pathophysiology references. 1. Burney RO, Giudice LC: Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511-519. doi:10.1016/j.fertnstert.2012.06.029 2. Saha R, Pettersson HJ, Svedberg P, et al: Heritability of endometriosis. Fertil Steril 104 (4):947-952, 2015. doi: 10.1016/j.fertnstert.2015.06.035. Symptoms and Signs of Endometriosis. Some women with extensive endometriosis are asymptomatic; some with minimal disease have incapacitating pain.. The classic triad of symptoms of endometriosis is dysmenorrhea, dyspareunia, and infertility. Cyclic midline pelvic pain preceding or during menses (dysmenorrhea) and pain in the abdomen during sexual intercourse (deep dyspareunia) are typical and can be progressive and chronic (lasting . Endometriosis is suspected in women with infertility, particularly if accompanied by pelvic pain.. Adnexal masses (endometriomas) are also typical. Intermenstrual bleeding is possible; ovarian dysfunction can cause premature loss of estrogen and progesterone production from the ovarian follicle, leading to premature breakdown of the endometrial support.. # Interstitial cystitis with suprapubic pain, dysuria, urinary frequency, and urge incontinence is common in women with endometriosis (1).. Symptoms often lessen or resolve during pregnancy. Endometriosis tends to become inactive after menopause because estrogen and progesterone levels decrease.. Symptoms and signs can vary depending on location of implants.. Ovaries: Formation of an endometrioma (a cystic mass localized to an ovary), which occasionally ruptures or leaks, causing acute abdominal pain and peritoneal signs Adnexal structures: Formation of adnexal adhesions, resulting in a pelvic mass or pain Bladder: Dysuria, hematuria, suprapubic or pelvic pain (particularly during urination), urinary frequency, urge incontinence, or a combination Large intestine: Dyschezia, abdominal bloating, diarrhea or constipation, or rectal bleeding during menses Extrapelvic structures: Vague abdominal pain (sometimes). Pelvic examination may be normal, or findings may include cervix deviated from midline, retroverted and fixed uterus, fixed ovarian mass, ovarian tenderness, thickened or nodular rectovaginal septum, or nodules on the uterosacral ligament. Rarely, lesions can be seen on the vulva or cervix or in the vagina, umbilicus, or surgical scars.. Symptoms and signs reference. 1. Wu CC, Chung SD, Lin HC: Endometriosis increased the risk of bladder pain syndrome/interstitial cystitis: A population-based study. Neurourol Urodyn. 2018;37(4):1413-1418. doi:10.1002/nau.23462. Diagnosis of Endometriosis. Direct visualization, usually during pelvic laparoscopy Biopsy Sometimes pelvic ultrasound or MRI. Diagnosis of endometriosis is suspected based on typical symptoms. Misdiagnosis as pelvic inflammatory disease, urinary tract infection, or irritable bowel syndrome is common. Negative cervical and/or urine cultures suggest the possibility of endometriosis.. The diagnosis of endometriosis must be confirmed by direct visualization, usually via pelvic laparoscopy but sometimes via laparotomy, pelvic examination, sigmoidoscopy, or cystoscopy. Biopsy is not required, but results confirm the diagnosis.. Macroscopic appearance (eg, clear, red, blue, brown, black) and size of implants vary during the menstrual cycle. However, typically, early lesions are clear or red (hemorrhagic). As the blood in the. # lesions oxidizes, they turn purple, then brown; they then turn to bluish or purplish brown spots that are . Microscopically, endometrial glands and stroma are usually present. Stromal elements in the absence of glandular elements indicate a rare variant of endometriosis called stromal endometriosis.. Imaging tests may not reliably detect endometriosis. However, a pelvic ultrasound or MRI showing an ovarian cyst consistent with an endometrioma is highly suggestive of the diagnosis. The presence and size of ovarian endometriomas are part of the staging system for endometriosis (stage III: small endometriomas; stage IV: large endometriomas), and a decrease in endometrioma size can show response to treatment.. Because endometrial tissue has a unique MR signal, MRI is becoming increasingly useful for evaluating patients who may have endometriosis (1). T1- and T2- weighted MRI can detect some endometriotic lesions in the pelvis, particularly larger lesions. Hemorrhage in the fallopian tubes or in an ovarian cyst without an increase in blood flow suggests endometriosis. Multiple large areas of endometriosis located in the cul de sac indicate severe (stage IV) endometriosis.. No laboratory tests contribute to the diagnosis of endometriosis, although biomarkers such as plasma microRNA are being studied in clinical trials (2).. Pearls & Pitfalls. - Consider endometriosis if patients have persistent cyclic pelvic pain, particularly if they also have dyspareunia or infertility.. Staging endometriosis helps physicians formulate a treatment plan and evaluate response to therapy. According to the American Society for Reproductive Medicine, endometriosis may be classified as stage I (minimal), II (mild), III (moderate), or IV (severe), based on. - Number, location, and depth of implants- Presence of endometriomas and filmy or dense adhesions (see table Stages of Endometriosis). # Other classification or clinical outcome prediction systems have been developed for endometriosis, but few have been found to be clinically useful. The endometriosis fertility index (EFI) has been found to correlate with spontaneous pregnancy rates (without use of assisted reproductive technologies) after surgery for endometriosis, however results varied across studies (3).. Diagnosis references. 1. Guerriero S, Saba L, Pascual MA, et al: Transvaginal ultrasound vs magnetic resonance imaging for diagnosing deep infiltrating endometriosis: systematic review and meta-analysis. Ultrasound Obstet Gynecol 51 (5):586-595, 2018. doi: 10.1002/uog.189612. Nisenblat V, Bossuyt PM, Shaikh R, et al: Blood biomarkers for the non-invasive diagnosis of endometriosis. Cochrane Database Syst Rev 2016;2016(5):CD012179. Published 2016 May 1. doi:10.1002/14651858.CD0121793. Vesali S, Razavi M, Rezaeinejad M, et al: Endometriosis fertility index for predicting non-assisted reproductive technology pregnancy after endometriosis surgery: a systematic review and meta-analysis. BJOG. 2020;127(7):800-809. doi:10.1111/1471-0528.16107. Treatment of Endometriosis. - Nonsteroidal anti-inflammatory drugs (NSAIDs)- Estrogen-progestin contraceptives- Medications to suppress ovarian function- Surgical resection or ablation of endometriotic tissue- Total abdominal hysterectomy with or without bilateral salpingo-oophorectomy, if disease is severe and the patient has completed childbearing. Patients with suspected endometriosis are often treated empirically first. If symptoms are controlled with noninvasive measures, surgery can be avoided.. # Symptomatic medical treatment begins with analgesics (usually NSAIDs) and hormonal contraceptives. If these are ineffective, patients are counseled about proceeding with more intensive pharmacologic treatment (GnRH analogs, aromatase inhibitors, or danazol) or undergoing laparoscopy for confirmation of the diagnosis and concomitant treatment.. Diagnostic laparoscopy is done to detect endometriosis or other etiologies of symptoms. If endometriosis is present, lesions are treated during the same procedure. Conservative surgical treatment is excision or ablation of endometriotic implants and removal of pelvic adhesions. Ovarian cystectomy can be performed if an ovarian endometrioma is present. More definitive treatment must be individualized based on the patient's age, symptoms, and desire to preserve fertility and on the extent of the disorder.. Following surgical treatment of endometriosis, hormonal contraceptives or other medications are typically given. In most patients, endometriosis recurs within 6 months to 1 year after surgery alone or when medications are discontinued, unless ovarian function is permanently and completely ablated.. Total abdominal hysterectomy with or without bilateral salpingo- oophorectomy is considered definitive treatment of endometriosis. However, endometriosis can recur even after hysterectomy in premenopausal women or those on estrogen therapy.. Pharmacologic therapy. Usually, NSAIDs are used to relieve pain. They may be all that is needed if symptoms are mild and the patient has completed childbearing.. Medications that suppress ovarian function inhibit the growth and activity of endometriotic implants. Pharmacologic treatment is effective for controlling pain but does not change fertility rates in women with minimal or mild endometriosis.. The following hormonal contraceptives are commonly used as initial therapy:. - Continuous combination (estrogen-progestin) contraceptives- Progestins, for patients who have contraindications to estrogen therapy. The following medications are usually used only if symptoms are not well controlled with NSAIDs or hormonal contraceptives:. - Gonadotropin-releasing hormone (GnRH) agonists (eg, leuprolide) and antagonists (eg, elagolix)- Aromatase inhibitors (eg, anastrozole, letrozole)- Danazol. GnRH agonists initially increase hypothalamic GnRH secretion, but continued use then temporarily decreases pituitary release of follicle- stimulating hormone (FSH), resulting in a decrease in estrogen production by the ovaries; however, treatment is limited to . # The GnRH antagonist elagolix directly decreases GnRH secretion and thus suppresses pituitary release of FSH and estrogen production by the ovaries. It is available in 2 different doses; the higher dose is available to treat dyspareunia as well as other symptoms of endometriosis. Long- term use may result in bone loss. If treatment lasts . The GnRH antagonist relugolix combined with estradiol 1 mg and norethindrone . Aromatase inhibitors may be considered when GnRH analogs are ineffective in suppressing endometriosis, because some endometriosis implants have intrinsic aromatase activity and can produce estrogen from conversion of circulating androgen precursors (1).. Danazol, a synthetic androgen and an antigonadotropin, inhibits ovulation. However, its androgenic adverse effects limit its use.. Cyclic or continuous combination oral contraceptives given after GnRH analogs or aromatase inhibitors may slow disease progression and are warranted for women who are not planning to conceive a pregnancy immediately after discontinuing those more intensive medications.. Surgery. Most women with moderate to severe endometriosis are treated most effectively by ablating or excising as many implants as possible while restoring pelvic anatomy and preserving fertility as much as possible. Superficial endometriotic implants can be ablated. Deep, extensive implants should be excised.. Specific indications for laparoscopic surgery include. - Moderate to severe pelvic pain that does not respond to medications- Endometrioma- Significant pelvic adhesions- Fallopian tube obstruction- A desire to become pregnant within a few months after surgery- Dyspareunia (surgical treatment is second-line treatment unless performed during diagnostic laparoscopy). Laparoscopic ablation or resection is the most common surgical procedure for an endometriotic implant; peritoneal or ovarian lesions can sometimes be electrocauterized, excised, or, uncommonly, vaporized with a laser. Endometriotic implants usually recur within 1 to 2 years without medications. Hormonal treatment of endometriosis is contraindicated during pregnancy, so patients with infertility are usually counseled to try to conceive soon after surgery.. Ovarian cystectomy is indicated if an ovarian endometrioma is present.. # After laparoscopy or cystectomy, fertility rates are inversely proportional to the severity of endometriosis. If resection is incomplete, GnRH agonists are sometimes given during the perioperative period, but whether this tactic increases fertility rates is unclear. Laparoscopic resection of the uterosacral ligaments with electrocautery or a laser may reduce midline pelvic pain.. Rectovaginal endometriosis, the most severe form of the disease, can be treated with the usual treatments for endometriosis; however, colon resection or surgery may be required to prevent obstruction of the colon.. Hysterectomy with or without bilateral salpingo- oophorectomy should usually be reserved for patients who have moderate to severe pelvic pain, have completed childbearing, and prefer a definitive procedure. Hysterectomy removes adhesions or implants that adhere to the uterus or cul- de- sac.. If women . Treatment reference. 1. Ferrero S, Gillott DJ, Venturini PL, Remorgida V: Use of aromatase inhibitors to treat endometriosis-related pain symptoms: a systematic review. Reprod Biol Endocrinol. 2011;9:89. Published 2011 Jun 21. doi:10.1186/1477-7827-9-89. Key Points. - Endometriosis is the presence of endometrial tissue implanted in the pelvis outside the uterine cavity, most commonly the ovaries, broad ligaments, posterior cul-de-sac, uterosacral ligaments, and peritoneum.- The classic triad of symptoms is dysmenorrhea, dyspareunia, and infertility, but symptoms may also include dysuria and dyschezia.- For suspected endometriosis, treat pain with analgesics (eg, NSAIDs) and hormonal contraceptives.- If initial medications are ineffective, proceed with more intensive pharmacologic treatment (GnRH analogs, aromatase inhibitors, or danazol) or laparoscopy.- Perform diagnostic laparoscopy to confirm the diagnosis with visual inspection; a biopsy is not mandatory but may aid in the diagnosis.- During laparoscopy, ablate or excise as many implants as possible, lyse adhesions to restore normal pelvic anatomy, and remove endometriomas; depending on patient. # fertility goals, usually use medications that suppress ovarian function to inhibit the growth and activity of endometriotic implants.- Endometriosis has a staging system based on severity; the stage does not correlate with severity of symptoms.- Reserve hysterectomy with or without bilateral salpingo- oophorectomy for women who have completed childbearing or who prefer a definitive procedure..	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6942487e54784be5aa89d8ea436f5396	MSD	子宫内膜癌	# Endometrial Cancer. (Uterine Cancer). By Pedro T. Ramirez, MD, Houston Methodist Hospital; Gloria Salvo, MD, MD Anderson Cancer Center Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Sept 2023. Endometrial cancer is usually endometrioid adenocarcinoma. Typically, it manifests as postmenopausal uterine bleeding. Diagnosis is by biopsy. Staging is surgical. Treatment requires hysterectomy, bilateral salpingo- oophorectomy, and, for high- risk histology, usually pelvic and para- aortic lymphadenectomy. For advanced cancer, radiation therapy, endocrine therapy, or chemotherapy is usually indicated.. Etiology \| Pathology \| Symptoms and Signs \| Diagnosis \| Treatment \| Prognosis \| Key Points \| More Information. Endometrial cancer is more common in high- resource countries where obesity rates are high. In the United States, this cancer is the 4th most common cancer among women. The American Cancer Society estimates that in 2023, approximately 66,200 new cases of endometrial cancer will be diagnosed and that approximately 13,030 women will die of this cancer (1). Approximately . In the United States, endometrial cancer incidence is higher than average in Black, American Indian, and Alaska Native women (Hispanic 26.1/100,000; Non- Hispanic American Indian or Alaska Native 28.8; Non- Hispanic Asian or Pacific Islander 22.7; Non- Hispanic Black 29.4; Non- Hispanic White 27.6) (3). Mortality is highest in Black women (Hispanic 4.3/100,000; Non- Hispanic American Indian or Alaska Native 4.5; Non- Hispanic Asian or Pacific Islander 3.5; Non- Hispanic Black 9.1; Non- Hispanic White 4.6) (3).. Endometrial cancer affects mainly postmenopausal women. Median patient age at diagnosis is 63 years (3). Most cases are diagnosed in women aged 55 to 64 years.. General references. 1. American Cancer Society: Key Statistics for Endometrial Cancer. Accessed July 14, 2023. 2. American Cancer Society: Cancer Facts & Figures 2023. Atlanta: American Cancer Society. Accessed July 14, 2023.. # 3. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program: Cancer Stat Facts: Uterine Cancer. Accessed July 14, 2023. Etiology of Endometrial Cancer. Risk factors for endometrial cancer are. Unopposed estrogen (high serum levels of estrogen and no or low progesterone)- Age . Increased exposure to extrinsic or intrinsic estrogen may be associated with. Obesity Polycystic ovary syndrome or other ovulatory dysfunction Estrogen therapy without progesterone Nulliparity Early menarche Late menopause Estrogen- producing tumors. Most endometrial cancers are caused by sporadic mutations. However, in approximately . Pathology of Endometrial Cancer. Endometrial cancer is usually preceded by endometrial hyperplasia. Endometrial carcinoma is commonly classified into 2 types.. Type I (non- aggressive) tumors are more common, are usually estrogen- responsive, and are usually diagnosed in women with obesity and at younger ages (perimenopause or early in menopause). They are preceded by endometrial hyperplasia. These tumors are usually low- grade; the prognosis is good. Endometrioid adenocarcinoma (grades 1 and 2) is the most common histology. These tumors may be microsatellite instability and have mutations in PTEN, PIK3CA, KRAS, and CTNNB1.. # Type II (aggressive) tumors are usually high- grade and include grade 3 endometrioid carcinomas and tumors with nonendometrioid histology (eg, serous, clear cell, mixed cell, undifferentiated, mixed, mesonephric- like, gastrointestinal mucinous- type, and carcinosarcoma). They tend to occur in older women. Approximately 10 to . Endometrioid adenocarcinomas account for approximately 75 to . There are 4 distinct molecular subtypes of endometrioid endometrial carcinomas (4):. - POLE ultramutated (POLEmut): Characterized by pathogenic mutations in the exo nuclease domain of DNA polymerase-ε, resulting in an ultra-high tumor mutational burden and a good prognosis- Mismatch repair-deficient (MMRd): Has loss of mismatch repair proteins, resulting in microsatellite instability and an intermediate prognosis- No specific molecular profile (NSMP): Has no single identifying molecular feature and tumor stage- and grade-dependent outcomes and an intermediate prognosis- p53-mutant: Has a low tumor mutational burden and high somatic copy-number alterations resulting in a poor prognosis. Determining the molecular subtype, if feasible, adds valuable information to the standard clinicopathological risk factors to classify patients with endometrial cancer into risk groups, predict prognosis, and guide treatment recommendations.. Uterine papillary serous carcinomas (10%), clear cell carcinomas (< 5%), and carcinosarcomas (< 5%) are considered more aggressive, high- risk histologies and are associated with a higher incidence of extrauterine disease at presentation. Carcinosarcomas used to be categorized as sarcomas but are now considered and treated as high- grade epithelial tumors (carcinomas).. Mucinous carcinomas are typically low- grade; the prognosis is good. KRAS mutations are common in these tumors.. Other histopathologic types of endometrial carcinoma are neuroendocrine, undifferentiated, and mixed carcinoma (composed of more than one type, with at least . Endometrial cancer may spread as follows:. - From the surface of the uterine cavity to the cervical canal- Through the myometrium to the serosa and into the peritoneal cavity- Via the lumen of the fallopian tube to the ovary, broad ligament, and peritoneal surfaces- Via the bloodstream, leading to distant metastases- Via the lymphatics. The higher (more undifferentiated) the grade of the tumor, the greater the likelihood of deep myometrial invasion, pelvic or para- aortic lymph node metastases, or extrauterine spread.. # Pathology references. Pathology references1. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al: Integrated genomic characterization of endometrial carcinoma [published correction appears in Nature 2013 Aug 8;500(7461):242]. Nature 497(7447):67- 73, 2013. doi:10.1038/nature121132. Faber MT, Frederiksen K, Jensen A, et al: Time trends in the incidence of hysterectomy- corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978- 2014. Gynecol Oncol 146(2):359- 367, 2017. doi:10.1016/j.ygyno.2017.05.0153. Lu KH, Broaddus RR: Endometrial cancer. N Engl J Med 383(21):2053- 2064, 2020. doi:10.1056/NEJMra15140104. WHO Classification of Tumours Editorial Board: 2020 WHO Classification of Tumours, 5th Edition, Volume 4: Female Genital Tumors.. Symptoms and Signs of Endometrial Cancer. Symptoms and Signs of Endometrial CancerMost (> 90%) women with endometrial cancer present with abnormal uterine bleeding (eg, postmenopausal bleeding, premenopausal intermenstrual bleeding, ovulatory dysfunction). Depending on age and risk factors, 6 to 19% of women with postmenopausal bleeding have endometrial cancer (1).. Symptoms and signs reference. Symptoms and signs reference1. Clarke MA, Long BJ, Del Mar Morillo A, et al: Association of endometrial cancer risk with postmenopausal bleeding in women: a systematic review and meta- analysis. JAMA Intern Med 178(9):1210- 1222, 2018. doi:10.1001/jamainternmed.2018.2820. Diagnosis of Endometrial Cancer. Endometrial biopsy. The following suggest endometrial cancer:. Postmenopausal bleeding Abnormal bleeding in premenopausal women (intermenstrual bleeding, ovulatory dysfunction), particularly in women . If endometrial cancer is suspected, outpatient endometrial biopsy is done; sensitivity is . If biopsy results are inconclusive or suggest precancer (eg, complex hyperplasia with atypia) or car- r dilation and curettage (D & C), often with hysteroscopy, is done.. # Once endometrial cancer is diagnosed, pretreatment evaluation includes a complete blood count (CBC) and other blood tests (serum electrolytes, kidney, and liver). A chest x- ray is done. If an abnormality is seen on chest x- ray, CT should be done. The following should be considered:. Pelvic MRI to determine the origin of the tumor (cervix or uterus) and local extension- For high- grade carcinomas, chest, abdomen, and pelvic CT- If metastatic disease is suspected based on physical examination or blood tests, positive emission tomography (PET)- CT. Because endometrial cancer sometimes results from an inherited mutation, genetic counseling and/or testing should be considered if patients are . Staging. Staging of endometrial cancer is based on non- aggressive versus aggressive histology; extent of spread, including invasion depth, extension to surrounding structures, and extrauterine or lymph node metastases; lymphovascular space invasion; and molecular classification (see table FIGO Staging of Uterine Corpus Carcinoma and Carcinosarcoma).. Staging is surgical and includes exploration of the abdomen and pelvis, biopsy or excision of suspicious extrauterine lesions, total abdominal hysterectomy, and, in patients with high- risk features (grade 1 or 2 cancer plus deep myometrial invasion, grade 3 cancer, all cancers with high- risk histology), pelvic and para- aortic lymphadenectomy. Staging can be done via laparotomy, laparoscopy, or robotic- assisted surgery. If cancer appears to be confined to the uterus, an alternative to pelvic and para- aortic lymphadenectomy is sentinel lymph node mapping.. # # # * In all stages, the grade of the lesion, the histologic type, and LVSI must be recorded.. † If available and feasible, molecular classification testing (POLEmut, MMRd, NSMP, p53abn) is encouraged in all patients with endometrial cancer for prognostic risk- group stratification and as factors that might influence adjuvant and systemic treatment decisions.. ‡ Low- grade endometrioid endometrial carcinomas (EECs) involving both the endometrium and the ovary are considered to have a good prognosis, and no adjuvant treatment is recommended, only if all criteria are met to distinguish disease limited to low- grade endometrioid carcinomas involving the endometrium and ovaries (Stage IA3) from extensive spread of the endometrial carcinoma to the ovary (Stage IIIA1). These criteria are: (1) no more than superficial myometrial invasion is present (< 50%); (2) absence of extensive/substantial LVSI; (3) absence of additional metastases; and (4) the ovarian tumor is unilateral, limited to the ovary, without capsule invasion/rupture.. § LVSI as defined as extensive/substantial, ≥ 5 vessels involved.. ¶ Micrometastases are considered to be metastatic involvement (pN1 (m)). The prognostic significance of isolated tumor cells (ITCs) is unclear. The presence of ITCs should be documented and is regarded as pN0(i+). According to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th ed, macrometastases are > 2 mm in size, micrometastases are 0.2–2 mm and/or > 200 cells, and isolated tumor cells are ≥ 0.2 mm and ≤ 200 cells.. ¶ Micrometastases are considered to be metastatic involvement (pN1 (m)). The prognostic significance of isolated tumor cells (ITCs) is unclear. The presence of ITCs should be documented and is regarded as pN0(i+). According to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th ed, macrometastases are > 2 mm in size, micrometastates are 0.2–2 mm and/or > 200 cells, and isolated tumor cells are ≥ 0.2 mm and ≤ 200 cells.. Berek JS, Matias- Guiu X, Creutzberg C, et al: FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet 2023;162(2):383- 394. doi:10.1002/ijgo.14923. # - FIGO Stages I and II are based on surgical/anatomical and histologic findings. For POLEmut or p53abn status, the FIGO stage is modified in the early stage of the disease. This is depicted in the FIGO stage by the addition of "m" for molecular classification, and a subscript is added to denote POLEmut or p53abn status. MMRd or NSMP status do not modify early FIGO stages; however, these molecular classifications should be recorded for the purpose of data collection. When molecular classification reveals MMRd or NSMP, it should be recorded as Stage Im or Stage Im and Stage Ilm or Stage Ilm.- FIGO Stages III and IV are based on surgical/anatomical findings. The stage category is not modified by molecular classification; however, the molecular classification should be recorded if known, as Stage IlIm or Stage IVm with the appropriate subscript for the purpose of data collection. For example, when molecular classification reveals p53abn, it should be recorded as Stage Illm or Stage IVm.. Sentinel lymph node mapping in endometrial cancer. Sentinel lymph node (SLN) mapping can be considered for the surgical staging of cancer that appears confined to the uterus—stage I (2). In many centers, SLN mapping is currently the standard for cancers with high- risk histology—ie, papillary serous carcinoma, clear cell carcinoma, and carcinosarcoma (3).. The role of SLN mapping in endometrial cancer has been evaluated in several studies. The FIRES trial showed that in patients with clinical stage I endometrial cancer, SLN mapping with indocyanine green (ICG) is highly accurate for the diagnosis of endometrial cancer metastases; it was recommended as a replacement for complete lymphadenectomy (4). SLN mapping is done as for cervical cancer using the same tracers (blue dye, technetium- 99 . Where to inject the tracer in patients with endometrial carcinoma has been controversial. Evidence suggests that in endometrial cancer, cervical injection with ICG results in a higher detection rate than hysteroscopic injection, and anatomic nodal distribution is similar (6). Dye is usually injected into the cervix both superficially (1 to . If sentinel lymph nodes are identified bilaterally, no lymphadenectomy is indicated, regardless of tumor characteristics. If one side (or both) has no identified sentinel node, complete lymphadenectomy is necessary on that side. Whether dissection of the para- aortic nodes is necessary is left up to surgeon discretion.. The most common locations of pelvic SLNs are. - Medial to the external iliac blood vessels- Ventral to the internal iliac blood vessels- In the superior part of the obturator region. Less common locations are the iliac and/or presacral regions.. A complete pelvic lymphadenectomy should be done when any of the following occur:. # Mapping does not detect any SLNs in patients with high- risk tumors. A hemipelvis cannot be mapped. There are any suspicious or grossly enlarged nodes, regardless of mapping.. An ongoing phase III randomized trial (ENDO- 3) is evaluating SLN biopsy with no retroperitoneal node dissection compared with no nodal dissection in clinical stage 1 FIGO grade 1 to 3 endometrioid, clear cell, serous, or carcinosarcoma (Z).. Diagnosis references. 1. ACOG (American College of Obstetricians and Gynecologists) Committee Opinion No. 734: The role of transvaginal ultrasonography in evaluating the endometrium of women with postmenopausal bleeding. Obstet Gynecol 131 (5):e124-e129, 2018. doi:. 10.1097/AOG.0000000000002631. 2. Cusimano MC, Vicus D, Pulman K, et al: Assessment of sentinel lymph node Biopsy vs lymphadenectomy for intermediate- and high-grade endometrial cancer staging. JAMA Surg 156 (2):157-164, 2021. doi: 10.1001/jamasurg.2020.5060. 3. Schlappe BA, Weaver AE, McGree ME, et al: Multicenter study comparing oncologic outcomes after lymph node assessment via a sentinel lymph node algorithm versus comprehensive pelvic and paraaortic lymphadenectomy in patients with serous and clear cell endometrial carcinoma. Gynecol Oncol 156 (1):62-69, 2020. doi: 10.1016/j.ygyno.2019.11.002. 4. Rossi EC, Kowalski LD, Scalici J, et al: A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): A multicentre, prospective, cohort study. Lancet Oncol 18 (3):384-392, 2017. doi: 10.1016/S1470-2045(17)30068-2. 5. Segarra-Vidal B, Dinoi G, Zorrilla-Vaca A, et al: Minimally invasive compared with open hysterectomy in high-risk endometrial cancer. Obstet Gynecol 138 (6):828-837, 2021. doi: 10.1097/AOG.0000000000004606. 6. Rossi EC, Jackson A, Ivanova A, Boggess JE: Detection of sentinel nodes for endometrial cancer with robotic assisted fluorescence imaging: cervical versus hysteroscopic injection. Int J Gynecol Cancer 23 (9):1704-1711, 2013. doi: 10.1097/IGC.0b013e3182a616f6. 7. Obermair A, Nicklin J, Gebski V, et al: A phase III randomized clinical trial comparing sentinel node biopsy with no retroperitoneal node dissection in apparent early-stage endometrial cancer - ENDO-3: ANZGOG trial 1911/2020. Int J Gynecol Cancer 31(12):1595-1601, 2021. doi:10.1136/ijgc-2021-003029. Treatment of Endometrial Cancer. - Total hysterectomy and bilateral salpingo-oophorectomy- Pelvic and para-aortic lymphadenectomy for grade 1 or 2 with deep (> 50%) myometrial invasion, any grade 3, and for all cancers with high-risk histology- Pelvic radiation therapy with or without chemotherapy for stage II or III- Multimodal therapy usually recommended for stage IV. # (See also National Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms.). Endometrial cancer should be removed en bloc, usually by doing a total hysterectomy and bilateral salpingo- oophorectomy. Intrapertoneal tumor fragmentation or morcellation must be avoided.. Surgery can be done by any route (vaginal, open, robotic, laparoscopic). For patients with tumors confined to the uterus, minimally invasive surgery is the preferred approach because its rate of perioperative and postoperative complications is lower, hospital stays are shorter (1), cost is lower, and oncologic outcomes are comparable (2).. Evidence generally supports comparable oncologic outcomes for laparoscopic surgery and laparotomy. In the Gynecologic Oncology Group LAP2 study, women with clinical stage I to IIA uterine cancer were randomly assigned to have laparoscopic surgery or laparotomy in a 2 to 1 ratio. The study did not demonstrate the statistical noninferiority of the laparoscopic approach. However, after a median follow- up time of 59 months, survival rates for both approaches were similar; 5- year overall survival rate was . In patients with grade 1 or 2 endometrial cancer and . If patients have any of the following, pelvic and para- aortic lymphadenectomy is also done (unless SLN mapping identified bilateral SLNs):. - Grade 1 or 2 cancer with deep (. If SLNs are identified bilaterally, no lymphadenectomy is indicated, regardless of tumor characteristics. If a sentinel node is not identified on one side, complete lymphadenectomy is necessary on that side.. Stage II or III endometrial cancer requires pelvic radiation therapy with or without chemotherapy. Treatment of stage III cancer must be individualized, but surgery is an option; generally, patients who have combined surgery and radiation therapy have a better prognosis. Except in patients with bulk- - parametrial disease, a total abdominal hysterectomy and bilateral salpingo- oophorectomy s done.. # Treatment of stage IV endometrial cancer is variable and patient- dependent but typically involves a combination of surgery, radiation therapy, and chemotherapy. Occasionally, endocrine therapy should also be considered.. Treatment of stage IV endometrial cancer is variable and patient- dependent but typically involves a combination of surgery, radiation therapy, and chemotherapy. Occasionally, endocrine therapy should also be considered (6).. Several cytotoxic drugs (particularly carboplatin plus paclitaxel) are effective. They are given mainly to women with metastatic or recurrent cancer. Another option is doxorubicin.. For advanced cancer, chemotherapy with carboplatin and paclitaxel has been the standard. However, recent data support the use of lenvatinib, a multitargeted tyrosine kinase inhibitor of VEGF (vascular endothelial growth factor) receptors, and pembrolizumab, a monoclonal antibody that inhibits programmed cell death- 1 (PD- 1) activity. A recent phase II trial showed an objective response rate of . Advanced or recurrent cancer. Several studies have shown a benefit for more targeted therapy for recurrent cancer as an alternative to standard chemotherapy (usually carboplatin and paclitaxel). In a phase I trial of patients with recurrent endometrial cancer, the combination of everolimus (an mTOR inhibitor) and letrozole (an aromatase inhibitor) showed a clinical benefit rate of . In patients with recurrent uterine papillary serous carcinoma, standard chemotherapy with carboplatin and paclitaxel has been the routine recommendation. However, recent data from a prospective phase II trial suggest that adding trastuzumab provides further benefit. In this trial, patients who had uterine serous carcinoma and who tested positive for human epidermal growth factor receptor 2 (HER2)/neu were randomized to either carboplatin plus paclitaxel (control arm) for 6 cycles or carboplatin plus paclitaxel plus IV trastuzumab (experimental arm). The addition of trastuzumab increased progression- free survival from 8 months to 12.6 months (9).. The combination of chemotherapy and immunotherapy has shown synergistic effects in endometrial cancer treatment. In a phase III global randomized double- blind placebo- controlled trial, dostarlimab plus carboplatin- paclitaxel compared with placebo plus carboplatin- paclitaxel significantly increased progression- free survival (PFS) among patients with advanced (stage III or IV) or recurrent endometrial cancer (PFS at 24 months was . Adding pembrolizumab to chemotherapy appears to provide additional PFS benefit for patients with advanced or recurrent endometrial cancer. A phase III randomized double- blind placebo- cor in patients with stage III- IVB mismatch repair- deficient endometrial cancer treated with cher. (paclitaxel plus carboplatin) with pembrolizumab compared with chemotherapy with placebo found. # increased PFS in the pembrolizumab group (PFS . Fertility preservation in endometrial hyperplasia and early endometrial cancer. Patients with complex endometrial hyperplasia and atypia have up to a . If young patients with grade 1 tumors and no myometrial invasion (documented by MRI) wish to preserve fertility, progestin alone is an option. approximately 46 to . Alternatively, use of a levonorgestrel- releasing intrauterine device (IUD) is being increasingly used to treat patients with complex atypical hyperplasia or grade 1 endometrial cancer. In a prospective, single- arm trial, the 12- month pathologic response rate was . Surgery is recommended if conservative treatment is not effective (endometrial cancer is still present after 6 to 9 months of treatment) or if patients have completed childbearing. Fertility- sparing treatment is contraindicated in patients with high- grade endometrioid adenocarcinomas, uterine papillary serous carcinoma, clear cell carcinoma, or carcinosarcoma.. In young women with stage IA or IB endometrioid adenocarcinoma, ovarian preservation is safe and recommended.. High-risk histologies. Uterine papillary serous carcinoma, clear cell carcinomas, and carcinosarcomas are considered histologically aggressive, high- risk cancers and are thus more likely to have spread outside the uterus at presentation.. Multimodality therapy is typically recommended for these histologically aggressive endometrial tumors. Primary treatment includes abdominal hysterectomy, bilateral salpingo- oophorectomy with pelvic and para- aortic lymphadenectomy, and omental and peritoneal biopsies.. In patients with gross extrauterine disease, cytoreduction should be done to reduce the bulk of the tumor to no gross residual disease.. Adjuvant therapy for papillary serous and clear cell carcinomas depends on the stage:. - Stage IA without myometrial invasion and without residual disease in the hysterectomy specimen: Observation and close follow-up (an acceptable approach). # Other stage IA and IB or stage II cancers: Usually vaginal brachytherapy followed by systemic chemotherapy with carboplatin and paclitaxel More advanced disease: Standard chemotherapy with carboplatin and paclitaxel. Adjuvant therapy for carcinosarcoma also depends on the stage:. Stage IA without myometrial invasion and without residual disease in the hysterectomy specimen: Observation and close follow- up (an acceptable approach) All other stages: Usually systemic chemotherapy with ifosfamide plus paclitaxel. Treatment references. 1. Walker JL, Piedmonte MR, Spirtos NM, et al: Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. Clin Oncol 27 (32):5331-5336, 2009. doi: 10.1200/JCO.2009.22.32482. Galaal K, Donkers H, Bryant A, Lopes AD: Laparoscopy versus laparotomy for the management of early stage endometrial cancer. Cochrane Database Syst Rev 10 (10):CD006655, 2018. doi: 10.1002/14651858.CD006655.pub33. Walker JL, Piedmonte MR, Spirtos NM, et al: Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study. J Clin Oncol 30 (7):695-700, 2012. doi: 10.1200/JCO.2011.38.86454. Janda M, Gebski V, Davies CC, et al: Effect of total laparoscopic hysterectomy vs total abdominal hysterectomy on disease-free survival among women with stage I endometrial cancer: A randomized clinical trial. JAMA 317 (12):1224-1233, 2017. doi: 10.1001/jama.2017.20685. Kumar S, Podratz KC, Bakkum-Gamez JN, et al: Prospective assessment of the prevalence of pelvic, paraaortic and high paraaortic lymph node metastasis in endometrial cancer. Gynecol Oncol 132(1):38-43, 2014. doi:10.1016/j.ygyno.2013.10.0026. Decruze SB, Green JA: Hormone therapy in advanced and recurrent endometrial cancer: a systematic review. Int J Gynecol Cancer 17(5):964-978, 2007. doi:10.1111/j.1525-1438.2007.00897.x7. Makker V, Rasco D, Vogelzang NJ, et al: Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: An interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 20 (5):711-718, 2019. doi: 10.1016/S1470-2045(19)30020-88. Slomovitz BM, Jiang Y, Yates MS, et al: Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol 33 (8):930-936, 2015. doi: 10.1200/JCO.2014.58.34019. Fader AN, Roque DM, Siegel E, et al: Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu. J Clin Oncol 36 (20):2044-2051, 2018. doi: 10.1200/JCO.2017.76.596610. Mirza MR, Chase DM, Slomovitz BM, et al: Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N Engl J Med 388(23):2145-2158, 2023. doi:10.1056/NEJMoa221633411. Eskander RN, Sill MW, Beffa L, et al: Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. N Engl J Med 388(23):2159-2170, 2023. doi:10.1056/NEJMoa230231212. Westin SN, Fellman B, Sun CC, et al: Prospective phase II trial of levonorgestrel intrauterine device: Nonsurgical approach for complex atypical hyperplasia and early-stage endometrial cancer. Am J Obstet Gynecol 224 (2):191.e1-191.e15, 2021. doi: 10.1016/j.ajog.2020.08.032. # Prognosis is worse with higher- grade tumors, more extensive spread, and older patient age.. Average 5- year survival rates for patients with endometrial cancer are (1). Stage I or II: 70 to . Overall, . Prognosis reference. 1. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program: Cancer Stat Facts: Uterine Cancer. Accessed August 31, 2023. Key Points. - Endometrial cancer is one of the most common cancers among women.- Prognosis is better with type I tumors, which are grade 1 or 2 endometrioid adenocarcinomas; they tend to be estrogen-responsive and diagnosed at a younger age.- Recommend endometrial sampling for women with abnormal uterine bleeding, particularly those . More Information. The following English- language resource may be useful. Please note that THE MANUAL is no responsible for the content of this resource.. # National Cancer Institute: Endometrial Cancer Treatment: This web site provides information about endometrial cancer, its classification, staging, and treatment by stage..	None	None	None
aa82c541deb24991bdaf37705df9fe84	MSD	子宫肉瘤	# Uterine Sarcomas. By Pedro T. Ramirez, MD, Houston Methodist Hospital; Gloria Salvo, MD, MD Anderson Cancer Center Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Sept 2023. Uterine sarcomas are a group of disparate, aggressive cancers of the uterine corpus. Common manifestations include abnormal uterine bleeding and pelvic pain or mass. For suspected uterine sarcoma, endometrial biopsy or dilation and curettage may be done, but results are often falsely negative; most sarcomas are diagnosed histologically after hysterectomy or myomectomy. Treatment requires total abdominal hysterectomy and bilateral salpingooophorectomy; for advanced cancer, chemotherapy and sometimes radiation therapy are indicated.. Symptoms and Signs \| Diagnosis \| Treatment \| Prognosis \| Key Points \| More Information. Uterine sarcomas are rare, accounting for 2 to . Risk factors for uterine sarcomas are. - Prior pelvic radiation- Tamoxifen use. Uterine sarcomas include. - Leiomyosarcoma (the most common subtype [63%])- Endometrial stromal sarcoma (21%)- Undifferentiated uterine sarcoma. Rare uterine mesenchymal sarcoma subtypes include. - Adenosarcomas- Perivascular epithelioid cell tumor (PEComas)- Rhabdomyosarcoma. # Carcinosarcomas used to be categorized as sarcomas but are now considered and treated as high- grade epithelial tumors (carcinomas).. High- grade uterine sarcomas tend metastasize hematogenously, most often to the lungs; lymph node metastases are uncommon.. General reference. 1. American Cancer Society: Key Statistics for Uterine Sarcoma. Accessed July 14, 2023.. Symptoms and Signs of Uterine Sarcomas. Most sarcomas manifest as abnormal uterine bleeding and, less commonly, as pelvic pain, a feeling of fullness in the abdomen, a mass in the vagina, frequent urination, or a palpable pelvic mass.. Diagnosis of Uterine Sarcomas. Histology, most often after surgical removal. Symptoms suggesting uterine sarcoma usually prompt transvaginal ultrasonography and endometrial biopsy or dilation and curettage (D & C). However, these tests have limited sensitivity for sarcoma. Endometrial stromal sarcoma and uterine leiomyosarcoma are often incidentally diagnosed histologically after hysterectomy or myomectomy.. If cancer is identified preoperatively, CT or MRI is typically done. If uterine sarcoma is diagnosed after surgical removal, imaging is recommended, and surgical re- exploration can be considered to complete staging.. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) is not usually done when patients have uterine sarcoma because this genetic syndrome increases risk of endometrial carcinoma, not sarcoma.. Staging. Staging is done surgically (see tables FIGO Surgical Staging of Uterine Sarcoma: Leiomyosarcoma and Endometrial Stromal Sarcoma and FIGO Surgical Staging of Uterine Sarcoma: Adenosarcoma).. # # Treatment of Uterine Sarcomas. - Total abdominal hysterectomy and bilateral salpingo-oophorectomy- Usually adjuvant pelvic radiation therapy- Chemotherapy for advanced or recurrent cancers. # (See also National Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Uterine Sarcomas.). Treatment of uterine sarcomas is total abdominal hysterectomy and bilateral salpingo- oophorectomy.. Uterine sarcomas should be removed en bloc; morcellation is contraindicated. If a specimen is fragmented during surgery, imaging is recommended to check for metastases, and re- exploration can be considered. Treatment with chemotherapy is also recommended.. The ovaries may be preserved in certain patients with early- stage uterine leiomyosarcoma if they wish to retain hormonal function. Additional surgical resection should be based on intraoperative findings.. Lymphadenectomy in patients with leiomyosarcoma or endometrial stromal sarcoma is not indicated because there is evidence that the risk of lymph node metastases is minimal . For inoperable sarcomas, pelvic radiation therapy with or without brachytherapy and/or systemic therapy is recommended.. Adjuvant radiation therapy is typically used and appears to delay local recurrence but does not improve overall survival rate.. Chemotherapy agents are typically used when tumors are advanced or recur; drugs vary by tumor type.. Some preferred regimens are. - Doxorubicin- Docetaxel/gemcitabine (preferred for leiomyosarcoma). Overall, response to chemotherapy is poor.. Metastatic or unresectable uterine leiomyosarcomas have a poor prognosis. A multicenter randomized open- label superiority phase III trial in patients with metastatic or unresectable leiomyosarcomas showed that first- line therapy with doxorubicin plus trabectedin compared with doxorubicin alone resulted in significantly increased median progression- free survival (12.2 versus 6.2 months; adjusted hazard ratio, 0- 41) (3).. Endocrine therapy is used for patients with endometrial stromal sarcoma or hormone receptor- positive uterine leiomyosarcoma. Progestins are frequently effective. Endocrine therapy may include:. - Medroxyprogesterone acetate- Megestrol acetate- Aromatase inhibitors- GnRH (gonadotropin-releasing hormone) agonists. Treatment references. 1. Smith ES., Jansen C., Miller KM, et al: Primary characteristics and outcomes of newly low-grade endometrial stromal sarcoma. Int J Gynecol Cancer 32(7):882-890, 2022.. # Jul 4. doi:10.1136/ijgc- 2022- 003383. 2. Leitao MM, Sonoda Y, Brennan MF, et al: Incidence of lymph node and ovarian metastases in leiomyosarcoma of the uterus. Gynecol Oncol 91(1):209-212, 2003. doi:10.1016/s0090-8258(03)00478-53. Pautier P, Italiano A, Piperno-Neumann S, et al: Doxorubicin alone versus doxorubicin with trabectedin followed by trabectedin alone as first-line therapy for metastatic or unresectable leiomyosarcoma (LMS-04): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol 23(8):1044-1054, 2022. doi:10.1016/S1470-2045(22)00380-1. Prognosis for Uterine Sarcomas. Prognosis for patients with uterine sarcomas is generally poorer than that with endometrial carcinoma of similar stage; survival is generally poor when the cancer has spread beyond the uterus.. In one study, 5- year survival rates were (1). - Stage I: 51%- Stage II: 13%- Stage III: 10%- Stage IV: 3%. Most commonly, the cancer recurs locally, in the abdomen, or the lungs.. Prognosis reference. 1. American Cancer Society: Survival Rates for Uterine Sarcoma. Accessed August 31, 2023.. Key Points. - Uterine sarcomas are uncommon.- Symptoms include abnormal vaginal bleeding, a mass in the vagina, pelvic pain, a feeling of fullness in the abdomen, and frequent urination.- Prognosis is generally worse than that with endometrial carcinoma of similar stage.- Treat most patients with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and adjuvant radiation.- Treat patients who have endometrial stroma sarcoma and hormone receptor-positive leiomyosarcomas with endocrine therapy.- Treat inoperable sarcomas with radiation therapy and/or chemotherapy.. More Information. # The following English- language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.. National Cancer Institute: Uterine Cancer: This web site provides links to information about genetics and treatment of uterine sarcomas (a type of uterine cancer), as well as links to statistics and supportive and palliative care..	None	None	None
4dc63232e9f24ee5bdf022fbc78ab203	MSD	子宫肌瘤	# Uterine Fibroids. (Leiomyomas; Myomas). By Charles Kilpatrick, MD, MEd, Baylor College of Medicine Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Feb 2025 \| Modified May 2025. Uterine fibroids (leiomyomas) are benign smooth muscle tumors of the uterus. Fibroids frequently cause abnormal uterine bleeding and pelvic pressure and sometimes urinary or bowel symptoms, infertility, or pregnancy complications. Diagnosis is by pelvic examination or ultrasound or other imaging studies. Treatment of patients depends on symptoms, desire for fertility, and patient preferences. Treatment may include estrogen- progestin contraceptives, progestin therapy, tranexamic acid, gonadotropin- releasing hormone agonists/antagonists, uterine artery embolization, and surgical procedures (eg, myomectomy, hysterectomy).. Symptoms and Signs \| Diagnosis \| Treatment \| Key Points. Uterine fibroids (leiomyomas) are smooth muscle tumors that usually arise from the myometrium and are the most common pelvic tumor. Many fibroids are small or asymptomatic.. In the United States, prevalence of uterine fibroids by age 50 is approximately . Although patients are often concerned about cancer in fibroids, sarcomatous change occurs in . Most patients with fibroids have multiple fibroids. Anatomic locations of fibroids in the uterus are. - Subserosal- Intramural- Submucosal. Occasionally, fibroids develop in the broad ligament (intraligamentous), cervix, or, rarely, fallopian tubes. Some fibroids are pedunculated, and others are sessile. Submucosal fibroids may extend into the uterine cavity (intracavitary submucosal fibroids) or prolapse through the uterine cervix (prolapsed fibroid).. # The International Federation of Gynecology and Obstetrics (FIGO) classification system for causes of abnormal uterine bleeding (PALM- COEIN system) has a subclassification for location of fibroids and the degree to which they protrude into the endometrial cavity (4).. # # the first number refers to the relationship with the endometrium and the second number refers to the relationship to the serosa.. Definitions: Endometrium = glandular lining of the uterine cavity (also referred to as the endometrial cavity); myometrium = smooth muscle layer of the uterus, located between the endometrium and serosa; serosa = thin outer lining of the uterus that faces the peritoneal (abdominal) cavity, composed of mesothelium and loose connective tissue.. Adapted from Munro MG, Critchley HOD, Fraser IS; FIGO Menstrual Disorders Committee. The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions [published correction appears in Int J Gynaecol Obstet. 2019 Feb;144(2):237]. Int J Gynaecol Obstet. 2018;143(3):393- 408. doi:10.1002/ijgo.12666.. Each fibroid develops from a single smooth muscle cell, making them monoclonal in origin. Because they respond to estrogen, fibroids tend to enlarge during the reproductive years and decrease in size after menopause.. Fibroids may outgrow their blood supply and degenerate. Degeneration is described as hyaline, myxomatous, calcific, cystic, fatty, red (usually only during pregnancy), or necrotic.. Fibroids. IMAGE. (U.S. NAVY PHOTOGRAPH). References. 1. Baird DD, Dunson DB, Hill MC, et al. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol 188(1):100-107, 2003.. # doi:10.1067/mob.2003.99. 2. Pavone D, Clemenza S, Sorbi F, et al. Epidemiology and Risk Factors of Uterine Fibroids. Best Pract Res Clin Obstet Gynaecol 46:3-11, 2018. doi:10.1016/j.bpobgyn.2017.09.0043. Kho KA, Lin K, Hechanova M, Richardson DL. Risk of Occult Uterine Sarcoma in Women Undergoing Hysterectomy for Benign Indications [published correction appears in Obstet Gynecol. 2016 May;127(5):968. doi: 10.1097/AOG.0000000000001427]. Obstet Gynecol. 2016;127(3):468-473. doi:10.1097/AOG.00000000000012424. Munro MG, Critchley HOD, Fraser IS; FIGO Menstrual Disorders Committee. The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions [published correction appears in Int J Gynaecol Obstet. 2019 Feb;144(2):237]. Int J Gynaecol Obstet 143(3):393-408, 2018. doi:10.1002/ijgo.12666. Symptoms and Signs of Uterine Fibroids. Many fibroids are asymptomatic; approximately 15 to . Bulk symptoms, including chronic pelvic pain or pressure, result from the size or position of fibroids or uterine enlargement due to fibroids (2). Urinary symptoms (eg, urinary frequency or urgency) can result from bladder compression, and intestinal symptoms (eg, constipation) can result from intestinal compression.. Less commonly, fibroids grow and degenerate or torsion of pedunculated fibroids occurs, and severe acute pain can result.. Fibroids may be associated with infertility, especially submucosal fibroids. During pregnancy fibroids are usually asymptomatic, but may cause pain, recurrent spontaneous abortion, premature uterine contractions, placental abruption, or abnormal fetal presentation. Fibroids may also cause postpartum hemorrhage, especially if located in the lower uterine segment (3).. Symptoms and signs references. 1. Havryliuk Y, Setton R, Carlow JJ, et al. Symptomatic Fibroid Management: Systematic Review of the Literature. JSLS 21(3):e2017.00041, 2017. doi:10.4293/jsLS.2017.000412. Soliman AM, Margolis MK, Castelli-Haley J, Fuldeore MJ, Owens CD, Coyne KS. Impact of uterine fibroid symptoms on health-related quality of life of US women: evidence from a cross-sectional survey. Curr Med Res Opin. 2017;33(11):1971-1978. doi:10.1080/03007995.2017.13721073. Qidwai GI, Caughey AB, Jacoby AF. Obstetric outcomes in women with sonographically identified uterine leiomyomata. Obstet Gynecol. 2006;107(2 Pt 1):376-382. doi:10.1097/01. AOG.0000196806.25897.7c. # Imaging (ultrasound, saline infusion sonography, or MRI). The diagnosis of uterine fibroids is clinical and is likely if bimanual pelvic examination detects an enlarged, irregular, mobile uterus.. If an enlarged, irregular, mobile uterus is a new finding or if pelvic examination findings have changed (eg, increased uterine size, possible adnexal mass, fixed mass, new finding of tenderness), imaging studies should be performed to evaluate for fibroids or other gynecologic pathology (eg, ovarian masses). Imaging may also be indicated if the patient has new symptoms (eg, bleeding, pain).. Pelvic ultrasound (usually transvaginal) is typically the preferred first- line imaging test (1).. If submucosal fibroids are suspected due to abnormal uterine bleeding or infertility, saline infusion sonography may be performed. In saline infusion sonography, saline is instilled into the uterus, improving visualization of the uterine cavity. Alternatively, hysteroscopy can be used to directly visualize suspected submucosal uterine fibroids and, if needed, to biopsy or resect small fibroids.. MRI is typically performed if an ultrasound or other factors (eg, rapid growth of a presumed fibroid, fixed pelvic mass) suggest a diagnosis of a variant of leiomyomas (eg, smooth muscle tumors of uncertain malignant potential) or a malignant uterine mass (eg, leiomyosarcoma) (2). MRI is also commonly used in patients prior to myomectomy to determine fibroid location.. Patients with postmenopausal bleeding with or without fibroids should be evaluated for uterine cancer.. Diagnosis references. 1. Mension E, Carmona F, Vannuccini S, Chapron C. Clinical signs and diagnosis of fibroids from adolescence to menopause. Fertil Steril. 2024;122(1):12-19. doi:10.1016/j.fertnstert.2024.05.003 2. Expert Panel on GYN and OB Imaging, Ascher SM, Wasnik AP, et al. ACR Appropriateness Criteria Fibroids. J Am Coll Radiol. 2022;19(11S):S319-S328. doi:10.1016/j.jacr.2022.09.019. Treatment of Uterine Fibroids. Hormonal or nonhormonal medications to decrease bleeding (eg, nonsteroidal anti- inflammatory drugs [NSAIDs], tranexamic acid, estrogen- progestin contraceptives, or progestins) - Myomectomy (to preserve fertility) or hysterectomy - Sometimes other procedures (eg, uterine fibroid embolization). Treatment options can be classified as medical, procedural, or surgical.. Asymptomatic fibroids do not require treatment. Patients with small and stable size fibroids can be reevaluated periodically (eg, every 12 months).. # For symptomatic fibroids, pharmacologic options are typically used first, prior to considering procedural or surgical treatments. Medications are effective in some patients but are often suboptimal. In perimenopausal women with mild symptoms, expectant management is often preferred because symptoms may resolve as fibroids decrease in size after menopause.. Medications to treat fibroids. For control of abnormal uterine bleeding due to fibroids, oral hormonal or nonhormonal medications may be used as first- line therapy. These medications do not decrease fibroid size, and thus do not treat bulk symptoms (eg, pelvic pain and pressure). First- line pharmacologic options include. - Estrogen-progestin contraceptives- Progestins (eg, levonorgestrel intrauterine device [IUD])- Tranexamic acid- Nonsteroidal anti-inflammatory drugs (NSAIDs). For patients who also desire contraception, estrogen- progestin contraceptives or a levonorgestrel IUD may be good options.. Exogenous progestins can partially suppress estrogen stimulation of uterine fibroid growth. Oral progestin therapy may be cyclic (10 to 14 days of each menstrual cycle) or continuous (daily); examples of medications and dosages include medroxyprogesterone acetate 5 to . Depot medroxyprogesterone acetate . Tranexamic acid (an antifibrinolytic) can reduce uterine bleeding by up to . NSAIDs can be used to treat pain and may slightly decrease bleeding volume (2).. Medications that may be used to reduce fibroid growth in addition to treating abnormal uterine bleeding due to fibroids include. - GnRH analogs- Antiprogestins- Selective estrogen receptor modulators (SERMs)- Danazol. GnRH analogs are either agonists (eg, leuprolide) or antagonists (elagolix and relugolix) that inhibit the hypothalamic- pituitary- ovarian axis and induce hypogonadism, resulting in a decrease in estrogen production. In general, these medications should not be used in the long term because rebound growth to pretreatment size within 6 months is common. GnRH analog use is often limited by hypoestrogenic. # adverse effects such as menopausal symptoms, unfavorable changes in lipid profile, and/or decreased bone density. To prevent bone demineralization when these medications are used long term, clinicians should consider giving patients supplemental estrogen (add- back therapy), such as a low- dose estrogen- progestin combination.. GnRH analogs are used if other medications have not been effective and bleeding is persistent, and the patient is anemic. Alternatively, they are given preoperatively to reduce fibroid and uterine volume, making surgery technically more feasible and reducing blood loss during surgery.. GnRH agonists may be given as follows:. - IM or subcutaneously (eg, leuprolide 3.75 mg IM every month, goserelin 3.6 mg subcutaneously every 28 days)- As a subdermal pellet- As nasal spray (eg, nafarelin). GnRH antagonists are available in oral preparations formulated for low- dose add- back therapy to limit hypoestrogenic adverse effects.. For antiprogestins (eg, mifepristone), the dosage is 5 to 50 mg once a day for 3 to 6 months. This dose is lower than the 200- mg dose used for termination of pregnancy; thus, this dose must be mixed specially by a pharmacist and may not always be available.. SERMs (eg, raloxifene) may help reduce fibroid growth, but whether they can relieve symptoms as well as other medications is unclear.. Danazol, an androgenic agonist, can suppress fibroid growth but has a high rate of adverse effects (eg, weight gain, acne, hirsutism, edema, hair loss, deepening of the voice, flushing, sweating, vaginal dryness) and is thus rarely used.. Procedures to treat fibroids. Uterine artery embolization is an image- guided treatment option that aims to cause infarction of fibroids throughout the uterus while preserving normal uterine tissue. For this procedure, the uterus is visualized using fluoroscopy, catheters are placed in the femoral artery and advanced into the uterine artery, and then embolic particles are used to occlude blood supply to the fibroids.. After this procedure, women recover more quickly than after hysterectomy or myomectomy, but rates of complications (eg, bleeding, uterine ischemia) and return visits tend to be higher. Treatment failure rates are up to 25% and are higher if bilateral uterine arteries are not embolized (3); in such cases, definitive treatment with hysterectomy is required.. Patients who are considering further childbearing should be counseled that uterine artery embolization may increase certain obstetric outcomes, including spontaneous abortion, cesarean delivery, and postpartum hemorrhage (4).. Magnetic resonance- guided focused ultrasound surgery is a uterine- sparing, percutaneous procedure that uses high- intensity ultrasound waves to ablate fibroids. Data are limited about the safety. # of pregnancy after this procedure, and further investigation is needed (5).. Surgery for fibroids. Surgery is usually reserved for women with one or more of the following characteristics:. A rapidly enlarging pelvic mass Recurrent uterine bleeding refractory to medications Severe or persistent pain or pressure (eg, that requires pain medications for control or that is intolerable to the patient) A large uterus that has a mass effect in the abdomen, causing urinary or intestinal symptoms or compressing other organs and causing dysfunction (eg, hydronephrosis, urinary frequency, dyspareunia) Infertility (if submucosal fibroids may be interfering with conception) Recurrent spontaneous abortion (if pregnancy is desired). Other factors favoring surgery are a patient's desire for definitive treatment.. For patients with severe bleeding, gonadotropin- releasing hormone (GnRH) agonists may be given before surgery to shrink fibroid tissues; these medications often stop menses and allow blood counts to increase.. Radiofrequency fibroid ablation uses real- time ultrasound to identify the fibroids and apply radiofrequency energy from a handpiece using a laparoscopic or transv cervical approach.. Myomectomy can be performed open, laparoscopically or hysteroscopically (using an instrument with a wide- angle telescope and electrical wire loop for excision), with or without robotic techniques.. Hysterectomy can also be done laparoscopically, vaginally, or by laparotomy.. Most indications for myomectomy and hysterectomy are similar, and patients should be counseled about risks and benefits of each procedure.. If women desire future pregnancy or uterine conservation, myomectomy is performed (6). Multiple myomectomy can be more technically difficult than hysterectomy. Multiple myomectomy often involves increased bleeding, postoperative pain, and adhesions, and may increase risk of uterine rupture during subsequent pregnancies.. Factors that favor hysterectomy include. - The patient does not desire future childbearing.- Hysterectomy is a definitive treatment. After myomectomy, new fibroids may begin to grow again, and about . # Hysterectomy would treat or decrease the risk of another disorder (eg, cervical intraepithelial neoplasia, endometrial hyperplasia, endometriosis, ovarian cancer in women with a BRCA mutation, Lynch syndrome).. If hysterectomy or myomectomy is done laparoscopically, techniques must be used to remove the fibroid tissue through the small laparoscopic incisions or vagina. Morcellation is a term that describes cutting fibroids or uterine tissue into small pieces; this may be done with a scalpel or an electromechanical device. Morcellation should not be used in patients with suspected uterine cancer or significant risk factors, particularly for uterine sarcoma. Prior to surgery for presumed fibroids, patients should be evaluated for uterine cancer (Z). Women who have surgery for presumed uterine fibroids may have an unsuspected, undiagnosed sarcoma or other uterine cancer; estimated incidence varies from 1 in 300 to . Choice of treatment. Treatment of uterine fibroids should be individualized, but the following factors can help with the decision:. Asymptomatic fibroids: No treatment, continue to follow patient Symptomatic fibroids, particularly if future pregnancy is desired: Oral medications or myomectomy Severe symptoms when other treatments were ineffective, particularly if pregnancy is not desired: Uterine artery embolization or hysterectomy (high- intensity focused sonography is used in some countries) Postmenopausal women: Patients with postmenopausal bleeding should be evaluated for uterine cancer. If results are benign or pressure symptoms are the main issues, a trial of expectant management is reasonable (because symptoms tend to remit as fibroids decrease in size after menopause). Treatment references. 1. Lukes AS, Moore KA, Muse KN, et al. Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial. Obstet Gynecol. 2010;116(4):865-875. doi:10.1097/AOG.0b013e3181f20177 2. Bofill Rodriguez M, Dias S, Jordan V, et al. Interventions for heavy menstrual bleeding; overview of Cochrane reviews and network meta-analysis. Cochrane Database Syst Rev. 2022;5(5):CD013180. Published 2022 May 31. doi:10.1002/14651858.CD013180.pub2 3. Spies JB, Bruno J, Czeyda-Pommersheim F, Magee ST, Ascher SA, Jha RC. Long-term outcome of uterine artery embolization of leiomyomata. Obstet Gynecol. 2005;106(5 Pt 1):933-939. doi:10.1097/01.AOG.0000182582.64088.84 4. Homer H, Saridogan E. Uterine artery embolization for fibroids is associated with an increased risk of miscarriage. Fertil Steril. 2010;94(1):324-330. doi:10.1016/j.fertnstert.2009.02.069. # 5. Zou M, Chen L, Wu C, Hsu C, Xiong Y. Pregnancy outcomes in patients with uterine fibroids treated with ultrasound-guided high-intensity focused ultrasound. BJOG. 2017;124 Suppl 3:30-35. doi:10.1111/1471-0528.147426. Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org; Practice Committee of the American Society for Reproductive Medicine. Removal of myomas in asymptomatic patients to improve fertility and/or reduce miscarriage rate: a guideline. Fertil Steril. 2017;108(3):416-425. doi:10.1016/j.fertnstert.2017.06.0347. American College of Obstetricians and Gynecologists' Committee on Gynecologic Practice. Uterine Morcellation for Presumed Leiomyomas: ACOG Committee Opinion, Number 822 [published correction appears in Obstet Gynecol. 2021 Aug 1;138(2):313]. Obstet Gynecol 137(3):e63-e74, 2021. doi:10.1097/AOG.000000000000042918. Hartmann KE, Fonnesbeck C, Surawicz T, et al. Management of Uterine Fibroids [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2017 Dec. (Comparative Effectiveness Review, No. 195.). Key Points. - In the United States, prevalence of uterine fibroids by age 50 is approximately . Copyright © 2025 Merck & Co., Inc., Rahway, NJ, USA and its affiliates. All rights reserved..	None	None	None
da7975f3660c4f0287c7c5d25dc6daef	MSD	子宫腺肌病	# Uterine Adenomyosis. By Charles Kilpatrick, MD, MEd, Baylor College of Medicine Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Feb 2023. Uterine adenomyosis is the presence of endometrial glands and stroma in the uterine musculature. Symptoms include heavy menstrual bleeding, dysmenorrhea, and pelvic pain. Diagnosis is with a pelvic examination that detects a diffusely enlarged uterus and with transvaginal ultrasonography or MRI. Treatment is hormonal medications or hysterectomy.. Symptoms and Signs \| Diagnosis \| Treatment \| Key Points. In uterine adenomyosis, ectopic endometrial tissue infiltrates the myometrium. This tends to induce diffuse uterine enlargement (globular uterine enlargement). The uterus may double or triple in size but typically does not exceed the size of a uterus at 12 weeks' gestation.. True prevalence is unknown, partly because making the diagnosis is difficult. However, adenomyosis is most often detected incidentally in women who are being evaluated for endometriosis, fibroids, or pelvic pain. Higher parity increases risk.. Symptoms and Signs of Uterine Adenomyosis. Common symptoms of uterine adenomyosis are heavy menstrual bleeding, dysmenorrhea, and anemia. Chronic pelvic pain may also be present.. Symptoms may resolve after menopause.. Diagnosis of Uterine Adenomyosis. - Pelvic examination - Usually ultrasonography or MRI. Uterine adenomyosis is suggested by symptoms and diffuse uterine enlargement seen during a pelvic examination in patients without endometriosis or fibroids. Transvaginal ultrasonography and MRI are commonly used for diagnosis, although definitive diagnosis requires histology after hysterectomy.. # Hysterectomy. The most effective treatment for uterine adenomyosis is hysterectomy.. Hormonal treatments similar to those used to treat endometriosis may be tried. Treatment with combined estrogen/progestin oral contraceptives can be tried but is usually unsuccessful. A levonorgestrel- releasing intrauterine device (IUD) may help control dysmenorrhea and bleeding.. Key Points. Key Points- In uterine adenomyosis, the uterus may double or triple in size.- It commonly causes heavy menstrual bleeding, dysmenorrhea, and anemia and may cause chronic pelvic pain; symptoms may resolve after menopause.- Diagnose by transvaginal ultrasonography and/or MRI; however, definitive diagnosis requires histology after hysterectomy.- The most effective treatment is hysterectomy, but hormonal treatments (eg, oral contraceptives) can be tried..	None	None	None
28b592fafd034c68842325bc1c513f7b	MSD	孕早期阴道流血	# 孕早期阴道流血. 作者：Emily E. Bunce, MD, Wake Forest School of Medicine; Robert P. Heine, MD, Wake Forest School of Medicine Reviewed By Oluwatosin Goje, MD, MSck, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University 已审核/已修订7月2023\|修改的3月2024. 病因评估 \| 治疗 \| 关键点. 大约 . 阴道流血也与其他不良妊娠结局有关，如以下：. - 低出生体重儿- 早产- 死产- 围产期死亡. 参考文献. 1. Everett C: Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice. BMJ 315(7099):32-34, 1997.doi:10.1136/bmj.315.7099.32. 病因. 孕早期阴道流血可能由产科或非产科疾病引起（见表孕早期阴道流血的原因）。. 孕早期阴道流血最危险的原因是. - 异位妊娠. 黄体囊肿破裂虽然不太常见，但也是可能的，并可能导致腹腔出血和潜在的休克。. 最常见的原因是. - 自然流产（先兆，难免，不全，完全，稽留流产）. # # 评估. 孕妇出现阴道流血时应立即进行评估。. 孕妇出现阴道流血时应立即进行评估。异位妊娠或严重阴道出血（如不可避免或不完全流产、出血性黄体囊肿破裂）可导致失血性休克。应进行血型和筛查或交叉配血，并在评估过程中尽早建立静脉通路，以防发生此类并发症。. # 病史. 现病史应包括下述：. 预计预产期（以及这是基于上次月经还是超声波检查）- 当前妊娠期间产科并发症和既往检查或并发症的任何风险因素- 描述出血量，包括浸透了多少卫生棉以及是否有血凝块或组织通过- 疼痛的存在或缺乏. 应向患者询问，以确定出血是否确实来自阴道。尿路或胃肠道出血有时会被误认为是阴道出血。. 如果有腹痛，则应明确腹痛的起病，部位，持续时间，特点。. 系统回顾应注明发热，寒战，腹痛或盆腔痛，阴道分泌物，和神经系统症状如头晕，头痛，昏厥或近昏厥。. 既往病史应包括妊娠率（确诊妊娠次数）、产次（足月和早产次数）、流产次数（自然流产或人工流产）以及宫外孕和自然流产的风险因素。. 体格检查. 对妊娠期患者的评估应包括常规产前评估，以评估产妇和胎儿状况，包括. 产妇生命体征评估腹部检查子宫高度- 有时，盆腔检查- 胎儿心率听诊对胎儿状态的评估- 有时进行盆腔超声检查（取决于症状和胎龄）. 旨在评估阴道出血的体格检查包括检查发烧的生命体征和血容量不足的体征（心动过速、低血压）。. 评估着重于腹部和盆腔检查。腹部触诊了解有无压痛、腹膜刺激征（肌卫、肌紧张、反跳痛）和子宫大小。多普勒听胎心。. 盆腔检查包括外阴视诊，窥阴器检查和双合诊检查。清除阴道顶的血和妊娠产物；妊娠物应送病理明确诊断。. 检查宫颈有无分泌物、扩张、损伤、息肉，以及宫颈口有无组织物。. 双合诊检查有无宫颈举痛，附件包块或压痛，以及子宫大小。. 危险信号. 要特别注意以下情况：. - 血流动力学不稳定（血压低，心率快，或两者都有）- 脉搏或血压的直立性改变- 昏厥或近昏厥- 腹膜刺激征（反跳痛，肌紧张，肌卫）- 发热，寒战，脓性阴道分泌物. # 临床表现解析. 临床表现有助于提示病因但很少能够诊断（见表阴道流血的一些原因）。然而，宫颈扩张加胎儿组织排出，腹部痉挛性疼痛强烈提示自然流产，流产合并感染可伴有严重的感染征象（发热，中毒表现，脓性或血性分泌物）。即使没有典型的表现，也不能除外先兆或稽留流产，当然必须排除最严重的情况——异位妊娠破裂。. 异位妊娠的典型表现包括严重腹痛，腹膜刺激征，有压痛的附件包块，但也可能临床表现不典型，即使阴道流血不多，疼痛不明显，也应时刻警惕这种可能。. 辅助检查. 尿检可以确认妊娠。明确妊娠的妇女应做一系列检查：. beta- hCG的定量检测水平ABO血型和Rh血型通常行超声检查. 进行Rh测试以决定是否需要Rho（D）免疫球蛋白防止孕妇致敏。如果出血多，应行包括血常规，血型加不规则抗体筛查，或者交叉配血。对于大出血或休克，还测定凝血酶原时间/部分凝血活酶时间（PT/PTT）、纤维蛋白原水平和纤维蛋白裂解产物。. 盆腔超声检查可以明确宫内妊娠。如果获得了完整的妊娠产物，也建议经阴道盆腔超声检查来确认完全流产和没有保留的妊娠产物。如果病人处于休克状态或大出血，应行床旁超声检查。. 定量β- hCG水平有助于解释超声结果，但由于变异性，有时还有多胎妊娠，特定的hCG水平与胎龄之间没有绝对相关性。. 然而，即使经阴道超声检查未发现宫内妊娠，仍有可能发生宫内妊娠。没有确定的beta- hCG水平可以排除宫内妊娠。判别区是β- hCG水平，超过该水平，经阴道超声应能够观察到带有卵黄囊的孕囊，这一发现证实了宫内妊娠。级别 . 超声检查可以帮助鉴别黄体囊肿破裂和妊娠滋养细胞疾病。它可以显示不完全流产、流产合并感染及稽留流产患者宫腔内的妊娠物。. 如果患者情况稳定，异位妊娠可能不大，可门诊随访beta- hCG水平。正常情况下，至孕41天的beta- hCG倍增时间是1.4到2.1天；异位妊娠（和流产）的beta- hCG水平低于相应停经时间，倍增也较慢。如果临床上中度或高度怀疑异位妊娠（例如，大出血，附件压痛，或两者都有），可行诊断性刮宫或或扩张清宫术(D&C)，或诊断性腹腔镜检查。. 诊断参考. 1. Connolly A, Ryan DH, Stuebe AM, Wolfe HM: Reevaluation of discriminatory and threshold levels for serum β-hCG in early pregnancy. Obstet Gynecol 121(1):65-70, 2013.doi:10.1097/aog.0b013e318278f421 2. Doubilet PM, Benson CE. Further evidence against the reliability of the human chorionic gonadotropin discriminatory level. J Ultrasound Med 30 (12):1637-1642.. # 治疗. 孕早期阴道出血的治疗针对病因：. - 异位妊娠破裂：立即腹腔镜或者开腹手术- 未破裂异位妊娠：可以用甲氨蝶呤或者经腹腔镜或开腹行输卵管切开或输卵管切除术- 先兆流产或不可避免的流产：血流动力学稳定的患者予预期治疗- 不完全流产或稽留流产：诊刮或清宫- 完全流产：产科随访- 感染性流产：如果在超声检查中发现妊娠产物残留，则需要静脉注射抗生素并紧急排空清宫. Rh阴性血型、阴道出血或异位妊娠的妇女应给予Rho（D）免疫球蛋白以防止同种免疫。. 关键点. - 如果患者在怀孕初期出现阴道流血，要时刻警惕宫外孕；症状可能轻微或严重。- 自然流产是孕早期阴道流血最常见的原因。- 孕早期阴道流血的患者应经常检查Rh血型，以决定是否需要Rh0（D）免疫球蛋白。.	None	None	None
dd22e396b2d04537ac84642fe9d80f13	MSD	孕激素避孕注射剂仅含孕激素的口服避孕药、长效醋酸甲羟孕酮、孕激素植入剂	# Progestin Contraceptive Injections. (Depot Medroxyprogesterone Acetate). By Frances E. Casey, MD, MPH, NYU Grossman Long Island School of Medicine Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Jul 2023 \| Modified Aug 2023. Various contraceptive progestin injections are available worldwide.. Depot medroxyprogesterone acetate (DMPA) is a long- acting injectable formulation of medroxyprogesterone acetate in a crystalline suspension.. With DMPA, pregnancy rates in the first year are . DMPA is available in two different formulations; it may be given as an IM (150 mg) or subcutaneous injection (104 mg) every 3 months. The injection site should not be massaged because doing so may increase the rate of absorption. Effective contraceptive hormonal serum levels are usually attained as early as 24 hours after injection and are maintained for at least 14 weeks although levels may be high enough to remain effective for up to 16 weeks.. If the interval between injections is . DMPA may also be given immediately after a spontaneous or induced abortion or immediately postpartum regardless of breastfeeding status.. Noristerat (NET- EN), which is not available in the United States, is a long- acting injectable formulation of norethisterone enanthate in a castor oil benzyl benzoate suspension. Pregnancy rates are the same as with DMPA. NET- EN may be given as an IM injection (200 mg) deep into the gluteal or deltoid muscles, typically every 8 weeks, but the interval can be extended to 12 weeks after the first 6 months of use. As with DMPA, the injection site should not be massaged. Effective contraceptive hormonal serum levels are usually attained within 72 hours. If the interval between injections is . Contraindications and adverse effects. # There are few contraindications for progestin injections, and these are similar to progestin- only oral contraceptives.. The most common adverse effect of progestin injections is irregular vaginal bleeding. In the 3 months after the first injection, approximately . Because DMPA has a long duration of action, ovulation may be delayed after the medication is discontinued. After the last injection, a regular menstrual cycle resumes in about half the women within 6 months and in about three fourths within 1 year. However, ovulation may be delayed for up to 18 months. After ovulation occurs, fertility is usually rapidly restored. For women using NET- EN, return to ovulation occurs more rapidly, with an average of 3 months, and return to fertility within 6 months (1).. Women typically gain 1.5 to . In some studies, 1 to . Headache is a common reason for stopping progestin injections, but severity tends to decrease over time. Most women using progestin injections do not have headaches, and preexisting tension headaches or migraines usually do not worsen.. Although bone mineral density may decrease when estrogen levels are low due to progestin injection use, there is no evidence of increased fracture risk, and bone density scanning is not recommended (6, 7). Adolescent and young women who use progestin injections, like those who do not, should participate in physical activity, weight bearing exercise, and consume supplemental calcium and vitamin D. Bone density typically returns to baseline after injections are discontinued.. Mild, reversible deterioration of glucose tolerance may occur. While it is known that DMPA can alter lipoproteins, lowering high- density lipoproteins (HDL) and increasing the ratio of low- density lipoproteins (LDL) to HDL, this effect appears to be temporary and improve within 36 months of DMPA use. A similar effect would be expected with NET- EN. Unlike estrogen- based methods, progestin injections do not increase the risk of hypertension (8).. DMPA does not appear to increase the risk of breast, ovarian, or cervical cancer.. Benefits. Progestin injections are associated with a decreased risk of. # Endometrial cancer Pelvic inflammatory disease Iron deficiency anemia. Some evidence suggests DMPA may reduce the incidence of painful crisis in women with sickle cell disease.. Progestin injections may be an appropriate contraceptive option for patients with a seizure disorder because it does not interact with antiseizure medications that induce liver enzymes.. References. 1. Fotherby K, Howard G: Return of fertility in women discontinuing injectable contraceptives. J Obstet Gynaecol (Lahore) 6 Suppl 2:S110-S115, 1986. doi:10.3109/01443618609081724 2. Westhoff C, Truman C, Kalmuss D, et al: Depressive symptoms and Depo-Provera. Contraception 57(4):237-240, 1998. doi:10.1016/s0010-7824(98)00024-9 3. Singata-Madliki M, Carayon-Lefebvre d'Hellencourt F, Lawrie TA, et al: Effects of three contraceptive methods on depression and sexual function: An ancillary study of the ECHO randomized trial. Int J Gynaecol Obstet 154(2):256-262, 2021. doi:10.1002/ijgo.13594 4. Gupta N, O'Brien R, Jacobsen LJ, et al: Mood changes in adolescents using depot-medroxyprogesterone acetate for contraception: a prospective study. J Pediatr Adolesc Gynecol 14(2):71-76, 2001. doi:10.1016/s1083-3188(01)00074-2 5. Lawrie TA, Hofmeyr GJ, De Jager M, et al: A double-blind randomised placebo controlled trial of postnatal norethisterone enanthate: the effect on postnatal depression and serum hormones. Br J Obstet Gynaecol 105(10):1082-1090, 1998. doi:10.1111/j.1471-0528.1998.tb09940.x 6. Kaunitz AM, Miller PD, Rice VM, et al: Bone mineral density in women aged 25-35 years receiving depot medroxyprogesterone acetate: recovery following discontinuation. Contraception 74(2):90-99, 2006. doi:10.1016/j.contraception.2006.03.010 7. Rosenberg L, Zhang Y, Constant D, et al: Bone status after cessation of use of injectable progestin contraceptives. Contraception 76(6):425-431, 2007. doi:10.1016/j.contraception.2007.08.010 8. Berenson AB, Rahman M, Wilkinson G: Effect of injectable and oral contraceptives on serum lipids. Obstet Gynecol 114(4):786-794, 2009. doi:10.1097/AOG.0b013e3181b76bea.	None	None	None
5156c425e2af4d87a89030eca33bcaef	MSD	宫内节育器	# Intrauterine Device (IUDs; IUD). By Frances E. Casey, MD, MPH, NYU Grossman Long Island School of Medicine Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Jul 2023 \| Modified Oct 2023. In the United States, . In the United States, available IUDs include levonorgestrel- releasing IUDs and an intrauterine copper contraceptive.. Levonorgestrel- releasing IUDs include. - A 13.5-mg IUD (14 mcg a day) is effective for 3 years and has a 3-year cumulative pregnancy rate of . The intrauterine copper contraceptive is effective for 10 years; it has a cumulative 12- year pregnancy rate of . # # \* Evidence supports use for 12 years.. Insertion of the IUD. Clinicians do not need to do a Papanicolaou (Pap) test or human papillomavirus (HPV) test before they insert an IUD, unless the patient is due for cervical cancer screening. Testing for sexually transmitted infections (STIs)—gonorrhea and chlamydia—prior to IUD insertion should be based on "risk- based" screening (age ≤ 25 years, multiple sexual partners, inconsistent condom use, and/or history of a STI) (5). However, clinicians do not need to wait for results of STI testing before they insert an IUD. If results are positive, patients should be treated with appropriate antibiotics; the IUD is left in place. If purulent cervical discharge is observed just before planned IUD insertion, the IUD is not inserted and STI testing is done; the infection, if present, is then treated, and the IUD is inserted after treatment of the infection is complete.. The package insert for the IUD should be read before insertion to review the insertion technique. When IUDs are inserted, sterile technique is used as much as possible. Bimanual examination should be done to determine the position of the uterus and a tenaculum should be placed on the anterior lip of the cervix to stabilize the uterus, straighten the uterine axis, and help ensure correct placement of the IUD. A uterine sound device may be used to measure the length of the uterine cavity before IUD insertion. Before insertion, a paracervical block may be used to decrease pain during insertion (6).. An IUD may be inserted at any time during the menstrual cycle if a woman has not had unprotected intercourse during the past month.. A routine follow- up visit after IUD insertion is not necessary. Patients should be counseled to return for evaluation if they experience symptoms or complications (eg, pain, heavy bleeding, abnormal vaginal discharge, fever, expulsion) or are dissatisfied with the method (7).. An IUD may be inserted immediately after an induced or a spontaneous abortion during the 1st or 2nd trimester and immediately after delivery of the placenta in a cesarean or vaginal delivery.. Contraindications. # Most women can use an IUD. Contraindications include the following:. Anatomic abnormalities that distort the uterine cavity Current pelvic infection, usually pelvic inflammatory disease (PID), mucopurulent cervicitis with a suspected STI, pelvic tuberculosis, septic abortion, or puerperal endometritis or sepsis within the past 3 months Unexplained vaginal bleeding Pregnancy Gestational trophoblastic disease with persistently elevated serum beta- human chorionic gonadotropin (beta- hCG) levels (a relative contraindication because supporting data are lacking) Known cervical cancer or endometrial cancer For levonorgestrel- releasing IUDs, breast cancer or allergy to levonorgestrel For copper T380 IUDs, Wilson disease or allergy to copper. Conditions that do not contraindicate IUDs include the following:. Contraindications to contraceptives that contain estrogen (eg, history of venous thromboembolism, smoking . Adverse effects. Vaginal bleeding is often irregular in the first several months after insertion of a levonorgestrel- releasing IUD. Bleeding then stops completely within 1 year in up to . An intrauterine copper contraceptive may cause heavier menstrual bleeding and more severe cramping, which can be relieved by nonsteroidal anti- inflammatory drugs (NSAIDs; eg, ibuprofen).. Women should be told about these effects before the IUD is inserted because this information may help them decide which type of IUD to choose.. Potential benefits. Levonorgestrel- releasing IUDs are associated with a decreased risk of endometrial cancer and ovarian cancer. Data about whether they increase the risk of breast cancer are conflicting (8).. # If a woman has had unprotected intercourse within the past 7 days, an intrauterine copper contraceptive or a 52- mg levonorgestrel- releasing IUD may be inserted as emergency contraception.. Complications. Average IUD expulsion rates are usually . The uterus is perforated in about 1/1000 IUD insertions. Perforation typically occurs at the time of IUD insertion. Sometimes only the distal part of the IUD penetrates; then over the next few months, uterine contractions force the IUD into the peritoneal cavity. If the strings are not visible during pelvic examination, clinicians may do one or more of the following:. - Use a cytobrush to attempt to sweep the strings out of the cervical canal- Gently probe the uterine cavity with an IUD hook, sound, or biopsy instrument (unless pregnancy is suspected), being careful not to push the IUD further into the uterine cavity or myometrium- Do ultrasonography; alligator forceps may be used under sonographic guidance (9). If the IUD is not seen, an abdominal x- ray is taken to exclude an intraperitoneal location. Intraperitoneal IUDs may cause intestinal adhesions. IUDs that have perforated the uterus are removed via laparoscopy.. If expulsion or perforation is suspected, a backup contraceptive method should be used.. Rarely, salpingitis (pelvic inflammatory disease [PID]) develops during the first month after insertion because bacteria are displaced into the uterine cavity during insertion; however, this risk is low and routine antibiotic prophylaxis is not indicated. If PID develops, antibiotics should be given. The IUD need not be removed unless the infection persists despite antibiotics. IUD strings do not provide access for bacteria. Except during the first month after insertion, IUDs do not increase the risk of pelvic inflammatory disease.. If Actinomyces- like organisms on a Pap test in women with no symptoms of infection does not require antibiotics nor IUD removal.. The incidence of ectopic pregnancy is much lower in IUD users than in women using no contraceptive method because IUDs effectively prevent pregnancy. However, if a women becomes pregnant while an IUD is in place, she should be told that risk of ectopic pregnancy is increased, and she should be evaluated promptly.. References. 1. Nelson A, Apter D, Hauck B, et al: Two low-dose levonorgestrel intrauterine contraceptive systems: a randomized controlled trial [published correction appears in Obstet Gynecol 123(5):1109, 2014]. Obstet Gynecol 122(6):1205-1213, 2013. doi:10.1097/AOG.0000000000000019. # 2. Jensen JT, Lukkari-Lax E, Schulze A, et al: Contraceptive efficacy and safety of the 52-mg levonorgestrel intrauterine system for up to 8 years: findings from the Mirena Extension Trial. Am J Obstet Gynecol 227(6):873.e1-873.e12, 2022. doi:10.1016/j.ajog.2022.09.0073. Creinin MD, Schreiber CA, Turok DK, et al: Levonorgestrel 52 mg intrauterine system efficacy and safety through 8 years of use. Am J Obstet Gynecol 227(6):871.e1-871.e7, 2022. doi:10.1016/j.ajog.2022.05.0224. Long-term reversible contraception. Twelve years of experience with the TCu380A and TCu220C. Contraception 56(6):341-352, 1997.5. Grentzer JM, Peipert JE, Zhao Q, et al: Risk-based screening for Chlamydia trachomatis and Neisseria gonorrhoeae prior to intrauterine device insertion. Contraception 92(4):313-318, 2015. doi:10.1016/j.contraception.2015.06.0126. Mody SK, Farala JP, Jimenez B, et al: Paracervical block for intrauterine device placement among nulliparous women: A randomized controlled trial, Obstet Gynecol 132 (3): 575-582, 2018. doi: 10.1097/AOG.00000000000027907. Curtis KM, Jatlaoui TC, Tepper NK, et al: U.S. Selected Practice Recommendations for Contraceptive Use, 2016. MMWR Recomm Rep 65 (4):1-66, 2016. doi: 10.15585/mmwr.rr6504a18. Jareid M, Thalabard JC, Aarflot M, et al: Levonorgestrel-releasing intrauterine system use is associated with a decreased risk of ovarian and endometrial cancer, without increased risk of breast cancer: Results from the NOWAC Study. Gynecol Oncol 149 (1), 127-132, 2018, doi.org/10.1016/j.ygyno.2018.02.0069. Prabhakaran S, Chuang A: In-office retrieval of intrauterine contraceptive devices with missing strings. Contraception 83(2):102-106, 2011. doi:10.1016/j.contraception.2010.07.004. Key Points. - IUDs are highly effective contraceptives and have minimal systemic effects, and IUDs need to be changed only every 3, 5, 8, or 10 years depending on the IUD chosen.- Types include levonorgestrel-releasing IUDs (effective for 3 to 8 years, depending on the type) and an intrauterine copper contraceptive (effective for 10 years, with a 12-year pregnancy rate of . # sound, or biopsy instrument (unless pregnancy is suspected), and if needed, do ultrasonography or take an abdominal x- ray to check for location..	None	None	None
7f07f232ad084a9183a4a222ba79c988	MSD	宫颈平滑肌瘤	# Cervical Leiomyomas. (Cervical Myomas; Cervical Fibroids). By Charles Kilpatrick, MD, MEd, Baylor College of Medicine Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Feb 2025. Cervical leiomyomas are benign smooth- muscle tumors. Symptoms may include abnormal vaginal bleeding, vaginal discharge, and dyspareunia. Diagnosis is with pelvic examination or sometimes imaging. Treatment is observation or surgical removal.. Symptoms and Signs \| Diagnosis \| Treatment \| Key Points. Cervical leiomyomas are uncommon. Uterine leiomyomas (fibroids) commonly occur in the uterine corpus and are usually present in patients with cervical fibroids. Large cervical leiomyomas may partially obstruct the urinary tract. Cervical leiomyomas do not prolapse, but some submucosal fibroids prolapse through the cervical canal into the vagina. Prolapsed submucosal leiomyomas sometimes ulcerate, become infected, bleed, or a combination.. Symptoms and Signs of Cervical Leiomyomas. Cervical leiomyomas can be symptomatic. A common symptom is bleeding, which may be irregular or heavy, sometimes causing anemia. Dyspareunia may occur. Infection may cause pain, bleeding, or discharge.. Urinary outflow obstruction causes hesitancy, dribbling, or urinary retention; urinary tract infections may develop.. Diagnosis of Cervical Leiomyomas. - Pelvic examination- Sometimes imaging. Diagnosis of cervical leiomyomas is by physical examination. Some are palpable during bimanual examination. Ultrasound or MRI can help with the diagnosis.. On speculum examination, sometimes a prolapsed submucosal leiomyoma is visible at or beyond the external cervical os. Typically, these are pedunculated and mobile, which differentiates them from. # cervical leiomyomas, which are usually sessile. A prolapsed submucosal leiomyoma may be friable and ulcerated.. Transvaginal ultrasound or MRI is done for the following reasons:. To confirm an uncertain diagnosis To exclude urinary outflow obstruction To identify additional leiomyomas To distinguish between a prolapsed submucosal leiomyoma and a true cervical leiomyoma. Hemoglobin or hematocrit is measured to exclude anemia.. A biopsy is done if needed to rule out other types of cervical masses.. Treatment of Cervical Leiomyomas. Removal of symptomatic leiomyomas. Treatment of cervical leiomyomas is similar to treatment of fibroids (1). Small, asymptomatic leiomyomas are not treated. Most symptomatic cervical leiomyomas are removed by myomectomy (particularly if childbearing capacity is important) or, if myomectomy is technically difficult, by hysterectomy.. Prolapsed leiomyomas can be removed transvaginally.. Treatment reference. 1. Ferrari F, Forte S, Valenti G, et al. Current Treatment Options for Cervical Leiomyomas: A Systematic Review of Literature. Medicina (Kaunas). 2021;57(2):92. Published 2021 Jan 21. doi:10.3390/medicina57020092. Key Points. Cervical leiomyomas are benign.. Cervical leiomyomas can cause symptoms, mainly bleeding; large leiomyomas may partially obstruct the urinary tract.. Diagnose cervical leiomyomas by pelvic examination and sometimes transvaginal ultrasound or MRI.. Surgically remove symptomatic cervical leiomyomas, usually by myomectomy but, if myomectomy is not possible, by hysterectomy.. # .	None	None	None
09237371613c4235888f9e0d66bf56ac	MSD	宫颈息肉	# Cervical Polyps. By Charles Kilpatrick, MD, MEd, Baylor College of Medicine Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Feb 2023. Cervical polyps are common benign growths of the cervix and endocervix. Most cervical polyps are asymptomatic, but some cause vaginal bleeding. Diagnosis is with pelvic examination. Treatment is polypectomy, usually as a minor outpatient procedure.. Symptoms and Signs \| Diagnosis \| Treatment \| Key Points. Cervical polyps occur in about 2 to . Symptoms and Signs of Cervical Polyps. Most cervical polyps are asymptomatic, but they may bleed between menses or after intercourse or become infected, causing purulent vaginal discharge (leukorrhea).. Endocervical polyps are usually reddish pink, glistening, and . Cervical Polyp. IMAGE. # Diagnosis of Cervical Polyps. Vaginal speculum examination. Diagnosis of cervical polyps is by vaginal speculum examination.. Cervical cytology should be done.. Treatment of Cervical Polyps. Excision. Polyps that cause bleeding or discharge should be removed. Excision is usually a minor procedure and can be done in the office by grasping the base with forceps and twisting off the polyp (polypectomy). Typically polypectomy is not painful and does not require local anesthetics. Bleeding after excision is rare and can be controlled with chemical cautery.. If bleeding or discharge persists after treatment, endometrial biopsy is done to exclude cancer.. Key Points. Key Points- Cervical polyps are common benign growths of the cervix and endocervix; they are usually benign.- Most are asymptomatic, but some cause bleeding or become infected, causing purulent vaginal discharge.- Diagnose by vaginal speculum examination.- If polyps cause symptoms, remove them; if bleeding or discharge persists after removal, biopsy is required to exclude cancer..	None	None	None
08057e20c5c44f53a534fe417e4032fb	MSD	宫颈癌	# Cervical Cancer. By Pedro T. Ramirez, MD, Houston Methodist Hospital; Gloria Salvo, MD, MD Anderson Cancer Center Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Sept 2023. Cervical cancer is usually squamous cell carcinoma; adenocarcinoma is less common. The cause of most cervical cancers is human papillomavirus (HPV) infection. Cervical neoplasia is often asymptomatic; the first symptom of cervical cancer is usually irregular, often postcoital, vaginal bleeding. Diagnosis is by a cervical Papanicolaou test and biopsy. Staging is clinical, combined with imaging and pathology results when available. Treatment usually involves surgical resection for early- stage disease or chemoradiation therapy for locally advanced disease. If the cancer has widely metastasized, chemotherapy is often used alone or, sometimes, followed by pelvic radiation.. Pathology \| Symptoms and Signs \| Diagnosis \| Treatment \| Prognosis \| Key Points \| More Information. (See also Cervical Cancer Screening and Prevention.). In the United States, cervical cancer is the 3rd most common gynecologic cancer and the 15th most common cancer among women (1). Mean age at diagnosis is 50; it is frequently diagnosed in women aged 35 to 44 years. The National Cancer Institute estimates that in 2023, there will be 13,960 new cases of invasive cervical cancer and 4310 deaths (2). Worldwide, almost . Risk factors associated with cervical cancer include. - Human papillomavirus (HPV) infection- Cervical intraepithelial neoplasia- Increased potential exposure to sexually transmitted diseases (eg, early age at first sexual activity or first childbirth, multiple sex partners, high-risk sex partners)- History of vulvar or vaginal squamous intraepithelial neoplasia or cancer- Anal intraepithelial neoplasia or cancer- Oral contraceptive use- Cigarette smoking. # Immunodeficiency. ImmunodeficiencyThe precursor to cervical cancer is cervical intraepithelial neoplasia (CIN). The great majority of cases of CIN and invasive cervical cancer are caused by persistent infection with human papillomavirus (HPV), transmitted mainly through sexual activity. Most (70%) of precancerous and invasive disease can be directly attributed to HPV types 16 or 18; however, 99% of cervical cancer specimens contain DNA from one of more than 14 high- risk HPV genotypes (5, 6). The incidence of cervical cancer has decreased steadily over the past several decades because of HPV vaccination, cervical cancer screening, and treatment of CIN.. General references. General references1. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program: Cancer Stat Facts: Common Cancer Sites. Table: How Do Cancer Rates Compare? National Cancer Institute. Bethesda, MD. Accessed July 14, 2023.2. National Cancer Institute: Cancer Stat Facts: Cervical Cancer. Accessed July 14, 2023.3. Sung H, Ferlay J, Siegel RL, et al: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71 (3):209- 249, 2021. doi: 10.3322/caac.216604. Bhatla N, Aoki D, Sharma DN, Sankaranarayanan R: Cancer of the cervix uteri: 2021 update. Int J Gynaecol Obstet 155 Suppl 1(Suppl 1):28- 44, 2021. doi:10.1002/ijgo.138655. Joste NE, Ronnett BM, Hunt WC, et al: Human papillomavirus genotype- specific prevalence across the continuum of cervical neoplasia and cancer. Cancer Epidemiol Biomarkers Prev 24 (1): 230- 240, 2015. doi: 10.1158/1055- 9965. EPI- 14- 07756. Walboomers JMM, Jacobs MV, Manos MM, et al: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189 (1):12- 19, 1999. doi: 10.1002/(SICI)1096- 9896(199909)189:1<12::AID- PATH431>3.0. CO;2- F. Pathology of Cervical Cancer. The cervix is composed of stroma and epithelium. The ectocervix protrudes into the vagina and is lined with squamous epithelium. The endocervix (a canal that passes from the internal os to the external os) is lined with columnar epithelium. Nearly all cervical carcinomas originate in the transformation zone, which surrounds the external os; the transformation zone is an area of squamous metaplasia between the original and current squamocolummar junction (1).. Cervical intraepithelial neoplasia (CIN) is graded as. 1: Mild cervical dysplasia 2: Moderate dysplasia 3: Severe dysplasia and carcinoma in situ. CIN3 is unlikely to regress spontaneously; if untreated, it may, over months or years, penetrate the basement membrane, becoming invasive carcinoma.. # About 80 to . Invasive cervical cancer usually spreads by direct extension into surrounding tissues or via the lymphatics to the pelvic and para- aortic lymph nodes. Hematogenous spread is possible but rare.. If cervical cancer spreads to the pelvic or para- aortic lymph nodes, the prognosis is worse, and the location and size of the radiation therapy field is affected.. Pathology reference. 1. Bhatla N, Aoki D, Sharma DN, et al: Cancer of the cervix uteri: 2021 update. Int J Gynaecol Obstet 155 Suppl 1:28-44, 2021. doi: 10.1002/ijgo.13865. Symptoms and Signs of Cervical Cancer. Early cervical cancer is often asymptomatic. When symptoms occur, they usually include irregular vaginal bleeding, which is most often postcoital, but may occur spontaneously between menses. Larger cancers are more likely to bleed spontaneously and may cause a foul- smelling vaginal discharge or pelvic pain. More widespread cancer may cause obstructive uropathy, back pain, and leg swelling due to venous or lymphatic obstruction.. Diagnosis of Cervical Cancer. - Papanicolaou (Pap) test (cervical cytology)- Biopsy. Cervical cancer may be suspected during a routine gynecologic examination. Further evaluation is required for patients with. - A visible cervical lesion- Abnormal vaginal bleeding. Cervical cancer is usually diagnosed when cervical cytology and/or HPV testing detects abnormalities. Findings are usually microscopic, but in some cases there is a cervical lesion. A large tumor may be exophytic and necrotic, but a lesion may also be smaller and less distinctive. Biopsy should be performed for any cervical lesion for which there is a suspicion of malignancy.. Reporting of cervical cytology results is standardized (see table Bethesda Classification of Cervical Cytology [1]). Further evaluation with cytology, HPV testing, or colposcopy is indicated if atypical or cancerous cells are found and/or HPV testing is positive. Colposcopy (examination of the vagina and cervix with a magnifying lens) is used to identify areas that require biopsy; endocervical curettage is also often performed.. Cone biopsy (conization) is required if the diagnosis is uncertain and high- grade CIN or invasive cancer is suspected; a cone of tissue is removed using a loop electrical excision procedure (LEEP), laser, or scalpel. # (cold knife).. Cervical Cancer. IMAGE. SCIENCE PHOTO LIBRARY. Loop Electrosurgical Excision Procedure (LEEP). IMAGE. # # # * Use of an automated device for scanning should be reported, as should adjunctive tests (eg, HPV) and their results.. † If there is no cellular evidence of neoplasia, the report should state negative for intraepithelial lesion or malignancy here or in the general categorization.. ‡ Cellular changes of HPV infection—previously called koilocytosis, koilocytotic atypia, and condylomatous atypia—are included in the category of low- grade squamous intraepithelial lesion.. CIN = cervical intraepithelial neoplasia; CIS = carcinoma in situ; HPV = human papillomavirus; IUD = intrauterine device; NOS = not otherwise specified.. Adapted from the Bethesda System 2014, National Institutes of Health.. Staging. Cervical cancer staging underwent a major revision in 2018. The previous International Federation of Obstetrics and Gynecology (Federation Internationale de Gynecologie et d'Obstetrique, or FIGO) 2009 staging system allowed only clinical examination, cervical biopsy, and a few additional tests to assign the stage. The FIGO 2018 staging system allows, when available, cross- sectional imaging (eg, ultrasonography, CT, MRI, positron emission tomography [PET], PET- CT, MRI- PET), and surgical pathology results to supplement clinical findings in all stages. Imaging and pathology results are optional because they may be not available in low- and middle- resource countries, where cervical cancer is more common (2, 3, 4).. Other changes in the 2018 staging system include the following:. - Horizontal spread of the tumor is no longer considered part of stage IA1 and IA2. - Stage I is subdivided into 3 subgroups according to tumor size (IB1 ≤ 2 cm, IB2> 2 to ≤ 4 cm, and IB3 > 4 cm) instead of 2 subgroups (stages IB1 and IB2, which used only 4 cm as a cutoff value). - Lymph node status is now part of the staging system. Positive pelvic nodes are now stage IIIC1 and positive paraortic nodes are stage IIIC2. Micrometastases in the lymph nodes are considered positive; however, these isolated tumor cells do not change the stage to III, but they should be recorded. If lymph nodes are classified as positive by imaging studies, an "r" is added to the stage (eg, IIIC1r, IIIC2r); if they are classified as positive by pathology results, a "p" is added (IIIC1p, IIIC2p [2, 3, 4]).. If the stage is higher than A2, CT or MRI of the abdomen and pelvis is typically done to better determine tumor size, parametrial involvement, vaginal compromise, and nodal metastases. PET with CT (PET/CT). # is often used to check for spread beyond the cervix. If PET/CT, MRI, or CT is not available, cystoscopy, sigmoidoscopy, chest x- ray, and IV urography, when clinically indicated, may be used for staging.. # # \* Imaging and pathology, if available, can be used to supplement clinical findings when determining tumor size and extent in all stages. Pathologic findings supersede imaging and clinical findings. Depth of invasion should be measured from the base of the epithelium (surface or glandular) from which it originates.. t Vascular space involvement (venous or lymphatic) should not alter staging. Lateral extension of the lesion is no longer considered.. The notation r (imaging) and/or p (pathology) should be added to indicate the methods used to assign stage IIIC (eg, stage IIICp). The type of imaging or pathology technique used should always be documented. If the stage is in doubt, the lower stage should be assigned.. FIGO = International Federation of Obstetrics and Gynecology (Federation Internationale de Gynecologie et d'Obstetrique). Based on Bhatla N, Aoki D, Sharma DN, et al: Cancer of the cervix uteri: 2021 update. Int J Gynaecol Obstet 155 Suppl 1:28- 44, 2021. doi: 10.1002/ijgo.13865. When imaging tests suggest that pelvic or para- aortic lymph nodes are grossly enlarged (> 2 cm), surgical exploration, typically with a retroperitoneal approach, may be indicated. Its sole purpose is to remove enlarged lymph nodes so that radiation therapy can be more precisely targeted and more effective.. Diagnosis references. 1. Nayar R, Wilbur DC: The Pap test and Bethesda 2014. Cancer Cytopathology, 123: 271-281, 2015. doi:10.1002/cncy.21521 2. Bhatla N, Berek JS, Cuello Fredes M, et al: Revised FIGO Staging for Carcinoma of the Cervix Uteri. Int J Gynaecol Obstet 145 (1):129-135, 2019. doi: 10.1002/ijgo.12749. # 3. Bhatla N, Berek JS, Cuello Fredes M, et al: Corrigendum to "Revised FIGO staging for carcinoma of the cervix uteri" [Int J Gynecol Obstet 145(2019) 129-135]. Int J Gynaecol Obstet 147(2):279-280, 2019. doi: 10.1002/ijgo.12969 4. Bhatla N, Aoki D, Sharma DN, Sankaranarayanan R: Cancer of the cervix uteri: 2021 update. Int J Gynaecol Obstet 155 Suppl 1(Suppl 1):28-44, 2021. doi:10.1002/ijgo.13865. Treatment of Cervical Cancer. Surgery alone for microinvasive disease Surgery or curative radiation therapy if there is no spread to parametria or beyond Radiation therapy and chemotherapy (chemoradiation) if there is spread to parametria or beyond Chemotherapy for metastatic and recurrent cancer. Treatment of cervical cancer may include surgery, radiation therapy, and chemotherapy. If radical hysterectomy is indicated but patients are not ideal candidates for it, chemoradiation is used and has similar oncologic outcomes.. Stage IA1 (no lymphovascular space invasion). Treatment of stage IA1 involves. Conization or simple hysterectomy. Microinvasive cervical cancer, defined as FIGO stage IA1 with no lymphovascular space invasion (LVSI), has a . Simple hysterectomy should be done if patients are not interested in preserving fertility or if margins are positive after conization. If margins are positive, sentinel lymph node (SLN) mapping should be considered, and if patients are interested in preserving fertility, repeat conization is an alternative.. Sentinel lymph node mapping for cervical cancer. Sentinel lymph node (SLN) mapping is an alternative to full pelvic lymphadenectomy for patients with early- stage (IA1 with lymphovascular space invasion, IB1, IB2, or IIA1) cervical cancer (1) because only 15 to . For SLN mapping, blue dye, technetium- 99 (99Tc), or indocyanine green (ICG) is directly injected into the cervix, usually at 3 and 9 o'clock. During surgery, SLNs are identified by direct visualization of blue dye, by a camera to detect the fluorescence of ICG, or by a gamma probe to detect 99Tc. SLNs are commonly located medial to the external iliac vessels, ventral to the hypogastric vessels, or in the superior part of the obturator space.. # Ultrastaging of all SLNs is done to detect micrometastasis and isolated tumor cells (low- volume disease). Any grossly suspicious node must be removed regardless of mapping. If there is no mapping on a hemipelvis, a side- specific lymphadenectomy is done. In the 2018 FIGO staging system, only macrometastases and micrometastases are considered when classifying cases as IIIC; isolated tumor cells do not change the stage, they are considered pN0.. Detection rates for SLN mapping are best for tumors . Stage IA1 (with lymphovascular space invasion) and stage IA2. For stage IA1 with LVSI or stage IA2, recommended treatments include. - Modified radical hysterectomy and pelvic lymphadenectomy (with or without SLN mapping)- External pelvic radiation therapy with brachytherapy. Criteria for radiation therapy after radical hysterectomy. Criteria used to determine whether pelvic radiation with concurrent chemotherapy should be done after radical hysterectomy include the following (see table Sedlis Criteria for External Pelvic Radiation After Radical Hysterectomy):. - Presence of lymphovascular space invasion- Depth of invasion- Tumor size. Patients with a combination of risk factors, such as large tumor size . Risk factors such as positive margins and/or pathologically confirmed positive pelvic lymph nodes and/or microscopic involvement of the parametrium are considered higher risk. In a randomized trial, the estimated 4- year survival rates for patients with stage IB cervical cancer and high- risk factors were . # Stages IB1, IB2, and IIA1. For stages IB1, IB2, and IIA1, the standard recommendation is. - Open radical hysterectomy with bilateral pelvic lymphadenectomy (with or without SLN mapping). Radical hysterectomy includes resection of the uterus (including the cervix), parts of the cardinal and uterosacral ligaments, the upper 1 to 2 cm of the vagina, the pelvic lymph nodes and parametrium. The Querleu & Morrow classification system describes four types of radical hysterectomy based on the lateral extent of resection; a few subtypes take nerve preservation and paracervical lymphadenectomy into account (6).. Results from a randomized trial showed that minimally invasive surgery (laparoscopy or robot- assisted laparoscopy) resulted in a lower overall survival rate and a higher recurrence rate than total abdominal radical hysterectomy (7). Therefore, open radical hysterectomy is recommended as the appropriate approach.. When patients are not considered ideal candidates for surgery because of comorbidities, another valid option is external pelvic radiation therapy and brachytherapy with or without concurrent platinum- based chemotherapy.. # Another treatment option is radical hysterectomy and bilateral pelvic lymphadenectomy (with or without para- aortic lymphadenectomy), sometimes with adjuvant radiation therapy (see table Sedlis Criteria for External Pelvic Radiation After Radical Hysterectomy).. If extracervical spread is noted during radical hysterectomy, the procedure should be aborted, and postoperative radiation therapy with concurrent chemotherapy is recommended to prevent local recurrence (8).. Stages IB3, IIA2, IIB, III, and IVA. The standard therapy for stages IB3, IIA2, IIB, III, and IVA cancer is. - External pelvic radiation therapy with brachytherapy and concurrent platinum-based chemotherapy. To determine the extent of the radiation field, clinicians may evaluate spread to para- aortic lymph nodes clinically (abdominal CT and/or MRI) or surgically (pelvic and para- aortic lymphadenectomy). In a randomized trial, oncologic outcomes did not differ significantly in patients with stage IIB through IVA staged clinically compared with those staged surgically before chemoradiation. In this study, laparoscopic staging appeared to be safe, did not delay primary treatment, and resulted in upstaging in . When cancer is limited to the cervix and/or pelvic lymph nodes, the standard recommendation is. - External beam radiation therapy, followed by brachytherapy (local radioactive implants, usually using cesium) to the cervix. Radiation therapy may cause acute complications (eg, radiation proctitis and cystitis) and, occasionally, late complications (eg, vaginal stenosis, intestinal obstruction, rectovaginal and vesicovaginal fistula formation).. Chemotherapy (cisplatin or carboplatin) is usually given with radiation therapy, often to sensitize the tumor to radiation.. Although stage IVA cancers are usually treated with radiation therapy initially, pelvic exenteration (excision of all pelvic organs) may be considered. If after radiation therapy, cancer remains but is confined to the central pelvis, exenteration is indicated and cures up to . Stage IVB and recurrent cancer. Chemotherapy is the primary treatment for stage IVB cervical cancer. Response rates are approximately . In a randomized trial, adding bevacizumab to combination chemotherapy (cisplatin plus paclitaxel or topotecan plus paclitaxel) resulted in an improvement of 3.7 months in median overall survival in patients with recurrent, persistent, or metastatic cervical cancer (11).. # Metastases outside the radiation field appear to respond better to chemotherapy than does previously irradiated cancer or metastases in the pelvis.. A systematic review of observational studies included 2424 patients with stage IVB squamous cell, adenocarcinoma, or adenosquamous carcinoma of the cervix and found improved overall survival associated with definitive . Clinicians should consider testing for mismatch repair (MMR) and microsatellite instability (MSI), PD- L1 (programmed cell death- ligand 1) expression, and/or NTRK gene fusion if patients have recurrent, progressive, or metastatic cervical cancer. Results can help predict responses to immunotherapies such as PD- L1 inhibitors.. Few effective second- line treatments exist for women with recurrent or metastatic cervical cancer.. In a randomized, placebo- controlled trial, adding pembrolizumab to chemotherapy, improved progression- free and overall survival in patients with persistent, recurrent, or metastatic cervical cancer (13).. Tisotumab vedotin showed clinically meaningful and durable antitumor activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer (14).. Fertility-sparing surgery. Fertility- sparing surgery is an option in some patients who have early- stage cervical cancer (IA1 with LVSI, IA2, IB1, some cases of IB2) and who wish to preserve fertility.. Surgical treatment of cervical cancer does not include oophorectomy unless ovaries appear abnormal. In young patients having surgery, ovarian preservation is particular important to avoid premature menopause. Before pelvic radiation, ovaries may be moved outside the radiation field (oophoropexy) to avoid toxic exposure. Patients should be counseled about the benefit of preserving ovary function versus the risk of potential ovarian metastases. In a study of 3471 patients who had stage Ib through IIb cervical cancer treated with a radical hysterectomy, the cancer metastasized to the ovaries in . Surgical options for uterine conservation include. - Radical trachelectomy with nodal evaluation- Cervical conization. Radical trachelectomy is removal of the cervix, parametria immediately adjacent to the cervix, upper 2 cm of the vagina, and pelvic lymph nodes. The uterus is conserved and is reattached to the upper vagina, preserving the potential for fertility. Candidates for this procedure are patients with the following:. - Histologic subtypes such as squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma (not neuroendocrine or small cell carcinoma or sarcoma). # - Stage IA1/grade 2 or 3 with lymphovascular space invasion- Stage IA2- Stage IB1. Invasion of the upper cervix and lower uterine segment should be excluded by MRI before surgery. Rates of recurrence and death are similar to those after radical hysterectomy. If patients who have this procedure plan to have children, delivery must be cesarean. After a radical trachelectomy, fertility rates range from 50 to . Radical trachelectomy can be performed via vaginal surgery, laparotomy, laparoscopy, or robotic- assisted surgery. There has been concern about the safety of radical trachelectomy using minimally invasive approaches (laparoscopy or robotic- assisted surgery) compared with laparotomy. In one retrospective study of patients with early- stage cervical cancer . For patients with low- risk, early- stage cervical cancer, conization with pelvic nodal evaluation may be an alternative to radical trachelectomy. In a single- arm, prospective study, conservative surgery (cervical conization or simple hysterectomy with nodal evaluation) appeared to be safe and feasible in women with low- risk, early- stage cervical cancer; the 2- year recurrence rate was . An ongoing prospective study (CONTESSA) is evaluating the role of neoadjuvant chemotherapy followed by fertility- sparing surgery in patients who have tumors 2 to 4 cm and who wish to preserve fertility (19).. Treatment references. 1. National Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer. Version 1.2023. October 26, 2021. Accessed July 14, 2023. 2. Sedlis A, Bundy BN, Rotman MZ, et al: A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study. Gynecol Oncol 73 (2):177-183, 1999. doi: 10.1006/gyno.1999.5387 3. Rotman M, Sedlis A, Piedmonte MR, et al: A phase III randomized trial of postoperative pelvic irradiation in stage IB cervical carcinoma with poor prognostic features: Follow-up of a Gynecologic Oncology Group Study. Int J Radiat Oncol Biol Phys 65 (1):169-176, 2006. doi: 10.1016/j.ijrobp.2005.10.019 4. Peters WA, Liu PY, Barrett RJ, et al: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 18 (8):1606-1613, 2000. doi: 10.1200/JCO.2000.18.8.1606 5. Monk BJ, Wang J, Im S, et al: Rethinking the use of radiation and chemotherapy after radical hysterectomy: a clinical-pathologic analysis of a Gynecologic Oncology Group/Southwest Oncology Group/Radiation Therapy Oncology Group trial. Gynecol Oncol 96 (3):721-728, 2005. doi: 10.1016/j.ygyno.2004.11.007 6. Querleu D, Morrow CP: Classification of radical hysterectomy. Lancet Oncol 9 (3):297-303, 2008. doi: 10.1016/S1470-2045(08)00074-3. # 7. Ramirez PT, Frumovitz M, Pareja R, et al: Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med 379 (20): 1895-1904, 2018. doi: 10.1056/NEJMoa1806395. 8. Cibula D, Dostalek L, Hillemanns P, et al: Completion of radical hysterectomy does not improve survival of patients with cervical cancer and intraoperatively detected lymph node involvement: ABRAx international retrospective cohort study. Eur J Cancer 143:88-100, 2021. doi:. ABRAx international retrospective cohort study. Eur J Cancer 143:88- 100, 2021. doi:. 10.1016/j.ejca.2020.10.037. 9. Marnitz S, Tsunoda AT, Markus P, et al: Surgical versus clinical staging prior to primary chemoradiation in patients with cervical cancer FIGO stages IIB-IVA: Oncologic results of a prospective randomized international multicenter (Uterus-11) intergroup study. Int J Gynecol Cancer 30:1855-1861, 2020. doi:10.1136/ijgc-2020-001973. 10. Ruengkhachorn I, Leelahpatanadit C, Therasakvichya S, et al: Oncologic outcomes of stage IVB or persistent or recurrent cervical carcinoma patients treated with chemotherapy at Siriraj Hospital: Thailand's largest tertiary referral center. Int J Gynecol Cancer 26(6):1154-1161, 2016. doi:10.1097/IGC.0000000000000712. 11. Tewari KS, Sill MW, Long HJ. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370 (8):734-743, 2014. doi: 10.1056/NEJMoa1309748. 12. Viveros-Carreño D, Vieira-Serna S, Grillo-Ardila CF, et al: Definitive pelvic radiotherapy for patients with newly diagnosed stage IVB cervical cancer: a systematic review. Int J Gynecol Cancer 33(7):1057-1062, 2023. Published 2023 Jul 3. doi:10.1136/ijgc-2023-004465. 13. Colombo N, Dubot C, Lorusso D, et al: Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med 385 (20):1856-1867, 2021. doi: 10.1056/NEJMoa2112435. 14. Coleman RL, Lorusso D, Gennigens C, et al: Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 22(5):609-619, 2021. doi:10.1016/S1470-2045(21)00056-5. 15. Shimada M, Kigawa J, Nishimura R, Yamaguchi S, et al: Ovarian metastasis in carcinoma of the uterine cervix. Gynecol Oncol 101 (2):234-237, 2006. doi: 10.1016/j.ygyno.2005.10.004. 16. Salvo G, Ramirez PT, Leitao M, et al: Open vs minimally invasive radical trachelectomy in early-stage cervical cancer: International Radical Trachelectomy Assessment Study. Am J Obstet Gynecol 226 (1):97.e1-97.e16, 2022. doi: 10.1016/j.ajog.2021.08.029. 17. Schmeler KM, Pareja R, Aldo Lopez Blanco AL, et al: ConCerv: A prospective trial of conservative surgery for low-risk early-stage cervical cancer. Int J Gynecol Cancer 31 (10):1317-1325, 2021. doi: 10.1136/ijgc-2021-002921. 18. Plante M, Kwon JS, Ferguson et al: An international randomized phase III trial comparing radical hysterectomy and pelvic node dissection (RH) vs simple hysterectomy and pelvic node dissection (SH) in patients with low-risk early-stage cervical cancer (LRESCC): A Gynecologic Cancer Intergroup study led by the Canadian Cancer Trials Group (CCTG CX.5-SHAPE). [abstract taken from J Clin Oncol 41(suppl 17; abstract LBA5511), 2023. doi: 10.1200/JCO.2023.41.17_suppl.LBA551119. Plante M, van Trommel NE, Schaafsma M, et al: 2022-RA-678-ESGO CONTESSA/NEOCON-F trial: Assessing the effectiveness and safety of neoadjuvant chemotherapy followed by fertility-sparing surgery in FIGO 2018 stage IB2 cervical cancer. International Journal of Gynecologic Cancer 32:A20, 2022. . # Prognosis for Cervical Cancer. The most common histologic types of cervical cancer (squamous cell carcinoma, adenocarcinoma) usually metastasize to distant sites only when the cancer is locally advanced or recurrent. The 5- year survival rates are as follows:. Stage I:80 to . Nearly . Adverse prognostic factors include. Lymph node involvement Large tumor size and volume Deep cervical stromal invasion Parametrial invasion Lymphovascular space invasion (LVsI) Nonsquamous histology. Key Points. Key Points- Consider cervical cancer if women have abnormal cervical cancer screening (HPV or Pap test) results, visible cervical lesions, or abnormal, particularly postcoital, vaginal bleeding.- Do a colposcopy and/or biopsy to further evaluate and confirm the diagnosis.- Stage cervical cancer clinically, using biopsy, pelvic examination, and available imaging, including chest x- ray; also use ultrasonography, PET/CT, MRI, or CT and surgical pathology, if available.- Treatment is surgical resection for early- stage cancer, radiation therapy plus chemotherapy for locally advanced cancer, and chemotherapy for metastatic and recurrent cancer.- Recommend HPV vaccination for children, before first sexual activity.. More Information. # The following English- language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.. National Cancer Institute: Cervical Cancer Treatment: This web site provides general information about cervical cancer and information about classification, staging, treatment by stage, and cervical cancer during pregnancy..	None	None	None
18f9f0046586432aa6d5b236e212d88a	MSD	异常子宫出血	# Abnormal uterine bleeding. (Dysfunctional Uterine Bleeding). Author: JoAnn V. Pinkerton, MD, University of Virginia Health System Reviewed By Oluwatosin Goje, MD, MScF, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/revised January 2023 \| Revised March 2024. Abnormal uterine bleeding (AUB) in women of childbearing age is a bleeding pattern that is inconsistent with normal menstrual cycle parameters (frequency, regularity, duration, and volume). The PALM- COEIN system categorizes the causes of AUB as structural (polyps, adenomyosis, leiomyoma [fibroid] or malignancy or hyperplasia) or nonstructural (coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, not yet classified). Evaluation is by menstrual history, pelvic examination, hormone blood tests, and often transvaginal ultrasonography. Treatment depends on the cause but may include nonhormonal or hormonal drugs or surgery (eg, hysteroscopy, myomectomy, hysterectomy).. Pathophysiology \| Etiology \| Symptoms and Signs \| diagnosis \| treat \| Key Points. (See Gastrointestinal Bleeding). Abnormal uterine bleeding (AUB) is a common problem. Ovulatory dysfunction (anovulation or oligoovulation) is the most common cause of AUB in women of reproductive age, most commonly in women . Pathophysiology of AUB. In an anovulatory cycle, estrogen is produced but no corpus luteum is formed. Therefore, the normal cyclical secretion of progesterone does not occur, and estrogen stimulates the endometrium without inhibition. Without progesterone resistance, the endometrium continues to proliferate and eventually outgrows its blood supply; it is then incompletely shed, with irregular bleeding, sometimes heavy or lasting for days. If this abnormal process occurs repeatedly, it is possible to develop endometrial hyperplasia, sometimes even with atypical hyperplasia or cancer cells.. When abnormal uterine bleeding occurs in a woman with an ovulatory cycle, progesterone secretion is delayed; irregular shedding of the endometrium may occur because estrogen levels are low, approaching the bleeding threshold (which occurs during menstruation). Abnormal uterine bleeding. # with ovulation can also occur in obese women if estrogen levels are high, resulting in alternating amenorrhea and irregular or prolonged bleeding.. complication. Chronic heavy or prolonged uterine bleeding may lead to iron deficiency anemia.. If AUB is due to ovulatory dysfunction, infertility may also be present.. Causes of AUB. The causes of AUB in nonpregnant women of childbearing age can be classified as structural or nonstructural to help determine the cause and treatment. The PALM- COEIN classification system can be used (1). PALM- COEIN is a mnemonic for structural causes (PALM) and nonstructural causes (COEIN) of abnormal bleeding (see figure PALM- COEIN classification system).. AUB due to ovulatory dysfunction (AUB- O) is the most common type of nonstructural AUB and the most common cause. AUB- O can be caused by any disorder or condition that causes anovulation or oligoovulation (irregular or infrequent ovulation—see table Some Causes of Ovulatory Dysfunction). Causes of ovulatory dysfunction include. - Changes in the menstrual cycle (menarche, irregular periods, pregnancy)- Hyperprolactinemia- Hypothyroidism- Cyclic menarche or perimenopause- Primary ovarian insufficiency- Idiopathic (occurs sometimes when gonadotropin levels are normal). During perimenopause, AUB- O may be an early sign of ovarian insufficiency; follicles are still developing, but despite increasing follicle- stimulating hormone (FSH) levels, they are not producing enough estrogen to trigger ovulation.. About . # endometrium); the rapid decline in estrogen causes spotting before ovulation.. Other causes of ovulatory dysfunction are systemic disorders (eg, liver or kidney disease, Cushing syndrome). Severe physical or emotional stress or malnutrition are typical causes of hypothalamic amenorrhea, but some women have infrequent ovulation and, therefore, infrequent menstruation. In some cases, AUB- O is idiopathic (occurring sometimes in the presence of normal gonadotropin levels).. Other nonstructural causes of AUB include. - Coagulation disorders- Endometrial factors (eg, endometritis)- Latrogenic (eg, breakthrough bleeding from hormonal contraceptives). AUB structural types include. - Cervical or endometrial polyps- Adenomyosis- Leiomyoma (uterine fibroids)- Uterine or cervical cancer. Etiology reference. 1. Munro MG, Critchley HOD, Fraser IS, FIGO (International Federation of Gynecology and Obstetrics) Menstrual Disorders Committee : The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions. Int J Gynaecol Obstet 143 (3):393-408, 2018. doi: 10.1002/ijgo.12666. Symptoms and signs of AUB. Compared with normal menstruation, abnormal uterine bleeding may cause the following (see table Normal Menstrual Parameters [1]). - More frequent (< 24 days)- Irregular (frequency of cycles varies ≥ 8 to 10 days)- Bleeding involving more days (> 8 days)- Involving increased blood loss (> 80 mL [or amount reported by the patient]) during menstruation (heavy menstrual bleeding).- Occurs during menstrual periods (intermenstrual bleeding). # * Based on Munro MG, Critchley HOD, Fraser IS for the FIGO (International Federation of Gynecology and Obstetrics) Menstrual Disorders Committee): The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years.. Patients who are ovulating usually have menstrual cycles that are of normal frequency and regularity, but they may have heavy menstrual bleeding or bleeding between periods. Symptoms that suggest patients are ovulating include cyclic breast tenderness, premenstrual bloating, or mood changes) and mid- cycle cramping pain (mittelschmerz). Daily body temperature (basal body temperature) rises slightly after ovulation and falls after the next menstrual period begins.. Uterine bleeding in patients with AUB- O occurs at unpredictable times, may vary greatly in volume, and is not associated with cyclical changes in basal body temperature.. Symptoms and Signs. 1. Munro MG, Critchley HOD, Fraser IS for the FIGO (International Federation of Gynecology and Obstetrics) Menstrual Disorders Committee): The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions. Int J Gynaecol Obstet 143 (3):393-408, 2018.doi: 10.1002/ijgo.12666 Epub 2018 Oct 10.. # Menstrual history- Pregnancy test, complete blood count (CBC), and hormone measurements (eg, thyroid- stimulating hormone [TSH], prolactin)- Pelvic imaging studies, usually transvaginal ultrasonography- Sometimes surgery (endometrial sampling or hysteroscopy). When the amount or timing of vaginal bleeding is inconsistent with normal menstruation, women should be evaluated to determine the cause of the abnormal uterine bleeding. Pregnancy should be excluded, both in young adolescent girls and in perimenopausal women.. The pattern of abnormal uterine bleeding often suggests a possible cause (eg, regular periods and prolonged or excessive bleeding suggest a structural abnormality; irregular bleeding or amenorrhea is usually due to ovulatory dysfunction) and helps guide the choice of laboratory or imaging tests.. Coagulopathy should be considered in adolescents who have anemia or require hospitalization for bleeding and in patients with a family history or other risk factors for coagulopathy.. Laboratory tests. To do some checks:. - Urine or blood pregnancy test- Complete blood count (CBC)- Thyroid-stimulating hormone (TSH), prolactin, and sometimes progesterone levels or urine luteinizing hormone (LH). All women of childbearing age with AUB should undergo pregnancy testing.. CBC tests are done routinely. Anemia may be severe in women with frequent heavy menstrual bleeding. If iron deficiency anemia is suspected in women with chronic heavy bleeding, serum ferritin levels, which reflect the body's iron stores, are measured.. TSH levels are usually measured, and prolactin levels are measured, even in the absence of galactorrhea, because thyroid disease and hyperprolactinemia are common causes of AUB.. To determine whether the patient is anovulatory or ovulating, some clinicians measure serum progesterone levels during the luteal phase (after day 14 of a normal menstrual cycle or after basal body temperature rises, as in this phase). Progesterone levels . Other tests are done based on the results of the history and physical examination and may include the following:. # If polycystic ovary syndrome is suspected, testosterone and dehydroepiandrosterone sulfate (DHEAS) levels If polycystic ovary syndrome is suspected, blood sugar and lipid levels, blood pressure, and body mass index should be measured If ovarian insufficiency is suspected, measurement of FSH and estradiol levels Coagulation tests if there are risk factors for coagulopathy., bruising, and bleeding. Tests done to rule out other causes of vaginal bleeding include. Cervical cancer screening tests (eg, Papanicolaou [Pap] test, human papillomavirus [HPV] test) if women require routine screening or biopsy if suspicious cervical lesions are found during a pelvic examination If pelvic inflammatory disease or cervicitis is suspected, testing for Neisseria gonorrhoeae and Chlamydia trachomatis. Imaging or surgery. Transvaginal ultrasound is part of the evaluation of most patients with AUB. Specifically, it is done if a woman has any of the following:. Bleeding patterns, other symptoms, or pelvic examination that suggest structural pathology or inability to adequately examine the pelvic organs Risk factors for endometrial cancer (eg, obesity, diabetes, hypertension, polycystic ovary syndrome, chronic anovulation, other disorders associated with long- term exposure to unopposed estrogens ) Age . Transvaginal ultrasonography can detect structural abnormalities, including most polyps, fibroids, other masses, ovarian abnormalities, adenomyosis, and endometrial thickening.. If focal endometrial thickening is noted, hysteroscopy or saline- infused sonohysterography is indicated to identify smaller intrauterine masses (eg, endometrial polyps, submucosal uterine fibroids). Hysteroscopy is useful in evaluating such abnormalities; this can determine whether to proceed to a more invasive hysteroscopy for intrauterine mass removal. Hysteroscopy can also be performed directly if sonohysterography is not indicated. Both can be done in the office.. In some women with postmenopausal bleeding, measurement of the thickness of the endometrium (endometrial streaks) during transvaginal ultrasonography may be a first- line test to evaluate for endometrial neoplasia (hyperplasia or cancer). Endometrial sampling is indicated if a woman has. Risk factors for endometrial cancer (eg, current or recent tamoxifen treatment) Persistent or recurring bleeding Endometrial thickness . In premenopausal women, measurement of endometrial thickness is not used to assess endometrial neoplasia because it varies throughout the menstrual cycle (1):. # During menstruation:2to4 mm Early proliferative phase (cycle days 6 to 14):5 to 7 mm Late proliferative stage: . MRI provides detailed images that are useful for planning surgery but is expensive and is not the first- line imaging test for patients with AUB.. Endometrial sampling is often recommended to rule out hyperplasia or cancer in women with any of the following conditions:. Age . In endometrial sampling (which can be done as an office endometrial biopsy or dilation and curettage), only about . Directed biopsies (hysteroscopy) can be done to directly visualize the endometrial cavity and to perform targeted biopsies of focal endometrial abnormalities.. Evaluation References. 1. Weerakkody Y, Fahrenhorst-Jones T, Sharma R, et al.: Endometrial thickness. Radiopaedia.org. Accessed 1/3/23.. Treatment of AUB. To control bleeding, nonsteroidal anti- inflammatory drugs (NSAIDs), tranexamic acid, or hormone therapy can be used. Iron for iron deficiency anemia (if available) Sometimes surgery to treat structural disorders (eg, hysteroscopic myomectomy, uterine fibroid embolization) Hysterectomy for endometrial cancer; progestin therapy or hysterectomy for endometrial hyperplasia. Medications. # Nonhormonal drugs for treating abnormal uterine bleeding have fewer risks and adverse effects than hormonal therapy and can be taken intermittently during bleeding. They are mainly used to treat women who wish to become pregnant, women who want to avoid hormonal therapy, or women who have heavy, regular bleeding (menorrhagia). Options include:. Nonsteroidal anti- inflammatory drugs (NSAIDs), which can reduce bleeding by . Hormonal therapy (such as estrogen/progestin birth control pills, progestins, a long- acting progestin- releasing intrauterine device) is usually first tried in women who want to avoid pregnancy or who are perimenopausal. This therapy does the following:. Inhibit endometrial hyperplasia; Re- establishing regular menstrual habits Reduce menstrual flow. Contraceptive hormonal therapy is continued for as long as the patient wishes. Once bleeding has been controlled for several months, the patient can choose to continue hormonal therapy or stop treatment to see if AUB persists.. Combined estrogen/progestin oral contraceptives (OCs) are usually used. Oral contraceptives, whether used cyclically or sequentially, can control abnormal uterine bleeding in women with ovulatory dysfunction. In addition, for women who have heavy menstrual bleeding (for example, due to uterine fibroids or adenomyosis), OCs may reduce menstrual bleeding. Oral contraceptives containing only progestins do not control heavy bleeding. Benefits of COCs include. Menstrual blood loss reduced by . The risks of OCs depend on the type of OC, dose, duration of use, and patient factors.. Progestins may be used in the following situations:. There are contraindications to estrogen use (eg, patients with cardiovascular risk factors or prior deep vein thrombosis). Patient refuses estrogen. Cyclic progestin therapy (medroxyprogesterone acetate 10 mg/day orally or norethindrone acetate 2.5 to 5 mg/day orally) given 21 days per month may be more predictable than COCs for withdrawal bleeding. Cyclic natural progesterone (micronized progesterone) 200 mg/day may be given 21 days per month, particularly in women of childbearing potential; however, it causes drowsiness and does not reduce bleeding as much as progestins.. # Patients taking noncompetitive cyclic progestins or progestins should use contraception if they wish to prevent pregnancy. Contraceptive progestin options include. - Levonorgestrel-releasing IUD: It is up to . Other treatments occasionally used to treat abnormal uterine bleeding due to ovulatory disorders include. - Gonadotropin-releasing hormone (GnRH) agonists or antagonists: These drugs suppress ovarian hormone production and cause amenorrhea; they are used to shrink uterine fibroids or the endometrium before surgery. However, hypoestrogenic adverse effects of GnRH (eg, osteoporosis) limit its use to 6 months; low-dose hormone supplementation is usually required. GnRH agonists are effective after 7 to 14 days because they initially cause a surge in luteinizing hormone and follicle-stimulating hormone (1, 2). Gonadotropin-releasing hormone antagonists rapidly and reversibly suppress female gonadotropins and ovarian sex hormones and reduce heavy bleeding. With either class of drugs, supplemental low-dose estrogen and progestin therapy may also be needed.- Danazol: It can reduce menstrual blood loss (by causing endometrial atrophy) but is not often used because it has many androgenic adverse effects that can be mitigated by using lower doses or vaginal preparations. Danazol must be used continuously to be effective, generally for about 3 months. Danazol is used only when other treatments are contraindicated.. If you want to become pregnant and your bleeding is not light, you can try inducing ovulation with clomiphene (50 mg orally on days 5 to 9 of your cycle).. Surgical method. Hysteroscopy and curettage (D & C) may be both therapeutic and diagnostic; it may be the treatment of choice when anovulatory bleeding is severe or hormonal therapy is ineffective. Structural causes such as polyps or fibroids may be found or removed during hysteroscopy. This procedure may reduce bleeding, but in some women it can cause amenorrhea due to scarring of the endometrium (Asherman syndrome).. Endometrial ablation (eg, laser, roller, cutting, heat, or cryotherapy) can control heavy bleeding in 60 to . Treatment of fibroids includes. # - Uterine artery embolization is a minimally invasive procedure that uses a fluoroscopic lens to visualize the fibroid. A catheter is inserted into the femoral artery and embolic particles are injected through the catheter to block the blood supply to the fibroid.- Myomectomy (removal of uterine fibroids) can be done hysteroscopy for submucosal fibroids and laparoscopy or through laparotomy for intramural or submural fibroids.. Laparoscopic, abdominal, or vaginal hysterectomy may be recommended for patients who refuse hormone therapy or who, despite other treatments, have symptomatic anemia or a poor quality of life due to persistent irregular bleeding.. Emergency treatment. Emergency measures are only used in rare cases of heavy bleeding. The patient's hemodynamic status is stabilized with intravenous crystalloids, blood products, and other measures as needed. If bleeding persists, a bladder catheter is inserted into the uterus and inflated with 30 to . In very rare cases, heavy bleeding in anovulatory AUB is treated with conjugated estrogens, . Treatment of endometrial hyperplasia. For postmenopausal women with atypical endometrial hyperplasia, total hysterectomy should be chosen.. In premenopausal women, atypical adenomatous endometrial hyperplasia can be treated with medroxyprogesterone acetate . Benign cystic or adenomatous hyperplasia can be treated with cyclic high- dose progestins (eg. cyclic medroxyprogesterone acetate) or insertion of an intrauterine device that releases a sustained- release progestin or levonorgestrel, with repeat biopsy after 3 months of treatment.. Treatment references. 1. Schlaff WD, Ackerman RT, Al-Hendy A, et al.: Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med 382 (4):328-340, 2020. doi: 10.1056/NEJMoa19043512. de Lange ME, Huirne JAE: Linzagolix: An oral gonadotropin-releasing hormone receptor antagonist treatment for uterine fibroid-associated heavy menstrual bleeding. Lancet 400 (10356):866-867, 2002. doi: 10.1016/S0140-6736(22)01781-0. # 3. Mentrikoski MJ, Shah AS, Hanley KZ, et al.: Assessing endometrial hyperplasia and carcinoma treated with progestin therapy. Am J Clin Pathol 38 (4):524-534, 2012. doi: 10.1309/AJCPM2TSDDF1MHBZ. Key Points. - Abnormal uterine bleeding is a common medical problem; ovulatory dysfunction is the most common cause of abnormal uterine bleeding.- Testing for treatable causes of bleeding; testing may include pregnancy testing, CBC and ferritin, measurement of hormone levels (TSH, prolactin, progesterone), and often ultrasonography, office hysteroscopy, and endometrial sampling.- For women at risk, endometrial sampling is done to check for endometrial hyperplasia or cancer.- If medical control of bleeding is required, use NSAIDs, tranexamic acid, estrogen/progestin OCs, levonorgestrel-releasing intrauterine devices, gonadotropin agonists or antagonists, or other hormones for treatment.- Treat structural disease or bleeding that does not respond to drugs with surgery (eg, hysteroscopy, endometrial ablation, hysterectomy)..	None	None	None
3dd7b2e8963e47988d2378ef54508fe0	MSD	甲状腺疾病功能减退	# Overview of Thyroid Function. By Laura Boucai, MD, Weill Cornell Medical College Glenn D. Braunstein, MD, Cedars- Sinai Medical Center Reviewed/Revised Feb 2024. Synthesis and Release of Thyroid Hormones \| Laboratory Testing of Thyroid Function \| Screening for Thyroid Dysfunction \| Radioactive Iodine Uptake and Imaging. The thyroid gland, located in the anterior neck just below the cricoid cartilage, consists of 2 lobes connected by an isthmus. Follicular cells in the gland produce the 2 main thyroid hormones:. - Tetraiodothyronine (thyroxine, T4) - Triiodothyronine (T3). These hormones act on cells in virtually every body tissue by combining with nuclear receptors and altering expression of a wide range of gene products. Thyroid hormone is required for normal brain and somatic tissue development in the fetus and neonate, and, in people of all ages, thyroid hormone regulates protein, carbohydrate, and fat metabolism.. T4 has minimal hormonal activity, but its long half- life (8 days) serves as a reservoir or prohormone for T3. T4 is converted (in most tissues) to T3, the active form that binds to nuclear receptors, and to reverse T3 (rT3), an inactive form of thyroid hormone without metabolic activity. Levels of rT3 increase in certain diseases.. Parafollicular cells (C cells) in the thyroid secrete the hormone calcitonin, which is released in response to hypercalcemia and lowers serum calcium levels (see Regulation of Calcium Metabolism).. Synthesis and Release of Thyroid Hormones. Synthesis of thyroid hormones requires iodine (see figure Synthesis of Thyroid Hormones). Iodine, ingested in food and water as iodide, is actively concentrated by the thyroid and converted to organic iodine (organification) within follicular cells by thyroid peroxidase. The follicular cells surround a space (follicle) filled with colloid, which consists of thyroglobulin, a glycoprotein containing tyrosine within its matrix. Tyrosine in contact with the membrane of the follicular cells is iodinated at 1 (monoiodotyrosine) or 2 (diiodotyrosine) sites and then coupled to produce the 2 forms of thyroid hormone.. - Diiodotyrosine + diiodotyrosine → T4 - Diiodotyrosine + monoiodotyrosine → T3. Synthesis of Thyroid Hormones. # T3 and T4 remain incorporated in thyroglobulin within the follicle until the follicular cells take up thyroglobulin as colloid droplets. Once inside the thyroid follicular cells, T3 and T4 are cleaved from thyroglobulin.. Free T3 and T4 are then released into the bloodstream, where they are bound to serum proteins for transport. The primary transport protein is thyroxine- binding globulin (TBG), which has high affinity but low capacity for T3 and T4. TBG normally carries approximately . The other binding proteins are. - Thyroxine-binding prealbumin (transthyretin), which has high affinity but low capacity for T4- Albumin, which has low affinity but high capacity for T3 and T4. Approximately . # All reactions necessary for the formation and release of T3 and T4 are controlled by thyroid- stimulating hormone (TSH), which is secreted by pituitary thyrotropic cells. TSH secretion is controlled by a negative feedback mechanism in the pituitary: Increased levels of free T4 and T3 inhibit TSH synthesis and secretion, whereas decreased levels increase TSH secretion. TSH secretion is also influenced by thyrotropin- releasing hormone (TRH), which is synthesized in the hypothalamus. The precise mechanisms regulating TRH synthesis and release are unclear, although negative feedback from thyroid hormones inhibits TRH synthesis.. Most circulating T3 is produced outside the thyroid in peripheral tissues by monodeiodination of T4. Only one fifth of circulating T3 is secreted directly by the thyroid.. Laboratory Testing of Thyroid Function. Thyroid-stimulating hormone (TSH) measurement. TSH measurement is the best means of determining thyroid dysfunction (see table Results of Thyroid Function Tests in Various Clinical Situations). Normal TSH levels rule out hyperthyroidism or hypothyroidism, except in patients with central hypothyroidism due to disease in the hypothalamus or pituitary gland or in rare patients with pituitary resistance to thyroid hormone. Serum TSH can be falsely low in very sick people, especially in patients receiving glucocorticoids or dopamine (see Euthyroid Sick Syndrome).. Changes in the serum TSH level in the presence of normal levels of serum T4, free T4, serum T3, and free T3 define the syndromes of subclinical hyperthyroidism (low serum TSH) and subclinical hypothyroidism (elevated serum TSH).. # # Total serum T4 is a measure of bound and free hormone. Changes in levels of thyroid hormone- binding serum proteins (TBG or albumin) produce corresponding changes in total T4, even though levels of physiologically active free T4 are unchanged. Thus, a patient may have physiologically normal free T4 levels but have an abnormal total serum T4 level. Free T4 in the serum can be measured directly, avoiding the pitfalls of interpreting total T4 levels.. Free T4 index is a calculated value that corrects total T4 for the effects of varying amounts of thyroid hormone- binding serum proteins and thus gives an estimate of free T4 when total T4 is measured. The thyroid hormone- binding ratio or T4 resin uptake is used to estimate protein binding. Free T4 index is readily available and compares well with direct measurement of free T4.. Triiodothyronine (T3) measurement. Triiodothyronine (T3) measurementTotal serum T3 and free T3 can also be measured. Because T3 is tightly bound to TBG (although 10 times less so than T4), total serum T3 levels are influenced by alterations in serum TBG level and by medications that affect binding to TBG. Free T3 levels in the serum are measured by the same direct and indirect methods (free T3 index) described for T4 and are used mainly for evaluating thyrotoxicosis.. Thyroxine-binding globulin (TBG). Thyroxine- binding globulin (TBG)TBG can be measured. It is increased in pregnancy, by estrogen therapy, or by use of estrogen- progestin oral contraceptives, and in the acute phase of infectious hepatitis. TBG may also be increased by an X- linked mutation in the gene encoding TBG. It is most commonly decreased by illnesses that reduce hepatic protein synthesis, use of anabolic steroids, the nephrotic syndrome, and excessive corticosteroid use. Large doses of certain medications, such as phenytoin and aspirin and their derivatives, displace T4 from its binding sites on TBG, which spuriously lowers total serum T4 levels.. Autoantibodies to thyroid peroxidase. Autoantibodies to thyroid peroxidaseAutoantibodies to thyroid peroxidase are present in almost all patients with Hashimoto thyroiditis (some of whom also have autoantibodies to thyroglobulin) and in most patients with Graves disease. These autoantibodies are markers of autoimmune disease but probably do not cause disease. However, an autoantibody directed against the thyroid- stimulating hormone receptor (thyroid- stimulating immunoglobulin [TSI]) on the thyroid follicular cell is responsible for the hyperthyroidism in Graves disease. Antibodies against T4 and T3 may be found in patients with autoimmune thyroid disease and may affect T4 and T3 measurements but are rarely clinically significant.. Thyroglobulin. ThyroglobulinThe thyroid is the only source of thyroglobulin, which is readily detectable in the serum of healthy people and is usually elevated in patients with nontoxic or toxic (producing thyroid hormone and causing symptomatic hyperthyroidism) goiter. The principal use of serum thyroglobulin measurement is in evaluating patients after near- total or total thyroidectomy (with or without iodine- 131 ablation) for differentiated thyroid cancer. Normal or elevated serum thyroglobulin values indicate the presence of residual normal or cancerous thyroid tissue in patients receiving TSH- suppressive doses of levothyroxine or after withdrawal of levothyroxine. However, thyroglobulin antibodies interfere with thyroglobulin measurement.. # Screening for thyroid disease is recommended in many states and countries for all newborns to detect congenital hypothyroidism, which may impair normal development if untreated (1).. Routine screening for asymptomatic adults, including pregnant women without known risk factors for thyroid disease, is not recommended due to insufficient evidence of a benefit (2). For patients with risk factors, the serum TSH should be measured and is the best test to screen for both hyperthyroidism and hypothyroidism.. Because of the increased prevalence of subclinical hypothyroidism (defined as elevated serum TSH but normal T4 levels) in older adults, some authorities recommend screening on an annual basis for those > age 70 years, although serum TSH level has been shown to increase with age without indicating disease. This increase has led to overtreatment in up to . Screening references. 1. Rose SR, Wassner AJ, Wintergerst KA, et al. Congenital Hypothyroidism: Screening and Management. Pediatrics 2023;151(1):e2022060420. doi:10.1542/peds.2022-060420 2. Thyroid Disease in Pregnancy: ACOG Practice Bulletin, Number 223. Obstet Gynecol 2020;135(6):e261-e274. doi:10.1097/AOG.00000000000003893 3. Somwaru LL, Arnold AM, Joshi N, Fried LP, Cappola AR. High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women aged 65 and over. J Clin Endocrinol Metab 2009;94(4):1342-1345. doi:10.1210/jc.2008-1696. Radioactive Iodine Uptake and Imaging. Radioactive iodine uptake can be measured. A trace amount of radioiodine is given orally or intravenously; a scanner then detects the amount of radioiodine taken up by the thyroid. The preferred radioiodine isotope is iodine- 123, which exposes the patient to minimal radiation (much less than iodine- 131). Thyroid iodine- 123 uptake varies widely with iodine ingestion and is low in patients exposed to excess iodine.. The test is valuable in the differential diagnosis of hyperthyroidism (high uptake in Graves disease, low uptake in thyroiditis). It may also help in the calculation of the dose of iodine- 131 needed for treatment of hyperthyroidism.. Imaging using a scintillation camera can be done after radioisotope administration (radioiodine or technetium 99m pertechnetate) to produce a graphic representation of isotope uptake. Focal areas of increased (hot) or decreased (cold) uptake help distinguish areas of possible cancer (thyroid cancers exist in <1% of hot nodules compared with 10 to 20% of cold nodules).. # Copyright © 2025 Merck & Co., Inc., Rahway, NJ, USA and its affiliates. All rights reserved..	None	None	None
68e5b14db0e34418ab7a78b6cbc3ab94	MSD	盆腔炎PID	# Pelvic Inflammatory Disease (PID). By Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Mar 2023 \| Modified Oct 2023. Pelvic inflammatory disease (PID) is a polymicrobial infection of the upper female genital tract: the cervix, uterus, fallopian tubes, and ovaries; abscess may occur. PID may be caused by sexually transmitted infections. Common symptoms and signs include lower abdominal pain, irregular vaginal bleeding, cervical discharge, and cervical motion tenderness. Long- term complications may include infertility, chronic pelvic pain, and ectopic pregnancy. Diagnosis includes polymerase chain reaction testing of cervical specimens for Neisseria gonorrhoeae and chlamydiae, microscopic examination of cervical discharge (usually), and ultrasonography or laparoscopy (occasionally). Treatment is with antibiotics.. Etiology \| Symptoms and Signs \| Diagnosis \| Treatment \| Key Points. Pelvic inflammatory disease (PID) may involve the cervix, uterus, fallopian tubes, and/or ovaries. Infection of the cervix (cervicitis) causes mucopurulent discharge. Infection of the fallopian tubes (salpingitis) and uterus (endometritis) tend to occur together. If severe, infection can spread to the ovaries (oophoritis) and then the peritoneum (peritonitis). Salpingitis with endometritis and oophoritis, with or without peritonitis, is often called salpingitis even though other structures are involved. Pus may collect in the tubes (pyosalpinx), and an abscess may form (tubo- ovarian abscess).. Etiology of PID. PID results from microorganisms ascending from the vagina and cervix into the uterus and fallopian tubes. The sexually transmitted infections Neisseria gonorrhoeae and Chlamydia trachomatis are common causes of PID. Mycoplasma genitalium, which is also sexually transmitted, can also cause or contribute to PID. Incidence of sexually transmitted PID is decreasing; . PID usually also involves other aerobic and anaerobic bacteria, including pathogens that are associated with bacterial vaginosis. Vaginal microorganisms such as Haemophilus influenzae, Streptococcus agalactiae, and enteric gram- negative bacilli can be involved in PID, as can Ureaplasma species. Vaginal inflammation and bacterial vaginosis help in the ascending spread of vaginal microorganisms.. # Risk factors. Pelvic inflammatory disease commonly occurs in women . Risk factors include. Previous PID Presence of bacterial vaginosis or a sexually transmitted infection. Other risk factors, particularly for gonorrheal or chlamydial infection, include. Younger age Nonwhite race Low socioeconomic status Multiple or new sex partners or a male partner who does not use a condom Douching. Symptoms and Signs of PID. Pelvic inflammatory disease commonly causes lower abdominal pain, fever, cervical discharge, and abnormal uterine bleeding, particularly during or after menses.. Cervicitis. In cervicitis, the cervix is erythematous and friable (bleeds easily). Mucopurulent discharge is common; usually, it is yellow- green and can be seen exuding from the endocervical canal.. Acute salpingitis. Lower abdominal pain is usually present and bilateral but may be unilateral, even when both tubes are involved. Pain may also occur in the upper abdomen. Nausea and vomiting are common when pain is severe. Irregular bleeding (caused by endometritis) and/or fever each occur in up to one third of patients.. Occasionally, dyspareunia or dysuria occurs.. Even women with inflammation that is severe enough to cause scarring have minimal or no symptoms.. In the early stages, signs may be mild or absent. Later, cervical motion tenderness, guarding, and rebound tenderness are common.. PID due to N. gonorrhoeae is usually more acute and causes more severe symptoms than that due to C. trachomatis, which can be indolent. PID due to M. genitalium, like that due to C. trachomatis, is also mild and should be considered in women who do not respond to first- line therapy for PID.. # Complications. Fitz- Hugh- Curtis syndrome (perihepatitis that causes upper right quadrant pain) may result from acute gonococcal or chlamydial salpingitis. Infection may become chronic, characterized by intermittent exacerbations and remissions.. A tubo- ovarian abscess (collection of pus in the adnexa) develops in about . Hydrosalpinx is fimbrial obstruction and tubal distention with nonpurulent fluid; it is usually asymptomatic but can cause pelvic pressure, chronic pelvic pain, dyspareunia, and/or infertility.. Salpingitis may cause tubal scarring and adhesions, which commonly result in chronic pelvic pain, infertility, and increased risk of ectopic pregnancy.. Diagnosis of PID. High index of suspicion Pelvic examination Cervical tests for N. gonorrhoeae and C. trachomatis. Index of suspicion should be high, particularly in reproductive- age women and girls with risk factors, because clinical presentation is variable and even minimally symptomatic infection may have severe sequelae.. PID is suspected when women of reproductive age have lower abdominal pain or cervical or unexplained vaginal discharge, particularly with fever. PID is also considered when irregular vaginal bleeding, dyspareunia, or dysuria is unexplained.. A presumptive diagnosis of PID should be made and treatment initiated for sexually active young women and other women at risk for STIs if they are experiencing pelvic or lower abdominal pain, no cause for the illness other than PID can be identified, and if 1 or more of the following 3 minimum clinical criteria are present on pelvic examination:. Cervical motion tenderness Uterine tenderness Adnexal tenderness. In addition, on pelvic examination, a palpable adnexal mass suggests tubo- ovarian abscess.. If PID is suspected, NAAT (nucleic acid amplification test) of cervical specimens for N. gonorrhoeae and C. trachomatis (which is about . # The white blood cell count may be elevated but is not helpful diagnostically. A pregnancy test should be performed in reproductive- age women.. If a patient cannot be adequately examined because of tenderness, imaging studies are done as soon as possible. Ultrasonography is the preferred first- line test. If ultrasound is not available or is inconclusive, other imaging modalities like CT scan may be performed to evaluate for abscess formation, including tubo- ovarian abscess.. Other indications for imaging are if an adnexal or pelvic mass is suspected clinically or if patients do not respond to antibiotics within 48 to 72 hours. In such cases, ultrasonography or CT scan is done as soon as possible to exclude tubo- ovarian abscess, pyosalpinx, and disorders unrelated to PID (eg, ectopic pregnancy, adnexal torsion).. If the diagnosis is uncertain after ultrasonography or other imaging modalities, or if empiric treatment for PID fails, laparoscopy should be done; purulent peritoneal material noted during laparoscopy is the diagnostic gold standard.. Pearls & Pitfalls. - If clinical findings suggest PID but the pregnancy test is positive, evaluate for ectopic pregnancy.. Differential diagnosis. If a pregnancy test is positive, ectopic pregnancy, which can produce similar findings, should be considered.. Other common causes of pelvic pain include endometriosis, adnexal torsion, ovarian cyst rupture, and appendicitis. Differentiating features of these disorders are discussed elsewhere in The Manual.. Fitz- Hugh- Curtis syndrome may mimic acute cholecystitis but can usually be differentiated by evidence of salpingitis during pelvic examination or, if necessary, with ultrasonography.. Treatment of PID. - Antibiotics to cover N. gonorrhoeae, C. trachomatis, and organisms in the vaginal floras. When a PID diagnosis is suspected but cervical infection has not been confirmed or the patient does not meet all clinical criteria, empiric treatment of PID is given for several reasons:. - Test results may take a few days.- Diagnosis based on clinical criteria can be inaccurate.- Not treating minimally symptomatic PID can result in serious complications.. Antibiotics are given empirically to cover N. gonorrhoeae, C. trachomatis, and vaginal flora, including anaerobes, and are modified based on laboratory test results.. # Pearls & Pitfalls. - Treat empirically for PID whenever the diagnosis is suspected, because test results may take time and be inconclusive, diagnosis based on clinical criteria can be inaccurate, and not treating minimally symptomatic PID can result in serious complications.. Patients with cervicitis or clinically mild to moderate PID do not require hospitalization. Outpatient treatment regimens (see table [Regimens for Treatment of Pelvic Inflammatory Disease]) usually also aim to eradicate bacterial vaginosis, which often coexists.. Sex partners of patients with . # TABLE. Regimens for Treatment of Pelvic Inflammatory Disease. # Recommendations are from the Centers for Disease Control and Prevention. Workowski KA, Bachmann LH, Chan PA, et al: Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep 70(4):1- 187, 2021 doi:10.15585/mmwr.rr7004a1. † Intramuscular or oral therapy can be considered for mild to moderate acute PID because the clinical outcomes with intramuscular/oral and parenteral therapy are similar. If patients do not respond to oral therapy within 72 hours, they should be reevaluated to confirm the diagnosis, and intravenous therapy should be given.. ‡ If patient weighs . § This regimen may be considered if the patient has a cephalosporin allergy, if community prevalence and individual risk of gonorrhea are low, and if follow- up is likely. Tests for gonorrhea must be done before therapy is started, and the following management is recommended:. - Positive culture for gonorrhea: Treatment based on results of antimicrobial susceptibility- Identification of quinolone-resistant Neisseria gonorrhoeae or antimicrobial susceptibility that cannot be assessed: Consultation with an infectious disease specialist.. # If patients do not improve after treatment that covers the usual pathogens, PID due to M. genitalium should be considered. Patients may be treated empirically with moxifloxacin 400 mg orally once a day for 7 to 14 days (eg, for 10 days).. Women with PID are usually hospitalized if any of the following are present:. Uncertain diagnosis, with inability to exclude a disorder requiring surgical treatment (eg, appendicitis)- Pregnancy- Severe symptoms or high fever- Tubo- ovarian abscess- Inability to tolerate or follow outpatient therapy (eg, due to vomiting)- Lack of response to outpatient (oral) treatment. In these cases, IV antibiotics (see table Regimens for Treatment of Pelvic Inflammatory Disease) are started as soon as cultures are obtained and are continued until patients have been afebrile for 24 hours.. Tubo- ovarian abscess may require more prolonged IV antibiotic treatment. Treatment with ultrasound- or CT- guided percutaneous or transvaginal drainage can be considered if response to antibiotics alone is incomplete (1). Laparoscopy or laparotomy is sometimes required for drainage. Suspicion of a ruptured tubo- ovarian abscess requires immediate laparotomy. In women of reproductive age, surgery should aim to preserve the pelvic organs (with the hope of preserving fertility).. Treatment reference. 1. Goje O, Markwei M, Kollikonda S, et al: Outcomes of minimally invasive management of tubo-ovarian abscess: A systematic review. J Minim Invasive Gynecol 28 (3):556-564, 2021. doi: 10.1016/j.jmig.2020.09.014. Key Points. - The sexually transmitted pathogens Neisseria gonorrhoeae and Chlamydia trachomatis are common causes of PID, but infection is often polymicrobial.- PID can cause tubal scarring and adhesions, which commonly result in chronic pelvic pain, infertility, and increased risk of ectopic pregnancy.- Because even minimally symptomatic infection may have severe sequelae, index of suspicion should be high.- PCR and cultures are accurate tests; however, if results are not available at the point of care, empiric treatment is usually recommended.- Hospitalize women with PID based on clinical criteria (see above).. # Copyright © 2025 Merck & Co., Inc., Rahway, NJ, USA and its affiliates. All rights reserved..	None	None	None
67e22e2d16cb4a8d92ad85800a98c4c8	MSD	绝经更年期激素治疗	# Menopause. By JoAnn V. Pinkerton, MD, University of Virginia Health System Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Jul 2023 \| Modified Jun 2024. Menopause is the permanent cessation of menses (amenorrhea) due to loss of ovarian follicular function. Clinical manifestations may include hot flushes, night sweats, sleep disruption, and genitourinary syndrome of menopause (symptoms and signs due to estrogen deficiency, such as vulvovaginal atrophy). Diagnosis is clinical, based retroactively on the absence of menses for 12 months. Manifestations may be treated (eg, with lifestyle modification, complementary and alternative medicine, nonhormonal therapy, and/or hormone therapy).. Physiology \| Symptoms and Signs \| Diagnosis \| Treatment \| Menopausal Hormone Therapy \| Key Points \| Additional Information. In the United States, the average age of physiologic menopause is 51 years old. Factors such as smoking, living at high altitude, and undernutrition may cause menopause to occur at a younger age.. The aging of the female reproductive system before and after menopause is described in stages (see table Stages of Menopause).. Reproductive stage: Includes the time from menarche through the menopausal transition Perimenopause: Refers to several years (duration varies greatly) before and the 1 year after the last menses; typically the most symptomatic phase because hormone levels are fluctuating Menopausal transition: Occurs during the perimenopause stage; includes the typically 4 to 8 years that lead up to the final menstrual period; characterized by changes in the menstrual pattern; divided into early and late stages Postmenopause: Refers to the time after the final menstrual period; divided into early and late stages. The menopausal transition lasts longer in women who smoke and in women who were younger at onset of menopausal transition (1). Black women experience a longer menopausal transition than White women (2).. Premature ovarian failure (primary ovarian insufficiency) is cessation of menses due to noniatrogenic ovarian failure before age 40. Contributory factors are thought to be primarily genetic or autoimmune.. # General references. 1. Paramsothy P, Harlow SD, Nan B, et al: Duration of the menopausal transition is longer in women with young age at onset: The multi-ethnic Study of Women's Health Across the Nation. Menopause 24 (2):142-149, 2017. doi: 10.1097/GME.0000000000000736. # 2. El Khoudary SR, Greendale G, Crawford SL, et al: The menopause transition and women's health at midlife: a progress report from the Study of Women's Health Across the Nation (SWAN). Menopause 26(10):1213-1227, 2019. doi: 10.1097/GME.0000000000001424. Physiology of Menopause. As ovaries age, their response to the pituitary gonadotropins follicle- stimulating hormone (FSH) and luteinizing hormone (LH) decreases, initially causing the following:. - A shorter follicular phase (with shorter and less regular menstrual cycles)- Fewer ovulations- Decreased progesterone production (see figure The idealized cyclic changes in pituitary gonadotropins, estradiol (E2), progesterone (P), and uterine endometrium during the normal menstrual cycle). During the menopausal transition and postmenopause, estrogen levels fluctuate and eventually decrease significantly, but the changes in other hormones vary.. Estradiol levels can rise above normal if double ovulation and luteal out- of- phase (LOOP) events (ie, premature formation of a follicle due to the major surge in FSH during the luteal phase) occur. In general, the number of viable follicles decreases; eventually, the remaining follicles do not respond, and the ovaries produce very little estradiol. Estrogens continue to be produced by peripheral tissues (eg, fat, skin) from androgens (eg, androstenedione, testosterone). However, the total estrogen level gradually decreases during the 5 years after menopause, and estrone replaces estradiol as the most common estrogen.. Decreased levels of ovarian inhibin and estrogen, which inhibit pituitary release of LH and FSH, result in a substantial increase in circulating LH and FSH levels.. Changes in androgens around the time of menopause include a decrease in androstenedione levels by half. The decrease in testosterone, which begins in young adulthood, does not accelerate during menopause because the stroma of the postmenopausal ovary and adrenal gland continue to secrete substantial amounts.. Superficial cells in the vagina are lost, leading to a more alkaline pH. As a result, the number of lactobacilli decreases and pathogenic bacteria overgrow, increasing the risk of vaginal infections and inflammation.. Symptoms and Signs of Menopause. Changes in the menstrual cycle usually begin during a woman's 40s, with variation in cycle length. A persistent difference in consecutive menstrual cycle length of . # The marked fluctuations in estrogen levels may contribute to other perimenopausal symptoms and signs such as. Breast tenderness Changes in menstrual flow Moodiness Exacerbation of menstrual migraines. Symptoms can last from 6 months to . Vasomotor. Hot flushes (hot flashes) and/or night sweats due to vasomotor instability affect 75 to . Women feel warm or hot and may perspire, sometimes profusely; core temperature increases. The skin, especially of the face, head, and neck, may become red and warm. The episodic flush, which may last from 30 seconds to 5 minutes, may be followed by chills. Flushes may manifest during the night as night sweats.. Other etiologies of hot flushes or night sweats should also be considered (eg, lymphoma, tuberculosis, mycobacteria avium), particularly if these symptoms do not occur around the time of menopause or do not respond to hormone therapy.. The mechanism of hot flushes is unknown, but they are thought to result from changes in the thermoregulatory center located in the hypothalamus. The range of core body temperatures that is comfortable to the woman decreases; as a result, a very small increase in core body temperature can trigger heat release as a hot flush.. In a survey study from 1996 to 2017 in the United States, women who self- identified as Black had the highest prevalence and longest duration of hot flashes and were most bothered by them, while the prevalence in those who identified as Japanese or Chinese was the lowest and prevalence in self- identified Hispanic and White women was in- between the range (2). Lower socioeconomic status was associated with an increased incidence of hot flashes, independent of race/ethnicity.. Vaginal. Vaginal symptoms include dryness, dyspareunia, and occasionally irritation and itching. As estrogen production decreases, vulvar and vaginal mucosae become thinner, drier, more friable, and less elastic, and vaginal rugae are lost.. Genitourinary syndrome of menopause includes symptoms and signs due to estrogen and androgen deficiency such as. - Vulvovaginal atrophy- Urinary urgency. # Dysuria- Frequent urinary tract infections and/or vaginitis. Neuropsychiatric. Neuropsychiatric changes (eg, poor concentration, memory loss, depressive symptoms, anxiety) may transiently accompany menopause. Many women experience these symptoms during perimenopause and assume that menopause is the cause. However, evidence supporting a connection between menopause and these symptoms is mixed (3). Also, these symptoms are not directly related to the decreases in estrogen levels that occur with menopause.. Recurrent night sweats can contribute to insomnia, fatigue, irritability, and poor concentration by disrupting sleep. However, during menopause, sleep disturbances are common even among women who do not have hot flushes.. Cardiovascular. CardiovascularAfter menopause, levels of low- density lipoprotein (LDL) cholesterol increase in women. Levels of high- density lipoprotein (HDL) cholesterol remain about the same as before menopause. The change in LDL levels may partly explain why atherosclerosis and thus coronary artery disease become more common among women after menopause. However, whether these changes result from aging or from the decrease in estrogen levels after menopause is unclear. Until menopause, the high estrogen levels may protect against coronary artery disease.. Musculoskeletal. Up to . Other symptoms. Menopause is a normal, healthy phase in a woman's life, but each woman has a unique experience.. Quality of life may decrease if symptoms are severe or if less common symptoms of menopause, such as joint aches and pains, develop. For some women (eg, those with a history of endometriosis, dysmenorrhea, menorrhagia, premenstrual syndrome, or menstrual migraine), quality of life improves after menopause.. Some postmenopausal women experience burning mouth syndrome.. Symptoms and signs references. Symptoms and signs references1. Avis NE, Crawford SL, Greendale G, et al: Duration of menopausal vasomotor symptoms over the menopause transition (Study of Women's Health Across the Nation). JAMA Intern Med 175 (4):531- 539, 2015. doi: 10.1001/jamainternmed.2014.80632. El Khoudary SR, Greendale G, Crawford SL, et al: The menopause transition and women's health at midlife: a progress report from the Study of Women's Health Across the Nation (SWAN). Menopause 26(10):1213- 1227, 2019. doi:10.1097/GME.0000000000001424. # 3. Gold EB, Sternfeld B, Kelsey JL, et al: Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age. Am J Epidemiol 152(5):463-473, 2000. doi:10.1093/aje/152.5.463. Diagnosis of Menopause. Menstrual history- Rarely follicle- stimulating hormone (FSH) levels. Perimenopause is likely in patients in their 40s who have symptoms and signs of perimenopause. However, pregnancy, amenorrhea due to other etiologies, or abnormal uterine bleeding due to uterine cancer should be considered. Primary ovarian insufficiency should be suspected in women with prolonged amenorrhea at . Timing of cessation of ovarian function is categorized based on age, as follows:. Premature menopause: . Diagnosis of menopause is clinical; it is confirmed retroactively when a woman has had no menses for 12 months and there is no other suspected cause.. Vulvovaginal atrophy on pelvic examination supports the diagnosis.. FSH levels may be measured, but this test is rarely necessary except perhaps in women who have had a hysterectomy and in women who are younger than the usual age of menopause. A single measurement may not be informative, because levels fluctuate during the menopausal transition. Consistently elevated levels confirm menopause.. Treatment of Menopause. - Nonpharmacologic measures (eg, cognitive-behavioral therapy, clinical hypnosis)- Hormone therapy (estrogens, progestogens, and selective estrogen receptor modulators)- Nonhormonal medications (eg, selective serotonin reuptake inhibitors, neurokinin receptor antagonists). (See also the American College of Gynecologists and Obstetricians' Practice Bulletin No. 141. ). Treatment of menopause is symptomatic (eg, to relieve hot flushes and symptoms due to vulvovaginal atrophy).. Patient education about the physiologic causes of menopause and possible symptoms and signs helps patients manage the changes that occur.. # In addition to treatment of menopausal symptoms, postmenopausal women should be screened for osteoporosis if they meet the following criteria:. Those who have a high risk of fracture (eg, patients with a family history of osteoporosis) Those who have a history of eating disorders, a low body mass index (BMI), chronic corticosteroid use, gastric bypass surgery, Crohn disease, a malabsorption syndrome, or a prior fragility fracture or other risk factors for estrogen deficiency beyond menopause All women . Nonpharmacologic measures. Nonpharmacologic options shown to be effective in randomized trials for the treatment of vasomotor symptoms (1) include cognitive- behavioral therapy (2, 3) and clinical hypnosis (4, 5). These treatments may also improve sleep and sexual function.. For women with obesity, weight loss is effective, particularly during early perimenopause (6, 7).. Stellate ganglion blockade is also effective for vasomotor symptoms of menopause (8). This procedure is also to treat migraine and complex regional pain syndrome and involves injection of an anesthetic at the lower cervical or upper thoracic region of the anterior cervical spine.. Many different types of nonpharmacologic interventions have been suggested to manage menopausal symptoms. The following measures are not recommended by the North American Menopause Society because there are insufficient or negative data about their efficacy in reducing vasomotor symptoms (1):. Cooling techniques (eg, lowering the thermostat, using fans, layered or light clothing, cooling sheets or other bedding) Avoiding triggers (eg, spicy food, alcohol, caffeine) Dietary modifications Exercise Yoga Relaxation Paced respiration (taking several slow, deep breaths with inhaling through the nose and exhaling through the mouth) Mindfulness- based interventions Chiropractic interventions Acupuncture Calibration of neural oscillations. Many of these interventions have other health benefits and a low potential for harm. For example, a healthy diet is important for health promotion and chronic disease prevention, and exercise, yoga, and relaxation techniques may improve sleep and reduce stress. Individual women may find some of these measures helpful for vasomotor symptoms. However, clinicians should counsel women against using unproven methods that are invasive or have other potential for harm (eg, extreme diets). In addition,. # the benefits of unproven treatments do not outweigh the burden on patients if measures are expensive, time- consuming, or physically demanding.. Over- the- counter vaginal lubricants and moisturizers help relieve vaginal dryness. Sexual intercourse or other vaginal stimulation helps preserve vaginal elasticity in menopausal patients.. Hormone therapy. Hormone therapy with estrogen, a progestogen, or both is the most effective treatment for menopausal symptoms. To prevent endometrial neoplasia in women with a uterus (ie, have not had a hysterectomy), estrogen must be given in combination with a progestogen (to oppose the effect of estrogen on the endometrium); the exception to this is very low dose vaginal estrogen therapy (used for genitourinary syndrome of menopause), which can be given without a progestogen. Another option for women with a uterus is the combination of conjugated estrogens with bazedoxifene.. Selective estrogen receptor modulators (SERMs). Ospemifene, a SERM, can be used to treat dyspareunia due to vaginal atrophy if women are not able to self- administer vaginal estrogen therapy or vaginal dehydroepiandrosterone (eg, if they have severe arthritis). Ospemifene may increase the risk of venous thrombosis.. Bazedoxifene is given with conjugated estrogens and does not require concurrent use of a progestogen; it can relieve hot flushes, improve sleep, prevent bone loss, and lessen symptoms of vaginal atrophy.. In women at high risk of breast cancer and in need of prevention of bone loss or fracture, raloxifene may be used with risks of slight increase in hot flashes, leg cramps, or venous thrombosis. No increased risk of stroke was seen but, in women at high risk of cardiac disease, a small increase in fatal stroke was seen (9).. The SERMs tamoxifen and raloxifene have been used primarily for their antiestrogenic properties and not to relieve menopausal symptoms.. Nonhormonal medications. In well- designed, randomized controlled trials, nonhormonal medications that have proven efficacy for management of vasomotor symptoms are as follows (however, all of these medications are less effective than hormone therapy) (1):. Neurokinin receptor antagonists Selective serotonin reuptake inhibitors (SSRIs) Serotonin- norepinephrine reuptake inhibitors (SNRIs) Gabapentin Oxybutynin. Two nonhormonal medications are approved by the US Food and Drug Administration (FDA) specifically for hot flushes: a low dose (7.5 mg once a day) of paroxetine salt (an SSRl) and fezolinetant (a selective neurokinin- 3 receptor antagonist) (10, 11, 12).. # For fezolinetant, potential side effects include abdominal pain, diarrhea, difficulty sleeping, back pain, hot flushes, and rare reports of liver injury. Liver function tests are needed before starting fezolinetant and every 3 months for first 9 months of treatment. Fezolinetant is contraindicated in patients using CYP1A2 inhibitors (eg, ciprofloxacin, cimetidine, and other medications).. Oxybutynin, an anticholinergic that is used to treat overactive bladder, also effectively treats vasomotor symptoms (doses in studies have included 2.5 or 5 mg twice daily; or up to 15 mg extended- release once daily) (13). Gabapentin (300 mg up to 3 times daily) has been shown to be effective and well- tolerated (14). However, pregabalin is not recommended due to limited efficacy data and risk of adverse effects, including potential substance misuse. Other nonhormonal medications that are not recommended are suvorexant (a dual orexin- receptor antagonist), due to limited efficacy data, and clonidine, because it is less effective than other nonhormonal treatment options (1).. Herbal or dietary supplements. A wide variety of dietary supplements have been suggested to manage menopausal symptoms. There are no supplements with proven efficacy for vasomotor symptoms, and their use is not recommended by the North American Menopause Society (1).. Supplements that have limited or inconsistent evidence of benefit include soy food and soy extracts, soy metabolite equol, pollen extract, ammonium succinate, lactobacillus acidophilus, and rhubarb. Supplements with no demonstrated evidence of benefit include black cohosh, evening primrose oil, wild yam, omega- 3 fatty acid, and cannabinoids.. Some herbal preparations or other supplements interact with other medications. Because not all complementary and alternative medicine therapies are efficacious and safe, clinicians should discuss the risks and benefits of these therapies to make sure that women are well- informed (15).. Treatment references. 1. The 2023 nonhormone therapy position statement of The North American Menopause Society. Menopause 30(6):573-590, 2023. doi:10.1097/GME.0000000000002200 2. Mann E, Smith MJ, Hellier J, et al: Cognitive behavioural treatment for women who have menopausal symptoms after breast cancer treatment (MENOS 1): a randomised controlled trial. Lancet Oncol 13(3):309-318, 2012. doi:10.1016/S1470-2045(11)70364-3 3. Ayers B, Smith M, Hellier J, Mann E, Hunter MS: Effectiveness of group and self-help cognitive behavior therapy in reducing problematic menopausal hot flushes and night sweats (MENOS 2): a randomized controlled trial. Menopause 19(7):749-759, 2012. doi:10.1097/gme.0b013e31823fe835 4. Elkins G, Marcus J, Stearns V, et al: Randomized trial of a hypnosis intervention for treatment of hot flashes among breast cancer survivors. J Clin Oncol 26(31):5022-5026, 2008. doi:10.1200/JCO.2008.16.6389 5. Elkins GR, Fisher WI, Johnson AK, et al: Clinical hypnosis in the treatment of postmenopausal hot flashes: a randomized controlled trial. Menopause 20(3):291-298, 2013. doi:10.1097/gme.0b013e31826ce3ed 6. Thurston RC, Ewing LJ, Low CA, et al: Behavioral weight loss for the management of menopausal hot flashes: A pilot study. Menopause 22 (1):59-65, 2015. doi: 10.1097/GME.0000000000000274. # 7. Huang AJ, Subak LL, Wing R, et al: An intensive behavioral weight loss intervention and hot flushes in women [published correction appears in Arch Intern Med 170(17):1601, 2010]. Arch Intern Med 170(13):1161-1167, 2010. doi:10.1001/archinternmed.2010.162. 8. Walega DR, Rubin LH, Banuvar S, et al: Effects of stellate ganglion block on vasomotor symptoms: findings from a randomized controlled clinical trial in postmenopausal women. Menopause 21(8):807-814, 2014. doi:10.1097/GME.0000000000000194. 9. Liu JH: Selective estrogen receptor modulators (SERMS): keys to understanding their function. Menopause 27(10):1171-1176, 2020. doi:10.1097/GME.00000000000001585. 10. Johnson KA, Martin N, Nappi RE, et al: Efficacy and safety of fezolinetant in moderate-to-severe vasomotor symptoms associated with menopause: a phase 3 RCT [published online ahead of print, 2023 Feb 3]. J Clin Endocrinol Metab dgad058, 2023. doi:10.1210/clinem/dgad058. 11. Lederman S, Ottery FD, Cano A, et al: Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet 401(10382):1091-1102, 2023. doi:10.1016/S0140-6736(23)00085-5. 12. Pinkerton JV, Redick DL, Homewood LN, Kaunitz AM: Neurokinin receptor antagonist, fezolinetant, for treatment of menopausal vasomotor symptoms [published online ahead of print, 2023 Apr 25]. J Clin Endocrinol Metab dgad209, 2023. doi:10.1210/clinem/dgad209. 13. Simon JA, Gaines T, LaGuardia KD: Extended-Release Oxybutynin Therapy for VMS Study. Group: Extended-release oxybutynin therapy for vasomotor symptoms in women: a randomized clinical trial. Menopause 23(11):1214-1221, 2016. doi:10.1097/GME.00000000000000773. 14. Loprinzi CL, Diekmann B, Novotny PJ, et al: Newer antidepressants and gabapentin for hot flashes: a discussion of trial duration. Menopause 16(5):883-887, 2009. doi:10.1097/gme.0b013e31819c46c7. 15. Johnson A, Roberts L, Elkins G: Complementary and alternative medicine for menopause. J Evid Based Integr Med 24:2515690X19829380, 2019. doi: 10.1177/2515690X19829380. Menopausal Hormone Therapy. Hormone therapy (estrogen, a progestogen, or both) is the most effective treatment for menopausal symptoms (1). It is used to relieve vasomotor and other systemic menopausal symptoms, treat symptoms due to vulvovaginal atrophy, and, for some patients, prevent or treat osteoporosis.. Menopausal hormone therapy improves quality of life for many women by relieving their symptoms but does not improve quality of life for and should not be routinely given to asymptomatic postmenopausal women.. If hormone therapy is needed to control menopausal symptoms, clinicians should determine the most appropriate type, dose, route of administration, and duration, based on goals of treatment and individual health risks. Potential benefits and harms due to hormone therapy should be periodically reevaluated.. For healthy women with bothersome menopausal symptoms who are . # women at risk of bone loss or fracture, hormone therapy reduces bone loss and incidence of fractures and can be used in women who are not candidates for first- line medications for osteoporosis.. Starting hormone therapy in women who are . Unless the clinical recommendation is clear, shared decision- making is recommended because of the following:. - Potential benefits and harms of hormone therapy can be complicated.- The net benefit and harm can be marginal.- Health risks may change with age.. Choice of systemic hormone therapy. Women who have a uterus (ie, have not had a hysterectomy) are usually given estrogen, and this must be given in combination with a progestogen (progesterone or synthetic progestin), because unopposed estrogen increases risk of endometrial hyperplasia and cancer.. For systemic estrogen therapy, oral, transdermal (patch, lotion, spray, or gel), or vaginal forms may be used. Treatment should start with the lowest dose; the dose is increased every 2 to 4 weeks as needed. Doses vary by preparation. Examples of preparations and low doses for systemic therapy include. - 0.3 mg conjugated estrogen orally once daily- 0.5 mg estradiol orally once daily- 0.014 to 0.375 mg a day estradiol as a patch applied to the skin once or twice weekly- 0.05mg a day estradiol vaginal ring inserted every 3 months. There are also daily estradiol skin gels and sprays available in varying doses.. The progestogen is taken continuously (ie, daily) or sequentially (cyclically; 12 to 14 consecutive days of every 4 week). Examples of preparations and doses are. - Medroxyprogesterone acetate: 2.5 mg for continuous use and 5 mg for sequential use- Micronized progesterone (a natural rather than synthetic progesterone): 100 mg for continuous use and 200 mg for sequential use- Levonorgestrel 52 mg (releases 20 mcg a day for 5 years, 10 mcg a day from 5 to 8 years) intrauterine device. Bleeding due to progestogen withdrawal is less likely with continuous therapy, although irregular bleeding can occur during the first 6 to 9 months of therapy.. Combination products of estrogen and a progestogen are available as pills and transdermal patches.. - Pills (eg, 0.3 mg conjugated estrogens plus medroxyprogesterone acetate 1.5 mg once daily; norethindrone acetate 0.1 mg plus estradiol 0.5 mg once daily). # - Patches (eg, estradiol 0.045 mg plus levonorgestrel 0.015 mg a day released by a patch applied to the skin once weekly). For women who have had a hysterectomy, systemic estrogen therapy is used alone.. An alternative to systemic estrogen therapy is combination conjugated estrogen/bazedoxifene (a selective estrogen receptor modulator [SERM]). This is a good option for women with a history of breast tenderness or bleeding on estrogen therapy and those with a family history of breast cancer. Bazedoxifene acts as an estrogen receptor antagonist in the endometrium and protects against endometrial cancer; thus, a progestogen is not needed. Conjugated estrogen/bazedoxifene relieves hot flushes, improve sleep, prevent bone loss, and lessen symptoms of vaginal atrophy. Benefits of conjugated estrogen/bazedoxifene include a lower incidence of breast tenderness and abnormal uterine bleeding than with other forms of menopausal hormone therapy; incidence is similar to that with placebo. Breast density and incidence of breast cancer did not increase in women who were followed for 2 years (2). Risk of venous thromboembolism is similar to that with estrogen, but conjugated estrogen/bazedoxifene appears to protect the endometrium and potentially the breast. Bazedoxifene as a single medication is not available in the United States.. Progestogens are sometimes used alone (eg, medroxyprogesterone acetate . Genitourinary syndrome of menopause treatment. When the only symptoms are urogenital, vaginal hormone therapy is preferred. Topical forms (eg, creams; vaginal tablets, suppositories, or rings) may be more effective for urogenital symptoms than oral forms and are sometimes used in addition to systemic therapy if these symptoms are not adequately treated.. Vaginal estradiol tablets, suppositories, rings, or creams in low doses (eg, 4 or 10 mcg for tablets, 7.5 mcg rings, . Intravaginal dehydroepiandrosterone (DHEA) may relieve vaginal dryness and other symptoms of vaginal atrophy; it is available and effective for relief of dyspareunia due to menopause (3).. When low- dose vaginal estrogen or DHEA or ospemifene is used, a progestogen is not needed; however, there are no long- term endometrial safety data for these medications (1).. # Ospemifene, a SERM, can be used to treat dyspareunia due to vaginal atrophy if women are not able to self- administer vaginal estrogen therapy or dehydroepiandrosterone (eg, if they have severe arthritis) or if they prefer to use an oral medication other than estrogen (4). In women who have recently been taking hormone therapy, hot flushes may temporarily increase, but in most women, hot flushes resolve after about 6 weeks. Ospemifene may increase the risk of venous thrombosis.. If symptoms are mild or estrogen is contraindicated, nonhormone over- the- counter treatments (eg, vaginal lubricants, moisturizers) may be sufficient (1).. For moderate to severe genitourinary symptoms, treatments include. - Intravaginal estrogen- Intravaginal DHEA- Systemic hormone therapy- Ospemifene. For women at high risk of breast cancer, small amounts of topical estradiol may be used after consultation with their oncologist (5).. Osteoporosis management. Estrogen therapy has beneficial effects on bone density and reduces the incidence of fractures in postmenopausal women (not particularly those with osteoporosis). In one large study, hormone therapy reduced the incidence of fractures by . - Women are at significant risk of osteoporosis.- They choose not to take first-line medications for osteoporosis.- They are . Risks and adverse effects. Risks with systemic estrogen therapy or combined estrogen/progestogen therapy include. - Breast cancer- Venous thromboembolism- Coronary artery disease- Stroke- Endometrial cancer, mainly if women who have a uterus take estrogen without a progestogen- Gallbladder disease- Dementia- Stress urinary incontinence. # Estrogen therapy may be contraindicated in women who have had or are at high risk of breast cancer, stroke, coronary artery disease, or thrombosis.. The risk of endometrial cancer is higher in women who have a uterus and are given unopposed estrogen therapy. Nevertheless, any vaginal bleeding in a woman on any type of hormone therapy should immediately be evaluated to rule out endometrial cancer.. The risk of breast cancer begins to increase after 3 to 5 years of combination therapy when the standard dose (eg, conjugated estrogen 0.625 mg and medroxyprogesterone acetate at 2.5 mg once/day) is used (7). In the Women's Health Initiative randomized trial that compared oral conjugated estrogens with or without medroxyprogesterone acetate, when estrogen was used alone, risk of breast cancer was slightly lower at 7 years, but this benefit appeared to disappear after 10 to 15 years of use (8).. The risk of venous thromboembolism and stroke may be lower with low- dose transdermal estrogen rather than oral estrogen. Older postmenopausal women (> 10 years past menopause or > 60 years old when they start hormone therapy) are at higher risk of coronary artery disease when they are given oral standard dose combination therapy (9, 10).. Data on dementia are mixed. Among participants ≥ 65 years old in the Women's Health Initiative trial, menopausal hormone therapy increased dementia risk, with results for combination conjugated estrogens and medroxyprogesterone acetate more adverse than for estrogens alone (9). But for those aged 50 to 55 years at randomization, neutral results were seen at an average of 7.2 years post- intervention.. Incidence of gallbladder disease and urinary incontinence may be increased with systemic combination therapy or estrogen alone. However, low- dose vaginal estrogen therapy decreases incidence of recurrent urinary tract infections and improves stress and urgency incontinence (11). Risk of all these disorders is very low in healthy women who take hormone therapy for a short time after menopause.. Progestogens may have adverse effects (eg, abdominal bloating, breast tenderness, increased breast density, headache, increased LDL); micronized progesterone appears to have fewer adverse effects, but may cause drowsiness (which can be minimized by taking at bedtime). Progestogens may increase the risk of thrombosis. There are no long- term safety data for progestogens.. Before prescribing hormone therapy and periodically as therapy continues, clinicians should discuss its risks and benefits with women.. Hormone therapy references. 1. The 2022 Hormone Therapy Position Statement of The North American Menopause Society. Advisory Panel: The 2022 hormone therapy position statement of The North American Menopause Society. Menopause 9(7):767-794, 2022. doi:10.1097/GME.000000000002028 2. Pinkerton JV, Pickar JH, Racketa J, et al: Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis prevention. Climacteric 15 (5):411-418, 2012. doi: 10.3109/13697137.2012.696289 3. Labrie F, Archer DF, Koltun W, et al: Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of. # the genitourinary syndrome of menopause. Menopause 23 (3):243- 256, 2016. doi: 10.1097/GME.0000000000000571. 4. Constantine G, Graham S, Portman DJ, et al: Female sexual function improved with osemifene in postmenopausal women with vulvar and vaginal atrophy: Results of a randomized, placebo-controlled trial. Climacteric 18 (2): 226-232, 2015. doi:10.3109/13697137.2014.954996. 5. Faubion SS, Larkin LC, Stuenkel CA, et al: Management of genitourinary syndrome of menopause in women with or at high risk for breast cancer: consensus recommendations from The North American Menopause Society and The International Society for the Study of Women's Sexual Health. Menopause 2 5(6):596-608, 2018. doi: 10.1097/GME.0000000000001121. 6. Rossouw JE, Anderson GL, Prentice RL, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 288 (3):321-333, 2002. doi:10.1001/jama.288.3.321. 7. Chlebowski RT, Hendrix SL, Langer RD, et al: Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289(24):3243-3253, 2003. doi:10.1001/jama.289.24.3243. 8. Chlebowski RT, Rohan TE, Manson JE, et al: Breast cancer after use of estrogen plus progestin and estrogen alone: analyses of data from 2 Women's Health Initiative randomized clinical trials. JAMA Oncol 1(3):296-305, 2015. doi:10.1001/jamaoncol.2015.0494. 9. Manson JE, Chlebowski RT, Stefanick ML, et al: Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA 310(13):1353-1368, 2013. doi:10.1001/jama.2013.278040. 10. Cho L, Kaunitz AM, Faubion SS, et al: Rethinking Menopausal Hormone Therapy: For Whom, What, When, and How Long?. Circulation 147(7):597-610, 2023. doi:10.1161/CIRCULATIONAHA.122.061559. 11. Christmas MM, Iyer S, Daisy C, et al: Menopause hormone therapy and urinary symptoms: a systematic review [published online ahead of print, 2023 May 16]. Menopause 10.1097/GME.0000000000002187, 2023. doi:10.1097/GME.0000000000002187. Key Points. - In the United States, menopause occurs at an average age of 51. Symptoms of menopause tend to be maximal during the few years before and the year after menopause (during perimenopause), except for symptomatic vulvovaginal atrophy, which may worsen over time.- Up to . # consider low- dose vaginal estrogen creams, tablets, suppositories, or rings; other options include oral ossemifene or intravaginal DHEA suppositories.. - Before prescribing hormone therapy and periodically as therapy continues, talk to women about the potential benefits and harms (eg, deep venous thrombosis, pulmonary embolism, stroke, breast cancer; low risk of gallbladder disease, stress urinary incontinence); potential harms are greater for women who start hormone therapy after age 60 or who are . - If women choose hormone therapy to relieve hot flushes, prescribe estrogen plus, for women with a uterus, a progestogen or prescribe conjugated estrogen/bazedoxifene.. - Individualize treatment with hormone therapy to maximize benefits and minimize harms, and periodically reevaluate benefits and harms; low-dose transdermal hormone therapy may have less risk of deep venous thrombosis and stroke.. - Consider SSRIs (eg, paroxetine salt), SNRIs (eg, venlafaxine), neurokinin receptor antagonists (eg, fezolinetant), and gabapentin as alternatives to hormone therapy for relieving hot flushes.. - Effective nonpharmacologic options include cognitive-behavioral therapy, hypnosis, and possibly weight loss.. Additional Information. The following English- language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.. Pinkerton JV: Hormone Therapy for Postmenopausal Women. N Engl J Med 382(5):446- 455, 2020. doi:10.1056/NEJMcp1714787.	None	None	None
2eb1d4dade23445c90d74d9d7c26febb	MSD	血小管疾病	# Overview of Platelet Disorders. Overview of Platelet DisordersBy David J. Kuter, MD, DPhil, Harvard Medical SchoolJerry L. Spivak, MD; MACP, Johns Hopkins University School of MedicineReviewed/Revised May 2024 \| Modified Sept 2024. Etiology \| Symptoms and Signs \| Diagnosis \| Treatment. Platelets are circulating cell fragments that function in the clotting system. Thrombopoietin helps control the number of circulating platelets by stimulating the bone marrow to produce megakaryocytes, which in turn shed platelets from their cytoplasm. Thrombopoietin is produced in the liver at a constant rate; its circulating level is determined by how much is bound to circulating platelets and possibly to bone marrow megakaryocytes and the extent to which circulating platelets are cleared. Platelets circulate for 7 to 10 days. About one third are always transiently sequestered in the spleen.. The platelet count is normally 140,000 to 440,000/mcL (140 to . Platelet disorders include. An abnormal increase in platelets (thrombocythemia and reactive thrombocytosis) A decrease in platelets (thrombocytopenia) Platelet dysfunction. Any of these conditions, even those in which platelets are markedly increased, may cause defective formation of hemostatic plugs and bleeding.. The risk of bleeding is inversely proportional to the platelet count and platelet function (see table Platelet Count and Bleeding Risk). When platelet function is reduced (eg, as a result of uremia or the use of a nonsteroidal anti- inflammatory drug [NSAID], aspirin, or another medication), the risk of bleeding increases.. # Etiology of Platelet Disorders. Thrombocythemia and thrombocytosis. Essential thrombocythemia is a myeloproliferative neoplasm (previously called a myeloproliferative disorder) involving overproduction of platelets because of a clonal abnormality of a hematopoietic stem cell. There is no correlation between the platelet count and risk of thrombosis, but some patients with extreme thrombocytosis (ie, . Reactive thrombocytosis is platelet overproduction in response to another disorder. There are many causes, including acute infection, chronic inflammatory disorders (eg, rheumatoid arthritis, inflammatory bowel disease, tuberculosis, sarcoidosis), iron deficiency, and certain cancers. Reactive thrombocytosis is not typically associated with an increased risk of thrombosis or bleeding.. Thrombocytopenia. Causes of thrombocytopenia can be classified by mechanism (see table Classification of Thrombocytopenia) and include. - Decreased platelet production- Increased splenic sequestration of platelets with normal platelet survival- Increased platelet destruction or consumption (both immunologic and nonimmunologic causes)- Dilution of platelets. # # A large number of medications may cause thrombocytopenia, typically by triggering immunologic destruction.. Overall, the most common specific causes of thrombocytopenia include. - Pregnancy (gestational thrombocytopenia: HELLP syndrome [hemolysis, elevated liver enzymes, and low platelets]) (1)- Medications that cause immune-mediated platelet destruction (commonly, heparin, trimethoprim/sulfamethoxazole, rarely quinine [cocktail purpura] or abciximab), and rarely vaccinations (eg, influenza; shingles; measles, mumps, and rubella; COVID-19)- Medications and substances that cause dose-dependent bone marrow suppression (eg, chemotherapeutic agents, ethanol)- Systemic infection- Immune disorders (eg, immune thrombocytopenia [ITP], antiphospholipid syndrome, systemic lupus erythematosus). # Platelet dysfunction. Platelet dysfunctionPlatelet dysfunction may stem from an intrinsic platelet defect or from an extrinsic factor that alters the function of normal platelets. Dysfunction may be hereditary or acquired. Hereditary disorders of platelet function consist of von Willebrand disease, the most common hereditary hemorrhagic disease, and inherited platelet function disorders, which are much less common. Acquired disorders of platelet dysfunction are commonly due to diseases (eg, renal failure) as well as to aspirin and other medications such as NSAIDs.. Etiology reference. Etiology reference1. _Ergerty AE, Kuter DJ_. How I Treat Thrombocytopenia in Pregnancy. Blood Published online November 22, 2023. doi:10.1182/blood.2023020726. Symptoms and Signs of Platelet Disorders. Platelet disorders result in a typical pattern of bleeding:. Multiple petechiae in the skin (typically most evident on the lower legs)- Scattered small ecchymoses at sites of minor trauma or venipuncture sites- Mucosal bleeding (oropharyngeal, nasal, gastrointestinal, genitourinary)- Excessive bleeding after surgery- Extensive menstrual bleeding. # Manifestations of Platelet Disorders. Petechiae in Immune Thrombocytopenia (ITP). By permission of the publisher. From Deitcher S. In Atlas of Clinical Hematology. Edited by JO Armitage. Philadelphia, Current Medicine, 2004.. Ecchymoses in Immune Thrombocytopenia. By permission of the publisher. From Deitcher S. In Atlas of Clinical Hematology. Edited by JO Armitage. Philadelphia, Current Medicine, 2004.. # Ecchymoses. EcchymosesEcchymoses are the large purple bruises seen on the leg of this patient.. DR P. MARAZZI/SCIENCE PHOTO LIBRARY. Petechiae (Hard Palate). Petechiae are characterized by small red spots as seen here on the palate of this patient.. DR P. MARAZZI/SCIENCE PHOTO LIBRARY. Heavy gastrointestinal bleeding and bleeding into the central nervous system are rare but may be life threatening. However, bleeding into tissues (eg, deep visceral hematomas or hemarthroses) rarely occurs with thrombocytopenia; instead, patients usually have immediate and superficial bleeding following an injury. Bleeding into the tissues (often delayed for up to a day after trauma) suggests a coagulation disorder (eg, hemophilia).. Diagnosis of Platelet Disorders. - Clinical presentation of petechiae and mucosal bleeding- Complete blood count (CBC) with platelets, coagulation studies, peripheral blood smear. # Sometimes bone marrow aspiration. Sometimes von Willebrand antigen, platelet- binding activity, and multimer studies Platelet disorders are suspected in patients with petechiae and mucosal bleeding. A CBC with platelet count, coagulation studies, and a peripheral blood smear are obtained. Excessive platelets and thrombocytopenia are diagnosed based on the platelet count. Coagulation studies are normal unless there is a simultaneous coagulopathy. In patients with a normal CBC, platelet count, international normalized ratio (INR), and partial thromboplastin time (PTT), platelet or vessel wall dysfunction is suspected.. Pearls & Pitfalls. Suspect platelet or vessel wall dysfunction in patients with petechiae and/or hemorrhage but with normal platelet count and coagulation test results.. Thrombocytopenia. Peripheral smear examination is important in patients with thrombocytopenia because automated platelet counts sometimes show pseudo thrombocytopenia due to platelet clumping caused by the ethylenediaminetetraacetic acid (EDTA) reagent present in most blood collection tubes. Also, schistocytes may be seen, which can indicate valvular hemolysis, thrombotic thrombocytopenic purpura (TTP), hemolytic- uremic syndrome (HUS), or disseminated intravascular coagulation (DIC—see table Peripheral Blood Findings in Thrombocytopenic Disorders).. Bone marrow aspiration is often indicated if the smear shows abnormalities other than thrombocytopenia, such as nucleated red blood cells (RBCs) or abnormal or immature white blood cells (WBCs). Bone marrow aspiration reveals the number and appearance of megakaryocytes and is the definitive test for many disorders that cause bone marrow failure. If the bone marrow is normal but the spleen is enlarged, increased splenic sequestration is the likely cause of thrombocytopenia. If the bone marrow is normal and the spleen is not enlarged, excess platelet destruction is the likely cause.. However, normal number and appearance of megakaryocytes does not always indicate normal platelet production. For example, in many patients with immune thrombocytopenia (ITP), platelet production may be decreased despite the normal appearance and increased number of megakaryocytes. In fact, bone marrow examination is rarely required in patients who present with typical features of immune thrombocytopenia.. The immature platelet fraction (IPF) in peripheral blood is sometimes a useful measure in patients with thrombocytopenia, since it is elevated when the bone marrow is producing platelets and not increased when bone marrow platelet production is reduced, similar to the reticulocyte count in anemia.. Measurement of antiplatelet antibodies may be clinically useful in some patients to distinguish ITP from other causes of thrombocytopenia (1). HIV testing is done in patients with or at risk of HIV infection, hepatitis B or hepatitis C infection, or HIV and hepatitis coinfection.. # # BY PERMISSION OF THE PUBLISHER. FROM TEFFERI A, LI C. IN ATLAS OF CLINICAL HEMATOLOGY. EDITED BY JO ARMITAGE. PHILADELPHIA, CURRENT MEDICINE, 2004.. Suspected platelet dysfunction. In patients with platelet dysfunction, a medication is the suspected cause if symptoms began only after the patient started taking a potentially causative medication (eg, aspirin, prasugrel, clopidogrel, ticagrelor, abciximab). Platelet dysfunction caused by medications may be severe, but specialized tests are rarely needed.. A hereditary cause is suspected if there is a lifelong history of easy bruising; bleeding after tooth extractions, surgery, childbirth, or circumcision; or heavy menstruation. In the case of a suspected hereditary cause, von Willebrand factor (VWF) antigen and VWF activity studies are routinely done.. In patients with suspected hereditary dysfunction, platelet aggregation tests may identify a defect in how the platelet responds to various platelet agonists (adenosine diphosphate [ADP], collagen, thrombin) and thereby demonstrate the type of platelet defect.. Platelet dysfunction caused by most systemic disorders is typically mild and of minor clinical importance; in these patients, the causative systemic disorder is the clinical concern, and hematologic tests are unnecessary. However, patients with renal failure may develop significant bleeding.. Diagnosis reference. 1. Al-Samkari H, Rosovsky RP, Karp Leaf RS: A modern reassessment of glycoprotein-specific direct platelet autoantibody testing in immune thrombocytopenia. Blood Adv 4(1):9-18, 2020. doi: 10.1182/bloodadvances.2019000868. Treatment of Platelet Disorders. - Stopping medications that impair platelet function- Thrombopoietin receptor agonists (TPO-RA). # Rarely platelet transfusions Rarely antifibrinolytic agents. In patients with thrombocytopenia or platelet dysfunction, medications that further impair platelet function, particularly aspirin and other nonsteroidal anti- inflammatory drugs (NSAIDs), should not be given. Patients who are already taking such medications should consider alternatives, such as acetaminophen, or simply stop using them.. Patients may require platelet transfusion, but transfusions are given only in limited situations. For example, platelet transfusion is the mainstay of therapy for patients with platelet dysfunction and active bleeding or for those in need of an invasive procedure. Prophylactic transfusions are used sparingly because they may lose their effectiveness with repeated use due to the development of platelet alloantibodies.. If decreased production is the cause of thrombocytopenia, transfusions, TPO- RA (eg, romiplostim, eltrombopag, avatrombopag), or antifibrinolytic agent (eg, aminocaproic acid, tranexamic acid) are reserved for patients with any of the following:. Active bleeding Severe thrombocytopenia (eg, platelet count . If platelet destruction is the cause of thrombocytopenia, transfusions are reserved for life- threatening, central nervous system, or ocular bleeding. Other options include splenectomy, immunosuppressive agents (including corticosteroids), TPO- RA, and fostamatinib (a spleen tyrosine kinase inhibitor)..	None	None	None
2f803b5c403342498cc529485e953d67	MSD	血管性血友病	# Von Willebrand Disease. By David J. Kuter, MD, DPhil, Harvard Medical SchoolJerry L. Spivak, MD; MACP, Johns Hopkins University School of MedicineReviewed/Revised May 2024. Von Willebrand disease (VWD) is a hereditary quantitative deficiency or functional abnormality of von Willebrand factor, which causes platelet dysfunction. Bleeding tendency is usually mild. Screening tests usually show a normal platelet count and, possibly, a slightly prolonged partial thromboplastin time (PTT). Diagnosis is based on low levels of von Willebrand factor antigen and von Willebrand factor activity (ristocetin cofactor activity). Treatment involves control of bleeding with replacement therapy (virally inactivated, intermediate- purity factor VIII concentrate) or desmopressin.. Symptoms and Signs \| Diagnosis \| Treatment \| Key Points. (See also Overview of Platelet Dysfunction.). Von Willebrand factor (VWF) is synthesized and secreted by vascular endothelium to form part of the perivascular matrix. Von Willebrand factor promotes the platelet adhesion phase of hemostasis by binding with a receptor on the platelet surface membrane (glycoprotein Ib/IX), thus connecting the platelets to the vessel wall. VWF also binds factor VIII and is required to maintain normal plasma factor VIII levels. Levels of VWF can temporarily increase in response to stress, exercise, pregnancy, inflammation, or infection.. Von Willebrand disease is classified into 3 main types:. - Type 1: A quantitative deficiency of VWF, which is the most common form and is an autosomal dominant disorder. VWD concentration and activity are both reduced proportionally.- Type 2: A qualitative impairment in synthesis and function of VWF that can result from various genetic abnormalities and is an autosomal dominant disorder. VWD activity is reduced more than VWF concentration.- Type 3: A rare autosomal recessive disorder in which patients who are homozygous have no detectable VWF.. Four different type 2 subtypes are recognized, distinguished by different functional abnormalities of the VWF molecule:. # In type 2A, VwF fails to bind to platelets and there is a reduction in high molecular weight VWF multimers. In Type 2B, platelets avidly bind high molecular weight VwF, resulting in increased clearance of platelets and high molecular weight VwF multimers. In type 2M, there is decreased platelet binding of VwF and VwF levels are reduced. VwF multimer distribution is preserved, but the ratio of VwF activity to concentration is reduced. In type 2 N, there is impaired binding of VwF to factor Vlll and significant reduction in factor VIII levels (ie, to 1 to . Although VwD, like hemophilia A, is a hereditary disorder that may cause factor Vll deficiency, the factor Vlll deficiency in VwD is usually only moderate (ie, to 20 to . Acquired von Willebrand disease is rare and is characterized by low levels of VwF due to decreased production or increased clearance of VwF from the circulation. It occurs in patients with lymphoproliferative, myeloproliferative, and autoimmune disorders.. Symptoms and Signs of Von Willebrand Disease. Bleeding manifestations in type 1 von Willebrand disease (VwD) include bruising, mucosal bleeding, bleeding from small skin cuts that may stop and start over hours, increased menstrual bleeding, and sometimes bleeding after surgical procedures (eg, tooth extraction, tonsillectomy). Platelets function well enough that petechiae and purpura rarely occur.. Patients with type 3 VwD may additionally experience spontaneous major bleeding under the skin (hematomas) and are at particular risk of life- threatening bleeding with many minor and major surgical procedures.. Diagnosis of Von Willebrand Disease. Total plasma von Willebrand factor (VwF) antigen concentration VwF function testing Plasma factor Vlll level Partial thromboplastin time (PTT). Von Willebrand disease is suspected in patients with unexplained bleeding, particularly those with a family history of a similar bleeding diathesis. Screening coagulation tests reveal a normal platelet count, normal international normalized ratio (INR), and sometimes a slightly prolonged PTT (1). Bleeding time testing is unreliable and no longer done.. Diagnosis requires measuring total plasma VwF antigen, VwF function as determined by the ability of plasma to support agglutination of normal platelets by ristocetin (ristocetin cofactor activity), and the plasma factor VIII level. Stimuli (such as pregnancy and inflammation) that temporarily increase VwF. # levels can cause false- negative results in type I VWD; tests may need to be repeated after the resolution of such stimuli.. In the type 1 form of VWD, results are concordant; ie, VWF antigen, VWF function, and plasma factor VIII level are equally depressed. The degree of depression varies from about 15 to . Type 2 subtypes are suspected if test results are discordant, ie, VWF antigen is higher than expected for the degree of abnormality in ristocetin cofactor activity. VWF antigen is higher than expected because the VWF defect in type 2 is qualitative (loss of high molecular weight VWF multimers) not quantitative. Diagnosis is confirmed by demonstrating a reduced concentration of large VWF multimers on agarose gel electrophoresis. Further specialized functional studies of high molecular VWF binding allow identification of the 4 specific type 2 subtypes.. Patients with type 3 VWD have no detectable VWF and a marked deficiency of factor VIII.. In most women with type 1 VWD, VWF levels commonly return to normal during pregnancy.. Diagnosis reference. 1. James PD, Connell NT, Amger B, et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv 2021;5(1):280-300. doi:10.1182/bloodadvances.2020003265. Treatment of Von Willebrand Disease. - Desmopressin- von Willebrand factor (VwF) replacement when necessary- Tranexamic acid. Patients with von Willebrand disease (VwD) are treated only if they are actively bleeding or are undergoing an invasive procedure (eg, surgery, dental extraction). Treatment guidelines of the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia are available (1).. For patients with type 1 VwD, desmopressin, an analog of vasopressin (antidiuretic hormone) that stimulates release of VwF into the plasma and may increase levels of factor VIII, can be helpful. Desmopressin is usually ineffective in type 2 and in type 3 VwD. In type 2B VwD, desmopressin can exacerbate thrombocytopenia.. To ensure adequate response to desmopressin, physicians give patients a test dose and measure the response of VwF antigen. Desmopressin 0.3 mcg/kg given in . # One dose of desmopressin is effective for about 4 to 6 hours. About 48 hours must elapse for new stores of VwF to accumulate, permitting a second injection of desmopressin to be as effective as the initial dose. For many patients, intra- nasal desmopressin may be as effective as IV treatment and is often useful to prevent bleeding during minor surgical procedures. Frequent use can lead to hyponatremia.. For patients with type 2 VwD, those with type 3 VwD, or those with type 1 VwD who are undergoing more extensive invasive procedures, treatment involves replacement of VwF by infusion of intermediate- purity factor VIII concentrates, which contain components of VwF. These concentrates are virally inactivated and therefore do not transmit HIV infection or hepatitis. Because they do not cause transfusion- transmitted infections, these concentrates are preferred to the previously used cryoprecipitate. High- purity factor VIII concentrates are prepared by immunoaffinity chromatography and contain no VwF and should not be used. Evidence for efficacy of factor VIII concentrates in VwD is mainly from observational studies.. For women with heavy menstrual bleeding due to VwD, a brief period of treatment with tranexamic acid by mouth or intranasal desmopressin may decrease bleeding. Tranexamic acid may also be of use for patients with type 1 and type 2 VwD undergoing minor surgical procedures (eg, dental extraction, skin biopsy, excisional breast biopsy).. Treatment reference. 1. Connell NT, Flood VH, Brignardello-Petersen R, et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv 2021;5(1):301-325. doi:10.1182/bloodadvances.2020003264. Key Points. - Patients with von Willebrand disease have easy bruising and purpura, usually mucosal, and rarely joint bleeding.- Screening tests reveal a normal platelet count, normal INR, and sometimes a slightly prolonged PTT.- Confirming tests include total plasma von Willebrand factor (VwF) antigen, VwF function (VwF ristocetin cofactor assay), and plasma factor VIII level.- Desmopressin or sometimes intermediate-purity factor VIII concentrate is given for active bleeding and before an invasive procedure.- Oral tranexamic acid may be helpful in women with excessive menstrual bleeding or for minor surgical procedures.. # .	None	None	None
7c39d2045910431eb29f043bab4443a1	MSD	阴道出血	# Vaginal bleeding. By Shubhangi Kesavan, MD, Cleveland Clinic Learner College of Medicine, Case Western Reserve University Reviewed By Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/revised June 2024 \| Revised August 2024. Etiology \| Pathophysiology \| Evaluate \| treat \| Geriatrics Overview \| Key Points. The causes, diagnosis, and treatment of abnormal vaginal or uterine bleeding vary according to reproductive stage or status: premenarche, childbearing age, pregnancy, or menopause. This article discusses abnormal vaginal bleeding in nonpregnant women of childbearing age and postmenopausal women.. (See also Vaginal Bleeding During Early or Late Pregnancy and Children.. Causes of vaginal bleeding. Patients may seek medical attention for vaginal bleeding, but bleeding can originate from anywhere in the female reproductive tract, including the vulva, vagina, cervix, uterus, fallopian tubes, or ovaries. Vaginal bleeding that originates in the uterus is called abnormal uterine bleeding (AUB). In addition, bleeding that appears vaginal may originate from the urinary tract or gastrointestinal tract.. Vulvar bleeding Causes include. Infectious or inflammatory disorders, particularly those that cause ulcers or erosions (eg, genital herpes simplex, syphilitic chancre, bullous pemphigoid) or vulvar pruritus, may result in excoriation if the patient scratches the lesion and/or surrounding skin or mucous membranes (eg, lichen sclerosus). Physical trauma (eg, falls with direct impact to the vulva, sexual assault) Vulvar surgery (such as biopsy or female genital mutilation) Benign lesions (eg, epidermal cysts, condyloma acuminatum, angiokeratoma, chondroid lesions) Vulvar intraepithelial neoplasia or squamous cell carcinoma or other malignancies (eg, melanoma). Any vulvar lesion may bleed due to friction (such as contact with clothing).. Vaginal bleeding Causes include. Urogenital syndrome of menopause. # Infections or lesions caused by infections (eg, bacterial vaginosis, genital warts, vaginal ulcers)- Physical trauma (eg, sexual or other penetration, retained tampons, sexual assault)- Radiation therapy- Benign lesions (eg, Gartner duct cysts, vaginal adenosis, polyps, urethral caruncle)- Vaginal intraepithelial neoplasia or squamous cell carcinoma or other malignancies (eg, clear cell carcinoma)- Rarely, toxic epidermal necrolysis and Stevens- Johnson syndrome. Causes of abnormal uterine bleedingAUB is classified into structural and nonstructural etiologies according to the PALM- COEIN classification system (1, 2).. Structural causes of AUB include. Pcervical polyps or endometrial polyps Adenomyosis L Leiomyoma (uterine fibroids) Malignant neoplasm or hyperplasia of uterus or cervix. Nonstructural causes of AUB include. C. Coagulation disorders O Ovulatory dysfunction E Endometritis (eg, chronic endometritis) Hormonal (eg, breakthrough bleeding during oral contraceptive use) No Not yet classified. Ovulatory dysfunction is the most common cause of AUB in women of childbearing age. There are many other specific causes of AUB that fall into the PALM- COIEN category (see table Some Causes of Uterine Bleeding in Nonpregnant Adult Women ).. The PALM- COIEN system describes the causes of uterine bleeding. Causes of cervical bleeding include. Cervicitis Cervical Endometriosis Severe pelvic organ prolapse Physical trauma (eg, sexual or other penetration, sexual assault) Cervical polyps, cysts, papillomas/warts Cervical intraepithelial neoplasia or cancer. Bleeding from the ovaries or fallopian tubes is not a common cause of vaginal bleeding. Bleeding from these organs is more likely to occur within the abdominal cavity; however, the blood may pass through the uterus and may not be noticed until it passes through the vagina. Causes of fallopian tube bleeding include. # - Fallopian tube inflammation- Fallopian tube cancer. Ovarian bleeding Causes include. - Ruptured ovarian cyst- Ovarian cancer. PALM-COEIN classification system. # # 1. American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Gynecology.: Practice Bulletin No. 128: Diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012 (reaffirmed 2024);120(1):197-206.doi:10.1097/AOG.0b013e318262e3202. American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Gynecology.: Practice Bulletin No. 136: Management of abnormal uterine bleeding associated with ovulatory dysfunction. Obstet Gynecol 2013 (reaffirmed 2022); 122 (1):176-185.doi: 10.1097/01.AOG.0000431815.52679.bb. Pathophysiology of vaginal bleeding. Most abnormal vaginal bleeding includes. - Hormonal abnormalities of the hypothalamic-pituitary-ovarian axis- Benign structural diseases (eg, uterine fibroids)- Infectious or inflammatory diseases (eg, cervicitis, chronic endometritis)- Gynecological malignancies- Bleeding disorders (uncommon). Ovulatory dysfunction is caused by endocrine abnormalities. As a result, ovulation does not occur, or ovulation occurs infrequently or irregularly. In anovulatory cycles, the corpus luteum cannot form, and therefore progesterone. Without of progesterone, estrogen can cause the endometrium to continue to grow, and eventually the blood supply cannot support its excessive proliferation. As a result, the endometrium is shed irregularly and incompletely, and bleeding is irregular, sometimes heavy or lasts for a long time.. Benign structural diseases (e.g., uterine fibroids, adenomyosis) may cause abnormal bleeding because they interfere with the function of the myometrium (muscle layer of the uterus). The blood vessels of the endometrium or cervical polyps are dense and fragile and bleed easily.. Evaluation of vaginal bleeding. Abnormal vaginal bleeding may be acute or chronic. When a patient presents with vaginal bleeding, the two first questions to be determined are whether the bleeding is severe enough to require emergency care and whether the patient is pregnant. Unrecognized pregnancy must be suspected and diagnosed in women of childbearing age because some causes of vaginal bleeding during pregnancy (such as ectopic pregnancy) can be life threatening.. Medical history. History of present illness The patient should first be asked about the onset of bleeding, including the timing and relationship to any causative factors. How the patient noticed the bleeding and how she determined that the bleeding was vaginal should be discussed. Bleeding on toilet paper or in the toilet. # bowl, and sometimes blood on underwear or panty liners, may be of genital, urinary, or gastrointestinal origin.. The following questions should be asked to understand the characteristics of the bleeding:. Timing of onset: When the bleeding began and whether there were any possible contributing factors Pattern: intermittent or continuous; related to menstrual cycle or sexual activity Duration Amount: spotting, light bleeding, normal or heavier menstrual flow; heavy bleeding may be indicated by wetting a pad or tampon every 1 to 2 hours, passing blood clots, and/or feeling faint Relationship to other symptoms: Presence of pelvic or abdominal pain or pressure, fever, or urinary or bowel symptoms. Clinicians should also ask the following:. Menstrual history, including date of last normal menstrual period, age at menopause (when appropriate), cycle length and regularity, and amount and duration of typical menstrual bleeding Whether abnormal bleeding has occurred before and whether the cause has been found Sexual history, including possible sexual assault. Normal menstrual cycles have ranges for frequency (every 24 to 38 days), regularity (length of longest and shortest cycle differ by . Review of systems should seek symptoms suggesting possible causes, including the following:. Missed periods, breast engorgement, and nausea: Pregnancy- related bleeding Vaginal dryness and pain during vaginal intercourse: genitourinary syndrome of menopause Bleeding after sex: Cervical cancer Fever, pelvic pain, vaginal discharge: Pelvic inflammatory disease Irregular menstruation and heavy bleeding after several months of no menstruation: Ovulatory dysfunction Heavy, regular menstrual periods and pelvic pressure: Uterine fibroids Sudden onset of unilateral pelvic pain, especially mid- cycle and/or during sexual intercourse: Ruptured ovarian cyst Chronic pelvic or abdominal pain, bloating, changes in bowel habits, or weight loss: Gynecologic cancer Easy bruising and excessive bleeding during tooth brushing, minor lacerations, or venipuncture: Bleeding disorders. # Past medical history should identify disorders known to cause vaginal bleeding, including recent pregnancy, chronic menstrual irregularities, or known structural disorders (eg, uterine fibroids, adenomyosis). Clinicians should identify risk factors for gynecologic cancers, including endometrial cancer (obesity, diabetes, unopposed estrogens [intrinsic, due to chronic ovulatory dysfunction, or exogenous, due to long- term estrogen use without the need for progestins]), or a family history of colorectal or endometrial cancer before age 50 (suggesting Lynch syndrome), and cervical cancer (abnormal or inadequate cervical cancer screening, immunosuppression).. Medications Specific questions should be included regarding the use of hormonal contraceptives, menopausal hormone therapy, other hormones, and other medications that may cause AUB (eg, anticoagulants, progestin- only contraceptives).. Family history should ask about bleeding problems or gynecologic cancers.. The social history should include questions such as history of domestic violence or recent sexual assault.. Physical examination. Vital signs are reviewed for fever and symptoms of hypovolemia (eg, tachycardia, hypotension). During the general examination, clinicians should look for signs of anemia (eg, conjunctival pallor).. The abdomen is examined for distension, tenderness, and masses (particularly an enlarged uterus).. Perform a pelvic examination. External examination and speculum examination help identify lesions or evidence of physical trauma to the vulva, vagina, cervix, and urethra. A bimanual examination assesses the size, mobility, consistency, tenderness, and contour of the uterus (eg, uneven shape due to fibroids) and the size, mobility, and tenderness of the ovaries. If gastrointestinal bleeding is suspected, a rectal examination is performed.. Physical examination findings suggestive of systemic or gynecologic disorders that may cause abnormal uterine bleeding include:. Hirsutism, acne, obesity, and enlarged ovaries: Polycystic ovary syndrome Warm, moist, or dry skin, eye abnormalities, tremors, abnormal reflexes, or a goiter: Thyroid disorder Nipple discharge: Hyperprolactinemia An enlarged liver, jaundice, asterixis (shaky wrists), or an enlarged spleen: Liver disease Abdominal masses or ascites: Cancer, including gynecologic cancers (abdominal masses alone may be uterine fibroids) Multiple bruises, petechiae, purpura, or bleeding from mucous membranes (such as the gums): A bleeding disorder. Red flags. The following findings are of particular concern:. # - Irregular menstruation, unprotected sex, nausea, or a history of breast tenderness: Possible bleeding related to pregnancy- Heavy, ongoing bleeding: May cause anemia, hemodynamic instability, or shock- Bleeding after sex: Possible cervical cancer- Postmenopausal vaginal bleeding: Uterine cancer possible. Interpretation of clinical findings. Severe hypovolemia or hemorrhagic shock is unlikely except after prolonged amenorrhea or with heavy bleeding due to uterine fibroids or (rarely) due to ruptured ovarian cysts.. In women of childbearing age, examination may detect genital tract lesions or a pelvic mass or other findings (eg, pelvic tenderness, cervical friability) to identify the source of bleeding and suggest a cause. Vulvar, vaginal, or cervical lesions or vaginal or cervical discharge may be caused by infection or a benign or malignant tumor. Cervical bleeding without obvious visible lesions may be cervical intraepithelial neoplasia or cancer. A firm, nodular, enlarged, mobile uterus is likely a fibroid. A globular, soft, enlarged uterus may be adenomyosis. However, a fixed pelvic mass suggests cancer or an inflammatory disorder (eg, pelvic inflammatory disease).. Patients with normal pelvic examination and irregular menstruation who meet the following criteria: Ovulatory dysfunction should be further evaluated to determine if an endocrine disorder is present. Patients who begin to have irregular vaginal bleeding who have taken only progestin - only contraceptives in the past 6 months or are currently taking estrogen- progestin contraceptives for . In postmenopausal women, vaginal bleeding should prompt further evaluation for gynecologic cancer. Auxiliary tests. All women of childbearing age who have vaginal bleeding should have a urine or blood pregnancy test, regardless of menstrual or sexual history. A urine pregnancy test may not detect pregnancy before 5 weeks of gestation. If the urine test is negative and pregnancy is suspected, a quantitative serum beta- human chorionic gonadotropin (beta- hCG) test should be done. Vaginal bleeding during pregnancy requires specific management (see Vaginal Bleeding in Early Pregnancy and Vaginal Bleeding in Late Pregnancy).. Blood tests are done to evaluate suspected complications or causes and may include (1). - Anemia: For massive, prolonged, persistent, or recurrent bleeding, complete blood count (CBC); iron studies (serum iron, total iron-binding capacity [TIBC], and ferritin) if anemia is confirmed and not due to iron deficiency (eg, based on microcytic, hypochromic red blood cell [RBC] indices); for acute massive bleeding, blood typing and cross-matching to prevent transfusion- Endocrine disorders: Thyroid disease (thyroid-stimulating hormone), polycystic ovary syndrome (total testosterone, 17-hydroxyprogesterone, DHEA sulfate), or. # hyperprolactinemia (prolactin), depending on history and symptoms; menopause is not a disease, but if menopausal status is uncertain, follicle- stimulating hormone. Liver Disease: Liver Tests. - Bleeding disorders: For menorrhagia, screen patient history for risk factors; if screening is positive, measure platelet count, prothrombin time (PT), activated partial thromboplastin time, and fibrinogen; if von Willebrand disease is suspected, measure von Willebrand factor antigen, ristocetin cofactor assay, and factor VIII. Risk factors for a positive bleeding disorder in the medical history screening include any of the following (2):. - Heavy menstrual bleeding since menarche- One of the following: Postpartum bleeding, bleeding related to surgery, or bleeding from dental treatment- Two or more of the following symptoms: bruises . Imaging studies, including pelvic ultrasonography, should be done if any of the following occur :. - Suspected structural lesions (based on history or examination)- Risk factors for endometrial cancer. Endometrial sampling is indicated for patients with abnormal uterine bleeding.. - Age . Sampling can be done via endometrial biopsy or dilation and curettage (D&C).. Secondary evaluation with saline- infused sonohysterography can help characterize small intrauterine lesions (eg, endometrial polyps, submucous myomas). Hysteroscopy is the gold standard for diagnosing structural intrauterine causes of abnormal uterine bleeding.. Vulvar or vaginal biopsy is done if examination reveals a lesion that may be cancerous or if the diagnosis is unclear.. Cervical biopsy If the cervix is the source of bleeding and there is a cervical lesion or an abnormal Pap test result, a biopsy is indicated. If the test is normal and the patient has not had a recent Pap test, a Pap test is done to detect cervical bleeding.. Evaluation References. # 1. American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Gynecology.: Practice Bulletin No. 128: Diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012 (reaffirmed 2024);120(1):197-206.doi:10.1097/AOG.0b013e318262e3202. Kouides PA, Conard J, Peyvandi F, Lukes A, Kadir R: Hemostasis and menstruation: appropriate investigation for underlying disorders of hemostasis in women with excessive menstrual bleeding. Fertil Steril. 2005;84(5):1345-1351.doi:10.1016/j.fertnstert.2005.05.035. Treatment of vaginal bleeding. The two main goals of treating vaginal bleeding are. - Control of active bleeding- Treat or manage the underlying cause to prevent further episodes. Vaginal bleeding may be severe, and hemodynamic instability or hemorrhagic shock requires immediate fluid management and transfusion therapy to correct severe anemia. Hemodynamically stable women with mild to moderate anemia can usually be managed with fluid replacement. Iron deficiency anemia may require several months of supplemental oral iron.. Acute, severe bleeding is most likely caused by vaginal laceration, cervical cancer, or abnormal uterine bleeding.. Any vaginal lacerations should be repaired.. For bleeding cervical cancer, patients should be managed in the operating room by an experienced gynecologic surgeon. The lesion may be cauterized, but more extensive surgery may be required.. For acute, heavy uterine bleeding, hormonal therapy is the preferred initial treatment. Treatment options include: intravenous conjugated estrogens, combined estrogen/progestin oral contraceptives, oral progestins, or tranexamic acid. The decision depends on the patient's medical history and contraindications to the medication.. Patients with hemodynamic instability, severe bleeding, or contraindications or ineffective medical therapy require surgical treatment. Surgical treatment includes: dilation and curettage, hysteroscopic procedures (such as polypectomy, myomectomy, ablation, intrauterine balloon insertion), and bilateral uterine artery embolization guided by interventional radiology. If bleeding cannot be controlled by these measures or the patient requires definitive treatment, hysterectomy is performed.. After acute management or for nonacute bleeding, treatment of vaginal bleeding should be directed at the cause.. Geriatrics Essentials: Vaginal Bleeding. # Postmenopausal bleeding (> 12 months after last menstrual period) is abnormal and requires further evaluation to exclude cancer unless it is clearly due to cessation of exogenous hormones.. In women not taking exogenous hormones, the most common cause of postmenopausal bleeding is endometrial atrophy, but endometrial hyperplasia or cancer should be excluded.. Vaginal examinations may be difficult for some older women because lack of estrogen causes vaginal atrophy, narrowing, tenderness, and sometimes labial adhesions. For these patients, a pediatric speculum may be more comfortable.. Key Points. - The causes, diagnosis, and treatment of abnormal vaginal or uterine bleeding vary depending on reproductive stage or status: premenarche, childbearing age, pregnancy, or menopause.- Abnormal uterine bleeding may be due to structural (polyps, adenomyosis, uterine fibroids, malignancy) or nonstructural (coagulopathy, ovulatory dysfunction, endometrial or iatrogenic) disease. Ovulatory dysfunction is the most common cause of abnormal uterine bleeding in women of childbearing age.- Patients may present to a doctor with vaginal bleeding, but bleeding may originate from any part of the female reproductive tract, including the vulva, vagina, cervix, uterus, fallopian tubes, or ovaries, or from the urinary tract or gastrointestinal tract.- If abnormal vaginal bleeding occurs, a pregnancy test is indicated for women of childbearing age, even if the medical history does not suggest pregnancy.- Evaluate postmenopausal vaginal bleeding and do endometrial sampling or other cancer testing.- Severe acute uterine bleeding is treated with fluids, blood transfusions (if needed), hormone therapy (such as intravenous conjugated estrogens), and, if necessary, surgery..	None	None	None
2d8bf719ff6f4fe78a6367dca8d2eade	MSD	雌激素-孕激素避孕药，尤其是漏服、连续用药或长期使用时	# Oral Contraceptives. By Frances E. Casey, MD, MPH, NYU Grossman Long Island School of Medicine Oluwatosin Goje, MD, MSCR, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Reviewed/Revised Jul 2023 \| Modified Aug 2023. Adverse Effects \| Benefits \| Drug Interactions \| Initiation \| Key Points. Oral contraceptives (OCs) are steroid hormones that inhibit the release of gonadotropin- releasing hormone (GnRH) by the hypothalamus, thus inhibiting the release of the pituitary hormones that stimulate ovulation. OCs also affect the lining of the uterus, decreasing the likelihood of implantation of an embryo, and cause the cervical mucus to thicken, making it impervious to sperm. If used consistently and correctly, OCs are an effective form of contraception.. OCs may be started at any age from menarche until menopause.. OCs may be a combination of the hormone estrogen and a progestin or a progestin alone.. Combination oral contraceptives. For most combination oral contraceptives, an active pill (estrogen plus progestin) is taken daily for 21 to 24 days. Then, an inactive (placebo) pill is taken daily for 4 to 7 days to allow for withdrawal bleeding. In a few formulations, the placebo pill contains iron and folate (folic acid); in others, this pill is not truly inactive but contains a lower dose of ethinyl estradiol than the pills used during the other weeks. Combination OCs are also available in extended- cycle formulations (with 84 active pills, one to be taken each day, followed by 7 days of placebo pills) or as continuous- use formulations (active pills every day, with no placebo pills).. Most combination OCs contain 10 to 35 mcg of ethinyl estradiol. Estradiol valerate may be used instead of ethinyl estradiol. The doses of estrogen and progestin are the same throughout the month in some combination OCs (monophasic pills); they change throughout the month in others (multiphasic pills).. All combination OCs have similar efficacy; the pregnancy rate after 1 year is . Contraindications to combined estrogen-progestin contraceptives (pills, patch, vaginal ring).. Combination OCs or other estrogen- progestin contraceptives (patch, vaginal ring) must be used with caution in some women (for more information, see the US Medical Eligibility Criteria for Contraceptive Use, 2016 and Update to US Medical Eligibility Criteria for Contraceptive Use, 2016: Updated recommendations for the use of contraception among women at high risk for HIV infection).. # The risk of adverse effects of estrogen- progestin contraceptives varies, depending on the risk factor and associated complications. Estrogen- progestin contraceptive use represents an unacceptable health risk in patients with the following characteristics:. - . Estrogen- progestin contraceptive use represents a theoretical or proven risk that usually outweighs the advantages in patients with the following characteristics:. - . # - Bariatric surgery with a malabsorption due to shortening the functional small intestinal length (eg, Roux-en-Y gastric bypass or biliopancreatic diversion)- Current treatment with fosamprenavir, rifampin, rifabutin, lamotrigine, or certain antiseizure medications. Progestin-only oral contraceptives. To be effective, progestin- only OCs must be taken at the same time of day, every day. The same dose is taken daily, and no inactive pills are included. Breakthrough bleeding is a common adverse effect.. Progestin- only OCs provide effective contraception primarily by thickening the cervical mucus and preventing sperm from passing through the cervical canal and endometrial cavity to fertilize the egg. In some cycles, these OCs also suppress ovulation, but this effect is not the primary mechanism of action. Pregnancy rates with perfect and typical use of progestin- only OCs are similar to those with combination OCs.. Contraindications to progestin-only contraceptives (pills, implants, injections). Progestin- only OCs are commonly prescribed when women wish to take OCs but estrogen is contraindicated.. Women with current breast cancer should not take progestin- only pills, implants, or injections.. Progestin- only contraceptive use represents a theoretical or proven risk that usually outweighs the advantages in patients with the following characteristics:. - Past breast cancer and no evidence of current disease for 5 years- Unexplained vaginal bleeding- Current and history of ischemic heart disease- Severe (decompensated) cirrhosis, hepatocellular adenoma, or liver cancer- History of jejunal bypass surgery (for progestin-only pills)- Current treatment with rifampin, rifabutin, or certain antiseizure medications (for progestin-only pills)- Ischemic heart disease, severe hypertension, or multiple risk factors for atherosclerotic cardiovascular disease (for progestin contraceptive injections)- Vascular disease, including due to diabetes or systematic lupus erythematosus (for progestin contraceptive injections). (For more information, see the US Medical Eligibility Criteria for Contraceptive Use, 2016 and Update to US Medical Eligibility Criteria for Contraceptive Use, 2016: Updated recommendations for the use of contraception among women at high risk for HIV infection.). Adverse Effects of Oral Contraceptives. # Although oral contraceptives may have some adverse effects, the overall risk of these effects is small. Bloating, breast tenderness, nausea, and headache are the most common adverse effects.. Patients on combined OCs may develop amenorrhea or breakthrough bleeding (bleeding while taking the active pills) with prolonged duration of use. Either of these effects may be managed by changing to a pill with a higher estrogen dose. Progestin- only pills often cause irregular vaginal bleeding.. In some women, ovulation remains inhibited for a few months after they stop taking OCs, but there is no long- term effect on fertility. OCs do not adversely affect the outcome of pregnancy when conception occurs during or after their use.. Estrogens increase aldosterone production and cause sodium retention, which can cause dose- related, reversible increases in blood pressure (BP) and in weight (up to about . Most progestins used in OCs are related to 19- nortestosterone and are androgenic. Norgestimate, etonogestrel, and desogestrel are less androgenic than levonorgestrel, norethindrone, norethindrone acetate, and ethynodiol diacetate. Androgenic effects may include acne, nervousness, and an anabolic effect resulting in weight gain. If a woman gains . The incidence of deep venous thrombosis and thromboembolism (eg, pulmonary embolism) increases as the estrogen dose is increased. With OCs that contain 10 to 35 mcg of estrogen, risk is 2 to 4 times the risk at baseline. However, this increased risk is still much lower than the risk associated with pregnancy. The progestins in combination OCs may also affect this risk. OCs that contain levonorgestrel appear to have a lower risk than OCs that contain drospirenone or desogestrel. Risk is probably increased because steroid hormones increase production of clotting factors in the liver and increase platelet adhesion. If deep vein thrombosis or pulmonary embolism is suspected in a woman taking OCs, OCs should be stopped immediately until results of diagnostic tests can confirm or exclude the diagnosis. Also, OCs should be stopped at least 1 month before any major surgery that requires immobilization for a long time and should not be taken again until 1 month afterward. Women with a history of or at high risk for venous thromboembolism should not use OCs that contain estrogen.. Study results vary regarding use of OCs and risk of breast cancer (1). Some studies have found a small increased risk in current or recent users (2).. Risk of cervical cancer is slightly increased in women who have used OCs for . Central nervous system effects of OCs may include nausea, vomiting, headache, depression, and sleep disturbances. Although increased stroke risk has been attributed to OCs, low- dose combination OCs do not appear to increase risk of stroke in healthy, normotensive, nonsmoking women. Nonetheless, if focal neurologic symptoms, aphasia, or other symptoms that may herald stroke develop,. # OCs should be stopped immediately. Smokers over 35 should not use contraceptives that contain estrogen because of the increased risk of myocardial infarction and/or stroke.. Although progestins may cause reversible, dose- related insulin resistance, use of OCs with a low progestin dose rarely results in hyperglycemia.. Serum high- density lipoprotein (HDL) cholesterol levels may decrease when OCs with a high progestin dose are used but usually increase when OCs with low progestin and estrogen doses are used. The estrogen in OCs increases triglyceride levels and can exacerbate preexisting hypertriglyceridemia. Most alterations in serum levels of other metabolites are not clinically significant. Thyroxine- binding globulin capacity may increase in OC users; however, free thyroxine levels, thyroid- stimulating hormone levels, and thyroid function are not affected.. Levels of pyridoxine, folate, B complex vitamins, ascorbic acid, calcium, manganese, and zinc decrease in OC users; vitamin A levels increase. None of these effects is clinically significant, and vitamin supplementation is not advised as an adjunct to OC use.. OCs should not be taken if cholestasis or jaundice developed with previous use. Women who have had cholestasis of pregnancy (idiopathic recurrent jaundice of pregnancy) may become jaundiced if they take OCs, and OCs should be used with caution.. Risk of developing gallstones does not appear to be increased by use of low dose OCs.. Rarely, benign hepatic adenomas, which can spontaneously rupture, develop. Incidence increases as duration of use and OC dose increase; adenomas usually regress spontaneously after OCs are stopped.. Melasma occurs in some women; it is accentuated by sunlight and disappears slowly after OCs are stopped. Because treatment is difficult, OCs are stopped when melasma first appears. OCs do not increase risk of melanoma.. Adverse effects references. 1. Fitzpatrick D, Pirie K, Reeves G, et al: Combined and progestagen-only hormonal contraceptives and breast cancer risk: A UK nested case-control study and meta-analysis. PLoS Med 20(3):e1004188, 2023. Published 2023 Mar 21. doi:10.1371/journal.pmed.1004188 2. ACOG Practice Advisory: Hormonal contraception and risk of breast cancer. American College of Obstetricians and Gynecologists. Published 2018, reaffirmed 2022. 3. Iversen L, Sivasubramaniam S, Lee AJ, et al: Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners' Oral Contraception Study. Am J Obstet Gynecol 216(6):580.e1-580.e9, 2017. doi:10.1016/j.ajog.2017.02.002. Benefits of Oral Contraceptives. OCs have some very important health benefits. High- and low- dose combination OCs decrease the risk of (1). # Endometrial cancer by . They also decrease the risk of functional ovarian cysts, benign ovarian tumors, abnormal uterine bleeding due to ovulatory dysfunction, dysmenorrhea, premenstrual dysphoric disorder, iron deficiency anemia, and benign breast disorders. Salpingitis, which can impairs fertility, occur less frequently in OC users.. Benefits reference. Benefits reference1. Iversen L, Sivasubramaniam S, Lee AJ, et al: Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners' Oral Contraception Study. Am J Obstet Gynecol 216(6):580. e1- 580. e9, 2017. doi:10.1016/j.ajog.2017.02.002. Drug Interactions of Oral Contraceptives. Although OCs can slow the metabolism of certain drugs (eg, meperidine), these effects are not clinically important.. Some drugs can induce liver enzymes (eg, cytochrome P- 450 enzymes) that accelerate transformation of OCs to less biologically active metabolites. Women who take these drugs should not be given OCs concurrently unless other contraceptive methods are unavailable or unacceptable. These drugs include certain antiseizure drugs (most commonly phenytoin, carbamazepine, barbiturates, primidone, topiramate, and oxcarbazepine), ritonavir- boosted protease inhibitors, rifampin, and rifabutin. Lamotrigine should not be used with OCs because OCs can decrease lamotrigine levels and affect seizure control.. Initiation of Oral Contraceptives. Before oral contraceptives are started, clinicians should take a thorough medical, social, and family history to check for potential contraindications to use. Blood pressure is measured, and a urine pregnancy test is done. OCs should not be prescribed unless blood pressure is normal and results of the urine pregnancy test are negative. A physical examination, although often done when OCs are started, is not required. However, a physical examination is recommended within 1 year of OC initiation. A follow- up visit in 3 months may be useful for discussing potential adverse effects and for rechecking blood pressure. OCs can be prescribed for 13 months at a time.. OCs may be started on the same day as the contraceptive visit (often called the quick- start method). The day of the week and time in the menstrual cycle are not important to when OCs are started. However, if OCs are started . Progestin- only OCs must be taken every day, at the same time every day. If . # to taking the OC daily.. For combination OCs, timing is not as stringent. However, if combined OC users miss taking a pill one day, they are advised to take 2 pills the next day. If they forget to take a pill for 2 days, they should resume taking the OC each day and should use a backup contraceptive method for 7 days. If they forget to take a pill for 2 days and have had unprotected sex in the 5 days before forgetting to take the pill, they can consider taking emergency contraception.. The timing for starting combination OCs after pregnancy varies:. After a 1st- trimester spontaneous or induced abortion: Started immediately For deliveries at 12 to 28 weeks gestation: Started within 1 week if women have no other significant risk factors for thromboembolism After a delivery at . In . Progestin- only OCs may be used immediately postpartum.. If women have a history of a liver disorder, tests to confirm normal liver function should be done before OCs are prescribed. Women at risk of diabetes (eg, those who have a family history, who have had gestational diabetes, who have had high- birth- weight infants, or who have physical signs of insulin resistance such as acanthosis nigricans) require plasma glucose screening and a complete serum lipid profile annually. Use of low- dose OCs is not contraindicated by abnormal glucose or lipid test results, except for triglycerides . Key Points. - Oral contraceptives (OCs) are generally well tolerated but may cause headache, nausea, bloating, or breast tenderness.- Progestin-only OCs may cause irregular bleeding and must be taken at the same time every day to be effective.- OCs may be taken from menarche until menopause if they have no contraindications.- Combination OCs increase the risk of venous thromboembolism to 2 to 4 times the risk at baseline, but this risk is less than that associated with pregnancy.. # - Study results vary regarding use of OCs and risk of breast cancer, but some studies have found a small increased risk in current or recent users; OCs decrease the risk of ovarian cancer and endometrial cancer.- Before OCs are prescribed, a thorough patient history is required; a physical examination is not required but ideally should be done within 1 year after OCs are started..	None	None	None
812467c218184482b10728430da505bd	NCCN 临床实践指南	阴道癌01-30	# NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Vaginal Cancer. Version 3.2025 — December 16, 2024. NCCN.org. NCCN recognizes the importance of clinical trials and encourages participation when applicable and available. Trials should be designed to maximize inclusiveness and broad representative enrollment.. Continue. # Nadeem R. Abu- Rustum, MD Q/Chair Memorial Sloan Kettering Cancer Center. Susana M. Campos, MD, MPH, MS† Vice Chair Dana- Farber/Brigham and Women's Cancer Center. Catheryn M. Yashar, MD § Immediate Past Vice- Chair UC San Diego Moores Cancer Center. Rebecca Arend, MD O O'Neal Comprehensive Cancer Center at UAB. Emma Barber, MD Ω Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Kristin Bradley, MD § University of Wisconsin Carbone Cancer Center. Rebecca Brooks, MD Ω UC Davis Comprehensive Cancer Center. Junzo Chino, MD § Duke Cancer Institute. Hye Sook Chon, MD Ω Moffitt Cancer Center. Marta Ann Crispens, MD Ω Vanderbilt- Ingram Cancer Center. Shari Damast, MD § Yale Cancer Center/ Smilow Cancer Hospital. Christine M. Fisher, MD, MPH § University of Colorado Cancer Center. Peter Frederick, MD Ω Roswell Park Comprehensive Cancer Center. David K. Gaffney, MD, PhD § Huntsman Cancer Institute at the University of Utah. Stephanie Gaillard, MD, PhD† Johns Hopkins Kimmel Cancer Center. Robert Giuntoli II, MD Ω Abramson Cancer Center at the University of Pennsylvania. Scott Glaser, MD § City of Hope National Medical Center. Brooke E. Howitt, MD # Stanford Cancer Institute. Lisa Landrum, MD, PhD Ω Indiana University Melvin and Bren Simon Comprehensive Cancer Center. Jayanthi Lea, MD Ω UT Southwestern Simmons Comprehensive Cancer Center. Nita Lee, MD, MPH Ω The UChicago Medicine Comprehensive Cancer Center. Gina Mantia- Smaldone, MD Ω Fox Chase Cancer Center. Andrea Mariani, MD Ω Mayo Clinic Comprehensive Cancer Center. David Mutch, MD Ω Siteman Cancer Center at Barnes- Jewish Hospital and Washington University School of Medicine. Christa Nagel, MD Ω The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute. Larissa Nekhlyudov, MD, MPH Dana- Farber/Brigham and Women's Cancer Center. Karina Nieto, MD § Case Comprehensive Cancer Center/ University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute. Mirna Podoll, MD # Vanderbilt- Ingram Cancer Center. Kerry Rodabaugh, MD Ω Fred & Pamela Buffett Cancer Center. Ritu Salani, MD, MBA Ω UCLA Jonsson Comprehensive Cancer Center. John Schorge, MD Ω St. Jude Children's Research Hospital/ The University of Tennessee Health Science Center. Jean Siedel, DO, MS Ω University of Michigan Rogel Cancer Center. Rachel Sisodia, MD Ω Mass General Cancer Center. Pamela Soliman, MD, MPH Ω The University of Texas MD Anderson Cancer Center. Stefanie Ueda, MD Ω UCSF Helen Diller Family Comprehensive Cancer Center. Renata Urban, MD Ω Fred Hutchinson Cancer Center. Emily Wyse ¥ Patient Advocate. NCCN Nicole McMillian, MS Vaishnavi Sambandam, PhD. Continue. \Omega. \S. # VAGINAL CANCER SUBCOMMITTEE. Shari Damast, MD . Kristin Bradley, MD . Rebecca Brooks, MD . Junzo Chino, MD . Christine M. Fisher, MD, MPH . David K. Gaffney, MD, PhD . Mirna Podoll, MD . John Schorge, MD . Catheryn M. Yashar, MD . Continue. \Omega. # NCCN Vaginal Cancer Panel Members NCCN Vaginal Cancer Subcommittee Members Summary of the Guidelines Updates. Workup (VAG- 1) Invasive (Stage I- IVA), Primary Treatment (VAG- 2) Adjuvant Therapy (VAG- 3) Follow- up/Surveillance (VAG- 4) Locoregional Recurrence (VAG- 5) Stage IVB or Recurrent Distant Metastases (VAG- 6). Principles of Pathology (VAG- A) Principles of Imaging (VAG- B) Principles of Radiation (VAG- C) Systemic Therapy for Primary Vaginal Cancer (VAG- D) Principles of Surgery (VAG- E) Principles of Gynecologic Survivorship (VAG- F). Staging (ST- 1). ABBR- 1. Find an NCCN Member Institution: institutions. NCCN Categories of Evidence and Consensus: All recommendations are category 2A unless otherwise indicated. NCCN Categories of Evidence and Consensus. NCCN Categories of Preference: All recommendations are considered appropriate. NCCN Categories of Preference. The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2024.. # National Comprehensive Cancer Network. NCCN Guidelines Version 3.2025 Vaginal Cancer. Updates in Version 3.2025 of the NCCN Guidelines for Vaginal Cancer from Version 2.2025 include:. VAG-3. - Footnote j added: Principles of Systemic Therapy (VAG-D). - Footnote removed: Concurrent chemotherapy has been shown in many series to improve outcomes and is often used in stage II-IV disease. Concurrent platinum-containing chemotherapy with EBRT utilizes cisplatin as a single agent (or carboplatin if cisplatin intolerant). See Principles of Systemic Therapy (VAG-D).. VAG-4. - Footnote o revised: "Patient education including should include symptoms of potential recurrence, lifestyle...". VAG-5. - Locoregional recurrence; Prior EBRT ± brachytherapy; Central disease; Therapy for Relapse; Revised recommendation to streamline the pathway: Consider reirradiation or local excision in carefully selected patients.. VAG-A 2 of 2. - Pathologic Assessment for Vaginal Carcinoma; 11th bullet; Sub-bullets under Ancillary testing revised including:. - 5th bullet revised: "HPV-dependent associated vaginal...". - New bullets added:. - Recommend p53 IHC to determine p53 status in HPV-negative tumors (next-generation sequencing [NGS] is an acceptable alternative) - Consider programmed death ligand 1 (PD-L1) IHC for patients with recurrent, progressive, or metastatic disease. - HER2 IHC (with or without reflex to HER2 fluorescence in situ hybridization [FISH] for equivocal IHC) is recommended for advanced or recurrent/metastatic disease. - Consider comprehensive molecular profiling by an FDA-approved assay, or a validated test performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory including at least microsatellite instability (MSI), tumor mutational burden (TMB) testing, NTRK, and RET for predicting rare pan-tumor targeted therapy opportunities. - Mismatch repair (MMR) by IHC. - Bullets removed:. - Recommend ancillary testing to determine HPV status either by p16 IHC or RNA in situ hybridization (ISH) or DNA sequencing - Consider next-generation sequencing (NGS) and comprehensive molecular profiling as determined by an FDA-approved assay, or validated test performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.. - Consider the following biomarkers: Programmed death ligand 1 (PD-L1), Tumor mutational burden (TMB), p53 IHC, RET fusion, Microsatellite instability-high (MSI-H), NTRK fusion, HER2 IHC or FISH. VAG-B. - Workup; 1st bullet revised: "Pelvis MRI with and without IV-contrast and..." The contrast specification was removed from the bullet because the information is in footnote "a".. # Updates in Version 3.2025 of the NCCN Guidelines for Vaginal Cancer from Version 2.2025 include:. VAG-C 2 of 7. - External Beam Radiation Therapy/Intensity Modulated Radiation Therapy (EBRT/IMRT); 2nd bullet Planning/Treatment; EBRT diamond sub-bullets revised - 1st sub-bullet: "...organs at risk (OAR). Attention should be given to internal target motion in planning." - 3rd sub-bullet: A minimum of weekly portal images; daily image-guided RT (IGRT) is advised, especially if IMRT is utilized.. VAG-C 3 of 7. - Brachytherapy; Dose prescription; 3rd arrow sub-bullet: The sentence stating "The HDR data are more varied..." was a separate arrow sub-bullet and was combined with the sub-bullet regarding very-early stage vaginal cancers (<5 mm).. VAG-C 5 of 7. - Normal Tissue Dose Constraints; Hard Constraints revised as follows: - Bladder: Dmax <415% <57.5 Gy - Anorectum: Dmax <415% <57.5 Gy - Femoral Heads: Dmax <415% <55 Gy. VAG-C 6 of 7. - Rectum; ICRU Point (EQD2. VAG-D 1 of 2. - Systemic Therapy for Primary Vaginal Cancer - Recurrent or Metastatic Disease/Second-line or Subsequent Therapy - Cemiplimab move from Preferred to Other Recommended Regimens - Useful in Certain Circumstances: Repotrectinib added as an option for NTRK gene fusion-positive tumors. VAG-D 1A of 2. - The following footnote modification were made: - Footnote a is new: An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. - Footnote g: Recommended in patients whose tumors express PD-L1 (combined positive score [CPS] ≥1) as determined by an FDA-approved assay, or validated test performed in a CLIA-certified laboratory. - Footnote i: For the treatment of patients with unresectable or metastatic TMB-H [≥10 mutations/megabase (mut/Mb)] tumors, as determined by FDA-approved assay, or validated test performed in a CLIA-certified laboratory, that have progressed following prior treatment and who have no satisfactory alternative treatment options. - Footnote j is new: NTRK-positive tumors that are naïve to prior NTRK targeted therapy or have progressed on prior NTRK therapy. - Footnotes removed: - These agents may be considered when cisplatin and carboplatin are unavailable. - An FDA-approved biosimilar is an appropriate substitute for trastuzumab.. # Updates in Version 3.2025 of the NCCN Guidelines for Vaginal Cancer from Version 2.2025 include:. VAG-D 2 of 2. - Reference 19 updated: Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: DESTINY- PanTumor02 interim results. Presented at the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois: Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: DESTINY- PanTumor02 Phase II trial. J Clin Oncol 2024;42:47-58.. - Reference 20 is new: Solomon B, Drilon A, Lin JJ, et al. Repotrectinib in patients with NTRK fusion-positive advanced solid tumors, including non-small cell lung cancer: update from the phase 1/2 TRIDENT-1 trial. Poster presented at the European Society for Medical Oncology Congress; October 20-24, 2023; Madrid, Spain.. Updates in Version 2.2025 of the NCCN Guidelines for Vaginal Cancer from Version 1.2025 include:. MS- 1- The Discussion, which reflects the recommendations in the algorithm, has been added.. # WORKUPa. - History and physical (H&P) (include sexual history, immunosuppression, prior hysterectomy, smoking history, gynecologic and anorectal symptoms)- Pelvic exam (bimanual and rectovaginal), cervical evaluation and pap smear, colposcopy, vulvar evaluation- Rule out synchronous anorectal, cervical, endometrial, or vulvar primary with vaginal metastasis or extension, or recurrent disease from prior malignancyb- Consider examination under anesthesia (EUA) with biopsies (consider cystoscopy/proctoscopy) as clinically indicatedc- Imagingd- Complete blood count (CBC), comprehensive metabolic panel (CMP)- Human papillomavirus (HPV) and human immunodeficiency virus (HIV) testing in select patients. Multidisciplinary expertise is recommended. Consider referral to a center of expertise that specializes in the treatment of vaginal cancers. Only a minority of vaginal cancers originate in the vagina. The remaining are generally metastatic from other sites. If vaginal lesion(s) involve the cervix or vulva, it is not considered vaginal cancer and the appropriate treatment algorithm should be consulted (see NCCN Guidelines for Cervical Cancer or NCCN Guidelines for Vulvar Cancer).. # CLINICAL STAGE PATHOLOGIC FINDINGS PRIMARY TREATMENT. # POSTOPERATIVE RISK FACTORS. ADJUVANT THERAPY TO THE PRIMARY SITE. f Principles of Radiation Therapy (VAG- C). Chemoradiation may not be suitable for all patients. It should be used with caution in patients who are older, frail, and/or have multiple comorbidities. The management of positive margins for high- grade squamous intraepithelial lesion (HSIL) should be individualized. See Principles of Systemic Therapy (VAG- D). k In select patients, re- excision may be considered. See Principles of Surgery (VAG- E).. # FOLLOW-UP/SURVEILLANCE. - Interval H&P - every 3-6 mo for 2 y, - every 6-12 mo for 3-5 y, then annually based on patient's risk of disease recurrence - Consider cervical/vaginal cytology screening<sup>l,m</sup> as indicated for the detection of lower genital tract neoplasia (may include HPV testing) - Post-treatment imaging 3-4 mo to assess response - Further imaging as indicated based on symptoms or examination findings suspicious for recurrence<sup>d,n</sup> - Laboratory assessment (CBC, blood urea nitrogen [BUN], creatinine) as indicated based on symptoms or examination findings suspicious for recurrence - Clinical evaluation and management of potential long-term and late effects of treatment and patient education<sup>o</sup> (Also see Principles of Gynecologic Survivorship (VAG-F), NCCN Guidelines for Survivorship, and NCCN Guidelines for Smoking Cessation). WORKUP. Therapy for Relapse (Locoregional Recurrence) (VAG- 5). Treatment for Stage IVB or Recurrent Distant Metastases (VAG- 6). Principles of Imaging (VAG-B).. Regular cytology can be considered for detection of lower genital tract dysplasia, although its value in detection of recurrent genital tract cancer is limited. The accuracy of cytology results may be affected in patients who have received pelvic radiation. Recurrences should be proven by biopsy before proceeding to treatment planning. Patient education should include symptoms of potential recurrence, lifestyle, obesity, exercise, sexual health (including vaginal dilator use and lubricants/moisturizers, local estrogen and hormone therapy for menopause), smoking cessation, and nutrition counseling.. # # # PRINCIPLES OF PATHOLOGY. General Principles. General Principles- Vaginal carcinomas account for . # PRINCIPLES OF PATHOLOGY. Pathologic Assessment for Vaginal Carcinoma. Pathologic Assessment for Vaginal Carcinoma- Procedure type (ie, biopsy, local excision, partial vaginectomy, radical vaginectomy, trachelectomy)- Tumor site (upper, middle, or lower third)- Tumor size: include greatest dimension and additional two dimensions- Histologic types: HPV- associated squamous cell carcinoma, HPV- independent squamous cell carcinoma, HPV- associated vaginal adenocarcinoma, endometrioid carcinoma, clear cell carcinoma, mucinous carcinoma (gastric and intestinal types), mesonephric adenocarcinoma, carcinosarcoma, mixed tumor of the vagina, adenocarcinoma of skene gland origin, adenosquamous carcinoma, adenoid basal carcinoma, adenosarcoma, neuroendocrine carcinomas, and germ cell tumors- HPV- associated vaginal SILs are divided into the LSIL and HSIL categories; LSIL is associated with both low- and high- risk HPV types and HSIL is exclusively associated with high- risk HPV types- Histologic grade: well, moderately, and poorly differentiated- Lymphovascular space invasion (LVSI)- Precursor lesion(s): VAIN/SIL- Surgical resection margin status- Determination of primary site: Prior (<5 year) history of cervical or vulvar carcinoma must be excluded.- Ancillary testing - Recommend ancillary testing to determine HPV status either by p16 IHC or RNA in situ hybridization (ISH) or DNA sequencing - Recommend p53 IHC to determine p53 status in HPV- negative tumors (next- generation sequencing [NGS] is an acceptable alternative) - Consider programmed death ligand 1 (PD- L1) IHC for patients with recurrent, progressive, or metastatic disease - HER2 IHC (with or without reflex to HER2 fluorescence in situ hybridization [FISH] for equivocal IHC) is recommended for advanced or recurrent/metastatic disease - Consider comprehensive molecular profiling by an FDA- approved assay, or a validated test performed in a Clinical Laboratory Improvement Amendments (CLIA)- certified laboratory including at least microsatellite instability (MSI), tumor mutational burden (TMB) testing, NTRK, and RET for predicting rare pan- tumor targeted therapy opportunities- Mismatch repair (MMR) by IHC. # PRINCIPLES OF IMAGING<sup>a</sup>. Workup. - Pelvis MRI and vaginal gel to assess local disease extent (preferred). - Neck/chest/abdomen/pelvis/groin fluorodeoxyglucose (FDG)-PET/CT (preferred) or chest/abdomen/pelvis CT to evaluate for metastatic disease. - Other initial imaging should be based on symptomatology and clinical concern for metastatic disease.. Follow-up. - FDG-PET/CT (preferred) at 3-4 months after RT. - MRI if unable to obtain FDG-PET/CT or needed for clarification of FDG-PET/CT or exam findings. - Repeat imaging if clinically indicated.. # PRINCIPLES OF RADIATION. General Principles. General Principles- For the majority of vaginal cancers, radiation is used rather than surgery as primary treatment due to improved organ preservation. Preferred modalities for definitive management include either concurrent pelvic chemoradiation (platinum- based) + brachytherapy or EBRT + brachytherapy. The addition of brachytherapy to EBRT is preferred as the combination has been shown to improve control.- Overall treatment time should not extend beyond 8 weeks.- Treatment delays/interruptions need to be minimized.. External Beam Radiation Therapy/Intensity Modulated Radiation Therapy (EBRT/IMRT). Simulation. IMRT. \langle \rangle. - Dose Prescription. IMRT. \langle \rangle. # PRINCIPLES OF RADIATION. External Beam Radiation Therapy/Intensity Modulated Radiation Therapy (EBRT/IMRT) continued. Target Delineation. - Gross tumor volume (GTV) primary = Primary tumor delineated by exam (including EUA) and fusion with MRI and/or FDG-PET/CT. - Clinical target volume (CTV) primary = Entire vagina, paravaginal tissues, cervix, parametria, and GTV with 1- to 2-cm margin. Account for possible ITV as vaginal apex can move up to 2 cm in anterior-posterior (AP) direction. To develop an ITV, patients should be simulated with full and empty bladder. CTVs from both scans should be combined to create an ITV. If there is involvement of adjacent organs (ie, urethra or rectum), consider their inclusion in CTV. - CTV nodes = Pelvic nodal coverage of common iliac, internal and external iliac, presacral, and obturator nodes, and if lower third of vagina involved include inguinal nodes. Include para-aortic nodes if common iliac/para-aortic nodes involved. Include pelvic vessels with 7-mm expansion excluding bone/muscle/organs. Tumors involving the posterior vaginal wall and recto vaginal septum have an increased risk of spread to the presacral and mesorectal nodes; inclusion of the entire mesorectum should be considered in these cases. - Inguinofemoral node borders for distal vaginal cases: superior = acetabular roof; lateral = inguinofemoral vessels to medial sartorius/rectus femoris; posterior = posterior border of vessels; medial = pectineus muscle or 2.5-3 cm from vessels; anterior = anterior border of sartorius; caudal = top of lesser trochanter of femur. - Planning target volume (PTV) expansion 0.5-0.7 cm from CTV per institutional required margin to account for setup error based on image verification available. - Inferior field border should extend approximately 3 cm below the inferior extent of vaginal disease.. - Planning/Treatment EBRT. IMRT is used as a treatment technique to spare organs at risk (OAR). Attention should be given to internal target motion in planning. Consider treatment with full bladder to minimize bowel dose. A minimum of weekly portal images; daily image- guided RT (IGRT) is advised, especially if IMRT is utilized. Bolus may be necessary to adequately cover inguinal nodes.. # Brachytherapy. Simulation Intracavitary applicator (for 5-mm gross disease thickness) May be done with single channel, multichannel (Miami applicator), or partially shielded vaginal cylinder applicators Interstitial needles (>5- mm gross disease thickness)- perineal template applicator (ie, Syed), hybrid, or freehand; consider referral to treatment center with specialist/expertise Real- time image guidance with CT, MRI, or transrectal ultrasound (US). Dose Prescription. Brachytherapy to reach 70- 80 Gy EQD2 total dose (alpha/beta [a/β] ratio = 10) to high- risk CTV (HR- CTV) is generally recommended, with lower dose ranges of 70- 75 Gy considered in the lower vagina, and 75- 80 Gy total dose in the upper vagina. For bulky or poorly responsive disease in the upper vagina, dose escalation up to 85 Gy may be considered. Some treat entire vaginal surface to 60 Gy cumulative, followed by tumor boost to 70- 80 Gy, while others treat only the lesion plus a margin. Careful attention should be paid to dose tolerance of vaginal mucosa. The distal vagina has a lower tolerance than the proximal vagina.. For invasive cancers, common high dose- rate (HDR) fractionation regimens after 45 Gy to pelvis include 4.5- 6.5 Gy x 5 fractions to the HR- CTV. Either less fractionated or more fractionated regimens may be used, such as 7 Gy x 3 fractions or 3 Gy x 9- 10 fractions. Modulation of dose takes into consideration tumor location, extent of disease, response to EBRT, brachytherapy technique (intracavitary or interstitial), relationship to surrounding OARs, as well as other factors.. For very- early- stage vaginal cancers (<5 mm) not requiring EBRT, intracavitary brachytherapy alone may be used. Low dose- rate (LDR) data suggest improved outcomes with doses of approximately 60- 70 Gy EQD2 to the vaginal surface. The HDR data are more varied, with total doses in the range of 50- 60 Gy EQD2. The appropriate dose for each case needs to be individualized. Common regimens include 5 Gy x 8 fractions or 8 Gy x 5 fractions to the vaginal surface, with treatments delivered twice per week.. Dose Constraints: See (VAG- C 5 of 7). Target Delineation. Brachytherapy planning is highly individualized and should incorporate information from pre- EBRT and pre- brachytherapy imaging (preferably MRI), clinical drawings, fiducials, and exam findings. Careful understanding of vaginal anatomy and distribution of disease is required. Image- guided brachytherapy is strongly encouraged, with adaptation of volumes as tumor responds. Tumor extent, location, and response must all be considered when choosing the brachytherapy approach.. GTV: macroscopic gross residual tumor at time of brachytherapy by imaging and clinical exam HR- CTV: GTV + any abnormal/irregular vaginal wall within initial tumor extension + paravaginal/parametrial gray zones (if applicable). Planning/Treatment IGRT adaptive planning encouraged Attention to vaginal surface dose and surrounding dose to OARs Use biologically effective dose (BED) dose conversions to track EQD2 dose to normal tissues (a/β ratio = 3) and to vaginal target/HR- CTV (a/β ratio = 10). For further details, refer to GEC- ESTRO recommendations.6,8. Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF RADIATION. External Beam Boost. - Although brachytherapy is typically preferred, a carefully designed IMRT boost may be feasible in place of brachytherapy, if a similar EQD2 can be achieved without significant increased dose to the OARs. In such cases, total dose should aim for 65–70 Gy. - This may be appropriate for patients who are poor candidates for brachytherapy or where concern for toxicity is high, such as tumors that are extremely close to the rectum or anus.. Reirradiation. - IORT (category 3): IORT is a specialized technique that delivers a single, highly focused dose of radiation to an at-risk tumor bed or isolated unresectable residual disease during an open surgical procedure.. - Other techniques for reirradiation may include intracavitary or interstitial brachytherapy, SBRT, IMRT, or proton therapy. Such cases are highly individualized and depend on the target, proximity to critical organs, previous RT dose, extent of overlap, and time intervals since prior RT. The appropriate dose for each case needs to be individualized.. # PRINCIPLES OF RADIATION1-8. NORMAL TISSUE DOSE CONSTRAINT GUIDELINES FOR VAGINAL CANCER9-11. b In cases where an EBRT boost is used, vulvar constraints may be appropriate: Bladder: Dmax <65 Gy; Anorectum: Dmax <65 Gy; and Femoral heads: Dmax <55 Gy. Care should be taken to minimize dose to uninvolved and out- of- field external genitalia when possible but without compromising coverage of the PTV.. # PRINCIPLES OF RADIATION1-8. NORMAL TISSUE DOSE CONSTRAINT GUIDELINES FOR VAGINAL CANCER9- 11. Clinicians must balance the risks of normal tissue toxicity with tumor control, but suggested dose constraints are provided. Studies indicate that . # PRINCIPLES OF RADIATION REFERENCES. 1 Frank SJ, Jhingran A, Levenback C, Eifel PJ. Definitive radiation therapy for squamous cell carcinoma of the vagina. Int J Radiat Oncol Biol Phys 2005;62:138- 147. 2 Creasman WT, Phillips JL, Menck HR. The National Cancer Data Base report on cancer of the vagina. Cancer 1998;83:1033- 1040. 3 Rajagopalan MS, Xu KM, Lin JF, et al. Adoption and impact of concurrent chemoradiation therapy for vaginal cancer: a National Cancer Data Base (NCDB) study. Gynecol Oncol 2014;135:495- 502. 4 Miyamoto DT, Viswanathan AN. Concurrent chemoradiation for vaginal cancer. PLoS One 2013;8:e65048. 5 Orton A, Boothe D, Williams N, et al. Brachytherapy improves survival in primary vaginal cancer. Gynecol Oncol 2016;141:501- 506. 6 Kamrava M, Leung E, Bachand F, et al. GEC- ESTRO (ACROP)- ABS- CBG Consensus Brachytherapy Target Definition Guidelines for Recurrent Endometrial and Cervical Tumors in the Vagina. Int J Radiat Oncol Biol Phys 2023;115:654- 663. 7 Westerveld H, Schmid MP, Nout RA, et al. Image- guided adaptive brachytherapy (GABT) for primary vaginal cancer: Results of the International Multicenter RetroEMBRAVE cohort study. Cancers (Basel) 2021;13:1459. 8 Schmid MP, Fokdal L, Westerveld H, et al; GEC- ESTRO GYN Working Group. Recommendations from gynaecological (GYN) GEC- ESTRO working group - ACROP: Target concept for image guided adaptive brachytherapy in primary vaginal cancer. Radiother Oncol 2020;145:36- 44. 9 Klopp AH, Yeung AR, Deshmukh S, et al. Patient- reported toxicity during pelvic intensity- modulated radiation therapy: NRG Oncology- RTOG 1203. J Clin Oncol 2018;36:2538- 2544. Erratum in: J Clin Oncol 2019;37:761. Erratum in: J Clin Oncol 2020;38:1118. 10 Mell LK, Sirak I, Wei L, et al; INTERTECC Study Group. Bone marrow- sparing intensity modulated radiation therapy with concurrent cisplatin for stage IB- IVA cervical cancer: An international multicenter phase II clinical trial (INTERTECC- 2). Int J Radiat Oncol Biol Phys 2017;97:536- 545. 11 Pötter R, Tandrup K, Kirisits C, et al; EMBRACE Collaborative Group. The EMBRACE II study: The outcome and prospect of two decades of evolution within the GEC- ESTRO GYN working group and the EMBRACE studies. Clin Transl Radiat Oncol 2018;9:48- 60.. # NCCN Guidelines Version 3.2025 Vaginal Cancer. Footnotes on VAG-D 1A of 2. Note: All recommendations are category 2A unless otherwise indicated.. # a An FDA- approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. b The majority of cases in the vagina might be arising from another site. In these cases, one should refer to the corresponding NCCN Treatment Guidelines. Cisplatin, carboplatin, docetaxel, and paclitaxel may cause drug reactions. See NCCN Guidelines for Ovarian Cancer- Management of Drug Reactions (O- D) d Toxicity, especially when using extended- field RT, should be carefully considered when selecting an appropriate regimen for treatment. e If not used previously, these agents can be used as second- line or subsequent therapy as clinically appropriate. f NCCN Guidelines for the Management of Immunotherapy- Related Toxicities. g Recommended in patients whose tumors express PD- L1 (combined positive score [CPS] ≥1). h Checkpoint inhibitors and/or monoclonal antibodies included in this regimen may be continued as maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules. i For the treatment of patients with unresectable or metastatic TMB- H [≥10 mutations/megabase (mut/Mb)] tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. j NTRK- positive tumors that are naïve to prior NTRK targeted therapy or have progressed on prior NTRK therapy.. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 3.2025 Vaginal Cancer. SYSTEMIC THERAPY FOR VAGINAL CANCER REFERENCES. 1 Lorvidhaya V, Chitapanarux I, Sangruchi S, et al. Concurrent mitomycin C, 5- fluorouracil, and radiotherapy in the treatment of locally advanced carcinoma of the cervix: a randomized trial. Int J Radiat Oncol Biol Phys 2003;55:1226- 1232. 2 Pattaranutaporn P, Thirapakawong C, Chansilpa Y, et al. Phase II study of concurrent gemcitabine and radiotherapy in locally advanced stage IIIB cervical carcinoma. Gynecol Oncol 2001;81:404- 407. 3 Candelaria M, Garcia- Arias A, Cetina L, et al. Radiosensitizers in cervical cancer. Cisplatin and beyond. Radiat Oncol 2006;1:15. 4 Cerrotta A, Gardan G, Raspagliesi F, et al. Concurrent radiotherapy and weekly paclitaxel for locally advanced or recurrent squamous cell carcinoma of the uterine cervix. A pilot study with intensification of dose. Eur J Gynaecol Oncol 2002;23:115- 119. 5 Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med 2021;385:1856- 1867. 6 Tewari KS, Sill MW, Long HJ III, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 2014;370:734- 743. 7 Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin- containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2009;27:4649- 4655. 8 Moore DH, Blessing JA, McQuellon RP, et al. Phase II study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 2004;22:3113- 3119. 9 Moore KN, Herzog TJ, Lewin S, et al. A comparison of cisplatin/paclitaxel and carboplatin/paclitaxel in stage IVB, recurrent or persistent cervical cancer. Gynecol Oncol 2007;105:299- 303. 10 Kitagawa R, Katsumata N, Shibata T, et al. Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: the open- label randomized phase III trial. JCOG0505. J Clin Oncol 2015;33:2129- 2135. 11 Long HJ II, Bundy BN, Grendys EC Jr, et al. Randomized phase II trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol 2005;23:4626- 4633. 12 Weiss GR, Green S, Hannigan EV, et al. A phase II trial of carboplatin for recurrent or metastatic squamous carcinoma of the uterine cervix: a Southwest Oncology Group study. Gynecol Oncol 1990;39:332- 336. 13 Tinker AV, Bhagat K, Swenerton KD, Hoskins PJ. Carboplatin and paclitaxel for advanced and recurrent cervical carcinoma: the British Columbia Cancer Agency experience. Gynecol Oncol 2005;98:54- 58. 14 Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair- deficient cancer: results from the phase 2 KEYNOTE- 158 study. J Clin Oncol 2020;38:1- 10. 15 McGuire WP, Blessing JA, Moore D, et al. Paclitaxel has moderate activity in squamous cervix cancer. A Gynecologic Oncology Group study. J Clin Oncol 1996;14:792- 795. 16 Coleman RL, Lorusso D, Gennigens C, et al. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/ GOG- 3023/ENGOT- cx6): a multicentre, open- label, single- arm, phase 2 study. Lancet Oncol 2021;22:609- 619. 17 Tewari KS, Monk BJ, Vergote I et al. Survival with ceimiplimab in recurrent cervical cancer. N Engl J Med 2022;386:544- 555. 18 Naumann RW, Hollobeque A, Meyer T, et al. Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: Results from the phase I/II CheckMate 358 trial. J Clin Oncol 2019;37:2825- 2834. 19 Meric- Bemstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2- expressing solid tumors: DESTINYPanTumor02 Phase II trial. J Clin Oncol 2024;42:47- 58. 20 Solomon B, Drilon A, Lin JJ, et al. Repotrectinib in patients with NTRK fusion- positive advanced solid tumors, including non- small cell lung cancer: update from the phase 1/2 TRIDENT- 1 trial. Poster presented at the European Society for Medical Oncology Congress; October 20- 24, 2023; Madrid, Spain.. # PRINCIPLES OF SURGERY. Initial Diagnosis:. - Patients should be evaluated by a gynecologic oncologist prior to any surgical treatment for vaginal cancer.- Surgery is only recommended if a complete resection with clear margins is feasible without excessive morbidity and with likelihood that no adjuvant RT would be required.- EUA may be helpful to confirm diagnosis, obtain adequate tissue sampling for histologic evaluation and comprehensive molecular profiling such as PD-L1, and assess the extent of disease. Consider cystoscopy and proctoscopy concurrently to exclude bladder/rectal invasion. Perform evaluation of cervix and vulva to exclude other gynecologic primary sites.- In patients who are premenopausal, ovarian preservation or transposition should be considered when feasible.- Fiducial markers may be placed to define the extent of the vaginal lesion.- Definitive surgical management for vaginal cancer is not often utilized, and the alternative of radiation should be considered.- For microscopic lesions at the top of the vagina, upper vaginectomy ± hysterectomy may be reasonable. A radical hysterectomy may be appropriate for macroscopic lesions (<2 cm).- For proximal lesions involving the upper two thirds of the vagina, the pelvic lymph nodes should be assessed.- For distal lesions involving the lower 1/3 of the vagina, the inguinal lymph nodes should be assessed.- Vaginal reconstruction should be considered for appropriate candidates desiring such procedures.- For primary, untreated lesions in which resection would require excision of the urethra, bladder, or rectum, radiation is often preferred.- Vaginectomy may be considered for small lesions for which margins are likely to be negative. Every effort should be made to obtain negative margins.- Pelvic exenteration may be considered for recurrent or persistent disease localized to the pelvis or when primary RT is not feasible.. # Physical Effects. Gynecologic cancer treatment typically involves surgery, chemotherapy, hormone therapy, RT, and/or immunotherapy. These treatments cause acute, short- term, and long- term toxicities.. Surgical approaches may be extensive and pose risks such as adhesion formation, which may cause pain and may contribute to small bowel obstruction, urinary or gastrointestinal complications (eg, incontinence, diarrhea), pelvic floor dysfunction (manifested by a variety of urinary, bowel, and/or sexual effects), and lymphedema.. Chemotherapy agents vary, though commonly used regimens may pose a significant risk of neurotoxicity, cardiac toxicity, development of hematologic cancers, and cognitive dysfunction.. Long- term estrogen deprivation may cause symptoms such as hot flashes, vaginal dryness, and bone loss.. RT may cause long- term complications (eg, fibrosis, vulvovaginal atrophy) and may predispose patients to secondary cancers of the subcutaneous tissue, and/or underlying organs that are proximal to the radiation field.. Prior pelvic RT may contribute to bone loss and increase the risk of pelvic fractures. Consider bone density testing and prophylactic use of bisphosphonates, particularly in patients with osteoporosis. Immunotherapy use is emerging, and to date, long- term effects of these treatments are unknown.. Psychosocial Effects. Psychosocial effects after cancer may be psychological (eg, depression, anxiety, fear of recurrence, altered body image), financial (eg, return to work, insurance concerns), and/or interpersonal (eg, relationships, sexuality, intimacy) in nature.. Clinical Approach. All gynecologic cancer survivors should receive regular general medical care that focuses on managing chronic disease, monitoring cardiovascular risk factors, providing recommended vaccinations, and encouraging adoption of a healthy lifestyle.. In order to assess the late and long- term effects of gynecologic cancers, clinicians should comprehensively document the patient's history, conduct a thorough physical examination, and provide any necessary imaging and/or laboratory testing. All patients, whether sexually active or not, should be asked about genitourinary symptoms, including vulvovaginal dryness. Referral to appropriate specialty providers (eg, physical therapy, pelvic floor therapy, sexual therapy, psychotherapy) is recommended. As most treatments for gynecologic cancers will cause sexual dysfunction, early menopause, and infertility, special attention to the resultant medical and psychosocial implications is needed.. Post- radiation use of vaginal dilators and moisturizers is recommended. Local vaginal estrogen may be considered if symptomatic.. For treatment- related menopause, hormone therapy should be considered.. Communication and coordination with all clinicians involved in the care of survivors, including primary care clinicians, is critical. Providing cancer survivors with a summary of their treatment and recommendations for follow- up is recommended.. Additional Guidance. NCCN Guidelines for Distress Management NCCN Guidelines for Smoking Cessation NCCN Guidelines for Survivorship. Note: All recommendations are category 2A unless otherwise indicated.. # \*Pelvic sidewall is defined as the muscle, fascia, neurovascular structures, or skeletal portions of the bony pelvis. On rectal examination, there is no cancer- free space between the tumor and pelvic sidewall.. #	None	None	None
9b57457d9a91476bb85b77293e07e5d5	NCCN 临床实践指南	阴道癌31-55	# # Discussion. This discussion corresponds to the NCCN Guidelines for Vaginal Cancer (V.2.2025). Last updated on August 8, 2024.. Systemic Therapy for Recurrent or Metastatic Vaginal Cancer. 13. First- Line Systemic Therapy Options. 13. Second- Line/Subsequent Systemic Therapy Options. 15. Principles of Radiation Therapy. 18. Radiation Treatment Planning. 18. Brachytherapy. 19. External Beam Radiation Therapy/Intensity- Modulated Radiation Therapy. 20. External Beam Boost. 21. Reirradiation. 21. Concurrent Chemoradiation. 22. Normal Tissue Considerations. 22. Drug Reactions. 23. Gynecologic Survivorship. 23. Best Supportive Care. 24. Summary. 24. References. 25. Table of Contents. # National Comprehensive NCCN Guidelines Version 3.2025 NCCN Cancer Network. Overview. Vaginal cancer is a rare gynecologic malignancy representing . Persistent infection with high- risk HPV types has been detected in . Since patients with previous cervical carcinoma have a substantial risk of developing vaginal carcinoma, presumably because these sites share exposure and/or susceptibility to endogenous or exogenous carcinogenic stimuli, epidemiologic risk factors associated with cervical cancer are also shared risk factors for vaginal cancer that include a history of smoking, parity, oral contraceptive use, early age of onset of coitus, larger number of sexual partners, history of sexually transmitted disease, certain autoimmune diseases, and chronic immunosuppression. Smoking cessation should be advised in patients who current smoke, and patients who formerly smoked should continue to avoid smoking (see the NCCN Guidelines for Smoking Cessation and . In 2020, the World Health Organization (WHO) updated the Female Genital Tumors classification and recommends distinguishing between HPV- associated and HPV- independent SCC of the vagina. The majority of vaginal SCCs are HPV- associated with a non- keratinizing morphology and are in the proximal or intermediate third (Müllerian) portion of the vagina. Distal SCCs, also known as introitus carcinoma and that stem from the urogenital sinus, generally lack HPV association and are often keratinizing SCCs. WHO recommends that for vaginal carcinomas, molecular analyses (ie, HPV detection in situ) are not indicated for the diagnostic evaluation.. The NCCN Vaginal Cancer Guidelines subcommittee acknowledges that the 2020 version of the WHO classification discussed the integration of the immunohistochemical (IHC) and molecular profiles that has led to a better. # classification system that is now adapted in the 2020 WHO Classification of Female Genital Tumors.. Regardless of cancer subtype and HPV infection status, primary treatment with curative intent for patients with vaginal cancer typically consists of radiation, surgery, chemoradiation, or a combination of these treatments; options vary by cancer stage. By definition, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines. Guidelines Update Methodology. The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.. Literature Search Criteria. Prior to the development of this version of the NCCN Guidelines. The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase 2; Clinical Trial, Phase 3; Clinical Trial, Phase 4; Guideline; Randomized Controlled Trial; Meta- Analysis; Multi- center studies; Systematic Reviews; and Validation Studies.. The data from key PubMed articles as well as articles from additional sources deemed as relevant to these Guidelines as discussed by the Panel during the Guidelines development have been included in this version of the Discussion section. Recommendations for which high- level evidence is lacking are based on the Panel's review of lower- level evidence and expert opinion.. Sensitive/Inclusive Language Usage. NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation. NCCN Guidelines endeavor to use language that is person- first; not stigmatizing; anti- racist, anti- classist, anti- misogynist, anti- ageist, anti- ableist, and anti- weight- biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non- gendered language, instead focusing on organ- specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.. Diagnosis and Workup. The most significant signs of vaginal cancer are bleeding, discharge, and urine retention and rectal symptoms such as constipation or blood in the stool. However, up to . # cervical examination and pap smear, colposcopy, or vulvar screening. Cofactors for vaginal cancer include immunosuppression, prior hysterectomy, and cigarette smoking. As a synchronous or metachronous tumor, vaginal cancer is frequently found in combination with cervical cancer. With a rare cancer like vaginal cancer, it is important to consider synchronous anorectal, cervical, endometrial, or vulvar primary with vaginal metastasis or extension, or recurrent disease from prior malignancy. Only a minority of vaginal cancers originate in the vagina. The remaining are generally metastatic from other sites. If vaginal lesion(s) involve the cervix or vulva, they are not considered vaginal cancer, and the appropriate treatment algorithm should be consulted. Biopsy remains the gold standard for diagnosing vaginal cancer. This can be best accomplished by an examination under anesthesia (EUA) and should include inspection of the vaginal fornices and biopsies of the cervix.. Workup for these patients with suspicious symptoms includes history and physical, pelvic exam (bimanual and rectovaginal), cervical evaluation and pap smear, colposcopy, vulvar evaluation, imaging, complete blood count (CBC), comprehensive metabolic panel (CMP), and testing for HPV and human immunodeficiency virus (HIV) in select patients. Due to diverse diagnosis of vaginal cancer, multidisciplinary expertise is recommended.. For detailed surgical staging and imaging recommendations by stage and planned treatment approach, see "Principles of Surgery, Principles of Imaging and Staging" in the algorithm. Smoking cessation and counseling, as well as HIV testing (especially in younger patients), are recommended.. Principles of Staging and Surgery. Clinical Staging. Vaginal cancer is primarily staged clinically like cervical cancer. The staging is based on the results of a physical exam, biopsy, and imaging tests performed before treatment selection using 2009 International. Federation of Gynecology and Obstetrics (FIGO) staging. The FIGO Gynecologic Oncology Committee also recommends that imaging should be used to better define tumor volume and extension of disease wherever available.. The staging definition according to FIGO 2009 staging is as follows: stage IA, the cancer is only in the vagina and is . Principles of Pathology. Pathologic Assessment. The College of American Pathologists (CAP) protocol for primary carcinoma of the vagina is a useful guide for the examination of resection specimens: femalereproductive- vagina- resection- 20- 4201. pdf.. This CAP protocol was revised in February 2020 and reflects recent updates in AJCC staging (ie, AJCC Cancer Staging Manual, . # according to CAP protocol for vaginal carcinoma. Important elements of primary tumor evaluation include the procedure type (ie, biopsy, local excision, partial vaginectomy, radical vaginectomy, trachelectomy); tumor site (upper, middle, or lower third); tumor size to include greatest dimension and additional two dimensions; histologic types that include HPV- associated SCC, HPV- independent SCC, HPV- associated vaginal adenocarcinoma, endometrioid carcinoma, and clear cell carcinoma; histologic grade (well, moderately, and poorly differentiated); lymphovascular space invasion (LVS); precursor lesions (ValN/squamous intraepithelial lesion [SIL]); determination of primary site; and surgical resection margin status.. General Principles. Vaginal carcinomas account for . Other types of vaginal carcinomas are very rare and include HPV- associated vaginal adenocarcinoma, endometrioid carcinoma, clear cell carcinoma, mucinous carcinoma (gastric and intestinal types), mesonephric adenocarcinoma, carcinosarcoma, mixed tumor of the vagina, adenocarcinoma of skene gland origin, adenosquamous carcinoma, adenoid basal carcinoma, neuroendocrine carcinomas, adenosarcoma, and germ cell tumors.. Next- generation sequencing (NGS) and comprehensive molecular profiling as determined by a U.S. Food and Drug Administration (FDA)- approved assay, or validated test performed in a Clinical Laboratory Improvement Amendments (CLIA)- certified laboratory is recommended for the following biomarkers: programmed cell death ligand 1 (PD- L1), microsatellite instability- high (MSI- H), tumor mutational burden (TMB), NTRK fusion, RET fusion, HER2 IHC or fluorescence in situ hybridization (FISH), and p53 IHC.. Prognostic and Predictive Biomarkers. The data cited within this section are primarily for cervical cancer and have been generalized to vaginal cancer. Because of the uncommon nature of vaginal cancer its similarities to cervical cancer, many of the treatment recommendations are derived from those for cervical cancer. Several biomarker- based immune- oncologic agents have been added from the NCCN Guidelines for Cervical Cancer to the NCCN Guidelines for Vaginal Cancer in the management of vaginal cancer (see Systemic Therapy Recommendations) and the NCCN Panel recommends. # National Comprehensive NCCN Guidelines Version 3.2025 NCCN Cancer Network. comprehensive molecular profiling as determined by an FDA- approved assay, or a validated test performed in a CLIA- certified laboratory.. PD-L1. The NCCN Panel recommends PD- L1 testing by an FDA- approved assay, or a validated test performed in a CLIA- certified laboratory for patients with recurrent, progressive, or metastatic disease to help guide better treatment options in first- line, second- line, or subsequent therapy.15. The FDA approved pembrolizumab plus chemotherapy, with or without bevacizumab, for patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD- L1 (combined positive score [CPS] ≥1) based on the KEYNOTE- 826 study.15 The NCCN Panel also recommends this regimen as a preferred regimen (category 1) for first- line therapy for recurrent or metastatic vaginal cancer.. KEYNOTE- 158 is another phase 2 basket study that evaluated the use of pembrolizumab in multiple cancer types including cervical cancer.16 The interim results from previously treated patients with advanced cervical cancer demonstrated the durable antitumor activity and manageable safety of pembrolizumab monotherapy. Out of 98 patients treated, 82 (83.7%) had PD- L1- positive tumors (CPS ≥1), with 77 having previously received one or more lines of chemotherapy for recurrent or metastatic disease. The primary endpoint, overall response rate (ORR), was 12.2% (95% CI, 6.5%- 20.4%), with three complete and nine partial responses (PRs). All 12 responses were in patients with PD- L1- positive tumors, for an ORR of 14.6% (95% CI, 7.8%- 24.2%); 14.3% (95% CI, 7.4%- 24.1%) of these responses were in those who had received one or more lines of chemotherapy for recurrent or metastatic disease. Based on these results, the FDA granted accelerated approval of pembrolizumab for patients with advanced PD- L1- positive cervical cancer who experienced progression during or after chemotherapy. NCCN also recommends . Nivolumab, a checkpoint inhibitor, has shown efficacy in patients with recurrent/metastatic cervical cancer who received at least one prior chemotherapy regimen. The Checkmate- 358, phase 1- 2, single- arm trial evaluated 19 patients with advanced, pretreated, HPV- associated cervical tumors.17 The ORR was 26.3% (95% CI, 9.1%- 51.2%) and disease control rate was 68.4% (95% CI, 43.4%- 87.4%). The 12- month overall survival (OS) rate was 77.5% (95% CI, 50.5%- 91.0%). The phase 2 trial (NRG- GY002) showed low anti- tumor activity of nivolumab in 25 patients with pretreated persistent/recurrent cervical cancer; 36% of the patients had stable disease (90% CI, 20.2%- 54.4%) as best response with median duration of 5.7 months, and progression- free survival (PFS) and OS at 6 months was 16% and 78.4%, respectively.18,19. Based on the NCCN Guidelines for Cervical Cancer, the Panel continues to recommend nivolumab in the same category of "useful in certain circumstances" for second- line or subsequent therapy for vaginal cancer.. Mismatch Repair/Microsatellite Instability. Tumors with mismatch repair deficiency (dMMR) represent approximately 2% to 4% of all diagnosed cancers and have a unique genetic signature, harboring 10 to 100 times more mutations than mismatch repair- proficient tumors. These dMMR tumors have MSI- H and harbor 100 to 1000 somatic mutations that encode potential neoantigens and are likely to be immunogenic. The KEYNOTE- 158 trial included patients with non- colorectal MSI- H/dMMR tumors in cohort K and the results demonstrated the clinical benefit of pembrolizumab in patients with previously treated unresectable or metastatic MSI- H/dMMR non- colorectal cancer.20. # Of 233 patients with MSI- H/dMMR advanced non- colorectal cancer whose disease progressed on prior therapy with pembrolizumab, the ORR was . TMB. TMB, defined as the total number of somatic mutations per coding area of a tumor genome, is a measure of all non- synonymous coding mutations in a tumor exome; highly mutated tumors can produce many neoantigens, some of which might increase T- cell reactivity. High TMB has been demonstrated to be associated with treatment response to pembrolizumab.. In a prospective analysis of the multi- cohort, open- label, non- randomized phase 2 KEYNOTE- 158 study,21 the association between antitumor activity and tissue TMB (tTMB) in patients who received at least one dose of pembrolizumab was assessed and tTMB- high status identified a subgroup of patients who could have a robust tumor response to pembrolizumab monotherapy. Out of 790 TMB evaluable, treated patients enrolled by at least 26 weeks before data cutoff, 102 (13%) patients were tTMB- high (<10 mutations per megabase [mut/Mb]) and 688 (87%) patients had non- tTMB- high status. With a median study follow- up of 37.1 months, the objective responses were observed in 30 (29%; 95% CI, 21- 39) of 102 patients in the tTMB- high group and 43 (6%; 95% CI; 5- 8) of 688 patients in the non- tTMB- high group. Cervical cancer had the highest proportion of patients with tTMB- high status (21%) and objective responses were observed in 5 of 16 patients with . The NCCN Panel recommends TMB testing by an FDA- approved assay, or a validated test performed in a CLIA- certified laboratory, and recommends pembrolizumab as a preferred regimen for the treatment of patients with TMB- H [≥10 mut/Mb] tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options (second- line or subsequent therapy).. NTRK Gene Fusion. NTRK gene fusions are found in about . In another primary analysis, the efficacy and safety of larotrectinib was reported in 55 patients enrolled in three clinical studies who had locally advanced or metastatic tumors with NTRK gene fusions and had progressed on standard chemotherapy received previously. The three clinical trials included a phase 1 dose- finding study in adults, a phase 1-. # National Comprehensive NCCN Guidelines Version 3.2025 NCCN Cancer Network. 2 dose- finding study in a pediatric population, and a phase 2, single- arm, basket trial.24 The ORR of larotrectinib in these patients was . HER2. HER2 HER2 expression is observed in a wide range of solid tumors and is an established prognostic biomarker for breast, gastric, and colorectal cancers. Cervical cancer has shown an HER2 positivity rate of approximately . The DESTINY- PanTumor02 is an open- label, multicenter, phase 2 trial that evaluated trastuzumab deruxtecan (T- DXd) in 267 patients with HER2- expressing (IHC . RET Gene Fusion. RET gene fusion most commonly occur in thyroid and non- small cell lung cancers and are observed in . # National Comprehensive NCCN Guidelines Version 3.2025 NCCN Cancer Network. HPV Status/p16. High p16 expression was associated with long- term survival in individuals AFAB with primary carcinoma of the vagina, but the only independent predictors for survival were tumor size and histopathologic grade. The p16 and Ki- 67 expression might be useful in tumor grading, and p16 expression can be used as a marker for HPV positivity.35 The p16 marker has a significant prognostic value in vaginal cancers across all tumor stages. In a retrospective chart review from 1997 to . Patients with vaginal cancer . p53 IHC. p53 mutations are common in HPV- negative malignancies in older women, and they are linked to an increased risk of mortality.7 In vulvar cancer, p16 and p53 IHC have established prognostic value, stratifying patients into three groups based on the HPV and TP53 mutation status of the tumor. p53 positivity is associated with poor prognosis and significantly increased recurrence and disease- specific mortality in gynecologic cancers. 39 The TP53 mutations are present in typical keratinizing carcinomas and precursor lesions with elevated risk for . Primary Treatment. Primary TreatmentMost of the trial data cited within this section are primarily for cervical cancer that has been generalized to vaginal cancer.. Invasive (Stage I-IVA) Disease. The primary treatment for early- stage vaginal cancer is radiation therapy (RT) and surgical resection. For the majority of vaginal cancers, radiation is used rather than surgery as primary treatment due to improved organ preservation. For invasive stage I cancer, RT is the preferred regimen with only intracavitary brachytherapy in select favorable patients with small lesions . Another option for patients with invasive stage I disease is surgical resection with or without lymph node assessment only for select patients. Pelvic lymph nodes need to be assessed for proximal lesions involving the upper two thirds of the vagina, while inguinal lymph nodes should be assessed for distal lesions involving the lower one- third of the vagina. Surgery is only recommended if a complete resection with clear margins is feasible without excessive morbidity and with likelihood that no adjuvant RT would be required. Vaginectomy may be considered for small lesions for which margins are likely to be negative. For microscopic lesions at the top of the vagina, upper vaginectomy . # cm). Every effort should be made to obtain negative margins. With postoperative risk factor of close or positive margin(s) for invasive disease or positive lymph nodes, adjuvant RT or chemoradiation and/or brachytherapy is recommended. The management of positive margins for HSIL should be individualized.. For invasive stage II- IVA disease, the preferred modality for definitive management is platinum- based chemoradiation with brachytherapy. Concurrent chemotherapy has been shown in many series to improve outcomes and is often used in stage II- IV disease. Concurrent platinum- containing chemotherapy with EBRT utilizes cisplatin as a single agent (or carboplatin if cisplatin intolerant). EBRT with brachytherapy is also a recommended regimen for patients with stage II- IVA disease. The addition of brachytherapy to external beam is preferred as the combination has been shown to improve disease control.. For more information on the important phase 3 clinical trials underpinning treatment recommendations for cervical cancer that were adapted for vaginal cancer, see the NCCN Clinical Guidelines for Cervical Cancer.. Surveillance. The Panel agrees with the new Society of Gynecologic Oncology (SGO) recommendations for post- treatment surveillance.41 The recommended surveillance is based on the patient's risk for recurrence and personal preferences. History and physical examinations are recommended every 3 to 6 months for 2 years, every 6 to 12 months for another 3 to 5 years, and then annually.. Many of the recommendations for staging and follow- up of primary vaginal cancer are derived from cervical cancer and they have generalizability to vaginal cancer due to similar tumor biology. The radiation guidance and recommendations for cervical cancer can be extrapolated to vaginal cancer and the principles of post- chemoradiation tumor response . Annual cervical/vaginal cytology tests can be considered as indicated for detection of lower genital tract dysplasia (eg, for those who have had fertility- sparing surgery), which includes HPV testing. Some clinicians have suggested that rigorous cytology follow- up is not warranted because of studies stating that Pap smears did not detect recurrences in patients with stage I or II cervical cancer who were asymptomatic after treatment.41,43,44 Noting the inherent differences between these patients and the general screening population, the Panel does not recommend workup of low- grade squamous dysplasia detected during surveillance, but suggests that patients should follow up with a provider with specific expertise in this area. It is important to emphasize good clinical evaluation and a high index of suspicion, because the detection rate of recurrent genital tract cancer is low using cervical and vaginal cytology alone.45. Many other tests remain optional based on clinical indications, such as semiannual CBCs, blood urea nitrogen (BUN), and serum creatinine determinations. Patients with persistent or recurrent disease need to be evaluated using additional imaging studies as clinically indicated, biopsy with or without EUA, and surgical exploration in selected cases followed by therapy for relapse (see Therapy for Relapse).46 Comprehensive molecular profiling as determined by FDA- approved assay or a validated test performed in a CLIA- certified laboratory can be considered for better selection of systemic therapy. If tissue biopsy of metastatic site is not feasible or tissue is not available, comprehensive genomic profiling via a validated plasma circulating tumor DNA (ctDNA) assay can be considered.. # National Comprehensive NCCN Guidelines Version 3.2025 NCCN Cancer Network. Education of patients regarding symptoms suggestive of recurrence is recommended (eg, vaginal discharge; weight loss; anorexia; pain in the pelvis, hips, back, or legs; persistent coughing). Patients should also be counseled on healthy lifestyle, obesity, nutrition, exercise, sexual health (including vaginal dilator use and lubricants/molstarizers), hormone replacement therapy (local estrogen and hormone therapy for menopause), and potential long- term and late effects of treatment. Smoking cessation and abstinence should be encouraged.41 See the NCCN Guidelines for Survivorship, the NCCN Guidelines for Smoking Cessation, and . Cervical cancer survivors are at risk for second cancers such as vaginal cancer.47 Data suggest that patients who undergo RT for pelvic cancers are at risk for radiation- induced second cancers, especially at radiated sites near the cervix (eg, colon, rectum/anus, urinary bladder); therefore, careful surveillance is appropriate for these patients.48,49. Therapy for Relapse. Recurrences should be proven by biopsy before proceeding to treatment planning for recurrent disease.. Locoregional Recurrence. For patients who experience locoregional recurrences who have not undergone previous RT or who experience recurrences outside of the previously treated RT field, therapy for relapse includes tumor- directed EBRT and/or brachytherapy or EBRT with concurrent platinum- containing chemotherapy and/or brachytherapy. Typically, the chemoradiation for recurrence uses cisplatin as a single agent or carboplatin (if cisplatin intolerant).50,51 However, in those patients who have relapsed soon after completing initial chemoradiation with these regimens, other systemic therapy options might be considered or best supportive care could be offered (see NCCN Guidelines for Palliative Care).. For patients with locoregional recurrences with prior intracavitary brachytherapy only, individualized EBRT with/without systemic therapy and/or interstitial brachytherapy is recommended. Concurrent surgery is only recommended if a complete resection with clear margins is feasible without excessive morbidity.. Patients with central pelvic recurrent disease after prior EBRT and/or brachytherapy should be evaluated for pelvic exenteration with (or without) intraoperative RT (IORT), although IORT is category 3 for both cervical and vaginal cancers.52- 59 Surgical mortality is generally . For patients with noncentral recurrent disease, options include systemic therapy or resection with (or without) IORT (category 3 for IORT), reirradiation or best supportive care (see the NCCN Guidelines for Palliative Care), or participation in a clinical trial.. Patients who experience recurrence after second- line definitive therapy, either surgery or RT, have a poor prognosis. They can be treated with systemic therapy or best supportive care or can be enrolled in a clinical trial.. Stage IVB or Recurrent Distant Metastatic Disease. Limited Disease. For stage IVB patients or patients with recurrent metastases with limited disease, systemic therapy is one of the options. Comprehensive molecular profiling as determined by FDA- approved assay, or a validated test performed in a CLIA- certified laboratory can be considered for better. # selection of systemic therapy. Local treatment of the primary disease by chemoradiation with/without brachytherapy can be considered. Local treatment of metastases can also be considered that includes surgery for select patients or individualized EBRT or other local ablative therapies such as radiofrequency ablation, cryoablation, or stereotactic body RT (SBRT).. Disseminated Disease. Patients who develop distant metastases, either at initial presentation or at relapse, are rarely curable. Comprehensive molecular profiling as determined by FDA- approved assay can be considered for better selection of systemic therapy. For patients with disseminated disease, systemic therapy with/without palliative RT and best supportive care are recommended. Patients who may benefit from aggressive local therapy for oligometastatic disease include those with nodal, lung, liver, or bone metastases.63,64. The palliation of pelvic recurrences in heavily irradiated sites that are not amenable to local pain control techniques or to surgical resection is difficult.65 These sites are generally not responsive to chemotherapy. Adequately palliating the complications of pain and fistulae from these recurrences is clinically challenging.. ( overview). However, short courses of RT may provide symptomatic relief to patients with bone metastases, painful para- aortic nodes, or supraclavicular adenopathy.66- 68 For most other patients with distant metastases, an appropriate approach is a clinical trial, chemotherapy, or best supportive care (see NCCN Guidelines for Palliative Care).. Systemic Therapy Recommendations. The data cited within this section are primarily for cervical cancer and have been generalized to vaginal cancer. Because of the uncommon . Chemoradiation for Locally Advanced Vaginal Cancer. Concurrent chemoradiation, using platinum- containing chemotherapy (cisplatin alone [preferred]), is the treatment of choice for stages IB3, II, III, and IVA disease based on results from randomized clinical trials. These trials have shown that the use of concurrent chemoradiation results in a . # National Comprehensive NCCN Guidelines Version 3.2025 NCCN Cancer Network. National Comprehensive NCCN Guidelines Version 3.2025 NCCN Cancer NetworkConcurrent arms and the OS was not significant between the arms, the RT plus concurrent chemotherapy arm showed the least locoregional recurrence and the highest 5- year disease- free survival (DFS) when compared with the other arms. In particular, the difference in DFS and OS rate was highly significant when comparing the concurrent chemoradiation arm with the RT- only arm . The NCCN Panel has noted for all chemoradiation agents that the cost and toxicity profiles of these radiosensitizing agents should be considered when selecting an appropriate regimen for treatment and have strongly expressed that this is especially critical when these regimens are being used for extended- field RT where toxicities may be more severe.. Systemic Therapy for Recurrent or Metastatic Vaginal Cancer. Systemic therapy with or without radiation forms the basis of treatment of patients with recurrent or metastatic disease.. First-Line Systemic Therapy Options. Preferred Regimens. Pembrolizumab Plus Chemotherapy with or without Bevacizumab as First- Line Therapy. First- Line Systemic Therapy OptionsPreferred RegimensPembrolizumab Plus Chemotherapy with or without Bevacizumab as First- Line TherapyThe NCCN Guidelines for Cervical Cancer include two immunotherapy- based regimens as preferred, first- line therapy options for the treatment of PD- L1- positive recurrent or metastatic cancer, and that recommendation is extrapolated to vaginal cancer management as well. Pembrolizumab combined with chemotherapy with or without bevacizumab regimens is a preferred treatment option based on the results of the KEYNOTE- 826 study.15 In the primary analysis of the phase 3, KEYNOTE- 826 trial, which enrolled 617 patients (548 with PD- L1- positive CPS ≥1 tumors; 317 patients with CPS ≥10) with previously untreated persistent, recurrent, or metastatic cervical cancer, the addition of pembrolizumab to chemotherapy with or without bevacizumab improved PFS and OS versus the placebo group (PFS, 10.4 vs. 8.2 months, respectively; HR, 0.65; 95% CI, 0.53- 0.79; . # National Comprehensive NCCN Guidelines Version 3.2025 NCCN Cancer Network. of 28.6 and 10.5 months versus 16.5 and 8.2 months in the pembrolizumab plus chemotherapy arm versus the placebo plus chemotherapy arm, respectively (HR, 0.60; 95% CI, 0.49- 0.74; . Platinum- based chemotherapy (cisplatin or carboplatin)/paclitaxel with bevacizumab has been extensively investigated in clinical studies and is listed in the NCCN Guidelines as a preferred, first- line treatment option for patients with recurrent/metastatic vaginal cancer (based on the GOG 240 trial).. A randomized phase 3 trial (GOG 240) studied the addition of bevacizumab to combination chemotherapy regimens (cisplatin/paclitaxel/bevacizumab or topotecan/paclitaxel/bevacizumab) in 452 patients in the first- line setting of metastatic, persistent, or recurrent cervical cancer. Analysis of pooled data from the two chemotherapy regimens revealed significant improvements in OS among patients receiving bevacizumab (16.8 vs. 13.3 months; . The published data from a phase 3 randomized trial (JCOG0505) suggested that carboplatin/paclitaxel was non- inferior to cisplatin/paclitaxel in 253 patients with metastatic or recurrent cervical cancer.. A systematic review of the data on cisplatin/paclitaxel and carboplatin/paclitaxel regimens also suggested that lower toxicity carboplatin- based regimens appear to be an equally effective alternative to cisplatin- containing regimens for treating recurrent or metastatic cervical cancer.. Other Recommended Regimens. Cisplatin is generally regarded as the most active agent and is recommended as a first- line single- agent chemotherapy option for recurrent or metastatic vaginal cancer; reported response rates for cervical cancer are approximately 20% to 30%, with an occasional CR.. Cisplatin/paclitaxel, carboplatin/paclitaxel, topotecan/paclitaxel/bevacizumab, topotecan/paclitaxel, and. # National Comprehensive NCCN Guidelines Version 3.2025 NCCN Cancer Network. cisplatin/topotecan are also recommended as appropriate alternate options under the other recommended regimens category.84,93,99- 102 A randomized phase 3 study (GOG 169) in 264 patients compared cisplatin/paclitaxel versus cisplatin alone for metastatic, recurrent, or persistent cervical cancer. Patients receiving the 2- drug combination had a higher response rate . A phase 3 trial (GOG 204) compared four cisplatin- doublet regimens (cisplatin/paclitaxel, cisplatin/topotecan, cisplatin/gemcitabine, and cisplatin/ vinorelbine) in 513 patients with advanced metastatic or recurrent cervical cancer.102 The trial was closed early based on futility analysis, because it was apparent that the cisplatin/topotecan, cisplatin/gemcitabine, and cisplatin/ vinorelbine regimens were not superior to the control arm of cisplatin/paclitaxel. No significant differences in OS were seen; however, the trends for response rate, PFS, and OS (12.9 vs. 10 months) suggest that cisplatin/paclitaxel is superior to the other regimens. Cisplatin/paclitaxel was associated with less thrombocytopenia and anemia (but with more nausea, vomiting, infection, and alopecia) than the other regimens. While topotecan/paclitaxel was not shown to be . Based on previous studies, cisplatin/paclitaxel and carboplatin/paclitaxel have become the most widely used systemic regimens for metastatic or recurrent cervical cancer and this is also recommended for vaginal cancer. However, for patients who may not be candidates for taxanes, cisplatin/topotecan remains a reasonable alternative regimen.99. Second-Line/Subsequent Systemic Therapy Options. Immunotherapy as Preferred, Second- Line/Subsequent Therapy Increasingly available data from several prospective studies have demonstrated the effectiveness of immunotherapies or specific biomarker- based therapies in the setting of disease progression and have significantly transformed the management of cervical cancer. In addition, many biomarker- specific therapies have demonstrated meaningful clinical efficacy and durability regardless of the underlying tumor type leading to an increase in tumor- agnostic regulatory approvals.. Pembrolizumab as a Preferred, Second-Line/Subsequent Therapy. Pembrolizumab is an FDA- approved therapy for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy for PD- L1- positive tumors (CPS ≥1). It is also approved for unresectable or metastatic MSI- H/dMMR or TMB- H solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. In the NCCN Guidelines, pembrolizumab monotherapy is the preferred, second- line therapy option for recurrent/metastatic MSI- H/dMMR or TMB- H or PD- L1- positive tumors based on the results from KEYNOTE- 028 (phase 1b) and KEYNOTE- 158 (phase 2) trials.21,104,105. # National Comprehensive NCCN Guidelines Version 3.2025 NCCN Cancer Network. Cemiplimab as a Preferred, Second-Line/Subsequent Therapy. Cemiplimab as a Preferred, Second- Line/Subsequent TherapyCemiplimab is a PD- 1- blocking monoclonal activity shown to have anti- tumor activity against cervical cancer. The phase 3, randomized, Empower- Cervical- 1 clinical trial evaluated the efficacy of cemiplimab or investigator's choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) in patients with recurrent or metastatic cervical cancer who have progressed on prior therapy. The trial enrolled 608 patients, who had previously received one or more lines of systemic therapy for recurrence, and they were randomized to either receive cemiplimab or chemotherapy. The median OS and PFS were significantly longer in the cemiplimab arm than in the control arm (12 vs. 8.5 months; HR, 0.69; 95% CI, 0.56- 0.84; . In version 1.2025 of the NCCN Guidelines for Vaginal Cancer, cemiplimab was added as a preferred, second line/subsequent- therapy option.. Chemotherapy as Other Recommended, Second-Line/Subsequent Therapy. Other recommended agents that have shown responses or prolongation of PFS and may be useful as second- line therapy include bevacizumab,102 albumin- bound paclitaxel (ie, nab- paclitaxel),108 docetaxel,109 fluorouracil,110 gemcitabine,111 ifosfamide,112,113 irinotecan,114 mitomycin,115 pemetrexed,116 topotecan,117,118 and vinorelbine.119. Tisotumab vedotin- tftv is also recommended for second- line or subsequent therapy for recurrent or metastatic vaginal cancer based on the InnovaTV- 204 trial. This phase 2 single- arm study evaluated the efficacy of tisotumab vedotin- tftv in 102 patients with recurrent or metastatic cervical cancer who had progressed on previous systemic therapy. At the median follow- up of 10 months, the confirmed ORR was 24% (95% CI, 16- 33), which included a 7% CR and 17% PR, and the median DOR was 8.3 months (95% CI, 4.2- NR). Following the results from innovaTV- 201 and innovaTV- 204 trials that showed clinically meaningful and durable activity of tisotumab vedotin- tftv against pretreated recurrent/metastatic cervical cancer, the FDA granted accelerated approval for adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. The results from the phase 3, randomized, innovaTV- 301/ENGOT- cx12/GOG- 3057 trial were recently published at ESMO 2023. Among the 502 patients who were randomized (TV: 253; chemotherapy: 249); the TV arm had a 30% reduction in risk of death versus chemotherapy (HR, 0.70; 95% CI, 0.54- 0.89; . # 0.82]; . Biomarker-Directed, Useful in Certain Circumstances, Second-Line/Subsequent Therapy. The NCCN Guidelines for Vaginal Cancer have included a list of biomarkers with their associated targeted treatments as second- line/ subsequent therapies under "useful in certain circumstances" options. The Principles of Pathology section of the Guidelines provides recommendations for individual biomarkers that should be evaluated for targeted therapy.. Nivolumab for PD- L1- Positive Tumor. Nivolumab, a checkpoint inhibitor, has shown efficacy in patients with recurrent/metastatic cervical cancer who received at least one prior chemotherapy regimen. Based on Checkmate- 358 data (see Prognostic and Predictive Biomarkers section), this recommendation is part of the 1.2025 version of NCCN Guidelines for Vaginal Cancer.. Trastuzumab Deruxtecan for HER2- Positive Tumor. Another tumor- agnostic study evaluated the durability and clinically meaningful response of trastuzumab deruxtecan across multiple HER2- expressing (IHC . Based on the DESTINY- PanTumor02 trial (see Prognostic and Predictive Biomarkers section), Version 1.2025 of the NCCN Guidelines for Vaginal Cancer includes fam- trastuzumab deruxtecan- nxki as a category 2A, useful in certain circumstances, second- line/subsequent therapy option for HER2- positive tumors (IHC . Selpercatinib for RET Gene Fusion Tumor. Selpercatinib received tumor- agnostic approval by the FDA for patients with solid tumors with a RET gene fusion that has progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. The NCCN Panel recommends selpercatinib as a biomarker- directed second- line/subsequent therapy under useful in certain circumstances category for RET gene fusion- positive tumors given its efficacy in tumor- agnostic population. The NCCN Panel also specified that RET gene fusion testing may be considered for patients with vaginal cancer (see Prognostic and Predictive Biomarkers section).. TRK Inhibitors for NTRK Gene Fusion Tumor. In addition to selpercatinib, other targeted therapy regimens included in the NCCN Guidelines for Vaginal Cancer as biomarker- directed second- line/subsequent therapies that have been approved in a tumor- agnostic population are the TRK inhibitors, larotrectinib and entrectinib. Larotrectinib targets the TRK proteins that are encoded by the genes NTRK1, NTRK2, and NTRK3. NTRK gene fusions are found in about . # Principles of Radiation Therapy. RT is preferred in the management of vaginal cancer rather than surgery as primary treatment due to improved organ preservation. Preferred modalities for definitive management include either concurrent pelvic chemoradiation (platinum- based) and brachytherapy or EBRT and brachytherapy. The addition of brachytherapy to external beam is preferred as the combination has been shown to improve control. The overall treatment time should not extend beyond 8 weeks and treatment delays and interruptions need to be minimized.. The algorithm provides general RT dosage recommendations, which should not be interpreted as stand- alone recommendations because RT techniques and clinical judgment are an essential part of developing an appropriate treatment regimen.. Since vaginal cancer is rare, prospective trials of patients with vaginal cancer have not been feasible, and single- institutional reports of clinical outcomes spanning several decades have been the evidence for current treatment recommendations. The management of vaginal cancer is currently extrapolated from prospective studies of cervical cancer, due to their similarities in disease etiology.123 The radiation guidance and recommendations for cervical cancer can be extrapolated to vaginal cancer and the principles of post- chemoradiation tumor response evaluation are largely analogous.42. Radiation Treatment Planning. Technologic advances in imaging, computer treatment planning systems, and linear accelerator technology have enabled the more precise delivery of radiation doses to the pelvis. However, physical accuracy of dose delivery must be matched to a clear understanding of tumor extent, potential pathways of spread, and historical patterns of locoregional recurrence to avoid geographic misses.. Pelvic MRI with and without IV contrast and vaginal gel to assess local disease extent is the preferred workup. The neck/chest/abdomen/pelvis/ groin FDG- PET/CT is preferred to evaluate metastatic disease. The chest/abdomen/pelvis CT is also recommended. Other initial imaging should be based on symptomatology and clinical concern for metastatic disease.. CT- based treatment planning with conformal blocking and dosimetry is considered standard care for EBRT. As with cervical cancer, FIGO encourages the use of advanced imaging modalities (CT, MRI, and PET) to guide therapy, although in resource- poor settings the imaging findings may not be used to determine the stage to preserve the FIGO system.. In patients who are not surgically staged, FDG- PET imaging is useful to help define the nodal volume of coverage and may be useful postoperatively to confirm removal of abnormal nodes.124 FDG- PET/CT imaging is preferred at 3 to 4 months after RT. MRI is also needed if FDG- PET/CT is difficult to obtain or needed for clarification or exam findings. Repeating imaging is also recommended if clinically indicated. IMRT technique is preferred to minimize toxicities in definitive treatment of the pelvis with or without para- aortic treatment. Adaptive planning with image- guided RT (IGRT), especially if IMRT is utilized, is encouraged. Brachytherapy is an important component of definitive therapy in patients with vaginal cancer, although brachytherapy alone is not recommended for most tumors, even early- stage, due to a high recurrence rate.125 Brachytherapy is typically combined with EBRT in an integrated treatment plan. SBRT allows delivery of very high doses of focused EBRT and may be applied to isolated metastatic sites.126,127 Local ablative therapies such as SBRT are recommended for patients with stage IVB disease or patients with recurrent distant metastases, with limited disease.. Concepts regarding the gross tumor volume (GTV), clinical target volume (CTV), planning target volume (PTV), organs at risk (OARs), and. # dose- volume histogram (DVH) have been defined for use in image- guided adaptive brachytherapy (IGABT).128- 129. There are increasing efforts to use and standardize image- based volumetric brachytherapy approaches using MRI, CT, or ultrasound. International validation efforts with different studies including the EMBRACE- I study, which is a benchmark study that represents a positive breakthrough in the treatment of locally advanced cervical cancer, are underway.130- 136. Brachytherapy. Brachytherapy is encouraged for all suitable patients with primary vaginal cancer. Orton et al137 evaluated the impact of brachytherapy on survival in patients with vaginal cancer who received radiotherapy. Based on the two retrospective cohorts (women who received EBRT alone and those who received brachytherapy [alone or in combination of EBRT]), median OS for patients receiving EBRT alone was 3.6 years (95% CI, 3.0- 4.2 years) versus 6 years. Cox proportional hazard model revealed decreased risk of death among patients who received brachytherapy in the matched cohort (HR, 0.77; 95% CI, 0.68- 0.86). Brachytherapy reduced risk of death among patients in all stage groups, including 1 year (95% CI, 5.2- 7.2 years) for patients receiving brachytherapy . The choice of the brachytherapy modality is based on the residual tumor thickness following pelvic RT. For residual disease measuring . In a large retrospective multicenter study, IGABT for primary vaginal cancer demonstrated a high local control with acceptable morbidity. The results from this study illustrated that IGABT could play an important role in the treatment of vaginal cancer. This study assessed outcomes following the nowadays standing treatment for primary vaginal cancer with radio(chemo)therapy and IGABT in a multicenter patient cohort. Retrospective data collection included tumor and treatment characteristics of patients treated with CT- MRI- assisted- based IGABT. At a median follow- up of 29 months (interquartile range [IQR], 25- 57), 2- and 5- year local control were 86% and 83%; DFS was 73% and 66%, and OS was 79% and 68%, respectively. Univariate analysis showed improved local control in patients with T2- T4 tumors if . Ferrigno et al published a report on the comparative outcome of patients with cervical cancer treated with LDR and HDR brachytherapy.142 In this retrospective analysis, 190 patients were treated with LDR brachytherapy, and 118 patients were treated with HDR brachytherapy.. The OS, DFS, and local control at 5 years were better in the LDR group (69% vs. 55%, . # National Comprehensive NCCN Guidelines Version 3.2025 NCCN Cancer Network. between the two groups. For clinical stage III, although OS and DFS at 5 years were better in the LDR than in the HDR group . Thus, similar outcomes were observed for patients who were in stages I and II treated with either HDR or LDR brachytherapy. Although lower OS and DFS were observed for patients who were stage III treated with HDR brachytherapy, fewer late rectal complications were observed in this group. These findings were probably the result of the relatively low HDR brachytherapy dose delivered at Point A.. For very- early- stage vaginal cancers . Either less fractionated or more fractionated regimens may be used, such as 7 Gy x 3 fx or 3 Gy x 9 to 10 fx. Modulation of dose takes into consideration tumor location, extent of disease, response to EBRT, brachytherapy technique (intracavitary or interstitial), relationship to surrounding OARs, as well as other factors. The HDR data are more varied, with total doses in the range of 50 to 60 Gy EQD2. The appropriate dose for each case needs to be individualized.. External Beam Radiation Therapy/Intensity-Modulated Radiation Therapy. Definitive RT, which consists of a combination of EBRT and brachytherapy, has been shown to yield excellent outcomes.125 The advantage of RT is the preservation of the vagina as well as other organs.. Brachytherapy alone is not recommended for most tumors, even earlystage, due to a high recurrence rate.. Frank et al125 evaluated the outcomes and describe clinical treatment guidelines for patients with vaginal cancer treated with definitive RT. In this single- institution report, a total of 193 patients with vaginal cancer treated with definitive RT were reviewed to obtain patient information including treatment characteristics and surviving patients were followed for a median of 137 months.. At 5 years, disease- specific survival (DSS) rates were . A unified approach to techniques and prescription/fractionation schedules for both EBRT and IGABT is required and RetroEMBRACE and EMBRACE I studies have demonstrated that clinical outcome is related to dose prescription and technique. The EMBRACE II study is an interventional and observational multicenter study that aims to benchmark a high level of local, nodal, and systemic control while limiting morbidity, using an advanced target volume selection and contouring protocol for EBRT and a multiparametric brachytherapy dose prescription protocol for brachytherapy, and use of advanced EBRT (IMRT and IGRT) and brachytherapy (intracavitary/interstitial) techniques.143. The addition of brachytherapy to external pelvic radiation increases survival in stages III- IV. A retrospective analysis of patients with primary squamous, adenocarcinoma, and adenosquamous carcinoma of the vagina who were identified from the Mayo Clinic Cancer Registry (1998- 2018) to analyze clinical characteristics and survival of patients with. # National Comprehensive NCCN Guidelines Version 3.2025 NCCN Cancer Network. primary vaginal cancer by Yang et al.144 In a total of 124 patients, primary surgery in stage I- II patients had similar survival outcomes as compared to primary radiation, but postoperative RT rate was . General recommendations for radiation volumes and doses for both EBRT and brachytherapy are discussed in the algorithm.. External Beam Boost. Intensity- modulated RT is becoming more widely available; however, issues regarding target definition, patient and target immobilization, tissue deformation, toxicity, and reproducibility remain to be validated.145- 152 Dose- escalated IMRT (limiting V55 to below . An international, multicenter, phase 2 clinical trial (INTERTECC- 2) evaluated acute hematologic and Gl toxicity for 83 patients with cervical cancer who received weekly cisplatin concurrently with once- daily IMRT, followed by intracavitary brachytherapy.154 The primary endpoint was the occurrence of either acute grade . Several retrospective analyses suggest that prolonged RT treatment duration has an adverse effect on outcome.155- 159 Extending the overall treatment beyond 6 to 8 weeks can result in approximately a . Reirradiation. Techniques for re- irradiation may include IORT, intracavitary or interstitial brachytherapy, SBRT, IMRT, or proton therapy.160- 162 Such cases are highly customized and depend on the target, proximity to critical organs, previous RT dose, extent of overlap, and time intervals since prior RT. The appropriate dose for each case needs to be individualized.. IORT is a specialized technique that delivers a single, highly focused dose of radiation to an at- risk tumor bed or isolated unresectable residual disease during an open surgical procedure.137 It is particularly useful in patients with recurrent disease within a previously radiated volume. During IORT, overlying normal tissue (such as bowel or other viscera) can be manually displaced from the region at risk. IORT is typically delivered with electrons, brachytherapy, or miniaturized x- ray sources using preformed applicators of variable sizes matched to the surgically defined region at risk, which further constrains the area and depth of radiation exposure to. # avoid surrounding normal structures. For patients with locoregional recurrence who have received prior EBRT with/without brachytherapy, IORT is recommended as NCCN category 3 with major NCCN disagreement that the intervention is appropriate.. Other techniques for reirradiation may include intracavitary or interstitial brachytherapy, SBRT, IMRT, or proton therapy. Such cases are highly individualized and depend on the target, proximity to critical organs, previous RT dose, extent of overlap, and time intervals since prior RT. The appropriate dose for each case needs to be individualized.. Concurrent Chemoradiation. Based on small retrospective series and adaptation from cervical cancer, concurrent chemoradiation therapy (CCRT) may be used in vaginal cancer.. In a single- institution report, clinical outcomes in patients with primary vaginal cancer with RT or CCRT were reviewed.163 A total of 51 patients were treated with RT alone; 20 patients were treated with CCRT, recurrences were analyzed, and OS and DFS rates were estimated. The 3- year OS of the RT group was . The adoption rate of CCRT and its survival impact were analyzed using the National Cancer Database (NCDB), which included patients diagnosed with vaginal cancer who received definitive RT.164 Of the. 13,689 patients identified, 8222 . Normal Tissue Considerations. Planning for RT in vaginal cancer must consider the potential impact on surrounding critical structures, such as rectum, bladder, sigmoid, small bowel, and bone. Acute effects (ie, diarrhea, bladder irritation, fatigue) occur to some degree in most patients undergoing radiation and are typically magnified by concurrent chemotherapy. However, acute effects can often be managed with medications and supportive care, and they generally resolve soon after completion of radiation. To avoid treatment- related menopause, ovarian transposition can be considered before pelvic RT in select young patients (<45 years with early- stage disease).165- 167. Late complications from RT in patients with gynecologic cancer may include potential injury to bladder, rectum, bowel, and pelvic skeletal structures.168 The risk of major complications (eg, obstruction, fibrosis/necrosis, fistula) is related to the volume, total dose, dose per fraction, and specific intrinsic radiosensitivity of the normal tissue that is irradiated.169- 171 Careful blocking in order to minimize normal tissue exposure while maintaining tumor coverage is critical for optimal outcomes. In addition, patient- related conditions (ie, inflammatory bowel disease, collagen- vascular disease, multiple abdominal/pelvic surgeries, history of pelvic inflammatory disease, diabetes) influence determination of radiation dose and volumes.. # National Comprehensive NCCN Guidelines Version 3.2025 NCCN Cancer Network. For most patients, it is generally accepted that the whole pelvis can tolerate an EBRT dose of 45 to 50 Gy. Gross disease in the parametria or unresected nodes may be treated with tightly contoured external- beam boosts to 65 to 70 Gy. Care should be taken to minimize dose to uninvolved and out- of- field external genitalia when possible but without compromising coverage of the PTV. Brachytherapy to reach 70- 80 Gy EQD2 total dose is generally recommended, with lower dose ranges of 70- 75 Gy considered in the lower vagina, and 75- 80 Gy total dose in the upper vagina. For bulky or poorly responsive disease in the upper vagina, dose escalation . Normal tissue dose constraint guidelines for vaginal cancer have been added to the NCCN Guidelines for Vaginal Cancer. Although the suggested dose constraints are provided in the Guidelines, the NCCN Panel recommends that clinicians must balance the risks of normal tissue toxicity with tumor control.. Drug Reactions. Virtually all drugs have the potential to cause adverse reactions, either during or after infusion.172 In vaginal cancer treatment, drugs that more commonly cause adverse reactions include carboplatin, cisplatin, . Gynecologic Survivorship. Treatment for gynecologic cancer typically involves surgery, chemotherapy, hormone therapy, RT, and/or immunotherapy, which may cause acute, short term, and long- term toxicities. Surgical approaches may be extensive and cause adhesions to form, which in turn may cause pain and contribute to the development of small bowel obstruction, urinary or GI complications (eg, incontinence, diarrhea), pelvic floor dysfunction (manifested by a variety of urinary, bowel, and/or sexual effects), and lymphedema. Chemotherapy agents vary, though commonly used regimens may pose a significant risk of neurotoxicity, cardiac toxicity, cognitive dysfunction, and the development of hematologic cancers. Long- term estrogen deprivation may cause symptoms such as hot flashes, vaginal dryness, and bone loss. RT may cause long- term complications. # National Comprehensive NCCN Guidelines Version 3.2025 NCCN Cancer Network. (eg, fibrosis, stenosis, vulvovaginal atrophy) and may predispose patients to subsequent cancers of the skin, subcutaneous tissue, and/or underlying organs that are proximal to the radiation field. Use of immunotherapy agents in gynecologic cancers is emerging, and to date, long- term effects of these treatments are unknown.. Following completion of treatment, all gynecologic cancer survivors should receive regular general medical care that focuses on managing chronic diseases (eg, depression, diabetes, hypertension), monitoring cardiovascular risk factors, receiving recommended vaccinations, and encouraging adoption of a healthy lifestyle (eg, promoting exercise, smoking cessation). To assess the late and long- term effects of gynecologic cancers, clinicians should comprehensively document the patient's history, including prior treatment history, and conduct a thorough physical examination followed by necessary imaging and/or laboratory testing. As most treatments for gynecologic cancers will cause sexual dysfunction, early menopause, and infertility, special attention to the resultant medical and psychosocial implications is needed. All patients, whether sexually active or not, should be asked about genitourinary symptoms, including vulvovaginal dryness. Post- radiation use of vaginal dilators and moisturizers is recommended. Psychosocial effects may include psychological (eg, depression, anxiety, fear of recurrence, altered body image), financial (eg, return to work, insurance concerns), and interpersonal (eg, relationships, sexuality, intimacy). Patients should be referred to appropriate specialty providers (eg, physical therapy, pelvic floor therapy, sexual therapy, psychotherapy) as needed, based on prior treatment history and assessed risk of developing late effects and/or existing concerns. Communication and coordination with all clinicians involved in the care of survivors, including primary care clinicians, is critical. Providing survivors with a summary of their treatment and recommendations for follow- up is also recommended. To this end, the SGO has developed templates for gynecologic cancer- specific . Best Supportive Care. Best Supportive CarePatients with refractory systemic cancer warrant a comprehensive coordinated approach involving hospice care, pain consultants, and emotional and spiritual support, individualized to the situation (see the NCCN Guidelines for Palliative Care).. Summary. SummaryIn summary, vaginal cancer tends to be associated with older age (>60 years). The most common signs and symptoms of vaginal cancer include bleeding, discharge, and urine retention; in some cases, vaginal cancer is identified by rectal symptoms like constipation or blood in the stool. The primary technique to detect vaginal cancer is pelvic examination. Many of the recommendations for staging, treatment, and follow- up of primary vaginal cancer are derived from cervical cancer and they have generalizability to vaginal cancer due to similar tumor biology. If the diagnosis can be made in an early stage of vaginal cancer, then RT is the preferred recommendation, as well as surgery in select patients. EBRT, EBRT with brachytherapy, and CCRT with brachytherapy are recommended in the later stages of the disease. Preventive measures such as HPV vaccination, regular gynecologic examinations, and tests like Pap smear and cervicography aid in prevention and early diagnosis of the disease. The hope is that immunization against HPV will prevent persistent infection and therefore prevent specific HPV- associated cancers, including vaginal cancer..	None	None	None
7affd83975ef4ea797ba996f8caa7d42	NCCN临床实践指南	卵巢癌包括输卵管癌和原发性腹膜癌001-030	# NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 1.2025 — March 5, 2025. NCCN.org. NCCN recognizes the importance of clinical trials and encourages participation when applicable and available. Trials should be designed to maximize inclusiveness and broad representative enrollment.. NCCN Guidelines for Patients® available at www.nccn.org/patients. Continue. # \Deborah K. Armstrong, MD/Chair . \Eric L. Eisenhauer, MD . Ardeshir Hakam, MD Moffitt Cancer Center Angela Jain, MD Fox Chase Cancer Center Gottfried E. Konecny, MD UCLA Jonsson Comprehensive Cancer Center \Charles A. Leath III, MD, MSPH O'Neal Comprehensive Cancer Center at UAB Gary Leiserowitz, MD UC Davis Comprehensive Cancer Center Babak Litkouhi, MD Stanford Cancer Institute \Joyce Liu, MD, MPH + Dana- Farber/Brigham and Women's Cancer Center Lainie Martin, MD Abramson Cancer Center at the University of Pennsylvania \Daniela Matei, MD . Elena Ratner, MD, MBA . Sharon Robertson, MD, MPH . Kerry Rodabaugh, MD . John Schorga, MD . \Premal H. Thaker, MD . Shitanshu Uppal, MBBS, MBA . Roberto Vargas, MD . \Andrea Wahner Hendrickson, MD . \Theresa L. Werner, MD Huntsman Cancer Institute at the University of Utah. \*Emese Zsiros, MD, PhD . Frankie Jones Emily Kovach Swathi Ramakrishnan, PhD. Continue. \Omega. # NCCN Ovarian Cancer Panel Members Summary of the Guidelines Update. Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Clinical Presentation, Workup, Clinical Stage, Primary Treatment (OV- 1) Poor Surgical Candidate or Low Likelihood of Optimal Cytoreduction (OV- 2) Diagnosis by Previous Surgery: Findings and Primary Treatment (OV- 3) Pathologic Staging, Primary Chemotherapy/Primary Adjuvant Therapy (OV- 4) Post Primary Treatment: Maintenance Therapy (OV- 5) Monitoring/Follow- Up, Recurrent Disease (OV- 6) Disease Status, Therapy for Persistent Disease or Recurrence (OV- 7). Less Common Ovarian Cancers: Diagnosis (LCOC- 1) Carcinosarcoma (Malignant Mixed Mullerian Tumors) of the Ovary (LCOC- 2) Clear Cell Carcinoma of the Ovary (LCOC- 3) Mucinous Neoplasms of the Ovary (LCOC- 4) Grade 1 Endometrioid Carcinoma (LCOC- 5) Low- Grade Serous Carcinoma (LCOC- 6) Ovarian Serous Borderline Epithelial Tumors (Low Malignant Potential) (LCOC- 8) Malignant Sex Cord- Stromal Tumors (LCOC- 11) Malignant Germ Cell Tumors (LCOC- 12) Systemic Therapy Regimens - Malignant Germ Cell/Sex Cord- Stromal Tumors (LCOC- A) Surveillance - Malignant Germ Cell/Sex Cord- Stromal Tumors (LCOC- B). Principles of Surgery (OV- A) Principles of Pathology (OV- B) Principles of Systemic Therapy (OV- C) Management of Drug Reactions (OV- D) Staging (ST- 1) WHO Histologic Classification (OV- E) Abbreviations (ABBR- 1). Find an NCCN Member Institution: institutions. NCCN Categories of Evidence and Consensus: All recommendations are category 2A unless otherwise indicated. See NCCN Categories of Evidence and Consensus. NCCN Categories of Preference: All recommendations are considered appropriate. See NCCN Categories of Preference.. The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2025.. # Updates in Version 1.2025 of the NCCN Guidelines for Ovarian Cancer from Version 3.2024 include:. Global. - References have been updated throughout the Guidelines.- Imaging footnote revised throughout OV and LCOC algorithms: CT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) and with or without rectal contrast as needed. MRI is performed with gadolinium-based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast.. OV-1. - Workup. - Bullet 2 modified: Pelvis ultrasound, and/or abdomen/pelvis CT/MRI as clinically indicated.- Bullet 3 modified: Chest CT or chest x-ray as clinically indicated.. - Footnote c modified: Chest CT preferred If there is concern for metastatic or disseminated disease.. - Footnote e added: Reconsider REL as clinically indicated once pathologic diagnosis is available.. - Footnote h, last sentence added: For PARPi therapy in advanced stage disease, include measure of homologous recombination (HR) (OV-B). (Also for OV-2, OV-3, and OV-5).. OV-2. - Response pathway modified: Interval debulking surgery (IDS) with completion hysterectomy/BSO and cytoreduction. Consider hyperthermic intraperitoneal chemotherapy (HIPEC).. - Stable disease pathway modified: IDS with completion hysterectomy/BSO and cytoreduction. Consider HIPEC.. - Pathway added: LCOC with link to LCOC-1.. - Footnote r added: Neoadjuvant therapy does not apply to low malignant potential (LMP) or other noninvasive cancers (see LCOC-1). (Also for OV-3) - Footnote removed: Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin (100 mg/m. OV-3. - Diagnosis by previous surgery modified: Patient referred with newly diagnosed ovarian cancer, including less common ovarian cancers (LCOCs), after recent surgical procedure. - Bullet 5 modified: Imaging as clinically indicated (eg, C/A/P CT, chest CT, A/P MRI, PET/MRI, PET/CT, and/or pelvis ultrasound). - Bullet 8 added: REL as clinically indicated.. OV-5. - Stage II, III, IV, post primary treatment, bullet 1, sub-bullet modified: eg, C/A/P CT, chest CT, A/P MRI, PET/MRI, PET/CT and/or pelvis ultrasound (skull base to mid-thigh).. OV-6. - Bullet 3 modified: Imaging as clinically indicated (eg, C/A/P CT, chest CT, A/P MRI, PET/MRI, PET/CT and/or pelvis ultrasound) (skull base to mid-thigh) as clinically indicated.. OV-7. - Footnote jj modified: Patients who do not respond and progress on two consecutive therapy regimens without evidence of clinical benefits have diminished likelihood of benefitting from additional therapy (Griffiths RW, et al. Int J Gynecol Cancer 2011;21:58-65). Decisions to offer clinical trials, supportive care only, or additional therapy should be made on an highly individual basis.. # National NCCN Guidelines Version 1.2025 Comprehensive Ovarian Cancer NCCN Cancer Network. Updates in Version 1.2025 of the NCCN Guidelines for Ovarian Cancer from Version 3.2024 include:. - Footnote i, last sentence added: For PARPi therapy in advanced stage disease, include measure of HR (OV-B). (Also for LCOC-3) LCOC-4- Mucinous neoplasms of the ovary- Stage IA, IB, and IC carcinoma split into separate pathways.- Adjuvant therapy for each stage updated based on expansile or infiltrative pattern.- Footnote d added: Principles of Pathology (OV-B). LCOC-7- Bullet 4 modified: Imaging as clinically indicated (eg, C/A/P CT, chest CT, A/P MRI, PET/CT, PET/MRI) (skull base to mid-thigh) as clinically indicated. LCOC-9- Pathologic diagnosis pathway modified: Imaging G/A/P-CT with contrast if not previously done.- Bullet added: eg, C/A/P CT, chest CT, A/P MRI, PET/CT, or PET/MRI. LCOC-10- Bullet 5 modified: Imaging as clinically indicated: eg, C/A/P CT, chest CT, A/P MRI, PET/CT, PET/MRI (skull base to mid-thigh). (also for LCOC-13) LCOC-12- Incompletely staged, modified: Imaging if not previously done (eg, C/A/P CT, chest CT, A/P MRI, PET/CT, PET/MRI) with contrast (if not previously done). LCOC-A- Footnote removed: An FDA-approved biosimilar is an appropriate substitute for bevacizumab. LCOC-B- Surveillance for Malignant Germ Cell Tumors extensively revised.- Footnote a added: Only for those patients who have a residual ovary. OV-A (3 of 4)- Interval Debulking Surgery After Neoadjuvant Chemotherapy of Invasive Epithelial Ovarian Cancer- Bullet 2 modified: HIPEC with cisplatin (100 mg/m2) can be considered at the time of IDS for stage III disease. HIPEC can also be considered for suitable stage IV patients (category 2B) who have had a favorable response to neoadjuvant therapy both intraperitoneally and extraperitoneally, or in whom stage IV disease sites have completely resolved (eg, resolution of malignant pleural effusion) or are now deemed resectable. Sodium thiosulfate may be administered at the start of perfusion, followed by a continuous infusion, to allow for renal protection during HIPEC.- Bullet 5 modified: While systemic lymphadenectomy of clinical-negative nodes is not recommended, suspicious and/or enlarged nodes should be resected, if possible. Removal of lymph nodes noted to have potential metastasis at the time of initial diagnosis should be considered, even if not currently suspicious or enlarged. OV-A (4 of 4)- Special Circumstances, bullet 1, sub-bullet, second sentence added: Consider endometrial sampling to exclude synchronous primary or hyperplasia. OV-B (2 of 3)- Less Common Ovarian Cancers (LCOC)- Bullet 3, last sentence added: Features favoring primary ovarian carcinoma versus metastasis are: unilateral, "expansile" pattern of invasion, complex papillary pattern, size >10 cm, smooth external surface, microscopic cystic glands, necrotic luminal debris, mural nodules, and accompanying teratoma, adenofibroma, endometriosis, or Brenner tumor.. # NCCN Guidelines Version 1.2025 Ovarian Cancer. Updates in Version 1.2025 of the NCCN Guidelines for Ovarian Cancer from Version 3.2024 include: OV-B (2 of 3)(continued). - Bullet 4 added: Most early stage invasive mucinous ovarian cancers have an expansile pattern of growth characterized by complex glandular, papillary and/or cribriform architecture with a labyrinthine or anastomosing pattern and little or no intervening stroma. About . - Bullet 5 modified: Metastatic colorectal adenocarcinomas also usually are positive for CK20-and-CEA.. - Bullet 6, second sentence modified: Endometrioid adenocarcinomas are usually positive for cytokeratin 7 (CK7), PAX8, GA-125, and estrogen receptors.. OV- C (1 of 12). General. - Bullet 3, sub-bullet 2 modified: Patients of childbearing potential who desire fertility-sparing procedures should be referred to an appropriate fertility specialist (see Fertility, Reproductive Endocrine, and Sexual Health Considerations for Individuals with Ovaries in the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology).. - Bullet 8 added: An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. OV-C (2 of 12). - Language updated: "Surgery" has replaced "IDS" throughout this page.. - Bullet 2 modified: Any of the primary IV regimens for stage II-IV high-grade serous carcinoma and respective LCOCs can be used as neoadjuvant therapy before surgery. Neoadjuvant therapy does not apply to LMP and other noninvasive cancers. See OV-C (6 of 12) and LCOC-A.. - Bullet 4 modified: After neoadjuvant therapy and surgery any of the adjuvant therapy options for high-grade serious carcinoma (IV or IP/IV) and respective LCOCs can be considered. Neoadjuvant therapy does not apply to LMP and other noninvasive cancers. See OV-C (6 of 12) and LCOC-A. OV-C (3 of 12). - Principles of Maintenance PARP Inhibitor (PARPi) Therapy, bullet 3, sub-bullet 7 added: Current clinical HRD tests are proxy measures of HRD and lack accuracy in fully predicting functional HRD. HRD testing is recommended for those patients without germline BRCA1/2 mutations as HRD test status may provide information on the magnitude of benefit of PARP inhibitor maintenance therapy in these patients. The Panel considers the use of PARPi in patients who have HRP tumors, at present, to be of minimal benefit.. OV- C (4 of 12). - Bullet 9 moved from OV-C (9A of 12): Patients who do not respond and progress on two consecutive regimens without evidence of clinical benefits have diminished likelihood of benefitting from additional therapy (Griffiths RW, et al. Int J Gynecol Cancer 2011;21:58-60). Decisions to offer clinical trials, supportive care, or additional therapy should be made on an individual basis.. OV- C (5 of 12). - Mucinous carcinoma row header modified: Mucinous carcinoma (stage IA, IB, and IC, grades 1-3). OV-C (6 of 12). - Footnote h, sentence removed: See the NCCN Guidelines for Older Adult Oncology. - Footnote removed: An FDA-approved biosimilar is an appropriate substitute for bevacizumab. (also for OV-C [7 of 12], [8 of 12] and [9A of 12]). OV-C (8 of 12). - Useful in Certain Circumstances, Targeted Therapy. - Regimen added: Fam-trastuzumab deruxtecan-nxki (for HER2-positive tumors [IHC 3+ or 2+])(category 2B). - Regimen added: Mirvetuximab soravtansine-gynx (for FRα-expressing tumors [≥75% positive tumor cells]). - Regimen modified: Mirvetuximab soravtansine-gynx/bevacizumab (for FRα-expressing tumors [≥50% positive tumor cells]) (category 2B).. # Updates in Version 1.2025 of the NCCN Guidelines for Ovarian Cancer from Version 3.2024 include: OV-C (8 of 12)(continued). - Footnote y added: For patients treated with two prior lines of platinum-based therapy. - Footnote removed: Patients who progress on two consecutive regimens without evidence of clinical benefits have diminished likelihood of benefitting from additional therapy (Griffiths RW, et al. Int J Gynecol Cancer 2011;21:58-65). Decisions to offer clinical trials, supportive care, or additional therapy should be made on an individual basis. (Also for OV-C [9A of 12]). OV-C (9 of 12). - Useful in Certain Circumstances, Targeted Therapy - Regimen modified: Mirvetuximab soravtansine-gynx/bevacizumab (for FRA-expressing tumors . # National Comprehensive Cancer Network. NCCN Guidelines Version 1.2025 Epithelial Ovarian Cancer/Fallopian Tube Cancer/ Primary Peritoneal Cancer. NCCN Guidelines Index Table of Contents Discussion. CLINICAL PRESENTATION. WORKUP. CLINICAL STAGEi. PRIMARY TREATMENTi,j,k. Suspicious/ palpable pelvic mass on abdomen/ pelvis exam and/or ascites, abdominal distention. and/or. Symptoms without source of malignancy (ie, bloating, pelvis/ abdomen pain, difficulty eating or feeling full quickly, urinary symptoms [urgency or frequency]). Abdominal/pelvic exam Pelvis ultrasound, abdomen/ pelvis CT/MRI as clinically indicateda,b Chest CT as clinically indicateda,c Complete blood count (CBC), chemistry profile with liver function test (LFT) CA- 125 or other tumor markers as clinically indicatedd Evaluate performance status and nutritional status Gastrointestinal (GI) evaluation as clinically indicated Reproductive endocrinology and infertility (REI) evaluation as clinically indicatede Obtain family history f,g,h Refer to gynecologic oncologist for clinically suspicious lesions. Workup, Findings, and Primary Treatment (OV-3). Diagnosis by previous surgery or tissue biopsy (cytopathology). a CT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium- based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast. PET/CT, MRI, or PET/MRI may be indicated for indeterminate lesions if results will alter management. If there is concern for metastatic or disseminated disease. Other tumor markers may include inhibin, beta- human chorionic gonadotropin (β- hCG), alpha- fetoprotein, lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), CA 19- 9, and HE4. See Discussion for usefulness of diagnostic tests. Reconsider REI as clinically indicated once pathologic diagnosis is available. See NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate and NCCN Guidelines for Genetic/Familial High- Risk Assessment: Colorectal, Endometrial, and Gastric. Germline and somatic BRCA1/2 status informs maintenance therapy. In the absence of a BRCA1/2 mutation, homologous recombination deficiency (HRD) status may provide information on the magnitude of benefit of PARP inhibitor (PARPi) therapy. For PARPi therapy in advanced stage disease, include measure of homologous recombination (HR) (OV- B). Evaluation by a gynecologic oncologist is recommended for: All patients with suspected ovarian malignancies; published data demonstrate that primary assessment and debulking by a gynecologic oncologist results in a survival advantage. Patients being evaluated for neoadjuvant therapy prior to being considered a poor surgical candidate. Management of occult STICs. Consideration of laparoscopic evaluation to determine feasibility of debulking surgery in select patients. Endometrial biopsy as clinically indicated. Principles of Surgery (OV- A). Principles of Pathology (OV- B). May be an option for select patients with stage IC based on histology. Uterine preservation for potential future assisted reproductive approaches. See Principles of Systemic Therapy (OV- C) and Management of Drug Reactions (OV- D). Carcinosarcoma, clear cell, mucinous, low- grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord- stromal tumors, and germ cell tumors.. Note: All recommendations are category 2A unless otherwise indicated.. # NCCN Guidelines Version 1.2025 Epithelial Ovarian Cancer/Fallopian Tube Cancer/ Primary Peritoneal Cancer. POOR SURGICAL CANDIDATE OR LOW LIKELIHOOD OF OPTIMAL CYTOREDUCTION NEOADJUVANT THERAPY. See NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate and NCCN Guidelines for Genetic/Familial High- Risk Assessment: Colorectal, Endometrial, and Gastric. Germline and somatic BRCA1/2 status informs maintenance therapy. In the absence of a BRCA1/2 mutation, HRD status may provide information on the magnitude of benefit of PARPi therapy. For PARPi therapy in advanced stage disease, include measure of HR (OV- B). Evaluation by a gynecologic oncologist is recommended for: - All patients with suspected ovarian malignancies; published data demonstrate that primary assessment and debulking by a gynecologic oncologist results in a survival advantage. - Patients being evaluated for neoadjuvant therapy prior to being considered a poor surgical candidate. - Management of occult STICs. - Consideration of laparoscopic evaluation to determine feasibility of debulking surgery in select patients. - Endometrial biopsy as clinically indicated.. J Principles of Surgery (OV- A). k Principles of Pathology (OV- B). n See Principles of Systemic Therapy (OV- C) and Management of Drug Reactions (OV- D). P If biopsy is not feasible, cytopathology from ascites or pleural effusion combined with CA- 125:CEA ratio of . # NCCN Guidelines Version 1.2025 Epithelial Ovarian Cancer/Fallopian Tube Cancer/ Primary Peritoneal Cancer. DIAGNOSIS BY PREVIOUS SURGERY. FINDINGS. PRIMARY TREATMENT. Patient referred referred with newly diagnosed ovarian cancer, including less common ovarian cancers (LCOCs), after recent surgical procedure. a CT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium- based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast. d Other tumor markers may include inhibin, . i Evaluation by a gynecologic oncologist is recommended for:. All patients with suspected ovarian malignancies; published data demonstrate that primary assessment and debulking by a gynecologic oncologist results in a survival advantage. Patients being evaluated for neoadjuvant therapy prior to being considered a poor surgical candidate. Management of occult STICs. Consideration of laparoscopic evaluation to determine feasibility of debulking surgery in select patients. Endometrial biopsy as clinically indicated.. i Principles of Surgery (OV- A).. k Principles of Pathology (OV- B).. Neoadjuvant therapy does not apply to LMP and other noninvasive cancers (see LCOc- 1). s Although comprehensive surgical staging has not been shown to improve survival in patients with no evidence of residual disease, it can be important for determining the most appropriate postoperative management options, including selection of adjuvant and maintenance therapy.. # NCCN Guidelines Version 1.2025 Epithelial Ovarian Cancer/Fallopian Tube Cancer/ Primary Peritoneal Cancer. PATHOLOGIC STAGINGt,u. PRIMARY CHEMOTHERAPY/PRIMARY ADJUVANT THERAPYv. Less common ovarian cancers (LCOC), any stageo,u. n See Principles of Systemic Therapy (OV- C) and Management of Drug Reactions (OV- D). o Carcinosarcoma, clear cell, mucinous, low- grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord- stromal tumors, and germ cell tumors. Pathologists recommend categorizing serous ovarian cancer as either low- grade or high- grade. Grade 2 serous is considered high- grade. u Consider expert pathologic review to confirm histologic diagnosis. See WHO Histologic Classification (OV- E).. Note: All recommendations are category 2A unless otherwise indicated.. v Patients receiving primary chemotherapy will be monitored as follows: 1. Every 1- 3 cycles: Physical exam and consider pelvic exam 2. As indicated: Interim CBC and chemistry profiles 3. CA- 125 levels or other tumor markers as clinically indicated prior to each cycle of chemotherapy 4. C/A/P CT or MRI with contrast, PET/CT (skull base to mid- thigh), or PET as indicated.. # STAGE II, III, IVW POST PRIMARY TREATMENT. a CT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium- based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast.. h In the absence of a BRCA1/2 mutation, HRD status may provide information on the magnitude of benefit of PARPi therapy. For PARPi therapy in advanced stage disease, include measure of HR (OV- B).. n See Principles of Systemic Therapy (OV- C) and Management of Drug Reactions (OV- D).. w Post primary treatment recommendations for stage II- IV high- grade serous or grade 2/3 endometrioid carcinoma; consider for clear cell carcinoma or carcinosarcoma with a BRCA1/2 mutation.. 1 No definitive evidence of disease.. y Data are limited for maintenance therapy with a PARPi for patients with stage II disease.. After first- line therapy with bevacizumab, data are limited on maintenance therapy with a single- agent PARPi (olaparib, niraparib, or rucaparib) for patients with a germline or somatic BRCA1/2 mutation. However, based on the magnitude of benefit of PARPi maintenance therapy for other subgroups, single- agent PARPi can be considered.. # NCCN Guidelines Version 1.2025 Epithelial Ovarian Cancer/Fallopian Tube Cancer/ Primary Peritoneal Cancer. a CT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium- based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast. See NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate and NCCN Guidelines for Genetic/Familial High- Risk Assessment: Colorectal, Endometrial, and Gastric. See Principles of Systemic Therapy (OV- C) and Management of Drug Reactions (OV- D). There are data regarding the utility of CA- 125 for monitoring of ovarian cancer after completion of primary therapy. See The Society of Gynecologic Oncology (SGO) position statement and Discussion.. b Consider symptom management and best supportive care. See NCCN Guidelines for Palliative Care. Refer for palliative care assessment, if appropriate. c Surveillance imaging may be indicated when tumor markers are considered unreliable, the physical exam is unreliable, and/or there is a high risk of recurrence. dd Validated molecular testing should be performed in a CLIA- approved facility using the most recent available tumor tissue. Tumor molecular analysis is recommended to include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor- specific or tumor- agnostic benefit including, but not limited to, HER2 status (by IHC), BRCA1/2, HRD status, microsatellite instability (MSI), mismatch repair (MMR), tumor mutational burden (TMB), BRAF, FRα (FOLR1), RET, and NTRK if prior testing did not include these markers. More comprehensive testing may be particularly important in LCOc with limited approved therapeutic options (OV- B).. # See NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate and NCCN Guidelines for Genetic/Familial High- Risk Assessment. Colorectal, Endometrial, and Gastric. See Principles of Systemic Therapy (OV- C) and Management of Drug Reactions (OV- D). dd Validated molecular testing should be performed in a CLIA- approved facility using the most recent available tumor tissue. Tumor molecular analysis is recommended to include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor- specific or tumor- agnostic benefit including, but not limited to, HER2 status (by IHC), BRCA1/2, HRD status, MSI, MMR, TMB, BRAF, FRα (FOLR1), RET, and NTRK if prior testing did not include these markers. More comprehensive testing may be particularly important in LCOC with limited approved therapeutic options (OV- B). ee Tumor molecular testing prior to initiation of therapy for persistent/recurrent disease, if not previously done.. f Definitions of platinum- sensitive and platinum- resistant disease represent a spectrum of disease; clinical judgment and flexibility should be utilized in determining treatment options. 99 Data are limited on primary and maintenance therapy for recurrent/ persistent LCOC. hh During and after treatment for recurrence, patients should be evaluated as indicated with tumor markers and repeat imaging (with modalities previously used) to document response and/or disease status. ii Ancillary Palliative Surgical Procedures (OV- A 4 of 4). jj Patients who do not respond and progress on two consecutive regimens without evidence of clinical benefits have diminished likelihood of benefitting from additional therapy (Griffiths RW, et al. Int J Gynecol Cancer 2011;21:58- 65). Decisions to offer clinical trials, supportive care, or additional therapy should be made on an individual basis. kk Localized radiation therapy (RT) can be considered to palliate symptoms and/or for oligometastatic disease.. # NCCN Guidelines Version 1.2025 Epithelial Ovarian Cancer/Fallopian Tube Cancer/ Primary Peritoneal Cancer. f See NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate and NCCN Guidelines for Genetic/Familial High- Risk Assessment: Colorectal, Endometrial, and Gastric. j Principles of Surgery (OV- A). k Principles of Pathology (OV- B). n See Principles of Systemic Therapy (OV- C) and Management of Drug Reactions (OV- D). dd Validated molecular testing should be performed in a CLIA- approved facility using the most recent available tumor tissue. Tumor molecular analysis is recommended to include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor- specific or tumor- agnostic benefit including, but not limited to, HER2 status (by IHC), BRCA1/2, HRD status, MSI, MMR, TMB, BRAF, FRα (FOLR1), RET, and NTRK if prior testing did not include these markers. More comprehensive testing may be particularly important in LCOC with limited approved therapeutic options (OV- B). ee Tumor molecular testing prior to initiation of therapy for persistent/recurrent disease, if not previously done. ff Definitions of platinum- sensitive and platinum- resistant disease represent a spectrum of disease; clinical judgment and flexibility should be utilized in determining treatment options.. 99 Data are limited on primary and maintenance therapy for recurrent/persistent LCOC. hh During and after treatment for recurrence, patients should be evaluated as indicated with tumor markers and repeat imaging (with modalities previously used) to document response and/or disease status. ii Ancillary Palliative Surgical Procedures (OV- A of 4). kk Localized RT can be considered to palliate symptoms and/or for oligometastatic disease. l PARPi options include niraparib, olaparib, or rucaparib in patients with BRCA- mutated platinum- sensitive disease who have completed two or more lines of platinum- based therapy. Based on FDA indication, niraparib is limited to those with a deleterious or suspected deleterious germline BRCA mutation. Based on FDA indications, olaparib and rucaparib are limited to those with a deleterious or suspected deleterious BRCA mutation (germline or somatic). Caution should be used when using maintenance PARPi for longer than 24 months. There are limited data on the use of a maintenance PARPi in patients who previously received a PARPi. Combination bevacizumab/PARPi is not recommended for maintenance after recurrence therapy.. # a WHO Histologic Classification (OV-E). Due to emerging therapeutics for LCC, there is value in identifying potential pathways for rare cancers and it may be useful for clinical trial recruitment. Tumor molecular testing can be considered, if not previously done, as it may help guide treatment. There are limited data in these cancers given their infrequency and it will be difficult to acquire prospective data. Individualized treatment may be the best treatment for these rare tumors. [Committee on the State of the Science in Ovarian Cancer, et al. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington (DC): National Academies Press (US) Copyright 2016 by the National Academy of Sciences. All rights reserved; 2016. ]. c Principles of Surgery (OV- A). d Principles of Pathology (OV- B). e LCOc are typically diagnosed after surgery. See Workup (OV- 1).. # PATHOLOGIC DIAGNOSIS<sup>a</sup>. ADJUVANT TREATMENT<sup>f</sup>. MONITORING/FOLLOW- UP. <sup>a</sup> WHO Histologic Classification (OV- E). <sup>f</sup> See Principles of Systemic Therapy (OV- C) and Management of Drug Reactions (OV- D). <sup>g</sup> If not previously done, consider surgical staging and resection of residual disease (OV- 3). <sup>h</sup> If not previously done, consider germline and somatic testing (OV- B). <sup>i</sup> Germline and somatic BRCA1/2 status informs maintenance therapy. In the absence of a BRCA1/2 mutation, HRD status may provide information on the magnitude of benefit of PARPi therapy. For PARPi therapy in advanced stage disease, include measure of HR (OV- B). <sup>j</sup> Data are limited on primary and maintenance therapy for recurrent/persistent LCCC.. Note: All recommendations are category 2A unless otherwise indicated.. # NCCN Guidelines Version 1.2025 Clear Cell Carcinoma of the Ovary. PATHOLOGIC DIAGNOSIS<sup>a</sup>. ADJUVANT TREATMENT<sup>f</sup>. MONITORING/ FOLLOW- UP. # NCCN Guidelines Version 1.2025 Mucinous Neoplasms of the Ovary. PATHOLOGIC DIAGNOSIS<sup>a</sup> ADDITIONAL WORKUP. <sup>a</sup> WHO Histologic Classification (OV- E). <sup>d</sup> Principles of Pathology (OV- B). <sup>f</sup> See Principles of Systemic Therapy (OV- C) and Management of Drug Reactions (OV- D). <sup>g</sup> If not previously done, consider surgical staging and resection of residual disease (OV- 3). <sup>h</sup> If not previously done, consider germline and somatic testing (OV- B). <sup>j</sup> Data are limited on primary and maintenance therapy for recurrent/persistent LCOC. <sup>k</sup> Consider additional testing, including but not limited to upper and lower endoscopic evaluation, to aid in the identification of metastatic GI malignancies versus primary mucinous ovarian cancer.. # NCCN Guidelines Version 1.2025 Grade 1 Endometrioid Carcinoma. PATHOLOGIC DIAGNOSIS<sup>a</sup>. a WHO Histologic Classification (OV- E). f See Principles of Systemic Therapy (OV- C) and Management of Drug Reactions (OV- D). g If not previously done, consider surgical staging and resection of residual disease (OV- 3). h If not previously done, consider germline and somatic testing (OV- B).. J Data are limited on primary and maintenance therapy for recurrent/persistent LCOC. I MSI/MMR testing is recommended for all patients with endometrioid carcinoma. m Other hormonal therapy options include: aromatase inhibitors (ie, anastrozole, exemestane), leuprolide acetate, goserelin acetate, and tamoxifen.. # NCCN Guidelines Version 1.2025 Low-Grade Serous Carcinoma. PATHOLOGIC DIAGNOSIS<sup>a</sup>. # NCCN Guidelines Version 1.2025 Low-Grade Serous Carcinoma. MONITORING/FOLLOWUP FOR RECURRENCE. RECURRENCE THERAPY. Visits every 2- 4 mo for 2y, then 3- 6 mo for 3y, then annually after 5 y Physical exam including pelvic exam as clinically indicated - Tumor molecular testing if not previously done Imaging as clinically indicated (eg, C/A/P CT, chest CT, A/P MRI, PET/CT, or PET/MRI) (skull base to midthigh) CBC and chemistry profile as indicated CA- 125 or other tumor markers if initially elevated Refer for genetic risk evaluation, if not previously done Long- term wellness care (See NCCN Guidelines for Survivorship). Recurrent disease. Trametinib or Binimetinib (category 2B) or Dabrafenib . f See Principles of Systemic Therapy (OV-C) and Management of Drug Reactions (OV-D).. o Validated molecular testing should be performed in a CLIA- approved facility using the most recent available tumor tissue. Tumor molecular analysis is recommended to include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor- specific or tumor- agnostic benefit including, but not limited to, HER2 status (by IHC), BRCA1/2, HRD status, MSI, MMR, TMB, BRAF, FRa (FOLR1), RET, and NTRK if prior testing did not include these markers. More comprehensive testing may be particularly important in LCOC with limited approved therapeutic options (OV- B).. p CT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium- based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast.. q There are data regarding the utility of CA- 125 for monitoring of ovarian cancer after completion of primary therapy. See The Society of Gynecologic Oncology (SGO) position statement and Discussion. r See NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate and NCCN Guidelines for Genetic/Familial High- Risk Assessment: Colorectal, Endometrial, and Gastric. s There is no standard sequencing of drugs for recurrent disease. Considerations include prior therapies, disease burden, relative efficacy, and relative toxicity profile. t Consider secondary cytoreduction in patients with long disease- free interval, isolated masses rather than diffuse carcinomatosis on imaging, and/or bowel obstruction. u An aromatase inhibitor (ie, letrozole, anastrozole, exemestane) is preferred if not used previously. Fulvestrant, leuprolide acetate, or goserelin acetate is recommended if an aromatase inhibitor was given previously. v Data are limited on maintenance therapy for recurrent/resistant LCOC. See OV- 8 for maintenance options after platinum- based therapy, and patient selection criteria.. # PATHOLOGIC DIAGNOSIS<sup>a</sup>. ADJUVANT TREATMENT<sup>x</sup>. # PATHOLOGIC DIAGNOSISa. ADJUVANT TREATMENTx. a WHO Histologic Classification (OV-E). Principles of Surgery (OV-A). d Principles of Pathology (OV-B).. b CT is performed with oral and iodinated IV contrast (unless contraindicated due to anaphylaxis or significant renal dysfunction) with or without rectal contrast. MRI is performed with gadolinium- based contrast agents (unless contraindicated due to anaphylaxis) and is preferred in select patients with renal dysfunction over CT. Chest CT can be done with or without iodinated IV contrast.. w Chemotherapy (IV or IP) has not been shown to be beneficial in ovarian borderline epithelial tumors (LMP). x Standard recommendation includes a patient evaluation by a gynecologic oncologist. y For pathologically proven ovarian borderline epithelial tumors, lymph node evaluation may be considered on a case- by- case basis. z In patients who underwent USO, consider completion surgery (eg, contralateral USO, hysterectomy) after completion of childbearing (category 2B). aa If patient is medically unfit, or for those with unresectable residual disease.. # - Visits every 3–12 mo for up to 5 y, then as clinically indicated- Physical exam including pelvic exam as clinically indicated- CA-125<sup>q</sup> or other tumor markers every visit if initially elevated- CBC, chemistry profile as indicated- Imaging<sup>q</sup> as clinically indicated - eg C/A/P CT, chest CT, A/P MRI, PET/CT, or PET/MRI (skull base to mid-thigh)- Ultrasound as indicated for patients with fertility-sparing surgery. P CT is peed wth a and dtd rast (unss contded t anaphylxis or sigicant rl yction) wth or wthut ctal contrast. MR is peed wth gadlum- asd ct s (unss ontded t anaphylxis) and is prred in et pati wth ral yction over CT. Chest CT can be done with or without iodinated IV contrast. There are data regarding the utility of CA- 125 for montoring of ovarian cancer after completion of primary therapy. Se The Socity of Gynecologic Oncology (SGO) position statement and Discussion. w Chemotherapy (IV or IP) has not been shown to be beneficial in ovarian borderline epithelial tumors (LMP).. # NCCN Guidelines Version 1.2025 Malignant Sex Cord-Stromal Tumors. CLINICAL PRESENTATION/ DIAGNOSIS. RECURRENCE THERAPY. a WHO Histologic Classification (OV- E). b Lymphadenectomy may be omitted. c Principles of Surgery (OV- B). d Principles of Pathology (OV- B). e Lymphadenectomy may be omitted. f Inhibin levels can be followed for granulosa cell tumors.. dd Acceptable options include paclitaxel/carboplatin (preferred), EP (etoposide, cisplatin), or BEP (bleomycin, etoposide, cisplatin) (category 2B). ee See Principles of Systemic Therapy (OV- C) and Systemic Therapy Regimens for Malignant Germ Cell/Sex Cord/Stromal Tumors (LCOC- A). ff Localized RT can be considered to palliate symptoms and/or for oligometastatic disease.. # NCCN Guidelines Version 1.2025 Malignant Germ Cell Tumors. CLINICAL PRESENTATION/. \mathbb{P}. Note: All recommendations are category 2A unless otherwise indicated.. 99 Surgical principles for pediatric/young adult patients may differ from those for adult patients. See Principles of Surgery (OV- A). hh Repeat imaging if tumor markers plateau at significant abnormal level or rise. If imaging positive, follow pathway above for positive imaging and positive tumor markers.. # a WHO Histologic Classification (OV-E).. CT is pe wth d t t t g adi t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t. f1 Localized RT can be considered to palliate symptoms and/or for oligometastatic disease.. 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 immae t th i t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t h t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t s t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t e t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t o t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t u t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t c t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t b t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t w t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t n t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t a t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t r t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t f t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t. e referred to a tertiary care institution for HCT consultation and potentially curative therapy.. Note: All recommendations are category 2A unless otherwise indicated.. # NCCN Guidelines Version 1.2025 Malignant Germ Cell Tumors. PATHOLOGIC DIAGNOSIS. MONITORING/FOLLOW- UP AFTER ADJUVANT TREATMENT. THERAPY FOR RECURRENT/ PERSISTENT DISEASE. Any stage embryonal tumorii or Any stage endodermal sinus tumor (yolk sac tumor)ii or Stage II- IV dysgerminoma or Stage I, grade 2 or 3 or Stage II- IV immature teratoma or Any stage nongestational choriocarcinoma. a WHO Histologic Classification (OV- E) ee See Principles of Systemic Therapy (OV- C) and Systemic Therapy Regimens for Malignant Germ Cell/Sex Cord- Stromal Tumors (LCOC- A). ff Localized RT can be considered to palliate symptoms and/or for oligometastatic disease. ii Pediatric/adolescent patients with the following clinical presentations may consider observation or chemotherapy as treatment options: stage IA, IB dysgerminoma; stage IA, grade 1 immature teratoma; stage IA embryonal carcinomas; or stage IA yolk sac tumors. Consultation with a pediatric oncologist for pediatric/adolescent patients is recommended. II High- dose chemotherapy regimens vary among institutions. Some patients are potentially curable with HCT. Patients with potentially curable recurrent germ cell disease should be referred to a tertiary care institution for HCT consultation and potentially curative therapy.. # NCCN Guidelines Version 1.2025 Malignant Germ Cell/Sex Cord-Stromal Tumors. MALIGNANT GERM CELL TUMORSa,b,c. a See Principles of Systemic Therapy (OV- C) and see Discussion for references. b High- dose chemotherapy regimens vary among institutions. Some patients are potentially curable with HCT. Patients with potentially curable recurrent germ cell disease should be referred to a tertiary care institution for HCT consultation and potentially curative therapy.. c WHO Histologic Classification (OV- E). d Recommend pulmonary function test if considering bleomycin. e Consultation with a pediatric oncologist for pediatric/adolescent patients is recommended.. Note: All recommendations are category 2A unless otherwise indicated..	None	None	None
ad7224b36db04053b9c48271ca518090	NCCN临床实践指南	卵巢癌包括输卵管癌和原发性腹膜癌031-060	# NCCN Guidelines Version 1.2025 Malignant Germ Cell/Sex Cord-Stromal Tumors. # PRINCIPLES OF SURGERY1. General Considerations. - It is recommended that a gynecologic oncologist perform the appropriate surgery.. An open laparotomy including a vertical midline abdominal incision should be used in most patients with a suspected malignant ovarian/ fallopian tube/primary peritoneal neoplasm in whom a surgical staging procedure, a primary debulking procedure, an interval debulking procedure, or secondary cytoreduction is planned.. For select patients, a minimally invasive surgical approach may be used by an experienced surgeon to manage early- stage disease. Laparoscopy may be useful to evaluate whether optimal cytoreduction can be achieved in patients with newly diagnosed advanced- stage or recurrent disease.. Minimally invasive techniques can be used for select patients for interval debulking procedures. Patients who are unable to be optimally debulked using minimally invasive techniques should be converted to an open procedure.. - Intraoperative pathologic evaluation with frozen sections may assist in management.. Prior to surgery for ovarian cancer, counsel patients about port placement if intraperitoneal (IP) chemotherapy is being considered.. Operative Reports. Surgeons should describe the following in the operative report:. Extent of initial disease before debulking pelvis, mid- abdomen, or upper abdomen (cutoffs: pelvic brim to lower ribs). Amount of residual disease in the same areas after debulking. Complete or incomplete resection; if incomplete, indicate the size of the major lesion and total number of lesions. Indicate if miliary or small lesions.. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. PRINCIPLES OF SURGERY1. Newly Diagnosed Invasive Epithelial Ovarian Cancer Apparently Confined to the Ovaries, Fallopian Tubes, and Uterus (apparent stage IA- IIA) In general, every effort should be made during a primary cytoreduction procedure to achieve maximum cytoreduction of all pelvic disease and to evaluate for occult disease in the upper abdomen or retroperitoneum.. - On entering the abdomen, aspiration of ascites or peritoneal lavage should be performed for peritoneal cytologic examinations.- All peritoneal surfaces should be visualized, and any peritoneal surface or adhesion suspicious for harboring metastasis should be selectively excised or biopsied. In the absence of any suspicious areas, random peritoneal biopsies should be taken from the pelvis, paracolic gutters, and undersurfaces of the diaphragm (diaphragm scraping for Papanicolaou stain is an acceptable alternative).- BSO and hysterectomy should be performed with every effort to keep an encapsulated mass intact during removal.- For selected patients desiring to preserve fertility, USO or BSO with uterine preservation may be considered. Uterine preservation allows for potential future assisted reproductive approaches.- Omentectomy should be performed.- Para-aortic lymph node dissection should be performed by stripping the nodal tissue from the vena cava and the aorta bilaterally to at least the level of the inferior mesenteric artery and preferably to the level of the renal vessels.- The preferred method of dissecting pelvic lymph nodes is bilateral removal of lymph nodes overlying and anterolateral to the common iliac vessel, overlying and medial to the external iliac vessel, overlying and medial to the hypogastric vessels, and from the obturator fossa at a minimum anterior to the obturator nerve.2. Newly Diagnosed Invasive Epithelial Ovarian Cancer Involving the Pelvis and Upper Abdomen (stage >HB). In general, every effort should be made during a primary cytoreduction procedure to achieve maximum cytoreduction of all abdominal, pelvic, and retroperitoneal disease. Residual disease <1 cm defines optimal cytoreduction; however, maximal effort should be made to remove all gross disease since this offers superior survival outcomes.. Aspiration of ascites (if present) should be performed for peritoneal cytologic examinations. All involved omentum should be removed. Suspicious and/or enlarged nodes, identified on preoperative imaging or during surgical exploration, should be resected, if possible. Resection of clinically negative nodes is not required.. Procedures that may be considered for optimal surgical cytoreduction (in all stages) include bowel resection and/or appendectomy, stripping of the diaphragm or other peritoneal surfaces, splenectomy, partial cystectomy and/or ureteroneocystostomy, partial hepatectomy, partial gastrectomy, cholecystectomy, and/or distal pancreatectomy.. Select patients with low- volume residual disease after surgical cytoreduction for invasive epithelial ovarian or peritoneal cancer are potential candidates for IP therapy. In these patients, consideration should be given to placement of IP catheter with initial surgery.. # National NCCN Guidelines Version 1.2025 Comprehensive Ovarian Cancer/Fallopian Tube Cancer/Primary NCCN Cancer Network Peritoneal Cancer. PRINCIPLES OF SURGERY1. Interval Debulking Surgery After Neoadjuvant Chemotherapy of Invasive Epithelial Ovarian Cancer. As with a primary debulking procedure, every effort should be made to achieve maximum cytoreduction during an interval debulking procedure. Maximal effort should be made to remove all gross disease in the abdomen, pelvis, and retroperitoneum. Consultation with a gynecologic oncologist is recommended.. - IDS, including completion hysterectomy and BSO with staging, should be performed after 3-4 cycles of neoadjuvant chemotherapy for patients with a response to chemotherapy or stable disease. Alternate timing of surgery has not been prospectively evaluated but may be considered based on individual patient-centered factors.. - HIPEC with cisplatin . - All peritoneal surfaces should be visualized, and any peritoneal surface or adhesion suspicious for harboring metastasis should be selectively excised or biopsied.. - An omentectomy should be performed.. - While systematic lymphadenectomy of clinical-negative nodes is not recommended, suspicious and/or enlarged nodes should be resected, if possible.. - Procedures that may be considered for optimal surgical debulking include bowel resection and/or appendectomy, stripping of the diaphragm or other peritoneal surfaces, splenectomy, partial cystectomy and/or ureteroneocystostomy, partial hepatectomy, partial gastrectomy, cholecystectomy, and/or distal pancreatectomy.. Risk- Reducing Salpingo- Oophorectomy (RRSO) Protocol For information on when RRSO is indicated, see NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. Perform minimally invasive laparoscopic surgery. Survey upper abdomen, bowel surfaces, omentum, appendix (if present), and pelvic organs. Biopsy any abnormal peritoneal findings. Obtain pelvic washing for cytology (50 cc normal saline instilled and aspirated immediately). Perform total BSO, removing 2 cm of proximal ovarian vasculature/ IP ligament, all tube up to the cornula, and all peritoneum surrounding the ovaries and tubes, especially peritoneum underlying areas of adhesion between tube and/or ovary and the pelvic sidewall. Engage in minimal instrument handling of the tubes and ovaries to avoid traumatic exfoliation of cells. Both ovaries and tubes should be placed in an endobag for retrieval from the pelvis. Both ovaries and tubes should be processed by sectioning and extensively examining the fimbriated end (SEE- FIM) protocol. If occult malignancy or serous tubal intraepithelial carcinoma (STIC) is identified, provide referral to a gynecologic oncologist. The prevention benefits of salpingectomy alone are not yet proven. If considered, the fallopian tube from the fimbria to its insertion into the uterus should be removed. In addition, the fallopian tube should be processed and assessed as described above. The concern for risk- reducing salpingectomy alone is that patients are still at risk for developing ovarian cancer. In addition, in premenopausal patients, oophorectomy reduces the risk of developing breast cancer but the magnitude is uncertain. See NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate.. # Special Circumstances. Fertility- sparing surgery:. Fertility- sparing surgery with USO (preserving the uterus and contralateral ovary) or BSO (preserving the uterus) can be considered for patients with apparent early- stage disease and/or low- risk tumors (early- stage invasive epithelial tumors, LMP lesions, malignant germ cell tumors, mucinous tumors, or malignant sex cord- stromal tumors) who wish to preserve fertility. Consider endometrial sampling to exclude synchronous primary or hyperplasia. Refer to reproductive endocrinologist for evaluation and REI consultation as clinically indicated. Comprehensive surgical staging should still be performed to rule out occult higher stage disease but may be omitted in pediatric, adolescent, and young adult patients with clinically apparent early- stage malignant germ cell tumors based on the pediatric surgical literature.7. Mucinous tumors: Primary invasive mucinous tumors of the ovary are uncommon. Thus, the upper and lower GI tract should be carefully evaluated to rule out an occult GI primary with ovarian metastases, and an appendectomy need only be performed in patients with a suspected or confirmed mucinous ovarian neoplasm if it appears to be abnormal. A normal appendix does not require surgical resection in this setting. If mucinous histology is confirmed by intraoperative frozen section analysis and there are no suspicious lymph nodes, consider omitting lymphadenectomy.. Ovarian borderline epithelial (LMP) tumors: Although data show upstaging with lymphadenectomy, other data show that lymphadenectomy does not affect overall survival. However, omentectomy and multiple biopsies of peritoneum (the most common sites of peritoneal implants) may upstage patients in approximately . Secondary cytoreduction: A secondary cytoreduction procedure can be considered in patients with recurrent ovarian cancer who develop a recurrence more than 6 months since completion of initial chemotherapy, have a good performance status, have no ascites, and have an isolated focus or limited foci of disease amenable to complete resection. In addition to preoperative imaging, laparoscopy may be used to determine if complete resection can be achieved. Secondary cytoreduction can be performed with either open or minimally invasive approaches. Consider using validated scoring methods to assess suitability for secondary cytoreduction.. Ancillary Palliative Surgical Procedures8 These procedures may be appropriate in select patients: Paracentesis/indwelling peritoneal catheter Thoracentesis/pleurodesis/video- assisted thoracoscopy/indwelling pleural catheter Ureteral stents/nephrostomy Gastrostomy tube/intestinal stents/surgical relief of intestinal obstruction. 1Fleng d i 20171- 705. 7 Bile 201242429. 8. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. PRINCIPLES OF PATHOLOGY. General. The complete histologic classification from the WHO is included in the NCCN Guidelines (WHO Histologic Classification on OV- E). The WHO pathology manual is also a useful resource.. Most ovarian cancers, including the LCOC, are diagnosed after pathologic analysis of a biopsy or surgical specimen. Fine- needle aspiration (FNA) should be avoided for diagnosis of ovarian cancer in patients with presumed early stage disease to prevent rupturing the cyst and spilling malignant cells into the peritoneal cavity. However, FNA may be necessary in patients with bulky disease who are not candidates for primary debulking.2,3. Both primary peritoneal and fallopian tube cancers are usually diagnosed postoperatively (if there is no major involvement of the ovary) or preoperatively (if there is a biopsy and the patient has already had a bilateral salpingo- oophorectomy). Primary peritoneal and fallopian tube cancers are treated in the same manner as epithelial ovarian cancer.. The CAP protocol is a useful tool for pathology reports. Pathologic assessment should include:. \diamond. Tumor molecular analyses. In the upfront setting, choice of somatic testing should, at a minimum, optimize identification of molecular alterations that can inform use of interventions that have demonstrated benefit in this setting, including BRCA1/2, loss of heterozygosity (LOH), or homologous recombination deficiency (HRD) status in the absence of a germline BRCA mutation. In the recurrence setting, tumor molecular analysis is recommended to include, as appropriate, tests to identify potential benefit from targeted therapeutics that have tumor- specific or tumor- agnostic benefit including, but not limited to, HER2 status (by IHC), BRCA1/2, HRD status, microsatellite instability (MSI), mismatch repair (MMR), tumor mutational burden (TMB), BRAF, FRα (FOLR1), RET, and NTRK if prior testing did not include these markers. More comprehensive testing may be particularly important in less common histologies with limited approved therapeutic options. It is recommended that such testing be performed on the most recent available tumor tissue. Molecular analyses may be performed on circulating tumor DNA (ctDNA or liquid biopsy) when tissue- based analysis is not clinically feasible. . # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. PRINCIPLES OF PATHOLOGY. Less Common Ovarian Cancers (LCOC). A borderlinr t mri pthl ion wth c hctic s gng maly ut wtht frk inion. he terms for borderlin epithelial tumors (also known as LMP tumors or atypical proliferative tumors) have changed over the years. The 2023 CAP protocol for ovarian cancer uses borderline and does not use LMP.4 Borderine epithelial tumors are typically serous or mucinous; other histologic subtypes can also occur (WHO Histologic Classification on OV- E). The characteristic pathologic hallmark of typical epithelial ovarian cancer is the identification of peritoneal implants, which microscopically and/or macroscopically invade the peritoneum. A borderlin epithelial tumor may grossly resemble an invasive cancer. However, microscopic evaluation fails to reveal evidence of frank invasion by the tumor nodules, although rarely invasive implants (which continue to be consistent with the diagnosis of borderline epithelial lesions) can be identified microscopically by the pathologist.. Clear cell carcinomas are high- grade tumors that may arise in endometriosis. Most clear cell carcinomas express napsin A and are negative for WT1 and estrogen receptors.5. It is difficult to distinguish based on histology between primary mucinous ovarian carcinomas and Gl metastases.7,8,9 PAX8 immunostaining is typical of primary ovarian tumors, although the absence of PAX8 does not rule out ovary as the primary site,10 while SATB2 is consistent with colonic origin.11 Features favoring primary ovarian carcinoma versus metastasis are: unilateral, "expansile" pattern of invasion, complex papillary pattern, size . Most early stage invasive mucinous ovarian cancers have an expansile pattern of growth characterized by complex glandular, papillary and/ or cribriform architecture with a labyrinthine or anastomosing pattern and little or no intervening stroma. About . Metastatic colorectal adenocarcinomas also usually are positive for CK20. Endometrioid carcinomas may be associated with endometriosis.10,15 Endometrioid adenocarcinomas are usually positive for cytokeratin 7 (CK7), PAX8, and estrogen receptors. Endometrioid tumors are also very similar in appearance to sex cord- stromal tumors.5 Most pathologists now consider MMMTs to be a variant of poorly differentiated epithelial ovarian cancer (metaplastic carcinoma).16. Special Circumstances. Other cancers17,18 that can commonly involve the adnexa include: Uterine Cervical Cl (small and large bowel, pancreatic) . For risk- reducing surgery, pathologic assessment should include the following: Fallopian tubes should be processed by SEE- FIM of the tubes and then assessed to determine whether any evidence of cancer is present.4 The ovaries should also be carefully sectioned, processed, and assessed.4 The 2023 CAP protocol describes the process for sectioning the fallopian tubes and ovaries.4. Patients who have equivocal pathologic findings or who are referred to NCCN Member Institutions after having a previous diagnosis of ovarian cancer should have their pathology reviewed by pathologists at NCCN Member Institutions.. Note: All recommendations are category 2A unless otherwise indicated.. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. PRINCIPLES OF PATHOLOGY REFERENCES. Adhikari L, Hassell LA. World Health Organization Classification of Female Genital Tumours, 5th edition. IARC, 2020. Cannistra SA, Gershenson DM, Recht A. Ovarian cancer, fallopian tube carcinoma, and peritoneal carcinoma. In: DeVita Jr. VT, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology (Cancer Principles and Practice of Oncology), 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2014:1075- 1099. Vergote I, De Brabanter J, Fyles A, et al. Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Lancet 2001;357:176- 182. Crothers BA, Krishnamurti UG, Birdsong GG, et al. Protocol for the Examination of Specimens From Patients With Primary Tumors of the Ovary, Fallopian Tube, or Peritoneum. Based on AJCC/UICC TNM, 8th edition: Protocol web posting date: March 2023: College of American Pathologists, 2023. McCluggage WG, Judge MJ, Clarke BA, et al. Data set for reporting of ovary, fallopian tube and primary peritoneal carcinoma: recommendations from the International Collaboration on Cancer Reporting (ICCR). Mod Pathol 2015;28:1101- 1122. Fischerova D, Zikan M, Dundr P, Cibula D. Diagnosis, treatment, and follow- up of borderline ovarian tumors. Oncologist 2012;17:1515- 1533. Bruls J, Simons M, Overbeek LI, et al. A national population based study provides insight in the origin of malignancies metastatic to the ovary. Virchows Arch 2015;467:79- 86. McCluggage WG, Wilkinson N. Metastatic neoplasms involving the ovary: a review with an emphasis on morphological and immunohistochemical features. Histopathology 2005;47:231- 247. de Waal YR, Thomas CM, Oei AL, et al. Secondary ovarian malignancies: frequency, origin, and characteristics. Int J Gynecol Cancer 2009;19:1160- 1165. Madore J, Ren F, Filal M, et al. Characterization of the molecular differences between ovarian endometrioid carcinoma and ovarian serous carcinoma. J Pathol 2010;220:392- 400. Strickland S, Wasserman JK, Giassi A, et al. Immunohistochemistry in the diagnosis of mucinous neoplasms involving the ovary: the added value of SATB2 and biomarker discovery through protein expression database mining. Int J Gynecol Pathol 2016;35:191- 208. Lee K, Young RH. The distinction between primary and metastatic mucinous carcinomas of the ovary: gross and histologic findings in 50 cases. Am J Surg Pathol 2003;27:281- 292. Meagher NS, Gorringe KL, Wakefield M, et al. Gene- expression profiling of mucinous ovarian tumors and comparison with upper and lower gastrointestinal tumors identifies markers associated with adverse outcomes. Clin Canc Res 2022;28:5383- 5395. Kobel M, Kang EY, Lee S, et al. Infiltrative pattern of invasion is independently associated with shorter survival and desmoplastic stroma markers FAP and THBS2 in mucinous ovarian carcinoma. Histopathology 2024;84:1095- 1110. Mackay HJ, Brady MF, Oza AM, et al. Prognostic relevance of uncommon ovarian histology in women with stage III/IV epithelial ovarian cancer. Int J Gynecol Cancer 2010;20:945- 952. Berton Rigaud D, Devouassoux Shisheboran M, Ledermann JA, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for uterine and ovarian carcinosarcoma. Int J Gynecol Cancer 2014;24:S55- 60. Young RH. From Krakenberg to today: the ever present problems posed by metastatic tumors in the ovary. Part II. Adv Anat Pathol 2007;14:149- 177. Lee KR, Young RH. The distinction between primary and metastatic mucinous carcinomas of the ovary: gross and histologic findings in 50 cases. Am J Surg Pathol 2003;27:281- 292.. # PRINCIPLES OF SYSTEMIC THERAPY. General Principles General Principles of Systemic Therapy OV- C (1 of 12) Principles of Neoadjuvant Therapy OV- C (2 of 12) Principles of Maintenance PARP Inhibitor Therapy OV- C (3 of 12) Principles of Recurrence Therapy OV- C (4 of 12). Primary Systemic Therapy Regimens - Epithelial Ovarian/Fallopian Tube/Primary Peritoneal Stage I Disease OV- C (5 of 12) Stage II- IV Disease OV- C (6 of 12) Recommended Dosing OV- C (7 of 12). Acceptable Recurrence Therapies - Epithelial Ovarian/Fallopian Tube/Primary Peritoneal Platinum- Sensitive Disease OV- C (8 of 12) Platinum- Resistant Disease OV- C (9 of 12). # National NCCN Guidelines Version 1.2025 Comprehensive Ovarian Cancer/Fallopian Tube Cancer/Primary NCCN Cancer Network Peritoneal Cancer. PRINCIPLES OF SYSTEMIC THERAPY. General. Patients with ovarian, fallopian tube, or peritoneal cancer should be encouraged to participate in clinical trials during all aspects of their diagnosis and treatment. Prior to recommending chemotherapy, requirements for adequate organ function and performance status should be met. Prior to the initiation of any therapy: All patients with suspected stage IIIC or IV invasive epithelial ovarian cancer should be evaluated by a gynecologic oncologist prior to initiation of therapy to determine whether they are candidates for primary cytoreductive surgery (PCS). Patients of childbearing potential who desire fertility- sparing procedures should be referred to an appropriate fertility specialist (see Fertility, Reproductive Endocrine, and Sexual Health Considerations for Individuals with Ovaries in the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology). Goals of systemic therapy should be discussed. Consider scalp cooling to reduce incidence of alopecia for patients receiving chemotherapy with high rates of alopecia. Patients should be observed closely and treated for any complications during chemotherapy. Appropriate blood chemistry tests should be monitored. Appropriate dose reductions and modifications of chemotherapy should be performed depending on toxicities experienced and goals of therapy. After completion of chemotherapy, patients should be assessed for response during and following treatment and monitored for any long- term complications. Chemosensitivity/resistance and/or other biomarker assays are being used at some NCCN Member Institutions for decisions related to future chemotherapy in situations where there are multiple equivalent chemotherapy options available. The current level of evidence is not sufficient to supplant standard- to- care chemotherapy (category 3). An FDA- approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.. Definitions Used in the NCCN Guidelines for Ovarian Cancer. Adjuvant therapy: Drugs, radiation, or other forms of supplemental treatment following cancer surgery intended to decrease the risk of disease recurrence or to primarily treat residual disease, whether gross or microscopic, following surgical cytoreduction. Neoadjuvant therapy: Drugs, radiation, or other forms of treatment given prior to cancer surgery intended to reduce tumor burden in preparation for surgery. Recurrence therapy: Drugs, radiation, or other forms of treatment used to treat recurrent cancer, control symptoms, or increase length and/ or quality of life at the time of clinical, biochemical, or radiographic evidence of recurrent cancer following the initial treatment.. For Patients with Newly Diagnosed Ovarian, Fallopian Tube, or Primary Peritoneal Cancer:. If they are eligible for chemotherapy, patients should be informed about the different primary therapy options that are available- such as IV chemotherapy, a combination of IP and IV chemotherapy, or a clinical trial- so they can decide which is the most appropriate option. Prior to the administration of the combined IP and IV regimen, patients must be apprised of the increased toxicities with the combined regimen when compared to using IV chemotherapy alone (increased myelosuppression, renal toxicities, abdominal pain, neuropathy, Gl toxicities, metabolic toxicities, and hepatic toxicities). Patients considered for the IP cisplatin and IP/IV paclitaxel regimen should have normal renal function prior to starting, a medically appropriate performance status based on the future toxicities of the IP/IV regimen, and no prior evidence of medical problems that could significantly worsen during chemotherapy (eg, pre- existing neuropathy).. Prior to receiving and after receiving each cycle of IP cisplatin, adequate amounts of IV fluids need to be administered in order to prevent renal toxicity. After each cycle has been completed, patients need to be monitored carefully for myelosuppression, dehydration, electrolyte loss, end- organ toxicities (such as renal and hepatic damage), and all other toxicities. Patients often require IV fluids postchemotherapy in the outpatient setting to prevent or help treat dehydration.. Refer to the original references (Discussion) for full toxicity data, doses, schedule, and dose modifications.. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. PRINCIPLES OF SYSTEMIC THERAPY. Principles of Neoadjuvant Therapy. - Consider the histology of the primary tumor and the potential response to primary chemotherapy when evaluating for neoadjuvant chemotherapy.- Any of the primary IV regimens for stage II-IV high-grade serous carcinoma and respective LCOCs can be used as neoadjuvant therapy before surgery. Neoadjuvant therapy does not apply to LMP and other noninvasive cancers. See OV-C (6 of 12) and LCOC-A.- Bevacizumab-containing regimens should be used with caution before surgery due to potential interference with postoperative healing. If bevacizumab is being used as part of a neoadjuvant regimen, bevacizumab should be withheld from therapy for 4-6 weeks prior to surgery.- After neoadjuvant therapy and surgery, any of the adjuvant therapy options for high-grade serous carcinoma (IV or IP/IV) and respective LCOCs can be considered. Neoadjuvant therapy does not apply to LMP and other noninvasive cancers. See OV-C (6 of 12) and LCOC-A.- There are limited data for the use of IP chemotherapy regimens after neoadjuvant therapy and surgery. The following is an additional IP option after surgery: paclitaxel 135 mg/m2 IV on Day 1, carboplatin area under the curve (AUC) 6 IP on Day 1, and paclitaxel 60 mg/m2 IP on Day 8. a- A minimum of 6 cycles of treatment is recommended, including at least 3 cycles of adjuvant therapy after surgery. Patients with stable disease who are tolerating therapy may continue past 6 cycles.. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. PRINCIPLES OF SYSTEMIC THERAPY. Principles of Maintenance PARP Inhibitor (PARPi) Therapy. Post Primary Treatment. - Certain patients with newly diagnosed stage II-IV disease (high-grade serous, grade 2/3 endometrioid, or BRCA1/2-mutated clear cell carcinoma or carcinosarcoma) may benefit from maintenance therapy with PARPi if CR or PR is achieved after primary treatment with surgery and platinum-based first-line therapy. See OV-5 for PARPi options and patient selection criteria. Data are limited for use of maintenance PARPi post primary treatment in patients with stage II disease and for those with LCOC.. patients with stage II disease and for those with LCOC.. Post Recurrence Treatment. Patients with BRCA- mutated recurrent disease may benefit from maintenance therapy with PARPi after recurrence therapy, if in CR or PR after platinum- based recurrence therapy, and if no prior progression on a PARPi. See OV- 8 for PARPi options and patient selection criteria.. General Information on PARPi . Continued. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. PRINCIPLES OF SYSTEMIC THERAPY. Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer:. - Refer to the original references (Discussion) for full toxicity data, doses, schedule, and dose modifications.- Patients should be informed about the following:. 1) Availability of clinical trials, including the risks and benefits of various treatments, which will depend on the number of prior lines of chemotherapy the patient has received, and2) Performance status, end-organ status, and pre-existing toxicities from prior regimens. If appropriate, palliative care should also be discussed as a possible treatment choice. See NCCN Guidelines for Palliative Care.. - Tumor molecular testing is recommended if not previously done for persistent/recurrent disease. See Principles of Pathology (OV-B).- Because of prior platinum exposure, myelosuppression occurs more frequently with any myelotoxic agent given in the recurrent setting.- With repeat use of either carboplatin and/or cisplatin, patients are at an increased risk of developing a hypersensitivity reaction (also called an allergic reaction) that could be life-threatening. Thus, patients should be counseled about the risk that a hypersensitivity reaction may occur, educated about the signs and symptoms of hypersensitivity reactions, treated by medical staff who know how to manage hypersensitivity reactions, and treated in a medical setting where appropriate medical equipment is available in case of an allergic reaction. See Management of Drug Reactions (OV-D).. - Before any chemotherapy drug is given in the recurrent setting, the clinician should be familiar with the drug's metabolism (ie, renal, hepatic) and should make certain that the patient is an appropriate candidate for the drug (eg, that the patient has adequate renal or hepatic function).. - Clinicians should be familiar with toxicity management and appropriate dose reduction.. - The schedule, toxicity, and potential benefits of any treatment should be thoroughly discussed with the patient and caregivers. Patient education should also include a discussion of precautions and measures to reduce the severity and duration of complications.. - Patients who do not respond and progress on two consecutive regimens without evidence of clinical benefits have diminished likelihood of benefitting from additional therapy (Griffiths RW, et al. Int J Gynecol Cancer 2011;21:58-65). Decisions to offer clinical trials, supportive care, or additional therapy should be made on an individual basis.. Acceptable Recurrence Therapies for Platinum-Sensitive Disease (OV-C, 8 of 12). Acceptable Recurrence Therapies for Platinum- Resistant Disease (OV- C, 9 of 12). # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. PRINCIPLES OF SYSTEMIC THERAPY Primary Systemic Therapy Regimensc - Epithelial Ovarian/Fallopian Tube/Primary Peritoneal. Primary Therapy for Stage I Disease. See Discussion for references.. There are limited data on the primary systemic therapy regimens for these LCOC. Borderline disease with invasive implants may be treated as low- grade serous disease. See LCOC- 6 and LCOC- 8. For low- grade serous, maintenance letrozole is a category 2A recommendation. For grade I endometrioid, maintenance letrozole is a category 2B recommendation. Albumin- bound paclitaxel may be substituted for those experiencing a hypersensitivity reaction to paclitaxel. However, albumin- bound paclitaxel will not overcome infusion reactions in all patients. Individuals . Note: All recommendations are category 2A unless otherwise indicated.. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. Primary Systemic Therapy Dosing (OV-C, 7 of 12). h Individuals . Continued. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. PRINCIPLES OF SYSTEMIC THERAPY Primary Systemic Therapy Regimens<sup>1</sup> - Epithelial Ovarian (including LCOC)/Fallopian Tube/Primary Peritoneal. Primary Systemic Therapy Recommended Dosing. Paclitaxel/carboplatin every 3 weeks<sup>9,1</sup> - Paclitaxel 175 mg/m<sup>2</sup> IV followed by carboplatin<sup>m</sup> AUC 5- 6 IV Day 1 - Repeat every 21 days x 3- 6 cycles<sup>1</sup>. Paclitaxel/cisplatin every 3 weeks<sup>10,11</sup>. Paclitaxel 175 mg/m<sup>2</sup> IV followed by cisplatin 75 mg/m<sup>2</sup> IV - Repeat every 21 days x 3- 9 cycles. IV/IP Paclitaxel/cisplatin. - Paclitaxel 135 mg/m<sup>2</sup> IV continuous infusion<sup>n</sup> Day 1; cisplatin 75-100 mg/m<sup>2</sup> IP Day 2 after IV paclitaxel; paclitaxel 60 mg/m<sup>2</sup> IP Day 8- Repeat every 21 days x 6 cycles. IV/IP Paclitaxel/carboplatin<sup>12</sup>. - Paclitaxel 80 mg/m<sup>2</sup> IV on days 1, 8, and 15; carboplatin AUC 6 IP Day 1 after IV paclitaxel- Repeat every 21 days x 6-8 cycles. Paclitaxel weekly/carboplatin every 3 weeks<sup>9</sup>. - Dose-dense paclitaxel 80 mg/m<sup>2</sup> IV Days 1, 8, and 15 followed by carboplatin<sup>n</sup> AUC 5-6 IV Day 1- Repeat every 21 days x 6 cycles. Paclitaxel weekly/carboplatin weekly<sup>9</sup>. - Paclitaxel 60 mg/m<sup>2</sup> IV followed by carboplatin AUC 2 IV- Days 1, 8, and 15; repeat every 21 days x 6 cycles (18 weeks)<sup>k</sup>. Docetaxel/oxaliplatin/bevacizumab + maintenance bevacizumab. Docetaxel 75 mg/m<sup>2</sup> IV followed by oxaliplatin 85 mg/m<sup>2</sup> IV, and bevacizumab 15 mg/kg IV- Repeat every 21 days x 6 cycles- Continue bevacizumab 15 mg/kg IV every 21 days to complete 1 year of therapy. Individuals >70 Years and/or Those with Comorbidities. Paclitaxel 135/carboplatin<sup>9,13</sup>. - Paclitaxel 135 mg/m<sup>2</sup> IV + carboplatin AUC 5 IV given every 21 days x 3-6 cycles<sup>1</sup>. Paclitaxel weekly/carboplatin weekly<sup>9</sup>. - Paclitaxel 60 mg/m<sup>2</sup> IV over 1 hour followed by carboplatin AUC 2 IV over 30 minutes- Days 1, 8, and 15; repeat every 21 days x 6 cycles (18 weeks). Docetaxel/carboplatin<sup>1</sup>- Docetaxel 60- 75 mg/m<sup>2</sup> IV followed by carboplatin<sup>m</sup> AUC 5- 6 IV Day 1- Repeat every 21 days x 3- 6 cycles<sup>k</sup>. Carboplatin/liposomal doxorubicin<sup>1</sup>- Carboplatin AUC 5 IV + pegylated liposomal doxorubicin 30 mg/m<sup>2</sup> IV- Repeat every 28 days for 3- 6 cycles<sup>k</sup>. Paclitaxel/carboplatin/bevacizumab + maintenance bevacizumab<sup>9</sup> (ICON- 7)- Paclitaxel 175 mg/m<sup>2</sup> IV followed by carboplatin<sup>m</sup> AUC 5- 6 IV, and bevacizumab 7.5 mg/kg IV Day 1- Repeat every 21 days x 5- 6 cycles- Continue bevacizumab for up to 12 additional cycles. Paclitaxel/carboplatin/bevacizumab + maintenance bevacizumab<sup>9</sup> (GOG- 218)- Paclitaxel 175 mg/m<sup>2</sup> IV followed by carboplatin<sup>m</sup> AUC 6 IV Day 1. Repeat every 21 days x 6 cycles- Starting Day 1 of cycle 2, give bevacizumab 15 mg/kg IV every 21 days for up to 22 cycles. Docetaxel/carboplatin/bevacizumab + maintenance bevacizumab (GOG- 218)- Docetaxel 75 mg/m<sup>2</sup> IV followed by carboplatin<sup>m</sup> AUC 6 IV Day 1. Repeat every 21 days x 6 cycles- Starting Day 1 of cycle 2, give bevacizumab 15 mg/kg IV every 21 days for up to 22 cycles. See Discussion for references.. Albumin- bound paclitaxel may be substituted for those experiencing a hypersensitivity reaction to paclitaxel. However, albumin- bound paclitaxel will not overcome infusion reactions in all patients.. Regimen may be considered for those with poor performance status.. For stage I disease: 6 cycles is recommended for high- grade serous; 3- 6 cycles for all other ovarian cancer types. For stage II- IV disease: 6 cycles is recommended. Due to changes in creatinine methodology, changes regarding carboplatin dosing can be considered. See carboplatin dosing guidelines. The published randomized trial regimen used IV continuous infusion paclitaxel over 24 hours.. References on OV-C 10 of 12 Continued. # NCCN Guidelines Version 1.2025. Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. PRINCIPLES OF SYSTEMIC THERAPY. Acceptable Recurrence Therapies for Epithelial Ovarian (including LCOC)/Fallopian Tube/Primary Peritoneal Cancer. 9 Albumin- bound paclitaxel may be substituted for those experiencing a hypersensitivity reaction to paclitaxel. However, albumin- bound paclitaxel will not overcome infusion reactions in all patients. Tamoxifen is not recommended for low- grade serous carcinoma. Chemotherapy has not been shown to be beneficial in ovarian borderline epithelial tumors (LMP). In general, the panel would recommend combination, platinum- based regimens for platinum- sensitive recurrent disease based on randomized trial data, especially in first relapses. Contraindicated for patients at increased risk of GI perforation. If response after chemotherapy, bevacizumab can be continued as maintenance therapy until disease progression or unacceptable toxicity. Discontinue bevacizumab before initiating maintenance therapy with a PARPi. Many of these single- agent cytotoxic therapy options have not been tested in patients who have been treated with modern chemotherapy regimens. For patients treated with three or more prior chemotherapy regimens and whose cancer is associated with HRD defined by either: 1) a deleterious or suspected deleterious BRCA mutation; or 2) genomic instability and progression >6 months after response to the last platinum- based chemotherapy.. For patients with deleterious germline BRCA- mutated (as detected by an FDA- approved test or other validated test performed in a CLIA- approved facility) advanced ovarian cancer who have been treated with two or more lines of chemotherapy. For patients with deleterious germline and/or somatic BRCA mutated (as detected by an FDA- approved test or other validated test performed in a CLIA- approved facility) advanced ovarian cancer who have been treated with two or more lines of chemotherapy. For recommended dosing for individuals >70 years, see OV- C. 7 of 12. Validated molecular testing should be performed in a CLIA- approved facility using the most recent available tumor tissue. Tumor molecular analysis is recommended to include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor- specific or tumor- agnostic benefit including, but not limited to, HER2 status (by IHC), BRCA1/2, HRD status, MSI, MMR, TMB, BRAF, FRα (FOLR1), RET, and NTRK if prior testing did not include these markers. More comprehensive testing may be particularly important in LCOC with limited approved therapeutic options (OV- B).. For patients treated with two prior lines of platinum- based therapy.. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. PRINCIPLES OF SYSTEMIC THERAPY Acceptable Recurrence Therapies for Epithelial Ovarian (including LCOC)/Fallopian Tube/Primary Peritoneal Cancer. Note: All recommendations are category 2A unless otherwise indicated.. # NCCN Guidelines Version 1.2025Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. PRINCIPLES OF SYSTEMIC THERAPYAcceptable Recurrence Therapies for Epithelial Ovarian (including LCOC)P/Fallopian Tube/Primary Peritoneal CancerFOOTNOTES. Alumn- und pa t may stitutd for thx p y ctio pa. wer, alum- und pa t wil t ocome infusion reactions in all patients.. 1 Tamoxifen is not recommended for low- grade serous carcinoma. 0 Chemotherapy has not been shown to be beneficial in ovarian borderline epithelial tumors (LMP). 9 Contraindicated for patients at increased risk of Gl perforation. 1f reon h t t t before initiating maintenance therapy with a PARPi. s Many of the single- agent cytotoxic therapy options have not been tested in patients who have been treated with modern chemotherapy regimens. For pati th r r s w i i i BRCA mutation; or 2) genomic instability and progression . # National NCCN Guidelines Version 1.2025 Comprehensive Ovarian Cancer/Fallopian Tube Cancer/Primary NCCN Cancer Network Peritoneal Cancer. PRINCIPLES OF SYSTEMIC THERAPY REFERENCES. 1 Ray- Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first- line maintenance in ovarian cancer. N Engl J Med 2019;381:2416- 2428. 2 Hardesty MM, Krivak TC, Wright GS, et al. OVARIO phase II trial of combination piraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first- line platinum- based chemotherapy with bevacizumab. Gynecol Oncol 2022;166:219- 229. 3 Gonzalez- Martin A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2019;381:2391- 2402. 4 Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum- sensitive, recurrent ovarian cancer. 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Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015;33:244- 250. 29 Friedlander M, Hancock KC, Rischin D, et al. A Phase II, open- label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol 2010;119:32- 37. 30 Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum- sensitive high- grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open- label, phase 2 trial. Lancet Oncol 2017;18:75- 78. 31 Sugiyama T, Okamoto A, Enomoto T, et al. Randomized phase III trial of irinotecan plus cisplatin compared with paclitaxel plus carboplatin as first- line chemotherapy for ovarian clear cell carcinoma: JGOG3017/GCIG Trial. J Clin Oncol 2016;34:2881- 2887. 32 Salama A, Li S, Macrae E, et al. Dabrafenib and trametinib in patients with tumors with BRAF V600E mutations: Results of the NCI- MATCH trial subprotocol H. J Clin Oncol 2020;38:3895- 3904. 33 Doebele RC, Drilon A, Paz- Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion- positive solid tumours: integrated analysis of three phase 1- 2 trials. Lancet Oncol 2020;21:271- 282. 34 Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion- positive cancers in adults and children. N Engl J Med 2018;378:731- 739. 35 Solomon BJ, Drilon A, Lin JJ, et al. Repotrectinib in patients with NTRK fusion- positive advanced solid tumors, including non- small cell lung cancer: update from the phase 1/2 TRIDENT- 1 trial. Ann Oncol. 2023;34:S787- S788.. 36 Meric- Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2- expressing solid tumors: Primary results from the DESTINY- PanTumor02 phase II trial. J Clin Oncol 2024;42:47- 58. 37 Secord AA, Lewin SN, Murphy CG, Ceore SC, et al. The Efficacy and Safety of Mivetuximab Soravtansine in FRalpha- Positive, Third- Line and Later, Recurrent Platinum- Sensitive Ovarian Cancer: The Single- Arm Phase 2 PICCOLO Trial. Ann Oncol. 2024:S0923- 7534:04948- 2. 38 Gilbert L, Oaknin A, Matulonis UA, et al. Safety and efficacy of mivetuximab soravtansine, a folate receptor alpha (FRa)- targeting antibody- drug conjugate (ADC), in combination with bevacizumab in patients with platinum- resistant ovarian cancer. Gynecol Oncol 2023;170:241- 247. 39 Subbiah V, Wolf J, Konda B, et al. Tumour agnostic efficacy and safety of selpercatinib in patients with RET fusion- positive solid tumours other than lung or thyroid: a global, phase 1/2, multicentre, open- label trial (LIBRETTO- 001). Lancet Oncol 2022;23:1261- 1273. 40 Gershenson DM, Miller A, Brady W, et al. A randomized phase II/III study to assess the efficacy of trametinib in patients with recurrent or progressive low- grade serous ovarian or peritoneal cancer [abstract]. Ann Oncol 2019;30(Suppl):V897- V898. 41 Monk BJ, Grisham RN, Banerjee S, et al. MILO/ENGOT- ov11: Binimetinib versus physician's choice chemotherapy in recurrent or persistent low- grade serous carcinomas of the ovary, Fallopian tube, or primary peritoneum. J Clin Oncol 2020;38:3753- 3762. 42 Grisham RN, Vergote I, Banerjee SN, et al. Molecular results and potential biomarkers identified from MILO/ENGOT- ov11 phase 3 study of binimetinib versus physicians choice of chemotherapy (PCC) in recurrent low- grade serous ovarian cancer (LGSOC) [abstract]. J Clin Oncol 2021;39(Suppl):Abstract 5519. 43 Berton D, Banerjee S, Curigliano G, et al. Antitumor activity of dostarlimab in patients with mismatch repair- deficient (MMDR) tumors: a combined analysis of 2 cohorts in the GARNET study [abstract]. J Clin Oncol 2021;39(Suppl):Abstract 2564. 44 Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD- 1 blockade. Science 2017;357:409- 413. 45 Barber EL, Zsiros E, Lurain JR, et al. The combination of intravenous bevacizumab and metronomic oral cyclophosphamide is an effective regimen for platinum- resistant recurrent ovarian cancer. J Gynecol Oncol 2013;24:258- 264. 46 Rose PG, Blessing JA, Ball HG, et al. A phase II study of docetaxel in paclitaxel- resistant ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2003;88:130- 135.. # National NCCN Guidelines Version 1.2025 Comprehensive Ovarian Cancer/Fallopian Tube Cancer/Primary NCCN Cancer Network Peritoneal Cancer. PRINCIPLES OF SYSTEMIC THERAPY REFERENCES. 47 Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide as second- line therapy for platinum- resistant and platinum- sensitive ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1998;16:405- 410. 48 Mutch DG, Orlando M, Goss T, et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum- resistant ovarian cancer. J Clin Oncol 2007;25:2811- 2818. 49 Ferrandina G, Ludovisi M, Lorusso D, et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol 2008;26:890- 896. 50 Pujade- Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum- resistant recurrent ovarian cancer: The AURELIA open- label randomized phase III trial. J Clin Oncol 2014;32:1302- 1308. 51 Markman M, Blessing J, Rubin SC, et al. Phase II trial of weekly paclitaxel . 58 Poblete S, Caulkins M, Loecher C, et al. Pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer: Real- life clinical experience [abstract]. Ann Oncol 2022;33(Suppl): Abstract 569P. 59 Nagao S, Kogiku A, Suzuki K, et al. A phase II study of the combination chemotherapy of bevacizumab and gemcitabine in women with platinum- resistant recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Ovarian Res 2020;13:14. 60 Roque DM, Siegel E, Buza N, et al. Randomised phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum- resistant or refractory ovarian/ fallopian tube/primary peritoneal cancer. Br J Cancer 2022;126:1695- 1703. 61 O'Malley D, Oaknin A, Matulonis U, et al. Mirvetuximab soravtansine and bevacizumab in folate receptor alpha- positive ovarian cancer: efficacy in patients with and without prior bevacizumab [abstract]. International Gynecologic Cancer Society Annual Meeting 2022; Abstract 496. 62 O'Malley DM, Matulonis UA, Birrer MJ, et al. Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRa)- targeting antibody- drug conjugate (ADC), in combination with bevacizumab in patients with platinum- resistant ovarian cancer. Gynecol Oncol 2020;157:379- 385. 63 Kurnit CK, Sinno AK, Fellman BM, et al. Effects of gastrointestinal- type chemotherapy in women with ovarian mucinous carcinoma. Obstet Gyn 2019;134:1253- 1259. 64 Andre T, Louvet C, Maindrault- Goebel F, et al. CPT- 11 (irinotecan) addition to bimonthly, high- dose leucovorin and bolus and continuous- infusion 5- fluorouracil (FOLFIRI) for pretreated colorectal cancer. Eur J Canc 1999;35:1343- 1347. 65 Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first- line treatment of metastatic colorectal cancer: Results from the BICC- C study. J Clin Oncol 2007;25:4779- 4786. 66 Heinemann V, Fischer von Weikersthal L, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first- line treatment for patients with metastatic colorectal cancer (FIRE- 3): A randomised, open- label, phase 3 trial. Lancet Oncol 2014;15:1065- 1075.. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. MANAGEMENT OF DRUG REACTIONS. Overview. - Virtually all drugs used in oncology have the potential to cause adverse drug reactions while being infused, which can be classified as either infusion or allergic reactions.1- Infusion reactions are often characterized by milder symptoms (eg, hot flushing, rash).- Hypersensitivity (allergic) reactions are often characterized by more severe symptoms (eg, shortness of breath, generalized hives/itching, changes in blood pressure).- Most adverse drug reactions that occur are mild reactions, but more severe reactions can occur.2,3- Anaphylaxis is a rare type of very severe allergic reaction that can occur with platinum and taxane agents (and others less commonly), can cause cardiovascular collapse, and can be life-threatening.4-6- Drug reactions can occur either during infusion or following completion of infusion (and can even occur days later).- In gynecologic oncology treatment, drugs that more commonly cause adverse reactions include carboplatin, cisplatin, docetaxel, liposomal doxorubicin, oxaliplatin, and paclitaxel.1- Adverse reactions associated with biotherapeutic agents and taxane drugs (ie, docetaxel, paclitaxel) tend to be infusion-related and, in taxanes, are often attributed to the excipient (ie, Cremophor EL in paclitaxel, polysorbate 80 in docetaxel). These tend to occur during the first few cycles of treatment (although they can be seen during any infusion regardless of how many previous cycles were administered).- Adverse reactions associated with platinum drugs (ie, carboplatin, cisplatin), a true allergy, tend to occur following re-exposure to the inciting drug or less commonly at the completion of initial chemotherapy (ie, cycle 6 of a planned 6 treatments).3. - Preparation for a possible drug reaction- Patients and their families should be counseled about the possibility of a drug reaction and the signs and symptoms of one. Patients should be told to report any signs and symptoms of a drug reaction, especially after they have left the clinic (ie, delayed rash).- Clinicians and nursing staff should be prepared for the possibility of a drug reaction every time a patient is infused with a drug. Standing orders should be written for immediate intervention in case a severe drug reaction occurs and the treatment area should have appropriate medical equipment in case of a life-threatening reaction.5- Epinephrine (intramuscular [IM] 3.0 mL of 1 mg/mL solution/Epipen) should be used for any patient experiencing hypotension (systolic blood pressure of <90 mm Hg) with or without other symptoms of an allergic/hypersensitivity reaction during or shortly after any chemotherapy drug treatment. In the setting of acute cardiopulmonary arrest, standard resuscitation (advanced cardiovascular life support [ACLS]) procedures should be followed.- Desensitization refers to a process of rendering the patient less likely to react in response to an allergen and can be considered an option for patients who have had drug reactions.1,7-10- If a patient has previously had a very severe life-threatening reaction, the implicated drug should not be used again unless under guidance of an allergist or specialist with desensitization experience.. Continued on OV-D, 2 of 7. References on OV- D, 3 of 7. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. MANAGEMENT OF DRUG REACTIONS. Infusion Reactions. Infusion Reactions- Symptoms include: hot flushing, rash, fever, chest tightness, mild blood pressure changes, back pain, and chills.- Symptoms usually can be treated by decreasing the infusion rate and resolve quickly after stopping the infusion. However, patients who have had mild reactions to carboplatin, cisplatin, or oxaliplatin may develop more serious reactions even when the platinum drug is slowly infused; therefore, consider consultation with an allergist.11- Infusion reactions are more common with paclitaxel (27% of patients); however, mild reactions can occur with liposomal doxorubicin.11- If an infusion reaction has previously occurred in response to a taxane: - For mild infusion reactions (eg, flushing, rash, chills), patients may be rechallenged with the taxane if: 1) the patient, physician, and nursing staff are all comfortable with this plan; 2) the patient has been counseled appropriately; and 3) emergency equipment is available in the clinic area. - Typically the taxane infusion can be restarted at a much slower rate, and the rate can be slowly increased as tolerated as per the treating clinician's judgment.7,12 Note that this slow infusion is different from desensitization. - Many institutions have nursing policies that stipulate how to reinfuse the drug if the patient has had a prior infusion reaction.. Allergic Reactions (ie, True Drug Allergies). Allergic Reactions (ie, True Drug Allergies)- Symptoms include: rash, edema, shortness of breath (bronchospasm), syncope or pre- syncope, chest pain, tachycardia, hives/itching, changes in blood pressure, nausea, vomiting, chills, changes in bowel function, and occasionally feeling of impending doom.- Symptoms may continue to persist after stopping infusion and/or after treatment interventions.- Allergic reactions are more common with platinum drugs such as carboplatin (16% of patients), cisplatin, and oxaliplatin.12 Mild reactions can occur with platinum agents.12- Patients who are at higher risk of developing a hypersensitivity (allergic) reaction include those in the following settings: - Re- introduction of the drug after a period of no exposure and following multiple cycles of the drug during the first and subsequent exposures - IV administration of the drug rather than oral or IP administration - Those with allergies to other drugs - Those who have previously had a reaction- If an allergic reaction has previously occurred: - Consider consultation with an allergist (or qualified medical or gynecologic oncologist) and skin testing for patients who have experienced a platinum reaction (eg, carboplatin- hypersensitivity reaction).12- 14- Patients who have had mild reactions may develop more serious reactions even when the platinum drug is slowly infused.12- For more severe or life- threatening reactions—such as those involving blood pressure changes, dyspnea, tachycardia, widespread urticaria, anaphylaxis, or hypoxia—the implicated drug should not be used again unless under guidance of a specialist with desensitization experience. - If it is appropriate to give the drug again, patients should be desensitized prior to resuming chemotherapy even if the symptoms have resolved. Patients must be desensitized with each infusion if they previously had a drug reaction.1,7- 10. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. MANAGEMENT OF DRUG REACTIONS REFERENCES. 1 Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to chemotherapy: Outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 2008;122:574- 580. 2 Dizon DS, Sabbatini PJ, Aghajanian C, et al. Analysis of patients with epithelial ovarian cancer or fallopian tube carcinoma retreated with cisplatin after the development of a carboplatin allergy. Gynecol Oncol 2002;84:378- 382. 3 Markman M, Kennedy A, Webster K, et al. Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol 1999;17:1141- 1145. 4 Manivannan V, Decker WW, Stead LG, et al. Visual representation of National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis Network criteria for anaphylaxis. Int J Emerg Med 2009;2:3- 5. 5 Oswalt ML, Kemp SF. Anaphylaxis: office management and prevention. Immunol Allergy Clin North Am 2007;27:177- 191. 6 Sampson HA, Munoz- Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report- - second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Ann Emerg Med 2006;47:373- 380. 7 Lee CW, Matulonis UA, Castells MC. Rapid inpatient/outpatient desensitization for chemotherapy hypersensitivity: standard protocol effective in 57 patients for 255 courses. Gynecol Oncol 2005;99:393- 397. 8 Lee CW, Matulonis UA, Castells MC. Carboplatin hypersensitivity: A 6- hour 12 step protocol effective in 35 desensitizations in patients with gynecological malignancies and mast cell/IgE- mediated reactions. Gynecol Oncol 2004;95:370- 376. 9 Markman M, Hsieh F, Zanotti K, et al. Initial experience with a novel desensitization strategy for carboplatin- associated hypersensitivity reactions. J Cancer Research Clin Oncol 2004;130:25- 28. 10 Rose PG, Metz C, Link N. Desensitization with oxaliplatin in patients intolerant of carboplatin desensitization. Int J Gynecol Cancer 2014;24:1603- 1606. 11 Gabizon AA. Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy. Cancer Invest 2001;19:424- 436. 12 Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. Oncologist 2007;12:601- 609. 13 Markman M, Zanotti K, Peterson G, et al. Expanded experience with an intradermal skin test to predict for the presence or absence of carboplatin hypersensitivity. J Clin Oncol 2003;21:4611- 4614. 14 Zanotti KM, Rybicki LA, Kennedy AW, et al. Carboplatin skin testing: A skin- testing protocol for predicting hypersensitivity to carboplatin chemotherapy. J Clin Oncol 2001;19:3126- 3129.. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. MANAGEMENT OF DRUG REACTIONS. DRUG REACTION REACTION TO PLATINUM. MANAGEMENT/TREATMENTc. Drug Reaction to Taxane, Liposomal Doxorubicin, or Biotherapeutic Agents (OV-D, 6 of 7). a Most mild reactions are infusion reactions and more commonly are caused by taxanes (ie, docetaxel, paclitaxel), but can also occur with platinum agents (ie, carboplatin, cisplatin). b Most severe reactions are allergic reactions and more commonly are caused by platinum agents. c H1 blocker antihistamine (eg, diphenhydramine, hydroxyzine); H2 blockers (eg, cimetidine, famotidine); corticosteroids (eg, methylprednisolone, hydrocortisone, dexamethasone). d In the setting of acute cardiopulmonary arrest, standard resuscitation (ACLS) procedures should be followed.. e Mild reactions can progress to severe reactions by re- exposure. An allergy consultation may provide skin testing and evaluate sensitization and the risk for further, more severe reactions. f Referral to an academic center with expertise in desensitization is preferred. 1 Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to chemotherapy: Outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 2008;122:574- 580.. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. MANAGEMENT OF DRUG REACTIONS MANAGEMENT/TREATMENT. DRUG REACTION REACTION TO PLATINUM AGENTS. Drug Reaction to Toxane, Liposomal Doxorubicin, or Biotherapeutic Agents (OV-D, 6 of 7). a Most mild reactions are infusion reactions and more commonly are caused by taxanes (ie, docetaxel, paclitaxel), but can also occur with platinum agents (ie, carboplatin, cisplatin). b Most severe reactions are allergic reactions and more commonly are caused by platinum agents. c H1 blocker antihistamine (eg, diphenhydramine, hydroxyzine); H2 blockers (eg, cimetidine, famotidine); corticosteroids (eg, methylprednisolone, hydrocortisone, dexamethasone).. d In the setting of acute cardiopulmonary arrest, standard resuscitation (ACLS) procedures should be followed. f Referral to an academic center with expertise in desensitization is preferred. g For both taxanes and platinum analogues, it is preferred that anyone with a life- threatening reaction be evaluated and referred to an academic center if the drug is still considered first line. 1 Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to chemotherapy: Outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 2008;122:574- 580.. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. MANAGEMENT OF DRUG REACTIONS. DRUG REACTION REACTION TO TAXANE, LIPOSOMAL DOXORUBICIN, OR BIOTHERAPEUTIC AGENTS. MANAGEMENT/TREATMENTc. a Most mild reactions are infusion reactions and more commonly are caused by taxanes (ie, docetaxel, paclitaxel), but can also occur with platinum agents (ie, carboplatin, cisplatin). b Most severe reactions are allergic reactions and more commonly are caused by platinum agents. c H1 blocker antihistamine (eg, diphenhydramine, hydroxyzine); H2 blockers (eg, cimetidine, famotidine); corticosteroids (eg, methylprednisolone, hydrocortisone, dexamethasone).. h Consider switching to albumin- bound paclitaxel due to medical necessity (ie, hypersensitivity reaction), or consider switching to docetaxel; however, there are no data to support switching taxanes. Cross reactions have occurred and have been life- threatening. Some reactions to paclitaxel may occur because of the diluent.. 1 Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to chemotherapy: Outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 2008;122:574- 580.. # National NCCN Guidelines Version 1.2025 Comprehensive Ovarian Cancer/Fallopian Tube Cancer/Primary Cancer Network Peritoneal Cancer. DRUG REACTION REACTION TO TAXANE, LIPOSOMAL DOXORUBICIN, OR BIOTHERAPEUTIC AGENTS. MANAGEMENT OF DRUG REACTIONS MANAGEMENT/TREATMENT. a Most mild reactions are infusion reactions and more commonly are caused by taxanes (ie, docetaxel, paclitaxel), but can also occur with platinum agents (ie, carboplatin, cisplatin). b Most severe reactions are allergic reactions and more commonly are caused by platinum agents. c H1 blocker antihistamine (eg, diphenhydramine, hydroxyzine); H2 blockers (eg, cimetidine, famotidine); corticosteroids (eg, methylprednisolone, hydrocortisone, dexamethasone).. d In the setting of acute cardiopulmonary arrest, standard resuscitation (ACLS) procedures should be followed. f Referral to academic center with expertise in desensitization is preferred. g For both taxanes and platinum analogues, it is preferred that anyone with a life- threatening reaction be evaluated and referred to an academic center if the drug is still considered first line. 1 Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to chemotherapy: Outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 2008;122:574- 580.. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. WHO HISTOLOGIC CLASSIFICATION1,2. 1 Reod wth pssio f Hkari HllA. Wd Hth onizatio f Gt Murs 5th itio. 2020. 2 3e t t 3e t..	None	None	None
b628b97c86ba4fbe8fd0476a58c5197b	NCCN临床实践指南	卵巢癌包括输卵管癌和原发性腹膜癌061-090	# NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. WHO HISTOLOGIC CLASSIFICATION1,2. 1 Reod wth pssio f dhi H. H tio f G 5th 2020. 2t tumors, primary site.. Note: All recommendations are category 2A unless otherwise indicated.. # Staging. Table 1 American Joint Committee on Cancer (AJCC) TNM and FIGO Staging System for Ovarian, Fallopian Tube, and Primary Peritoneal Cancer (8th ed., 2017). Primary Tumor (T). Used with the pemission of the merican Cole of Surgons, Chicago, Ilinois. The original source for this inotion is the AJCC Cancer Staging Manual, Eith Edition (2017) published by Springer International Publishing.. # Staging. StagingTable 1 (Continued)American Joint Committee on Cancer (AJCC)TNM and FIGO Staging System for Ovarian, Fallopian Tube, and Primary Peritoneal Cancer (8th ed., 2017). Regional Lymph Nodes (N). TNM FIGO. Regional Lymph Nodes (N)TNM FIGONX Regional lymph nodes cannot be assessedNO No regional lymph node metastasisNO(i+) Isolated tumor cells in regional lymph node(s) no greater than . Distant Metastasis (M). TNM FIGO. Distant Metastasis (M)TNM FIGOM0 No distant metastasisM1 IV Distant metastasis, including pleural effusion with positive cytology; liver or splenic parenchymal metastasis; metastasis to extra- abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity); and transmural involvement of intestineM1a IVA Pleural effusion with positive cytologyM1b IVB Liver or splenic parenchymal metastases; metastases to extra- abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity); transmural involvement of intestine. # Staging. Table 2. AJCC Prognostic GroupsTNM and FIGO Staging System for Ovarian, Fallopian Tube, and Primary Peritoneal Cancer (8th ed., 2017). # National NCCN Guidelines Version 1.2025 Comprehensive Ovarian Cancer/Fallopian Tube Cancer/Primary Cancer Network Peritoneal Cancer. ACLS advanced cardiovascular life support AUC area under the curve BSO bilateral salpingo- oophorectomy . ABBREVIATIONS. HCT hematopoietic cell transplant HIPEC hyperthermic intraperitoneal chemotherapy HR homologous recombination HRD homologous recombination deficiency IDS interval debulking surgery IHC immunohistochemistry IM intramuscular IP intraperitoneal LCOC less common ovarian cancers LDH lactate dehydrogenase LFT liver function test LMP low malignant potential LOH loss of heterozygosity MMMT malignant mixed Mullerian tumor MMR mismatch repair MSI microsatellite instability MSI- H microsatellite instability- high. PARPi PARP inhibitor PCS primary cytoreductive surgery PR partial response REI reproductive endocrinology and infertility RRSO risk- reducing salpingo- oophorectomy SEE- FIM sectioning and extensively examining the fimbriated end STIC serous tubal intraepithelial carcinoma TMB tumor mutational burden TMB- H tumor mutational burden- high TNM tumor node metastasis USO unilateral salpingo- oophorectomy. # NCCN Guidelines Version 1.2025 Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer Network. Discussion Table of Contents. This discussion corresponds to the NCCN Guidelines for Ovarian Cancer. The following pages were updated on July 25, 2022: MS- 2, MS- 17, MS- 35, MS- 36, MS- 92, MS- 93, MS- 94. Other sections up to MS- 82 were last updated on January 12, 2021. The remaining text (Follow- up Recommendations and subsequent sections) last updated November 11, 2017. Topotecan dosing on MS- 28 was changed August 17, 2021.. Overview .MS- 2 Literature Search Criteria and Guidelines Update Methodology ...MS- 3 Risk Factors for Ovarian Cancer. .MS- 3 Reproductive Risk Factors .MS- 3 Obesity, Smoking, and Lifestyle and Environmental Risk Factors .MS- 3 Family History and Genetic Risk Factors .MS- 3 Risk- Reducing Surgery for High- Risk Patients .MS- 4 Serous Tubal Intraepithelial Carcinoma (STIC) .MS- 4 Screening. .MS- 4 Symptoms of Ovarian Cancer. .MS- 4 Screening with Ultrasound and/or Serum CA- 125 .MS- 5 Screening with Other Biomarker Tests .MS- 7 Risk- Reducing Salpingo Oophorectomy (RRsO) Protocol .MS- 7 Recommended Workup .MS- 9 Patients Presenting with Clinical Symptoms/Signs .MS- 9 Workup for Patients Referred with Diagnosis by Previous Surgery .MS- 13 Diagnosis, Pathology, and Staging .MS- 14 Histologic Subtypes. .MS- 15 Staging .MS- 16 Molecular Testing .MS- 17 Primary Treatment. .MS- 18 Primary Surgery .MS- 18 Primary Treatment for Patients Referred with Diagnoses by Previous Surgery .MS- 23 Management After Primary Surgery .MS- 23 Nocadjuvant Chemotherapy .MS- 47. Interval Debulking Surgery After Neoadjuvant Chemotherapy of Invasive Epithelial Ovarian Cancer .MS- 58 Monitoring Response to Adjuvant Systemic Therapy .MS- 62 Options After First- Line Chemotherapy .MS- 63 Drug Reactions .MS- 78 Radiation Therapy .MS- 81 Follow- up Recommendations .MS- 82 Management of an Increasing CA- 125 Level .MS- 82 Recurrent Disease .MS- 83 Acceptable Recurrence Modalities .MS- 84 Less Common Ovarian Cancers .MS- 88 Recommended Workup .MS- 88 Surgery .MS- 89 Clear Cell Carcinoma .MS- 89 Mucinous Carcinomas .MS- 90 Low- Grade Serous Carcinoma .MS- 92 Endometrial Epithelial Carcinoma .MS- 94 Malignant Germ Cell Tumors .MS- 95 Malignant Sex Cord- Stromal Tumors .MS- 96 Carcinosarcomas (Malignant Mixed Mullerian Tumors) .MS- 97 Borderline Epithelial Tumors (Low Malignant Potential) .MS- 98 Summary .MS- 99 Recommended Readings .MS- 102 References .MS- 104. # Overview. Ovarian neoplasms consist of several histopathologic entities, with epithelial ovarian cancer accounting for the majority of malignant ovarian neoplasms (about . These NCCN Guidelines for Ovarian Cancer discuss cancers originating in the ovary, fallopian tube, or peritoneum and include recommendations for epithelial subtypes, including serous, endometrioid, carcinosarcoma (malignant mixed Müllerian tumors [MMMTs] of the ovary), clear cell, mucinous, and borderline epithelial tumors (also known as low malignant potential [LMP] tumors). The recommendations are primarily based on data from patients with the most common subtypes—high- grade serous and grade 2 and 3 endometrioid carcinoma. Also included in the guidelines are recommendations for less common ovarian cancers (LCOC), specifically carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low- grade serous carcinoma, grade 1 endometrioid carcinoma, borderline epithelial tumors, and non- epithelial subtypes including malignant sex cord- stromal tumors and germ cell tumors.. By definition, the NCCN Guidelines cannot incorporate all possible clinical variations and are not intended to replace good clinical judgment or individualization of treatments. Exceptions to the rule were discussed among panel members during the process of developing these guidelines.. A . # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer Network. Literature Search Criteria and Guidelines Update Methodology. Prior to the update of this version of the NCCN Guidelines for Ovarian Cancer, an electronic search of the PubMed database was performed to obtain key literature in ovarian cancer published since the previous Guidelines update, using the following search terms: ((ovarian OR fallopian OR (primary and peritoneal) OR ovary OR (sex and cord- stromal) or mullerian) AND (carcinoma OR cancer OR malignancy OR malignancies OR lesion OR tumor). The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes peer- reviewed biomedical literature. The search results were narrowed by selecting studies in humans published in English. Articles were also excluded if they: 1) involved investigational agents that have not yet received FDA approval; 2) did not pertain to the disease site; 3) were clinical trial protocols; or 4) were reviews that were not systematic reviews. The search results were further narrowed by selecting publications reporting clinical data, meta- analyses and systematic reviews of clinical studies, and treatment guidelines developed by other organizations.. The potential relevance of the PubMed search results was examined by the oncology scientist and panel chairs, and a list of selected articles was sent to the panel for their review and discussion at the panel meeting. The panel also reviewed and discussed published materials referenced in Institutional Review Comments or provided with Submission Requests. The data from key PubMed articles, as well as articles from additional sources deemed as relevant to these Guidelines and discussed by the panel, have been included in this version of the Discussion section (eg, e- publications ahead of print, meeting abstracts). Recommendations for which high- level evidence is lacking are based on the panel's review of lower- level evidence and expert opinion. The complete details of the Development and Update of the NCCN Guidelines are at www.NCCN.org.. Risk Factors for Ovarian Cancer. Reproductive Risk Factors. Epidemiologic studies have identified risk factors in the etiology of ovarian cancer.4,11,12 A . Obesity, Smoking, and Lifestyle and Environmental Risk Factors. Studies evaluating obesity as a risk factor for ovarian cancer have yielded inconsistent results,47 which may be due to associations between obesity and other ovarian cancer risk factors (eg, parity, oral contraceptive use, menopausal status).23,48,49 The risk associated with obesity may differ across ovarian cancer subtypes, and depend on the timing and reason for weight gain.39,48- 50 Smoking is associated with an increased risk for mucinous carcinomas but a decreased risk for clear cell carcinomas.11,51- 55 Environmental factors have been investigated, such as talc,56- 66 but so far they have not been conclusively associated with the development of this neoplasm.. Family History and Genetic Risk Factors. Family history (primarily patients having two or more first- degree relatives with ovarian cancer)—including linkage with BRCA1 and BRCA2 genotypes (hereditary breast and ovarian cancer [HBOC] syndrome) or families affected by Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC] syndrome)—is associated with increased risk of ovarian cancer, particularly early- onset disease.11,67- 88 In addition to mutations in. # BRCA1/2 and the genes associated with Lynch syndrome (eg, MLH1, MSH2, MSH6, PMS2),<sup>74,86,87,89- 92</sup> germline mutations in a variety of other genes have been associated with increased risk of ovarian cancer (eg, ATM, BRIP1, NBN, PALB2, STK11, RAD51C, RAD51D).<sup>73,74,89,92- 105</sup> Patients with mutations in BRCA1/2 account for only approximately . Risk-Reducing Surgery for High-Risk Patients. In those at high risk (with either BRCA1 or BRCA2 mutations), risk- reducing bilateral salpingo- oophorectomy (BSO) is associated with a reduced risk for breast, ovarian, fallopian tube, and primary peritoneal cancers.<sup>115- 119</sup> Prospective studies have shown that among patients at high risk due to BRCA1 or BRCA2 mutation, occult ovarian, fallopian tube, or primary peritoneal cancer is found in up to . Serous Tubal Intraepithelial Carcinoma (STIC). It is now generally accepted that the fallopian tube is the origin of many serous ovarian and primary peritoneal cancers, and that serous intraepithelial carcinoma of the fallopian tube (also known as serous tubal intraepithelial carcinoma [STIC]) is a precursor of most high- grade serous ovarian or peritoneal cancer.<sup>1,127,129- 139</sup> A referral to a gynecologic oncologist/comprehensive cancer center is recommended for . Screening. Symptoms of Ovarian Cancer. Because of the location of the ovaries and the biology of most epithelial cancers, it has been difficult to diagnose ovarian cancer at an earlier, more curable stage. Evaluations of patients with newly diagnosed ovarian cancer have resulted in consensus guidelines for ovarian cancer symptoms,<sup>139,141- 143</sup> which may enable earlier identification of patients who may be at an increased risk of having developed early- stage ovarian cancer.<sup>144,145</sup> Symptoms suggestive of ovarian cancer include: bloating, pelvic or abdominal pain, difficulty eating or feeling full quickly, and urinary symptoms (urgency or frequency), especially if these symptoms are new and frequent (. # Screening with Ultrasound and/or Serum CA-125. Screening with Ultrasound and/or Serum CA- 125The literature does not support routine screening for ovarian cancer in the (asymptomatic) general population,. and/or US).169- 172 Harms of screening included false positives in up to . # National Comprehensive NCCN Guidelines Version 1.2025 Cancer Network Ovarian Cancer. For those with high- risk factors (eg, BRCA mutations, family history of breast or ovarian cancer), RRSO is generally preferred over screening as it reduces the likelihood of breast, ovarian, fallopian tube, and primary peritoneal cancers.115- 119 For those who choose to defer or decline RRSO, some physicians use CA- 125 monitoring and endovaginal US.120,157,158,162 Strong supportive evidence for this approach is lacking, however, as several large prospective studies in high- risk patients have shown that these methods have low positive predictive value and do not improve ovarian cancer- related mortality.190- 194 However, prospective studies in high- risk patients have also shown that screening with CA- 125 and TVUS may improve the likelihood of diagnosis at an earlier stage,190,191,193 and . # Screening with Other Biomarker Tests. Screening with Other Biomarker TestsIn addition to CA- 125, there are a number of biomarkers that have been explored as possible screening tools for early detection of ovarian cancer.. There are a number of biomarker tests and prediction algorithms (based on a variety of factors, such as symptoms, imaging results, biomarkers, and patient characteristics) that have been developed for assessing the likelihood of malignancy among patients who have an adnexal mass (and have not yet had surgery). It is important to note that these tests are for preoperative assessment only, and none is suitable for ovarian cancer screening prior to detection of an adnexal mass; they are also not for use as stand- alone diagnostic tests. For example, the OVA1 test is a multivariate index assay (MIA) that uses five markers (including transthyretin, apolipoprotein A1, transferrin, beta- 2 microglobulin, and CA- 125) in preoperative serum to assess the likelihood of malignancy in patients with an adnexal mass for which surgery is planned, with the aim of helping community practitioners determine which patients to refer to a gynecologic oncologist for evaluation and surgery.. Risk-Reducing Salpingo Oophorectomy (RRsO) Protocol. Risk- Reducing Salpingo Oophorectomy (RRSO) ProtocolThe RRSO protocol is recommended for patients at risk for HBOC and is described in detail in the algorithm (see the Principles of Surgery in the algorithm). Selection of patients appropriate for this procedure is described in the NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, and Pancreatic (available at www.NCCN.org). In addition to reducing the risk of breast, ovarian, fallopian tube, and primary peritoneal cancers in patients at high risk,. This protocol recommends minimally invasive laparoscopic surgery. This procedure should include a survey of the upper abdomen, bowel surfaces, omentum, appendix (if present), and pelvic organs. Any abnormal peritoneal findings should be biopsied. Pelvic washing for cytology should be obtained, using approximately 55 cc normal saline instilled and aspirated immediately. The procedure should include total BSO, removing 2 cm of proximal ovarian vasculature or IP ligament, all of the fallopian tube up to the cornua, and all of the peritoneum surrounding the ovaries and fallopian tubes, especially the peritoneum underlying areas of adhesion between the fallopian tube and/or ovary and the pelvic. # sidewall.123 It is recommended to engage in minimal instrument handling of the tubes and ovaries to avoid traumatic exfoliation of cells.123 Both ovaries and tubes should be placed in an endobag for retrieval from the pelvis. Complete evaluation of the fallopian tubes is important, as prospective studies have found that roughly a half of the cases of occult disease identified by RRSO in BRCA1/2 mutation carriers were tubal neoplasms.118,120,122- 124 For pathologic assessment, fallopian tubes should be processed by sectioning and extensively examining the fimbriated end (SEE- Fim) of the tubes and then assessed to determine whether any evidence of cancer is present.128,228,229 The ovaries should also be carefully sectioned, processed, and assessed.128 The CAP protocol describes the process for sectioning the fallopian tubes and ovaries.230- 232 If occult malignancy or STIC is identified, the patient should be referred to a gynecologic oncologist.. Note that it is controversial whether a hysterectomy should also be done in patients undergoing RRSO. Some patients with elevated risk of ovarian cancer due to genetic risk factors or family history may also have elevated risk of endometrial cancer.233- 237 The relationship between BRCA mutations and uterine cancer has been evaluated in multiple studies, with some studies showing that BRCA mutation carriers are at higher risk of uterine/endometrial cancer compared with the general population or compared with those without BRCA mutations;238- 242 other studies showing no linkage243,244 or a lower risk of uterine cancer among BRCA mutation carriers;245 and some studies suggesting that increased risk is largely due to tamoxifen exposure.240,246 In a few studies of BRCA mutation carriers who underwent RRSO without hysterectomy and had no evidence of disease at the time of surgery, the post- surgery incidence of uterine cancer was higher compared with the general population,247- 249 but in other studies it was not elevated.250 Several studies found that BRCA1 mutations were linked to endometrial or uterine cancer, but BRCA2 mutations either were not associated with increased risk or were not . Certain pathogenic variants associated with Lynch syndrome have been linked to increased risk of endometrial and ovarian cancers, and associated with cases where both types of cancer develop in an individual patient or family.83,86- 88,90,251- 255 Certain reproductive factors, such as infertility, parity, and exposure to contraceptives, fertility drugs, and postmenopausal hormone therapy, are known to increase or decrease the risk of both ovarian and endometrial cancers.15,16,19,30,45,256- 258 Among patients with who underwent RRSO due to BRCA mutation, diagnosis of breast cancer, or family history of breast/ovarian cancer, and elected to have hysterectomy at the time of RRSO, several studies reported finding occult uterine disease, although the frequency varied.120,259- 262 Based on studies specifically focusing on patients with mutations associated with Lynch syndrome, however, discovery of occult endometrial cancer may be as frequent as occult ovarian/fallopian tube lesions, and the incidence of endometrial cancer may be significantly reduced by prophylactic hysterectomy.263,264 One large population- based study of individuals with premenopausal primary breast cancer showed that prophylactic BSO plus hysterectomy reduced the risk of new primary breast cancer and improved breast- cancer associated mortality; neither procedure alone significantly modified these risks, and the effect was not seen in those with postmenopausal breast cancer.265 See the NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, and Pancreatic (available at www.NCCN.org) for further discussion of selection of patients who may benefit from hysterectomy at the time of RRSO.. The prevention benefits of salpingectomy alone are not yet proven.266- 276 If salpingectomy alone is considered, the fallopian tube from the fimbria to its insertion into the uterus should be removed; the fallopian tubes should. # also be carefully processed and assessed as described above for BSO.123,128 The concern for risk- reducing salpingectomy alone is that the individuals are still at risk for developing ovarian cancer. In addition, in premenopausal individuals, oophorectomy reduces the risk of developing breast cancer but the magnitude is uncertain.277 For further discussion of residual risks of cancer, see the NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, and Pancreatic (available at www.NCCN.org).. The risks of surgery include injury to the bowel, bladder, ureter, and vessels.122,261,278- 280 For both patients who are premenopausal and those who are postmenopausal at time of RRsO, menopause symptoms may emerge, re- emerge, or worsen.281- 287 RrSO may also have long- term impacts on sexual functioning and quality of life (QOL).281,282,285,286,288- 297 Although the existing limited data suggest that management with hormone replacement therapy (HRT) likely does not increase risk of breast cancer in BRCA mutation carriers undergoing RRsO,288,298- 303 the efficacy of HRT for symptom management in this population is debated.281- 285,293,294,296,300- 302 RRsO in premenopausal individuals increases risk of certain cardiovascular conditions (eg, coronary heart disease, cardiac arrhythmias, hyperlipidemia), chronic obstructive pulmonary disease, arthritis, asthma, osteoporosis, and mental health conditions (cognitive dysfunction, depression, anxiety).281,304,310. Recommended Workup. Patients with ovarian cancer may present in several different ways. Some present with clinical signs and/or symptoms, which upon imaging reveal a pelvic mass and potentially evidence of metastasis. For other patients, ovarian cancer is an incidental finding during a surgery or other procedure. Recommended workup for each of these presentations is described below.. Patients Presenting with Clinical Symptoms/Signs. Clinical symptoms that warrant further workup for possible ovarian cancer include suspicious/palpable pelvic mass found on an abdominal/pelvic exam, ascites, abdominal distention, and/or symptoms (ie, bloating, pelvic/abdominal pain, difficulty eating for feeling full quickly, and urinary symptoms, such as increased urgency or frequency).144 Clinical signs might include abdominal distension/ascites and a mass noted on abdominal/pelvic examination. Further workup for these patients should include imaging, laboratory studies, evaluation of nutritional status, GI evaluation if indicated, and family history. Each of these elements of workup is described in greater detail below.. Imaging. The primary workup for patients with clinical signs or symptoms of ovarian cancer should include an abdominal/pelvic US and/or abdominal/pelvic CT/MRI scan. US is typically used for initial evaluation, as it has been shown to be effective at triaging the majority of adnexal masses into benign or malignant categories.311- 313 Other imaging modalities may be helpful when the results of US are indeterminate (ie, either the organ of origin or malignant potential is unclear), and may improve assessment of metastases, staging, and preoperative planning.311,313,314 Abdominal/pelvic MRI may be useful for determining malignant potential of adnexal masses if US is not reliable or results are indeterminate.311- 313,315- 319 FDG- PET/CT scan may also be useful for indeterminate lesions.320- 322 The NCCN Panel recommends PET/CT or MRI for indeterminate lesions if they will alter management.. Various imaging methods and algorithms for evaluating imaging results have been proposed for preoperatively distinguishing benign from malignant adnexal masses, with the goal of determining which patients should have surgery and/or be referred to a gynecologic oncologist for further evaluation and surgery. Multiple US- based imaging algorithms for. # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer NCCN Cancer Network. predicting malignancy have been developed and tested prospective studies comparing preoperative US results to final diagnosis after surgery.323- 327 The most thoroughly tested of these are the International Ovarian Tumor Analysis (IOTA) Simple Rules algorithm, based on five US features;186,328- 337 and the IOTA logistic regression model (LR2), which combines five US variables with age.186,338- 341 A variety of MRI- based approaches for distinguishing benign from malignant masses have been explored in prospective trials comparing preoperative MRI results to final postoperative diagnosis, although these approaches have been less thoroughly tested than the US techniques. Examples include proton MR spectroscopy,342 diffusion- weighted imaging (DwI),343- 345 apparent diffusion coefficient (ADC) maps,346 3.0 Tesla (3T) MRI,347 and dynamic contrast- enhanced (DCE) MRI.348 Although both US and MRI are recommended options for preoperative imaging, the NCCN Guidelines are silent regarding the exact techniques used for each, and do not endorse any specific model for preoperative triage.. For assessment of abdominopelvic metastases for preoperative staging, estimation of resectability, and surgical planning, abdominal/pelvic CT or MRI are generally more useful than US.314,315,318,349- 351 Although CT is preferred in some circles, MRI has been shown to provide equivalent accuracy for staging and comparable accuracy for predicting peritoneal tumor volume, and can be useful if CT results are inconclusive.314 For assessing advanced disease, FDG- PET/CT may also be useful if CT results are indeterminate, and has been shown to have higher accuracy than CT for detection of metastases.314,321,352- 355. Although there is no direct evidence that chest x- ray or chest CT is necessary, panel members felt that it should be part of the overall evaluation of a patient before surgical staging if clinically indicated. CT of the chest can detect pleural or pulmonary metastases, as well as pleural . Laboratory Studies and Biomarker Tests. Appropriate laboratory studies for patients presenting with clinical symptoms/signs of ovarian cancer include CBC and chemistry profile with liver function test.. Laboratory Studies and Biomarker TestsAppropriate laboratory studies for patients presenting with clinical symptoms/signs of ovarian cancer include CBC and chemistry profile with liver function test.A number of specific biomarkers and algorithms using multiple biomarker test results have been proposed for preoperatively distinguishing benign from malignant tumors in patients who have an undiagnosed adnexal/pelvic mass. Biomarker tests developed and evaluated in prospective trials comparing preoperative serum levels to postoperative final diagnosis include serum HE4 and CA- 125, either alone or combined using the Risk of Ovarian Malignancy Algorithm [ROMA] algorithm;185,187,356- 371 the MIA (brand name OVA1) based on serum levels of five markers: transthyretin, apolipoprotein A1, transferrin, beta- 2 microglobulin, and CA- 125154,212- 216,372; and the second- generation MIA (MIA2G, branded name OVERA) based on CA- 125, transferrin, apolipoprotein A1, follicle- stimulating hormone [FSH], and HE4.184,373 The FDA has approved the use of ROMA, OVA1, or OVERA for estimating the risk for ovarian cancer in those with an adnexal mass for which surgery is planned, and have not yet been referred to an oncologist.217,374,375 Although the American Congress of Obstetricians and Gynecologists (ACOG) has suggested that ROMA and OVA1 may be useful for deciding which patients to refer to a gynecologic oncologist,376 other professional organizations have been non- committed.161,312,377 Not all studies have found that multi- biomarker assays improve all metrics (ie, sensitivity, specificity, positive predictive value, negative predictive value) for prediction of malignancy compared with other methods (eg, imaging, single- biomarker tests, symptom index/clinical assessment).185,215,357,378- 380 Currently, the NCCN Panel does not recommend the use of these. # biomarker tests for determining the status of an undiagnosed adnexal/pelvic mass.. Nonetheless, the NCCN Guidelines do include CA- 125 testing as a possible element of preoperative workup, if clinically indicated. This recommendation is based on data showing that serum CA- 125 levels correlate with extent of disease, and may have prognostic value, so may help in treatment planning.381- 385 Serum CA- 125 levels tend to correlate with the clinical course of disease, especially in those with elevated pretreatment levels, so can be useful for monitoring response to therapy and surveillance for recurrence.4,382,384- 396. Some evidence suggests that HE4 may be a useful prognostic marker in patients with ovarian cancer, decreases during response to treatment, and may improve early detection of recurrence relative to CA- 125 alone.397- 424 NCCN Panel members sometimes test HE4 in patients who do not have elevated CA- 125, as HE4 can be useful for future monitoring in such patients. However, because results vary across studies,425- 427 the NCCN Guidelines currently do not recommend routine HE4 as part of preoperative workup.. In addition to CA- 125, the NCCN Guidelines mention that other tumor markers may be used as part of preoperative workup, if clinically indicated: inhibin, alpha- fetoprotein [AFP], beta- human chorionic gonadotropin [beta- hCG], lactate dehydrogenase [LDH], carcinoembryonic antigen [CEA], and CA19- 9. Serum levels of these markers can be elevated in patients with certain LCOCs, and correlate with disease course in some of these patients. Measurement of these markers prior to surgery can help to assess for LCOC (see Less Common Ovarian Cancers), and facilitate future monitoring during surveillance after treatment, especially in patients who do not have elevated serum CA- 125 at baseline and/or have tumor types in which CA- 125 level is less likely to be informative.395. For example, AFP, beta- hCG, and LDH are markers for malignant germ cell tumors that can be helpful in intraoperative diagnosis, preoperative planning, and post- treatment monitoring for recurrence.376,395,428- 436 AFP can be produced by endodermal sinus (yolk sac) tumors, embryonal carcinomas, polyembryomas, and immature teratomas; beta- hCG can be produced by choriocarcinomas, embryonal carcinomas, polyembryomas, and, in low levels, in some dysgerminomas; and LDH can be a marker for dysgerminoma.428,429 Some studies in young patients presenting with an ovarian mass have found that high levels of AFP and beta- hCG were correlated with higher likelihood of malignancy,436,437 or linked to specific subtypes,431,438,439 suggesting that these markers may help with intraoperative diagnosis to determine whether fertility- sparing surgery is an option. High serum AFP levels and poor decline in serum AFP levels after treatment appear to be associated with worse outcomes in patients with germ cell tumors.432,438- 443 High serum beta- CG may also be correlated with poorer prognosis.432,444 High levels of serum LDH have been correlated with more extensive disease and poor outcomes in some patients with ovarian germ cell tumors.443,445- 447 If a patient with a germ cell tumor or sex chord stromal tumor has elevated levels of one or more of these markers at baseline, and levels decline after treatment, then the marker(s) is more likely to be useful for follow- up for recurrence.448 AFP and hCG are commonly used to monitor for recurrence in patients with germ cell tumors (GCTs), and have included clinical trials for detection of recurrence.448- 451. Sex cord- stromal tumors of the ovary, particularly granulosa cell tumors, can produce inhibin, and inhibin expression level in tumor tissue and serum have been proposed as diagnostic markers.395,452- 461 Some studies have shown that serum levels of inhibin A and B, particularly inhibin B, correlate with extent of disease in patients with granulosa cell tumors, decreasing during treatment and then increasing again prior to relapse, leading to the proposal that serum inhibin monitoring may be helpful for. # National Comprehensive NCCN Guidelines Version 1.2025 NCCN Cancer Ovarian Cancer Network. long- term follow- up.462- 467 In some cases of ovarian stromal tumor inhibin levels are not elevated, however, so this marker is not useful for monitoring response to treatment.468. Elevated serum CEA is a marker associated with gastrointestinal (GI) primary cancers, but can also occur in patients with ovarian malignancies, particularly mucinous tumors.4,469- 471 Because of its association with GI cancers, some advocate for further GI imaging in patients with high serum CEA.142,469 A ratio of serum CA- 125 to CEA . Evaluation of Nutritional Status and Gastrointestinal (Gl) Evaluation Workup should also include evaluation of the patient's nutritional status, and Gl evaluation if clinically indicated. Patients with ovarian cancer often present with bloating, pelvic or abdominal pain, difficulty eating, or feeling full quickly,144 which can lead to changes in dietary habits that result in poor nutritional status. Poor nutritional status has been linked to higher risk of suboptimal surgery, surgical complications, and poor survival, especially in older patients.495- 501 There are a variety of ways to assess nutritional status, including body weight, body mass index, anthropometrics, serum protein, serum albumin, transferrin, lymphocyte . Given that GI cancers and primary mucinous carcinoma of the ovary can both cause serum CEA elevation,4,469- 477 and can both present with adnexal masses, GI tract evaluation is especially important in these patients to determine whether patients have metastases to the ovary or primary mucinous carcinoma of the ovary (see Mucinous Carcinomas).527 The presence of a pancreatic mass or widespread abdominal disease should also increase suspicion for primary GI cancer.. Family History and Genetic Testing. Obtaining a family history and referral to a genetic counselor is an important part of workup, as some patients may have hereditary traits that may inform future treatment and determine whether family members should be screened. Primary treatment (surgery and chemotherapy) should not be delayed for a genetic counselling referral, however, as genetic test results are not needed for selection of primary surgery and/or chemotherapy, and delay in treatment is associated with poorer outcomes.528,529 Recommendations regarding genetic testing can be found in the NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, and Pancreatic and the NCCN Guidelines for. # Genetic/Familial High- Risk Assessment: Colorectal (available at www.NCCN.org).. Although germline and/or somatic BRCA1 and BRCA2 status may inform future options for maintenance therapy, BRCA testing for the purpose of informing treatment is not needed until after there is histologic confirmation of ovarian, fallopian tube, or primary peritoneal cancer (eg, after primary surgery or confirmation by biopsy). See Molecular Testing section below.. Prediction of Malignancy, Referral to a Gynecologic Oncologist. There are a number of prediction algorithms that combine multiple factors, such as symptoms, imaging results, biomarkers, and patient characteristics, to predict the likelihood of malignancy among patients who have an undiagnosed adnexal mass (ie, a mass detected by clinical exam or imaging that has not yet been resected and definitively diagnosed by pathology).316,338,351,371,530 These algorithms were developed with the goal of reducing the number and/or extent of unnecessary surgeries by using the likelihood of malignancy to determine which patients are most likely to benefit from surgery, and/or identify cases to be referred to a gynecologic oncologist for further testing and surgery. Many of these algorithms have been tested in prospective trials comparing preoperative prediction to postoperative histologically confirmed diagnosis, including IOTA Assessment of Different NEoplasias in the adneXa (ADNEX), which uses patient age, type of center (oncology referral vs other), serum CA- 125, and six US variables;316,330,351,532 Risk of Malignancy Indexes (RMI- 1 through 4), which use US features, patient menopausal status, and serum CA- 125;339,358,359,533- 539 combining symptom index (SI) with CA- 125 and HE4 results;153 and the (early) ACOG/SGO referral guidelines based on patient age, CA- 125 level, physical findings, imaging results, and family history.351,371,540 Several prospective studies have compared multiple algorithms or algorithms versus other metrics to determine which most accurately predicts malignancy.212,214,215,338,357- 359,378,379. Currently the NCCN Guidelines do not endorse any of these methods. Because primary assessment and debulking by a gynecologic oncologist is associated with improved survival, all patients with lesions suspected to be ovarian malignancies (based on clinical evidence) should be referred to an experienced gynecologic oncologist for evaluation- - both to assess suitability for different primary surgical options and to select the best method for obtaining the material needed for definitive diagnosis.147,218- 221 A gynecologic oncologist should be involved in assessing whether a patient is a suitable surgical candidate and/or an appropriate candidate for neoadjuvant therapy, and consideration of laparoscopic evaluation to determine feasibility of debulking surgery. A gynecologic oncologist should also be consulted for management of occult STICs.. Workup for Patients Referred with Diagnosis by Previous Surgery. Patients are on occasion referred to NCCN Member Institutions after having a previous diagnosis of ovarian cancer by surgery or tissue biopsy (cytopathology). At times, patients with newly diagnosed ovarian cancer have had cytoreductive surgery and comprehensive staging procedures (ie, having met the standards for surgical staging of the Gynecologic Oncology Group [GOG]).541 In some instances, referral occurs after incomplete surgery and/or staging (eg, uterus and/or adnexa intact, omentum not removed, incomplete lymph node dissection, residual disease that is potentially resectable, surgical stage not completely documented, occult invasive carcinoma found at time of risk reduction surgery). The components of surgical staging are listed in the algorithm (see Principles of Surgery in the algorithm).. Workup procedures are very similar for patients having undiagnosed or diagnosed pelvic masses at the time of referral. In these cases, evaluation by a gynecologic oncologist is important for determining whether the previous surgery was adequate or an additional surgery is needed. Prior imaging studies and operative notes should be reviewed to determine. # National Comprehensive NCCN Guidelines Version 1.2025 NCCN Cancer Ovarian Cancer Network. additional workup needed and to inform treatment approach. Additional imaging may be needed to screen for distant disease and evaluate for residual disease not removed during the previous surgery. Imaging options include chest/abdominal/ pelvic CT or MRI, PET/CT, and/or US. All imaging should be performed with contrast unless contraindicated. Pathology review of tissue from the previous surgery is important for confirming diagnosis and cancer type. CBC and chemistry profile with LFTs should be obtained, and CA- 125 or other tumor markers should be measured if indicated to corroborate likely diagnosis and to serve as baseline for future follow- up. See section above on Laboratory Studies and Biomarker Tests. If not previously done, workup should include obtaining a family history, genetic risk evaluation, and germline and somatic testing, if not previously done. Recommendations regarding genetic testing can be found in the NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, and Pancreatic and the NCCN Guidelines for Genetic/Familial High- Risk Assessment: Colorectal (available at www.NCCN.org). As described in the Molecular Testing section below, germline and/or somatic BRCA1/2 testing informs selection of maintenance therapy (after first- line platinum- based chemotherapy). Molecular analysis of tumor tissue from the previous surgery may be warranted. In the absence of a BRCA1/2 mutation, homologous recombination deficiency status may provide information on the magnitude of benefit of PARP inhibitor maintenance therapy (category 2B).. Diagnosis, Pathology, and Staging. Most ovarian cancers, including the LCOC, are diagnosed after pathologic analysis of a biopsy or surgical specimen, which may occur preoperatively, intraoperatively, or postoperatively. If possible, fine- needle aspiration (FNA) should be avoided for diagnosis of ovarian cancer in patients with presumed early- stage disease to prevent rupturing the cyst and spilling malignant cells into the peritoneal cavity; however, FNA may be necessary in patients who are not candidates for primary debulking, such as those . Primary peritoneal and fallopian tube cancers are treated in the same manner as epithelial ovarian cancer, so distinguishing these three possible primary sites is less crucial than ruling out other cancers that commonly involve the adnexa, such as uterine, cervical, gastro intestinal (small and large bowel, pancreatic) cancers or lymphoma;544,545 benign ovarian and non- ovarian conditions also need to be ruled out (eg, serous cystadenoma).546 In addition, metastases to the ovaries need to be ruled out (see Mucinous Carcinomas).. The CAP protocol is a useful tool for pathology reports, and has been updated for consistency with the AJCC Cancer Staging Manual, 8th edition.230,547 Based on the CAP protocol (Version 1.1.1.0; Feb 2020)230 and panel consensus, the NCCN Guidelines recommend that pathologic assessment should include the following elements: all tumor site(s) (eg, ovary, fallopian tube, pelvic/abdominal peritoneum, uterus, cervix, omentum); all tumor size(s); for ovarian/fallopian tumors, surface involvement (present/absent/cannot determine), specimen integrity (capsule/serosa intact/fractured/fragmented); histologic type and grade; extension and/or implants (if sampled/dentified); cytology results from peritoneal/ascitic fluid/washings and pleural fluid; the number and location of lymph nodes examined, and size of largest lymph node metastatic deposits; and evidence of STIC, endometriosis [particularly if in continuity with endometrioid or clear cell carcinoma], and endosalpingiosis.. # The complete histologic classification from the WHO is included in the NCCN Guidelines. The WHO pathology manual is also a useful resource.1,548. Histologic Subtypes. Epithelial ovarian cancer has four main subtypes, including serous, endometrioid, mucinous, and clear cell; most patients (about . Ovarian borderline epithelial tumors, also called LMP tumors or atypical proliferative tumors, are another type of primary epithelial lesions. The terms for borderline epithelial tumors have changed over the years, and recent CAP protocols do not use "LMP."230,562 Borderline tumors have cytologic characteristics suggesting malignancy, and may grossly resemble an invasive cancer, but microscopic evaluation shows no evidence of frank invasion by the tumor nodules, although rarely invasive implants (which continue to be consistent with the diagnosis of borderline epithelial lesions) can be identified microscopically by the pathologist. The characteristic pathologic hallmark of typical epithelial ovarian cancer is the identification of peritoneal implants, which microscopically and/or macroscopically invade the peritoneum. Borderline epithelial tumors are typically serous or mucinous; but other histologic subtypes can also occur (see WHO Histologic Classification in the algorithm).1,230. Carcinosarcomas arising in the ovary, fallopian tubes, or peritoneum, also called carcinomas of Mullerian origin or MMMTs, are biphasic, with both malignant epithelial and sarcomatous elements. Clonality studies suggest . Germ cell tumors are a non- epithelial subtype, and include dysgerminomas, immature teratomas, embryonal tumors, and endodermal sinus (yolk sac) tumors.1 Malignant sex cord- stromal tumors, another non- epithelial subtype, are rare and include granulosa cell tumors (most common) and Sertoli- Leydig cell tumors.1. In some cases, it can be difficult to distinguish between cancer subtypes. For example, high- grade endometrioid tumors can be difficult to distinguish from high- grade serous tumors.549 Some endometrioid tumors look similar to clear cell tumors, while others may resemble sex cord- stromal tumors.549 Immunohistochemistry (IHC) with certain markers may help with differential diagnosis. Whereas most . Stage at diagnosis, prognosis, the typical course of disease, and responsiveness to specific therapies vary across cancer. # subtypes.. Staging. The NCCN Guidelines for Ovarian Cancer reflect the importance of stage and grade of disease on prognosis and treatment recommendations. Ovarian cancer is classified primarily as stages I to IV using the FIGO (International Federation of Gynecology and Obstetrics) staging system, which was approved by the AJCC and incorporated into the AJCC Cancer Staging Manual . A pathology and staging cancer protocol is available from the College of American Pathologists (CAP) for examination of specimens from patients with primary tumors of the ovary, fallopian tube, or peritoneum, including pTNM requirements from the AJCC Staging Manual . # Molecular Testing. Upon pathologic confirmation of ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, patients should be referred for a genetic risk evaluation and germline and somatic testing (if not previously done). This recommendation for germline and somatic testing is intentionally broad so that the genetic counselor and treating oncologist have the latitude to order whichever molecular tests they consider necessary based on evaluation of the individual patient and their cancer family history. Since germline and/or somatic BRCA1/2 testing informs selection of maintenance therapy for those with stage II- IV disease who are in complete response (CR) or partial response (PR) after first- line platinumbased chemotherapy, NCCN Panel members agree that it is important to establish BRCA1/2 mutation status for patients who may be eligible for maintenance therapy following completion of platinum- based first- line chemotherapy. Homologous recombination status (e.g., homologous recombination deficient [HRD] vs. homologous recombination proficient [HRP]) may provide information on the magnitude of benefit of PARP inhibitor maintenance therapy for those without a BRCA1/2 mutation. For additional recommendations on workup, staging and primary treatment for ovarian cancer, fallopian tube cancer, and primary peritoneal cancer, please refer to OV- 1 in the guidelines on . With the availability of next- generation sequencing technology, the panel discussed whether comprehensive tumor molecular analysis should be recommended for all patients. Some panel members stated that comprehensive tumor testing may not be necessary for certain patients in the upfront setting, specifically those with a germline mutation in BRCA1/2 or other homologous recombination/DNA repair pathway genes. However, some patients (such as those who lack a BRCA1/2 mutation or experience disease recurrence) may benefit from a more thorough tumor molecular analysis to inform additional targeted therapy options. The panel agreed . Therefore, the current guidelines recommend tumor molecular analysis both in the upfront setting and upon recurrence (OV- B 1 of 3). The goal of tumor testing in the upfront setting is to optimize identification of molecular alterations that can inform the use of interventions with demonstrated benefit in this setting, such as PARP inhibitors. Molecular alterations that should be probed for in this setting include BRCA1/2 status, loss of heterozygosity, or homologous recombination status, in the absence of a germline BRCA mutation.. Other tumor tissue molecular markers may inform selection of treatment for persistent or recurrent disease but testing for these is not needed until the disease has proven to be refractory or at time of relapse. The panel recommends that tumor molecular analysis in the recurrence setting should include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor- specific or tumor- agnostic benefit. These include (but are not limited to): BRCA1/2, HR status, microsatellite instability (MSI), mismatch repair (MMR), tumor mutational burden (TMB), BRAF, and NTRK, if prior testing did not include these markers. The panel emphasizes that more comprehensive tumor analysis may be particularly important for less common histologies with limited approved treatment options. Prior to selection of systemic therapy for refractory or recurrent disease, validated tumor molecular testing should be performed in a Clinical Laboratory Improvement Amendments (CLIA)- approved facility using the most recent available tumor tissue.. # Primary Treatment. Primary TreatmentPrimary treatment for presumed ovarian, fallopian tube, or primary peritoneal cancer usually consists of appropriate surgical staging and debulking surgery, followed in most (but not all) patients by systemic chemotherapy.13,142,218,581,582 However, for some patients with early- stage disease, surgery alone (followed by observation) may be sufficient as primary treatment. In addition, for certain histologic subtypes, adjuvant therapy with hormonal agents are options that may be considered. NACT with interval debulking surgery (IDS) should be considered in patients with advanced- stage ovarian cancer who are not good candidates for upfront primary debulking surgery (PDS) due to advanced age, frailty, poor performance status, comorbidities, or who have disease unlikely to be optimally cytoreduced.480,583 Emerging data support an increasing role of PARP inhibitors in the management of ovarian cancer.584 In the primary treatment setting, PARP inhibitors have been incorporated as NCCN- recommended maintenance therapy options for select patients after first- line chemotherapy. Each of these primary treatment options, including maintenance therapy options after first- line chemotherapy, are described in more detail below. As described above, for all patients with suspected or confirmed ovarian cancer a gynecologic oncologist should be involved in assessing whether a patient is a suitable surgical candidate and/or an appropriate candidate for neoadjuvant therapy, and consideration of laparoscopic evaluation to determine feasibility of debulking surgery. The NCCN Guidelines recommend symptom management and best supportive care for all patients; individuals should be referred for palliative care assessment if appropriate (see the NCCN Guidelines for Palliative Care, available at www.NCCN.org).161,585,586. Primary Surgery. Based on published improved outcomes, it is recommended that a gynecologic oncologist be the provider to determine the best surgical approach and perform the appropriate primary surgery.219- 221 An open . For most patients presenting with suspected malignant ovarian, fallopian tube, or primary peritoneal neoplasm, initial surgery should include a hysterectomy (if uterus present) and BSO with comprehensive staging and debulking as indicated.13,588,589 This is the recommended approach for stage IA- IV if optimal cytoreduction appears feasible, the patient is a surgical candidate, and fertility is not a concern. It is described in greater detail below in the section entitled Debulking Surgery for Newly Diagnosed Disease.. For patients with early- stage disease who wish to preserve fertility, less extensive surgery may be an option, as described in the section entitled Fertility- Sparing Options for Stage I Disease.. NACT with IDS should be considered for patients with advanced- stage ovarian cancer who are not good candidates for PDS due to advanced age, frailty, poor performance status, comorbidities, or who have disease unlikely to be optimally cytoreduced.480,583 The anticipated benefit from NACT therapy is to allow for medical improvement of the patient and/or clinical response that would increase the likelihood of optimal. # cytoreduction at IDS. Patients treated with NACT and IDS should also receive postoperative adjuvant chemotherapy. See sections entitled Neoadjuvant Chemotherapy and Interval Debulking Surgery. As described in the section entitled Laparoscopic Evaluation Prior to Resection, for certain patients with bulky disease, a minimally invasive procedure may be appropriate for obtaining biopsy material to confirm diagnosis and/or for molecular testing, and for determining whether optimal cytoreduction is possible.. Open Laparotomy Versus Minimally Invasive Techniques. In most cases where surgery is recommended as part of primary treatment for suspected malignant ovarian, fallopian tube, or primary peritoneal neoplasm, it should be performed by open laparotomy including a vertical midline abdominal incision. The surgical guidelines emphasize that an open laparotomy should be used for most patients undergoing surgical staging, primary debulking, interval debulking, or secondary cytoreduction.. Improvement of minimally invasive methods and selection of appropriate patients are the topics of much study and debate.590- 620 Minimally invasive techniques are commonly used for early- stage disease (or presumed early- stage disease), and some studies have shown no difference in surgical outcomes, recurrence rates, or survival for those who received minimally invasive versus open surgical staging.591,593- 595,598- 600,604,611- 614,621- 625 If signs of lymph node metastasis or localized carcinomatosis are found, lymphadenectomy and complete pelvic peritonectomy may be feasible using minimally invasive techniques.608 The NCCN Guidelines indicate that in early- stage disease, minimally invasive techniques to achieve the surgical goals may be considered in selected patients if performed by an experienced gynecologic oncologist.315,588,601,626,627. Studies in patients undergoing PDS for advanced disease have shown that debulking and surgical staging is technically feasible using minimally invasive techniques, and hysterectomy and unilateral salpingo . Laparoscopic Evaluation Prior To Resection. In select patients with advanced- stage disease, minimally invasive procedures (assessment laparoscopy) may be used to assess whether optimal cytoreduction is likely to be achieved by PDS, in order to determine whether NACT may be a better initial treatment option.628- 639 A randomized trial assessed whether laparoscopy would be useful to predict the ability to achieve optimal cytoreduction (<1 cm residual disease). Optimal cytoreduction was achieved in 90% (92/102) of patients randomized to the assessment laparoscopy arm compared to 61% (60/99) of patients who were randomized to the laparotomy without assessment laparoscopy arm (relative risk [RR], 0.25; 95% CI, 0.13- 0.47; . # Fertility-Sparing Options for Stage I Disease. Fertility- Sparing Options for Stage I DiseaseFertility preservation is an evolving field and area of active research, with many approaches being explored, and many patient- and case- specific factors to consider, especially for those with malignancies.. USO or BSO, comprehensive surgical staging should still be performed in most patients to rule out occult higher- stage disease, because data show that approximately . Debulking Surgery for Newly Diagnosed Disease. Debulking surgery for Newly Diagnosed DiseaseDebulking surgery is widely accepted as an important component of initial treatment for patients with clinical stage II, III, or IV disease, and multiple retrospective studies have contributed to the understanding of the extent of debulking needed to achieve maximal cytoreduction.. # For patients with newly diagnosed epithelial ovarian cancer apparently confined to an ovary or to the pelvis, the goal of surgery is to achieve complete cytoreduction of all pelvic disease and to evaluate for occult disease in the upper abdomen or retroperitoneum. For patients with newly diagnosed invasive epithelial ovarian cancer involving the pelvis and upper abdomen, the goal is to achieve optimal cytoreduction of all abdominal, pelvic, and retroperitoneal disease.. On entering the abdomen, aspiration of ascites or peritoneal lavage should be performed for peritoneal cytologic examinations. For obvious disease beyond the ovaries, cytologic assessment of ascites and/or lavage specimens will not alter stage or management. For patients with disease apparently confined to an ovary or to the pelvis, all peritoneal surfaces should be visualized, and any peritoneal surface or adhesion suspicious for harboring metastasis should be selectively excised or biopsied. In the absence of any suspicious areas, random peritoneal biopsies should be taken from the pelvis, paracolic gutters, and undersurfaces of the diaphragm.. Hysterectomy and BSO should be performed. Although hysterectomy is recommended for most patients, USO or BSO with uterine preservation may be considered for selected patients with apparent stage IA/IB disease desiring to preserve fertility (See Fertility- Sparing Options for Stage I Disease). Every effort should be made to keep an encapsulated ovarian mass intact during removal.543,598 For young patients who will abruptly enter menopause after surgery, various supportive care measures may be used to help decrease hot flashes and other symptoms, and potentially reduce the risk of other systemic comorbidities that are more likely with surgical menopause.699- 702 HRT has not been shown to worsen survival in premenopausal patients with gynecologic cancers, but limited perspective data exist.703,704. For patients with disease apparently confined to an ovary or to the pelvis (presumed stage I/II), omentectomy should be performed to rule out higher- stage disease. For patients with disease involving the pelvis and upper abdomen (stage III/IV), all involved omentum should be removed.. The use of systematic lymphadenectomy is an area of controversy. For patients with presumed early stage, a randomized trial showed that systematic aortic and pelvic lymphadenectomy improved detection of metastatic nodes compared with node sampling (positive nodes found in 9 vs. . For patients with advanced ovarian cancer, some early prospective studies suggested that systematic lymphadenectomy improved survival.713,714 An early international randomized trial in patients with stage IIB- IV (optimally debulked) epithelial ovarian cancer found that systematic lymphadenectomy improved PFS compared with resection of bulky nodes only, although OS was not improved, operating times were longer, and more patients required blood transfusions.715 A randomized study of patients with stage IA- IV disease undergoing second look surgery found that although systematic lymphadenectomy increased detection of nodal metastases compared with resection of bulky nodes only (positive nodes found in . # associated with longer operating times, more blood loss and transfusions, and longer hospital stays.716 More recently, a large randomized trial (LION, NCT00712218) found that in patients with stage IIIB- IV ovarian cancer who had macroscopically complete resection and normal nodes both before and during surgery, lymphadenectomy did not improve PFS or OS, and was associated with increased rates of serious postoperative complications and mortality within 60 days after surgery.717 However, meta- analyses that included data from retrospective and observational studies have found that systematic lymphadenectomy improves OS in patients with advanced disease, even though PFS is not improved.706,707,718- 720. Pelvic and para- aortic lymph node dissection is recommended for patients with disease confined to affected ovaries or to the pelvis, and for those with more extensive disease who have tumor nodules outside the pelvis that are 2 cm or less (presumed stage IIIB). Para- aortic lymph node dissection should be performed by stripping the nodal tissue from the vena cava and the aorta bilaterally to at least the level of the inferior mesenteric artery and preferably to the level of the renal vessels. The preferred method of dissecting pelvic lymph nodes is removal of lymph nodes overlying and anterolateral to the common iliac vessel, overlying and medial to the external iliac vessel, overlying and medial to the hypogastric vessels, and from the obturator fossa at a minimum anterior to the obturator nerve.541. For those with more extensive disease outside of the pelvis (nodules . Some surgeons classify debulking based on the number of procedures. Procedures that may be considered for optimal surgical cytoreduction (in all stages) include: bowel resection and/or appendectomy, stripping of the diaphragm or other peritoneal surfaces, splenectomy, partial cystectomy and/or ureteroneocystostomy, partial hepatectomy, partial gastrectomy, cholecystectomy, and/or distal pancreatectomy.690,695,722. Extensive resection of upper abdominal metastases is recommended as part of debulking for patients who can tolerate this surgery, as it is associated with improved PFS and OS.690,695. Select patients with low- volume residual disease after surgical cytoreduction for stage II or III invasive epithelial ovarian or peritoneal cancer are potential candidates for IP therapy.723,724 In these patients, consideration should be given to placement of an IP catheter with initial surgery.588. Surgical Considerations for Mucinous Tumors. Since primary invasive mucinous tumors of the ovary are uncommon, it is important to establish the primary site in patients with these tumors. Thus, the upper and lower GI tract should be carefully evaluated to rule out an occult GI primary with ovarian metastases, and an appendectomy need only be performed in patients with a suspected or confirmed mucinous ovarian neoplasm if it appears to be abnormal.725- 727 A normal appendix does not require surgical resection in this setting.. Surgical Considerations for Ovarian Borderline Epithelial (LMP) Tumors. Although data show upstaging with lymphadenectomy, other data show that lymphadenectomy does not affect OS.728- 735 However, omentectomy and multiple biopsies of peritoneum (the most common sites of peritoneal implants) may upstage patients and may affect prognosis,734,736- 741 although some retrospective studies did not find association with prognosis.729,742- 744. # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer NCCN Network. Ancillary Palliative Surgical Procedures. Patients presenting with symptoms may benefit from ancillary palliative procedures performed during primary or secondary cytoreductive surgery. Decisions on the use of ancillary procedures should be made in conjunction with a gynecologic oncology surgeon or a practitioner familiar with ovarian cancer patterns of recurrence. Palliative surgical procedures that may be appropriate in select patients include paracentesis or insertion of an indwelling peritoneal catheter, thoracentesis, pleurodesis, videoassisted thoracoscopy, or insertion of a pleural catheter, nephrostomy, or use of ureteral stents, gastrostomy tube, intestinal stents, or surgical relief of intestinal obstruction.. Analysis of Surgical Specimens. As described in the section entitled Diagnosis, Pathology, and Staging, surgical specimens should undergo pathology assessment to determine/confirm diagnosis, determine histologic subtype, and determine stage. Molecular testing is also appropriate for most patients; see Molecular Testing section above for detailed recommendations.. Primary Treatment for Patients Referred with Diagnoses by Previous Surgery. For patients referred with newly diagnosed ovarian cancer after a recent surgical procedure, primary treatment depends on the findings noted during the workup and evaluation performed by a gynecologic oncologist, including the type of cancer, apparent stage, and the extent of residual disease. For those with an epithelial cancer and no evidence of residual disease on workup, further surgical staging is not needed if adjuvant chemotherapy is planned. For select subtypes, observation is an alternative to adjuvant chemotherapy in patients with stage IA/IB (Table 2). For patients with these subtypes and presumed stage IA/IB (and no evidence of residual disease), surgical staging can be considered if the patient would be a candidate for observation or reduced number of cycles . For patients who have an epithelial cancer and evidence of residual disease on workup, tumor cytoreductive surgery is recommended if the residual disease appears resectable. Following cytoreductive surgery, adjuvant treatment recommendations depend on cancer type and stage. If the residual disease appears unresectable, patients should be treated with NACT and IDS, and postoperative adjuvant chemotherapy could be considered (see sections on Neoadjuvant Chemotherapy and Interval Debulking Surgery).. Management After Primary Surgery. In the NCCN Guidelines for Ovarian Cancer, adjuvant therapy is defined as drugs or other forms of supplemental treatment following cancer surgery intended to decrease the risk of disease recurrence or to primarily treat residual disease, whether gross or microscopic, following surgical cytoreduction. Most patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer should receive adjuvant systemic chemotherapy after primary surgery. Postoperative observation is an option for select patients with stage I disease, depending on cancer histologic type and. # substage, as shown in Table 2. Observation is considered an option in these select groups of stage I patients either because survival is greater than . A large variety of regimens and approaches have been tested in prospective randomized trials as postoperative therapy for patients with newly diagnosed ovarian cancer. Most of these regimens have included intravenous (IV) chemotherapy, but IP administration of chemotherapy has also been tested, as have targeted agents and drugs from other classes.. Recent trials have shown that maintenance therapy after postoperative platinum- based chemotherapy can have a positive impact on PFS in patients with advanced disease, so integration of maintenance therapy as part of postoperative management is increasing in prevalence and importance.. Based on results of phase III randomized trials, the NCCN Guidelines include several options for postoperative treatment (within 6 weeks) in patients with advanced epithelial cancers: platinum- based IV chemotherapy, platinum- based IV/IP chemotherapy, and platinum- based IP chemotherapy plus bevacizumab, as outlined in Table 3. Specific options and supporting data for each of these categories of treatment are described in greater detail in the sections below. For stage I disease, data are more limited, and while the NCCN Guidelines include some platinum- based IV chemotherapy options, IP/IV chemotherapy and use of bevacizumab are not recommended approaches for stage I disease (Table 2). Specific options for stage I disease are also discussed in a subsequent section. For certain rarer cancer types, there are additional recommended adjuvant treatment options, including additional chemotherapy options, chemotherapy/bevacizumab regimens (stage II- IV only), and hormonal therapies (Table 2 and Table 3). More information on these options can be found in subsequent sections for specific LCOCs..	None	None	None
8b391ad15f8147659bfb8113fa2ff539	NCCN临床实践指南	卵巢癌包括输卵管癌和原发性腹膜癌091-120	# # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer Network. Paclitaxel 175/carboplatin, Paclitaxel weekly/carboplatin weekly, Docetaxel/carboplatin, Carboplatin/liposomal doxorubicin, Paclitaxel weekly/carboplatin every 3 weeks (q3weeks), Paclitaxel/carboplatin/bevacizumab . For all patients, the goals of postoperative therapy and considerations for selection and management during therapy should be discussed prior to the initiation of therapy. As for all aspects of their diagnosis and treatment of ovarian, fallopian tube, or peritoneal cancer, patients should be encouraged to participate in clinical trials. Chemosensitivity/resistance and/or other biomarker assays have been proposed for informing decisions related to future chemotherapy in situations where there are multiple equivalent chemotherapy options available, but the current level of evidence is not sufficient to support standard- of- care chemotherapy (category 3). Prior to recommending chemotherapy, requirements for adequate organ function and performance status should be met.. During drug- based therapy, patients should be observed closely and treated for any complications. Appropriate blood chemistry tests should be monitored. Appropriate dose reductions and modifications of chemotherapy should be performed depending on toxicities experienced and goals of therapy. Consider scalp cooling to reduce incidence of alopecia for patients receiving chemotherapy with high rates of alopecia.755. Options for IV Chemotherapy. Comparison of IV chemotherapy regimens for postoperative treatment of newly diagnosed ovarian cancer has been the subject of many prospective randomized trials. Most of these trials have failed to show significant differences between regimens in efficacy outcomes (eg, PFS, OS), but many have shown differences in toxicity profile, ability to complete the planned therapy, and QOL. For this reason, the NCCN Guidelines include a number of recommended options for postoperative IV chemotherapy in patients with newly diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer. The NCCN- recommended options for platinum- based IV chemotherapy to treat stage II- IV epithelial disease are summarized in Table 4, along with the list of trials that tested these regimens (last column). Table 5, Table 6, and Table 7 summarize the results of randomized trials that tested these recommended regimens. The most commonly used regimen, paclitaxel 175/carboplatin, has been considered the standard postoperative chemotherapy for ovarian cancer for many years, so there are many studies in which it has been tested (Table 5, Table 6, and Table 7). The history supporting these options is summarized below.. # # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer Network. b Doublets not recommended in the NCCN Guidelines. . # # # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer. b. Results from multiple early trials suggested that regimens that included a platinum agent resulted in better response rates and PFS (compared with other chemotherapy options).783,784 Subsequent trials aimed at determining which platinum- based combinations are the most effective and safe.. Selecting a Platinum Agent. Multiple randomized trials compared carboplatin versus cisplatin, either alone or in combination with other agents (examples in Table 5 and 6).767- 770,785- 790 All of these trials showed equivalent efficacy, but differences in toxicity profiles and QOL. Cisplatin was associated with higher rates of neurotoxicity, GI toxicities (eg, nausea, emesis), renal toxicity, metabolic toxicities, anemia, and alopecia, while carboplatin was associated with higher rates of thrombocytopenia and granulocytopenia.767- 770,785- 790 The AGO- OVAR- 3 study found that QOL was significantly better with carboplatin/paclitaxel versus cisplatin/paclitaxel, both in global QOL metrics and on various subscades.769,770 Several randomized studies tested alternating carboplatin and cisplatin every other course, but found that efficacy was similar and toxicity somewhat worse than using carboplatin for every course.774,790 Based on results from all these studies carboplatin is the recommended platinum agent for postoperative IV chemotherapy in patients with newly diagnosed ovarian, fallopian tube, and primary peritoneal cancers.. Selecting a Non-Platinum Agent (for Use in Combination with a Platinum Agent). Many different chemotherapy agents have been tested in combination with platinum agents as options for IV chemotherapy in newly diagnosed ovarian cancer. Large randomized trials have compared various platinum- based doublet, triplet, and quadruplet combinations with cyclophosphamide, paclitaxel, docetaxel, topotecan, doxorubicin, epirubicin, gemcitabine, topotecan, and melphalan.764,765,773,775- 777,779- 782,791- 797 Trials that compared platinum- based doublets with cyclophosphamide versus paclitaxel showed that paclitaxel was associated with significantly better response rate, PFS and OS.791- 793 Thus, paclitaxel is preferred over cyclophosphamide for platinum- based combination therapy in the first- line setting. Based on results from randomized trials showing improved safety and QOL with carboplatin/paclitaxel versus cisplatin/paclitaxel (Table 5),767- 770 carboplatin/paclitaxel became the "standard" combination therapy option for postoperative first- line IV chemotherapy in patients with ovarian, fallopian tube, or primary peritoneal cancer. Most subsequent trials used this doublet, usually paclitaxel . # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer NCCN Cancer Network. Two other platinum- based doublets have shown similar efficacy to carboplatin/paclitaxel, but with different safety profiles.764,765 The SCOTROC1 study found that docetaxel/carboplatin resulted in similar PFS, OS, and global QOL scores as paclitaxel/carboplatin, and was associated with lower rates of neurotoxicity, arthralgia, myalgia, alopecia, and abdominal pain, but higher rates of other adverse events (AEs) (GI, peripheral edema, allergic reactions, and nail changes [Table 7]).765 The MITO- 2 trial found that pegylated liposomal doxorubicin/carboplatin was associated with a higher response rate but similar PFS and OS as paclitaxel/carboplatin (Table 7).764 pegylated liposomal doxorubicin/carboplatin was associated with higher rates of certain hematologic toxicities, skin toxicity, and stomatitis, but lower rates of neurotoxicity and alopecia than the paclitaxel/carboplatin control.764 Global QOL and most functional domains and symptom scales were the same across treatment arms, and pegylated liposomal doxorubicin/carboplatin was associated with worse scores for certain patient- reported toxicities.764 Therefore, this regimen may be useful in select patients at high risk for neurotoxicity or those who would like to avoid alopecia. The docetaxel/carboplatin and liposomal doxorubicin/carboplatin regimens are both recommended options in the NCCN Guidelines (Table 4), and may be considered for patients who are at high risk for neuropathy (eg, patients with diabetes).798. Randomized trials testing platinum- based triplet or quadruplet regimens have generally found that these do not improve efficacy but are associated with worse toxicity when compared with platinum- based doublets773,775- 777,779- 782 or single- agent platinum regimens.794,795 Examples of platinumbased triplet and quadruplet regimens that have been compared with the standard paclitaxel/carboplatin regimen are in Table 5 and 6. One study showed that adding gemcitabine to carboplatin/paclitaxel actually resulted in worse PFS compared with carboplatin/paclitaxel alone (Table 5 and 6).780. Carboplatin/Paclitaxel Dosing Options. As noted above, for postoperative first- line treatment of ovarian cancer, the most commonly used dosing for IV carboplatin/paclitaxel combination therapy is paclitaxel . Two randomized trials (MITO- 7 and ICON8) compared standard paclitaxel/carboplatin dosing with weekly paclitaxel (60 or . # Comprehensive Cancer Network. NCCN Guidelines Version 1.2025 Ovarian Cancer. Options for Stage I, Epithelial Cancer Types. Options for Stage I, Epithelial Cancer TypesMost of the patients had stage III- IV disease in randomized trials testing IV chemotherapy as postoperative first- line treatment for ovarian cancer. More recent trials allowed patients with stage II- IV disease, but only some included patients with select stage I disease (Table 5, Table 6, and Table 7). Therefore, the list of recommended options is much shorter for patients with stage I disease, as summarized in Table 8, which also shows trials that tested the recommended regimens (last column). Patients with stage I disease were included in randomized trials comparing IV paclitaxel/carboplatin (standard dosing) with single- agent carboplatin (ICON3), docetaxel/carboplatin (SCOTROC1), pegylated liposomal. doxorubicin/carboplatin (MITO- 2),764 and weekly paclitaxel/weekly carboplatin (MITO- 7 and ICON8).757- 759 Of these, the first three are recommended options for stage I disease in epithelial cancer types. Paclitaxel weekly/carboplatin weekly is more logistically challenging to administer and is therefore not often used in the setting of stage I disease, given the lower risk of recurrence (compared with more advanced disease). Patients with stage I disease have also been included in some randomized trials testing triplet or quadruplet regimens,773,780,795,796 but the added toxicity of these regimens with no clear impact on efficacy makes options inappropriate for stage I.. # Note that carboplatin dosing may be revised based on changes in serum creatinine methodology (see FDA carboplatin dosing statement). The AUC of 5 to 6 for carboplatin reflects contemporary treatment. For the first cycle of pegylated liposomal doxorubicin, infuse at 1 mg/min and make sure that the patient does not have a reaction.. # Adjuvant Chemotherapy Options for Patients with Advanced Age and/or Comorbidities. Adjuvant systemic chemotherapy is considered an essential component of care for patients with ovarian, fallopian tube, or primary peritoneal cancers. For most patients with epithelial cancer types and stage I disease, first- line systemic therapy generally consists of intravenous (IV) platinum- based chemotherapy, with paclitaxel . Unfortunately, patients with advanced age (≥70 years) and/or comorbidities may be less likely to tolerate certain combination chemotherapy regimens, leading to discontinuation before the regimen is completed.771,798,803- 805 For example, patients aged 70 years or older undergoing paclitaxel/carboplatin- based therapy may be at higher risk of febrile neutropenia, anemia, diarrhea, asthenia, thromboembolic events, or hypertension (associated with bevacizumab).771,803 Studies have suggested that risk of severe toxicity, discontinuation of adjuvant chemotherapy, and even worse overall survival (OS) may be correlated with increased age (even among older patients); functional status or depression at baseline (as quantified by the Hospital Anxiety and Depression Scale [HADS]), Activities of Daily Living (ADL) score, Instrumental Activities of Daily Living (IADL) score, and social activities . As patients . Prior versions of the guidelines recommended carboplatin monotherapy as an option for patients . More recently, Elderly Women with Ovarian Cancer (EWOC)- 1, an open- label, phase 2 randomized trial, evaluated carboplatin monotherapy (AUC 5- 6, every 3 weeks [q3w]) alongside two other carboplatin combination regimens (weekly paclitaxel . Data from this study suggested that carboplatin monotherapy was associated with significantly worse outcomes than the carboplatin- combination therapy regimens in this patient population.812 The median. # OS was 7.4 months (95% CI, 5.3- 32.2) in the carboplatin monotherapy group, whereas the median OS was 17.3 months (95% CI, 10.8- 32.2) in the weekly carboplatin- paclitaxel group and not reached in the carboplatin- paclitaxel every 3 weeks group. The hazard ratio (HR) for inferior overall survival of the carboplatin monotherapy group versus the carboplatin- paclitaxel q3w group was 2.79 (95% CI, 1.57- 4.96; . Due to the worse survival outcomes associated with carboplatin monotherapy compared with the carboplatin- combination regimens, the trial was prematurely terminated on the recommendation of the independent data monitoring committee. Therefore, based on these data, the NCCN panel no longer recommends carboplatin monotherapy as an option for patients who are . The following regimens are recommended in the guidelines as options for those . - Paclitaxel . The latter option can also be considered for patients with poor performance status. Please refer to the Principles of Systemic Therapy section in the guidelines for a complete list of recommended primary. therapy regimens and dosing recommendations for ovarian, fallopian tube, and primary peritoneal cancers.. # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer NCCN Cancer Network. Number of Cycles. Number of CyclesRecommendations for the number of cycles of treatment vary with the stage of the disease. Panel members had an extensive discussion about the number of cycles of chemotherapy that should be recommended for patients with advanced- stage disease. There is no evidence confirming that more than 6 cycles of combination chemotherapy are required for initial chemotherapy. Early randomized studies showed that patients treated with 8 or 10 cycles of adjuvant first- line platinum- based IV chemotherapy had similar survival but experienced worse toxicity than those treated with only 5 cycles. \[814,815\] For the regimens recommended in the NCCN Guidelines (for postoperative first- line IV chemotherapy), most of the supporting phase III randomized trials tested 6 cycles of therapy (see Table 5, Table 6, and Table 7). Although cross- trial comparisons should be interpreted with caution, the few trials that used greater than 6 cycles, \[776,777,781,782\] did not appear to show better outcomes than those that used 6 cycles. Also, it has been noted that among the two trials showing improved efficacy with first- line cisplatin/paclitaxel versus cisplatin/cyclophosphamide in patients with advanced ovarian cancer, the later trial that allowed continuation beyond 6 cycles, up to 9 cycles reported a smaller treatment effect (on PFS and OS) and had higher rates of neurotoxicity, suggesting that treatment beyond 6 cycles is unlikely to provide additional clinical benefit. \[791,792\] One randomized trial (NCT00102375) showed that adding 4 cycles of topotecan after 6 cycles of carboplatin/paclitaxel did not improve PFS or OS, or even response among those with measurable disease (Table 6). \[776\] The phase III randomized trial GOG- 157 compared 3 versus 6 cycles of paclitaxel/carboplatin as postoperative first- line IV chemotherapy for patients with stage I- II epithelial ovarian cancer at high risk, defined as stage IA/IB with grade 3 or clear cell, or stage IC/II with any grade. \[801,802\] For the intent- to- treat (ITT) population, the number of cycles did not have . Toxicity. ToxicityAll of these regimens have different toxicity profiles. The docetaxel/carboplatin regimen is associated with increased risk for neutropenia; the IV paclitaxel/carboplatin regimen is associated with increased risk of sensory peripheral neuropathy; and dose- dense paclitaxel is associated with increased risk of anemia and decreased QOL. \[760,762,764,765\] Note that there are no agents to prevent chemotherapy- induced peripheral neuropathy. \[816\]. Targeted Agents. Bevacizumab in the First- Line Setting. Two phase 3 randomized trials, GOG- 0218 and ICON7, tested the effects of adding bevacizumab during first- line platinum- based combination chemotherapy and as single- agent maintenance therapy after first- line chemotherapy (for patients who had not progressed during initial treatment with chemotherapy + bevacizumab). \[817- 819\] The study design and results from these trials are summarized in Table 10.. # B. Treatment Regimens. # National Comprehensive NCCN Guidelines Version 1.2025 NCCN Cancer Ovarian Cancer Network. or Arm 3 (median OS, 43.4 months; HR, 0.96; 95% CI, 0.85–1.09).821 Exploratory analysis of disease- specific survival yielded similar results. Subgroup analysis showed no treatment- dependent differences in OS for patients with stage III disease, but did yield interesting results for patients with stage IV disease. Arm 1 and 2 had no significant difference in OS, but Arm 3 showed significantly longer OS compared with Arm 1 (42.8 mo vs. 32.6 mo; HR, 0.75; 95% CI, 0.59–0.95).821 Primary analysis of GIG ICON7 after a median of 19.4 months follow- up showed improved PFS with bevacizumab (HR [95%CI], 0.81 [0.70–0.94]; . Bevacizumab in the First-Line Setting: Efficacy. In GOG- 0218, although PFS was similar for patients treated with carboplatin/paclitaxel (Arm 1, control) versus those who also had bevacizumab during initial treatment (Arm 2, carboplatin/paclitaxel/bevacizumab), patients treated with carboplatin/paclitaxel/bevacizumab followed by maintenance with single- agent bevacizumab (Arm 3) had a 3- month improvement in median PFS compared with the control arm (See Table 10A).817,820 OS was not significantly different across all three arms (Table 10A), even after long- term follow- up.817,820,821 The effects of treatment on PFS and OS were non- proportional over time, however, with the greatest difference between arms around 15 months, and the Kaplan- Meier curves converging again about 9 months later. Results from ICON7 were similar, with results from the primary analysis (median follow- up 19.4 months) showing longer PFS with carboplatin/paclitaxel/bevacizumab, followed by single- agent bevacizumab maintenance therapy (Arm 2) compared with carboplatin/paclitaxel along (Arm 1).818 Analyses after longer follow- up (median 48.9 months), however, showed no significant treatment- dependent differences in PFS or OS (Table 10A).819 Again the effects were non- proportional over time, with the treatment- dependent differences in PFS and OS increasing to a peak between 12–18 months, and the Kaplan- Meier curves subsequently converging.819. For both GOG- 0218 and ICON7, outcomes with upfront paclitaxel/carboplatin/bevacizumab plus single- agent bevacizumab maintenance (Arm 3 in GOG- 0218, Arm 2 in ICON7) were compared with . # National Comprehensive NCCN Guidelines Version 1.2025 NCCN Cancer Ovarian Cancer Network. An exploratory analysis of GOG- 0218, including 1195 patients with DNA samples that could be sequenced, showed that the presence of mutations in BRCA1, BRCA2, or non- BRCA homologous recombination repair (HRR) genes was associated with longer PFS and OS relative to patients with no mutations in these genes, even after adjusting for treatment, stage, size of residual disease, and performance status at baseline.824 For patients without mutations in any of these genes, the addition of bevacizumab (to up- front chemotherapy and as maintenance) was associated with improved PFS (median PFS for Arm 1 vs. Arm 3: 10.6 vs. 15.4 months; HR, 0.71 [95% CI, 0.60- 0.85]; . Bevacizumab Safety and Quality of Life. Based on earlier studies, toxicities that may occur in patients treated with bevacizumab and are of particular concern, may require intervention, and often lead to treatment discontinuation include the following: pain (grade . Data from both GOG- 0218 and ICON7 showed that most toxicities developed during the chemotherapy phase of treatment, although there were a few AEs of concern that continued to develop during the bevacizumab maintenance phase, including hypertension, high- grade pain, proteinuria, and thromboembolism.817 Exploratory analyses tried to identify factors that might be associated with increased risk of bevacizumab- associated AEs.825,826 Analysis of GI- related AEs in GOG- 0218 identified inflammatory bowel disease (IBD), and bowel resection at primary surgery as being associated with increased risk of grade . Both GOG- 0218 and ICON7 reported some small but statistically significant differences between treatment arms in the global measures of QOL. Analyses of GOG- 0218 showed that QOL improved somewhat during the course of the study across all arms (FACT- O TOI scores improved from ~67- 68 to ~76- 68).817,827 Results showed slightly worse QOL for patients treated with bevacizumab during the chemotherapy phase (FACT- O TOI scores . # were no statistically significant differences in QOL scores for patients treated with bevacizumab during chemotherapy only (Arm 2) versus bevacizumab during chemotherapy plus maintenance (Arm 3),<sup>827</sup> which further supports the idea that bevacizumab maintenance did not impact QOL. For FACT- O TOI scores, the threshold for clinically meaningful differences has been suggested to be 5–7 points. Results from ICON7 showed that for both arms QOL improved somewhat over the course of the trial, during both the chemotherapy phase and the maintenance phase.<sup>818,828</sup> However, these increases were smaller in the bevacizumab arm (Arm 2), such that QOL scores were better in the control arm (Arm 1) versus the bevacizumab arm (Arm 2) at the end of chemotherapy (week 18; mean QLQ- C30 score difference of 6.1 points; . NCCN Recommendations. Based on results from GOG- 0218 and ICON7, the NCCN Guidelines include bevacizumab- containing regimens as options for first- line . # AUC, area under the curve; CR, complete response; IV, intravenous; PR, partial response. a Includes high- grade serous, grade 2/3 endometrioid, clear cell carcinoma stage IC only for mucinous, low- grade serous, and grade 1 endometrioid. b These options are primarily for patients aged ≤70 years, with good performance status, and without comorbidities. For patients who are >70 years, have poor performance score, or have comorbidities, see alternate treatment options discussed in the section entitled Options for Patients Who Are >70 years or Have Comorbidities or Poor Performance Score.. c NCCN- recommended number of cycles. d NCCN Category of Evidence and Consensus.. For patients with BRCA1/2 wild- type or unknown mutation status who are in CR/PR after chemotherapy plus bevacizumab, maintenance options include bevacizumab alone (category 2A) or bevacizumab + olaparib (category 2A). See Options After First- Line Chemotherapy section for more information.. For patients with a BRCA1/2 mutation in CR/PR after chemotherapy plus bevacizumab, maintenance therapy options include: bevacizumab + olaparib (category 1), olaparib monotherapy (category 2A), or niraparib monotherapy (category 2A). See Options After First- Line Chemotherapy section for more information.. GOG- 0218 did not include patients with stage I- II disease, and ICON7 included patients with stage I- IIA disease only if they were considered "high risk" because of poor differentiation (high grade) or clear cell histology (Table 10A). Due to these entry criteria and the results of subgroup analysis suggesting that bevacizumab may only be beneficial in . # GOG- 0218 and ICON7 included patients primarily with ovarian cancer, but also some with primary peritoneal or fallopian tube cancer.. Bevacizumab Biosimilars. In September 2017 the FDA approved the first bevacizumab biosimilar, ABP- 215, as bevacizumab- awwb, for use in certain indications in a number of cancers (ie, colorectal cancer, non- squamous non- small cell lung cancer [NSCLC], glioblastoma, renal cell carcinoma, cervical cancer), but not including any indications in ovarian, fallopian tube, or primary peritoneal cancers due to regulatory exclusivity.. Intraperitoneal/Intravenous Regimen. IP chemotherapy has been explored as an option for ovarian cancer based on the idea that localized delivery could improve efficacy, particularly against microscopic spread and peritoneal carcinomatosis, with an acceptable safety profile. Although results from smaller randomized trials . # Comprehensive Cancer Network. NCCN Guidelines Version 1.2025 Ovarian Cancer. option similar to the regimen used in GOG- 172 was added to the NCCN Guidelines (Table 13) for patients with optimally debulked (<1 cm residual) stage III disease.724 Those with optimally debulked stage II disease may also receive IP chemotherapy, as the NCCN Panel has decided that many of the regimens tested in stage III- IV should also be offered to patients . # # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer NCCN Network. a All trials enrolled newly diagnosed, previously untreated/chemotherapy- naive patients, with an epithelial cancer type. b All patients were treated with surgery followed by chemotherapy. c Percentages for each cancer type were not reported, but trial inclusion criteria allowed OC, FTC, and PPC. d HR and P- values are for comparison with control arm (IV regimen). e Patients who discontinued therapy due to AEs.. In the large randomized trials that showed that IP/IV benefit, most of the patients had serous or endometrioid disease, and high- grade tumor histology (Table 12), so it is unclear whether patients with LCOCs will benefit from IP/IV chemotherapy. In the NCCN Guidelines, the clear cell carcinoma and carcinosarcoma are the only LCOCs for which IP/IV chemotherapy is a recommended option, as these cancer types are associated with higher risk of poor outcomes.6,871- 873 Patients with carcinosarcoma were not included in the randomized trials testing IP/IV chemotherapy, but . Enthusiasm for IP/IV chemotherapy has waned considerably due to the results of GOG- 0252, a large randomized trial in patients with stage II/III optimally resected (. # For the recommended IP chemotherapy regimen (Table 13), the IP paclitaxel was infused over 24 hours in the clinical trial (GOG- 172).724 A 3- hour infusion of paclitaxel has not been proven to be equivalent to a 24- hour infusion, although a 3- hour infusion has been reported to be more convenient, easier to tolerate, and less toxic.774 Note that in all the supporting trials and in the NCCN Guidelines, IP regimens include IV regimens so that systemic disease can also be treated.. The IP paclitaxel/cisplatin regimen is associated with leukopenia, infection, fatigue, renal toxicity, abdominal discomfort, and neurotoxicity.724,863- 865,867 In GOG- 172, only . Prior to the administration of the combined IP and IV regimen, patients must be apprised of the increased toxicities with the combined regimen when compared to using IV chemotherapy alone (increased myelosuppression, renal toxicities, abdominal pain, neuropathy, Gl toxicities, metabolic toxicities, and hepatic toxicities). Patients who are candidates for the IP cisplatin and IP/IV paclitaxel regimen should have normal renal function before starting, a medically appropriate PS based on the future toxicities of the IP/IV regimen, and no previous evidence of medical problems that could significantly worsen during chemotherapy, such as preexisting neuropathy. Reasons for discontinuing the IP regimen . Neoadjuvant Chemotherapy. In the NCCN Guidelines for Ovarian Cancer, neoadjuvant therapy refers to treatment (eg, drugs and other treatments) that is given to reduce the tumor burden before cancer surgery. The therapeutic benefit of NACT followed by IDS remains controversial (see below).480,694,878- 885. For advanced- stage epithelial ovarian cancer, including fallopian tube and primary peritoneal cancers, the best outcomes have been observed in patients whose primary treatment included complete resection of all visible disease and combination chemotherapy.868 Therefore, the NCCN Guidelines recommend that primary treatment for presumed advanced- stage disease consist of appropriate surgical debulking plus systemic chemotherapy in most patients. For most patients presenting with suspected advanced- stage malignant ovarian, fallopian tube, or primary peritoneal cancer, initial surgery should include a hysterectomy and BSO with comprehensive staging and debulking as indicated.13,541,588 PDS is the recommended approach for advanced- stage disease if the patient is a surgical candidate, optimal cytoreduction (residual disease . # Comprehensive Cancer Network. NCCN Guidelines Version 1.2025 Ovarian Cancer. preferably removal of macroscopic disease [R0]) appears feasible, and fertility is not a concern. NACT with IDS should be considered for patients with advanced- stage disease who are not good candidates for PDS due to advanced age, frailty, poor performance status, comorbidities, or disease that is unlikely to be optimally cytoreduced. The anticipated benefit from NACT would be to allow for medical improvement and/or clinical response that would increase the likelihood of optimal cytoreduction at IDS. Patients treated with NACT and IDS should also receive postoperative adjuvant chemotherapy.. Randomized Trials Comparing NACT Versus Conventional Treatment. Several prospective randomized trials have compared an NACT approach (with IDS and postoperative chemotherapy) versus conventional treatment. (PDS plus postoperative chemotherapy; Table 14).481- 483,639,640 These trials focused on patients with FIGO stage IIC- IV ovarian, fallopian tube, or primary peritoneal cancer that was deemed unlikely to be completely resected. As shown in Table 14, the NACT regimens tested in these trials typically consisted of 3- 4 cycles of upfront chemotherapy, followed by IDS with the goal of maximum cytoreduction, followed by 3- 4 cycles of postoperative chemotherapy. Several of these trials (ie, EORTC 55971,483 SCORPION,639 JCOG0602482) allowed IDS in the neoadjuvant arm only for patients experiencing response or stable disease after NACT. The control arms in these trials consisted of PDS (with the goal of maximum cytoreduction) followed by postoperative chemotherapy to a total of 6 to 8 cycles. Specific chemotherapy regimens used in these trials are shown in Table 15.481- 483,639,640. # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer Network. # of pelvis . In EORTC 55971, OS . In CHORUS, patients were included if suspected FIGO stage III- IV based on imaging/clinical evidence, but after surgery only . In CHORUS, analyses of subgroups showed that residual disease after surgery was prognostic for OS in both treatment groups. Post- hoc subgroup analyses showed that there was no treatment- dependent difference in OS for any of the subgroups evaluated based on age, cancer stage, tumor size (prior to surgery), performance score, or type of chemotherapy (single- agent carboplatin vs. carboplatin/paclitaxel).. In SCORPION, patients with stage IV required to have pleural infusion or any resectable disease. All patients were required to have a predictive index of 8- 12 and no mesenteric retraction. All patients had S- LPS for histologic confirmation and to assess tumor load (predictive index). The proportion of patients with poorly differentiated histology was not reported. However, . In SCORPION, PDS was associated with a higher rate of upper abdominal procedures . JCOG0602 did not require histologic confirmation of diagnoses at trial entry. Diagnosis was based on both imaging and cytology of ascites, pleural effusions, or fluids obtained by centesis.. In JCOG0602, patients in the control arm were allowed to have IDS for residual . In the study reported by Liu et al, . Although there was some variability across these trials, results in general demonstrated that patients treated with NACT had improved surgical outcomes (eg, shorter operative time, less blood loss, fewer high- grade surgical complications or surgery- related AEs, shorter hospital stay), less extensive and complicated surgeries needed to achieve optimal cytoreduction, and a lower risk of postoperative death (Table 14).481- 483,639,640 Most of these trials found that NACT increased the likelihood of achieving optimal cytoreduction and/or removal of all macroscopic disease (R0).. Although an NACT approach was associated with improved surgical outcomes and less residual disease after surgery, trials that reported PFS and OS found no significant differences when compared with the conventional PDS approach (Table 14). For some of these trials, post hoc analyses were conducted to determine whether there are any subgroups of patients for whom NACT may improve PFS or OS. Although analyses of CHORUS did not identify any subgroups with treatment- dependent differences in PFS or OS, analyses of EORTC 55971 and a pooled analysis of the per protocol populations from EORTC 55971 and CHORUS. # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer Network. showed that NACT (with IDS and adjuvant chemotherapy) may improve PFS and/or OS in patients with more extensive disease, but conventional treatment (PDS and postoperative chemotherapy) was associated with better PFS and/or OS in patients with less extensive disease.583,887,889. Importantly, for some of these trials (ie, EORTC 55971, CHORUS) the median PFS and OS for both treatment arms (Table 14) were inferior to those reported in randomized studies of patients undergoing PDS followed by postoperative IV chemotherapy for advanced disease (OS mean, . Selection of Patients for NACT. Based on the results from randomized trials shown in Table 14, the NCCN Guidelines recommend considering neoadjuvant therapy for patients with bulky disease that is unlikely to be optimally cytoreduced by up- front surgery. The panel considers the current evidence to be insufficient for justifying NACT as an option for patients who by assessment of a gynecologic oncologist are likely to be optimally cytoreduced by upfront surgery. When selecting patients for NACT with IDS, the cancer type of the primary tumor and potential response to primary chemotherapy should be considered. NACT is not appropriate for patients with non- epithelial cancer types (eg, sex cord- stromal or germ- cell tumors). NACT is not appropriate for patients with disease apparently confined to the ovary. NACT can also be considered for patients who are poor surgical candidates, such as those with poor performance score, in the hopes that tumor load reduction may improve their condition and thereby reduce perioperative risks. At least one of the randomized trials in Table 14 (Liu. 2017^{640}). NCCN recommendations for workup and selection of patients for NACT are aligned with the eligibility criteria and protocols used in the randomized controlled trials shown in Table 14. For these trials, preoperative evaluations and debulking surgeries were performed by gynecologic oncologists; some trials included additional requirements to ensure that the surgeons had sufficient experience performing the procedures.481- 486,639,640 The NCCN Ovarian Cancer Panel emphasizes that evaluation by a gynecologic oncologist is important for determining the most appropriate method of obtaining tissue for histologic confirmation and of determining the extent of disease. This recommendation is consistent with those from SGO and ASCO.480. Most of the trials in Table 14 required confirmation of staging and diagnosis based on imaging plus histology of a biopsy specimen or cytology of ascites or pleural effusion. Some trials had additional entry criteria based on serum CA- 125 and CEA levels, and some required additional diagnostic tests to rule out other types of malignancies. Laparoscopy to evaluate extent of disease and feasibility of resection was required in one of these trials (SCORPION) and also frequently used in the other randomized trials shown in Table 14. Reports from several of these trials noted that for some patients, the assignment of histologic type and disease stage was revised after biopsy or laparoscopic evaluation, and sometimes revised after debulking surgery.481- 483,639 The NCCN Guidelines recommend histologic confirmation of diagnosis and cancer subtype based on analysis of tumor tissue. If biopsy is not feasible, cytopathology from ascites or pleural effusion combined with a CA-. # 125:CEA ratio of . Regimen Options for Patients Treated with NACT. A wide variety of platinum- based regimens have been used in clinical trials testing NACT plus IDS and postoperative chemotherapy. All of the . # # MS- 54.	None	None	None
2f64cd18ab4c462e940c4c2f4cbacf92	NCCN临床实践指南	卵巢癌包括输卵管癌和原发性腹膜癌121-150	# AUC, a d i t t t NS, no significant difference between arms; OL, open-abel; OS, overall survival; PFS, progression-ree survival; R, randomized; R0, no macroscopic residual disease; RCT, randomized controlled trial; wks, weeks. a l f th t t t the goal f maxm cction) pti th m f c r f r e thwise specified, the same regimen was used both as neoadjuvant and postoperative, and agents were administered on day 1 of each cycle. In some trials, only patients meeting certain requirements were allowed to have IDS and/or postoperative chemotherapy. b In SWOG 009, patients with stage I were required to have large pelic mass and/or bulky abdominal disease and/or malignant pleural effusion; patients with stage IV were required to have malignant pleural effusion. In SWOG 0009, 58 patients were eligible for NACT and 45 completed NACT. Patients were required to have . # Bevacizumab- Containing Regimens for Patients Treated with NACT Several prospective trials have explored whether adding bevacizumab to platinum- based regimens improves outcomes for patients treated with NACT. Preliminary results from GEICO 1205/NOVA found that adding . # National Comprehensive NCCN Guidelines Version 1.2025 NCCN Cancer Ovarian Cancer Network. National Comprehensive NCCN Guidelines Version 1.2025 NCCN Cancer Network®trial used a similar carboplatin/paclitaxel regimen, but did not find a significant difference in the rate of grade 3- 5 AEs for patients treated without versus with bevacizumab (63% vs. 62%).<sup>896</sup> Results from ALTHALYA also showed no difference between treatment arms for CR rate prior to IDS, percent of patients with no macroscopic residual disease after IDS, or surgical outcomes (operative time, length of hospital stay, length of stay in intensive care unit, frequency of blood transfusions, and rate of postoperative complications).<sup>896</sup> Taken together, results from these trials indicate that although platinum- based regimens that include bevacizumab have acceptable safety for patients treated with an NACT approach, more data are needed to determine whether the addition of bevacizumab impacts PFS. The NCCN Guidelines include two bevacizumab- containing regimens as options for NACT and post- IDS chemotherapy (Table 17). It is important to note that all of the prospective trials in Table 15 and Table 16 that allowed use of bevacizumab in the NACT setting used a washout period before (and sometimes after) IDS, usually of at least 28 days.<sup>639,894- 896</sup> Bevacizumab- containing regimens should be used with caution before IDS due to potential interference with postoperative healing. If bevacizumab is being used as part of a neoadjuvant regimen, bevacizumab should be withheld from therapy for at least 6 weeks prior to IDS.. Intraperitoneal/Intravenous Regimens for Patients Treated with NACTSeveral trials have explored the use of IP/IV regimens in patients treated with an NACT approach. Both SWOG S0009 and OV21/PETROC tested postoperative IP/IV regimens for patients who had platinum- based NACT followed by optimal cytoreduction by IDS.<sup>892,897</sup> In SWOG S0009, among patients with a 50% or greater decrease in CA- 125 level during NACT, optimal debulking by IDS (<1 cm and malignant pleural resolved), and postoperative IP/IV chemotherapy, median PFS (29 months) and OS (34 months) compared favorably with results from other trials using IV regimens (Table 16).<sup>892</sup> To determine whether postoperative IP/IV . Based on these results, the NCCN Guidelines include both the cisplatin/paclitaxel IP/IV regimen and the carboplatin/paclitaxel IP/IV regimen as options for postoperative therapy in patients who have received NACT and IDS (Table 17). Given the lack of survival improvement in OV21/PETROC, more data are needed to establish whether postoperative IP chemotherapy provides clinical benefit in patients who have received IV NACT and IDS. Recent results from the phase III randomized controlled GOG- 0252 trial have also called into question the value of postoperative IP chemotherapy for patients with advanced- stage disease treated with PDS.<sup>870</sup> Although earlier trials showed improved PFS and/or OS with IP versus IV chemotherapy,<sup>724,863,864,868</sup> results from GOG- 0252 showed no improvement.<sup>870</sup> However, unlike previous trials, all regimens used in GOG- 0252 contained bevacizumab, which may have compensated for the effect of IP chemotherapy administration.. Number of Chemotherapy Cycles Before and After IDS. As shown in Table 16, results from the PRIMOVAR- 1 phase II randomized trial showed that treatment with 3 versus 2 cycles of NACT did not impact. # response rate, extent of cytoreduction achieved in IDS, operative time, extent of surgery needed, or PFS or OS.893 Nonetheless, because most of the randomized trials testing NACT protocols used 3 to 4 cycles before IDS (Table 15 and Table 16), the NCCN Guidelines indicate that 3 to 4 cycles of NACT before IDS is preferred, although surgery after 4 to 6 cycles may be used based on the clinical judgment of the treating gynecologic oncologist.. After 3 to 4 cycles of NACT, patients should be evaluated by a gynecologic oncologist to determine the likelihood of optimal cytoreduction. For patients whose disease responded to NACT and are likely to have optimal cytoreduction, IDS with completion hysterectomy/BSO and cytoreduction should be performed. Those with stable disease after 3 to 4 cycles of NACT can consider IDS (with completion hysterectomy/BSO, and cytoreduction), but also should consider either 1) switching to treatment for persistent/recurrent disease; or 2) treatment with additional cycles of NACT (to a total of . Most of the trials testing NACT regimens used at least 3 cycles of adjuvant chemotherapy after IDS, or indicated that the total number of cycles should be 6 to 8 (Table 14, 15, and 16). The NCCN Guidelines recommend that regardless of the number of cycles of NACT received, IDS should always be followed by adjuvant chemotherapy. For all patients who undergo NACT plus IDS, a minimum of 6 cycles of treatment is recommended, including at least 3 cycles of adjuvant therapy after IDS.. Patients with stable disease who are tolerating therapy may continue past 6 cycles.. Interval Debulking Surgery After Neoadjuvant Chemotherapy of Invasive Epithelial Ovarian Cancer. Analyses of data from multiple prospective trials found that the extent of residual disease after NACT plus IDS was prognostic for PFS and OS.481,483,640,893 As shown in Table 14, 15, and 16, these trials reported optimal cytoreduction in . # All interval debulking procedures should include completion hysterectomy and BSO with comprehensive staging. All peritoneal surfaces should be visualized, and any peritoneal surface or adhesion suspicious for harboring metastasis should be selectively excised or biopsied. Suspicious and/or enlarged nodes should be resected, if possible. Removal of lymph nodes noted to have potential metastasis at the time of initial diagnosis should be considered, even if the nodes are not currently suspicious or enlarged. An omentectomy should be performed, and additional procedures that may be considered include bowel resection and/or appendectomy, stripping of the diaphragm or other peritoneal surfaces, splenectomy, partial cystectomy and/or ureteroneocystostomy, partial hepatectomy, partial gastrectomy, cholecystectomy, and/or distal pancreatectomy.. Hyperthermic Intraperitoneal Chemotherapy at the Time of IDS Hyperthermic intraperitoneal chemotherapy (HIPEC) is a technique in which chemotherapy is delivered in a heated solution perfused throughout the peritoneal space. The rationale for hyperthermic delivery is that heat can increase penetration of the chemotherapy at the peritoneal surface and enhance the sensitivity of cancer cells to chemotherapy by inhibiting DNA repair. Concerns about the inconvenience of delivery and toxicities associated with postoperative IP/IV chemotherapy motivated researchers to determine whether HIPEC could improve safety and QOL. Although raising body temperature carries substantial risks, methods have been developed for raising the temperature of the IP space with minimal increase in the temperature of the rest of the body.. Over the past several decades a few randomized trials (Table 18) and numerous prospective nonrandomized trials have reported on the use of HIPEC in patients with ovarian cancer. HIPEC methods have evolved over the years to reduce intraoperative and postoperative complications. Both "open" and "closed" abdominal techniques have been . Given the risks associated with HIPEC, prospective studies have focused on using HIPEC immediately after debulking (as part of the same procedure) in patients with high- volume IP disease (FIGO stage III- IV at diagnosis or recurrence), particularly those with peritoneal carcinomatosis, who are at risk for widespread residual microscopic disease even after resection to no visible disease. Compared with postoperative IP therapy, intraoperative IP administration may enable better perfusion of the. # peritoneal space because adhesions will not yet have formed. Patients with less extensive disease were excluded because they are less likely to have widespread microscopic disease after debulking, and therefore the potential benefit is unlikely to outweigh risks of the procedure. Patients with distant extra- abdominal metastases were often excluded from HIPEC studies because of concerns that IP therapy would not be effective treatment for extra- peritoneal disease.. Only a few phase III prospective comparative studies have tested whether HIPEC improves outcomes for patients with advanced ovarian cancer (summarized in Table 18). The most recent and largest . Because of these positive results, the NCCN Guidelines now include an option to consider HIPEC at the time of IDS in patients with stage III disease treated with NACT. Similar to the trial, which required patients to have response or stable disease after 3 cycles of NACT and which treated patients with postoperative chemotherapy (3 cycles), the NCCN Guidelines recommend HIPEC as an option for patients who have response or stable disease after NACT (3 cycles preferred, but 4- 6 allowed) and recommend that all patients treated with NACT and IDS . In most prospective studies testing HIPEC, the surgery prior to HIPEC was conducted with the goal of maximal cytoreduction (R0 resection) and involved TAH/BSO, omentectomy, and a variety of other procedures, depending on the extent of disease. Optimal cytoreduction (residual disease . The NCCN- recommended HIPEC agent is cisplatin, . # recommendation based on the regimen selected for NACT or postoperative chemotherapy.. # Comprehensive Cancer Network. NCCN Guidelines Version 1.2025 Ovarian Cancer. Abbreviations: AE, adverse event; AUC, area under the curve; CC, completeness of cytoreduction score; CC- 0, no residual disease; CC- 1, residual nodules . Trial excluded patients with metastases outside of peritoneal surfaces (eg, extra- abdominal, parenchymal, bulky retroperitoneal). Major or minor postoperative complications included both those related to surgery and those related to chemotherapy. Grade 1 was defined as no complications; grade 2, minor complications; grade 3, major complications requiring reoperations or ICR admission; grade 4, in- hospital mortality. Greater extent of resection and lower PCI were correlated with improved OS. Excluded patients with pleural disease or lung metastasis, . Monitoring Response to Adjuvant Systemic Therapy. After completion of chemotherapy, patients should be assessed for response during and following treatment and monitored for any long- term complications. Consider symptom management and best supportive care, and refer for palliative care assessment, if appropriate. See NCCN Guidelines for Palliative Care and NCCN Guidelines for Survivorship (available at www.NCCN.org).. Patients who have completed primary treatment for stage I disease (surgery alone or with adjuvant systemic therapy) should be monitored for recurrence. See Follow- up Recommendations below.. For patients who have completed postoperative chemotherapy as part of primary therapy for stage II- IV disease, imaging is recommended as clinically indicated to determine the extent of disease, if any. Recommended imaging modalities include chest/abdominal/pelvic CT, MRI, PET/CT, or PET (skull base to mid- thigh). All imaging should be performed with contrast unless contraindicated. Patients who have CR, with no evidence of disease, or PR may be eligible for maintenance. # therapy as described in the next section (Options After First- Line Chemotherapy). Those with stable, persistent, or progressive disease should be managed as described in the section entitled Therapy for Persistent Disease or Recurrence.. Options After First-Line Chemotherapy. After initial treatment (eg, surgery followed by chemotherapy), patients should undergo regular clinical re- evaluation. Observation with follow- up is recommended for patients who had stage I disease at presentation and have no signs of new disease. Recommendations for surveillance during observation are in the Monitoring/Follow- up section (within the Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer section in the algorithm).. For patients who had stage II- IV disease at presentation, options following surgery and chemotherapy depend on the success of these interventions. These patients should be evaluated with imaging as clinically indicated to determine the extent of residual disease or progression and screen for new metastases. Imaging should include chest/abdominal/pelvic CT, MRI, PET/CT, or PET (skull base to mid- thigh).. Patients with persistent disease or progression during initial treatment should be treated with second- line approaches (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Therapy for Persistent Disease or Recurrence in the algorithm and Recurrent Disease section below).936,937. For patients with advanced- stage (stages II- IV) disease who, after primary therapy (surgery plus chemotherapy), are in complete clinical remission (ie, complete response [CR], defined as no definitive evidence of disease936,937), partial remission (ie, partial response [PR]), or stable disease, recommended options depend on the extent of their response and the type of primary chemotherapy they received (see Post- Primary. Treatment: Maintenance Therapy within the Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer section of the algorithm). These recommendations have been revised several times recently due to emerging data from clinical trials, summarized in Tables 19, 20, and 21. These recent data and their impact on the recommendations are discussed in the sections below.. Bevacizumab Maintenance Therapy. As described in detail in the previous section entitled Bevacizumab in the First- Line Setting, results from the phase III GOG- 0218 and ICON7 trials support the use of single- agent bevacizumab maintenance therapy for patients with stage II- IV disease who experience response or stable disease after postoperative chemotherapy with one of the carboplatin/paclitaxel/bevacizumab regimens used in these trials (and recommended by NCCN).817- 819 Based on these results bevacizumab monotherapy was a recommended option for maintenance for patients with stage II- IV disease who were in CR/PR after a primary treatment with surgery and one of the bevacizumab- containing regimens recommended in the first- line setting. However, due to results from subsequent trials showing benefit from PARP inhibitors, as described below, bevacizumab monotherapy is no longer recommended for patients with BRCA1/2 mutations, but is still recommended as an option for patients who have wild- type or unknown BRCA1/2 mutation status (in CR/PR after a recommended bevacizumab- containing first- line chemotherapy regimen), as these patients have fewer PARP inhibitor options (See Table 23).. PARP Inhibitor Maintenance Therapy After Primary Chemotherapy Several PARP inhibitors have been shown to be active in recurrent ovarian cancer,938- 945 and have been FDA approved for multiple indications in ovarian cancer (summarized in Table 22); the corresponding recommendations can be found in the NCCN Guidelines algorithm for Post- Primary Treatment: Maintenance Therapy (OV- 5), Therapy for. # Persistent Disease or Recurrence (OV- 7) and Principles of Systemic Therapy: Acceptable Recurrence Therapies for Epithelial Ovarian (including LCOC)/Fallopian Tube/Primary Peritoneal Cancer (OV- C 7 and 8 of 10).. More recently, several phase III double- blind, randomized trials have tested PARP inhibitors as maintenance therapy for patients with newly . # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer NCCN Network. e First- line therapy was for 6 cycles, maintenance for 30. Veliparib dose during chemotherapy was . Abreviations: CA- 125, cancer antigen 125; CR, complete response; HRD, homologous recombination deficient; HRP, homologous recombination proficient; IDS, interval debulking surgery (after neoadjuvant therapy); NED, no evidence of disease; NR, not reported; PDS, upfront primary debulking surgery; PR, partial response; RCT, randomized controlled trial; ULN, upper limit of normal.. All patients had newly diagnosed, histologically confirmed disease. Data show percent of total randomized population . In SOLO- 1, other cancer types were mixed endometrioid and serous. In PAOLA- 1, other cancer types included clear cell, undifferentiated, or other; entry criteria allowed high- grade serous, high- grade endometrioid, and other non- mucinous with deleterious germline BRCA1/2 mutation. In PRIMA, study entry criteria required high- grade serous or high- grade endometrioid histology, yet 17 patients were listed as "other" without further explanation. VELIA entry criteria required histologic confirmation of high- grade serous, and no data on this were reported.. For PAOLA- 1 and PRIMA, homologous recombination deficiency was defined as BRCA1/2 mutation or an GIS . Entry criteria for PRIMA required patients to have either 1) stage II disease with visible residual tumor after primary surgery; 2) inoperable stage II disease; or 3) any stage IV disease (residual disease after surgery not required). . # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer Network. f Information is based on entry criteria because data were not reported. g In SOLO- 1, . h In SOLO- 1 and PAOLA- 1, CR was defined as NED on imaging (no measurable/assessable disease) and CA- 125 . Olaparib Monotherapy. The SOLO- 1 trial demonstrated a remarkable improvement in PFS with single- agent olaparib versus placebo as maintenance therapy for patients with a germline or somatic BRCA1/2 mutation who had a CR/PR after first- line platinum- based chemotherapy (Table 19).752 The risk of progression or death was . SOLO- 1 excluded patients who received bevacizumab as part of primary systemic therapy, so the efficacy of single- agent olaparib after chemotherapy/bevacizumab primary therapy is unknown. Nonetheless, the benefit from olaparib was sizeable and significant across many subgroups analyzed.752,946 It is important to note that the effects of maintenance olaparib on PFS ( . PFS curves converging well before 40 months, even for the high- risk groups shown to benefit most from bevacizumab.819,820 In addition, the exploratory analysis of GOG- 0218 based on BRCA mutation status suggests that bevacizumab may not improve PFS in patients with BRCA1/2 mutations.824 The PAOLA- 1 trial (described in the next section) suggested that maintenance olaparib could provide PFS benefit in patients who had bevacizumab during first- line chemotherapy.753 For these reasons single- agent olaparib is a category 1 option only for patients who did not have bevacizumab as part of primary therapy, but is a category 2A option for patients who received prior bevacizumab, provided that they were in a CR or PR after completion of chemotherapy (Table 23). The NCCN Panel included a footnote to make it clear that data are limited on the use of single- agent olaparib after first- line platinum- based chemotherapy plus bevacizumab, but that evidence from other subgroups suggests that it should be considered as an option for these patients.. Olaparib + Bevacizumab. The phase III double- blind, randomized PAOLA- 1 trial demonstrated a remarkable improvement in PFS (HR, 0.59) when olaparib (vs. placebo) was added to maintenance bevacizumab in patients who have a CR or PR after first- line platinum- taxane chemotherapy plus bevacizumab for advanced disease (Table 19).753 Unlike SOLO- 1, PAOLA- 1 included both patients with and without BRCA1/2 mutations. Subgroup analyses showed that similar to the SOLO- 1 trial, for patients with BRCA1/2 mutations, maintenance olaparib reduced the risk of progression or death by approximately . # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer NCCN Cancer Network. the PFS benefit of adding olaparib to bevacizumab maintenance was similar and significant regardless of BRCA mutation type (BRCA1 vs. BRCA2).947 Based on these results, maintenance with bevacizumab . PAOLA- 1 also showed that adding olaparib to maintenance bevacizumab resulted in a smaller but still significant improvement in PFS for those with BRCA1/2 wild- type or unknown (Table 19).753 Due to the smaller magnitude of this effect, the NCCN Guidelines include olaparib . In PAOLA- 1 the population without BRCA1/2 mutations was further subdivided based on results of MyChoice CDx (Myriad Genetic Laboratories), a proprietary tumor tissue assay that uses multiple molecular tests and combines several metrics (loss of heterozygosity [LOH],948 telomeric allelic imbalance [TAI],949 and large- scale state transitions [LST]950 to determine the genomic instability score (GIS), a proxy measure for the presence of homologous recombination deficiency.951,952 A GIS cutoff of 42 was used to define homologous recombination deficiency status based on a prior analyses of a population of breast and ovarian cancer cases showing that this cutoff identified . OS results from PAOLA- 1 were not mature.. Niraparib Monotherapy. Similar to the SOLO- 1 results for olaparib monotherapy, the PRIMA trial demonstrated a remarkable improvement in PFS with single- agent niraparib (versus placebo) as maintenance therapy for patients with a BRCA1/2 mutation who were in a CR/PR after first- line platinum- based chemotherapy (Table 19).754 Based on these results the NCCN Guidelines include single- agent niraparib as a maintenance therapy option for patients with BRCA1/2 mutations who have completed primary treatment including surgery and platinum- based first- line therapy (Table 23). PRIMA likely did not include many patients who had prior bevacizumab as part of primary systemic therapy, so for patients with a BRCA1/2 mutation maintenance niraparib is a category 1 option for those who had first- line platinum- based chemotherapy without bevacizumab, and a category 2A option for those who had bevacizumab in conjunction with first- line platinum- based chemotherapy (Table 23).. Unlike SOLO- 1, the presence of a BRCA1/2 mutation was not part of the entry criteria for the PRIMA trial. PRIMA included patients who did not have deleterious mutations in BRCA1/2, and results showed significant PFS improvement with niraparib (vs. placebo) for the overall population. Subgroup analyses showed that the effect of maintenance niraparib on PFS was still significant among patients without a BRCA1/2 mutation (HR,. # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer NCCN Cancer Network. 0.71 . As in PAOLA- 1, in PRIMA the patient group without BRCA1/2 mutation was further subdivided into homologous recombination deficient and proficient based on a GIS cutoff of 42 using the MyChoice CDx (Myriad Genetic Laboratories).754 Results showed that the PFS effect of niraparib (vs. placebo) remained significant for the smaller subgroup of patients with homologous recombination deficiency but no BRCA1/2 mutation, and was significant, with a trend toward smaller magnitude, for the homologous recombination- proficient subgroup (Table 19).754 Because of these results, the NCCN Panel chose to include the following footnote relating to the use of maintenance niraparib: in the absence of a BRCA1/2 mutation, homologous recombination deficiency status may provide information on the magnitude of benefit of PARP inhibitor therapy (category 2B).. OS data from the interim analysis was reported (Table 19), but it is premature to draw conclusions from those results.. Veliparib. The phase III VELIA study design was similar to GOG- 0218 and ICON7 bevacizumab trials in that it tested the effect of adding veliparib during first- line chemotherapy and as subsequent single- agent maintenance after . PARP Inhibitor Safety. Table 21 summarizes key safety data for the four phase III trials testing PARP inhibitor therapy as maintenance following first- line systemic therapy. Across trials, PARP inhibitor maintenance was associated with higher rates of a number of common non- hematologic AEs, such as fatigue/asthenia, nausea, and vomiting (Table 21). These non- hematologic AEs tended to be low- grade and rarely led to study- drug discontinuation.752- 755 PARP inhibitor therapy was also associated with increased risk for a number of hematologic AEs, such as anemia,. # neutropenia, and thrombocytopenia (Table 21). Hematologic AEs were the most common high- grade AEs (grade . In the SOLO- 1, PAOLA- 1, PRIMA, and VELIA trials, there were no statistically significant differences between treatment arms in the heath- related QOL metrics evaluated.. # FDA-Approved Indications for Maintenance Therapy After First-Line Systemic Therapy. Although 3 PARP inhibitors (olaparib, rucaparib, and niraparib) are approved for single- agent maintenance therapy in select patients who are . # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer NCCN Network. treatment after response to first- line chemotherapy in patients with newly diagnosed advanced disease (Table 22). The FDA- approved indications are for patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a CR/PR to first- line platinum- based chemotherapy (Table 22). The FDA indication for single- agent olaparib in this setting is limited to those with a deleterious or suspected deleterious BRCA mutation, and the FDA indication for bevacizumab plus olaparib in this setting is limited to those with homologous recombination deficiency, . Maintenance with single- agent bevacizumab is FDA approved in this setting for patients with stage III- IV epithelial ovarian, fallopian tube, or primary peritoneal cancer that has been treated with surgical resection and combination carboplatin/paclitaxel/bevacizumab (Table 22).. # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer NCCN Network. NCCN Recommendations for Maintenance After Primary Chemotherapy. For patients who have completed primary surgery and systemic therapy, the NCCN- recommended options for the treatment of patients who have completed primary therapy are summarized in Table 23, including maintenance therapy options. The recommended options depend on disease stage, agents used for primary systemic therapy, response to . # therapy options. As illustrated in Table 23, there are several key discrepancies between the FDA labels and NCCN Guidelines recommendations.. 1) The FDA-approved indication for maintenance bevacizumab is limited to patients with stage III-IV disease, whereas the NCCN Guidelines include this as an option for stage II disease. The rationale for this is discussed below in the section on Selecting Patients for Maintenance Therapy, Disease Stage.. 2) The FDA-approved indication for maintenance bevacizumab is not qualified based on BRCA1/2 mutation status. In contrast, the NCCN Guidelines single-agent bevacizumab maintenance is limited to those without a BRCA1/2 mutation. The rationale for this is discussed above in the section entitled Olaparib + Bevacizumab.. 3) The FDA-approved indication for olaparib/bevacizumab combination maintenance therapy does not specify that patients must have had prior bevacizumab, whereas the NCCN Guidelines restrict this option to those with prior bevacizumab, as there are no prospective randomized trial data to suggest that maintenance bevacizumab provides any clinical benefit to those who did not receive prior bevacizumab in combination with platinum-based chemotherapy.. 4) The FDA-approved indication for olaparib/bevacizumab combination maintenance therapy is restricted to patients with. BRCA1/2 mutations or genomic instability, presumably based on the results of the subgroup analysis in PAOLA- 1 showing no PFS benefit for those without homologous recombination deficiency. The NCCN Guidelines include olaparib/bevacizumab combination maintenance therapy as an option regardless of homologous recombination deficiency status, choosing instead to focus on the PFS benefit observed for the larger subgroup of patients without BRCA1/2 mutation (not further subdivided by homologous recombination deficiency status).. 5) The FDA-approved indication for niraparib maintenance is not restricted by BRCA1/2 mutation status or whether bevacizumab was given in combination with platinum-based chemotherapy. In the NCCN Guidelines, however, for patients who received bevacizumab as part of primary therapy, niraparib is a maintenance option only for those with a BRCA1/2 mutation. The rationale for this is described in the section above entitled Niraparib Monotherapy.. When determining whether a patient is a candidate for maintenance after first- line therapy, and selecting among recommended maintenance therapy options, it is important to consider the eligibility criteria and characteristics of the patient population enrolled in the trials supporting the maintenance therapy options. The following sections describe considerations for selecting maintenance therapy.. # # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer NCCN Cancer Network. After first- line therapy with bevacizumab, data are limited on maintenance therapy with a single- agent PARP inhibitor (olaparib or niraparib) for patients with a BRCA1/2 mutation. However, based on the magnitude of benefit of PARP inhibitor maintenance therapy for other subgroups, single- agent PARP inhibitors can be considered. e FDA indication column indicates options consistent with an FDA- approved indication.. Selecting Patients for Maintenance Therapy. Diagnosis and Cancer Type. As shown in Table 20, the trials testing PARP inhibitors as maintenance therapy after first- line systemic therapy enrolled patients with newly diagnosed, histologically confirmed ovarian, primary peritoneal, or fallopian tube cancer. The FDA indications in this setting for olaparib, olaparib . Although most patients in the trials testing PARP inhibitor maintenance after primary therapy had high- grade serous histology . Disease Stage. The trials testing PARP inhibitor maintenance therapy after first- line treatment all required patients to have FIGO stage III- IV, and most patients had stage III disease . The GOG- 0218 and ICON7 regimens for first- line platinum- based chemotherapy with concurrent bevacizumab followed by single- agent maintenance bevacizumab are recommended in the NCCN Guidelines as options for stage III- IV disease, and the NCCN Panel recommends that these can be considered for patients with stage II disease. They are not recommended for stage I disease. Use in stage II should take into consideration that GOG- 0218 included only stage III- IV,817 and although ICON7 included patients with high- risk stage I/II, sub- analyses showed the greatest benefit from bevacizumab among patients with more advanced disease, with no significant impact of bevacizumab on OS for patients with earlier stage disease.819 The corresponding FDA- approved indication for carboplatin/paclitaxel/bevacizumab followed by single- agent bevacizumab is limited to stage III- IV disease (Table 22).. # National Comprehensive NCCN Guidelines Version 1.2025 Cancer Ovarian Cancer Network. BRCA1/2 Mutation Status. BRCA1/2 Mutation StatusBecause BRCA1/2 mutation status is important for selection of maintenance therapy in patients with stage II- IV disease that responds to primary treatment, the NCCN Guidelines recommend screening for BRCA1 and BRCA2 mutations earlier in the course of workup and primary treatment. Genetic risk evaluation and BRCA1/2 testing should be initiated as soon as the diagnosis has been confirmed histologically by evaluation of tumor tissue. Primary chemotherapy should not be delayed for a genetic counseling referral, because delay between surgery and start of chemotherapy is associated with poorer outcomes,. Homologous Recombination Deficiency. Homologous Recombination DeficiencyThere is consensus that the presence of a deleterious germline or somatic mutation in BRCA1 or BRCA2 confers a level of homologous recombination deficiency that is clinically relevant to the selection of therapy for patients with ovarian cancer. However, for patients with ovarian cancer who do not have a deleterious or suspected deleterious mutation in BRCA1 or BRCA2, various molecular markers and metrics have been proposed to determine whether the cancer is associated with a clinically relevant level of homologous recombination deficiency. Different methods and cutoffs were used in the PAOLA- 1, PRIMA, and VELIA trials.. Primary Treatment. Primary TreatmentAll four trials testing PARP inhibitor maintenance after primary treatment included both patients who had received upfront PDS followed by adjuvant chemotherapy, as well as patients who had received NACT with IDS and adjuvant chemotherapy (Table 20). For trials with reported data regarding the types of primary surgery received (ie, SOLO- 1, PAOLA- 1, VELIA), more than half of the patients had upfront PDS, most of the remainder had NACT and IDS, and very few did not have any primary surgery (. In contrast to the other three trials, the PRIMA trial required that patients with stage III have either unresectable disease or visible residual disease after primary surgery, and likely included more patients treated with IDS (vs. PDS), such that a much smaller proportion of the population had a surgery that resulted in no macroscopic disease. For PRIMA the data on primary surgeries received and extent of residual disease after surgery were not reported clearly. The PRIMA report did not include subgroup analyses based on type of surgery or residual disease after surgery, but did show that the PFS benefit associated with maintenance niraparib was significant for both those with and those without prior NACT.. # National Comprehensive NCCN Guidelines Version 1.2025 NCCN Cancer Ovarian Cancer Network. In SOLO- 1, PAOLA- 1, and PRIMA, most patients had at least 6 cycles of platinum- based chemotherapy as part of primary treatment (Table 20). Both IV regimens and IP/IV regimens were allowed in SOLO- 1 and PAOLA- 1.752,753 In the NCCN Guidelines, all the IV and IP/IV regimens recommended for neoadjuvant/adjuvant primary chemotherapy in patients with stage II- IV high- grade serous or endometrioid disease include 6 cycles of platinum- based combination chemotherapy (See Principles of Systemic Therapy: Primary Systemic Therapy Regimens in the algorithm).. SOLO- 1, PAOLA- 1, and PRIMA required patients to have CR or PR before initiation of maintenance therapy, and most had CR after primary systemic therapy, although the definitions of CR and PR varied (Table 20). Subgroup analyses in SOLO- 1 and PRIMA showed that PFS benefit from single- agent PARP inhibitor maintenance was significant regardless of depth of response (CR vs. PR) after first- line systemic therapy.752,754 VELIA did not require that patients have CR or PR after primary chemotherapy as a criterion for receiving veliparib maintenance therapy, and did not report response rate for the overall population.755. The NCCN recommendations for maintenance bevacizumab and PARP inhibitors apply to patients with a CR (no evidence of disease) or PR after debulking surgery and chemotherapy, including those treated with PDS followed by adjuvant chemotherapy, and those treated with NACT, IDS, and adjuvant chemotherapy. Maintenance therapy is not recommended for patients who have progressive or stable disease on primary treatment; these patients should be treated with recurrence therapy options as shown in Therapy for Persistent Disease or Recurrence in the Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer section of the algorithm.. Maintenance Therapies No Longer Recommended. Paclitaxel Maintenance Therapy. Based on results from the randomized GOG- 178 trial, paclitaxel used to be a post- remission therapy option for patients with stages II- IV and CR after first- line therapy. In patients with CR after initial 5- 6 cycles of platinum/paclitaxel combination, those receiving 12 versus 3 additional cycles of paclitaxel sustained a PFS advantage (22 vs. 14 months; . Pazopanib Maintenance Therapy. Pazopanib used to be a recommended post- remission therapy option for patients with stages II- IV disease in clinical CR after first- line chemotherapy. This recommendation was based on the AGO- OVAR 16 phase III randomized trial showing improved PFS with pazopanib versus placebo (17.9 vs. 12.3 months; HR, 0.77; 95% CI, 0.64- 0.91; . # erythrodysesthesia, and that many of these toxicities were contributing to an increased rate of treatment discontinuation (discontinuation rate due to AEs for pazopanib vs. control: . Drug Reactions. Virtually all drugs have the potential to cause adverse reactions while being infused, which can be classified as infusion reactions or allergic reactions, and can occur either during the infusion or following completion of the infusion (even days later).<sup>966,970</sup> Drugs used in gynecologic oncology treatment that more commonly cause adverse reactions include carboplatin, cisplatin, docetaxel, liposomal doxorubicin, oxaliplatin, and paclitaxel.<sup>970</sup> Drug reactions can occur with either IV or IP administration of these drugs.<sup>971</sup> Most of these drug reactions are mild infusion reactions, but more severe hypersensitivity (allergic) reactions and life- threatening anaphylaxis can occur.<sup>971- 974</sup>. Symptoms of (mild) infusion reactions include hot flushing, rash, fever, chest tightness, mild blood pressure changes, back pain, and chills (Table 24). Adverse reactions associated with taxane drugs (ie, docetaxel, paclitaxel) and biotherapeutic agents tend to be mild infusion- related reactions, are often attributed to cremophor in paclitaxel, and tend to occur during the first few cycles of treatment (although they can be seen during any infusion regardless of how many previous cycles were administered).. Mild infusion reactions are common with paclitaxel (27% of patients),<sup>975</sup> but mild reactions can also occur with liposomal doxorubicin,<sup>976</sup> docetaxel, or even platinum agents (ie, carboplatin, cisplatin).. Allergic reactions (ie, true drug allergies) are more common with platinum agents such as carboplatin (16% of patients), cisplatin, and oxaliplatin,<sup>975,977</sup> and tend to occur following re- exposure to the inciting drug or less commonly at the completion of initial chemotherapy (ie, cycle 6 of a planned 6 treatments).<sup>974</sup> Symptoms of allergic reactions include rash, edema, shortness of breath (bronchospasm), syncope or presyncope, chest pain, tachycardia, generalized hives/itching, changes in blood pressure, nausea, vomiting, chills, changes in bowel function, and occasionally feeling of impending doom (Table 24). Symptoms of allergic reactions may continue to persist after stopping infusion and/or after treatment interventions. Patients who are at higher risk of developing a hypersensitivity (allergic) reaction include those undergoing re- introduction of the drug after a period of no exposure and following multiple cycles of the drug during the first and subsequent exposures;<sup>978,979</sup> those undergoing IV administration of the drug rather than oral or IP administration; those with allergies to other drugs; and those who have previously had a reaction. Severe allergic reactions include those that cause shortness of breath, changes in blood pressure requiring treatment, and GI symptoms (eg, nausea, vomiting). Anaphylaxis is a rare type of very severe allergic reaction that can occur with the platinum and taxane agents (and others less commonly), can cause cardiovascular collapse, and can be life- threatening.<sup>972,973,980</sup> Life- threatening allergic reactions such as anaphylaxis are distinguished from other severe reactions by acute onset, generalized hives, respiratory compromise, and severe hypotension (Table 24).. # Preparation for a Possible Drug Reaction. Patients and their families should be counseled about the possibility of a drug reaction and the signs and symptoms of one. Patients should be told to report any signs and symptoms of a drug reaction, especially after they have left the clinic (ie, delayed rash). Clinicians and nursing staff should be prepared for the possibility of a drug reaction every time a patient is infused with a drug. Standing orders should be written for immediate intervention in case a severe drug reaction occurs and the treatment area should have appropriate medical equipment in case of a life- threatening reaction. Epinephrine (intramuscular 0.3 mL of 1 mg/mL solution/EpiPen) should be used for any patient experiencing hypotension . Management of Drug Reactions. Algorithms are provided for management of mild, severe, and life- threatening reactions (summarized in Table 25). These drug reaction algorithms are also useful for patients with other gynecologic cancers (eg, cervical, vulvar, and uterine cancers) who are receiving carboplatin, cisplatin, docetaxel, liposomal doxorubicin, oxaliplatin, or. # paclitaxel. The management recommendations depend on the severity of the reaction and the type of drug that caused the reaction (platinum vs. non- platinum [taxane, liposomal doxorubicin, or biotherapeutic agents]; see Table 25). Typically, the infusion should be stopped for patients having a reaction. The one exception to this rule is that mild infusion reactions occurring during first exposure to a platinum agent may be managed by decreasing the infusion rate and administering an H1 blocker antihistamine (eg, diphenhydramine or hydroxyzine), and usually resolve after stopping the infusion. Whereas H1 blocker antihistamine such as diphenhydramine or hydroxyzine is recommended for managing drug reactions, regardless of severity, H2 blockers such as cimetidine and famotidine are reserved for severe or life- threatening reactions.. Corticosteroids are also generally reserved for severe or life- threatening reactions, but may be needed for mild reactions to platinum agents in patients with prior exposure, if symptoms do not quickly resolve after administering an H1 blocker. IM epinephrine is recommended for life- threatening reactions, but may sometimes be needed for severe (but not life- threatening) reactions, or for mild reactions to platinum agents if symptoms are not responding to other interventions. Life- threatening reactions require oxygen and nebulized bronchodilators, and saline bolus may also be needed for life- threatening reactions to platinum agents. Standard resuscitation procedures (ie, ACLS) should be followed for patients with acute cardiopulmonary arrest.982- 985. # Rechallenge and Desensitization. Recommendations for rechallenge and desensitization depend on the number and severity of the previous reactions. Patients who have had mild reactions to a drug may develop more serious reactions upon re- exposure even when the drug is slowly infused.975 Therefore, for patients who have experienced a reaction to a platinum agent, consider consultation with an allergist (or qualified medical or gynecologic oncologist) for skin testing and to evaluate sensitization and the risk for further, more severe reactions.975,981,986,987 Skin testing is associated with false- negative results.988,989 In cases of prior mild infusion reaction to the first exposure of a platinum or non- platinum agent, rechallenge may be attempted if the patient, physician, and nursing staff are all comfortable with this plan, the patient has been counseled appropriately, vital signs remain stable, emergency equipment is available in the clinic area, and the patients has received premedication with H1 blocker antihistamine, corticosteroids (eg, methylprednisolone, hydrocortisone, dexamethasone), and H2 blockers (eg, cimetidine, famotidine).990- 993 For rechallenge with non- platinum agents after mild reaction to first exposure, slower infusion rate should be used. Typically, a taxane infusion can be re- started at a much slower rate, and the rate can be slowly increased as tolerated as per the treating clinician's judgment.975,994 Many institutions have policies that stipulate how to reinfuse the drug if the patient has had a prior infusion reaction.. Note that this rechallenge with slow infusion is different from desensitization. Desensitization refers to a process of rendering the patient less likely to react in response to an allergen, and can be considered an option for patients who have had drug reactions.970,994- 996 For patients with allergic reactions, various desensitization protocols have been published.967,970,987,994,995,997- 1001 To maximize safety, patients may be desensitized in an intensive care unit.970,998 Almost all patients complete the desensitization protocol with only mild breakthrough reactions (about . If a mild allergic reaction is suspected, and it is appropriate to administer the drug again, patients should be desensitized prior to resuming chemotherapy even if the symptoms have resolved.968 Patients must be desensitized with each infusion if they previously had a drug reaction.994- 996 Data suggest that an extended infusion schedule and use of premedication may decrease the number of hypersensitivity reactions to carboplatin.978,1007. Radiation Therapy. Whole abdominal radiation therapy is rarely used for epithelial ovarian, primary peritoneal, and fallopian tube cancers at NCCN Member Institutions. It is not included as a treatment recommendation in the NCCN Guidelines for Ovarian Cancer. Palliative localized RT is an option for symptom control in patients with recurrent disease (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Therapy for. # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer NCCN Network. National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer\n\nPersistent Disease or Recurrence in the algorithm).. Follow-up Recommendations. Follow- up Recommendations\n\nRecurrent disease may be identified clinically (eg, pelvic pain, weight loss), biochemically (ie, elevated CA- 125 levels), and/or with imaging. After the completion of primary surgery and chemotherapy in patients with all stages of ovarian cancer (or Fallopian tube cancer or primary peritoneal cancer) who have had a CR, the standard recommendation is observation with follow- up to monitor for recurrent disease. Recommendations for monitoring are described in the algorithm and also apply to some of the LCOC (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Monitoring/Follow- up in the algorithm).\n\nChest/abdominal/pelvic CT, MRI, FDG- PET/CT, FDG- PET scans (skull base to mid- thigh), and chest x- ray may be ordered if clinically indicated; imaging is done with contrast unless contraindicated.. If the CA- 125 level was initially elevated, then measurement of a CA- 125 level or other tumor markers is recommended. A multi- institutional European trial assessed the use of CA- 125 for monitoring for ovarian cancer recurrence after primary therapy.. Management of an Increasing CA-125 Level. Management of an Increasing CA- 125 Level\n\nThe care of patients in a clinical complete remission is somewhat controversial; this includes patients who are found to have an increasing CA- 125 level (during routine monitoring and follow- up) but no signs or symptoms of recurrent disease (eg, pelvic pain, bloating, obstruction), following an evaluation including a negative pelvic examination and negative chest/abdominal/pelvic CT scans.. Recurrence therapy refers to drugs, radiation, or other treatment that is given to decrease tumor burden, control symptoms, or increase length and/or QOL for patients with recurrent disease. After the documentation of an increased CA- 125 level (ie, biochemical relapse), the median time for a clinical relapse is 2 to 6 months. Data suggest that immediate treatment for biochemical relapse is not beneficial; therefore, immediate treatment is a category 2B recommendation in the NCCN Guidelines.. # immediate treatment (category 2B) (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Therapy for Persistent Disease or Recurrence in the algorithm). Because tamoxifen and other hormonally active agents have a defined response rate for patients with recurrent disease who have progressed after platinum- based chemotherapy,1026 these agents are frequently administered to patients who have only a rising CA- 125 level1027 as evidence of tumor progression.1028 Tamoxifen, other hormonal agents, or other recurrence therapy are acceptable recommendations for this clinical situation (category 2B for all).. Recurrent Disease. The prognosis is poor either 1) for patients who progress after 2 consecutive chemotherapy regimens without ever sustaining a clinical benefit (refractory),1029 or 2) for those whose disease recurs in less than 6 months (platinum resistant). Note that progression is typically defined using RECIST (Response Evaluation Criteria in Solid Tumor) criteria.937 Panel members emphasized the importance of clinical trials to identify agents active in this group of patients.1030,1031 Because their disease was resistant to the primary induction regimen, retreatment with a platinum compound or paclitaxel is not generally recommended. Although panel members do not recommend retreatment with platinum agents, they recognize that altering the schedule of paclitaxel may produce secondary responses.1032,1033 Before any drug is given in the recurrent setting, the clinician should be familiar with the drug's metabolism and should make certain that the patient is an appropriate candidate for the drug (eg, that the patient has adequate renal or hepatic function). Clinical judgment must be used when selecting postoperative chemotherapy.. Options for patients with platinum- resistant disease or for those with stages II to IV disease who have a PR include clinical trial, recurrence therapy (see Principles of Systemic Therapy: Acceptable Recurrence. Therapies for Epithelial Ovarian Cancer [including LCOC]/Fallopian Tube/Primary Peritoneal Cancer in the algorithm),1034 and/or best supportive care (see NCCN Guidelines for Palliative Care, available at www.NCCN.org). Although palliative care is appropriate at many stages during the disease course, an assessment for palliative care is especially appropriate for those with platinum- resistant disease who may be receiving continuous systemic therapy. Patients who relapse 6 months or more after initial chemotherapy are termed platinum sensitive.1035,1036 Combination platinum- based chemotherapy for a total of 6 cycles is preferred for first recurrence (category 1) in patients with platinum- sensitive disease (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Therapy for Persistent Disease or Recurrence in the algorithm); other recurrence therapies are also an option.1036,1037 Possible regimens are discussed in the following section (see Acceptable Recurrence Modalities in this Discussion).. Patients with ovarian cancer will often be retreated with multiple courses of recurrence therapy. Caution should be used in patients who receive multiple sequential courses of chemotherapy, because they may experience excessive toxicity and may not be able to tolerate doses used for first- line recurrence therapy; thus, clinical judgment should be used when selecting doses (see Principles of Systemic Therapy in the algorithm). Potential ancillary palliative, surgical, and/or supportive care procedures for selected patients are summarized in the algorithm (see Principles of Surgery in the algorithm).1038- 1043 Secondary cytoreductive surgery can be considered for patients who recur (ie, radiographic and/or clinical relapse) after a long disease- free interval (6 months or more).694,1044- 1049 A meta- analysis suggests that survival increases for patients with recurrent disease who have complete debulking.696 The duration of the disease- free interval has not been established, although panel members agreed that it should be at least 6 months before surgery is considered.588,1050. # Although chemotherapy/resistance assays and/or other biomarker assays are being used in some NCCN Member Institutions to aid in selecting chemotherapy in situations where multiple equivalent chemotherapy options are available; the current level of evidence (category 3) is not sufficient to supplant standard- or- care chemotherapy.1031,1032 The NCCN Panel feels that in vitro chemosensitivity testing to choose a chemotherapy regimen for recurrent disease situations should not be recommended (category 3), owing to the lack of demonstrable efficacy for such an approach. ASCO also does not recommend use of chemotherapy sensitivity and resistance assays, unless in a clinical trial setting.1053 Note that a category 3 recommendation reflects strong disagreement about the intervention. At least 3 different NCCN Member Institutions must agree to include the category 3 intervention in the guideline, otherwise it is deleted.. Regardless of which regimen is selected initially, reevaluation should follow after 2 to 4 cycles of chemotherapy (depending on the agent) to determine if patients benefited from chemotherapy. Patients who primarily progress on 2 consecutive chemotherapy regimens without evidence of clinical benefit may not benefit from additional therapy.1029 Decisions to offer supportive care, additional therapy, or clinical trials should be made on a highly individual basis. Localized RT can also provide effective palliation when radiation ports are tailored to specific symptomatic disease sites.1008,1009. Acceptable Recurrence Modalities. The NCCN Panel feels that no single therapeutic agent should be currently recommended as the treatment of choice for recurrent ovarian carcinoma. Some regimens and agents are preferred based on expert opinion primarily for reasons of decreased toxicity and/or marginally increased effectiveness (see Principles of Systemic Therapy: Acceptable Recurrence Therapies for Epithelial Ovarian (including LCOC)/Fallopian Tube/Primary Peritoneal Cancer in the algorithm).877 A meta- analysis of . Preferred Therapies. The consensus of the NCCN Panel for the treatment of recurrent disease is summarized in the algorithm (see Principles of Systemic Therapy: Acceptable Recurrence Therapies for Epithelial Ovarian (including LCOC)/Fallopian Tube/Primary Peritoneal Cancer in the algorithm). Platinum- based combination chemotherapy is recommended (category 1) for a total of 6 cycles for platinum- sensitive recurrence (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Therapy for Persistent Disease or Recurrence in the algorithm).1035,1036 For patients with platinum- sensitive disease who cannot tolerate combination therapy, the preferred single agent is carboplatin or cisplatin.1036,1054,1055 Preferred combinations for platinum- sensitive recurrent disease include carboplatin/paclitaxel (category 1),1036 carboplatin/liposomal doxorubicin (category 1),1056- 1058 carboplatin/weekly paclitaxel,760 carboplatin/albumin- bound paclitaxel (for taxane hypersensitivity), carboplatin/docetaxel,1059,1060 carboplatin/gemcitabine (which has been shown to improve PFS),1036,1054,1055 cisplatin/gemcitabine, or carboplatin/gemcitabine/bevacizumab.1054. The category 1 recommendation for carboplatin/liposomal doxorubicin is based on recent data and uniform consensus from the panel.1056,1057,1061- 1064 Carboplatin/liposomal doxorubicin is equivalent to carboplatin/paclitaxel but has a different toxicity profile. Carboplatin/liposomal doxorubicin is easier to tolerate; patients tend to discontinue therapy with carboplatin/paclitaxel more often than they do with carboplatin/liposomal doxorubicin. Other combination regimens,.	None	None	None
5249001f9322445d95a2294050d6831a	NCCN临床实践指南	卵巢癌包括输卵管癌和原发性腹膜癌151-169	# National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer NCCN Cancer Network. including those with bevacizumab, are discussed in the following paragraphs. For the 2017 update (Version 1), the NCCN Panel added a recommendation (category 2A) for carboplatin/albumin- bound paclitaxel as recurrence therapy for those with platinum- sensitive disease and confirmed taxane hypersensitivity. Preliminary data from a phase 2 study of carboplatin/nab- paclitaxel in platinum- sensitive patients indicated that the overall response rate was . For platinum- resistant disease, non- platinum- based agents or regimens are preferred (ie, docetaxel, oral etoposide, gemcitabine, weekly paclitaxel with or without pazopanib, liposomal doxorubicin with or without bevacizumab, weekly paclitaxel/bevacizumab, topotecan with or without bevacizumab); sequential therapy using single agents is typically used.943,1066 A phase 2 trial (MITO- 11) assessed weekly paclitaxel with (or without) pazopanib in patients with platinum- resistant or refractory advanced ovarian cancer.1066 The data show that PFS was increased in the paclitaxel/pazopanib arm when compared with paclitaxel alone (median 6.35 months . The response rate of the following agents appears to be similar: topotecan, . Other Potentially Active Agents. Other potentially active agents include altretamine, capecitabine, cyclophosphamide, doxorubicin, ifosfamide, irinotecan, melphalan, oxaliplatin, paclitaxel, nanoparticle albumin- bound paclitaxel (nab- paclitaxel), pemetrexed, and vinorelbine (see Principles of Systemic Therapy: Acceptable Recurrence Therapies for Epithelial Ovarian (including LCOC)/Fallopian Tube/Primary Peritoneal Cancer in the algorithm).1073,1077- 1081 Nab- paclitaxel has an overall response rate of . # phase 2 trial in 36 patients, the overall response rate was . Bevacizumab. Based on phase 2 trials, panel members feel that single- agent bevacizumab is a preferred option in patients who have recurrent disease (especially those with ascites), which is reflected in the category 2A recommendation for bevacizumab alone for those with either platinum- sensitive or platinum- resistant disease.542,943,1098,1099 The response rate for single- agent bevacizumab is about . Several phase 3 randomized trials have assessed combination therapy with bevacizumab for recurrent ovarian cancer (ie, AURELIA, OCEANS).1104,1105 The AURELIA trial assessed bevacizumab combined with chemotherapy- either liposomal doxorubicin, weekly paclitaxel, or topotecan- versus chemotherapy alone in patients with advanced platinum- resistant ovarian cancer. For patients receiving bevacizumab/chemotherapy, the primary endpoint of PFS was 6.7 months versus 3.4 months with chemotherapy alone. The median OS was 16.6 . A phase 3 randomized trial (OCEANS) assessed carboplatin/gemcitabine with and without bevacizumab in patients with platinum- sensitive recurrent ovarian cancer who had not previously received bevacizumab. In the OCEANS trial, PFS was increased in patients receiving the chemotherapy/bevacizumab arm when compared with chemotherapy alone (12.4 vs. 8.4 months, . A recent phase 3 randomized trial (GOG- 0213) assessed recurrence combination therapy with carboplatin/paclitaxel/bevacizumab in patients with platinum- sensitive recurrent ovarian cancer.1108 Those receiving chemotherapy/bevacizumab had slightly increased median OS when. # compared with chemotherapy alone (42.2 months [95% CI, 37.7–46.2] versus 37.3 months (32.6–39.7) (HR, 0.829; 95% CI, 0.683–1.005; . PARP Inhibitors. Olaparib. Data suggest that olaparib (AZD2281), which is a PARP inhibitor, is active in select patients (those with BRCA1 and BRCA2 mutations have higher response rates than those who are BRCA negative), especially those with platinum- sensitive disease.938- 943 If disease is resistant or refractory to platinum, then a lower response rate to olaparib is observed.939,941 A trial assessed olaparib in individuals with recurrent advanced ovarian cancer; the overall response rate was . A recent phase 3 randomized trial (SOLO2/ENGOT- Ov21) assessed olaparib (tablets) as maintenance therapy for those . For the 2017 update (Version 3), the NCCN Panel recommends that olaparib (tablets) be considered as maintenance therapy for those with ovarian cancer who have received 2 or more lines of chemotherapy based on this trial (SOLO2/ENGOT- Ov21) and the FDA approval.944 Note that olaparib is transitioning from capsules (original FDA approval) to tablets for the maintenance and recurrence therapy indications. Olaparib tablets (100 mg and 150 mg) should not be substituted with olaparib capsules (50 mg) because of differences in the dosing and bioavailability of each formulation.. Rucaparib. Rucaparib is also an oral PARP inhibitor.1113 A recent phase 2 trial (ARIEL2) assessed rucaparib as recurrence therapy for patients with platinum- sensitive ovarian cancer.1114 PFS was increased in patients (n = 40) with BRCA mutations (12.8 months [95% CI, 9.0–14.7]) when compared with wild type (n = 70) (5.2 months [95% CI, 3.6–5.5]) (HR,. # National Comprehensive NCCN Guidelines Version 1.2025 NCCN Cancer Ovarian Cancer Network. 0.27; . Niraparib. Niraparib is another oral PARP 1/2 inhibitor.<sup>1116</sup> A phase 3 trial (NOVA) assessed niraparib as maintenance therapy for patients whose platinum- sensitive ovarian cancer responded to recurrence therapy.<sup>1116</sup> For the 2017 update (Version 1), the NCCN Panel added a recommendation to repeat the prior imaging to assess response. Data showed that niraparib increased PFS regardless of whether patients had a BRCA mutation when compared with placebo. Patients receiving niraparib without a germline BRCA mutation had increased PFS (12.9 months vs. 3.8 months). Individuals with a germline BRCA mutation had a much greater increase in PFS (21.0 vs. 5.5 months) (HR, 0.27; . Less Common Ovarian Cancers. Less Common Ovarian CancersThe LCOC include carcinosarcomas (MMMTs), clear cell carcinoma, mucinous carcinoma, low- grade (grade 1) serous/endometrioid epithelial carcinoma, borderline epithelial tumors, malignant sex cord- stromal tumors, and malignant germ cell tumors.<sup>139</sup> The complete histologic classification for ovarian cancer from the WHO describes the different types of LCOC (see WHO Histologic Classification in the algorithm).<sup>1</sup> The AJCC/FIGO staging system for ovarian cancer is also used to stage the LCOC (see Staging: Table 1 and other staging tables in the algorithm). Panel members believe there is value in identifying pathways that may serve as therapeutic targets for the LCOC because of the promise of new and novel approaches to treatment.<sup>139</sup> However, there are limited data for these rare histologies because of their infrequency and it will be difficult to acquire prospective data. Clinical trials for eligible patients and individualized treatment plans, for those who are ineligible for trials, may be the most suitable approaches to treatment in these patients at this time. The different IV and IV/IP chemotherapy regimens used for high- grade serous ovarian cancer may also be recommended for patients with LCOC; however, the recommendations are only category 2A for LCOC because of the limited data.. Recommended Workup. Recommended WorkupPatients may obtain consultation at an NCCN Member Institution for recommendations and treatment of an undiagnosed pelvic mass, or for management of a previously biopsied malignant ovarian tumor. Many such patients come to NCCN Member Institutions after having had previous surgery at other institutions. Patients having a histologically undiagnosed. # pelvic mass should undergo evaluation and staging as described in the algorithm (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Workup in the algorithm). The diagnosis of LCOC is often not made until after surgery for a suspicious pelvic mass (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Primary Treatment in the algorithm). Therefore, the workup for LCOC is the same as for other types of ovarian cancer except that tumor markers are measured and other testing is done to determine the specific histopathology (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Workup in the algorithm). Tumor markers may include CA- 125, inhibin, beta- hCG, alfa- fetoprotein, and carcinoembryonic antigen (CEA). Individuals younger than 35 years with a pelvic mass should have AFP levels measured to assess for germ cell tumors and to rule out pregnancy.433- 435 A GI tract evaluation is recommended for mucinous histology to determine whether an occult GI primary has metastasized to the ovaries.527 An intraoperative frozen section evaluation is recommended for those who would like to maintain their fertility (see next section).. Surgery. In contrast to high- grade serous epithelial ovarian cancer or MMMTs, many patients with other LCOC present at an early stage. Some of the tumors may be confined to one ovary. Thus, some of these patients are candidates for fertility- sparing surgery, which may be done laparoscopically (see Principles of Surgery in the algorithm).675,676,679,1118- 1122 Fertility- sparing surgery may be performed (if technically feasible) if the intraoperative frozen section results are positive for apparent early- stage tumors and/or low- risk tumors (ie, malignant germ cell tumors, borderline epithelial tumors, clinical stage I epithelial ovarian tumors, clinical stage I mucinous tumors, or clinical stage I sex cord- stromal tumors).675,676,679,1119- 1122 Patients who do not desire fertility preservation; those who have a clinical stage II, III, or IV epithelial ovarian cancer; those . Patients may have been referred to an NCCN Member Institution after receiving a diagnosis of an LCOC tumor. The recommended initial surgical recommendation depends on the specific histologic diagnosis. Often, patients have been comprehensively staged (having met the standards for surgical staging of the GOG) and have undergone cytoreductive surgery. In some instances, they are referred after having had incomplete staging (ie, uterus and/or adnexa intact, omentum not removed, surgical stage not documented).. Clear Cell Carcinoma. Clear cell carcinomas are considered high- grade tumors; they are more common than the other LCOC.562 Most clear cell carcinomas are negative for WT1 and estrogen receptors.562 The NCCN Guidelines provide an algorithm for clear cell carcinomas (see Less Common Ovarian Cancers: Clear Cell Carcinoma of the Ovary and WHO Histologic Classification in the algorithm).1 Because patients are typically diagnosed with clear cell carcinoma after pathologic analysis of a surgical specimen, the workup for suspicious or palpable pelvic masses is done before surgery as described in the algorithm (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Workup in the algorithm).. Primary treatment for these patients includes completion surgery with comprehensive staging followed by postoperative therapy (see Less Common Ovarian Cancers: Clear Cell Carcinoma of the Ovary in the algorithm).1123 Fertility- sparing surgery is not recommended for stage IA to C clear cell carcinomas. Lymphadenectomy has been shown to improve survival.1124 The staging system for high- grade serous ovarian and primary peritoneal cancer is also used for clear cell carcinomas (see Staging:. # National Comprehensive NCCN Guidelines Version 1.2025 NCCN Cancer Ovarian Cancer Network. Table 1 in the algorithm).547 Lynch syndrome is associated with risk for endometrioid carcinomas, clear cell carcinomas, and papillary serous carcinomas.1125- 1127 For patients with stage IA to IC disease, recommended postoperative treatment is the standard IV taxane- carboplatin regimens (with paclitaxel or docetaxel) used for high- grade serous ovarian cancer.1124 Fertility- sparing surgery and/or observation/monitoring are an option for patients with unilateral clear cell borderline tumors (see Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the algorithm). For patients with stage II to IV clear cell carcinoma, postoperative treatment is standard regimens used for epithelial ovarian cancer (eg, IV carboplatin with paclitaxel, docetaxel, or liposomal doxorubicin). Patients with advanced clear cell carcinoma have a poor prognosis.1123,1124 Data suggest that 6 or 3 cycles of postoperative chemotherapy are equivalent for patients with clear cell carcinoma.62,1128. Mucinous Carcinomas. Mucinous tumors are unusual because they may be very large cystic masses that may fill the abdomen and pelvis; this presentation often suggests mucinous histology. Patients with mucinous carcinoma of the ovary are often diagnosed with early- stage disease and have a good prognosis; the 5- year DFS is about . Patients are typically diagnosed with mucinous carcinoma after surgery for a suspicious pelvic mass (see Epithelial Ovarian Cancer/Fallopian Tube. Cancer/Primary Peritoneal Cancer: Primary Treatment in the algorithm). Therefore, the initial workup is the same as for other types of ovarian cancer (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Workup in the algorithm). Primary treatment for these patients includes completion surgery with comprehensive staging followed by postoperative therapy or observation (see Less Common Ovarian Cancers: Mucinous Carcinoma of the Ovary in the algorithm).527 An appendectomy is also recommended at primary surgery in patients with suspected or confirmed mucinous ovarian tumors. Fertility- sparing surgery is an option for select patients with stage I mucinous tumors (see Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the algorithm). The staging system for high- grade serous epithelial ovarian cancer and primary peritoneal cancer is also used for mucinous carcinomas (see Staging: Table 1 in the algorithm).547. The additional workup includes a GI tract evaluation and CEA level for patients with mucinous histology to determine whether patients have either occult GI primary that has metastasized to the ovaries or primary mucinous carcinoma of the ovaries (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Workup in the algorithm).527 Metastases to the ovaries are more common, and primary mucinous tumors of the ovaries are uncommon; it is difficult to distinguish between metastatic adenocarcinomas to the ovaries and primary mucinous carcinomas.574- 576 PAX8 immunostaining may be useful.574. Postoperative observation and monitoring are recommended for patients with stage IA or IB mucinous tumors because most of these tumors are benign or borderline.527,562 For patients with stage IC mucinous carcinomas, postoperative options include: 1) observation; 2) IV carboplatin with either paclitaxel or docetaxel; 3) 5- FU/leucovorin/oxaliplatin GI regimen; or 4) capecitabine/oxaliplatin (GI regimen).527 Some clinicians feel the GI regimens are appropriate because. # mucinous carcinomas of the ovary are similar to GI tumors.. # Low-Grade Serous Carcinoma. Low- Grade Serous CarcinomaLow- grade serous carcinoma is a subtype of serous carcinoma that is considered pathologically distinct from the more commonly diagnosed high- grade serous carcinoma, and represents less than . Primary Treatment. Primary TreatmentPrimary treatment for low- grade serous carcinomas is comprised of completion surgery with comprehensive staging, followed by adjuvant therapy or observation.. Recommendations for adjuvant treatment are stratified by stage in the guidelines (see LCOC- 6). Postoperative observation is a category 2A recommendation for patients with stage IA and IB disease and a category 2B recommendation for those with stage IC disease. Several adjuvant systemic therapy options, including paclitaxel/platinum- containing regimens, are recommended for patients with stage IC or stage II- IV disease, although there are limited data on systemic therapy regimens in patients with low- grade serous carcinoma in general.. Patients with low- grade serous carcinomas may also benefit from maintenance hormone therapy following adjuvant chemotherapy. One database study observed that patients with stage II- IV low- grade serous carcinoma who received maintenance hormone therapy after completing primary cytoreductive surgery and first- line platinum- based chemotherapy experienced longer progression- free survival (PFS) than those who did not receive maintenance hormone therapy (median PFS, 64.9 vs. 26.4 months; . Adjuvant hormone therapy as a substitute for adjuvant chemotherapy is another potential option for these patients.. # National Comprehensive NCCN Guidelines Version 1.2025 Ovarian Cancer NCCN Cancer Network. Monitoring/Follow-up for Recurrent Disease. Monitoring/Follow- up for Recurrent DiseaseUnfortunately, patients with low- grade serous carcinoma, particularly those with advanced stage disease, may experience disease relapse; therefore, continued monitoring of these patients is essential. The guidelines recommend monitoring for potential recurrence of low- grade serous carcinoma through follow- up visits every 2 to 4 months for 2 years, followed by 3 to 6 months for 3 years, and then annually after 5 years (see LCOC- 7). These visits should consist of a physical examination, including a pelvic examination. Tumor molecular testing is recommended, if not previously done; more comprehensive somatic genetic testing may be particularly important in low- grade serous carcinoma, which has limited approved therapeutic options. Imaging and complete blood count (CBC)/chemistry profile are also recommended, as clinically indicated. CA- 125 or other tumor markers should be assessed if initially elevated. Refer patients for a genetic risk evaluation, if not previously done. For guidance on long- term wellness care for patients who have been treated for low- grade serous carcinoma, please refer to the NCCN Guidelines for Survivorship (www.NCCN.org).. Recurrence Therapy. Recurrence TherapyThe NCCN Guidelines recommend several options for patients with recurrent low- serous carcinoma (see LCOC- 7). Secondary cytoreduction can be considered for patients with a long disease- free interval, isolated masses rather than diffuse carcinomatosis on imaging, and/or bowel obstruction. Systemic therapy is another option for this patient population; however, the guidelines emphasize that there is no standard sequencing of drugs for recurrent disease. Therefore, each patient should be evaluated on an individual basis, taking into consideration prior therapies, disease burden, molecular profile, and the relative efficacy and toxicity profile before initiating systemic therapy. Recommended systemic therapies for this patient population in this setting include chemotherapy (if not previously used) and hormonal therapy.579,1144. setting include chemotherapy (if not previously used) and hormonal therapy.579,1144. However, it has been reported that low- grade serous carcinoma may be more chemo- resistant than high- grade serous carcinoma in the recurrent setting.1145 Thus, effective systemic options for recurrent low- grade serous carcinoma have remained an unmet need. Importantly, recent studies have suggested that MEK inhibitors have activity in recurrent low- grade serous carcinoma. A phase 2/3 open- label, randomized study evaluated the efficacy and safety of trametinib, a MEK1/2 inhibitor, compared with five standard- of- care options (SOC; paclitaxel, pegylated liposomal doxorubicin, topotecan, letrozole, or tamoxifen) in 260 patients with recurrent low- grade serous carcinoma.1146 The median progression- free survival was 13.0 months in the trametinib arm, compared with 7.2 months in the standard- of- care group (HR, 0.48; 95% CI, 0.36- 0.64; . The efficacy and safety of another MEK1/2 inhibitor, binimetinib, was evaluated in a phase 3 open- label study in 303 patients with recurrent low- grade serous carcinoma.1147 Patients were randomized to receive either binimetinib or physician's choice chemotherapy (PCC; pegylated liposomal doxorubicin, paclitaxel, or topotecan). The median PFS for the binimetinib group was 9.1 versus 10.6 months in the PCC group (HR, 1.21; 95% CI, 0.79- 1.86; . # National Comprehensive NCCN Guidelines Version 1.2025 NCCN Cancer Ovarian Cancer Network. certain endpoints, such as PFS by local investigator assessment (12.5 months in the binimetinib group compared with 11.6 months in the PCC group) and ORR by BICR ( . Recently a new option became available for patients with recurrent low- grade serous carcinoma with a BRAF V600E mutation. In June 2022, the U.S. Food and Drug Administration granted accelerated approval to selective BRAF inhibitor dabrafenib in combination with trametinib for the treatment of adult and pediatric patients (6 years and older) with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options.1148- 1150 This approval was based on several studies; one of these was the phase 2 open- label single- arm NCI- MATCH trial (subprotocol H), where dabrafenib in combination with trametinib was evaluated in patients with solid tumors, lymphoma, or multiple myeloma who progressed on at least one standard therapy.1151 Out of the 29 patients included in the primary analysis, five had low- grade serous carcinoma and one had mucinous- papillary serous adenocarcinoma of peritoneum. The ORR of the overall population was . In addition to the options described above, other acceptable systemic recurrence therapies listed in the Principles of Systemic Therapy section of the guidelines (OV- C 8 of 11 and OV- C 9 of 11, available on can be considered. Clinical trial enrollment and observation are other recommended options for patients with recurrent low- grade serous carcinoma.. In response to the availability of novel treatment options for recurrent low- grade serous carcinoma, the NCCN panel has developed a new algorithm page with recommendations for the management of recurrent low- grade serous carcinoma; please refer to LC0C- 7 for additional details.. Endometrial Epithelial Carcinoma. Section development in progress. # Malignant Germ Cell Tumors. Malignant Germ Cell TumorsThese malignant tumors include dysgerminomas, immature teratomas, embryonal tumors, and endodermal sinus (yolk sac) tumors (see the Less Common Ovarian Cancers: Malignant Germ Cell Tumors and the WHO Histologic Classification in the algorithm).<sup>1</sup> They mainly occur in younger individuals who are often diagnosed with stage I disease; the median age at diagnosis is 16 to 20 years.<sup>428,1152</sup> Germ cell tumors are the predominant ovarian tumor in this age group.<sup>470</sup> The recommended workup may include pulmonary function studies if bleomycin is being considered (see Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer: Workup in the algorithm).<sup>433,1153</sup> In young individuals (<35 years) with a pelvic mass, AFP levels can indicate the presence of germ cell tumors.<sup>433- 435</sup> However, pregnancy should also be ruled out. Gonadal dysgenesis is a risk factor for germ cell tumors.<sup>470</sup> Malignant germ cell tumors have an excellent prognosis.<sup>1154</sup> After appropriate treatment, 5- year survival is more than 85%.<sup>1152,1155,1156</sup>. Treatment. Fertility- sparing surgery is recommended for those desiring fertility preservation, regardless of stage (see Less Common Ovarian Cancers: Malignant Germ Cell Tumors in the algorithm).428,679,1156- 1159 Surgery for children or adolescents may differ from that for adults (see Principles of Surgery in the algorithm). In children or adolescents with early- stage germ cell tumors, comprehensive staging may be omitted.685,1160 Completion surgery with comprehensive staging is recommended as initial surgery for patients who do not desire fertility preservation (see Less Common Ovarian Cancers: Malignant Germ Cell Tumors in the algorithm).470 The staging system for high- grade serous ovarian and primary peritoneal cancer is also used for malignant germ cell tumors (see Staging: Table 1 in the algorithm).547 After comprehensive surgical staging, observation with monitoring is recommended for patients with stage I dysgerminoma or stage I, grade 1 immature teratoma.1161 If patients have had incomplete . After surgery, observation with surveillance is the recommended option for patients with stage I dysgerminoma or stage I, grade I immature teratoma based on European and pediatric reports.448,450,451,1162 Observation or chemotherapy may be considered for children or adolescents with select stage IA or IB tumors (see Less Common Ovarian Cancers: Malignant Germ Cell Tumors in the algorithm).428,448,1162- 1165 For patients with stage II to IV malignant dysgerminomas or immature teratomas, postoperative chemotherapy is recommended (see Principles of Systemic Therapy: Systemic Therapy Regimens - Malignant Germ Cell/Sex Cord- Stromal Tumors in the algorithm).. Postoperative chemotherapy for 3 to 4 cycles with bleomycin/etoposide/cisplatin (BEP) (category 2B for 3 vs. 4 cycles) is recommended for: 1) any stage embryonal tumors or endodermal sinus tumors; 2) stages II to V dysgerminoma; or 3) stage I, grade 2 to 3, or stage II to IV immature teratoma (see the Principles of Systemic Therapy: Systemic therapy Regimens - Malignant Germ Cell/Sex Cord- Stromal Tumors in the algorithm).<sup>1153,1166- 1168</sup> If considering the use of bleomycin, pulmonary function tests are recommended.<sup>1153,1155</sup> The 4- cycle BEP regimen is recommended (category 2A) as the standard regimen. Although most clinicians avoid a 3- week BEP regimen, some feel that a 3- week BEP regimen (3 cycles) may be useful in patients with low- risk or stage 1 disease, although this is a category 2B recommendation; the Memorial Sloan Kettering Cancer Center criteria can be used to identify. # tumors that are low risk.444,448,1169- 1175 In select patients with stage IB to III dysgerminoma for whom minimizing toxicity is critical, 3 courses of etoposide/carboplatin can be used (carboplatin . Surveillance recommendations for germ cell tumors are described in the algorithm (see Surveillance for Malignant Germ Cell and Sex Cord- Stromal Tumors in the algorithm).1017 Patients achieving a complete clinical response after chemotherapy should be observed clinically every 2 to 4 months with AFP and beta- HCG levels (if initially elevated) for 2 years. For those with abnormal markers and definitive recurrent disease, options (category 2B) include: 1) high- dose chemotherapy;1177 or 2) consider additional chemotherapy (see Principles of Systemic Therapy: Systemic Therapy Regimens - Malignant Germ Cell/Sex Cord- Stromal Tumors in the algorithm). Referral of these patients to a tertiary care center for stem- cell transplant consultation and potentially curative therapy is strongly recommended. Several case reports suggest that patients who have received chemotherapy for germ cell tumors may later present with growing teratoma syndrome.1178- 1181. Residual or Recurrent Disease. For patients having radiographic evidence of residual tumor (after surgery and chemotherapy) but with normal AFP and beta- HCG, consider surgical resection of the tumor; observation with monitoring is also an option. Clinical judgment should be used regarding the frequency of imaging.1182 Further options depend on which findings are present: residual malignancy, benign teratoma, or necrotic tissue (see Therapy for Recurrent/Persistent Disease for Malignant Germ Cell Tumors in the algorithm). For patients with definitive residual disease and with persistently elevated AFP and/or beta- HCG after first- line chemotherapy, . Patients with recurrent or residual malignancy after multiple chemotherapeutic regimens may be treated with a recurrence modality (see Principles of Systemic Therapy: Acceptable Systemic Therapy Regimens - Malignant Germ Cell/Sex Cord- Stromal Tumors in the algorithm), including potentially curative high- dose chemotherapy or TIP. Other regimens include VAC (vincristine, dactinomycin, cyclophosphamide), VelP (vinblastine, ifosfamide, cisplatin), VIP (bioposide, ifosfamide, cisplatin), cisplatin/metoposide, docetaxel/carboplatin, paclitaxel/carboplatin, paclitaxel/gemcitabine, paclitaxel/ifosfamide, docetaxel, paclitaxel, RT, or supportive care only.1171,1184- 1188 These recurrence regimens (see Principles of Systemic Therapy: Systemic Therapy Regimens - Malignant Germ Cell/Sex Cord- Stromal Tumors in the algorithm) are not generalizable for all of the uncommon histology tumors; therefore, patients should be referred to tertiary care institutions for treatment.. Malignant Sex Cord-Stromal Tumors. Malignant sex cord- stromal tumors are rare and include granulosa cell tumors (most common) and Sertoli- Leydig cell tumors; they are typically associated with a good prognosis.660,1189 Most patients with granulosa tumors present with early- stage disease; the disease is typically indolent.659 The complete histologic classification for ovarian cancer from the WHO includes the different types of sex cord- stromal tumors; it is important to determine whether the sex cord- stromal tumor is benign or malignant (see WHO Histologic Classification: Sex Cord- Stromal Tumors in the algorithm).1 The staging system for high- grade serous ovarian and. # primary peritoneal cancer is also used for sex cord- stromal tumors (see Staging: Table 1 in the algorithm).547. Patients with stage IA or IC sex cord- stromal tumors desiring to preserve their fertility should be treated with fertility- sparing surgery (see Less Common Ovarian Cancers: Malignant Sex Cord- Stromal Tumors in the algorithm).658,659,1190,1191 Although complete staging is recommended for all other patients, lymphadenectomy may be omitted for tumors grossly confined to the ovary.1192 For patients who choose fertility- sparing surgery, completion surgery (category 2B) should be considered after childbearing is finished. Postoperative options in the NCCN Guidelines have category 2B recommendations (see Less Common Ovarian Cancers: Malignant Sex Cord- Stromal Tumors in the algorithm).1190 For patients with high- risk stage I tumors (tumor rupture, stage 1C, poorly differentiated tumor, and tumor size . Surveillance recommendations for malignant sex cord- stromal tumors are provided in the algorithm, which are based on the SGO recommendations (see Surveillance for Malignant Germ Cell and Sex Cord- Stromal Tumors in the algorithm).1017 Prolonged surveillance is recommended for granulosa cell tumors, because they can recur years later (eg, 30 years).660,1158,1189,1198 For patients with stage II to IV tumors who . Carcinosarcomas (Malignant Mixed Mullerian Tumors). MMMTs are rare tumors with a poor prognosis; they are the most aggressive tumors in the algorithm.1203- 1206 Most pathologists now consider MMMTs to be a variant of poorly differentiated epithelial ovarian cancer (metaplastic carcinoma).566 Patients with MMMTs are not candidates for fertility- sparing surgery regardless of age or stage. The staging system for ovarian and primary peritoneal cancer is also used for MMMTs (see Staging: Table 1 in the algorithm).547,1205. Optimal surgical debulking is recommended for patients with MMMTs (see Principles of Surgery in the algorithm).1205,1207- 1209 After complete surgical staging, several postoperative chemotherapy regimens are recommended for patients with stage I to IV MMMT. Patients with stage I to IV MMMT or recurrence may be treated using the same primary chemotherapy regimens that are recommended for epithelial ovarian cancer; for the 2017 update (Version 1), the panel decided these chemotherapy regimens are preferred options (see Principles of Systemic Therapy: Primary Systemic Therapy Regimens in the algorithm).566,1210- 1215 For example, IV carboplatin with either paclitaxel, docetaxel, or liposomal doxorubicin are recommended for patients with stage I- IV MMMT. The IP chemotherapy regimen described for ovarian cancer can be used for select patients with. # MMMT. Other recommended postoperative chemotherapy options include cisplatin/ifosfamide (category 2A), carboplatin/ifosfamide (category 2A), and ifosfamide/paclitaxel (category 2B).<sup>66,1203,1210,1216</sup> After treatment, the surveillance and follow- up recommendations for epithelial ovarian cancer are also used for MMMTs.. Borderline Epithelial Tumors (Low Malignant Potential). Diagnosis. Borderline epithelial tumors are rare tumors and are managed differently than high- grade carcinomas (see Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the algorithm).<sup>1118,1217</sup> Five- year survival exceeds . The terms for borderline epithelial tumors (also known as LMP tumors or atypical proliferative tumors) have changed over the years.<sup>562</sup> The 2016 and 2017 CAP cancer protocols for ovarian cancer use borderline and do not use LMP.<sup>1223,1224</sup> Borderline epithelial tumors are typically serous or mucinous; other histologic subtypes can also occur (see WHO Histologic Classification in the algorithm).<sup>1,1118</sup>. The characteristic pathologic hallmark of typical epithelial ovarian cancer is the identification of peritoneal implants, which microscopically and/or macroscopically invade the peritoneum. A borderline epithelial tumor may grossly resemble an invasive cancer. However, microscopic evaluation fails to reveal evidence of frank invasion by the tumor nodules, although rarely invasive implants (which continue to be consistent with the . Treatment. Surgery is the primary treatment for borderline epithelial tumors, including standard ovarian cancer debulking surgery or fertility- sparing surgery depending on the surgical evaluation and other factors (see Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the algorithm).<sup>1225</sup> Treatment guidelines for borderline epithelial tumors depend on the histologic and clinical characteristics, the age of the patient,<sup>1220</sup> and whether invasive implants are present. Patients should be evaluated by a gynecologic oncologist. At NCCN Member Institutions, patients may be initially evaluated with an undiagnosed pelvic mass or with an established diagnosis of borderline epithelial tumor. NCCN Panel Members are less likely to recommend aggressive treatment after surgery; observation is one of several possible approaches.<sup>1118,1226</sup> Although the staging system for epithelial ovarian cancer is used for borderline epithelial tumors, the NCCN Guidelines use the presence or absence of invasive implants to determine the need for postoperative therapy (see Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the algorithm).. Patients with a borderline epithelial tumor who desire to maintain their fertility may undergo surgery limited to a USO (preserving the uterus, contralateral ovary, and contralateral Fallopian tube) with resection of residual disease.<sup>675,676,1227</sup> BSO and preserving the uterus is an option for select patients. If the patient does not desire fertility- sparing surgery, standard ovarian cancer surgery (TAH, BSO, and debulking as needed) and resection of residual disease are recommended. Data do not show increased survival with lymphadenectomy and omentectomy for borderline epithelial tumor, although upstaging does occur.<sup>728,1228</sup> Lymph node evaluation may be considered on a case- by- case basis.. # Comprehensive Cancer Network. NCCN Guidelines Version 1.2025 Ovarian Cancer. For patients with known borderline epithelial tumors who had incomplete previous surgery and/or were incompletely staged at the time of their initial laparotomy, recommendations depend on whether invasive implants are present and whether fertility preservation is desired (see the prior incomplete surgical resection pathway in Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the algorithm). Patients who want to preserve their fertility should have fertility- sparing surgery and resection of residual disease. Some clinicians feel that the appearance of invasive implants on the peritoneal surfaces in patients with borderline epithelial tumors portends a less favorable prognosis; therefore, postoperative chemotherapy with the same regimens used for low- grade (grade 1) serous epithelial ovarian cancer can be considered for these patients (see Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the algorithm).1210,1220,1220 Postoperative IV carboplatin with either docetaxel or paclitaxel is recommended. The benefit of chemotherapy, either IP or IV, is controversial in patients with borderline epithelial tumors. The significance of invasive implants remains under investigation.1118,1230 The benefit of postoperative chemotherapy has not been demonstrated for patients who have no microscopically demonstrable invasive implants.1231 Although observation is an option for all patients, it is a category 3 recommendation for patients with invasive implants and a category 2B recommendation for patients without invasive implants (see Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the algorithm).. Follow-up. Treatment recommendations after surgery depend on the presence or absence of invasive implants. The initial therapeutic approach for patients having invasive implants may include treatment with the same chemotherapeutic regimens used for low- grade (grade 1) serous epithelial ovarian cancer or observation (category 3) (see Less Common Ovarian. Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the algorithm).1230 Patients with no invasive implants may be observed (category 2B) and monitored (see Monitoring/Follow- Up in Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the algorithm).1219,1232 Patients who chose fertility- sparing surgery should be monitored by US examinations if necessary. After childbearing is completed, completion surgery should be considered (category 2B).1118. Relapse. At the time of clinical relapse, surgical evaluation and debulking are recommended if appropriate. Patients who have low- grade invasive carcinoma or invasive implants from borderline epithelial tumors may be treated using the same recommendations as for low- grade (grade 1) serous epithelial ovarian cancer; those with high- grade invasive implants may be treated using the same recommendations as for epithelial ovarian cancer (see Recurrence Therapy in Less Common Ovarian Cancers: Ovarian Borderline Epithelial Tumors [Low Malignant Potential] in the algorithm). Observation is recommended for those with noninvasive disease.. Summary. Eithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country's fifth most common cause of cancer mortality in females. More than . # malignant sex cord- stromal tumors, and malignant germ cell tumors. Primary peritoneal and Fallopian tube cancers are treated in the same manner as epithelial ovarian cancer.. The complete histologic classification for ovarian cancer from the WHO describes the different types of LCOC. Panel members believe there is value in identifying pathways that may serve as therapeutic targets for the LCOC because of the promise of new and novel approaches to treatment. However, there are limited data for these rare histologies because of their infrequency and it will be difficult to acquire prospective data. Clinical trials for eligible patients, and individualized treatment plans for those who are not eligible for trials, may be the most suitable approaches to treatment in these patients at this time.. Most ovarian cancers, including the LCOC, are diagnosed after pathologic analysis of a biopsy or surgical specimen. Based on published improved outcomes, it is recommended (category 1) that a gynecologic oncologist perform the primary surgery. Primary treatment for presumed ovarian cancer consists of appropriate surgical staging and debulking surgery, followed in most (but not all) patients by systemic chemotherapy. Debulking surgery is the initial treatment recommendation for patients with clinical stage II, III, or IV disease. For most patients, initial surgery should include hysterectomy, BSO, and debulking as needed. Procedures that may be considered for optimal surgical debulking include: radical pelvic dissection, bowel resection and/or appendectomy, lymphadenectomy, diaphragm or other peritoneal surface stripping, splenectomy, partial hepatectomy, partial gastrectomy, or partial cystectomy and/or ureteroneocystostomy, cholecystectomy, and/or distal pancreatectomy. Most patients have a hysterectomy with BSO, omentectomy, and lymphadenectomy of suspicious/enlarged nodes. Patients with low- volume residual disease after surgical debulking for stage II or III invasive epithelial ovarian or peritoneal cancer are candidates for IP therapy. In . For a young patient who wishes to maintain fertility, a USO (preserving the uterus and contralateral ovary) and comprehensive surgical staging may be adequate for select unilateral stage I tumors (stage 1A and 1C, but not stage 1B) and/or low- risk ovarian tumors (ie, early- stage, grade 1 tumors; borderline tumors). For those with stage IB tumors who wish to maintain fertility, a BSO (preserving the uterus) and comprehensive surgical staging are recommended.. Most patients with epithelial ovarian cancer receive postoperative systemic chemotherapy. Consideration of palliative care interventions is appropriate at several stages during the disease course. Recommendations regarding initial primary systemic therapy include IV with [or without] IP options. All of the regimens (including the combined IV/IP chemotherapy) may be used for epithelial ovarian, primary peritoneal, and Fallopian tube cancers; some of these regimens are recommended for some of the LCOC. NACT may be considered (category 1) for patients with bulky stage III to IV disease or high- risk surgical candidates; a gynecologic oncologist should make this assessment before NACT is administered.. For all patients, the NCCN Guidelines recommend symptom management, best supportive care, and long- term wellness care; patients should be referred for palliative care assessment if appropriate. Patients should be educated about signs and symptoms suggestive of recurrence such as pelvic pain, bloating, early satiety, obstruction, weight loss, and fatigue. Recurrent disease may be identified clinically (eg, pelvic pain, weight loss), biochemically (ie, elevated CA- 125 levels), and/or with imaging. The NCCN Guidelines recommend a number of different regimens and agents. # for recurrence therapy; some of them are designated as preferred regimens. Patients with ovarian cancer will often be retreated with multiple courses of recurrence therapy. Patients who relapse 6 months or more after initial chemotherapy are termed platinum sensitive. Those who relapse after less than 6 months are termed platinum resistant. Platinum- based combination chemotherapy is preferred in patients with platinum- sensitive disease, especially for first recurrence. For platinum- resistant disease, non- platinum- based agents or regimens are preferred. Some of the new additions for 2017 include: 1) carboplatin/liposomal doxorubicin for first- line therapy; 2) niraparib and olaparib for maintenance therapy; and 3) rucaparib, carboplatin/albumin- bound paclitaxel, and carboplatin/paclitaxel/bevacizumab for recurrence therapy.. # Recommended Readings. Alberts DS, Green S, Hannigan EV, et al. Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer. J Clin Oncol 1992;10:706- 717. &. Armstrong D, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34- 43. &. Bell J, Brady MF, Young RC, et al. Randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial ovarian carcinoma: A Gynecologic Oncology Group study. Gynecol Oncol 2006;102:432- 439.. Berton- Rigaud D, Devouassoux- Shisheboran M, Ledermann JA, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for uterine and ovarian carcinosarcoma. Int J Gynecol Cancer 2014;24(9 Suppl 3):S55- 60.. Brown J, Friedlander M, Backes FJ, et al. Gynecologic Cancer Intergroup (GCIG) consensus review for ovarian germ cell tumors. Int J Gynecol Cancer 2014;24(9 Suppl 3):S48- 54.. Cristea M, Han E, Salmon L, Morgan RJ. Practical considerations in ovarian cancer chemotherapy. Ther Adv Med Oncol 2010;2:175- 187.. Committee on the State of the Science in Ovarian Cancer. Ovarian Cancers: Evolving Paradigms in Research and Care, Washington (DC): National Academies Press (US) Copyright 2016 by the National Academy of Sciences. All rights reserved; 2016.. Eisenhauer EL, Abu- Rustum NR, Sonoda Y, et al. The addition of extensive upper abdominal surgery to achieve optimal cytoreduction improves survival in patients with stages I/IC- IV epithelial ovarian cancer. Gynecol Oncol 2006;103:1083- 1090.. Fader AN, Rose PG. Role of surgery in ovarian carcinoma. J Clin Oncol 2007;25:2873- 2883. &. Goff BA, Mandel LS, Drescher CW, et al. Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer 2007;109:221- 227.. Gourley C, Farley J, Provencher DM, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for ovarian and primary peritoneal low- grade serous carcinomas. Int J Gynecol Cancer 2014;24(9 Suppl 3):S9- 13.. Harter P, Gershenson D, Lhomme C, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for ovarian tumors of low malignant potential (borderline ovarian tumors). Int J Gynecol Cancer 2014;24(9 Suppl 3):S5- 8.. Katsumata N, Yasuda M, Takahashi F, et al. Dose- dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open- label, randomised controlled trial. Lancet 2009;374:1331- 1338.. Kurman RJ, Carcangiu ML, Harrington CS, et al. WHO Classification of Tumours of Female Reproductive Organs, 4th Edition. WHO/IARC Classification of Tumours. Vol. 6. Lyon: IARC Publications; 2014.. Ledermann JA, Luvero D, Shafer A, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for mucinous ovarian carcinoma. Int J Gynecol Cancer 2014;24(9 Suppl 3):S14- 9.. # Morice P, Denschlag D, Rodolakis A, et al. Recommendations of the Fertility Task Force of the European Society of Gynecologic Oncology about the conservative management of ovarian malignant tumors. Int J Gynecol Cancer 2011;21:951- 963.. Okamoto A, Glasspool RM, Mabuchi S, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for clear cell carcinoma of the ovary. Int J Gynecol Cancer 2014;24(9 Suppl 3):S20- 5.. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: Gynecologic Oncology Group study. J Clin Oncol 2003;21:3194- 3200. &. Ray- Coquard I, Brown J, Harter P, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for ovarian sex cord stromal tumors. Int J Gynecol Cancer 2014;24(9 Suppl 3):S42- 7.. Swenerton K, Jeffrey J, Stuart G, et al. Cisplatin- cyclophosphamide versus carboplatin- cyclophosphamide in advanced ovarian cancer: a randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1992;10:718- 726. &. Trimbos JB, Parmar M, Vergote I, et al. International Collaborative Ovarian Neoplasm trial 1 and Adjuvant Chemotherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early- stage ovarian carcinoma. J Natl Cancer Inst 2003;95:105- 112.. Walker JL, Armstrong DK, Huang HQ, et al. Intraperitoneal catheter outcomes in a phase III trial of intravenous versus intraperitoneal chemotherapy in optimal stage III ovarian and primary peritoneal cancer: a Gynecologic Oncology Group Study. Gynecol Oncol 2006;100:27- 32. &. Young RC, Walton LA, Ellenberg SS, et al. Adjuvant therapy in stage I and stage II epithelial ovarian cancer. N Engl J Med 1990;322:1021- 1027. &. References marked with the symbol "&" provide the basis for the algorithms..	None	None	None
50759142da1842aa95b601003aee9955	NCCN临床实践指南	妊娠滋养细胞肿瘤01-30	# NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Gestational Trophoblastic Neoplasia. Version 2.2025 — January 31, 2025NCCN.org. NCCN recognizes the importance of clinical trials and encourages participation when applicable and available. Trials should be designed to maximize inclusiveness and broad representative enrollment.. Continue. # National NCCN Guidelines Version 2.2025 Comprehensive Gestational Trophoblastic Neoplasia NCCN Cancer Network. Nadeem R. Abu- Rustum, MD Q/Chair Memorial Sloan Kettering Cancer Center. Susana M. Campos, MD, MPH, MS Vice Chair Dana- Farber/Brigham and Women's Cancer Center. Rebecca Arend, MD O O'Neal Comprehensive Cancer Center at UAB. Emma Barber, MD O Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Kristin Bradley, MD S University of Wisconsin Carbone Cancer Center. Rebecca Brooks, MD O UC Davis Comprehensive Cancer Center. Junzo Chino, MD S Duke Cancer Institute. Hye Sook Chon, MD O Moffitt Cancer Center. Marta Ann Crispens, MD O Vanderbilt- Ingram Cancer Center. Shari Damast, MD S Yale Cancer Center/ Smilow Cancer Hospital. Christine M. Fisher, MD, MPH S University of Colorado Cancer Center. Peter Frederick, MD O Roswell Park Comprehensive Cancer Center. David K. Gaffney, MD, PhD S Huntsman Cancer Institute at the University of Utah. Stephanie Gaillard, MD, PhD Johns Hopkins Kimmel Cancer Center. Robert Giuntoli II, MD O Abramson Cancer Center at the University of Pennsylvania. Scott Glaser, MD S City of Hope National Medical Center. Brooke E. Howitt, MD Stanford Cancer Institute. Kari Kendra, MD, PhD T/Liaison The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute. Jayanthi Lea, MD O UT Southwestern Simmons Comprehensive Cancer Center. Lisa Landrum, MD, PhD O Indiana University Melvin and Bren Simon Comprehensive Cancer Center. Nita Lee, MD, MPH O The UChicago Medicine Comprehensive Cancer Center. Gina Mantia- Smaldone, MD O Fox Chase Cancer Center. Andrea Mariani, MD O Mayo Clinic Comprehensive Cancer Center. David Mutch, MD O Siteman Cancer Center at Barnes- Jewish Hospital and Washington University School of Medicine. Christa Nagel, MD O The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute. Continue. Larissa Nekhlyudov, MD, MPH Dana- Farber/Brigham and Women's Cancer Center. Karina Nieto, MD S Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute. Chika Nwachukwu, MD, PhD S UC San Diego Moores Cancer Center. Mirna Podoll, MD Vanderbilt- Ingram Cancer Center. Kerry Rodabaugh, MD Fred & Pamela Buffett Cancer Center. Ritu Salani, MD, MBA O UCLA Jonsson Comprehensive Cancer Center. John Schorge, MD O St. Jude Children's Research Hospital/ The University of Tennessee Health Science Center. Jean Siedel, DO, MS O University of Michigan Rogel Cancer Center. Rachel Sisodia, MD O Mass General Cancer Center. Pamela Soliman, MD, MPH O The University of Texas MD Anderson Cancer Center. Stefanie Ueda, MD O UCSF Helen Diller Family Comprehensive Cancer Center. Renata Urban, MD Fred Hutchinson Cancer Center. Emily Wyse Patient Advocate. NCCN. Nicole McMillian, MS Vaishnavi Sambandam, PhD. Q Gynecologic oncology Internal medicine Medical oncology Pathology Patient advocacy. \S. # # NCCN Gestational Trophoblastic Neoplasia (GTN) Panel Members NCCN GTN Subcommittee Members Summary of the Guidelines Updates. Hydatidiform Mole. Workup, Initial Treatment, Monitoring, Findings and Additional Evaluation (HM- 1) Persistent Post- Molar GTN (HM- 2) Principles of Imaging (HM- A). Gestational Trophoblastic Neoplasia (GTN). Workup (GTN- 1) Primary Treatment for Low- Risk GTN (GTN- 2) Treatment for Persistent GTN (GTN- 3) Primary Treatment for High- Risk GTN (GTN- 4) Primary Treatment for Intermediate Trophoblastic Tumor: PSTT and ETT (GTN- 5). Principles of Pathology (GTN- A) Principles of Imaging (GTN- B) Principles of Surgical Management of GTN (GTN- C) Systemic Therapy for GTN (GTN- D) Principles of Gynecologic Survivorship (GTN- E). Staging (ST- 1). Abbreviations (ABBR- 1). The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2025.. # Updates in Version 2.2025 of the NCCN Guidelines for Gestational Trophoblastic Neoplasia from Version 1.2025 include:. Gestational Trophoblastic Neoplasia (GTN) GTN- D 6 of 7. - High-Risk GTN: Footnote regarding Nivolumab and hyaluronidase-nvhy subcutaneous injection is new: Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and administration instructions compared to IV nivolumab. (Also for GTN-D 7 of 7). MS-1. - The Discussion has been updated to reflect the changes in the algorithm.. Updates in Version 1.2025 of the NCCN Guidelines for Gestational Trophoblastic Neoplasia from Version 1.2024 include:. Hydatidiform Mole General A new section for Principles of Imaging (HM- A) was added. Imaging recommendations were removed throughout the Hydatidiform Mole algorithm and added within the new HM- A page. The Updates below denote the imaging recommendations that were removed and placed in HM- A.. HM-1. - Workup: 2nd bullet revised: Chest x-ray Imaging Removed: Pelvic ultrasound Foonote removed: If the chest x-ray is positive for metastases, then perform chest/abdominal/pelvic (C/A/P) CT with contrast and brain MRI with or without contrast and manage as GTN after initial uterine evacuation. - Footnote is new: Principles of Imaging (HM-A). HM-2. - Staging: 2nd bullet revised: Imaging (chest-x-ray or chest/abdominal/pelvic [C/A/P]CT) Removed: Doppler pelvic ultrasound - Footnotes removed Doppler pelvic ultrasound is used to confirm absence of pregnancy, measure uterine size, and determine volume and vasculature of tumor within the uterus. If the chest x-ray is normal, no further imaging is indicated before commencing treatment. If the chest x-ray shows metastases, C/A/P CT scan with contrast and brain MRI with or without are indicated.. Gestational Trophoblastic Neoplasia (GTN) General. GTN-B. - A new section for Principles of Imaging was added. Imaging recommendations were removed throughout the GTN algorithm and added within the new GTN-B page. The updates below include the imaging recommendations that were removed from the algorithm and placed in GTN-B.. # Updates in Version 1.2025 of the NCCN Guidelines for Gestational Trophoblastic Neoplasia from Version 2.2024 include:. Gestational Trophoblastic Neoplasia (GTN)- continued. GTN- 1. Workup. - 4th bullet; Sub-bullets removed . - Brain MRI (preferred) with or without contrast or CT with contrast if pulmonary metastasis . - Footnote b revised to remove the sentence: If contrast is contraindicated, other imaging techniques such as MRI may be considered.. - Footnote d revised: If hCG is elevated, but hyperglycosylated hCG is normal; quiescent GTN may be diagnosed and left untreated although at a low level that is stable over time (and false positive hCG ruled out), quiescent GTN is possible, and close follow-up, rather than immediate treatment may be considered.. GTN-3. - Good response to initial therapy followed by rapid rise in hCG level (hCG . GTN-4. - Treatment; EMA/CO; If brain metastases; 2nd arrow sub-bullet, 1st diamond sub-bullet revised: "Stereotactic brain body radiation therapy (SBRT) . GTN-5. Primary Treatment for PSTT and ETT. - Non-metastatic (Stage I): Hysterectomy with salpingectomy . - Footnote removed: Consider FDG-PET/CT for follow-up at the completion of chemotherapy and then every 6-12 months for 2-3 years.. GTN- D Systemic Therapy for GTN. - General: The duration of administration for the regimens was added throughout the dosing pages.. GTN- D 1 of 7- IV clarified as IV push for Methotrexate and Dactinomycin dosing. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. Updates in Version 1.2025 of the NCCN Guidelines for Gestational Trophoblastic Neoplasia from Version 2.2024 include:. GTN-D 2 of 7. - Footnote a is new: An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. - Footnote b revised: Use granulocyte colony-stimulating factor (G-CSF) as primary prophylaxis with etoposide/cisplatin or etoposide/carboplatin-based regimens. See NCCN Guidelines for Hematopoietic Growth Factors. An FDA-approved biosimilar is an appropriate substitute for filgrastim and pegfilgrastim. (Also for GTN-D 3 of 7 through GTN-D 7 of 7). GTN-D 6 of 7. - High-Risk GTN: Additional Agents/Regimens Shown to Have Some Activity in Treating Multiagent Chemotherapy-Resistant GTN; Useful in Certain Circumstances: The following regimen and dose schedule added - Nivolumab + ipilimumab - Nivolumab 240 mg IV every 2 weeks - Ipilimumab 1 mg/kg IV every 6 weeks. GTN-D 7 of 7. - Intermediate Trophoblastic Tumor (PSTT and ETT) - Useful in Certain Circumstances; Additional agents/regimens shown to have some activity in treating multiagent chemotherapy-resistant GTN: Nivolumab + ipilimumab added as an option. ABBR-1. - The abbreviations page was updated to correspond with the algorithm changes.. MS-1. - The Discussion has been updated to reflect the changes in the algorithm.. # NCCN Guidelines Version 2.2025 Hydatidiform Mole. a Principles of Imaging (HM-A).. b If hCG is elevated with no evidence of disease on imaging, consider possibility of luteinizing hormone (LH) crossover, pituitary hCG, or phantom hCG. Consult with laboratory medicine/pathology to test for phantom hCG with serial dilution study or comparison of serum to urine hCG. Use largest curette feasible. Sharp curettage after suction. Use uterotonic drugs after initiating evacuation of uterus. Consider adding tranexamic acid (TXA) if necessary. Oxytocin receptors may be absent. d Prophylactic chemotherapy with methotrexate or dactinomycin may be considered at the time of evacuation of a hydatidiform mole in patients at high risk for post- molar GTN (age . Note: All recommendations are category 2A unless otherwise indicated.. # # PRINCIPLES OF IMAGING. Initial Workup. Hydatidiform mole - Pelvis ultrasound - Chest x- ray. If the chest x- ray is positive for metastases, then perform chest/abdomen/pelvis (C/A/P) CT with contrast and brain MRI with or without contrast and manage as GTN after initial uterine evacuation.. Staging. Persistent post- molar GTN. Pelvis ultrasound Pelvic ultrasound is used to confirm absence of pregnancy, measure uterine size, and determine volume and vasculature of tumor within the uterus. Chest x- ray or C/A/P CT scan with contrast If the chest x- ray is normal, no further imaging is indicated before commencing treatment. If the chest x- ray shows metastases, C/A/P CT scan with contrast and brain MRI with or without contrast are indicated.. # WORKUP (unless previously done). aIf visible lesions are seen in lower genital tract, do NOT biopsy due to risk of hemorrhage. b Principles of Imaging (GTN- B) cIf hCG is elevated with no evidence of disease on imaging, consider the possibility of LH crossover or phantom hCG. Consult with laboratory medicine/pathology to test for phantom hCG with serial dilution study or comparison of serum to urine hCG. dIf hCG is elevated, although at a low level that is stable over time (and false positive hCG ruled out), quiescent GTN is possible, and close follow- up, rather than immediate treatment may be considered. e See FIGO Staging System for GTN (ST- 1) and Prognostic Scoring Index for GTN (ST- 2). f Principles of Pathology (GTN- A). gConsider consultation with a clinician or center with expertise in management of gestational trophoblastic diseases. hPrognostic scoring is not valid for intermediate tumors.. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. DIAGNOSIS. TREATMENT. PRIMARY TREATMENT FOR LOW-RISK GTN. DIAGNOSIS. MONITORING DURING TREATMENT RESPONSE ASSESSMENT. FOLLOW-UP/ SURVEILLANCEm. hCG assay every month for 12 months Contraception (oral contraceptives preferred)n. i Regimens are continued until 2- 3 full cycles past normalization of the hCG. Hysterectomy with salpingectomy or repeat endometrial curettage may be considered if there is localized disease in the uterus. Hysterectomy is preferred and where fertility preservation is not desired. Leave ovaries in situ, even in presence of theca lutein cysts. See Principles of Surgical Management (GTN- C). k See Systemic Therapy for GTN (GTN- D) for specific recommendations. Lybol C, et al. Gynecol Oncol 2012;125:576- 579. m Principles of Gynecologic Survivorship (GTN- E). n Oral contraceptives are preferred over IUDs because they suppress endogenous LH/FSH, which may interfere with hCG measurement at low levels.. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. gConsider consultation with a clinician or center with expertise in management of gestational trophoblastic diseases. Hysterectomy with salpingectomy or repeat endometrial curettage may be considered if there is localized disease in the uterus. Hysterectomy is preferred where fertility preservation is not desired. Leave ovaries in situ, even in presence of theca lutein cysts. See Principles of Surgical Management (GTN- C). kSee Systemic Therapy for GTN (GTN- D) for specific recommendations.. m Principles of Gynecologic Survivorship (GTN- E). o Post- treatment imaging is not routinely recommended for follow- up after hCG normalization in patients with post- molar GTN or choriocarcinoma, where hCG is a reliable tumor marker. It may be necessary to follow patients with brain metastases with MRI brain with contrast for 2- 3 years. See Principles of Imaging (GTN- B).. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. DIAGNOSIS. # PRINCIPLES OF PATHOLOGY. Procedure- D&C- Hysterectomy- Other. Pathologic Diagnosis of Benign, Noninvasive Hydatidiform Mole. - Report histologic type only.- If myometrial or vascular invasion is present (ie, invasive mole), use pathologic assessment for malignant GTN below.. # PRINCIPLES OF PATHOLOGY. Pathologic Assessment for Malignant Gestational Trophoblastic Tumora. - Tumor site (ie, uterine corpus, cervix, other, cannot be determined)- Tumor size (measured in cm)- Histologic type - Hydatidiform mole, invasive - Choriocarcinoma - PSTT - ETT - Malignant trophoblastic tumor, type cannot be determined- Tissue/organ involvement (list all organs submitted for evaluation involved by tumor)- Specimen margin status (where applicable; when negative, may also include closest margin and distance to closest margin)- Lymphovascular space invasion (LVSI). Immunohistochemical Markers for Differential Diagnosis of GTN1,2,3. - GATA-3 is a sensitive marker for both benign and malignant trophoblast proliferations, and may be useful in distinguishing GTN from non-GTN tumors.. References. 1 WHO Classification of Tumours Editorial Board. Female Genital Tumours WHO Classification of Tumours, 5th Edition, Volume 4;2020. 2 College of American Pathologists: Protocol for the Examination of Specimens From Patients With Primary Gestational Trophoblastic Malignancy. 2017. Available at: trophoblast- 17protocol- 4000. pdf. 3 Chi DS, Berchuck A, Dizon DS, et al. Table 26.2: Immunohistochemical Markers for Differential Diagnosis of GTD. Principles and Practice of Gynecologic Oncology. Lippincott Williams & Wilkins; 2017:745.. # PRINCIPLES OF IMAGING<sup>a</sup>. Initial Workup. GTN. C/A/P CT scan with contrast. - If contrast is contraindicated, other imaging techniques such as MRI may be considered. - Brain MRI (preferred) with or without contrast or CT with contrast (if pulmonary metastasis) - Pelvis ultrasound or MRI with and without contrast. Staging. - Persistent GTN - Repeat imaging workup (above) to check for metastasis and recalculate WHO score based on imaging.. Follow-up/Surveillance. - Low-risk GTN. - Post-treatment imaging is not routinely recommended for follow-up after hCG normalization in patients with post-molar GTN or choriocarcinoma, where hCG is a reliable tumor marker. - It may be necessary to follow patients with brain metastases with MRI brain with and without contrast for 2-3 years.. - High-risk GTN. - Post-treatment imaging is not routinely recommended for follow-up after hCG normalization in patients with post-molar GTN or choriocarcinoma, where hCG is a reliable tumor marker. - It may be necessary to follow patients with brain metastases with MRI brain with and without contrast for 2-3 years.. - Intermediate trophoblastic tumor: PSTT and ETT (non-metastatic and metastatic disease). - Post-treatment imaging is indicated for follow-up after treatment of PSTT and ETT, where hCG is a less reliable tumor marker.. - Consider FDG-PET/CT (whole body) at the completion of chemotherapy and then FDG-PET/CT or CT C/A/P every 6-12 months for 2-3 years.. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. PRINCIPLES OF SURGICAL MANAGEMENT OF GTN. - Chemotherapy is the mainstay of treatment for GTN; however, surgery plays an important role in specific clinical circumstances.- Hysterectomy is not required in the treatment of GTN; most patients can be cured without hysterectomy.- For patients who do not desire future fertility with low-risk disease, hysterectomy can decrease the number of cycles of chemotherapy needed to achieve remission.- Hysterectomy can also be considered in rare cases of uterine-confined, chemo-resistant disease or in cases of hemorrhage requiring repeated transfusion.- Hysterectomy can be performed via minimally invasive or open approach without compromise in oncologic outcomes. Ovarian removal is not necessary.- Lung metastasis can be a site of chemotherapy-resistant disease. For these highly selected patients, resection of pulmonary metastasis can improve cure rates.- Craniotomy can be considered in rare cases of GTN with brain metastases, including active intracranial hemorrhage, raised intracranial pressure, and impending cerebral herniation.. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. SYSTEMIC THERAPY FOR GTN. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. SYSTEMIC THERAPY FOR GTN. High- Risk GTN: Primary Therapy Options<sup>a,b</sup>. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. SYSTEMIC THERAPY FOR GTN. High- Risk GTN: Primary Therapy Options<sup>a,b</sup> – Continued. a FDA- approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. b Use G- CSF as primary prophylaxis with etoposide/cisplatin or etoposide/carboplatin- based regimens. See NCCN Guidelines for Hematopoietic Growth Factors. c Round filgrastim dose to the nearest trial size by institution- defined weight limits. d Dosing schedules also apply to the Intermediate Trophoblastic Tumor (PSTT and ETT) regimens listed on GTN- D 7 of 7.. Note: All recommendations are category 2A unless otherwise indicated.. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. SYSTEMIC THERAPY FOR GTN. a FDA- approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. b Use G- CSF as primary prophylaxis with etoposide/cisplatin or etoposide/carboplatin- based regimens. See NCCN Guidelines for Hematopoietic Growth Factors. c Round filgrastim dose to the nearest vial size by institution- defined weight limits. d Dosing schedules also apply to the Intermediate Trophoblastic Tumor (PSTT and ETT) regimens listed on GTN- D 7 of 7. e For dosing references, see page TEST- E in the NCCN Guidelines for Testicular Cancer.. Note: All recommendations are category 2A unless otherwise indicated.. # SYSTEMIC THERAPY FOR GTN. High- Risk GTN: Therapy for Methotrexate- Resistant GTN<sup>a,b</sup>. # SYSTEMIC THERAPY FOR GTN. High- Risk CTN: Additional Agents/Regimens Shown to Have Some Activity in Treating Multiagent Chemotherapy- Resistant GTN<sup>d,g</sup>. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. SYSTEMIC THERAPY FOR GTN. Intermediate Trophoblastic Tumor (PSTT and ETT)a,b,k,l. a FDA- approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. b Use G- CSF as primary prophylaxis with etoposide/cisplatin or etoposide/carboplatin- based regimens. See NCCN Guidelines for Hematopoietic Growth Factors. h NCCN Guidelines for Management of Immunotherapy- Related Toxicities. i Nivolumab and hyaluronidase- nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase- nvhy has different dosing and administration instructions compared to IV nivolumab. j Given on clinical trial protocol. k If feasible, perform hysterectomy with salpingectomy and excision of metastatic disease. l For dosing schedules, see High- Risk GTN sections GTN- D 3 of 7, GTN- D 4 of 7, and GTN- D 6 of 7.. Note: All recommendations are category 2A unless otherwise indicated.. # Physical Effects. - Gynecologic cancer treatment typically involves surgery, chemotherapy, hormone therapy, radiation therapy (RT), and/or immunotherapy. These treatments cause acute, short-term, and long-term toxicities.- Surgical approaches may be extensive and pose risks such as adhesion formation, which may cause pain and may contribute to small bowel obstruction, urinary or gastrointestinal complications (eg, incontinence, diarrhea), pelvic floor dysfunction (manifested by a variety of urinary, bowel, and/or sexual effects), and lymphedema.- Chemotherapy agents vary, though commonly used regimens may pose a significant risk of neurotoxicity, cardiac toxicity, development of hematologic cancers, and cognitive dysfunction.- Long-term estrogen deprivation may cause symptoms such as hot flashes, vaginal dryness, and bone loss.- RT may cause long-term complications (eg, fibrosis, vulvovaginal atrophy) and may predispose patients to secondary cancers of the subcutaneous tissue, and/or underlying organs that are proximal to the radiation field.- Prior pelvic RT may contribute to bone loss and increase the risk of pelvic fractures. Consider bone density testing and prophylactic use of bisphosphonates, particularly in patients with osteoporosis.- Immunotherapy use is emerging, and to date, long-term effects of these treatments are unknown.. Psychosocial Effects. Psychosocial effects after cancer may be psychological (eg, depression, anxiety, fear of recurrence, altered body image), financial (eg, return to work, insurance concerns), and/or interpersonal (eg, relationships, sexuality, intimacy) in nature.. Clinical Approach. All gncic c s r l t n i i factors, providing recommended vaccinations, and encouraging adoption of a healthy lifestyle. In order to asst the late and on- tem effts of gncologic cancers, clinicians should comprehensively document the patient's history, conduct a hough phsical xation, and proide any neary img and/ or ltoray sting. l patiens, whther suxly active or not, shoud be asked about genitourinary symptoms, including vulvovaginal dryness. Referral to appropriate specialty providers (eg, physical therapy, pelvic floor therapy, sexual therapy, psychotherapy) is recommended. As most treatments for gynecologic cancers will cause sexual dysfunction, early menopause, and infertility, special attention to the resultant medical and psychosocial implications is needed.. - Post-radiation use of vaginal dilators and moisturizers is recommended.. - For treatment-related menopause, hormone therapy should be considered.. - Communication and coordination with all clinicians involved in the care of survivors, including primary care clinicians, is critical. Providing cancer survivors with a summary of their treatment and recommendations for follow-up is recommended.. - In subsequent pregnancy:. - Recommend early ultrasound to confirm intrauterine pregnancy- Perform pathologic evaluation of placenta- Check hCG at 6 weeks postpartum to confirm return to negative. Additional Guidance. - NCCN Guidelines for Distress Management- NCCN Guidelines for Smoking Cessation- NCCN Guidelines for Survivorship. Note: All recommendations are category 2A unless otherwise indicated.. # FIGO STAGING SYSTEM FOR GTN<sup>a</sup>. # PROGNOSTIC SCORING INDEX FOR GTN<sup>a</sup>. - The total score for a patient is obtained by adding the individual scores for each prognostic factor.- FIGO Prognostic Score - Low risk: <7 - High risk: ≥7. #	None	None	None
403b30dfe7984e97a392f7bb11c2a509	NCCN临床实践指南	妊娠滋养细胞肿瘤31-45	# NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. # Discussion. Table of Contents. Overview 2 Guidelines Update Methodology 2 Literature Search Criteria 2 Sensitive/Inclusive Language Usage 2 Types of Gestational Trophoblastic Disease 3 Hydatidiform Mole 3 Presentation and Workup 3 Treatment 4 Follow- up 4 Post- Molar GTN 5 Gestational Trophoblastic Neoplasia 6 Presentation and Workup 6 Low- Risk GTN 6 First- Line Therapy 6 Second- Line Single- Agent Therapy 7 Second- Line Multiagent Therapy 8 High- Risk GTN 9 Primary Chemotherapy 9. Salvage Chemotherapy 10 Adjuvant Surgery 11 Intermediate Trophoblastic Tumors 12 Treatment Approach 12 Gynecologic Survivorship 13 References 15. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. Overview. Gestational trophoblastic disease (GTD) refers to a group of benign and malignant tumors that develop in the uterus from placental tissue. The pathogenesis of GTD is unique in that maternal tumors arise from gestational tissue that can have locally invasive or metastatic potential. Historical data on incidence of GTD varies widely by region, with higher incidence reported in Asia compared with Europe and North America. These differences are thought to be due at least in part to varying diagnostic criteria, reporting practices, quality of epidemiologic data, and diet and nutrition. In the United States, the reported incidence of GTD is approximately 1 out of every 1000 pregnancies.1- 4. The most common form of GTD is hydatidiform mole (HM), also known as molar pregnancy. HMs are considered a benign, premalignant disease. Malignant forms of GTD are collectively referred to as gestational trophoblastic neoplasia (GTN), and include invasive mole, choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). HM encompasses about . Guidelines Update Methodology. The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.. Literature Search Criteria. Prior to the update of this version of the NCCN Clinical Practice Guidelines (NCCN Guidelines) for Gestational Trophoblastic Neoplasia, an electronic search of the PubMed database was performed to obtain key literature in GTD published since the previous Guidelines update, using the following search terms: gestational trophoblastic OR choriocarcinoma OR . The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized Controlled Trial; Meta- Analysis; Systematic Reviews; and Validation Studies.. The data from key PubMed articles as well as articles from additional sources deemed as relevant to these Guidelines as discussed by the Panel during the Guidelines update have been included in this version of the Discussion section. Recommendations for which high- level evidence is lacking are based on the Panel's review of lower- level evidence and expert opinion.. Sensitive/Inclusive Language Usage. NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation. NCCN Guidelines endeavor to use language that is person- first; not stigmatizing; anti- racist, anti- classist, anti- misogynist, anti- ageist, anti- ableist, and anti- fat- biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non- gendered language, instead focusing on organ- specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.. Types of Gestational Trophoblastic Disease. HM occurs as a result of abnormal fertilization and is characterized as complete or partial based on differences in morphology, karyotype, and malignant potential. The majority of complete moles . Post- molar GTN, which includes invasive mole and choriocarcinoma, develops in about . Intermediate trophoblastic tumors (ITT), including PSTT and ETT, are rare subtypes of GTN with an incidence of about 1 in 100,000 pregnancies, representing approximately . ETT is a rare variant of PSTT that simulates carcinoma. Based on morphologic and histochemical features, it appears to develop from neoplastic transformation of chorionic- type intermediate trophoblast. ETT typically presents years after term delivery.. Hydatidiform Mole. Presentation and Workup. Patients with HM commonly present with vaginal bleeding, typically around 6 to 16 weeks of gestation. Due to widespread ultrasound screening during early pregnancy and accurate hCG testing, most cases of HM are detected prior to the onset of additional signs such as uterine enlargement beyond that expected for gestation date, preeclampsia, hyperemesis, anemia, and theca lutein ovarian cysts.2,3,5 Partial HMs tend to grow more slowly and may present later in the first or early second trimester, often with symptoms of incomplete or missed abortion and diagnosis made upon histologic examination of the curettage specimen.2,3. # Initial determination of suspected HM is often made based on ultrasound findings in combination with clinical symptoms and hCG levels. Due to hyperplastic trophoblastic cells in complete HM, many patients will have marked elevations in hCG, at times . Treatment. Initial treatment of HM in patients who wish to preserve fertility is suction dilation and curettage (D&C), preferably performed under ultrasound guidance to reduce the risk of uterine perforation.. Prophylactic chemotherapy at the time of uterine evacuation is controversial and may reduce the incidence of post- molar GTN by . Follow-up. Follow- up with hCG monitoring is essential following initial treatment of HM to ensure that hCG levels return to normal. The hCG molecules associated with GTD are more heterogenous and degraded than those associated with normal pregnancy.. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. Once normalized, recurrent elevation of hCG has been reported in . The NCCN Panel recommends hCG assay monitoring every 1 to 2 weeks until levels have normalized, defined in the guidelines as three consecutive normal assays. Patients should also use contraception; oral contraceptive pills are preferred over intrauterine devices because they suppress endogenous luteinizing hormone (LH)/follicle- stimulating hormone (FSH), which may interfere with hCG measurement at low levels and is preferred for at least 6 months. Following initial normalization, consider hCG measurement every 3 months for 6 months to ensure levels remain normal. If hCG levels remain persistently elevated (ie, plateau or rise), treat per the persistent post- molar GTN algorithm.. Post-Molar GTN. Post- molar GTN is typically diagnosed by hCG surveillance. The NCCN Guidelines use the FIGO staging criteria for post- molar GTN as meeting one of more of the following criteria after treatment for HM, as indicated by hCG monitoring26 and WHO prognostic scoring index for GTN27:. hCG levels plateau for 4 consecutive values over 3 weeks hCG levels rise . Assessment and staging of post- molar GTN should include history and physical examination (including pelvic exam), FIGO stage and prognostic score, pelvic ultrasound, and imaging (chest x- ray or [C/A/P] CT to assess for metastatic disease. Pelvic ultrasound is used to confirm the absence of pregnancy, measure uterine size, and to delineate the volume and vasculature of the tumor. If chest x- ray reveals no evidence of metastatic . Repeat D&C for all patients with WHO . For presence of metastatic disease, histopathologic diagnosis of choriocarcinoma, PSTT/ETT or extrauterine disease, follow recommendations for staging and treatment in the algorithms for GTN, which are stratified by risk group/prognostic score.. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. Gestational Trophoblastic Neoplasia. Presentation and Workup. Presentation and WorkupThe presentation of GTN can vary depending upon the antecedent pregnancy event and disease type and extent. Post- molar GTN, including invasive mole or choriocarcinoma, can be associated with irregular bleeding after initial treatment for molar pregnancy, an enlarged and irregular uterus, and bilateral ovarian enlargement. However, these signs may be absent in patients with choriocarcinoma associated with normal, non- molar pregnancies. Trophoblastic tumors have fragile vessels and as a result, metastatic lesions are often hemorrhagic. In addition to bleeding, metastatic lesions may be associated with neurologic or pulmonary symptoms. ETT and PSTT typically present with irregular uterine bleeding arising after some time has passed from a previous pregnancy.2,3,35. Workup for GTN includes history and physical examination and metastatic imaging workup, to include C/A/P CT scan with contrast (or MRI if contrast is contraindicated) as well as brain MRI (preferred) with or without contrast or CT with contrast if pulmonary metastasis. Pelvic ultrasound or MRI with or without contrast should also be performed. Visible lesions in the lower genital tract should not be biopsied due to hemorrhage risk. Additionally, the NCCN Panel recommends repeat CBC differential with platelets; liver, renal, and thyroid function testing; and hCG assay. If hCG is elevated with no evidence of disease on imaging, consider the possibility of LH crossover or phantom hCG.36,37 If hCG is elevated, although at a low level that is stable over time (and false positive hCG ruled out), quiescent GTN is possible, and close follow- up, rather than immediate treatment may be considered. Based on these findings, GTN should be staged and scored according to the current FIGO staging and prognostic scoring system.26,38 GTN staging is based on tumor location and extent: stage I disease is uterine- confined, stage II involves direct extension or metastasis to other genital structures, stage III disease is determined by lung metastasis, and stage IV disease includes non- pulmonary distant metastasis. The current. FIGO prognostic scoring system was adapted from the WHO classification, which incorporated prognostic factors from Bagshawe's scoring system.39,40 FIGO prognostic scoring is based on individual risk factors that have been shown to be predictive of GTN that is resistant to single- agent chemotherapy, such as age, antecedent pregnancy, interval from index pregnancy, pretreatment hCG, largest tumor size (including the uterus), site and number of metastases, and previous chemotherapy regimens that were unsuccessful. The sum of individual scores denotes the FIGO prognostic score of low- risk GTN (<7) or high- risk GTN (≥7).26,38,41 This prognostic scoring system is not valid for the ITTs ETT and PSTT.11. Histopathologic assessment is also recommended by the Panel as part of initial workup. The immunohistochemical (IHC) markers melanoma cell adhesion molecule (Mel- CAM/CD146), human placental lactogen (hPL), beta- human chorionic gonadotropin (βhCG), p63, cyclin E, and Ki- 67 are all differentially expressed between PSTT, ETT, and choriocarcinoma.16,42,43 GATA- 3 is a sensitive marker for both benign and malignant trophoblast proliferations, and may be useful in distinguishing GTN from non- GTN tumors. Given that recommended treatment regimens for each of these GTN subtypes differ significantly, accurate diagnosis is essential for avoiding unnecessary treatment and optimizing patient outcomes.. Low-Risk GTN. First-Line Therapy. Low- Risk GTNFirst- Line TherapyAs noted above, low- risk GTN is defined as a FIGO prognostic score of <7. Standard first- line treatment for low- risk GTN is single- agent chemotherapy using methotrexate or dactinomycin. Numerous studies have evaluated these agents, but differences in inclusion criteria and dosage regimens have made it challenging to determine a superior regimen. While some consider methotrexate to have a more favorable. # adverse effect profile, dactinomycin may achieve similar or better efficacy with a less- frequent infusion schedule.5,21,41,44,45 A 2016 Cochrane Database review of RCTs in low- risk GTN showed with moderate- certainty evidence that first- line methotrexate may be more likely to fail than dactinomycin (risk ratio [RR], 3.55; . Currently supported regimens of dactinomycin include a 5- day regimen (10- 12 mcg/kg or flat . Methotrexate regimens that are no longer recommended due to lesser efficacy include weekly IM methotrexate . The Guidelines note that a multiday methotrexate regimen is typically used as first- line therapy in low- risk GTN due to its generally favorable toxicity profile. Dactinomycin is often used as a secondary therapy for patients with methotrexate toxicity or effusions contradicting the use of methotrexate. Alternative single- agent options for treatment of low- risk GTN that are primarily used in Asia include etoposide and fluorouracil.41,49,50. Monitoring/Response Assessment During First- Line Therapy The NCCN Panel recommends monitoring chemotherapy response by hCG assay every 2 weeks, at the start of each treatment cycle.44 Upon hCG normalization, continuation of therapy is recommended for two to three additional treatment cycles past normalization to minimize the risk of recurrence (3- month cycles is preferred).3,6,21,51 Surveillance should include monthly hCG for 1 year, along with contraception (oral contraception preferred). Chemotherapy resistance is indicated by a plateau in hCG (<10% change) over three consecutive cycles or a rise in hCG (>10% change) over two consecutive cycles.5,44 Second- line chemotherapy is then indicated.. Second-Line Single-Agent Therapy. Currently, there are no RCT data on second- line therapy for low- risk GTN, but general evidence and consensus supports a change to the alternative single- agent chemotherapy for patients who have had a good initial. # response to chemotherapy but experience hCG plateau or re- elevation . Second- line dactinomycin is considered to have an acceptable response rate in patients with low levels of hCG, but multiagent chemotherapy may be favored in the second- line setting for patients whose hCG exceeds a given threshold.. Dactinomycin has been associated with a complete response rate of approximately . Second-Line Multiagent Therapy. For patients with poor response to single- agent chemotherapy or those who initially responded to initial therapy but experienced a subsequent rapid rise in hCG levels . Monitoring/Response Assessment During Second- Line Therapy For both single- agent and multiagent second- line therapy, hCG levels should be monitored every 2 weeks, but a more rapid response assessment is warranted if hCG levels plateau or rise. The Panel recommends additional treatment if patients experience an hCG plateau over two consecutive treatment cycles or an hCG rise over 1 cycle. For persistent disease after single- agent therapy with or without hysterectomy/salpingectomy, repeat workup to assess for metastasis and transition to EMA/CO combination therapy. For persistent or recurrent disease after EMA/CO combination therapy with or without hysterectomy/salpingectomy, treat per the high- risk GTN algorithm with platinum- based regimens and surgical resection as feasible.. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. High-Risk GTN. High- Risk GTNHigh- risk GTN is defined as a prognostic score . Primary Chemotherapy. EMA/CO, in which EMA and CO are given on alternate weeks, is the most commonly used initial regimen for high- risk disease. Based on existing evidence, this regimen is thought to provide the best combination of efficacy with acceptable toxicity for treating patients with high- risk GTN. Multiple groups have confirmed the efficacy of EMA/CO, reporting complete response rates of . Reports of other regimens that have been used in first- line treatment of high- risk GTN include EMA/EP (etoposide, methotrexate, dactinomycin alternating with etoposide, and cisplatin)72,73 and EP/EMA (etoposide and cisplatin alternating with etoposide, methotrexate, and dactinomycin).74. Due to the lack of RCTs in this setting, systematic reviews have been unable to draw conclusions regarding a superior combination regimen for primary treatment of high- risk GTN.. Induction Chemotherapy for Extensive Metastatic Disease. Induction Chemotherapy for Extensive Metastatic DiseasePatients with widespread metastatic GTN, as evidenced by prognostic score . Management of CNS Metastases. Management of CNS MetastasesAdditional treatment considerations are recommended for patients with central nervous system (CNS) metastases, who may require emergency intervention to manage intracranial bleeding or elevated intracranial pressure.. # every 6 hours for 12 doses, starting 32 hours after the start of the methotrexate infusion.. The Panel recommends that whole- brain radiation or stereotactic brain radiotherapy (SBRT) also be considered for patients with brain metastases.. Monitoring/Response Assessment During First- Line Therapy Monitoring and response assessment during first- line treatment of high- risk GTN is the same as for low- risk GTN. Patients who respond to primary chemotherapy but subsequently experience a low- level hCG plateau, those who have an incomplete response to primary treatment, and those who experience relapse from remission require further treatment (ie, salvage chemotherapy and/or adjuvant surgery).. Salvage Chemotherapy. Approximately . EMA/EP or EP/EMA regimens are considered the most appropriate therapy for patients who have responded to EMA/CO but have plateauing low hCG levels or have developed re- elevation of hCG after a complete response to EMA/CO.. EMA/EP for disease resistant to EMA/CO has been reported between . Additional drug combinations containing etoposide, and a platinum agent have been effective in patients who have developed disease resistant to methotrexate- containing regimens. The Panel prefers the use of the following four regimens for methotrexate- resistant GTN: TP/TE (paclitaxel and cisplatin alternating weekly with paclitaxel and etoposide), BEP (bleomycin, etoposide, and cisplatin), VIP (etoposide, ifosfamide, and cisplatin), and ICE (ifosfamide, carboplatin, and etoposide).. Etoposide- platinum- containing regimens require the use of granulocyte colony- stimulating factor (G- CSF) support to prevent neutropenic complications and treatment delays.. Additional Agents/Regimens with Potential Activity in Treatment-Resistant GTN. Several additional treatment regimens have been shown to have some activity when treating resistant GTN, including high- dose chemotherapy (HDC) with peripheral hematopoietic cell transplant, immunotherapy, and other chemotherapy regimens. For a subset of patients with resistant disease despite multidrug chemotherapy, HDC with autologous stem cell support has been reported to produce sustained complete responses.. # with 13 of 32 patients remaining disease free at the time of analysis following HDC with or without additional therapy.. Pembrolizumab is a monoclonal antibody that inhibits programmed cell death protein 1 (PD- 1), which functions as a checkpoint protein for regulation of various immune cells, including T cells with potential antitumor activity.. Avelumab, a PD- L1 inhibitor, may also be effective against treatment- resistant GTN. Results from a phase II study enrolling 15 patients with GTN who experienced disease progression after single- agent chemotherapy suggested that avelumab was effective in normalizing hCG levels in approximately half of the patients.. Gemcitabine, capecitabine, and fluorouracil may also have potential for treating GTN in this setting. Limited data have suggested activity of gemcitabine, administered with or without a platinum agent.. Nivolumab and ipilimumab combination is added to the additional Agents/Regimens shown to have some activity in treating multiagent chemotherapy- resistant GTN based on Patel SP et al.. Adjuvant Surgery. Adjuvant surgical procedures, especially hysterectomy with salpingectomy and pulmonary resection, may be required to manage high- risk, chemotherapy- resistant disease. Select patients with isolated disease, especially in the uterus and lungs, may be candidates for surgical resection.. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. Selective arterial embolization can be used to manage bleeding from the uterus/vagina or other tumor sites.124- 126 In one case series, nearly . Intermediate Trophoblastic Tumors. Whereas molar pregnancies and choriocarcinoma are derived from villous trophoblast (ie, cytotrophoblast and syncytiotrophoblast), ITTs (including PSTT and ETT) develop from extravillous trophoblast (ie, intermediate trophoblast). ITTs comprise approximately . PSTT and ETT are generally slow- growing tumors that can metastasize months or years after initial primary tumor development and often present with abnormal uterine bleeding or amenorrhea. The vast majority of ITTs secrete hCG, but at significantly lower levels compared with other types of GTN. As such, hCG is a less reliable tumor marker for these subtypes of GTN. At diagnosis, metastases are noted in . ITTs can be differentiated from other types of GTN via their histopathologic characteristics.11 In PSTT, IHC staining reveals the diffuse presence of Mel- CAM (CD146) and hPL, whereas hCG staining is only focal. Cytogenetic studies have revealed that PSTTs are more often diploid than aneuploid.135 Serum hPL measurements are not clinically . Due to the rarity of these tumors, generally small cohort sizes preclude rigorous statistical analysis of risk factors in ITT. The FIGO prognostic scoring system for GTN does not correlate well with outcomes in PSTT and ETT.11 Based on findings from the largest existing database, PSTT and ETT accounted for 125 of 54,743 cases of GTD . Treatment Approach. ITTs are relatively chemoresistant and thus follow a somewhat different treatment paradigm than invasive mole and choriocarcinoma, with surgical intervention playing a more critical role. Treatment of PSTT and ETT is mainly determined by presence or absence of metastatic disease, with some consideration given to high- risk factors. The survival rate is approximately . # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. Hysterectomy with salpingectomy, with or without pelvic lymph node biopsy, is the recommended treatment for nonmetastatic (stage I) disease. If the patient has any of the reported poor prognostic factors<sup>135</sup> such as . Monitoring and Surveillance. Post- treatment hCG levels should be monitored as indicated for GTN, although hCG is a less reliable tumor marker for ITTs versus post- molar GTN. The Panel recommends surveillance with FDG- PET/CT at the completion of chemotherapy and then every 6 to 12 months for 2 to 3 years.. Post-Treatment Recurrence or Progression of ITTs. Systemic therapy regimens recommended for primary treatment of metastatic disease may have some efficacy in patients experiencing recurrence or progression of nonmetastatic or metastatic ITTs. Alternatively, patients with metastatic ITTs may forego additional chemotherapy and instead receive best supportive care (see NCCN Guidelines for Palliative Care).. Gynecologic Survivorship. Treatment for gynecologic cancer typically involves surgery, chemotherapy, hormone therapy, radiation therapy, and/or immunotherapy, which may cause acute, short- term, and long- term toxicities. Surgical approaches may be extensive and cause adhesions to form, which in turn may cause pain and contribute to the development of small bowel obstruction, urinary or gastrointestinal complications (eg, incontinence, diarrhea), pelvic floor dysfunction (manifested by a variety of urinary, bowel, and/or sexual effects), and lymphedema.<sup>143,144</sup> Chemotherapy agents vary, though commonly used regimens may pose a significant risk of neurotoxicity, cardiac toxicity, cognitive dysfunction, and the development of hematologic cancers.<sup>145</sup> Long- term estrogen deprivation may cause symptoms such as hot flashes, vaginal dryness,. # NCCN Guidelines Version 2.2025 Gestational Trophoblastic Neoplasia. and bone loss. Radiation therapy may cause long- term complications (eg, fibrosis, stenosis, vulvovaginal atrophy)146,147 and may predispose patients to subsequent cancers of the skin, subcutaneous tissue, and/or underlying organs that are proximal to the radiation field.148 Use of immunotherapy agents in gynecologic cancers is emerging, and to date, long- term effects of these treatments are unknown.149,150. Following completion of treatment, all gynecologic cancer survivors should receive regular general medical care that focuses on managing chronic diseases (eg, depression, diabetes, hypertension), monitoring cardiovascular risk factors, receiving recommended vaccinations, and encouraging adoption of a healthy lifestyle (eg, promoting exercise, smoking cessation).151,152 In order to assess the late and long- term effects of gynecologic cancers, clinicians should comprehensively document the patient's history, including prior treatment history, and conduct a thorough physical examination followed by necessary imaging and/or laboratory testing.152 As most treatments for gynecologic cancers will cause sexual dysfunction, early menopause, and infertility, special attention to the resultant medical and psychosocial implications is needed. All individuals, whether sexually active or not, should be asked about genitourinary symptoms, including vulvovaginal dryness.153 Post- radiation use of vaginal dilators and moisturizers is recommended.146,154 Psychosocial effects may include psychological (eg, depression, anxiety, fear of recurrence, altered body image), financial (eg, return to work, insurance concerns), and interpersonal (eg, relationships, sexuality, intimacy).152 Patients should be referred to appropriate specialty providers (eg, physical therapy, pelvic floor therapy, sexual therapy, psychotherapy) as needed, based on prior treatment history and assessed risk of developing late effects and/or existing concerns.. Communication and coordination with all clinicians involved in the care of survivors, including primary care clinicians, is critical.152,155 During .	None	None	None
4fac4417d2bd42a4a7de14fdbbf06284	NCCN临床实践指南	子宫肿瘤001-030	# NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Uterine Neoplasms. Version 2.2025 — January 31, 2025. NCCN.org. NCCN recognizes the importance of clinical trials and encourages participation when applicable and available. Trials should be designed to maximize inclusiveness and broad representative enrollment.. NCCN Guidelines for Patients® available at www.nccn.org/patients. Continue. # National Comprehensive Cancer Network. NCCN Guidelines Version 2.2025 Uterine Neoplasms. Nadeem R. Abu- Rustum, MD Q/Chair Memorial Sloan Kettering Cancer Center. Susana M. Campos, MD, MPH, MS Vice Chair Dana- Farber/Brigham and Women's Cancer Center. Rebecca Arend, MD O'Neal Comprehensive Cancer Center at UAB. Emma Barber, MD O Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Kristin Bradley, MD S University of Wisconsin Carbone Cancer Center. Rebecca Brooks, MD OUC Davis Comprehensive Cancer Center. Junzo Chino, MD S Duke Cancer Institute. Hye Sook Chon, MD O Moffitt Cancer Center. Marta Ann Crispens, MD O Vanderbilt- Ingram Cancer Center. Shari Damast, MD S Yale Cancer Center/ Smilow Cancer Hospital. Christine M. Fisher, MD, MPH S University of Colorado Cancer Center. Peter Frederick, MD O Roswell Park Comprehensive Cancer Center. David K. Gaffney, MD, PhD S Huntsman Cancer Institute at the University of Utah. Stephanie Gaillard, MD, PhD Johns Hopkins Kimmel Cancer Center. Robert Giuntoli II, MD O Abramson Cancer Center at the University of Pennsylvania. Scott Glaser, MD S City of Hope National Medical Center. Brooke E. Howitt, MD Stanford Cancer Institute. Lisa Landrum, MD, PhD O Indiana University Melvin and Bren Simon Comprehensive Cancer Center. Jayanthi Lea, MD O UT Southwestern Simmons Comprehensive Cancer Center. Nita Lee, MD, MPH O The UChicago Medicine Comprehensive Cancer Center. Gina Mantia- Smaldone, MD O Fox Chase Cancer Center. Andrea Mariani, MD O Mayo Clinic Comprehensive Cancer Center. David Mutch, MD O Siteman Cancer Center at Barnes- Jewish Hospital and Washington University School of Medicine. Christa Nagel, MD O The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute. Larissa Nekhlyudov, MD, MPH Dana- Farber/Brigham and Women's Cancer Center. Karina Nieto, MD S Case Comprehensive Cancer Center/ University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute. Chika Nwachukwu, MD, PhD S UC San Diego Moores Cancer Center. Mirna Podoll, MD # Vanderbilt- Ingram Cancer Center. Kerry Rodabaugh, MD O Fred & Pamela Buffett Cancer Center. Ritu Salani, MD, MBA O UCLA Jonsson Comprehensive Cancer Center. John Schorge, MD O St. Jude Children's Research Hospital/ The University of Tennessee Health Science Center. Scott Schuetze, MD, PhD T Liaison University of Michigan Rogel Cancer Center. Jean Siedel, DO, MS O University of Michigan Rogel Cancer Center. Rachel Sisodia, MD O Mass General Cancer Center. Pamela Soliman, MD, MPH O The University of Texas MD Anderson Cancer Center. Stefanie Ueda, MD O UCSF Helen Diller Family Comprehensive Cancer Center. Renata Urban, MD O Fred Hutchinson Cancer Center. Emily Wyse ¥ Patient advocate. NCCN. Nicole McMillian, MS. Vaishnavi Sambandam, PhD. Continue. Q Gynecologic oncology Internal medicine Medical oncology Pathology Patient advocacy. \S. # National Comprehensive Cancer Network. NCCN Guidelines Version 2.2025 Uterine Neoplasms. NCCN Guidelines Index Table of Contents Discussion. NCCN Uterine Neoplasms Panel Members Summary of the Guidelines Updates. Uterine Neoplasms Uterine Neoplasms (UN- 1). Endometrial Carcinoma. Disease Limited to the Uterus (ENDO- 1) Suspected or Gross Cervical Involvement (ENDO- 2) Suspected Extrauterine Disease (ENDO- 3) Adjuvant Treatment for Surgically Staged Disease (ENDO- 4). (ENDO- 5). (ENDO- 6) Incompletely Surgically Staged (ENDO- 7) Criteria for Considering Fertility- Sparing Options (ENDO- 8) Surveillance (ENDO- 9) Locoregional Recurrence (ENDO- 10) Serous Carcinoma (ENDO- 11) Clear Cell Carcinoma (ENDO- 12) Undifferentiated/Dedifferentiated Carcinoma (ENDO- 13) Carcinosarcoma (ENDO- 14). Principles of Pathology and Molecular Analysis (ENDO- A) Principles of Imaging (ENDO- B) Principles of Evaluation and Surgical Staging (ENDO- C) Systemic Therapy for Endometrial Carcinoma (ENDO- D). Uterine Sarcoma Diagnosed After Total Hysterectomy or Supracervical Hysterectomy ± Bilateral Scalpingo- Oophorectomy (UTSARC- 1) Diagnosed by Biopsy or Myomectomy (UTSARC- 1) Low- Grade Endometrial Stromal Sarcoma (ESS) or Adenosarcoma Without Sarcomatous Overgrowth (UTSARC- 2) Adenosarcoma With Sarcomatous Overgrowth (UTSARC- 2) High- Grade ESS, Undifferentiated Uterine Sarcoma, Leiomyosarcoma, and Other Sarcomas Such as Perivascular epithelioid cell tumor (PEComa) (UTSARC- 3) Surveillance (UTSARC- 4) Recurrence (UTSARC- 5) Principles of Pathology and Molecular Analysis (UTSARC- A) Principles of Imaging (UTSARC- B) Systemic Therapy for Uterine Sarcoma (UTSARC- C). Uterine Neoplasms Principles of Radiation Therapy (UN- A) Principles of Gynecologic Survivorship (UN- B). Staging (ST- 1). Abbreviations (ABBR- 1). Find an NCCN Member Institution: institutions.. NCCN Categories of Evidence and Consensus: All recommendations are category 2A unless otherwise indicated.. See NCCN Categories of Evidence and Consensus.. NCCN Categories of Preference: All recommendations are considered appropriate.. See NCCN Categories of Preference.. The NCCN Guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network (NCCN) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2025.. # Updates in Version 2.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 1.2025 include:. Uterine Neoplasms ENDO- D 1 of 5. - Footnote revised: For adult patients with primary advanced endometrial carcinoma (post-surgery): stage IIIA, IIIB, or IIIC1 with measurable disease post surgery; stage IIIC1 with carcinosarcoma, clear-cell, serous, or mixed histology regardless of the presence of measurable disease, and stage IIIC2 or stage IV regardless of the presence of measurable disease.. ENDO-D 2A of 5. - Footnote regarding Nivolumab and hyaluronidase-nvhy subcutaneous injection is new: Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and administration instructions compared to IV nivolumab.. ENDO-D 4 of 5. - Reference 13 revised: Leslie K, Filiaci V, Mallen A, et al. Mutated p53 portends improvement in outcomes when bevacizumab is combined with chemotherapy in advanced/recurrent endometrial cancer: An NRG Oncology study. Gynecol Oncol 2021;161:113-124: Aghajanian C, Filiaci V, Dizon DS, et al. A phase II study of frontline paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus, or ixabepilone/carboplatin/bevacizumab in advanced/recurrent endometrial cancer. Gynecol Oncol 2018;150:274-281.. # Updates in Version 1.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2024 include:. General- The staging text box noted throughout the algorithm was revised: "All staging in guideline is based on updated 2009 FIGO staging...". UN- 1- Initial evaluation; 2nd bullet revised: "Complete blood count (CBC) (including platelets), liver function test..."- Footnote c: "... Principles of Pathology for Uterine Sarcoma and Molecular Analysis for Uterine Sarcoma (UTSARC- A)". Endometrial Carcinoma- ENDO- 2- Additional Workup: Cervical biopsy or pelvic pelvis MRI (if not previously done). ENDO- 7- The page for incompletely surgically staged was extensively revised.. ENDO- 7A- Footnote h added: Systemic Therapy for Endometrial Carcinoma (ENDO- D).- Footnote t is new: Consider omitting imaging for stage IA, grade 1- 2 endometrium- limited carcinoma.. ENDO- 8- Primary Treatment; New bullet added: Consider dual- progestin therapy [(megestrol or medroxyprogesterone) + levonorgestrel IUD]- Endometrial cancer present at 6- 12 mo pathway; Recommendation revised: TH/BSO with staging (preferred by 12 months)- Footnote removed: Gunderson CC, et al. Gynecol Oncol 2012;125:477- 482 and Hubbs JL, et al. Obstet Gynecol 2013;121:1172- 1180.. ENDO- 8- Primary Treatment; New bullet added: Consider dual- progestin therapy [(megestrol or medroxyprogesterone) + levonorgestrel IUD]- Endometrial cancer present at 6- 12 mo pathway; Recommendation revised: TH/BSO with staging (preferred by 12 months)- Footnote removed: Gunderson CC, et al. Gynecol Oncol 2012:125:477- 482 and Hubbs JL, et al. Obstet Gynecol 2013;121:1172- 1180.. ENDO-9. Surveillance. 2nd bullet revised: CA- 125 if initially elevated or serous histology 4th bullet revised: "Patient education regarding symptoms of potential recurrence, lifestyle, obesity, exercise, smoking cessation, sexual health (including vaginal dilator use and lubricants/moisturizers), nutrition counseling, and Clinical evaluation and management of potential long- term and late effects of treatment (Also see Principles of Gynecologic Survivorship (UN- B).... Footnote v revised: Principles of Gynecologic Survivorship (UN- B). Patient education should include symptoms of potential recurrence, lifestyle, obesity, exercise, sexual health (including vaginal dilator use, lubricants/moisturizers, and local estrogen and hormone therapy for menopause), smoking cessation, and nutrition counseling.. # Updates in Version 1.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2024 include:. ENDO- A Principles of Pathology ENDO- A 1 of 4. - Pathologic assessment for carcinoma; Sub-bullets removed - HER2 immunohistochemistry (IHC) testing (with reflex to HER2 fluorescence in situ hybridization [FISH] for equivocal IHC) is recommended for all serous and carcinosarcoma tumors. Consider HER2 testing for p53 abnormal carcinomas regardless of histology. - Estrogen receptor (ER) and progesterone receptor (PR) testing is recommended in the settings of stage III, stage IV, and recurrent disease.. ENDO-A 2 of 4 Principles of Molecular Analysis. - Bullets revised as follows:. - 1st bullet: "...no specific molecular profile (NSMP), and p53 abnormal aberrant.". - 3rd bullet: "Ancillary studies for POLE mutations (hotspot pathogenic mutations in the exonuclease domain), immunohistochemical (IHC) staining for mismatch repair (MMR) or MSI testing, and p53 IHC are strongly encouraged recommended to complement morphologic assessment regardless of histologic tumor type...". - 5th bullet: For tumors that are POLE mutated, MSI-H, or copy number-high p53 aberrant, or NMSP, clinical trial enrollment is strongly encouraged. - 7th bullet: Universal testing of endometrial carcinomas for MMR proteins is recommended. Evaluation for MMR status is commonly done using IHC. Molecular profiling via NGS panels or MSI PCR assay are acceptable alternatives is an acceptable alternative.. - 1st arrow sub-bullet: MSI testing is recommended if IHC results are equivocal.. - 3rd arrow sub-bullet: Genetic counseling, molecular analysis, and testing for all other MMR abnormalities is recommended. Genetic counseling for any suspected germline mutation is strongly recommended.. - 4th arrow sub-bullet: "...testing are recommended regardless of MMR or MLH1 promoter methylation results [see Lynch Syndrome (LS-1) (Hereditary Nonpolyposis Colorectal Cancer Syndrome) in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric].. - New bullets added. - HER2 IHC testing (with or without reflex to HER2 fluorescence in situ hybridization [FISH] for equivocal IHC) is recommended for all p53 aberrant carcinomas regardless of histology. - Estrogen receptor (ER) and progesterone receptor (PR) testing is recommended in the settings of stage III, stage IV, and recurrent disease.. ENDO- A 3 of 4 Principles of Molecular Analysis. - Term revised in figure: Pole hotspot pathogenic mutation. ENDO-A 4 of 4. - Reference 2 updated: Crothers BA, Harik LR, Krishnamurti UG, Turashvili G, Movahedi-Lankarani S, Birdsong GG, et al. Protocol for the examination of specimens from patients with carcinoma and carcinosarcoma of the endometrium. (Version 4.4.0.0) College of American Pathologists 2019 2023.. ENDO- B Principles of Imaging - Follow- up/Surveillance; 2nd bullet: New arrow sub- bullet added: Consider pelvic ultrasound surveillance for patients with ovarian preservation.. # National NCCN Guidelines Version 2.2025 Comprehensive Cancer Uterine Neoplasms Network. Updates in Version 1.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2024 include:. Endometrial Carcinoma- continued ENDO- C Principles of Evaluation and Surgical Staging ENDO- C 1 of 6 - Principles of Surgical Staging for Endometrial Cancer 4th bullet revised: "... and often comprises either SLN mapping and resection of sentinel nodes or a pelvic nodal dissection with or without para- aortic nodal dissection..." 5th bullet: "SLN mapping is preferred (see pages 2- 6 of ENDO- C)" reordered to be the 5th bullet. Previously it was the 7th bullet.. ENDO-C 2 of 6. - Principles of Sentinel Lymph Node(s) Mapping for Endometrial Cancer Staging; Bullets revised New bullet added: Indocyanine green (ICG) is the preferred imaging dye for SLN mapping 12th bullet revised: For cases of failed SLN mapping, reinjection of the cervix may be considered. An additional 1 mL in the non-detected side can be infiltrated in the superficial cervical area. Bullet removed: Indocyanine green (ICG) recently emerged as a useful imaging dye that requires a near-infrared camera for localization, provides a very high SLN detection rate, and is commonly used in many practices at the present time. ENDO-C 5 of 6. - Retroperitoneal evaluation text box revised: Excision of all mapped SLN with ultrastaging. ENDO- D Systemic Therapy for Endometrial Carcinoma ENDO- D 1 of 5. Chemoradiation Therapy. Other Recommended Regimens: The following agents changed from category 2A to category 2B - Capecitabine/mitomycin - Gemcitabine - Paclitaxel. Primary or Adjuvant Therapy (Stage I- IV); Preferred Regimens revised. The 4th and 5th bullets were combined as follows: Carboplatin/paclitaxel/trastuzumab (for stage III- IV HER2- positive uterine serous carcinoma or carcinosarcoma) Carboplatin/paclitaxel/bevacizumab (stage III- IV with measurable disease) added as an option Carboplatin/paclitaxel moved down the list to be the last regimen. Footnotes revised. Footnote a is new: An FDA- approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Footnote b: For stage II or IVA with measurable disease post surgery or stage IVB with or without measurable disease. For patients not meeting the eligibility criteria for NRG- GY018, carboplatin/paclitaxel + pembrolizumab should be considered for stage III- IV dMMR tumors (Van Gorp T, et al. Ann Oncol. Published online August 23, 2024).. Footnote e: For adult patients with primary advanced endometrial carcinoma (post surgery): stage IIIA, IIIB, or IIIC1 with measurable disease, stage IIIC1 with carcinosarcoma, clear- cell, serous, or mixed histology regardless of the presence of measurable disease, and stage IIIC2 or stage IV regardless of the presence of measurable disease.. Footnote f is new: For stage III with measurable disease post surgery and stage IV with or without measurable disease. Footnote removed: An FDA- approved biosimilar is an appropriate substitute for trastuzumab.. # National NCCN Guidelines Version 2.2025 Comprehensive Cancer Uterine Neoplasms Network. Updates in Version 1.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2024 include:. Endometrial Carcinoma- continued. ENDO-D 2 of 5. First- Line Therapy for Recurrent Disease; Preferred Regimens The 4th and 5th bullets were combined as follows: Carboplatin/paclitaxel/trastuzumab (for HER2- positive serous carcinoma or carcinosarcoma) Carboplatin/paclitaxel (category 1 for carcinosarcoma) moved down the list to be the last regimen Second- Line or Subsequent Therapy Other Recommended Regimens; Two agents added as options: . ENDO-D 2A of 5. The following footnote changes were made:. Footnote n revised: NCCN recommends TMB- H testing if not previously done. Pembrolizumab is indicated for patients with unresectable or metastatic tumors with TMB- H [≥10 mutations/megabase (mut/Mb)], as determined by an FDA- approved assay, or a validated test performed in a CLIA- certified laboratory; whose disease has progressed following prior treatment and who have no satisfactory alternative treatment options. Footnote s is new: NTRK- positive tumors that are naive to prior NTRK- targeted therapy or have progressed on prior NTRK therapy. Footnotes removed: . ENDO-D 3 of 5. Hormonal Therapy for Recurrent or Metastatic Endometrial Carcinoma; Other Recommended Regimens 3rd bullet; Aromatase inhibitors; Added: . ENDO-D 4 of 5. References updated to reflect changes in the algorithm. # Updates in Version 1.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2024 include:. Uterine Sarcoma UTSARC- 2 - Low- grade ESS or Adenosarcoma without sarcomatous overgrowth (SO) - Additional Therapy for Stage I: Revised: BSO (preferred). UTSARC-4. - Surveillance revised - 1st bullet: H&P exam every 3-4 mo (consider every 6 months for low-grade, early-stage sarcomas) for 2-3 y, then every 6-12 mo - 3rd bullet: "Patient education regarding symptoms of potential recurrence: lifestyle, obesity, exercise, nutrition, sexual health (including vaginal dilator use and lubricants/moisturizers), smoking cessation, nutrition counseling, and Clinical evaluation and management of potential long-term and late effects of treatment (also see Principles of Gynecologic Survivorship (UN-B))." - Footnote m revised: Principles of Gynecologic Survivorship (UN-B). Patient education should include symptoms of potential recurrence, lifestyle, obesity, exercise, sexual health (including vaginal dilator use, lubricants/moisturizers, and local estrogen and hormone therapy for menopause), smoking cessation, and nutrition counseling.. UTSARC- A Principles of Pathology and Molecular Analysis UTSARC- A 1 of 8. - Molecular Analysis for Sarcoma 2nd bullet revised: "... is informative for predicting rare pan-tumor targeted therapy opportunities and should include at least NTRK, MSI, RET-fusion, and TMB. Preferred on tissue; if tissue is not available, blood-based assays may be considered....". UTSARC- A 2 of 8 through UTSARC- A 7 of 8. - Table 1 was extensively revised.. UTSARC-A 8 of 8. - New references added. - Chapel DB, Nucci MR, Quade BJ, Parra-Herran C. Epithelioid leiomyosarcoma of the uterus: Modern outcome-based appraisal of diagnostic criteria in a large institutional series. Am J Surg Pathol 2022;46:464-475. - Chiang S, Vasudevaraja V, Serrano J, et al. TSC2-mutant uterine sarcomas with JAZF1-SUZ12 fusions demonstrate hybrid features of endometrial stromal sarcoma and PEComa and are responsive to mTOR inhibition. Mod Pathol 2022;35:117-127.. UTSARC- B 1 of 2 Principles of Imaging. - Follow-up/Surveillance; 2nd bullet revised: "Optional abdominal/pelvic abdomen/pelvis MRI and chest CT without contrast every 3-6 months...". # Updates in Version 1.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2024 include:. UTSARC- C Systemic Therapy for Uterine Sarcoma UTSARC- C 1 of 3. First- Line Therapy. - Preferred Regimens revised: Doxorubicin/dacarbazine (for LMS or ifosfamide ineligible) - Useful in Certain Circumstances - Biomarker-directed therapy; NTRK gene fusion-positive tumors: Repotrectinib added as an option - Selpercatinib added for RET-fusion positive tumors. Second- Line or Subsequent Therapy. Preferred Regimens revised: Trabectedin (for LMS) Other Recommended Regimens: Regorafenib added as an option.. Footnote is new: NTRK- positive tumors that are naive to prior NTRK- targeted therapy or have progressed on prior NTRK therapy. - Footnote revised: For the treatment of patients with unresectable or metastatic TMB- high (TMB- H) (≥10 mut/Mb) tumors, as determined by an FDA- approved assay, or a validated test performed in a CLIA- certified laboratory; that have progressed following prior treatment and have no satisfactory alternative treatment options.. Footnote removed: For LMS that has been treated with a prior anthracycline- containing regimen.. UTSARC-C 2 of 3. - Anti-Estrogen Hormone Therapy for Low-Grade ESS or Adenosarcoma Without SO or Hormone Receptor-Positive (ER/PR) Uterine Sarcomas. - Preferred Regimens - 1st bullet; For "Aromatase inhibitors for low-grade ESS or adenosarcoma without SO" the following agents added - Anastrozole - Letrozole - Exemestane - New bullet added: Consider gonadotropin-releasing hormone (GnRH) analogs with aromatase inhibitors in patients who are premenopausal and not suitable for surgery (BSO) - Other recommended Regimens revised - 1st bullet; For "Aromatase inhibitors (for ER/PR-positive uterine sarcomas)" the following agents added: - Anastrozole - Letrozole - Exemestane - Bullet removed: GnRH analogs (category 2B for low-grade ESS, adenosarcoma without SO, and ER/PR-positive uterine sarcomas). UTSARC-C 3 of 3. - New References added: - Solomon BJ, Drilon A, Lin JJ, et al. 1372P Repotrectinib in patients (pts) with NTRK fusion-positive (NTRK+) advanced solid tumors, including NSCLC: Update from the phase I/II TRIDENT-1 trial [abstract]. Ann Oncol 2023;34:S787-S788. - Subbiah V, Wolf J, Konda B, et al. Tumor-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol 2022;23:1261-1273. - Berry V, Basson L, Bogart E, et al. REGOSARC: Regorafenib versus placebo in doxorubicin-refractory soft-tissue sarcoma-A quality-adjusted time without symptoms of progression or toxicity analysis. Cancer 2017;123:2294-2302.. # NCCN Guidelines Version 2.2025 Uterine Neoplasms. INITIAL EVALUATIONa. - History and physical (H&P)- Complete blood count (CBC), liver function test [LFT], renal function tests, chemistry profile; and consider CA-125- Expert pathology review with additional endometrial biopsy as clinically indicatedb,c- Imagingd- Recommend molecular evaluation of tumor and evaluation for inherited cancer risk (ENDO-A and UTSARC-A)- For patients who are older with uterine cancer also see the NCCN Guidelines for Older Adult Oncology- Consider germline and/or multigene panel testing. All staging in guideline is based on 2009 FIGO staging. (ST- 1, ST- 2, ST- 3 and ST- 4). aInitial preoperative evaluation for known or suspected malignancy. bPreoperative imaging and biopsy may help to identify uterine sarcomas, although biopsy sensitivity is less than for endometrial cancer. If there is suspicion of malignancy, fragmentation/morcellation should be avoided. Se Principles of Pathology for Endometrial Carcinoma (ENDO- A) and Principles of Pathology and Molecular Analysis for Uterine Sarcoma (UTSARC- A). dSee Principles of Imaging for Endometrial Carcinoma (ENDO- B) and Principles of Imaging for Uterine Sarcoma (UTSARC- B). e Consider referral to a center of expertise that specializes in the treatment of malignant mesenchymal tumors (sarcoma). f Should be treated as a high- grade endometrial cancer. gAlso known as malignant mixed mesodermal tumor or malignant mixed Mullerian tumor, and including those with either homologous or heterologous stromal elements.. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. INITIAL CLINICAL FINDINGS (Endometrioid Histology)a. a (UN- 1) for classification of uterine neoplasms. b Disease is not amenable to resection or patient is not suitable for surgery based on comorbidities. c Principles of Pathology and Molecular Analysis (ENDO- A). d Minimally invasive surgery (MIS) is the preferred approach when technically feasible. See Principles of Evaluation and Surgical Staging (ENDO- C). e The degree of surgical staging to assess disease status depends on preoperative and intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO- C). f Ovarian preservation may be safe in select patients who are premenopausal with early- stage endometrioid cancer, normal- appearing ovaries, and no family history of breast/ovarian cancer or Lynch syndrome. Salpingectomy is recommended. g Principles of Radiation Therapy for Uterine Neoplasms (UN- A). h Systemic Therapy for Endometrial Carcinoma (ENDO- D).. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. INITIAL CLINICAL FINDINGS (Endometrioid Histology)a. a (UN- 1) for classification of uterine neoplasms. b Disease is not amenable to resection or patient is not suitable for surgery based on comorbidities. c Principles of Pathology and Molecular Analysis (ENDO- A). e The degree of surgical staging to assess disease status depends on preoperative and intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO- C).. g Principles of Radiation Therapy for Uterine Neoplasms (UN- A). h Systemic Therapy for Endometrial Carcinoma (ENDO- D). i Principles of Imaging (ENDO- B). j Clear demonstration of cervical stromal involvement.. # a (UN- 1) for classification of uterine neoplasms. b Disease is not amenable to resection or patient is not suitable for surgery based on comorbidities. c Principles of Pathology and Molecular Analysis (ENDO- A). e The degree of surgical staging to assess disease status depends on preoperative and intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO- C). g Principles of Radiation Therapy for Uterine Neoplasms (UN- A). h Systemic Therapy for Endometrial Carcinoma (ENDO- D). i Principles of Imaging (ENDO- B). k Consider ablative RT for 1- 5 metastatic lesions if hysterectomy is performed (category 2B) (Palma DA, et al. Lancet 2019;393:2051- 2058). l The surgical goal is to have no measurable residual disease.. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. All staging in guideline is based on 2009 FIGO staging. (ST- 1). CLINICAL FINDINGS (Endometrioid Histology)a. a (UN- 1) for classification of uterine neoplasms. e The degree of surgical staging to assess disease status depends on preoperative and intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO- C). g Principles of Radiation Therapy for Uterine Neoplasms (UN- A). h Systemic Therapy for Endometrial Carcinoma (ENDO- D). m Initiate EBRT as soon as the vaginal cuff is healed, preferably no later than 12 weeks after surgery. n Vaginal brachytherapy is strongly suggested if two risk factors are present.. # CLINICAL FINDINGS (Endometrioid Histology)a. All staging in guideline is based on 2009 FIGO staging. (ST-1) HISTOLOGIC GRADE/ADJUVANT TREATMENTg,h,m. Surgically stagede: Stage Ilo,p. Surveillance (ENDO- 9). a (UN- 1) for classification of uterine neoplasms. e The degree of surgical staging to assess disease status depends on preoperative and intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO- C). g Principles of Radiation Therapy for Uterine Neoplasms (UN- A). h Systemic Therapy for Endometrial Carcinoma (ENDO- D). m Initiate EBRT as soon as the vaginal cuff is healed, preferably no later than 12 weeks after surgery. o Consider additional imaging if not previously done. See Principles of Imaging (ENDO- B). p Adverse cervical risk factors including depth of stromal invasion, grade, LVS, and adverse fundal risk factors influencing therapy decisions for stage I disease (ENDO- 4), such as depth of myometrial invasion and LVS, may also impact the choice of adjuvant therapy for stage II disease. q Vaginal brachytherapy is also an option for grade 1 or 2, ≤50% myometrial invasion, no LVS, and microscopic cervical invasion (Harkenrider MM, et al. Int J Radiat Oncol Biol Phys 2018;101:1069- 1077).. Note: All recommendations are category 2A unless otherwise indicated.. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. All staging in guideline is based on 2009 FIGO staging. (ST- 1). CLINICAL FINDINGS (Endometrioid Histology)a. ADJUVANT TREATMENTg,h. Surgically stagede: Stage III, IVr. Systemic therapy . # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. CLINICAL INTRAUTERINE FINDINGS (Endometrioid Histology)a. # FOOTNOTES FOR ENDO-7. a (UN- 1) for classification of uterine neoplasms. e The degre of surgica staging to asess disease status depnds on preoperative and inroperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO- C). 9 Principles of Radiation Therapy for Uterine Neoplasms (UN- A). h Systemic Therapy for Endometrial Carcinoma (ENDO- D). 1 Principles of Imaging (ENDO- B). t Consider omitting imaging for stage IA, grade 1- 2 endometrium- limited carcinoma.. # CRITERIA FOR CONSIDERING FERTILITY-SPARING OPTIONS FOR MANAGEMENT OF ENDOMETRIAL CARCINOMA (All criteria must be met). Well- differentiated (grade 1) endometrioid adenocarcinoma on dilation and curettage (D&C) confirmed by expert pathology review - Disease limited to the endometrium on MRI (preferred) or transvaginal ultrasoundi - Absence of suspicious or metastatic disease on imaging - No contraindications to medical therapy or pregnancy - Patients should undergoing that fertility- sparing option is NOT standard of care for the treatment of endometrial carcinoma. MIS is the preferred approach when technically feasible. See Principles of Evaluation and Surgical Staging (ENDO- C). The degree of surgical staging to assess disease status depends on intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO- C). Principles of Imaging (ENDO- B). See Healthy Lifestyles (HL- 1) and Nutrition and Weight Management (SNWM- 1) in the NCCN Guidelines for Survivorship.. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. SURVEILLANCE. Principles of Radiation Therapy for Uterine Neoplasms (UN- A). Systemic Therapy for Endometrial Carcinoma (ENDO- D). Principles of Imaging (ENDO- B). Patient education should include symptoms of potential recurrence, lifestyle, obesity, exercise, sexual health (including vaginal dilator use, lubricants/moisturizers, and local estrogen and hormone therapy for menopause), smoking cessation, and nutrition counseling. Consider ablative RT for 1- 5 metastatic lesions if the primary cancer has been controlled (category 2B) (Palma DA, et al. Lancet 2019;393:2051- 2058).. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. CLINICAL PRESENTATION. THERAPY FOR RELAPSE. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma: Serous Carcinoma. Disease is not amenable to resection or patient is not suitable for surgery based on comorbidities. dMIS is the preferred approach when technically feasible. See Principles of Evaluation and Surgical Staging (ENDO- C). eThe degre f surgica staging to assss disase sttus depds on inraopative indings. Mutidisciplinary xpertise is recommeded. Se Principles of Evaluation and Surgical Staging (ENDO- C). g Principles of Radiation Therapy for Uterine Neoplasms (UN- A). h Systemic Therapy for Endometrial Carcinoma (ENDO- D). i Principles of Imaging (ENDO- B). cHER2 testing is recommended for advanced or metastatic disease.. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma:Clear Cell Carcinoma. All staging in guideline is based on 2009 FIGO staging. (ST-1). Disease is not amenable to resection or patient is not suitable for surgery based on comorbidities. dMIS is the preferred approach when technically feasible. See Principles of Evaluation and Surgical Staging (ENDO- C).. The degree of surgical staging to assess disease status depends on intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO- C). g Principles of Radiation Therapy for Uterine Neoplasms (UN- A). h Systemic Therapy for Endometrial Carcinoma (ENDO- D). i Principles of Imaging (ENDO- B).. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma: Undifferentiated/Dedifferentiated Carcinoma. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma: Carcinosarcoma. dMIS is the preferred approach when technically feasible. See Principles of Evaluation and Surgical Staging (ENDO- C). eThe degree of surgical staging to assess disease status depends on intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO- C). g Principles of Radiation Therapy for Uterine Neoplasms (UN- A). h Systemic Therapy for Endometrial Carcinoma (ENDO- D). i Principles of Imaging (ENDO- B).. cc HER2 testing is recommended for advanced or metastatic disease. dd Also known as malignant mixed mesodermal tumor or malignant mixed Mullerian tumor. ee Initiation of chemotherapy within 3- 6 weeks postoperatively should be considered. Vaginal brachytherapy can be interdigitated with chemotherapy starting 6 weeks postoperatively. f Consider EBRT if both high- grade epithelial components and sarcoma are dominant (>50% of sarcoma component in uterine tumor) (Matsuo K, et al. Surg Oncol 2018;27:433- 440).. # PRINCIPLES OF PATHOLOGYa,1,2,3. Procedure:. - TH/BSO: Total hysterectomy + bilateral salpingo-oophorectomy- RH: Radical hysterectomy. Pathologic Assessment for Carcinoma (including carcinoma, carcinosarcoma, and neuroendocrine carcinoma):. - Uterus- Hysterectomy type- Specimen integrity (intact, opened, morcellated, other)- Tumor site (endometrium, lower uterine segment, polyp)- Tumor size- Histologic type- Histologic grade (if applicable)- Myometrial invasion (depth of invasion in mm/myometrial thickness in mm)- Cervical stromal involvementb- LVSIc- Other tissue/organ involvement (fallopian tubes, ovaries, vagina, parametrium, peritoneum, omentum, other)- Peritoneal/ascitic fluid cytologyd- Lymph nodes (when resected)- Sentinel lymph nodes (SLNs) should undergo ultrastaging for detection of low-volume metastasis.e- Isolated tumor cells are staged N0(i+) and should not upstage patients, but should be considered in the discussion of adjuvant therapy.- Level of nodal involvement (ie, pelvic, common iliac, para-aortic)- Number of lymph nodes with isolated tumor cells, micrometastasis, and macrometastasis- Thorough gross evaluation of the SLN tissue specimen is recommended to ensure that lymph node tissue is included. This could be performed either by the surgeon (depending on experience/comfort level with gross evaluation) or by seeking an intraoperative pathology consultation.- Morphologic evaluation of endometrial carcinoma to determine histologic type—especially in high-grade cancers—is challenging and issues exist regarding diagnostic reproducibility.4,5. a Principles of Evaluation and Surgical Staging (ENDO-C).. bAdditional inomatio inluding depth of inasion in mm/cvical wall thicknes in mm may be requested by radation oncologist to aid in the decision for EBRT. Pathologis may be asked to quantit LVSI. The current definition of substantial LVSI is 4 (LVSI- involved vessels in at least one hematoxylin and eosin [H&E] slide) for defining clinically relevant LVSI in endometrial cancer (Peters EEM, et al. Int J Gynecol Path 2022;41:220- 226). dAlthough cytology by itelf does not affect FIGO staging, cytology results should stil be obtained because positive cytology is an adverse risk factor. Ultrastaging commonly entails thin serial sectioning of the gross SLN and review of multiple H&E- stained sections with or without cytokeratin immunohistochemistry (IHC) for all blocks of SLN. There is no standard protocol for lymph node ultrastaging. References. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. PRINCIPLES OF MOLECULAR ANALYSIS. - Molecular analysis of endometrial carcinoma has identified four clinically significant molecular subgroups associated with differing clinical prognoses: POLE mutations, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), no specific molecular profile (NSMP), and p53 aberrant.<sup>6,7</sup>- Retrospective analyses indicate that these four molecular subgroups may respond to therapy differently and therefore may require escalation or de-escalation of therapy compared to previous guidelines. Prospective randomized trials are ongoing to determine the role of a molecular profile-guided treatment strategy in the management of high-intermediate-risk and high-risk endometrial carcinomas.- Ancillary studies for POLE mutations (pathogenic mutations in the exonuclease domain), immunohistochemical (IHC) staining for mismatch repair (MMR) or MSI testing, and p53 IHC are recommended to complement morphologic assessment regardless of histologic tumor type.<sup>8</sup>- See Figure 1: Pathology and Genomics in Endometrial Carcinoma (ENDO-A 3 of 4).- Comprehensive molecular profiling is strongly encouraged via an FDA-approved assay, or a validated test performed in a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory, in the initial evaluation of uterine neoplasms.- For tumors that are POLE-mutated, MSI-H, p53 aberrant, or NSMP, clinical trial enrollment is strongly encouraged.- Molecular testing may be performed on the initial biopsy or D&C material or the final hysterectomy specimen.- Evaluation for MMR status is commonly done using IHC. Molecular profiling via NGS panels or MSI PCR assay are acceptable alternatives. - MSI testing is recommended if IHC results are equivocal. - MLH1 loss should be further evaluated for promoter methylation to assess for an epigenetic mechanism. - Genetic counseling for any suspected germline mutation is strongly recommended. - For those who have a strong family history of endometrial and/or colorectal cancer, genetic counseling and testing are recommended regardless of MMR or MLH1 promoter methylation results [see Lynch Syndrome (LS-1) in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric].- HER2 IHC testing (with or without reflex to HER2 fluorescence in situ hybridization [FISH] for equivocal IHC) is recommended for all p53 aberrant carcinomas regardless of histology.<sup>9-12</sup>- Estrogen receptor (ER) and progesterone receptor (PR) testing is recommended in the settings of stage III, stage IV, and recurrent disease.- Consider NTRK gene fusion testing for metastatic or recurrent endometrial carcinoma.- Consider tumor mutational burden (TMB) testing through an FDA-approved assay, or a validated test performed in a CLIA-certified laboratory.<sup>13</sup>. # PRINCIPLES OF MOLECULAR ANALYSIS. FIGURE 1: PATHOLOGY AND GENOMICS IN ENDOMETRIAL CARCINOMA (The decision to use molecular testing/classification depends on the availability of resources and the multidisciplinary team of each center.)<sup>f,g</sup>. Adapted with pemission from Murali R, Delar DF, Bean SM, et al. Eoving roles of histologic ealuation and molecular/genomic profiling in the management of endometrial cancer. J Nat Compr Canc Netw 2018;16:201- 209. 9Diagnostic algorithm for integrated genomic- pathologic classification of endometrial carcinomas.. # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS REFERENCES. American College of Obstetricians and Gynecologists. ACOG practice bulletin, clinical management guidelines for obstetrician- gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol 2005;106:413- 425. 2 Crothers BA Hanik LR, Krishnamurti CG, Turashvili G, et al. Protocol for the examination of specimens from patients with carcinoma and carcinosarcoma of the endometrium. (Version 4.4.0.0) College of American Pathologists 2023. 3 Longacre TA, Broaddus R, Chuang LJ, et al. Template for reporting results of biomarker testing of specimens from patients with carcinoma of the endometrium. Arch Pathol Lab Med 2017;141:1508- 1512. 4 Hoang LN, Kinloch MA, Leo JM, et al. Interobserver agreement in endometrial carcinoma histotype diagnosis varies depending on The Cancer Genome Atlas (TCGA)- based molecular subgroup. Am J Surg Pathol 2017;41:245- 252. 5 Thomas S, Hussein Y, Bandyopadhyay S, et al. Interobserver variability in the diagnosis of uterine high- grade endometrioid carcinoma. Arch Pathol Lab Med 2016;140:836- 843. 6 The Cancer Genome Atlas (TCGA) Research Network; Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013;497:67- 73. 7 Rios- Doria E, Momeni- Boroujeni A, Friedman CF, et al. Integration of clinical sequencing and immunohistochemistry for the molecular classification of endometrial carcinoma. Gynecol Oncol 2023;174:262- 272. 8 Murali R, Delair DF, Bean SM, et al. Evolving roles of histologic evaluation and molecular/genomic profiling in the management of endometrial cancer. J Natl Compr Canc Netw 2018;16:201- 209. 9 Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatin- paclitaxel versus carboplatin- paclitaxel- trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu. J Clin Oncol 2018;36:2044- 2051. 10 Moukarzel LA, Ferrando L, Da Cruz Paula A, et al. The genetic landscape of metaplastic breast cancers and uterine carcinosarcomas. Mol Oncol 2021;15:1024- 1039. 11 Crane E, Naumann W, Tait D, et al. Molecular variations in uterine carcinosarcomas identify therapeutic opportunities. Int J Gynecol Cancer 2020;30:480- 484. 12 Rottmann D, Snir OL, Wu X, et al. HER2 testing of gynecologic carcinosarcomas: tumor stratification for potential targeted therapy. Mod Pathol 2020;33:118- 127. 13 Merino DM, McShane LM, Fabrizio D, et al. Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project. J Immunother Cancer 2020;8:e000147..	None	None	None
bd2bd0b4569b44d781f11867aec45534	NCCN临床实践指南	子宫肿瘤031-060	# PRINCIPLES OF IMAGINGa,1-9. Initial Workup. Non- Fertility- Sparing Treatment. Non- Fertility- Sparing Treatment- Consider chest imaging (chest x- ray). If an abnormality is seen, then chest CT without contrast may be performed.- Consider pelvis MRI to establish the origin of the tumor (endocervical vs. endometrial) and assess local disease extent.- Consider preoperative pelvis ultrasound if uterine size is not clear on exam.- For high- grade carcinoma, b consider chest/abdomen/pelvis CT (preferred) to evaluate for metastatic disease.- For patients who underwent TH with incidental finding of endometrial cancer or whose cancer was incompletely staged (ENDO- 7) with uterine risk factors, c consider chest/abdomen/pelvis CT to evaluate for metastatic disease.- Consider neck/chest/abdomen/pelvis/groin fluorodeoxyglucose (FDG)- PET/CT if metastasis is suspected in select patients.- Other initial imaging should be based on symptomatology and clinical concern for metastatic disease. d Fertility- Sparing Treatment- Pelvis MRI (preferred) to exclude myoinvasion and assess local disease extent; pelvic transvaginal ultrasound if MRI is contraindicated or unavailable.- Consider chest imaging (chest x- ray). If an abnormality is seen, then chest CT without contrast may be performed.- Consider neck/chest/abdomen/pelvis/groin FDG- PET/CT if metastasis is suspected in select patients.- Other imaging should be based on symptomatology and clinical concern for metastatic disease. e. Follow-up/Surveillance. Non- Fertility- Sparing Treatment- Imaging should be guided by patient symptoms, risk assessment, and clinical concern for recurrent or metastatic disease. e- Fertility- Sparing Treatment- Repeat pelvis MRI (preferred) for patients with persistent endometrial carcinoma after 6- 9 months of ineffective treatment, especially if considering further fertility- sparing approaches.- Other imaging should be based on symptomatology and clinical concern for metastatic disease. e- Consider pelvis ultrasound surveillance for patients with ovarian preservation.. Suspected Recurrence or Metastasis. Abdomen/pelvis CT and/or chest CT is recommended based on symptoms or physical exam findings. e Consider whole body FDG- PET/CT and/or abdomen/pelvis MRI in select patients as clinically indicated.. MRI is peomed wth and wthout cotast and is peomed wth cotast uness contraindicated. Contrast is not requred for sreing chest CT. bHigh- grade endometrial carcinoma includes: poorly diferentiated endometrioid, serous, clear cell, undifferentiated carcinoma, and carcinosarcoma. Uterine risk factors identified post TH include: high- grade carcinomas (above criteria), myoinvasion . # PRINCIPLES OF IMAGING REFERENCES. 1Salani R, Khanna N, Frimer M, et al. An update on post- treatment survellance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations. Gynecol Oncol 2017;146:3- 10. 2Haldorsen IS, Salvesen HB. What is the best preoperative imaging for endometrial cancer? Curr Oncol Rep 2016;18:25. 3Eilt L, Reade CJ. Recommendations for follow- up care for gynecologic cancer survivors. Obstet Gynecol 2015;126:1207- 1214. 4Vargas HA, Akin O, Zheng J, et al. The value of MR imaging when the site of uterine cancer origin is uncertain. Radiology 2011;258:785- 792. 5Sohaia, Hgtho, Meri al. Rrt dmetril cacer patrs f rrt dse ad sment f prosis. R207;6228- 34 discussion 35- 36. 6Hensly ML, Barre BA, Baann K, et al. Gecologic Cancer InteGroup (GCG) consesus revie: uterine and ovarian leomyosarcomas. Int J Gynecol Cancer 2014;24(9 Suppl 3):S61- S66. 7Lakman Y, Katz S, Gdman DA, et al. Diastic permance of computed tomography for preoperative staging of patients with non- endometrioid carcinomas of the uterine corpus. Ann Surg Oncol 2016;23:1271- 1278. 8Colombo N, Creutzberg C, Amt et al; ESMO- ESGO- ESTRO Endometrial Consensus Conference Working Group. ESMO- ESGO- ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment and follow- up. Ann Oncol 2016;27:16- 41. 9 Sal E, Rockall AG, Freeman SJ, et al. The added role of MR imaging in treatment stratification of patients with gynecologic malignancies: what the radiologist needs to know. Radiology 2013;266:717- 740.. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. PRINCIPLES OF EVALUATION AND SURGICAL STAGING. Principles of Surgical Staging for Endometrial Cancer1- 15. - TH/BSO and lymph node assessment is the primary treatment for apparent uterine-confined endometrial carcinoma, unless patients desire (and are candidates for) fertility-sparing options (ENDO-8). Select patients with metastatic endometrial carcinoma are also candidates for hysterectomy (Principles of Pathology and Molecular Analysis [ENDO-A]).. - Endometrial carcinoma should be removed en bloc to optimize outcomes; intraperitoneal morcellation or tumor fragmentation should be avoided.. - TH/BSO and lymph node assessment may be performed by any surgical route (eg, laparoscopic, robotic, vaginal, abdominal), although the standard in those with apparent uterine-confined disease is to perform the procedure via a minimally invasive approach. Randomized trials, a Cochrane Database Systematic Review, and population-based surgical studies support that minimally invasive techniques are preferred in this setting due to a lower rate of surgical site infection, transfusion, venous thromboembolism, decreased hospital stay, and lower cost of care, without compromise in oncologic outcome.. - The lymph node assessment includes evaluation of the nodal basins that drain the uterus, and often comprises either SLN mapping and resection of sentinel nodes or a pelvic nodal dissection with or without para-aortic nodal dissection. This continues to be an important aspect of surgical staging in patients with uterine-confined endometrial carcinoma, as the procedure provides important prognostic information that may alter treatment decisions.. - SLN mapping is preferred (see pages 2-6 of ENDO-C).. - Pelvic lymph nodes from the external iliac, internal iliac, obturator, and common iliac nodes are frequently removed for staging purposes.. - Para-aortic nodal evaluation from the inframesenteric and infrarenal regions may also be utilized for staging in patients with high-risk tumors such as deeply invasive lesions, high-grade histology, and tumors of serous carcinoma, clear cell carcinoma, or carcinosarcoma.. - Excision of suspicious or enlarged lymph nodes in the pelvic or aortic regions is important to exclude nodal metastasis.. - Some patients may not be candidates for lymph node dissection.. - Visual evaluation of the peritoneal, diaphragmatic, and serosal surfaces with biopsy of any suspicious lesions is important to exclude extrauterine disease.. - While peritoneal cytology does not impact staging, FIGO and AJCC nonetheless recommend that surgeons continue to obtain this during the TH/BSO.. - Cytology results should not be taken in isolation to guide adjuvant therapy.. - Omental biopsy is commonly performed in those with serous carcinoma, clear cell carcinoma, or carcinosarcoma histologies.. - For stage II disease, TH/BSO is the standard procedure. RH should only be performed if needed to obtain negative margins.. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. PRINCIPLES OF EVALUATION AND SURGICAL STAGING WHEN SLN MAPPING IS USED. Principles of Sentinel Lymph Node(s) Mapping for Endometrial Cancer Staging10- 26. Prospective and retrospective studies demonstrate that compared to systemic lymphadenectomy (LND), SLN mapping with ultrastaging may increase the detection of lymph node metastasis with low false- negative rates in patients with apparent uterine- confined disease.10- 23,26 If SLN mapping is considered, the expertise of the surgeon and attention to technical detail is critical. Recent evidence indicates that SLN mapping may also be used in high- risk histologies (ie, serous carcinoma, clear cell carcinoma, carcinosarcoma).24,25. SLN mapping can be considered for the surgical staging of apparent uterine- confined malignancy when there is no metastasis demonstrated by imaging studies or no obvious extrauterine disease at exploration.. A cervical injection with dye has emerged as a useful and validated technique for identification of lymph nodes that are at high risk for metastases (ie, SLN in patients with early- stage endometrial cancer10,12).. Superficial . Injection into the uterine cervix provides excellent dye penetration to the uterine vessels and main uterine lymphatic trunks that condense in the parametria and appear in the broad ligament leading to pelvic and occasionally paraaortic sentinel nodes.. The uterine body lymphatic trunks commonly cross over the obliterated umbilical artery with the most common location of pelvic SLN being medial to the external iliac, ventral to the hypogastric, or in the superior part of the obturator region (see Figure 2 on ENDO- C 4 of 6).. A less common location is usually seen when the lymphatic trunks do not cross over the obliterated umbilical and move cephalad following the mesoureter; in these cases, the SLN is usually seen in the common iliac presacral region (see Figure 3 on ENDO- C 4 of 6). Indocyanine green (ICG) is the preferred imaging dye for SLN mapping.20,26,27. The radiolabeled colloid most commonly injected into the cervix is technetium- 99m (99mTC); colored dyes are available in a variety of forms (Isosulfan Blue . Low- volume nodal metastasis to SLN detected only by enhanced pathologic ultrastaging is another potential value to staging with SLN.10,21- 23. The key point to successful SLN mapping is adherence to the SLN algorithm, which requires the performance of a side- specific nodal dissection in cases of failed mapping and removal of any suspicious or grossly enlarged nodes regardless of mapping (see Figure 4 on ENDO- C 5 of 6).10- 12,23,25. For cases of failed SLN mapping, reinjection of the cervix may be considered. An additional 1 mL in the non- detected side can be infiltrated in the superficial cervical area.. If there is no mapping on a hemi- pelvis, then a side- specific LND is recommended. However, if expert gynecologic pathology is available, a frozen section to assess myoinvasion can be obtained and LND can be avoided if no myoinvasion or cervical invasion is identified.. SLN identification should always be done prior to hysterectomy, except in cases where a bulky uterus must be removed to allow access to iliac vessels and lymph nodes.. # PRINCIPLES OF EVALUATION AND SURGICAL STAGING WHEN SLN MAPPING IS USED. Principles of Sentinel Lymph Nodes) Mapping for Endometrial Cancer Staging (continued)10- 26. SLNs are processed using ultrastaging, which typically includes two components: serial sectioning with review of multiple hematoxylin and eosin (H&E)- stained slides with or without cytokeratin IHC staining.. Protocols of serial sectioning and ultrastaging vary among gynecologic pathologists. Comparison of two different ultrastaging protocols in endometrial cancer SLN did not reveal significant advantages when serial H&E sectioning and IHC staining were used.29. Recent data highlight the potential importance of ultrastaging for detection of low- volume metastasis. In general, SLN mapping allows for increased intraoperative surgical precision to identify nodes more likely to harbor metastasis combined with enhanced pathology protocols, which has been shown to increase the detection of nodal metastasis, which may alter stage and adjuvant therapy recommendations. Lymph nodes with isolated tumor cells should be clearly reported. In endometrial cancer, when isolated tumor cells are detected in the absence of macrometastasis and micrometastasis, the lymph node stage is designated pN0(i+).30. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. PRINCIPLES OF EVALUATION AND SURGICAL STAGING WHEN SLN MAPPING IS USED. Figure 1: Common cervical injection sites for mapping uterine cancera. Figure 3: Less common location of SLNs (green, arrow) usually seen when lymphatic trunks are not crossing over the umbilical ligament but following the mesoureter cephalad to common iliac and presacral region<sup>a</sup>. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. PRINCIPLES OF EVALUATION AND SURGICAL STAGING WHEN SLN MAPPING IS USED. Figure 4: The SLN algorithm for surgical staging of endometrial cancer<sup>b</sup>. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Endometrial Carcinoma. NCCN Guidelines Index Table of Contents Discussion. 1 American College of Obstetricians and Gynecologists. ACOG practice bulletin, clinical management guidelines for obstetrician- gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol. 2005;106:413- 425. 2Bakkum- Gamez JN, Gonzalez- Bosquet J, Laack NN, et al. Current issues in the management of endometrial cancer. Mayo Clin Proc 2008;83:97- 112. 3Edge SB, Byrd DR, Compton CC. AJCC Cancer Staging Manual, 7th edition. New York: Springer; 2010. 4Walker JL, Piedmonte MR, Spirtos NM, et al. Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J Clin Oncol 2009;27:5331- 5336. 5Kornblith AB, Huang HQ, Walker JL, et al. Quality of life of patients with endometrial cancer undergoing laparoscopic international federation of gynecology and obstetrics staging compared with laparotomy: a Gynecologic Oncology Group study. J Clin Oncol 2009;27:5337- 5342. 6Galaal K, Bryant A, Fisher AD, et al. Laparoscopy versus laparotomy for the management of early stage endometrial cancer. Cochrane Database Syst Rev 2012;9:CD006655. 7Scalici J, Laughlin BB, Finan MA, et al. The trend towards minimally invasive surgery (MIS) for endometrial cancer: an ACS NSQIP evaluation of surgical outcomes. Gynecol Oncol 2015;136:512- 515. 8Fader AN, Weise RM, Sinno AK, et al. Utilization of minimally invasive surgery in endometrial cancer care: a quality and cost disparity. Obstet Gynecol 2016;127:91- 100. 9Mannschreck D, Matsuno RK, Moriarty JR, et al. Disparities in surgical care among women with endometrial cancer. Obstet Gynecol 2016;128:526- 534. 10Abu- Rustum NR, Khoury- Collado F, Pandit- Taskar N, et al. Sentinel lymph node mapping for grade 1 endometrial cancer: is it the answer to the surgical staging dilemma? Gynecol Oncol 2009;113:163- 169. 11 Khoury- Collado F, Glaser GE, Zivanovic O, et al. Improving sentinel lymph node detection rates in endometrial cancer: how many cases are needed? Gynecol Oncol 2009;115:453- 455.. PRINCIPLES OF EVALUATION AND SURGICAL STAGING REFERENCES 12 Khoury- Collado F, Murray MP, Hensley ML, et al. Sentinel lymph node mapping for endometrial cancer improves the detection of metastatic disease to regional lymph nodes. Gynecol Oncol 2011;122:251- 254. 13 Frimer M, Khoury- Collado F, Murray MP, et al. Micrometastasis of endometrial cancer to sentinel lymph nodes: is it an artifact of uterine manipulation? Gynecol Oncol 2010;119:496- 499. 14 Leitao MM Jr, Khoury- Collado F, Gardner G, et al. Impact of incorporating an algorithm that utilizes sentinel lymph node mapping during minimally invasive procedures on the detection of stage IIIC endometrial cancer. Gynecol Oncol 2013;129:38- 41. 15 Holloway RW, Abu- Rustum NR, Backes FJ, et al. Sentinel lymph node mapping and staging in endometrial cancer: A society of gynecologic oncology literature review with consensus recommendations. Gynecol Oncol 2017;146:405- 415. 16 Kim CH, Soslow RA, Park KJ, et al. Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrial cancer staging. Int J Gynecol Cancer 2013;33:964- 970. 17 Barlin JN, Khoury- Collado F, Kim CH, et al. The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: Beyond removal of blue nodes. Gynecol Oncol 2012;125:531- 535. 18 Vidal F, Leguevaque P, Morton S, et al. Evaluation of the sentinel lymph node algorithm with blue dye labeling for early- stage endometrial cancer in a multicentric setting. Int J Gynecol Cancer 2013;23:1327- 1243. 19 Abu- Rustum NR. The Increasing credibility of sentinel lymph node mapping in endometrial cancer. Ann Surg Oncol 2013;20:353- 354. 20 Sinno AK, Fader AN, Roche KL, et al. A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer. Gynecol Oncol 2014;134:281- 286. 21 Holloway RW, Gupta S, Stavitski NM, et al. Sentinel lymph node mapping with staging lymphadenectomy for patients with endometrial cancer increases the detection of metastasis. Gynecol Oncol 2016;141:206- 210.. 22 Paley P, Veljovich DS, Press JZ, et al. A prospective investigation of fluorescence imaging to detect sentinel lymph nodes at robotic- assisted endometrial cancer staging. Am J Obstet Gynecol 2016;215:117. c1- 7. 23 Sinno AK, Peijnenberg E, Fader AN, et al. Reducing overtreatment: a comparison of lymph node assessment strategies for endometrial cancer. Gynecol Oncol 2016; 143:281- 286. 24 Schiavone MB, Zivanovic O, Zhou Q, et al. Survival of patients with uterine carcinosarcoma undergoing sentinel lymph node mapping. Ann Surg Oncol 2016;23:196- 202. 25 Soliman PT, Westin SN, Dioun S, et al. A prospective validation study of sentinel lymph node mapping for highrisk endometrial cancer. Gynecol Oncol 2017;146:234- 239. 26 Rossi EC, Kowalki LD, Scalici J, et al. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. Lancet Oncol 2017;18:384- 392. 27 Frumovitz M, Plante M, Lee PS, et al. Near- infrared fluorescence for detection of sentinel lymph nodes in women with cervical and uterine cancers (FILM): a randomised, phase 3, multicentre, non- inferiority trial. Lancet Oncol 2018;19:1394- 403. 28 Cormier B, Rozenholc AT, Gottlieb W, et al. Sentinel lymph node procedure in endometrial cancer: A systematic review and proposal for standardization of future research. Gynecol Oncol 2015;138:478- 485. 29 Euscher E, Sui D, Soliman P, et al. Ultrastaging of sentinel lymph nodes in endometrial carcinoma according to use of 2 different methods. Int J Gynecol Pathol 2018;37:242- 251. 30 Olawaiye AB, Mutch DG. Lymphnode staging update in the American Joint Committee on Cancer 8th Edition cancer staging manual. Gynecol Oncol 2018;150:7- 8.. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. An FDA- approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. For stage II or IVA with measurable disease post surgery or stage IVB with or without measurable disease. For patients not meeting the eligibility criteria for NRG- CX9108, carboplatin/paclitaxel + pembrolizumab should be considered for stage III- IV dMMR tumors (Van Gorp T, et al. Ann Oncol. Published online August 23, 2024). NCCN Guidelines for Management of Immunotherapy- Related Toxicities. Checkpoint inhibitors and/or monoclonal antibodies included in this regimen may be continued as maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules. For adult patients with primary advanced endometrial carcinoma: stage IIIA, IIIB, or IIIC1 with measurable disease post surgery, stage IIIC1 with carcinosarcoma, clear- cell, serous, or mixed histology regardless of the presence of measurable disease, and stage IIIC2 or stage IV regardless of the presence of measurable disease. For stage III with measurable disease post surgery and stage IV with or without measurable disease. For patients who have not received prior trastuzumab therapy.. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. Footnotes on ENDO-D 2A of 5. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. SYSTEMIC THERAPY FOR ENDOMETRIAL CARCINOMA FOOTNOTES FOR ENDO-D 2 OF 5. An FDA- approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. NCCN Guidelines for Management of Immunotherapy- Related Toxicities. Checkpoint initors and/or monclal antiodies inluded in this regmen may be coninued as maintenance thrapy. Refr to the original study protocol for maintenance therapy dosing schedules. 9 For patients who have not received prior trastuzumab therapy. h Cisplatin, carboplatin, iposomal doxorubicin, paclitaxel, and docetaxel may cause drug reactions (see NCCN Guidelines for Ovarian Cancer- Management of Drug Reactions [Ov- D]). Chemotherap regimens can be used for all carcinoma histologies. Carcinosarcomas are now considered and treated as high- grade carcinomas. These agents can be used as second- line or subsequent therapy as clinically appropriate. k For adult patients with recurrent endometrial carcinoma with or without measurable disease. ' Carbotatin/paclitaxel is preferred only for patients who have not received any prior systemic therapy. Can be considered as an option under the "Other Recommended Regimens" list if or when re- use is appropriate in the first- line setting for recurrent disease. m Docetaxel may be considered for patients in whom paclitaxel is contraindicated. n NCCN recommends TMB- H testing if not previously done. Pembrolizumab is indicated for patients with unresectable or metastatic tumors with TMB- H [>10 mutations/ megabase (mut/Mb)], whose disease has progressed following prior treatment and who have no satisfactory alternative treatment options. o For recurrent endometrial cancer, NCCN recommends MSI- H or dMMR testing if not previously done. p The cisplatin/doxorubicin/paclitaxel regimen is not widely used because of concerns about toxicity. Albumin- bound paclitaxel is a reasonable substitute for patients with a hypersensitivity to paclitaxel. If a skin test is done, and is positive, then the patient requires desensitization to paclitaxel. Albumin- bound paclitaxel is not a reasonable substitute for paclitaxel if the patient's skin test is positive. Bevacizumab may be considered for use in patients whose disease has progressed on prior cytotoxic chemotherapy. s Nivolumab and hyaluronidase- nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase- nvhy has different dosing and administration instructions compared to IV nivolumab. t NTRK- positive tumors that are naive to prior NTRK- targeted therapy or have progressed on prior NTRK therapy.. # NCCN Guidelines Version 2.2025 Endometrial Carcinoma. SYSTEMIC THERAPY FOR ENDOMETRIAL CARCINOMA. Hormonal therapy is typically used for lower- grade endometrioid histologies, preferably in patients with small tumor volume or an indolent growth pace.. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Endometrial Carcinoma. SYSTEMIC THERAPY FOR ENDOMETRIAL CARCINOMA - REFERENCES. 1 de Boer SM, Powell ME, Mileshkin L, et al. Toxicity and quality of life after adjuvant chemoradiotherapy versus radiotherapy alone for women with high- risk endometrial cancer (PORTEC- 3): an open- label, multicentre, randomised, phase 3 trial. Lancet Oncol 2016;17:1114- 1126. 2 Greven K, Winter K, Underhill K, et al. Final analysis of RTOG 9708: adjuvant postoperative irradiation combined with cisplatin/paclitaxel chemotherapy following surgery for patients with high- risk endometrial cancer. Gynecol Oncol 2006;103:155- 159. 3 Lorvidhaya V, Chitapanaarux I, Sangruchi S, et al. Concurrent mitomycin C, 5- fluorouracil, and radiotherapy in the treatment of locally advanced carcinoma of the cervix: a randomized trial. Int J Radiat Oncol Biol Phys 2003;55:1226- 1232. 4 Pattaranutaporn P, Thirapakawong C, Chansilpa Y, et al. Phase II study of concurrent gemcitabine and radiotherapy in locally advanced stage IIIB cervical carcinoma. Gynecol Oncol 2001;81:404- 407. 5 Candelaria M, Garcia- Arias A, Cetina L, A Dueñas- Gonzalez. Radiosensitizers in cervical cancer. Cisplatin and beyond. Radiat Oncol 2006;1:15. 6 Cerrotta A, Gardan G, Cavina R et al. Concurrent radiotherapy and weekly paclitaxel for locally advanced or recurrent squamous cell carcinoma of the uterine cervix. A pilot study with intensification of dose. Eur J Gynaecol Oncol 2002;23:115- 119. 7 Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med 2023;388:2159- 2170. 8 Van Gorp T, Cibula D, Lv W, et al. ENGOT- en11/GOG- 3053/KEYNOTE- B21: A randomised, double- blind, phase III study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high- risk endometrial cancer. Ann Oncol 2024;35:968- 980. 9 Powell MA, Bjorge L, Willmott L, et al. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin- paclitaxel in the randomized ENGOT- EN6/GOG- 3031/RUBY trial. Ann Oncol 2024;35:728- 738. 10 Westin SN, Moore K, Chon HS, et al. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first- line treatment for advanced endometrial cancer: The phase III DUO- E trial. J Clin Oncol 2024;42:283- 299.. 11 Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatin- paclitaxel compared with carboplatin- paclitaxel- trastuzumab in advanced (stage III- IV) or recurrent uterine serous carcinomas that overexpress Her2/ Neu (NCT01367002): Updated overall survival analysis. Clin Cancer Res 2020;26:3928- 3935. 12 Rose PG, Ali S, Moslemi- Kebria M, Simpkins F. Paclitaxel, carboplatin, and bevacizumab in advanced and recurrent endometrial carcinoma. Int J Gynecol Cancer 2017;27:452- 458. 13 Aghajanian C, Filiaci V, Dizon DS, et al. A phase II study of frontline paclitaxel/ carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus, or ixabepilone/ carboplatin/bevacizumab in advanced/recurrent endometrial cancer. Gynecol Oncol 2018;150:274- 281. 14 Miller DS, Filiaci VL, Mannel RS, et al. Carboplatin and paclitaxel for advanced endometrial cancer: Final overall survival and adverse event analysis of a phase I trial (NRG Oncology/GOG0209). J Clin Oncol 2020;38:3841- 3850. 15 Makker V, Colombo N, Casado Herraez A, et al. Lenvatinib plus pembrolizumab in previously treated advanced endometrial cancer: updated efficacy and safety from the randomized phase III Study 309/KEYNOTE- 775. J Clin Oncol 2023;41:2904- 2910. 16 Marth C, Moore RG, Bidzinski M, et al. First- Line Lenvatinib Plus Pembrolizumab Versus Chemotherapy for Advanced Endometrial Cancer: A Randomized, Open- Label, Phase III Trial. Journal of Clinical Oncology 2024;0:JCO- 24- 01326. 17 Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open- label, phase 2 KEYNOTE- 158 study. Lancet Oncol 2020;21:1353- 1365. 18 O'Malley DM, Bariani GM, Cassier PA, et al. Pembrolizumab in patients with microsatellite instability- high advanced endometrial cancer: Results from the KEYNOTE- 158 study. J Clin Oncol 2022;40:752- 761. 19 Oaknin A, Tinker AV, Gilbert L, et al. Clinical activity and safety of the anti- programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair- deficient endometrial cancer a nonrandomized phase 1 clinical trial. JAMA Oncol 2020;6:1766- 1772.. # SYSTEMIC THERAPY FOR ENDOMETRIAL CARCINOMA - REFERENCES. 20 Homesley HD, Filiaci V, Gibbons SK, et al. A randomized phase I trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: A Gynecologic Oncology Group study. Gynecol Oncol 2009;112:543- 552. 21 Brown J, Smith JA, Ramondetta L, et al. Combination of gemcitabine and cisplatin is highly active in women with endometrial carcinoma: Results of a prospective phase 2 trial. Cancer 2010;116:4973- 4979. 22 Picard M, Pur L, Caiado J, et al. Risk stratification and skin testing to guide re- exposure in taxane- induced hypersensitivity reactions. J Allergy Clin Immunol 2016;137:1154- 1164. 23 Aghajanian C, Sill MW, Darcy KM, et al. Phase I trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol 2011;29:2259- 2265. 24 Oza AM, Elit L, Tsao MS, et al. Phase I study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol 2011;29:3278- 3285. 25 Vergote I, Powell MA, Teneriello MG, et al. Second- line lenvatinib in patients with recurrent endometrial cancer. Gynecol Oncol 2020;156:575- 582. 26 Grisham RN, Adaniel C, Hyman DM, et al. Gemcitabine for advanced endometrial cancer: a retrospective study of the Memorial Sloan- Kettering Cancer Center experience. Int J Gynecol Cancer 2012;22:807- 11. 27 Homesley HD, Filiaci V, Markman M, et al. Phase I trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group Study. J Clin Oncol 2007;25:526- 531. 28 Azad NS, Gray RJ, Overman MJ, et al. Nivolumab is effective in mismatch repair- deficient noncolorectal cancers: Results from Arm Z1D- A Subprotocol of the NCI- MATCH (EAY131) study. J Clin Oncol 2020;38:214- 222. 29 Merio- Bornstam F, Makker V, Oakinin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2- expressing solid tumors: DESTINYPanTumor02 phase II trial. J Clin Oncol 2024;42:47- 58. 30 Solomon BJ, Drilon A, Lin JJ, et al. 1372P Repotrectinib in patients (pts) with NTRK fusion- positive (NTRK+) advanced solid tumors, including NSCLC: Update from the phase I/II TRIDENT- 1 trial [abstract]. Ann Oncol 2023;34:S787- S788.. # aPreoperative imaging and biopsy may help to identify uterine sarcomas, although biopsy sensitivity is less than for endometrial cancer. If there is suspicion of malignant mesenchymal sarcoma, fragmentation/morcellation should be avoided. b Principles of Pathology and Molecular Analysis (UTSARC- A). c Principles of Imaging (UTSARC- B). d For incidental finding of uterine sarcoma after TH/BSO or fragmented specimen: recommend imaging and consider additional surgical resection on an individual basis.. e Disease is not amenable to resection, or patient is not suitable for surgery based on comorbidities. f Oophorectomy is individualized for patients of reproductive age. Favor BSO if ER/PR positive. g Morcellation should be avoided. h Systemic Therapy (UTSARC- C). i Principles of Radiation Therapy for Uterine Neoplasms (UN- A).. # # NCCN Guidelines Version 2.2025 Uterine Sarcoma. PATHOLOGIC FINDINGS/ HISTOLOGIC GRADE. # NCCN Guidelines Version 2.2025 Uterine Sarcoma. SURVEILLANCE. THERAPY FOR RELAPSE. H&P exam every 3- 4 mo (consider every 6 months for low- grade, early- stage sarcomas) for 2- 3 y, then every 6- 12 mo Imaging Clinical evaluation and management of potential long- term and late effects of treatment (also see Principles of Gynecologic Survivorship (UN- B), NCCN Guidelines for Survivorship, and NCCN Guidelines for Smoking Cessation). # RECURRENCE. THERAPY FOR RELAPSE. # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS<sup>a,1,2</sup>. Procedure: - TH ± BSO: Total hysterectomy ± bilateral salpingo- oophorectomy and en bloc resection of tumor. Pathologic Assessment for Sarcoma (including LMS, adenosarcoma, ESS, and UUS):. - Expert gynecologic pathology review is highly recommended- Uterus. Hysterectomy type Specimen integrity (intact, opened, morcellated, other) Tumor size Myometrial invasion (for adenosarcoma only) Histologic type Histologic grade (for adenosarcoma only) LVS1. Other tissue/organ involvement (fallopian tubes, ovaries, vagina, parametrium, peritoneum, omentum, other) Peritoneal/ascitic fluid cytology (if collected)- Lymph nodes (when resected)- Level of nodal involvement<sup>b</sup> (ie, pelvic, common iliac, para- aortic)- Number of lymph nodes with metastasis. Molecular Analysis for Sarcoma:. - Recommend molecular profiling in gynecologic mesenchymal malignancies for accurate classification<sup>3</sup> (Table 1 [UTSARC-A 2 of 8]).- Comprehensive genomic profiling in setting of metastatic disease as determined by an FDA-approved assay, or a validated test performed in a CLIA-certified laboratory, is informative for predicting rare pan-tumor targeted therapy opportunities and should include at least NTRK, MSI, RET-fusion, and TMB. Preferred on tissue; if tissue is not available, blood-based assays may be considered.. Footnotes. a Also see Principles of Evaluation and Surgical Staging (ENDO- C). b Routine node dissection is not required in the absence of clinical suspicion of nodal involvement.. References. American College of Obstetricians and Gynecologists. ACOG practice bulletin, clinical management guidelines for obstetrician- gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol 2005;106:413- 425. 2 Krishnamurti U and Crothers BA. Protocol for the examination of specimens from patients with primary sarcoma of the uterus. College of American Pathologists 2021. REL_CAPCP.pdf 3 Parra- Herran C, Howitt BE. Uterine mesenchymal tumors: Update on classification, staging, and molecular features. Surg Pathol Clin 2019;12:363- 396.. Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS. Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS. There are a number of sarcomas reported as low- grade ESS harboring novel fusions and a subset behave more aggressively than typical low- grade ESS; data are evolving in this area for optimal classification.. Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS. Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS. Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS. Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS. 8q13 amplification and copy number gains of MYBL1 in a subset; NCOA2/3 fusions in a subset; rare FGFR2, KMT2C, DICER1, ATRX, and TP53 mutations; MDM2/CDK4 and TERT amplifications.. Note: All recommendations are category 2A unless otherwise indicated.. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Uterine Sarcoma. PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS REFERENCES. 1Chiang S, Samore W, Zhang L, et al. PGR gene fusions identify a molecular subset of uterine epithelioid leiomyosarcoma with rhabdoid features. Am J Surg Pathol 2016;43:810- 818. 2 Chapel DB, Nucci MR, Quade BJ, Parra- Herran C. Epithelioid leiomyosarcoma of the uterus: Modern outcome- based appraisal of diagnostic criteria in a large institutional series. Am J Surg Pathol 2022;46:464- 475. 3 Arias- Stella JA 3rd, Benayed R, Oliva E, et al. Novel PLAG1 gene rearrangement distinguishes a subset of uterine myxoid leiomyosarcoma from other uterine myxoid mesenchymal tumors. Am J Surg Pathol 2019;43:382- 388. 4 Yoon JY, Mariño- Enriquez A, Stickle N, et al. Myxoid smooth muscle neoplasia of the uterus: comprehensive analysis by next- generation sequencing and nucleic acid hybridization. Mod Pathol 2019;32:1688- 1697. 5 Lee CH, Ali RH, Rouzbanman M, et al. Cyclin D1 as a diagnostic immunomarker for endometrial stromal sarcoma with YWHAE- FAM22 rearrangement. Am J Surg Pathol 2012;36:1562- 1570. 6 Lee CH, Mariño- Enriquez A, Ou W, et al. The clinicopathologic features of YWHAE- FAM22 endometrial stromal sarcomas: a histologically high- grade and clinically aggressive tumor. Am J Surg Pathol 2012;36:641- 653. 7 Lee CH, Ou WB, Mariño- Enriquez A, et al. 14- 3- 3 fusion oncogenes in high- grade endometrial stromal sarcoma. Proc Natl Acad Sci U S A 2012;109:929- 934. 8Chiang S, Lee CH, Stewart CJR, et al. BCOR is a robust diagnostic immunohistochemical marker of genetically diverse high- grade endometrial stromal sarcoma, including tumors exhibiting variant morphology. Mod Pathol 2017;30:1251- 1261. 9Hoang LN, Aneja A, Conlon N, et al. Novel high- grade endometrial stromal sarcoma: a morphologic mimicker of myxoid leiomyosarcoma. Am J Surg Pathol 2017;41:12- 24. 10Juckett LT, Lin DI, Madison R, et al. A pan- cancer landscape analysis reveals a subset of endometrial stromal and pediatric tumors defined by internal tandem duplications of BCOR. Oncology 2019;96:101- 109.. 11 Lewis N, Soslow RA, Delair DP, et al. ZC3H7B- BCOR high- grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity. Mod Pathol 2018;31:674- 684. 12Marino- Enriquez A, Lauria A, Przybyl J, et al. BCOR internal tandem duplication in high- grade uterine sarcomas. Am J Surg Pathol 2018;42:335- 341. 13 Cotzia P, Benayed R, Mulianey K, et al. Undifferentiated uterine sarcomas represent underrecognized high- grade endometrial stromal sarcomas. Am J Surg Pathol 2019;43:662- 669. 14 Binzer- Panchal A, Hardell E, Viklund B, et al. Integrated molecular analysis of undifferentiated uterine sarcomas reveals clinically relevant molecular subtypes. Clin Cancer Res 2019;25:2155- 2165. 15Kolin DL,Dong F, Baltay M, et al. SMARCA4- deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus): a clinicopathologic entity distinct from undifferentiated carcinoma. Mod Pathol 2018;31:1442- 1456. 16Kolin DL, Quick CM, Dong F, et al. SMARCA4- deficient uterine sarcoma and undifferentiated endometrial carcinoma are distinct clinicopathologic entities. Am J Surg Pathol 2020;44:263- 270. 17 Bennett JA, Braga AC, Pinto A, et al. Uterine PEComas: A morphologic, immunohistochemical, and molecular analysis of 32 tumors. Am J Surg Pathol 2018;42:1370- 1383. 18 Folpe AL, Mentzel T, Lehri H- A, et al. Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature. Am J Surg Pathol 2005;29:1558- 1575. 19 Schoolmeester JK, Howitt BE, Hirsch MS, et al. Perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: clinicopathologic and immunohistochemical characterization of 16 cases. Am J Surg Pathol 2014;38:176- 188. 20Chiang S, Vasudevaraja V, Serrano J, et al. TSC2- mutant uterine sarcomas with JAZF1- SUZ12 fusions demonstrate hybrid features of endometrial stromal sarcoma and PEComa and are responsive to mTOR inhibition. Mod Pathol 2022;35:117- 127.. 21WHO Classification of Tumours Editorial Board. Female Genital Tumours. Lyon (France): International Agency for Research on Cancer; 2020. WHO Classification of Tumours, 5th ed.; vol. 4. 22 Dickson BC, Childs TJ, Colgan TJ, et al. Uterine tumor resembling ovarian sex cord tumor: A distinct entity characterized by recurrent NCOA2/3 gene fusions. Am J Surg Pathol 2019;43:178- 186. 23 Goebel EA, Hernandez Bonilla S, Dong F, et al. Uterine tumor resembling ovarian sex cord tumor (UTROSCT): A morphologic and molecular study of 26 cases confirms recurrent NCOA1- 3 rearrangement. Am J Surg Pathol 2020;44:30- 42. 24 Lee CH, Kao YC, Lee WR, et al. Clinicopathologic characterization of GREB1- rearranged uterine sarcomas with variable sex- cord differentiation. Am J Surg Pathol 2019;43:928- 942. 25 Leiner J, Le Loarer F. The current landscape of rhabdomyosarcomas: an update. Virchows Arch 2020;476:97- 108. 26 Pinto A, Kahn RM, Rosenberg AE, et al. Uterine rhabdomyosarcoma in adults. Hum Pathol 2018;74:122- 128. 27 de Kock L, Yoon JY, Apellaniz- Ruiz M, et al. Significantly greater prevalence of DICER1 alterations in uterine embryonal rhabdomyosarcoma compared to adenosarcoma. Mod Pathol 2020;33:1207- 1219. 28 Hodgson A, Amemiya Y, Seth A, et al. High- grade Mullerian adenosarcoma: genomic and clinicopathologic characterization of a distinct neoplasm with prevalent TP53 pathway alterations and aggressive behavior. Am J Surg Pathol 2017;41:1513- 1522. 29 Lee JC, Lu TP, Changou CA, et al. Genomewide copy number analysis of Mullerian adenosarcoma identified chromosomal instability in the aggressive subgroup. Mod Pathol 2016;29:1070- 1082. 30 Howitt BE, Sholl LM, Dal Cin P, et al. Targeted genomic analysis of Mullerian adenosarcoma. J Pathol 2015;235:37- 49. 31 Piscuoglio S, Burke KA, Ng CKY, et al. Uterine adenosarcomas are mesenchymal neoplasms. J Pathol 2016;238:381- 388.. # PRINCIPLES OF IMAGING<sup>a,1-9</sup>. Initial Workup. - Chest/abdomen/pelvis CT- For patients who underwent TH with incidental finding of uterine sarcoma or incompletely resected uterus/adnexa (ie, SCH, myomectomy, possible tumor fragmentation, intraperitoneal morcellation) perform chest/abdomen/pelvis CT or abdomen/pelvis MRI and chest CT without contrast to evaluate for metastatic disease.. - Consider pelvis MRI to evaluate local tumor extension or residual abnormality in cases where the uterus or adnexa were not resected or incompletely resected (ie, SCH, myomectomy, possible tumor fragmentation, intraperitoneal morcellation).- Consider neck/chest/abdomen/pelvis/groin FDG-PET/CT to clarify ambiguous findings.- Additional imaging should be based on symptomatology and clinical concern for metastatic disease.<sup>b</sup>. Follow-up/Surveillance. - Chest/abdomen/pelvis CT every 3-6 months for the first 3 years and then every 6-12 months for the next 2 years. Depending on histology grade and initial stage, consider imaging annually or every other year thereafter up to an additional 5 years.<sup>c</sup>- Optional abdomen/pelvis MRI and chest CT without contrast every 3-6 months for the first 3 years and then every 6-12 months for the next 2 years. Depending on histology, grade, and initial stage, consider imaging annually or every other year thereafter up to an additional 5 years.<sup>c</sup>- Consider neck/chest/abdomen/pelvis/groin FDG-PET/CT if metastasis is suspected in select patients.- Additional imaging should be based on symptomatology and clinical concern for metastatic disease.<sup>d</sup>. aMRI is p t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t h t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t. Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF IMAGING REFERENCES. 1Salani R, Khanna N, Frmer M, et al. An update on post- treatment survellance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations. Gynecol Oncol 2017;146:3- 10. 2Haldorsen IS, Salvesen HB. What is the best preoperative imaging for endometrial cancer? Curr Oncol Rep 2016;18:25. 3Elit L, Reade CJ. Recommendations for follow- up care for gynecologic cancer survivors. Obstet Gynecol 2015;126:1207- 1214. 4Vargas HA, Akin O, Zheng J, et al. The value of MR imaging when the site of uterine cancer origin is uncertain. Radiology 2011;258:785- 792. 5Sohaia, Hgtho L, Meron al. Rrt endometrial cancer: patrs of rrent ise and asment of prognosis. Cn Rdiol 2007;62:28- 34; discussion 35- 36. 6Hensley ML, Barre BA, Baamn K, et al. Gynologic Cancer InteGroup (GCG) consensus review: uterine and ovarian leomyosarcomas. Int J Gynecol Cancer 2014;24(9 Suppl 3):S61- S66. 7Lakman Y, Katz SS, Goldman DA, et al. Diagnostice performance of computed tomography for preoperative staging of patients with non- endometrioid carcinomas of the uterine corpus. Ann Surg Oncol 2016;23:1271- 1278. 8Colombo N, Creutzberg C, Amt et al; ESMO- ESGO- ESTRO Endometrial Consensus Conference Working Group. ESMO- ESGO- ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment and follow- up. Ann Oncol 2016;27:16- 41. 9Sal E, Rockall AG, Freeman SJ, et al. The added role of MR imaging in treatment stratification of patients with gynecologic malignancies: what the radiologist needs to know. Radiology 2013;266:717- 740.. # NCCN Guidelines Version 2.2025 Uterine Sarcoma. SYSTEMIC THERAPY FOR UTERINE SARCOMA<sup>a</sup> (Clinical trials strongly recommended). a NCCN Guidelines for Ovarian Cancer- Management of Drug Reactions (Ov- D). b If not used previously, first- line agents can be used as second- line or subsequent therapy as clinically appropriate. c NTRK- positive tumors that are naive to prior NTRK- targeted therapy or have progressed on prior NTRK therapy.. d For the treatment of patients with unresectable or metastatic TMB- H (≥10 mut/Mb) tumors that have progressed following prior treatment and have no satisfactory alternative treatment options. e For oncogenic or likely oncogenic mutations in BRCA2, may refer to definitions at oncokb.org.. Note: All recommendations are category 2A unless otherwise indicated..	None	None	None
209db8b381774505b4cbd8d78dafc7c6	NCCN临床实践指南	子宫肿瘤061-090	# SYSTEMIC ENDOCRINE THERAPY FOR UTERINE SARCOMA<sup>a</sup> (Clinical trials strongly recommended). # SYSTEMIC ENDOCRINE THERAPY FOR UTERINE SARCOMA REFERENCES. 1 P i t t t the phase /II TRIDENT- 1 trial [abstract]. Ann Oncol 2023;34:S787- S788. 3 Butryski JE, D'Adamo DR, Hornick JL, et al. Crizotinib in ALK- rearranged inflammatory myofibroblastic tumor. N Engl J Med 2010;363:1727- 1733. 4 Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK- rearranged non- small- cell lung cancer. N Engl J Med 2014;370:1189- 1197. 5Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK- positive non- small- cell lung cancer. N Engl J Med 2018;379:2027- 2039. 6t i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i is e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e o e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e u e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e a e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e h e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e 10 Shamas N, Yang T, Abidi A, et al. Clinical use of PARP inhibitor in recurrent uterine leiomyosarcoma with presence of a somatic BRCA2 mutation. Gynecol Oncol Rep 2022;42:101044. 11 Seligson ND, Kautto EA, Passen EN, et al. BRCA1/2 functional loss defines a targetable subset in leiomyosarcoma. Oncologist 2019;24:973- 979. 12 Pan M, Ganjoo K, Karam A. Rapid response of a BRCA2/TP53/PTEN- deleted metastatic uterine leiomyosarcoma to olaparib: A case report. Perm J 2021;25:20.251.. # PRINCIPLES OF RADIATION THERAPY FOR UTERINE NEOPLASMS. General Principles-Uterine Neoplasms. - RT is directed at sites of known or suspected tumor involvement and may include EBRT and/or brachytherapy. Imaging is required to assess locoregional extent and to rule out distant metastases before administration of RT. In general, EBRT is directed to the pelvis with or without the para-aortic region. Brachytherapy can be delivered: 1) to an intact uterus, either preoperatively or definitively; or 2) more commonly, to the vagina after hysterectomy. For the purposes of these guidelines, whole abdominal radiotherapy is not considered to be tumor-directed RT.- Chemoradiation can be given concurrently or sequentially.. Chemoradiation can be given concurrently or sequentially.. General Treatment Information. Target Volumes. - Pelvic radiotherapy should target the gross disease (if present), the lower common iliacs, external iliacs, internal iliacs, obturators, parametria, upper vagina/para-vaginal tissue, and presacral lymph nodes (in patients with cervical involvement).- Extended-field radiotherapy should include the pelvic volume and also target the entire common iliac chain and para-aortic lymph node region. The upper border of the extended field depends on the clinical situation but should at least be 1-2 cm above the level of the renal vessels.- Pelvic tissues at risk, especially in the post-hysterectomy setting, can be highly variable depending on bowel and bladder filling. In this situation, the internal target volume (ITV), which encompasses the range of organ movement and deformation, is considered the clinical target volume (CTV), and should be fully covered in the treatment volume.. # PRINCIPLES OF RADIATION THERAPY FOR UTERINE NEOPLASMS. General Treatment Information (continued). Dosing Prescription Regimen - External Beam. - External-beam doses for microscopic disease should be 45-50 Gy. CT treatment planning should be utilized, and intensity-modulated RT (IMRT) for normal tissue sparing should be considered, with appropriate attention to quality assurance (QA) and tissue interfraction mobility.. - Treating with IMRT technique is preferred to minimize toxicities in definitive treatment of the pelvis with or without para-aortic treatment. Regular use of image-guided RT (IGRT) with orthogonal imaging and/or routine volumetric imaging (such as cone beam CT) at the time of treatment delivery is essential to ensure appropriate coverage of targets and sparing of normal tissues.. - Postoperatively, if there is gross residual disease and the area(s) can be sufficiently localized, a boost can be added to a total dose of 60-70 Gy, respecting normal tissue sensitivity.. - For gross nodal disease, consider boost to 60-65 Gy while respecting normal tissue constraints.. - For neoadjuvant radiation, doses of 45-50 Gy are typically used. One could consider adding 1-2 high dose-rate (HDR) insertions to a total dose of 75-80 Gy low dose-rate (LDR) equivalent, to minimize risk of positive or close margins at hysterectomy.. - For pelvic-confined recurrent endometrial cancer without a prior history of radiation, fields would mirror adjuvant radiation. For reirradiation, fields should be limited to gross disease and target dose prescribed to maximize control while minimizing risk to normal tissues.. Dosing Prescription Regimen - Brachytherapy. - Initiate brachytherapy as soon as the vaginal cuff is healed, preferably 6-8 weeks after surgery but in general initiation of brachytherapy should not exceed 12 weeks. For vaginal brachytherapy, the dose should be prescribed to the vaginal surface or at a depth of 0.5 cm from the vaginal surface; the dose depends on the use of EBRT. The target for vaginal brachytherapy after hysterectomy should be no more than the upper two-thirds of the vagina; in cases of extensive LVSI or positive margins, a longer segment of the vagina may be treated.. - For postoperative HDR vaginal brachytherapy alone, regimens include 6 Gy x 5 fractions prescribed to the vaginal surface, or 7 Gy x 3 fractions or 5.5 Gy x 4 fractions prescribed to 5 mm below the vaginal surface. While 7 Gy x 3 fractions prescribed at a depth of 0.5 cm from the vaginal surface is a regimen used by many, the use of smaller fraction sizes may be considered to potentially further limit toxicity in selected patients.. - When HDR brachytherapy is used as a boost to EBRT, doses of 4-6 Gy x 2 to 3 fractions prescribed to the vaginal mucosa are commonly used.. - For medically inoperable uterine cancer, risk of extrauterine spread determines the combination of EBRT plus brachytherapy or brachytherapy alone. Brachytherapy doses for definitive therapy are individualized based on the clinical situation. When available, image-guided therapy should be used. Based on the best available evidence, an equivalent dose at 2 Gy (EQD2) fractions D90 of ≥24 Gy should be delivered to the uterus, cervix, and upper 1-2 cm of vagina if brachytherapy alone is used, and should be increased to 65 Gy for the combination of EBRT and brachytherapy. If an MRI is used as part of planning, the target dose for the gross tumor volume (GTV) would be an EQD2 of ≥80 Gy.. # PRINCIPLES OF RADIATION THERAPY FOR UTERINE NEOPLASMS. General Treatment Information (continued). Interstitial Brachytherapy. Interstitial brachytherapy is an advanced technique where multiple needles/catheters are inserted in the gross disease/target. Interstitial brachytherapy may be preferred to maximize dose to the target and minimize dose to the organs at risk (OARs) for cases where intracavitary brachytherapy is not possible, or anatomy favors interstitial brachytherapy. Three- dimensional treatment planning allows volumetric delineation of targets and OARs on CT and/or MRI with dose- volume histograms. Dose and fractionation depend on prior RT dose, target volume, and OAR doses.. Stereotactic Radiosurgery (SRS) and Stereotactic Body RT (SBRT) for Metastatic Disease. SRS and SBRT are radiation treatment modalities that utilize advanced three- dimensional anatomic targeting accuracy to deliver precise, ablative, high- dose ionizing radiation. The therapy maximizes the cell- killing effect of ionizing radiation while minimizing radiation- induced injury in adjacent sensitive normal tissues. SRS and SBRT demand precise target localization, reproducibility of patient setup, and a sharp radiation dose gradient. SRS is delivered exclusively to intracranial targets while SBRT describes stereotactic therapy to extracranial targets. SRS and SBRT are delivered in 1 to 5 fractions of therapy with the expectation of durable control at the radiated site.. # NCCN Guidelines Version 2.2025 Uterine Neoplasms. PRINCIPLES OF GYNECOLOGIC SURVIVORSHIP. Physical Effects. - Gynecologic cancer treatment typically involves surgery, chemotherapy, hormone therapy, RT, and/or immunotherapy. These treatments cause acute, short-term, and long-term toxicities.- Surgical approaches may be extensive and pose risks such as adhesion formation, which may cause pain and may contribute to small bowel obstruction, urinary or gastrointestinal complications (eg, incontinence, diarrhea), pelvic floor dysfunction (manifested by a variety of urinary, bowel, and/or sexual effects), and lymphedema.- Chemotherapy agents vary, though commonly used regimens may pose a significant risk of neurotoxicity, cardiac toxicity, development of hematologic cancers, and cognitive dysfunction.- Long-term estrogen deprivation may cause symptoms such as hot flashes, vaginal dryness, and bone loss.- RT may cause long-term complications (eg, fibrosis, vulvovaginal atrophy) and may predispose patients to secondary cancers of the subcutaneous tissue, and/or underlying organs that are proximal to the radiation field.- Prior pelvic RT may contribute to bone loss and increase the risk of pelvic fractures. Consider bone density testing and prophylactic use of bisphosphonates, particularly in patients with osteoporosis.- Immunotherapy use is emerging, and to date, long-term effects of these treatments are unknown.. Psychosocial Effects. Psychosocial effects after cancer may be psychological (eg, depression, anxiety, fear of recurrence, altered body image), financial (eg, return to work, insurance concerns), and/or interpersonal (eg, relationships, sexuality, intimacy) in nature.. Clinical Approach. All gynecologic cancer survivors should receive regular general medical care that focuses on managing chronic disease, monitoring cardiovascular risk factors, providing recommended vaccinations, and encouraging adoption of a healthy lifestyle. In order to assess the late and long- term effects of gynecologic cancers, clinicians should comprehensively document the patient's history, conduct a thorough physical examination, and provide any necessary imaging and/or laboratory testing. All patients, whether sexually active or not, should be asked about genitourinary symptoms, including vulvovaginal dryness. Referral to appropriate specialty providers (eg, physical therapy, pelvic floor therapy, sexual therapy, psychotherapy) is recommended. As most treatments for gynecologic cancers will cause sexual dysfunction, early menopause, and infertility, special attention to the resultant medical and psychosocial implications is needed. Post- radiation use of vaginal dilators and moisturizers is recommended. For treatment- related menopause, hormone therapy should be considered. Communication and coordination with all clinicians involved in the care of survivors, including primary care clinicians, is critical. Providing cancer survivors with a summary of their treatment and recommendations for follow- up is recommended.. Additional Guidance. - NCCN Guidelines for Distress Management- NCCN Guidelines for Smoking Cessation- NCCN Guidelines for Survivorship. # Staging-Uterine Carcinomas and Carcinosarcoma. Table 1 AJCC Tumor- Node- Metastases (TNM) and International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging Systems for Endometrial Cancer. Definitions for T, N, M. T FIGO Primary Tumor Stage TX Primary tumor cannot be assessed. T0 No evidence of primary tumor T1 I Tumor confined to the corpus uteri, including endocervical glandular involvement T1a IA Tumor limited to the endometrium or invading less than half the myometrium T1b IB Tumor invading one half or more of the myometrium T2 II Tumor invading the stromal connective tissue of the cervix but not extending beyond the uterus. Does NOT include endocervical glandular involvement T3 III Tumor involving serosa, adnexa, vagina, or parametrium T3a IIA Tumor involving the serosa and/or adnexa (direct extension or metastasis) T3b IIIB Vaginal involvement (direct extension or metastasis) or parametrial involvement T4 IVA Tumor invading the bladder mucosa and/or bowel mucosa (bullous edema is not sufficient to classify a tumor as T4). # Table 1 - Continued. M FIGO Distant Metastasis Stage. M0 No distant metastasis. M1 IVB Distant metastasis (includes metastasis to inguinal lymph nodes, intraperitoneal disease, lung, liver, or bone). (It excludes metastasis to pelvic or para- aortic lymph nodes, vagina, uterine serosa, or adnexa).. G Histologic Grade. GX Grade cannot be assessed G1 Well differentiated G2 Moderately differentiated G3 Poorly differentiated or undifferentiated. # Staging-Uterine Sarcoma. Table 3 AJCC Tumor- Node- Metastases (TNM) and International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging Systems for Uterine Sarcomas (includes Leiomyosarcoma and Endometrial Stromal Sarcoma). Leiomyosarcoma and Endometrial Stromal Sarcoma. T FIGO Primary Tumor Stage TX Primary tumor cannot be assessed. T0 No evidence of primary tumor T1 I Tumor limited to the uterus T1a IA Tumor 5 cm or less in greatest dimension T1b IB Tumor more than 5 cm T2 II Tumor extends beyond the uterus, within the pelvis T2a IIA Tumor involves adnexa T2b IIB Tumor involves other pelvic tissues T3 III Tumor infiltrates abdominal tissues T3a IIIA One site T3b IIIB More than one site T4 IVA Tumor invades bladder or rectum. N FIGO Regional Lymph Nodes Stage. NX Regional lymph nodes cannot be assessed NO No regional lymph node metastasis N0(i+) Isolated tumor cells in regional lymph node(s) no greater than 0.2 mm N1 IIIC Regional lymph node metastasis. M FIGO Distant Metastasis Stage M0 No distant metastasis M1 IVB Distant metastasis (excluding adnexa, pelvic, and abdominal tissues) G Histologic Grade GX Grade cannot be assessed G1 Well differentiated G2 Moderately differentiated G3 Poorly differentiated or undifferentiated. Table 4. AJCC Prognostic Stage Groups. Continued. Used wth pssio f th meric olge f Surgons, Chicago, Ilinois. The onal soure for this inomatio is the AJCC Cancer Staging Manual, Eith Edition (2017) published by Springer International Publishing.. # Staging- Uterine SarcomaTable 4AJCC Tumor- Node- Metastases (TNM) and International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging Systems for Uterine Sarcomas (includes Müllerian adenosarcoma). There is a discrepancy between the 2009 FIGO and 2017 AJCC staging documents in the tumor definitions for FIGO stages IB and IC. The NCCN Panel has chosen to use 2009 FIGO language as noted in Corrigendum to "FIGO staging for uterine sarcomas" [International Journal of Gynecology and Obstetrics (2009) 104:179]. Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing.. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Uterine Neoplasms. ABBREVIATIONS. # # Discussion This discussion corresponds to the NCCN Guidelines for Uterine Neoplasms. Last updated: April 28th, 2023.. Table of Contents. Overview 2 Guidelines Update Methodology 2 Literature Search Criteria. 2 Sensitive/Inclusive Language Usage 2 Initial Evaluation 3 Endometrial Cancer. Discu Molecular Analysis and Genetic Factors. 4 Diagnosis and Workup 5 Imaging 5 Disease Staging 5 Principles of Evaluation and Surgical Staging for Endometrial Carcinoma 6 Pathology. 6 Lymphadenectomy. 7 SLN Ultrastaging. 9 Minimally Invasive Procedures. 10 Primary Treatment. 11 Disease Limited to the Uterus. 12 Suspected or Gross Cervical Involvement. 13 Suspected Extrauterine Disease. 13 Adjuvant Therapy. 14 Uterine- Confined Disease. 14 Advanced Stage/Extrauterine Disease. 17 High- Risk Endometrial Carcinoma Histologies. 20 Overview. 20. Primary Treatment. 20 Treatment of Recurrent or Metastatic Disease. 21 Locoregional Recurrence. 21 Distant Metastases. 21 Hormonal Therapy. 22 Systemic Therapy. 22 Systemic Therapy Options for High- Risk Endometrial Histologies. 25 Radiotherapy Principles. 26 Post- Treatment Surveillance. 26 Hormone Therapy for Hypoestrogenism. 27 Uterine Sarcomas. 28 Overview. 28 Pathology and Molecular Analysis. 28 Low- Grade and High- Grade Endometrial Stromal Sarcoma (ESS). 29 Undifferentiated Uterine Sarcoma (UUS). 29 Uterine Leiomyosarcoma (uLMS). 30 Uterine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT). 30 Rhabdomyosarcoma. 30 Staging and Treatment. 31 Low- Grade Endometrial Stromal Sarcoma. 31 High- Grade Endometrial Stromal Sarcoma, Leiomyosarcoma, Undifferentiated Uterine Sarcoma, and PEComa. 32 Treatment of Recurrent or Metastatic Disease. 32 Systemic Therapy for Advanced, Metastatic/Recurrent or Inoperable Disease. 33 Post- Treatment Surveillance. 34 Drug Reactions. 34 Gynecologic Survivorship. 35 References. 37. # Overview. Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. It is estimated that 65,950 new uterine cancer cases will occur in 2022, with 12,550 deaths resulting from the disease. Stromal or mesenchymal sarcomas are uncommon subtypes accounting for approximately . Risk factors for uterine neoplasms include increased levels of estrogen (caused by obesity, diabetes, and high- fat diet), early age at menarche, nulliparity, late age at menopause, Lynch syndrome, ages between 55 and 64 years, and tamoxifen use.4- 7 Thus, the incidence of endometrial cancer is increasing because of increased life expectancy and obesity. The Summary of the Guidelines Updates describes the most recent revisions to the algorithms, which have been incorporated into this revised Discussion text (see the NCCN Guidelines for Uterine Neoplasms). The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) cannot incorporate all possible clinical variations and are not intended to replace good clinical judgment or individualization of treatments. "Many exceptions to the rule" were discussed among the members of the panel during the process of developing these guidelines. Recommendations in the NCCN Guidelines are category 2A unless otherwise noted.. Guidelines Update Methodology. The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.. Literature Search Criteria. Prior to the update of this version of the NCCN Guidelines for Uterine Neoplasms an electronic search of the PubMed database was performed to obtain key literature in uterine neoplasms published since the previous Guidelines update, using the following search terms: endometrial cancer or endometrial carcinoma or uterine sarcoma or endometrial stromal sarcoma or uterine leiomyosarcoma. The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes peer- reviewed biomedical literature.. The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized Controlled Trial; Meta- Analysis; Systematic Reviews; and Validation Studies.. The data from key PubMed articles as well as articles from additional sources deemed as relevant to these guidelines as discussed by the panel during the Guidelines update process have been included in this version of the Discussion section. Recommendations for which high- level evidence is lacking are based on the panel's review of lower- level evidence and expert opinion.. Sensitive/Inclusive Language Usage. NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation. NCCN Guidelines endeavor to use language that is person- first; not stigmatizing; anti- racist, anti- classist, anti- misogynist, anti- ageist, anti- ableist, and anti- fat- biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non- gendered language, instead focusing on organ- specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of. # all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.. Initial Evaluation. For patients with known or suspected uterine neoplasms, the initial preoperative evaluation/workup for known or suspected malignancy includes a history and physical examination, complete blood count (including platelets), expert pathology review with additional endometrial biopsy as indicated, imaging, recommendation of genetic evaluation of tumor and for inherited cancer risk, consideration of liver function tests (LFTs)/renal function tests or chemistry profile, and other studies (see Initial Evaluation and Principles of Imaging in the NCCN Guidelines for Uterine Neoplasms). Preoperative imaging and biopsy may help to identify uterine sarcomas, although biopsy sensitivity is less than that for endometrial cancer. An expert pathology review will determine whether a patient has a malignant epithelial tumor or a stromal/malignant mesenchymal tumor. Epithelial tumor types include pure endometrioid cancer and carcinomas with high- risk endometrial histology (including uterine serous carcinoma, clear cell carcinoma, carcinosarcoma [also known as malignant mixed Mullerian tumor (MMMT)], and undifferentiated/dedifferentiated carcinoma). Stromal or mesenchymal tumor types (interchangeable terms) include uterine leiomyosarcoma (uLMS), endometrial stromal sarcoma (ESS), undifferentiated uterine sarcoma (UUS, previously called high- grade undifferentiated endometrial . Endometrial Cancer. Data show that almost . Many physicians believe that adenocarcinoma of the endometrium is a more treatable malignancy because the early symptoms of metrorrhagia or post- menopausal vaginal bleeding often trigger patients to seek care when the disease is at an early and treatable stage. However, data show that the mortality rate for uterine cancer has increased more rapidly than the incidence rate. This increased mortality may be related to an increased rate of advanced- stage cancers, high- risk histologies (eg, serous carcinomas), and patients being diagnosed at an age . # Molecular Analysis and Genetic Factors. Molecular Analysis and Genetic FactorsMost endometrial cancer . The NCCN Guidelines for Uterine Neoplasms include a diagnostic algorithm for integrated genomic- pathologic classification of endometrial carcinomas based on the TCGA study and add that the decision to use molecular testing/classification depends on resource availability and each . Screening of the tumor for defective DNA MMR using immunohistochemistry (IHC) and/or MSI is used to identify which patients should undergo mutation testing for Lynch syndrome (see Lynch Syndrome in the NCCN Guidelines for Colorectal Cancer Screening available at. 26 At a minimum, universal testing of endometrial tumors for defects in DNA MMR is recommended (eg, MLH1, MSH2, MSH6). MSI testing is recommended if MMR results are equivocal. Testing may be performed on the initial biopsy or dilation and curettage (D&C) material or the final hysterectomy specimen. MLH1 loss should be further evaluated for promoter methylation to assess for an epigenetic process rather than a germline mutation.23 Genetic counseling, molecular analysis, and testing are recommended for patients with all other MMR abnormalities. Patients with a significant family history of endometrial and/or colorectal cancer (even for those without MMR defects, who are MSI- stable, or those without screening) should be referred for genetic counseling and evaluation (See Lynch Syndrome [Hereditary Non- Polyposis Colorectal Cancer] in the NCCN Guidelines for Genetic/Familial High- Risk Assessment: Colorectal available at Screening for genetic mutations should be considered, especially for. # patients . Diagnosis and Workup. Currently, there is no validated screening test for endometrial carcinoma.. Imaging. For detailed imaging recommendations by stage and planned treatment approach, see Principles of Imaging in the NCCN Guidelines for Uterine Neoplasms. Consideration of preoperative chest imaging (chest x- ray) is . Disease Staging. The FIGO (International Federation of Gynecology and Obstetrics) system is most commonly used for staging uterine cancer. The original 1970 criteria for staging endometrial cancer only used information gained from the presurgical evaluation (including physical examination and diagnostic fractional D&C). The 1970 staging system is rarely used today (eg, when the patient is not a surgical candidate).. Several studies demonstrated that clinical staging was inaccurate and did not reflect actual disease extent in . # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Uterine Neoplasms. In 2017, the AJCC Cancer Staging Manual was further updated (which took effect in January 2018).63. The 2009 FIGO staging system streamlined stages I and II of endometrial carcinoma. These revisions were made because the survival rates for some of the previous sub- stages were similar.61 Currently stage IA describes tumors with less than . In the 2009 FIGO staging the presence of positive peritoneal cytology no longer increases the disease stage, as its importance as an independent risk factor has been called into question.62 However, FIGO and AJCC continue to recommend that peritoneal washings be obtained and results be recorded (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma).64. Principles of Evaluation and Surgical Staging for Endometrial Carcinoma. Staging should be done by a team with expertise in imaging, pathologic evaluation, and surgery. The amount of surgical staging that is necessary to determine disease status depends on preoperative and intraoperative assessment by experienced surgeons. Pathologic nodal assessment for apparent uterine- confined endometrial cancer informs both stage and adjuvant therapy. However, if final pathology shows a noninvasive . Pathology. An expert pathologic review determines the specific epithelial histology of the tumor (endometrioid, serous, clear cell, carcinosarcoma, or undifferentiated). Morphologic evaluation of endometrial carcinoma to determine histologic type—especially in high- grade cancers—is challenging and issues exist regarding diagnostic reproducibility. The pathologic assessment of the uterus and the nodes is described in the algorithm. The assessment of the uterus includes the hysterectomy type, specimen integrity, tumor site and size, histologic type and grade if applicable, myometrial invasion (depth of invasion in mm/myometrial thickness in mm), cervical stromal involvement, and LVSI. Pathologists may be asked to quantify LVSI. The current definition of substantial LVSI is 4 or more LVSI- involved vessels in at least one hematoxylin and eosin (H&E) slide (for clinically relevant LVSI in endometrial cancer).65 The pathologic assessment should also include assessment of involvement by other tissues such as the fallopian tubes, ovaries, vagina, parametrium, peritoneum, and omentum. The assessment of peritoneal/ascitic fluid cytology should also be obtained. If nodal resection was performed, the level of nodal involvement (ie, pelvic, common iliac, para- aortic) should be determined. SLNs should undergo ultrastaging for the detection of low- volume metastases (LVMs). Ultrastaging commonly entails thin serial sectioning of the gross SLN and review of multiple H&E- stained sections with or without cytokeratin IHC for all blocks of SLN. There is no standard protocol for lymph node ultrastaging. See Principles of Pathology in the NCCN Guidelines for Endometrial Carcinoma. The Protocol for the Examination of Specimens From Patients With Carcinoma and Carcinosarcoma of the Endometrium from the College of American Pathologists (CAP) is a useful guide. # NCCN Guidelines Version 2.2025 Uterine Neoplasms. ( femalereproductive- endometrium- 18protocol- 4100. pdf). This CAP protocol was revised to reflect the updated pTNM requirements from the AJCC Cancer Staging Manual (8<sup>th</sup> edition) and 2015 FIGO Cancer Report.63,66. Estrogen receptor (ER) testing is recommended in the setting of stage III, IV, or recurrent endometrioid carcinoma. Evaluation of human epidermal growth factor receptor 2 (HER2) overexpression should also be considered. Rottmann et al recently showed that . As the grade of the tumor increases, the accuracy of intraoperative evaluation of myometrial invasion decreases (ie, assessment by gross examination of fresh tissue).73 In one study, the depth of invasion was accurately determined by gross examinations in . Lymphadenectomy. Previously, a full standard lymphadenectomy (ie, dissection and assessment of both pelvic and para- aortic nodes) was recommended for all patients; however, to decrease side effects, a more selective and tailored nodal evaluation approach that includes the SLN algorithm is recommended by the NCCN Panel.76 No randomized trial data support . Decisions about whether to perform lymphadenectomy, and, if done, to what extent (eg, pelvic nodes only or both pelvic and para- aortic nodes), can be made based on preoperative and intraoperative findings. Criteria have been suggested as indicative of low risk for nodal metastases: 1) less than . Nodal evaluation will identify those patients with nodal metastases. Identification of metastatic disease guides appropriate adjuvant treatment that has been shown to improve survival and decrease locoregional recurrence.. The question of whether to add para- aortic lymphadenectomy to pelvic node dissection has been debated. Prior studies have shown conflicting. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Uterine Neoplasms. information regarding the risk of para- aortic nodal metastases in patients without disease in the pelvic nodes.67,87,90,91 Para- aortic lymphadenectomy up to the renal vessels may be considered for selective patients, including those with pelvic lymphadenectomy or high- risk histologic features. Many surgeons do not do a full lymphadenectomy in patients with grade 1 early- stage endometrial cancer.76. In summary, lymph node dissection identifies patients requiring adjuvant treatment with radiation therapy (RT) and/or systemic therapy.92 A subset of patients may not benefit from lymphadenectomy; however, it may be difficult to preoperatively identify these patients. The NCCN Panel recommends that nodal evaluation be performed in patients with endometrial carcinoma, including para- aortic lymphadenectomy in patients who are at higher- risk (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma).6 SLN mapping is the preferred alternative to full lymphadenectomy in the setting of apparent uterine- confined disease. The SLN surgical algorithm is described below. Lymphadenectomy is not recommended for patients with uterine sarcoma as metastasis to the nodes is unusual.. Sentinel Lymph Node Mapping. The section on surgical staging (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma) includes recommendations about SLN mapping. SLN mapping may be considered for patients without suspicion of metastatic disease by preoperative imaging and no obvious extrauterine disease at exploration.93- 97 In SLN mapping, dye is injected into the cervix, which travels to the sentinel nodes. This has emerged as a useful and validated technique for identification of lymph nodes that are at high risk for metastases (ie, SLN in patients with early- stage endometrial cancer).98 Superficial (1- 3 mm) and optional deep (1- 2 cm) cervical injection leads to dye delivery to the main layers of lymphatic channel origins in the cervix and corpus, namely . A surgical SLN algorithm is proposed to decrease the false- negative rate in patients with apparent uterine- confined disease (see Figure 4 in Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma).93,106 SLN mapping may be most appropriate for those at low to intermediate risk for metastases and/or for those who may not tolerate a standard lymphadenectomy.97,99,107- 112 SLN identification should always be done prior to hysterectomy, except in cases where a bulky uterus must be removed to allow access to iliac vessels and LNs. For example, suspicious or grossly enlarged nodes should be removed regardless of SLN mapping results. In SLN mapping, the surgeon's expertise and attention to technical detail are critical. Patients may be able. # to avoid the morbidity of a standard lymphadenectomy with SLN mapping.111,113 Because SLNs identify the primary lymphatic pathway, this increases the yield of finding metastatic disease during the mapping process. For cases of failed SLN mapping, reinjection of the cervix may be considered. However, if SLN mapping fails, a reflex side- specific nodal dissection should be performed and any suspicious or grossly enlarged nodes should be removed regardless of mapping.93,112. A literature review and consensus recommendations for SLN mapping in endometrial cancer were released by the Society of Gynecologic Oncology (SGO).97 Close adherence to the NCCN SLN surgical algorithm was found to result in accurate prediction of pelvic lymph node metastasis with a less than . A systematic review of 17 studies with . SLN mapping should be done in institutions with expertise in this procedure. If patients have apparent distant metastatic disease (based on imaging and/or surgical exploration), removal of nodes for staging purposes is not necessary because it will not change management.43,49. Historically, SLN mapping was controversial in patients with high- risk histology (eg, serous carcinoma, clear cell carcinoma, carcinosarcoma).76,117 However, SLN mapping in patients with high- risk histologies (ie, grade 3, serous, clear cell, carcinosarcoma) has been reported with promising results as a potential alternative to complete lymphadenectomy.112,118,119 A recent multi- institutional retrospective study concluded that SLN mapping versus SLN mapping with lymphadenectomy in high- risk endometrial cancer did not impact survival outcomes.120 A recent prospective, multicenter cohort study (SENTOR- trial) examined the diagnostic accuracy of SLN mapping versus lymphadenectomy for intermediate- and high- grade endometrial cancer in 156 patients. Of 27 patients with nodal metastasis, SLN mapping correctly identified 26 of them . SLN Ultrastaging. In general, SLN mapping allows for increased intraoperative surgical precision to identify nodes more likely to harbor metastasis combined with enhanced pathology protocols, which has been shown to increase the. # detection of nodal metastasis, which may alter stage and adjuvant therapy recommendations. Studies have suggested that SLN ultrastaging leads to upstaging in . Ultrastaging typically includes two components: serial sectioning with review of multiple H&E- stained slides with or without cytokeratin IHC staining.123 Recent data highlight the potential significance and impact of SLN ultrastaging to improve the accuracy of detecting micrometastases.124. In a cohort of 508 patients who underwent SLN mapping, ultrastaging detected 23 additional cases of micrometastasis that would have been missed by conventional H&E staining.125 A multicenter study of 304 patients with presumed low- or intermediate- risk disease showed that SLN biopsy and ultrastaging detected metastatic SLNs in a 3- fold greater number of patients than standard lymphadenectomy.126. The implications and appropriate management of micrometastases and isolated tumor cells (ITCs), jointly referred to as LVM, detected via SLN ultrastaging are not yet clear.97,110,113,127- 131 Studies have recently begun to investigate the significance of ITCs discovered during SLN mapping in early- stage endometrial cancer. The AJCC . A retrospective review examined 844 patients with endometrial cancer that underwent SLN mapping.133 The majority of patients with ITCs, micrometastasis, and macrometastasis received adjuvant chemotherapy . A prospective observational study of 519 patients compared outcomes for patients with SLN macrometastasis, micrometastasis, and ITCs, taking into account adjuvant treatment.134 Patients with SLN ITCs had a significantly better 3- year progression- free survival (PFS) compared with patients with SLN macrometastasis (95.5% vs. 58.5%), and outcomes were similar between patients with negative SLNs, ITCs, and micrometastasis. Recurrence was detected in only 1 of 31 patients with ITCs (stage IB carcinosarcoma) and adjuvant treatment did not appear to influence outcomes. Based on these early data, it is unclear if patients with SLN ITCs would derive significant benefit from adjuvant treatment.135 Future evaluation of prognosis/outcome may need to prospectively examine the threshold for and impact of adjuvant therapy for patients with scattered ITCs.. Minimally Invasive Procedures. Over the past decade, practice has trended towards minimally invasive approaches to total abdominal hysterectomy (TH)/BSO and lymph node assessment in patients with early- stage endometrial cancer.136 Although these procedures may be performed by any surgical route (eg, laparoscopic, robotic, vaginal, abdominal), the standard in those with apparent uterine- confined disease is to perform the procedure via a minimally invasive approach. Randomized trials, a Cochrane Database Systematic Review, and population- based surgical studies support that minimally invasive techniques are preferred in the appropriate candidate due to a lower rate of surgical site infection, transfusion, venous thromboembolism, decreased hospital stay, and lower cost of care, without compromise in oncologic outcome.136- 142 Despite data showing that minimally invasive procedures result in lower perioperative complications and lower cost of care, racial and geographic disparities in access to minimally invasive surgical care have been observed.138,142. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Uterine Neoplasms. A randomized phase Ill trial evaluated laparoscopy for comprehensive surgical staging; patients . The LACE trial compared outcomes of patients with stage I endometrial carcinoma . Robotic surgery is a minimally invasive technology that has been increasingly used in the surgical staging of endometrial carcinoma due to its potential advantages over laparotomy, especially for patients who are overweight.150- 154 Prospective cohort and retrospective studies suggest that robotic approaches perform similarly to laparoscopy and result in comparable or improved perioperative outcomes.154- 159 Oncologic outcomes appear to be comparable to other surgical approaches, although longer- term outcomes are still being investigated.160- 162 In certain patients, robotic surgery may result in less frequent conversion to laparotomy when compared with laparoscopic approaches and also appears to be safe and feasible in patients at higher anesthesiologic risk.154,155,163. Costs for robotic equipment and maintenance remain high.164 150,151,160- 162,165 The SGO, American Association of Gynecologic Laparoscopists (AAGL), and American Congress of Obstetricians and Gynecologists (ACOG) have published guidelines or position statements about robotic surgery.166- 168 For reviews on the robotic- assisted surgery for gynecologic malignancies and associated cost issues, see Sinno and Fader and Gala et al.169,170. Primary Treatment. These NCCN Guidelines divide pure endometrioid cancer into three categories for delineating treatment: 1) disease limited to the uterus; 2) suspected or gross cervical involvement; and 3) suspected extrauterine disease. Most patients with endometrial cancer have stage I disease at presentation, and surgery (with or without adjuvant therapy) is recommended for patients who are medically operable. As a general principle, endometrial carcinoma should be removed en bloc to optimize outcomes; intraperitoneal morcellation should be avoided.171- 174. # Disease Limited to the Uterus. To stage patients who are medically operable with endometrioid histologies clinically confined to the fundal portion of the uterus, the recommended surgical procedure includes removal of the uterus and bilateral tubes and ovaries with lymph node and abdominal assessment (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma and in this Discussion and Lymphadenectomy and Sentinel Lymph Node Mapping in this Discussion).83 Ovarian preservation may be safe in select patients who are premenopausal with stage I endometrioid cancer.175- 177 Minimally invasive surgery is the preferred approach when technically feasible and is considered a quality measure by the SGO and the American College of Surgeons (www.sgo.org/quality- outcomes- and- research/quality- indicators; programs/cancer- programs/national- cancer- database/quality- of- care- measures).. During surgery, the intraperitoneal structures should be carefully evaluated, and suspicious areas should be biopsied. While not specifically affecting staging, FIGO and AJCC recommend that peritoneal cytology should be collected and results should be recorded. Cytology results should not be taken in isolation to guide adjuvant therapy. Enlarged or suspicious lymph nodes should be excised to confirm or rule out metastatic disease. Retroperitoneal node dissection with pathologic evaluation- in the absence of clinically apparent lymphadenopathy- is useful when using the 2009 FIGO staging criteria, but its routine use has been questioned (see Lymphadenectomy in this Discussion). For stage II patients, TH/BSO is the standard procedure. Radical hysterectomy should only be performed if needed to obtain negative margins.. Patients with apparent uterine- confined endometrial carcinoma are candidates for sentinel node mapping, which assesses the pelvic nodes bilaterally and may be less morbid than complete lymphadenectomy (see. Sentinel Lymph Node Mapping in this Discussion). Adherence to the NCCN SLN algorithm is critical.. Incomplete Surgical Staging. For patients with incomplete surgical staging and high- risk intrauterine features, imaging is recommended, especially in patients with higher grade histologies.178,179 Surgical restaging, including lymph node dissection, can also be done.87 Based on the imaging and/or surgical restaging results, recommended adjuvant treatment options are provided in the algorithm (see Adjuvant Treatment for Incompletely Surgically Staged in the NCCN Guidelines for Endometrial Carcinoma).. Fertility-Sparing Therapy. Although the primary treatment of endometrial cancer is usually hysterectomy, continuous progestin- based therapy may be considered for highly selected patients with grade 1, stage IA (noninvasive) disease who wish to preserve fertility.180- 184 Likewise, it may also be selectively used for young patients with endometrial hyperplasia who desire fertility preservation. The guidelines include an algorithm for fertility- sparing therapy in selected patients with biopsy- proven grade 1 (preferably by D&C), stage IA noninvasive endometrioid adenocarcinoma (see Criteria for Considering Fertility- Sparing Options in the NCCN Guidelines for Endometrial Carcinoma). The panel recommends consultation with a fertility expert and genetic evaluation of tumor and evaluation for inherited cancer risk. When considering fertility- sparing therapy, all of the criteria must be met as outlined in the algorithm (eg, no metastatic disease) and a negative pregnancy test must be ensured. Patients should also receive counseling that fertility- sparing therapy is not the standard of care for the treatment of endometrial carcinoma. TH/BSO with surgical staging is recommended after childbearing is complete, if therapy is not effective, or if progression occurs. Fertility- sparing therapy is not recommended for high- risk patients (eg, those with high- grade endometrioid. # adenocarcinomas, uterine serous carcinoma, clear cell carcinoma, carcinosarcoma, and uLMS).. Continuous progestin- based therapy may include megestrol acetate, medroxyprogesterone, or an intrauterine device (IUd) containing levonorgestrel.180,181,185 A complete response occurs in about . gls/pdf/survivorship.pdf).. In patients receiving progestin- based therapies, the NCCN Panel recommends close monitoring with endometrial sampling (biopsies or D&C) every 3 to 6 months. TH/BSO with staging is recommended: 1) after childbearing is complete; 2) if patients have documented progression on biopsy; or 3) if endometrial cancer is still present after 6 to 12 months of progestin- based therapy.184,186 Although some young patients who had subsequent negative endometrial biopsies after hormonal therapy were able to become pregnant . In a study of patients who are premenopausal and have stage IA to B endometrial cancer, median 16- year follow- up data suggest that ovarian preservation is safe and not associated with an increased risk of cancer- related mortality.175 Other studies also suggest that ovarian preservation may be safe in select patients.176,177. Suspected or Gross Cervical Involvement. For patients with suspected or gross cervical involvement (endometrioid histologies), cervical biopsy or pelvic MRI should be performed if not done previously (see Additional Workup in the NCCN Guidelines for Endometrial Carcinoma).176,179,180,181 If negative, patients are assumed to have disease that is limited to the uterus and are treated as previously described, although a radical hysterectomy may be performed when necessary to obtain negative margins. It may be difficult to distinguish primary cervical carcinoma from stage II endometrial carcinoma. Thus, for patients suitable for primary surgery, TH or radical hysterectomy is recommended along with BSO, cytology (peritoneal lavage), and evaluation of lymph nodes if indicated (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma).83 In these patients, radical or modified radical hysterectomy may improve local control and survival when compared with TH.192,193 Alternatively, the patient may undergo EBRT and brachytherapy (category 2B) followed by TH/BSO and surgical staging.. Suspected Extrauterine Disease. If extrauterine disease (endometrioid histologies) is suspected, imaging studies are recommended along with CA- 125 testing (see Additional Workup in the NCCN Guidelines for Endometrial Carcinoma). ER testing is recommended in the setting of stage II or IV endometrioid tumors. Patients with no evidence of extrauterine disease are treated using the guidelines for disease limited to the uterus. Patients with abdominal- or pelvic- confined disease require surgical intervention using TH/BSO with surgical staging and surgical debulking with the goal to have no measurable residual disease; several studies support debulking.83,194- 196 Consider preoperative chemotherapy.197 For distant visceral metastasis (eg, liver involvement), recommended options include systemic therapy with (or without) EBRT with (or without) TH/BSO and with (or without). # stereotactic body RT (SBRT). Ablative radiation can be considered for 1 to 5 metastatic lesions if disease is otherwise controlled (category 2B).198. Patients Not Suited for Primary Surgery. For uterine- confined disease not suitable for primary surgery, EBRT and/or brachytherapy is the preferred treatment approach. Alternatively, progestational agents (such as medroxyprogesterone acetate and megestrol acetate) and levonorgestrel IUD can also be considered for select patients (eg, estrogen and progesterone receptor- positive [ER/PR- positive]). Patients receiving hormonal therapy alone should be closely monitored by endometrial biopsy (eg, consider endometrial biopsies every 3- 6 months).37,199. For suspected gross cervical involvement in patients who are not suited for primary surgery, EBRT and brachytherapy is an effective treatment that can provide pelvic control and long- term PFS (see Principles of Radiation Therapy in the NCCN Guidelines for Uterine Neoplasms).200- 203 EBRT and brachytherapy may be administered with or without platinum- based chemosensitization, depending on the clinical situation and medical fitness of the patient. If rendered operable, local treatment consisting of surgery should follow. Systemic therapy alone is also a primary treatment option (category 2B), but should be followed by EBRT + brachytherapy if the patient remains inoperable.. Patients with unresectable extrauterine pelvic disease (ie, vaginal, bladder, bowel/rectal, nodal, or parametrial involvement) are typically treated with EBRT with (or without) brachytherapy with (or without) systemic therapy, followed by re- evaluation of tailored surgery.204- 207 Systemic therapy alone can also be considered. Based on treatment response, patients should be re- evaluated for surgical resection and/or RT.. Adjuvant Therapy. Uterine-Confined Disease. Thorough surgical staging provides important information to assist in selection of adjuvant therapy for endometrial tumors (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma). Patients with stage I endometrial cancer who have thorough surgical staging are stratified by adverse risk factors (ie, age, positive LVSI, tumor size, and lower uterine segment or surface glandular involvement).208,209 Recommended adjuvant treatment is outlined in the algorithm (see the NCCN Guidelines for Endometrial Carcinoma). Note that the treatment algorithm was revised in 2010 based on the updated FIGO staging.61 However, by necessity, much of the discussion in this manuscript has been based on data from patients staged using the older FIGO/AJCC staging system. The implications of stage migration should be considered when evaluating historical data.. The basic concept underlying the recommendations in the NCCN Guidelines is the trend toward selection of more aggressive adjuvant therapy for patients as tumor grade and myometrial and/or cervical invasion increase, as risk of systemic metastases increase.210- 212 In surgical stage I and II endometrial cancer, other pathologic factors that may influence the decision regarding adjuvant therapy include LVSI, patient age, tumor volume, depth of invasion, and lower uterine segment or cervical glandular involvement. When administering adjuvant RT, it should be initiated as soon as the vaginal cuff has healed, but no later than 12 weeks after surgery.. Significant controversy centers on how much adjuvant therapy is necessary in patients with surgical stage I endometrial cancer. The practice of surgical staging has led to a decrease in the use of adjuvant therapy for stage I endometrial carcinoma, which is reflected in the option of observation in the NCCN Guidelines for selected patients with low- risk. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Uterine Neoplasms. features (see section on Adjuvant Treatment in the NCCN Guidelines for Endometrial Carcinoma).92,209,210,213- 215 The NCCN Panel prefers observation for patients with stage IA, grade 1/2 disease, but strongly suggests treatment with adjuvant vaginal brachytherapy for those . The recommended postoperative (ie, adjuvant) treatment options for surgical stage II patients (using thorough surgical staging) are shown in the algorithm (see Adjuvant Treatment for stage II in the NCCN Guidelines for Endometrial Carcinoma). The NCCN Panel generally agrees on the role of adjuvant therapy for patients with an invasive cervical component if extrafascial hysterectomy is performed. However, for patients with stage II disease who have had a radical hysterectomy with negative surgical margins and no evidence of extrauterine disease, EBRT (preferred) and/or vaginal brachytherapy with (or without) systemic therapy (category 2B) are options. As with stage I disease, the presence of adverse risk factors (including depth of stromal invasion, grade, LVSI, and adverse fundal risk factors) should be considered when selecting adjuvant therapy for stage II disease.217. Adjuvant RT. Several phase III trials have assessed adjuvant therapy in patients with uterine- confined disease. In summary, the use of adjuvant RT improves pelvic control in patients with selected risk factors (and may improve PFS), but has not been shown to improve OS. However, many of the earlier trials had limitations as the patients were primarily low risk (ie, they had low- risk intrauterine pathologic risk factors). It is recognized that in patients with uterine- confined disease, there is a spectrum of risk based on intrauterine pathologic findings. Adverse intrauterine pathologic risk factors include high- grade tumors, deep myometrial invasion (and consequently more advanced stage), LVSI (especially extensive), and serous or clear cell carcinoma histologies.. Four trials have evaluated the role of adjuvant external- beam pelvic RT in patients with endometrial carcinoma. In two of these trials, the patients were not formally staged (Postoperative Radiation Therapy in Endometrial Carcinoma [PORTEC- 1], Aalders).218,229 In the third trial (ASTEC/EN.5), only . The PORTEC- 1 and GOG 99 trials suggested that external- beam pelvic RT provides a locoregional control benefit in selected patients with uterine- confined disease.218,222 Radiation was not shown to increase OS.223 It is important to note that the PORTEC 1 trial was powered to evaluate OS, although the GOG 99 trial was not. Similarly the Aalders' randomized trial found that RT reduced vaginal (ie, locoregional) recurrences but did not reduce distant metastases or improve survival.219 A pooled randomized trial (ASTEC/EN.5) suggested that adjuvant pelvic RT alone did not improve either relapse- free survival (ie, PFS) or OS in patients with intermediate- risk or high- risk early- stage endometrial cancer,. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Uterine Neoplasms. but there was an improvement in pelvic control.220 However, the ASTEC/EN.5 study is very controversial: . To help select the appropriate patient population that may benefit from adjuvant pelvic RT, the GOG 99 and PORTEC trials defined risk factors for patients at high- intermediate risk (HIR) for recurrence, although the definition differed between these trials.218,221 Risk factors for recurrence identified in both trials included higher age, deep myometrial invasion . retrospective evaluation demonstrated increased recurrence with extensive LVSI, as defined by the protocol.Due to concerns about potential toxicity of external- beam pelvic RT, the role of vaginal brachytherapy alone in uterine- confined disease has been evaluated. PORTEC- 2 randomly assigned patients to external- beam pelvic RT versus vaginal brachytherapy alone in uterine- confined disease. PORTEC- 2 showed excellent and equivalent vaginal and pelvic control rates with both adjuvant radiation approaches and no difference in OS.216 Given that vaginal brachytherapy is associated with significantly less toxicity than pelvic RT, vaginal brachytherapy alone is a reasonable choice for patients with uterine- confined endometrial cancer as defined in the PORTEC 2 trial.216,225- 233 The use of vaginal brachytherapy and/or whole pelvic RT should be carefully tailored to a patient's pathologic findings. Both PORTEC- 1 and PORTEC- 2 specifically excluded patients with 1998 FIGO stage 1C and grade 3 endometrial carcinoma (2009 FIGO stage IB, grade 3),61 thus, the use of adjuvant brachytherapy alone in this higher risk subset remains more controversial. PORTEC studies did not evaluate lymph nodes and, therefore, in the context of complete surgical staging and the lack of a survival benefit, the need for pelvic irradiation remains controversial in uterine- confined disease.. A meta- analysis evaluated results from studies that compared adjuvant postoperative EBRT with or without vaginal brachytherapy and vaginal brachytherapy alone in stage II endometrial cancer. EBRT + vaginal brachytherapy significantly reduced locoregional recurrence versus vaginal brachytherapy alone. OS was comparable in both arms.234. The GOG 249 trial examined vaginal cuff brachytherapy and 3 cycles of carboplatin/paclitaxel therapy (3 cycles) versus pelvic EBRT only in patients with high- risk, uterine- confined endometrial carcinoma . # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Uterine Neoplasms. plus chemotherapy arm compared with the pelvic EBRT arm. No significant between- group differences in vaginal or distant recurrence rates were observed. However, there were more extravaginal pelvic failures in the brachytherapy plus chemotherapy arm. At a median follow- up of 53 months, 3- year RFS was . Analysis of pooled data from PORTEC- 1 and PORTEC- 2 ranked the predictive power of multiple variables on patient outcomes examined in these trials. Patient age, tumor grade, and LVsI were highly predictive for locoregional relapse (LRR), distant relapse (DR), OS, and DFS, and treatment given (EBRT vs. vaginal brachytherapy) was predictive for LRR and DFS.208 The benefit of adjuvant EBRT in the highest risk spectrum of uterine- confined disease remains controversial. Most NCCN Panel Members feel that patients with deeply invasive grade 3 tumors should receive adjuvant treatment. Two large retrospective SEER analyses of patients with endometrial cancer found that adjuvant RT improved OS in those with high- risk disease.236,237 In a meta- analysis of randomized trials, a subset analysis found that adjuvant pelvic RT for stage I disease was associated with a trend towards a survival advantage in the highest- risk spectrum (eg, those with 1988 FIGO stage IC grade 3) but not in lower risk patients; however, other reviews have shown conflicting results.228,238- 242. The long- term follow- up study (median 20.5 years) of 568 patients with early- stage endometrial carcinoma enrolled in the Aalders trial compared long- term outcomes in patients who received vaginal brachytherapy plus EBRT versus vaginal brachytherapy alone. The findings suggested no statistical difference in OS between the study groups, and in this cohort, . Adjuvant Systemic Therapy. Patients with deeply invasive, grade 3, uterine- confined disease (2009 FIGO stage IB, grade 3 [formerly 1988 FIGO stage IC, grade 3]) have a relatively poor prognosis. Despite adjuvant therapy with pelvic RT, a significant number of patients continue to have a significant risk of distant metastases, and an optimal adjuvant therapy is still sought.221,222 Therefore, some clinicians suggested that adding systemic therapy to adjuvant RT may provide added therapeutic benefit (ie, decrease in distant metastases).210,243 Studies have evaluated the role of systemic therapy in highest risk uterine- confined disease.21,244 PFS is improved with adjuvant sequential chemotherapy.243 However, the NCCN Panel feels that adjuvant systemic therapy is a category 2B recommendation in this setting because an OS advantage has not been shown.243 The GOG- 249 phase 3 trial evaluated the benefit of adjuvant pelvic RT versus vaginal cuff brachytherapy plus 3 cycles of paclitaxel/carboplatin combination in 601 patients with high- intermediate and high- risk early- stage endometrial cancer. The 5- year RFS and OS were similar in both groups and superiority of any of these treatments were not demonstrated. Acute toxicity was greater in the combination therapy.245. Advanced Stage/Extraterine Disease. There is a consensus that patients with documented extrauterine disease are at increased risk for recurrence and need adjuvant therapy; however, the optimal form of adjuvant therapy has yet to be determined.246- 248 Patients with extrauterine disease confined to the lymph nodes or the adnexa may be treated with pelvic or extended- field RT alone or with chemotherapy (radiation is targeted to sites of nodal disease).249 However,. # systemic therapy is regarded as the foundation of adjuvant therapy for patients with extrauterine disease. The NCCN Guidelines include carboplatin/paclitaxel as the preferred systemic therapy option in the primary/adjuvant setting for advanced- stage disease or high- risk histologies.250- 252 The NCCN Guidelines recently added the pembrolizumab/carboplatin/paclitaxel and dostarlimab carboplatin/paclitaxel triplet regimens as Category 1, preferred, primary therapy options for stage III or IV disease based on the data from phase III NRG- GY018 and RUBY trials, respectively.253,254 The pembrolizumab/carboplatin/paclitaxel regimen is recommended for stage III or IVA with measurable disease or for stage IVB with or without measurable disease. Since the NRG- GY018 trial did not include patients with carcinosarcoma histology, the NCCN Panel do not recommend the pembrolizumab/carboplatin/paclitaxel treatment option for patients with carcinosarcoma disease. The dostarlimab carboplatin/paclitaxel option is recommended for patients with stage IIIA, IIIB, or IIIC1 with measurable disease, stage IIIC1 with carcinosarcoma, clear- cell, serous, or mixed histology regardless of the presence of measurable disease; and stage IIIC2 or stage IV disease regardless of the presence of measurable disease.. For stages III and IV disease, systemic therapy forms the mainstay of treatment and can be combined with EBRT with (or without) vaginal brachytherapy. The combination of therapies depends on assessment of both locoregional and distant metastatic risk. Combination therapy can be considered for stages IIIB and IIIC disease.. Previously, whole abdominal RT was used for carefully selected patients deemed at risk for peritoneal failure, and RT appeared to have provided therapeutic benefit in retrospective studies. However, it is considered too toxic and has largely been abandoned.255,256 A randomized phase III GOG (122) trial assessed optimal adjuvant therapy for patients with endometrial . The GOG 122 study established the role of adjuvant multiagent systemic chemotherapy for curative intent in patients with extrauterine disease. Thus, in the NCCN Guidelines, systemic therapy forms the established framework of adjuvant therapy for patients with stage III or IV disease. Whole abdominal RT as a single modality (as used in GOG 122) is considered inferior to chemotherapy and is too toxic; therefore, it is no longer recommended. For the purposes of these guidelines, whole abdominal RT is not considered to be tumor- directed RT (see Principles of Radiation Therapy in the NCCN Guidelines for Uterine Neoplasms).. Recurrences were frequent in both treatment arms of GOG 122, occurring in the pelvis and abdomen. Approximately . A follow- up study evaluated the role of chemotherapy "intensification" for this patient population. The GOG 184 trial compared two chemotherapy regimens (cisplatin and doxorubicin with [or without] paclitaxel) with tumor- directed radiation (involved- field radiation either to the pelvis or to the pelvis plus para- aortic nodes). Results indicate that the 3- drug regimen did not improve survival when compared with the 2- drug regimen after 3 years.	None	None	None
4443a4445e91456db285b1730ef4f26d	NCCN临床实践指南	子宫肿瘤091-108	# National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Uterine Neoplasms. of follow- up and that the more intensive chemotherapy resulted in greater toxicity (eg, hematologic toxicity, sensory neuropathy, myalgia).206. In a retrospective review of 116 patients with stage IIIC endometrial cancer, adjuvant RT significantly improved OS in patients with endometriod histology, high- grade tumors, and positive para- aortic lymph nodes. Conversely, patients with low- grade tumors and non- endometrioid histology who received RT had similar OS compared with those who did not.259 In a multicenter retrospective review of 73 patients with stage IIIA endometrial carcinoma, surgery followed by both chemotherapy and RT provided the highest 5- year OS.260 A prospective study of 122 patients with fully resected locally advanced disease suggested a potential benefit of adjuvant chemoradiation followed by chemotherapy, with an estimated 5- year PFS and OS of . Multimodality therapy is now the basis of randomized trials evaluating therapy. The phase 2, RTOG 9708 trial assessed 46 patients for safety, toxicity, recurrence, and survival when chemotherapy (cisplatin/paclitaxel) was combined with adjuvant radiation in patients with high- risk endometrial cancer. The trial participants included patients with grade 2 or 3 endometrial adenocarcinoma with either . The phase 3, PORTEc- 3 trial investigated the benefit of combined adjuvant chemotherapy and EBRT versus EBRT alone in 686 patients with endometrial cancer (stage I, grade 3 with deep invasion, LVsI, or both; stage II; stage Il; or any patient with stage I to Il serous or clear cell . The GOG- 258 phase 3 trial evaluated 707 patients with stage IlI or IVA, high- risk endometrial cancer who were randomly assigned 1:1 to receive chemoradiotherapy or chemotherapy only.266 This trial supported the benefit of using chemotherapy alone by concluding that the combined therapy was not associated with longer relapse- free survival when compared with chemotherapy alone . A follow- up molecular analysis was performed of the PORTEc- 3 trial to study the impact of chemoradiotherapy for each molecular subtype using tissue samples from the trial participants. The tumors were classified into . # NCCN Guidelines Version 2.2025 Uterine Neoplasms. High-Risk Endometrial Carcinoma Histologies. Overview. Uterine serous carcinomas, clear cell carcinomas, carcinosarcomas, and undifferentiated/dedifferentiated carcinomas are considered more aggressive histologic variants of malignant epithelial tumors, with a higher incidence of extrauterine disease at presentation.269- 276 Carcinosarcomas are aggressive tumors that are staged as high- grade endometrial cancer.277,278 Carcinosarcomas (also known as MMMTs) are metaplastic carcinomas and not uterine sarcomas; therefore, carcinosarcomas are included as part of the high- risk malignant epithelial tumors.273,276,279,280 Even patients with apparent early- stage disease may have distant metastases. Thus, fertility- sparing therapy is not recommended for these aggressive tumors. If done, SLN mapping should proceed with particular caution. Serous carcinomas, clear cell carcinomas, carcinosarcomas, and undifferentiated/dedifferentiated carcinomas are all considered high- risk histologies and high grade by default, although they are staged using the same FIGO/AJCC staging system as endometrial cancers.63 Patients with uterine serous carcinoma, clear cell carcinoma, carcinosarcoma, or undifferentiated/dedifferentiated carcinomas may present with pelvic masses, abnormal cervical cytology, or ascites in addition to postmenopausal bleeding. Both the NCCN Panel and the SGO recommend that CA- 125 and MRI or chest/abdominal/pelvic CT may be useful before surgery to assess if extrauterine disease is present; PET may also be useful.269 Patterns of failure often mimic those of ovarian cancer.. Primary Treatment. Suitable for Primary Surgery. Multimodality therapy is typically recommended for these histologically aggressive tumors. Primary treatment includes TH/BSO with surgical staging, peritoneal lavage for cytology, omental and peritoneal biopsies, . Additional treatment options are highly individualized and are based on the histology and stage of the tumor.287- 294 For patients with clear cell or serous carcinomas with no residual disease in the hysterectomy specimen, observation is the recommended option. For stage IA disease without myometrial invasion with negative peritoneal washings, options include vaginal brachytherapy with (or without) systemic therapy (category 2B for systemic therapy) or observation. If the washings are positive, both systemic therapy and vaginal brachytherapy are recommended.295,296 For patients with invasive stage IA, IB, or IL, options include systemic therapy with (or without) EBRT with (or without) vaginal brachytherapy; or EBRT with (or without) vaginal brachytherapy. For patients with clear cell or serous carcinoma at a more advanced stage (ie, stage III or IV), or with undifferentiated/dedifferentiated histology, systemic therapy with (or without) EBRT with (or without) vaginal brachytherapy is recommended.271,288,292,297. For the patients with carcinosarcoma histology at stage IA, systemic therapy and vaginal brachytherapy are recommended with an option for EBRT, if it has high- grade epithelial components and is sarcoma dominant (>50% of sarcoma component in uterine tumor).298 The panel notes that the initiation of chemotherapy within 3 to 6 weeks postoperatively should be considered and vaginal brachytherapy can be integrated with chemotherapy.. For patients with advanced histologies, whole abdominopelvic RT with (or without) vaginal brachytherapy is no longer recommended as a primary treatment option.205,297,299 288 Multimodality therapy including systemic therapy, EBRT, and vaginal brachytherapy appears to be more effective.. # Data are conflicting regarding the rate of abdominal recurrence in these patients.297,300- 304 Whole abdominal radiotherapy is not considered to be tumor- directed RT (see Principles of Radiation Therapy in the NCCN Guidelines for Uterine Neoplasms). As previously mentioned, tumor- directed RT refers to RT directed at sites of known or suspected tumor involvement and may include EBRT with (or without) vaginal brachytherapy. In general, tumor- directed EBRT is directed to the pelvis with (or without) the para- aortic region.. Not Suitable for Primary Surgery. For patients with disease that is not amenable to resection, or is not suitable for surgery due to comorbidities, the primary treatment option is EBRT with (or without) brachytherapy with (or without) systemic therapy and then re- evaluation for surgery. Alternatively, systemic therapy could be given first, and then patients can be re- evaluated for surgery before giving RT based on the tumor response. For patients with carcinosarcoma histology with unresectable tumor that has metastasized, the panel recommends systemic therapy with (or without) EBRT or best supportive care.. Treatment of Recurrent or Metastatic Disease. Locoregional Recurrence. Patients with local or regional recurrences (negative for distance metastases on radiologic imaging) can be evaluated for further treatment (see Clinical Presentation in the NCCN Guidelines for Endometrial Carcinoma). For recurrences confined to the vagina or the pelvis alone, second- line treatment (typically with RT and/or surgery or systemic therapy) can be effective and selection depends on prior therapy. For patients with no prior RT exposure at the recurrence site, the panel recommends EBRT with (or without) brachytherapy and systemic therapy, or surgery with (or without) intraoperative RT (IORT) and systemic therapy. For patients previously treated with brachytherapy only at the . For patients previously treated with EBRT at the recurrence site, recommended therapy for isolated relapse includes surgery with (or without) IORT (category 3 for IORT) plus or minus systemic therapy. Use of RT in the context of recurrence depends on the site of recurrence (inside or outside the prior radiation field), and dose of prior therapy. Reirradiation is used only in the context of limited disease for palliation and lack of other options. In selected patients, radical surgery (ie, pelvic exenteration) has been performed with reported 5- year survival rates approximating 20%.305- 308. Isolated vaginal recurrences treated with RT have good local control and 5- year survival rates of 50% to 70%.309- 311 Prognosis is worse if there is extravaginal extension or pelvic lymph node involvement.310 After RT, it is unusual for patients to have recurrences confined to the pelvis. The management of such patients remains controversial.. Additional therapy options for disease confined to vagina or paravaginal soft tissues include EBRT with (or without) brachytherapy with (or without) systemic therapy. EBRT and systemic therapy are also included as options for the additional treatment of pelvic lymph node recurrence, para- aortic or common iliac lymph node invasion, and upper abdominal or peritoneal recurrences as shown in the algorithm (see Additional Therapy in the NCCN Guidelines for Endometrial Carcinoma).. Distant Metastases. For gross upper abdominal residual disease, more aggressive treatment for relapse is recommended, as outlined for disseminated metastases in Therapy for Relapse in the NCCN Guidelines for Endometrial Carcinoma. For resectable isolated metastases, consider surgical resection and/or EBRT, or ablative therapy. Ablative RT can be considered for 1 to 5. # metastatic lesions if the primary cancer has been controlled (category 2B).198 Providers can also consider systemic therapy (category 2B). Further recurrences or disease not amenable to local therapy are treated as disseminated metastases. Treatment options for disseminated metastases are systemic therapy with (or without) palliative EBRT. For persistent progression of disseminated metastases, best supportive care is recommended (see the NCCN Guidelines for Palliative Care available at and overview).. Hormonal Therapy. The role of hormonal therapy in recurrent or metastatic cancer has been primarily evaluated in patients with endometrioid histologies only. Hormonal therapy is typically used for lower- grade endometrioid histologies, preferably in patients with small tumor volume or an indolent growth pace. Hormonal agents for treating metastatic disease include megestrol acetate with alternating tamoxifen, everolimus/letrozole combination, progestational agents (such as medroxyprogesterone acetate and megestrol acetate), aromatase inhibitors, tamoxifen alone, or fulvestrant.312- 317 No particular drug, dose, or schedule has been found to be superior. The main predictors of response in the treatment of metastatic disease are well- differentiated tumors, expression of ER/PR receptors, a long disease- free interval, and the location and extent of extrapelvic (particularly pulmonary) metastases.. For asymptomatic or low- grade disseminated metastases, hormonal therapy with progestational agents has shown good responses, particularly in patients with ER/PR- positive disease.318- 321 Tamoxifen has a . Everolimus combined with letrozole is recommended for recurrent disease of endometrioid histology. In the phase 2 trial, in patients with progressive or recurrent endometrial cancer who had received up to two prior therapies, the clinical benefit rate and objective response rate among 35 evaluable patients was . Other hormonal modalities have not been well- studied, and adjuvant therapy with hormonal agents has not been compared with cytotoxic agents.320,329 If disease progression is observed after hormonal therapy, cytotoxic chemotherapy can be considered. However, clinical trials or best supportive care (see the NCCN Guidelines for Palliative Care available at are appropriate for patients with disseminated metastatic recurrence who have a poor response to hormonal therapy and chemotherapy.. Systemic Therapy. Based on the current data, multiagent regimens are preferred for advanced disease, if tolerated. The NCCN Guidelines for Endometrial Carcinoma has updated the systemic therapy recommendation by including immunotherapy and chemotherapy- based combination regimens. # as preferred, first- line options for recurrent disease. The NRG- GY018, randomized, phase III trial evaluated the benefits of pembrolizumab/carboplatin/paclitaxel regimen over the carboplatin/paclitaxel regimen in 816 patients with stage III or IVA endometrial carcinoma with measurable disease, or stage IVB or recurrent disease of any histologic subtype, except for carcinosarcoma.254 The patients who had received adjuvant therapy at least 12 months before were included. The patients were stratified based on the dMMR or MMR- proficient (pMMR) status of the tumors. The PFS was . Based on the results from the NRG- GY018 and RUBY trials, the NCCN Panel has added pembrolizumab/carboplatin/paclitaxel (except for carcinosarcoma histology) and dostarlimab/ carboplatin/paclitaxel as Category 1, preferred, first- line therapy options for recurrent endometrial carcinoma.. Chemotherapy for endometrial cancer has been extensively studied.330,331 Other multiagent regimens such as carboplatin/paclitaxel, . Carboplatin and paclitaxel is an increasingly used regimen for advanced/metastatic or recurrent endometrial cancer; the response rate is about . A phase II trial initially examined the addition of bevacizumab to carboplatin and paclitaxel among 15 patients with advanced or recurrent endometrial carcinoma.339 Although this study was closed early due to the initiation of a national trial, a retrospective analysis was performed to include data from an additional 27 patients who had received carboplatin/paclitaxel/bevacizumab for advanced or recurrent disease.340 Collective median PFS was 20 months with a median OS of 56 months. An overall response rate (ORR) of . Other combination therapies such as cisplatin/doxorubicin, cisplatin/doxorubicin/paclitaxel, ifosfamide/paclitaxel (for carcinosarcoma),. # and cisplatin/ifosfamide (for carcinosarcoma) are added as subsequent- therapy options. A phase III randomized trial (GOG 177) compared 2 combination chemotherapy regimens in females with advanced/metastatic or recurrent endometrial carcinoma. The 273 participants were randomly assigned to 1) cisplatin/doxorubicin/paclitaxel; or 2) cisplatin/doxorubicin. The 3- drug regimen was associated with improved survival (15 vs. 12 months, . If multiagent chemotherapy regimens are contraindicated, then single- agent therapy options for recurrent disease include cisplatin, carboplatin, doxorubicin, liposomal doxorubicin, paclitaxel, albumin- bound paclitaxel, topotecan, temsirolimus, cabozantinib, and docetaxel (category 2B for docetaxel).320,346- 348321,349 When single agents are used as second- line treatment, responses range from . Useful in Certain Circumstances, Biomarker- Directed Therapies In the advanced endometrial cancer cohort . Further studies have indicated that pembrolizumab monotherapy is less active in patients with microsatellite- stable or pMMR disease versus MSI- H/dMMR disease. Only . # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Uterine Neoplasms. 827 patients with pMMR (MSI- stable), previously treated advanced endometrial cancer to receive pembrolizumab/lenvatinib combination or chemotherapy (doxorubicin or paclitaxel).366 The median PFS for the pembrolizumab/lenvatinib arm was 7.2 months versus 3.8 months for the chemotherapy arm (HR, 0.56; . Other anti- PD- 1 inhibitors, such as docetarlimab and nivolumab, have also shown antitumor activity against MSI- H tumors. Dostarlimab is being evaluated in the ongoing GARNET phase 1 trial for patients with advanced endometrial cancer with dMMR/MSI- H disease. The ORR after 16.3 months was . Nivolumab monotherapy has also demonstrated promising activity in endometrial carcinoma with dMMR tumors.367 The PD- L1 inhibitor, avelumab, has shown an ORR of . Systemic Therapy Options for High-Risk Endometrial Histologies. The NCCN Panel notes that the systemic therapy options recommended in the NCCN Guidelines can be used for all carcinoma histologies. Among these, carboplatin/paclitaxel is included as a category 1, preferred option for patients with carcinosarcoma histology. A randomized phase II study examined the addition of trastuzumab to carboplatin/paclitaxel for patients with advanced or recurrent HER2/neu- positive uterine serous carcinoma.368 Among patients with stage III/IV disease undergoing primary treatment . # NCCN Guidelines Version 2.2025 Uterine Neoplasms. Radiotherapy Principles. Radiotherapy PrinciplesRT has been a widely used modality in the treatment of patients with endometrial cancer; it clearly improves locoregional control. Tumor- directed RT refers to RT directed at sites of known or suspected tumor involvement and may include EBRT and/or vaginal brachytherapy.121 Imaging is required to assess locoregional extent and to rule out distant metastases before administration of RT. In general, EBRT is directed to the pelvis with or without the para- aortic region. Brachytherapy can be delivered: 1) to an intact uterus, either preoperatively or definitely; or 2) more commonly, to the vagina after hysterectomy. For the purposes of these guidelines, whole abdominal radiotherapy is not considered to be tumor- directed RT. The panel notes that chemoradiation can be given concurrently or sequentially. RT is described in detail in the algorithm, including target areas and doses for pelvic RT and brachytherapy (see Principles of Radiation Therapy in the NCCN Guidelines for Uterine Neoplasms). Although adjuvant RT is typically not associated with high rates of severe morbidity,374 studies have focused on subtle effects on quality of life (eg, diarrhea, bowel symptoms) that deserve further investigation.228,231,375 In the PORTEC- 2 trial, vaginal brachytherapy was associated with better quality of life when compared with EBRT without a significant detriment to outcome.229 Therefore, many patients who were previously treated with adjuvant EBRT are now appropriately treated with vaginal brachytherapy; this recommendation is reflected in the NCCN Guidelines. Patients treated with RT are prone to vaginal stenosis, which can impair sexual function. Individuals assigned female at birth can use vaginal dilators to prevent or treat vaginal stenosis. Dilator use can start 2 to 4 weeks after RT is completed and can be used indefinitely ( care/patient- education/vaginal- health).. Post-Treatment Surveillance. The recommended post- treatment surveillance protocol for endometrial cancer is shown in the algorithm (see Surveillance in the NCCN Guidelines for Endometrial Carcinoma).43,49 These recommendations recognize that the value of intensive surveillance has not been demonstrated in this disease; therefore, ancillary testing is not recommended.376,377. Patients with clinical stage I and stage II endometrial cancer have a recurrence rate of approximately . History and physical exam is recommended every 3 to 6 months for the first 2 to 3 years, and then every 6 to 12 months thereafter for up to the fifth year, then annually. For non- fertility sparing treatment, imaging should be guided by patient symptoms, risk assessment, and clinical concern for recurrent or metastatic disease. The indications of metastatic disease may include abnormal physical exam finding, bulky uterine tumor, vaginal or extrauterine involvement, delay in presentation or treatment, and abdominal or pulmonary symptoms. For fertility- sparing treatment, the panel recommends repeat pelvic MRI (preferred) for patients with persistent endometrial carcinoma after 6 to 9 months of failed medical therapy, especially if considering further fertility- sparing approaches. Abdominal/pelvic MRI and/or chest CT is recommended based on symptoms or physical exam findings. Whole body FDG- PET/CT and/or. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Uterine Neoplasms. abdomen/pelvis MRI can be considered in select patients as clinically indicated.. In the absence of recurrence, post- treatment surveillance provides psychosocial reassurance and improves quality of life for patients and their families. Health maintenance has been incorporated into the follow- up schedule (eg, blood pressure determination, breast examination, mammography as clinically indicated, stool guaiac test, immunizations). Patients should receive counseling and education regarding lifestyle, obesity, exercise, smoking cessation, sexual health, nutrition, and potential late or long- term effects of treatment (see the NCCN Guidelines for Survivorship (available at the NCCN Guidelines for Smoking Cessation (available at and 383 Other health problems that often coexist in patients with endometrial cancer can also be evaluated during follow- up.. Given the lack of prospective studies regarding the optimal frequency of post- treatment follow- up, the NCCN Panel believes that the algorithm represents a reasonable surveillance scheme. The use of vaginal cytology is no longer recommended for patients who are asymptomatic consistent with the SGO guidelines.376,377,380,384 Patients with stage I endometrial cancer have a low risk of asymptomatic vaginal recurrence . Hormone Therapy for Hypoestrogenism. After BSO, hypoestrogenism is associated with hot flashes, mood lability, vaginal dryness, pelvic soft tissue atrophy, osteoporosis, and an increased risk of cardiovascular disease. In patients who are postmenopausal, estrogen therapy was believed to reduce or reverse some of these signs and symptoms. However, patients who have had BSO for endometrial adenocarcinoma have usually been denied estrogen therapy for fear of inducing a higher relapse rate, because this cancer has historically been considered an estrogen- linked malignancy.387,388 As such, estrogen therapy for such patients remains controversial.. However, it has never been proven that relapse rates are higher in patients with endometrial cancer who receive estrogen therapy after hysterectomy. Several retrospective trials of estrogen therapy after treatment of early- stage endometrial cancer have shown no increase in tumor recurrence or cancer- related deaths.389- 391 In females with stage I to II endometrial cancer who had hysterectomy, a randomized trial of estrogen therapy versus placebo did not find an increased rate of recurrence or new malignancy; the median follow- up was 35.7 months.392 However, estrogen trials in postmenopausal females without a history of malignancy have demonstrated a significantly increased risk for breast cancer.393. Initially, the Women's Health Initiative (WHI) Estrogen- Alone Trial in females who had hysterectomy . # The NCCN Panel agrees that estrogen therapy is a reasonable option for patients who are at low risk for tumor recurrence, but initiating such therapy should be individualized and discussed in detail with the patient.396,397 If adjuvant treatment is carried out, there should be a 6- to 12- month waiting period before initiation of hormone therapy, and participation in clinical trials is strongly encouraged. Selective estrogen- receptor modulators (SERMs) may prove to be attractive options for hormone therapy.398,399 Long- term comparisons between conjugated estrogens and SERMs for hormone therapy are needed. Non- hormonal therapy may be considered in patients who are deemed poor candidates for hormone therapy (eg, people who smoke, those with a history of breast cancer, those with a history of multiple strokes).400,401. Uterine Sarcomas. Overview. Uterine sarcomas are uncommon malignant mesenchymal tumors, accounting for approximately . Pathology and Molecular Analysis. Expert gynecologic pathology review is recommended for the assessment and histologic differentiation of uterine sarcomas including uLMS, UUS,. ESS, and adenosarcoma.83 The pathologic assessment of the uterus should include hysterectomy type, specimen integrity (intact, opened, morcellated, or other), tumor size, myometrial invasion (for adenosarcoma only), histologic type, grade (for adenosarcoma only), and LVsI. The assessment should also include other tissues/organ involvement (fallopian tubes, ovaries, vagina, parametrium, omentum, or other).. Peritoneal/ascitic fluid cytology should also be done. If the lymph nodes are resected, the level of nodal involvement and the number of lymph nodes with metastasis should be determined. Routine node dissection is not required in the absence of clinical suspicion of nodal involvement.. Recent advances have expanded our understanding of the molecular features of these tumors, leading to the identification of genetic signatures that characterize some of the uterine sarcoma subtypes. Historically, mesenchymal tumors were primarily diagnosed using histopathologic criteria, and the results of molecular studies were not used in routine pathologic evaluation. However, given the overlap in histopathologic features of these tumors, molecular analysis (eg, identification of characteristic translocations) can help classify difficult cases and provide future therapeutic targets. The panel notes that comprehensive genomic profiling in the setting of metastatic disease with a validated and/or FDA- approved assay is informative for predicting rare pan- tumor- targeted therapy opportunities. The panel recommends testing of at least NTRK, MSI, and TMB proteins. Since the molecular profiling is informative in many mesenchymal malignancies for accurate classification,405 the NCCN Guidelines for Uterine Neoplasms include a table containing information on histologic and molecular findings, specific biomarkers, relevant confirmatory molecular tests, prognostic features, and other clinically useful information to help clinicians differentiate between and classify uterine sarcoma subtypes. This information is intended to complement histopathologic testing to improve differential diagnosis of relatively rare uterine sarcoma subtypes and provide safer, more effective care for. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Uterine Neoplasms. patients with the disease. The panel notes that this information is not exhaustive and intends to update these recommendations as more data becomes available.. Low- Grade and High- Grade Endometrial Stromal Sarcoma (ESS) ESSs are the second most common mesenchymal tumors of the uterus. ESSs are composed of cells resembling the endometrial stroma in the proliferative phase.404,406 LGESSs have distinct fingerlike patterns of myometrial invasion, and LVSl is usually present. ESS displays a heterogenous mix of morphologic and genetic features. A significant proportion of these tumors (ie, up to half) harbor JAZF1, PHF1, or EPC1 gene fusions and present as earlier- stage tumors.407- 410 The panel notes that diagnosis of low- grade ESS can be confirmed by identifying any lowgrade ESS- associated gene fusion by using FISH and/or targeted RNA sequencing, though the lack of rearrangement or fusion does not exclude the diagnosis. It is worth noting that in rare instances, low- grade ESS can transform into high- grade ESS (either at the time of primary diagnosis or recurrence), which will require histopathologic and molecular (eg, JAZF1 or PHF1 translocation) confirmation.. A higher- grade and more aggressively behaving ESS variant with a unique genetic rearrangement YwHAE::FAM22A/B, also known as YwHAE::NUTM2A/B, has been identified.411,412 This subtype is known as high- grade ESS. Another subtype of high- grade ESS harboring BCOR is either in the form of a ZC3H7B::BCOR fusion or an internal tandem duplication. Both ZC3H7B::BCOR fusion- positive and BCOR internal tandem duplication high- grade ESS have spindle and/or round cells embedded in myxoid matrix, and demonstrate strong and diffuse positivity for cyclin D1 and variable positivity for CD10, ER, and PR.413 IHC testing for CD10, cyclin D1, and BCOR and, in some cases, molecular analysis of BCOR alterations, may help differentiate between BCOR- altered high- grade ESS and myxoid uterine leiomyosarcoma . These findings provided support for subdividing ESS into distinct low- and high- grade entities based on histopathology, clinical behavior, and patient outcomes. The updated 2014 edition of the WHO Classification of Tumors of Female Reproductive Organs recognizes low- grade ESS and highgrade ESS as distinct histopathologic entities.414 The 5th edition on Female Genital Tumors in 2020 also recognizes BCOR- altered sarcomas as a distinct subtype of high- grade ESS.415. Unidifferentiated Uterine Sarcoma (UUS). UUSs are a group of high- grade/aggressive sarcomas characterized by infiltrative sheets of epithelioid and/or spindle cells that may be uniform or pleomorphic. As a class, it is a heterogenous group of high- grade mesenchymal neoplasms of the uterus that fail to meet the diagnostic threshold for other characterized uterine mesenchymal neoplasms. As such, UUS is usually reserved as a diagnosis of exclusion, after other defined uterine mesenchymal neoplasms have been excluded using a multiprong approach that often requires a combination of extensive IHC panel and next- generation sequencing (NGS) molecular analysis. For example, high- grade ESS is often misdiagnosed as UUS due to a shared lack of smooth muscle differentiation.416 The panel notes that molecular testing for BCOR alterations, which can occur in high- grade ESS as noted above, is useful to exclude a high- grade ESS diagnosis before rendering a diagnosis of UUS.. A subset of UUSs called SMARCA4- deficient uterine sarcomas (SDUSs) have distinctive morphology (eg, phylldiform architecture) along with biallelic inactivation of SMARCA4 that results in loss of SMARCA4/BRG1 expression. These tumors occur in younger patients and may be associated with very aggressive clinical behavior.417 The panel. # recommends analysis of SMARCA4/BRG1 by IHC and/or SMARCA4 by DNA sequencing to confirm a diagnosis of SDUS with otherwise appropriate morphologic and immunophenotypic features. However, loss of SMARCA4/BRG1 alone does not constitute a diagnosis of SDUS, and other aggressive malignancies such as undifferentiated endometrial carcinoma may show loss of expression of this protein.. Uterine Leiomyosarcoma (uLMS). uLMS are usually of the spindle cell (conventional) type, but less common variants with myxoid or epithelioid morphology also exist. Although morphology differs between subtypes, all express varying degrees of the smooth muscle markers, including desmin, smooth muscle actin (SMA), and caldesmon. The panel recommends an IHC panel including desmin and SMA to support a uLMS diagnosis, particularly if myxoid or epithelioid uLMS is suspected.. Myxoid uLMSs may appear histologically similar to BCOR- altered HGESSs or inflammatory myofibroblastic tumor (IMT). The panel recommends cyclin D1 and/or BCOR IHC to help exclude an HGESS diagnosis, as the latter is often overexpressed in HGESS. A subset . Uterine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT). UTROSCTs are very rare tumors with sex cord- like differentiation, but without a stromal component as observed in ESSs. Most of these tumors harbor either ESR1 or GREB1 fusions.419,420 The panel recommends an IHC panel that includes sex cord markers (eg, inhibin, calretinin, SF1, FOXL2); UTROSCTs are often positive for a broad range of biomarkers. In some cases, FISH or RNA sequencing for ESR1 or GREB1 fusions may be helpful to confirm the diagnosis. Approximately . Rhabdomyosarcoma. Uterine RMSs are an aggressive, heterogeneous group of tumors that are extremely rare in adult patients. Subtypes include alveolar, embryonal, and pleiomorphic; all express myogenic biomarkers (eg, myogenin and MyoD1).421 Therefore, the panel notes that diffuse expression of myogenic biomarkers by IHC can help confirm a uterine RMS diagnosis. Prognosis differs between subtypes, with embryonal RMS having the best prognosis of the 3 subtypes. Molecular alterations also differ between subtypes. . # NCCN Guidelines Version 2.2025 Uterine Neoplasms. Staging and Treatment. When evaluating suspected uterine sarcomas, biopsy may be helpful but is less sensitive than for endometrial cancers. The diagnosis of ESS and uLMS is often made after hysterectomy. The previous FIGO/AJCC staging systems for endometrial cancer were not appropriate for staging ESS and uLMS; patients were often upstaged when using the older AJCC staging system.423 A new staging system for ESS and uLMS from FIGO/AJCC took effect in 2009 accounting for the differences between uterine sarcomas and endometrial cancers.63,424. Confirmation of the type of mesenchymal malignancy by expert pathology review is critical. In addition, initial evaluation should include imaging of the chest/abdomen/pelvis by CT or combination MRI/CT. It is important to determine if the sarcoma is confined to the uterus or if extrauterine disease is present. Pelvic MRI can be used to evaluate local tumor extension or residual abnormality in cases where the uterus or adnexa were not resected or incompletely resected (ie, supracervical hysterectomy, myomectomy, possible tumor fragmentation, intraperitoneal morcellation). Neck/chest/abdomen/pelvis/groin FDG- PET/CT may be used to clarify ambiguous findings. If medically operable, then hysterectomy with (or without) BSO and en bloc resection of tumor is the initial treatment of choice for uterine sarcomas (see Primary Treatment in the NCCN Guidelines for Uterine Sarcoma).425. The panel recommends ER/PR testing for LMS, ESS, and adenosarcoma to guide decisions regarding management of the ovaries, particularly in young patients who are premenopausal. In general, BSO is favored for low- grade ESS or tumors expressing ER/PR, although management of the ovaries may be individualized in patients of reproductive- age.426 A systemic review and meta- analysis of 786 patients reported . Uterine sarcoma should be removed en bloc to optimize outcomes; intraperitoneal morcellation is contraindicated.171,174 For incidental diagnoses of uterine sarcoma after hysterectomy, or in the case of a fragmented specimen, imaging is recommended and re- exploration for surgical resection can be considered. The ovaries may be preserved in selected patients with early- stage uLMS who wish to retain hormonal function.429 Additional surgical resection should be individualized based on clinical scenarios and intraoperative findings. Lymphadenectomy is controversial.2,404,429- 432 High- grade uterine sarcomas tend to show hematogenous metastases to the lungs; lymph node metastases are uncommon.. For medically inoperable sarcomas, options include: systemic therapy and/or palliative EBRT with (or without) brachytherapy.. Low-Grade Endometrial Stromal Sarcoma. Recommended adjuvant therapy options for stage I ESS include BSO or observation (if menopausal or prior BSO). BSO with (or without) anti- estrogen hormone therapy is recommended for stages II to IV ESS. Adjuvant EBRT may be added for stage II, III, or IVA (category 2B). Palliative EBRT may be added for patients with stage IVB disease.404,433,434 Anti- estrogen hormone therapy is also recommended for ESSs that have recurred or are unresectable (see Therapy for Relapse in the NCCN Guidelines for Uterine Sarcoma).435 Given the histologic similarities between low- grade ESS and uterine adenosarcoma, the panel recommends similar adjuvant therapy options for adenosarcoma as provided for low- grade ESS. For patients with uterine adenosarcoma with sarcomatous overgrowth (SO) in advanced stages, the panel recommends BSO with a consideration of systemic therapy and EBRT. EBRT is palliative for stage IVB disease.. # Case series of patients with ESS suggest long disease- free intervals in the absence of specific therapy and raise questions about the use of adjuvant RT.436 Adjuvant radiotherapy in ESS has been demonstrated to reduce local recurrence rates but again with limited effect on survival.437,438 Because of concerns about radiation exposure, frequent routine surveillance imaging is no longer recommended for patients who are young and asymptomatic after primary therapy for ESS.439. Although anti- estrogen hormone therapy is recommended for low- grade ESS, studies have not yet determined the optimal therapeutic approach for high- grade ESS. However, due to the more aggressive nature of these tumors (eg, those with YWHAE- FAM22 rearrangements), the NCCN Panel has recommended that high- grade ESS be treated according to the algorithms in place for uLMS and UUS.. Typical hormone therapy for low- grade ESS or adenosarcoma without SO or ER/PR- positive uterine sarcoma includes aromatase inhibitors440 (preferred for low- grade ESS or adenosarcoma without SO), fulvestrant, megestrol acetate (category 2B for ER/PR- positive uterine sarcoma), or medroxyprogesterone acetate (category 2B for ER/PR- positive uterine sarcoma). Gonadotropin- releasing hormone [GnRH] analogs are also included as a category 2B option.404,429,435 For ER/PR- positive uterine sarcomas, the anti- estrogen hormone therapy should preferably be considered for patients with small tumor volume or an indolent growth pace.. High-Grade Endometrial Stromal Sarcoma, Leiomyosarcoma, Undifferentiated Uterine Sarcoma, and PEComa. The role of adjuvant radiotherapy in nonmetastatic disease is controversial. Most available data are retrospective except for a phase II randomized trial.441 Most retrospective studies of adjuvant RT suggest an improvement in local pelvic control but no appreciable or consistent improvement in OS, given the propensity of metastatic extrapelvic disease . The role of adjuvant systemic therapy is also poorly defined; however, adjuvant systemic therapy has been used because of the high risk of systemic relapse. Given the uncertainties regarding any adjuvant treatment for stage I high- grade ESS, uLMS, USS, and other sarcomas (such as PEComa) after complete resection, observation is the only option. A systemic review and meta- analysis concluded that adjuvant chemotherapy in early- stage uLMS was not beneficial in reducing locoregional and distant recurrences over observation.446 Because of the increased risk profile in patients with completely resected stage II and III tumors, the panel believes that it is appropriate to consider adjuvant systemic therapy and/or EBRT. Observation can be considered for patients with completely resected tumors with negative margins. (see Additional Therapy in the NCCN Guidelines for Uterine Sarcoma).447 In patients with stage IV, incompletely resected or metastatic disease, systemic therapy and/or EBRT is generally recommended. For stage IVB disease, systemic therapy with an option of palliative EBRT is recommended.. Treatment of Recurrent or Metastatic Disease. The recurrence rate is high in uLMS (50%- 70%).2 The guidelines provide recommendations based on tumor resectability and patients' prior RT. # exposure (see Therapy for Relapse in the NCCN Guidelines for Uterine Sarcoma). Treatment recommendations are made according to the site and nature of the recurrence.. Local recurrences are classified as recurrence in the vagina/pelvis with imaging that is negative for distant metastatic disease. Surgical and RT treatment pathways are provided. The surgical pathway for treating local recurrence in patients without prior RT exposure includes the option of IORT (category 3 for IORT). Preoperative EBRT with (or without) systemic therapy are also options to consider. For residual disease following surgery in patients without preoperative RT, EBRT with (or without) brachytherapy with (or without) systemic therapy can be considered. Primary RT offers an alternative pathway for treating localized recurrence in patients without prior exposure. EBRT should be given along with the option of brachytherapy and systemic therapy. For both the surgical and RT treatment pathways, further adjuvant systemic therapy should be considered after initial treatment.. Patients with local recurrence who have had prior RT exposure can be treated with: 1) surgery with the option of IORT with (or without) systemic therapy (category 3 for IORT); 2) systemic therapy; or 3) selected reirradiation with EBRT and/or brachytherapy. A retrospective analysis of patients with ESS suggested that cytoreductive resection improved OS in patients with recurrent lesions. 448. Systemic therapy with (or without) palliative EBRT or best supportive care is recommended for metastatic disease.449 For patients with isolated metastases that is resectable, surgical resection or other ablative therapy (eg, radiofrequency ablation, SBRT) may be appropriate. Patients with uLMS who experience longer time to recurrence may have improved survival outcomes following metastasectomy.450 Pre- or postoperative EBRT and/or systemic therapy can be considered. Observation may be an option in select, completely resected cases with no evidence of disease on . Systemic Therapy for Advanced, Metastatic/Recurrent or Inoperable Disease. If systemic therapy is used for treating high- grade uterine sarcoma, preferred first- line therapy options include single- agent doxorubicin, gemcitabine/docetaxel,455- 460 doxorubicin/ifosfamide, and doxorubicin/dacarbazine (see Systemic Therapy in the NCCN Guidelines for Uterine Sarcoma).404,406,449 Doxorubicin is an active single agent for uLMS and is less toxic than combination regimens.404,449. The LMS- 04 phase 3 randomized trial with 150 patients (67 with uLMS and 83 with soft- tissue LMS) tested the benefits of doxorubicin/trabectedin versus doxorubicin alone as first- line therapy. Median PFS for the combination arm was longer than for the doxorubicin arm (12.2 months vs. 6.2 months, respectively; HR, 0.41; 95% CI, 0.29- 0.58; . For second- line or subsequent therapy, trabectedin is included as a preferred option for unresectable or metastatic uLMS that has been treated with a prior anthracycline- containing regimen. Data indicate that trabectedin may be useful in patients who have exhausted standard chemotherapy.461- 464 The phase III data revealed a 2.7- month PFS benefit versus dacarbazine in metastatic liposarcoma or leiomyosarcoma that progressed after anthracycline- based therapy.465 Follow- up subgroup analysis of patients with uLMS (n = 232) revealed PFS of 4.0 months for trabectedin versus 1.5 months for dacarbazine (HR, 0.57; 95% CI, 0.41-. # 0.81; . Eribulin is included based on results from a phase III trial comparing the survival benefit of eribulin and dacarbazine in 452 patients with advanced leiomyosarcoma or adipocytic sarcoma.<sup>484</sup> Median OS was 13.5 and 11.5 months for eribulin and dacarbazine, respectively (HR, 0.77; 95% CI, 0.62- 0.95; . For first- line biomarker- directed therapies, the panel recently added crizotinib, ceritinib, brigatinib, lorlatinib, and alectinib for anaplastic lymphoma kinase (ALK) fusion- positive IMTs for uterine sarcomas based on the literature evidence derived from non- small cell lung cancer.<sup>485- 488</sup> The panel also recommends larotrectinib or entrectinib for NTRK gene fusion- positive tumors. For PEComa, albumin- bound sirolimus is recommended as a first- line therapy option and sirolimus, everolimus, temsirolimus are recommended as second- line or subsequent therapy options. Pembrolizumab has been added for the treatment of patients with unresectable or metastatic TMB- H tumors that have progressed following prior treatment and have no satisfactory alternative treatment options. Olaparib, rucaparib, and niraparib are included as second- line/subsequent therapy options for BRCA2- altered uLMS.<sup>489</sup>. Post-Treatment Surveillance. The recommended post- treatment surveillance protocol for uterine sarcoma is depicted in the algorithm (see Surveillance in the NCCN Guidelines for Uterine Sarcoma). History and physical exam is . Patients should receive education regarding the symptoms of recurrent disease. Patients with bleeding (vaginal, bladder, or rectal), decreased appetite, weight loss, pain (in the pelvis, abdomen, hip, or back), cough, shortness of breath, and swelling (in the abdomen or legs) should seek prompt evaluation and not delay until the next scheduled appointment. Imaging may be helpful in the detection of recurrence. Patients should be educated regarding healthy lifestyle choices, obesity, exercise, smoking cessation, nutrition, and potential long- term and late effects of treatment. See Principles of Gynecologic Survivorship within the NCCN Guidelines for Uterine Neoplasms (also see the NCCN Guidelines for Survivorship, NCCN Guidelines for Smoking Cessation, and x).<sup>381- 383</sup> The panel also recommends patient education regarding sexual health, vaginal dilator use, and vaginal lubricants or moisturizers.. Drug Reactions. Virtually all drugs have the potential to cause adverse hypersensitivity reactions, either during or after the infusion.<sup>490</sup> In gynecologic oncology treatment, drugs that more commonly cause adverse reactions include carboplatin, cisplatin, docetaxel, liposomal doxorubicin, and paclitaxel.. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 2.2025 Uterine Neoplasms. Most of these drug reactions are mild infusion reactions (ie, skin reactions, cardiovascular reactions, respiratory or throat tightness), but more severe allergic reactions (ie, life- threatening anaphylaxis) can occur.491- 493 In addition, patients can have mild allergic reactions or severe infusion reactions. Infusion reactions are more common with paclitaxel.494 Allergic reactions (ie, true drug allergies) are more common with platinum agents (ie, carboplatin, cisplatin).494,495. Management of drug reactions is discussed in the NCCN Guidelines for Ovarian Cancer.494 It is important to note that patients who have had severe life- threatening reactions should not receive the implicated agent again unless under the care of an allergist or expert in managing drug reactions. If a mild allergic reaction has previously occurred and it is appropriate to administer the drug again, a desensitization regimen should be used even if the symptoms have resolved; various desensitization regimens have been published and should be followed.496- 498 Patients must be desensitized with each infusion if they previously had a reaction. Almost all patients can be desensitized (about . Gynecologic Survivorship. Treatment for gynecologic cancer typically involves surgery, chemotherapy, hormone therapy, RT, and/or immunotherapy, which may cause acute, short- term, and long- term toxicities. Surgical approaches may be extensive and cause adhesions to form, which in turn may cause pain and contribute to the development of small bowel obstruction, urinary or gastrointestinal complications (eg, incontinence, diarrhea), pelvic floor dysfunction (manifested by a variety of urinary, bowel, and/or sexual effects), and lymphedema. Chemotherapy agents vary, though commonly used regimens may pose a significant risk of neurotoxicity, cardiac toxicity, cognitive dysfunction, and the development of hematologic cancers. Long- term estrogen deprivation may cause symptoms such as hot flashes, . Following completion of treatment, all gynecologic cancer survivors should receive regular general medical care that focuses on managing chronic diseases (eg, depression, diabetes, hypertension), monitoring cardiovascular risk factors, receiving recommended vaccinations, and encouraging adoption of a healthy lifestyle (eg, promoting exercise, smoking cessation). In order to assess the late and long- term effects of gynecologic cancers, clinicians should comprehensively document the patient's history, including prior treatment history, and conduct a thorough physical examination followed by necessary imaging and/or laboratory testing. As most treatments for gynecologic cancers will cause sexual dysfunction, early menopause, and infertility, special attention to the resultant medical and psychosocial implications is needed. All patients, whether sexually active or not, should be asked about genitourinary symptoms, including vulvovaginal dryness. Post- radiation use of vaginal dilators and moisturizers is recommended. Psychosocial effects may include psychological (eg, depression, anxiety, fear of recurrence, altered body image), financial (eg, return to work, insurance concerns), and interpersonal (eg, relationships, sexuality, intimacy). Patients should be referred to appropriate specialty providers (eg, physical therapy, pelvic floor therapy, sexual therapy, psychotherapy) as needed, based on prior treatment history and assessed risk of developing late effects and/or existing concerns. Communication and coordination with all clinicians involved in the care of survivors, including primary care clinicians, is critical. Providing survivors with a summary of their treatment and recommendations for follow- up is also recommended. To this end, the. # SGO has developed templates for gynecologic cancer- specific Survivorship Care Plans to aid survivors and their clinicians in summarizing cancer history, treatments received, possible side effects, and recommended follow- up..	None	None	None
0e2f622a630f432396e2843d7abae3e3	NCCN临床实践指南	宫颈癌001-030	# NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Cervical Cancer. Version 4.2025 — March 24, 2025. NCCN.org. NCCN recognizes the importance of clinical trials and encourages participation when applicable and available. Trials should be designed to maximize inclusiveness and broad representative enrollment.. NCCN Guidelines for Patients® available at www.nccn.org/patients. Continue. # NCCN Guidelines Version 4.2025 Cervical Cancer. Nadeem R. Abu- Rustum, MD Q/Chair Memorial Sloan Kettering Cancer Center Susana M. Campos, MD, MPH, MS Vice Chair Dana- Farber/Brigham and Women's Cancer Center Sudha Amarnath, MD S Case Comprehensive Cancer Center/ University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute Rebecca Arend, MD O'Neal Comprehensive Cancer Center at UAB Emma Barber, MD Robert H. Lurie Comprehensive Cancer Center of Northwestern University Kristin Bradley, MD S University of Wisconsin Carbone Cancer Center Rebecca Brooks, MD UC Davis Comprehensive Cancer Center Junzo Chino, MD Duke Cancer Institute Hye Sook Chon, MD Moffitt Cancer Center Marta Ann Crispens, MD Vanderbilt- Ingram Cancer Center Shari Damast, MD Yale Cancer Center/ Smilow Cancer Hospital Christine M. Fisher, MD, MPH S University of Colorado Cancer Center Peter Frederick, MD Roswell Park Comprehensive Cancer Center David K. Gaffney, MD, PhD S Huntsman Cancer Institute at the University of Utah. Stephanie Gaillard, MD, PhD Johns Hopkins Kimmel Cancer Center. Robert Giuntoli II, MD Abramson Cancer Center at the University of Pennsylvania. Scott Glaser, MD S City of Hope National Medical Center. Brooke E. Howitt, MD Stanford Cancer Institute. Kari Kendra, MD, PhD T/Liaison The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute. Lisa Landrum, MD PhD Q Indiana University Melvin and Bren Simon Comprehensive Cancer Center. Jayanthi Lea, MD UT Southwestern Simmons Comprehensive Cancer Center. Nita Lee, MD, MPH Q The UChicago Medicine Comprehensive Cancer Center. Gina Mantia- Smaldone, MD Q Fox Chase Cancer Center. Andrea Mariani, MD Q Mayo Clinic Comprehensive Cancer Center. David Mutch, MD S Siteman Cancer Center at Barnes- Jewish Hospital and Washington University School of Medicine. Christa Nagel, MD Q The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute. Larissa Nekhlyudov, MD, MPH Dana- Farber/Brigham and Women's Cancer Center. Karina Nieto, MD S Case Comprehensive Cancer Center/ University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute. Chika Nwachukwu, MD, PhD S UC San Diego Moores Cancer Center. Mirna Podoll, MD Vanderbilt- Ingram Cancer Center. Kerry Rodabaugh, MD Fred & Pamela Buffett Cancer Center. Ritu Salani, MD UCLA Jonsson Comprehensive Cancer Center. John Schorge, MD St. Jude Children's Research Hospital/ The University of Tennessee Health Science Center. Scott Schuetze, MD PhD University of Michigan Rogel Cancer Center. Jean Siedel, DO, MS Q University of Michigan Rogel Cancer Center. Rachel Sisodia, MD Mass General Cancer Center. Pamela Soliman, MD The University of Texas MD Anderson Cancer Center. Stefanie Ueda, MD UCSF Helen Diller Family Comprehensive Cancer Center. Renata Urban, MD Fred Hutchinson Cancer Center. Emily Wyse Patient Advocate NCCN Nicole McMillian, MS Vaishnavi Sambandam, PhD. Continue. Gynecologic oncology Internal medicine Medical oncology Pathology Patient advocacy. Radiotherapy/Radiation oncology *Discussion Section Writing Committee. # NCCN Cervical Cancer Panel Members Summary of the Guidelines Updates. Workup. Clinical Stage (CERV- 1) Stage IA1 (no LVSI), Stage IA2- IB1 (no LVSI), Stage IA1- IA2 (with LVSI), Stage IB1 not Meeting Conservative Surgery Criteria and Select IB2 (Fertility Sparing) (CERV- 2) Stage IA1 (no LVSI), Stage IA1 (with LVSI Based on Cone/LEEP) (Non- Fertility Sparing) (CERV- 3) Stage IA2- IB1 (Conservative Surgery Criteria Met) (Non- Fertility Sparing) (CERV- 4) Stage IB1 not Meeting Conservative Surgery Criteria, IB2, and Stage IIA1 (Non- Fertility Sparing) (CERV- 5) Stage IB3 and Stage IIA2 (Non- Fertility Sparing) (CERV- 5) Surgical Findings. Adjuvant Treatment (CERV- 6) Stage IIB- IVA (CERV- 7) Incidental Finding of Invasive Squamous or Usual Type Adenocarcinoma After Simple Hysterectomy (CERV- 8) and (CERV- 9) Surveillance (CERV- 10) Locoregional Recurrence (CERV- 11) Stage IVB or Recurrence with Distant Metastases (CERV- 12). Small Cell Neuroendocrine Carcinoma of the Cervix (NECC), Primary Workup (CERV- 13) Small Cell NECC, Locally advanced disease (IIA- IVA) (CERV- 14). Principles of Pathology (CERV- A) Principles of Imaging (CERV- B) Principles of Evaluation and Surgical Staging (CERV- C) Principles of Radiation Therapy (CERV- D) Sedlis Criteria for External Pelvic Radiation After Radical Hysterectomy In Node- Negative, Margin- Negative, Parametria- Negative Cases (CERV- E) Systemic Therapy for Cervical Cancer (CERV- F) Principles of Gynecologic Survivorship (CERV- G). Staging (ST- 1). ABBR- 1. The NCCN Guidelines for Cervical Cancer include the management of squamous cell carcinoma, adenosquamous carcinoma, adenocarcinoma of the cervix, and small cell neuroendocrine carcinoma of the cervix.. The NCCN Guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network (NCCN) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2025.. # Updates in Version 4.2025 of the NCCN Guidelines for Cervical Cancer from Version 3.2025 include:. CERV-5. - Footnote p is new: Induction chemotherapy (carboplatin/paclitaxel) followed by single agent cisplatin (or carboplatin) and radiation given according to the INTERLACE protocol could be considered.(McCormack M, et al. Lancet 2024;404:1525-1535). See Systemic Therapy for Cervical Cancer (CERV-F) (Also for CERV-F). CERV- F 1 of 3. - Chemoradiation; Other Recommended Regimens - New bullet and regimen added: - Induction chemotherapy (followed by chemoradiation): Carboplatin/paclitaxel. CERV- F 1A of 3. - Footnote g is new: Induction chemotherapy (carboplatin/paclitaxel) followed by single agent cisplatin (or carboplatin) and radiation given according to the INTERLACE protocol could be considered.(McCormack M, et al. Lancet 2024;404:1525-1535). CERV- F 3 of 3. - New reference added: McCormack M, Eminowicz G, Gallardo D, et al. INTERLACE investigators. Induction chemotherapy followed by standard chemoradiotherapy versus standard chemoradiotherapy alone in patients with locally advanced cervical cancer (GCG INTERLACE): an international, multicentre, randomised phase 3 trial. Lancet 2024;404(10462):1525-1535.. # Updates in Version 3.2025 of the NCCN Guidelines for Cervical Cancer from Version 2.2025 include:. CERV-7. - Stage II-IVA; Negative for metastasis; Primary Treatment revised: "...± pembrolizumab (category 1 for FIGO 2014 Stage III-IVA IIIA, IIIB, and IVA; category 2B for select FIGO 2018 stage III-IVA)"- Footnote t revised: "Concurrent platinum-containing chemotherapy with EBRT utilizes cisplatin as a single agent (or carboplatin if cisplatin intolerant). Pembrolizumab may be added as follows: Cisplatin (or carboplatin)/RT and pembrolizumab (for FIGO 2014 stage III-IVA IIIA, IIIB, and IVA: Category 1); Cisplatin (or carboplatin)/RT and pembrolizumab (for select FIGO 2018 stage III-IVA: category 2B). Category 2B is for FIGO 2018 stage IIIC purely on nodal metastasis without concomitant tumor characteristics defined in 2014 FIGO Stage IIIA-IIIB. If the FIGO 2018 staging of stage III overlaps with FIGO 2014 IIIA/IIIB staging, category 1 can be applied to cisplatin (or carboplatin) + pembrolizumab...". CERV-F 1 of 3. Chemoradiation; Preferred Regimens revised as follows. - Cisplatin + pembrolizumab - category 1: FIGO 2014 Stage III-IVA IIIA, IIIB, and IVA - category 2B: select FIGO 2018 stage III-IVA - Carboplatin + pembrolizumab if cisplatin intolerant - category 1: FIGO 2014 Stage III-IVA IIIA, IIIB, and IVA - category 2B: select FIGO 2018 stage III-IVA. CERV-F 1A of 3. - Footnote d revised: Concurrent platinum-containing chemotherapy with EBRT utilizes cisplatin as a single agent (or carboplatin if cisplatin intolerant). Pembrolizumab may be added with CRT as follows: Cisplatin (or carboplatin)/RT and pembrolizumab (FIGO 2014 stage III-IVA IIIA, IIIB, and IVA: category 1); Cisplatin (or carboplatin)/RT and pembrolizumab (select FIGO 2018 stage III-IVA: category 2B). Category 2B is for FIGO 2018 stage IIIC purely on nodal metastasis without concomitant tumor characteristics defined in 2014 FIGO Stage IIIA-IIIB. If the FIGO 2018 staging of stage III overlaps with FIGO 2014 IIIA/IIIB staging, category 1 can be applied to cisplatin or carboplatin) + pembrolizumab. Prescribing...". Updates in Version 2.2025 of the NCCN Guidelines for Cervical Cancer from Version 1.2025 include:. CERV-F 1A of 3. - Footnote m regarding Nivolumab and hyaluronidase-nvhy subcutaneous is new: Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and administration instructions compared to IV nivolumab.. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 4.2025 Cervical Cancer. Updates in Version 1.2025 of the NCCN Guidelines for Cervical Cancer from Version 4.2024 include:. General. General- The Guidelines have been extensively revised (including reordered page numbers and footnotes) to incorporate the SHAPE trial data (Plante M, Kwon JS, Ferguson S, et al. Simple versus Radical Hysterectomy in Women with Low- Risk Cervical Cancer. N Engl J Med 2024;390:819- 829. ).. CERV-1. Clinical Stages revised- Stage IA1; Stage IA2- Stage IA2; Stage IB1; Stage IB2- Incidental finding of invasive cancer at after simple (extrafascial) hysterectomy. CERV-2. CERV- 2- Stage IA2- IB1 conservative surgery criteria bullets revised:- 5th bullet: Depth of invasion ≤10 mm on LEEP/cone- 6th bullet: Negative imaging for metastatic locoregional disease (MRI recommended)- Primary Treatment (Fertility Sparing)- "Stage IA2- IB1 (based on cone biopsy and all conservative surgery criteria must be met)..."; Primary Treatment revised: Cone biopsy with negative margins + sentinel lymph node [SLN] mapping or pelvic lymphadenectomy or sentinel lymph node [SLN] mapping- New bifurcated pathways for Pelvic lymph node(s) negative and Pelvic lymph node(s) positive added- Stage IA1- IA2 with LVSI: "...(if positive margins, repeat cone biopsy or perform trachelectomy) + SLN mapping or pelvic lymphadenectomy (consider SLN mapping) or Radical trachelectomy + SLN mapping or pelvic lymphadenectomy (consider SLN mapping)"- Stage IB1 not meeting conservative surgery criteria; Select IB2: Radical trachelectomy + SLN mapping or pelvic lymphadenectomy + pelvic lymphadenectomy ± para- aortic lymphadenectomy (consider SLN mapping). CERV-3. CERV- 3- Primary Treatment (Non- Fertility Sparing)- Stage IA1 no LVSI- Negative margins and medically operable: Extrafascial Type A hysterectomy- Positive margins for dysplasia or carcinoma and medically inoperable: Consider repeat cone biopsy added as an option- Positive margins for dysplasia or carcinoma and medically operable: "...Extrafascial Type A (if margins positive for dysplasia) or modified Type B radical hysterectomy + SLN mapping or pelvic lymphadenectomy (if margins positive for carcinoma) (category 2B for node dissection) (consider SLN mapping)- New pathways added for Stage IA1 with LVSI (based on cone/LEEP)- Removed: Stage IA1- IA2 with LVSI. CERV-3A. CERV- 3A- Footnote removed: For patients who are at higher risk, such as those who are IA2 with LVSI, consideration can be given to adding concurrent platinum- containing chemotherapy with external beam RT (EBRT) utilizing cisplatin as a single agent (or carboplatin if cisplatin intolerant). (See Systemic Therapy for Cervical Cancer CERV- F). # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 4.2025 Cervical Cancer. Updates in Version 1.2025 of the NCCN Guidelines for Cervical Cancer from Version 4.2024 include:. CERV-4. - New Stage IA2-IB1 Primary Treatment (Non-Fertility Sparing) pathway with revised conservative surgery criteria added.- The conservative surgery criteria was revised as follows - Cone biopsy (preferred) - No LVS1 (preferred) - Negative cone margins (preferred) - Squamous cell (any grade) or usual type adenocarcinoma (grade 1 or 2 only) (preferred), or adenosquamous carcinoma - Tumor size ≤2 cm - Depth of invasion ≤10 mm on cone. If no conization, MRI must show <50% cervical stromal invasion - Negative imaging for metastatic disease (MRI recommended). CERV-5. - Clinical Stage revised: Stage IB3 and Stage IIA2 (also see CERV-6 for additional recommendations for non-primary surgery patients) - Primary Treatment (Non-Fertility Sparing) - Stage IB1 not meeting conservative surgery criteria; Stage IB2; Stage IIA1: Recommendation revised, "Type C1 radical hysterectomy + SLN mapping or pelvic lymphadenectomy (category 1) ± para-aortic lymphadenectomy (category 2B) (consider SLN mapping)... - Stage IB3 and Stage IIA2 revised: Type C1 radical hysterectomy + pelvic lymphadenectomy ± para-aortic lymphadenectomy (category 2B). CERV-6. - Positive pelvic nodes and/or Positive surgical margin and/or Positive parametrium pathway; Adjuvant Treatment: Revised, EBRT + concurrent platinum-containing chemotherapy (category 1) ± vaginal brachytherapy. CERV-7. - The algorithms for Stage IB3, Stage IIA2; Stage IIB, III, IVA were extensively revised and streamlined. - This is a new page that provides primary treatment recommendations for Stage IIB-IVA including - Primary treatment includes EBRT + concurrent platinum-containing chemotherapy + brachytherapy ± pembrolizumab (category 1 for FIGO 2014 Stage III-IVA; category 2B for FIGO 2018 stage III-IVA) - Footnote s is new: Extended field RT is recommended when para-aortic nodes are involved by imaging or confirmed on pathology. This may also be added in select patients with positive pelvic nodes such as common iliac metastasis. - Footnote t added: Concurrent platinum-containing chemotherapy with EBRT utilizes cisplatin as a single agent (or carboplatin if cisplatin intolerant). Pembrolizumab may be added as follows: Cisplatin (or carboplatin)/RT and pembrolizumab (for FIGO 2014 stage III-IVA: Category 1); Cisplatin (or carboplatin)/RT and pembrolizumab (for FIGO 2018 stage III-IVA: category 2B) (See Systemic Therapy for Cervical Cancer [CERV-F]). - Footnote removed: Concurrent platinum-containing chemotherapy with EBRT utilizes cisplatin as a single agent (or carboplatin if cisplatin intolerant). Pembrolizumab may be added with CRT ONLY for patients with FIGO 2014 Stage III-IVA cervical cancer.. # Updates in Version 1.2025 of the NCCN Guidelines for Cervical Cancer from Version 4.2024 include:. CERV-8. - Column header revised: Incidental Finding of Invasive Squamous or Usual Type Adenocarcinoma Career After Simple (Extrafascial) Hysterectomy (Also for CERV-9)- Stage IA1 pathway revised: No LVS1, negative margins- Stage IA1 with LVS1 and negative margins is a new algorithm pathway.- Revised: Stage IA2-IB1 cervical carcinoma (based on total hysterectomy [TH] and all conservative surgery criteria must be met): - Conservative surgery criteria revised - Negative margins - No LVS1 (preferred) - Squamous cell (any grade) or usual type adenocarcinoma (grade 1 or 2 only) (preferred) or adenosquamous carcinoma - Tumor size ≤2 cm - Depth of invasion ≤40 <10 mm - Negative imaging for metastatic disease (MRI recommended)- Treatment recommendation revised: "Pelvic EBRT + brachytherapy ± concurrent..." changed to "Pelvic EBRT ± brachytherapy ± concurrent..."- Any hysterectomy with a positive margin for cancer is a new algorithm pathway. CERV-9. - This page was extensively revised and contains treatment recommendations for Stage IA1-IA2 with LVS1 or Stage IB1-IB2 not meeting conservative surgery criteria AND negative margins on hysterectomy AND sedulis criteria not met or Positive margins/gross residual disease. CERV-10. - Surveillance; 5th bullet revised: Patient education regarding symptoms of potential recurrence, lifestyle, obesity, exercise, sexual health (eg, vaginal dilator use, lubricants/moisturizers, hormone therapy for menopause), smoking cessation, nutrition counseling, and Clinical evaluation and management of potential long-term and late effects of treatment (Also see Principles of Gynecologic Survivorship (CERV-G)...)- Footnote bb revised: Principles of Gynecologic Survivorship (CERV-G). Patient education should include symptoms of potential recurrence, lifestyle, obesity, exercise, sexual health (including vaginal dilator use and lubricants/moisturizers, local estrogen, and hormone therapy for menopause), smoking cessation, and nutrition counseling.. CERV-11. - First column revised: Local Locoregional recurrence- Top pathway revised: No prior RT or failure recurrence outside of previously-treated RT field. # National NCCN Guidelines Version 4.2025 Comprehensive Cancer Network@ Cervical Cancer. Updates in Version 1.2025 of the NCCN Guidelines for Cervical Cancer from Version 4.2024 include:. Small Cell Neuroendocrine Carcinoma of the Cervix (NECC). CERV- 13. - Staging designations added - Stage IA1-1B2 (Tumor ≤4 cm) - Stage IB3 (Tumor >4 cm) - Locally advanced disease (Stage I/A-IVA) - Metastatic disease (Stage IVB) - Primary Treatment; Stage IB3 (Tumor >4 cm) revised: Chemoradiation + brachytherapy (preferred) CERV-14 - First column revised: Locally advanced disease (HB3-IVA I/A-IVA). All Histologies. CERV- A Principles of Pathology. CERV- A 1 of 7 Squamous Cell Carcinoma, Adenocarcinoma, or Adenosquamous Carcinoma - 1st bullet; Procedure: Conization, trachelectomy, Type A hysterectomy, and Type B and C radical hysterectomy - New bullet added: Additional molecular testing and biomarkers - 3rd arrow sub- bullet revised: HER2 immunohistochemistry (IHC) testing (with or without reflex to HER2 fluorescence in situ hybridization [FISH] for equivocal IHC) is recommended for advanced, metastatic, or recurrent cervical carcinoma. - New arrow sub- bullet added: In the setting of metastatic or recurrent disease, consider comprehensive molecular profiling by an FDA- approved assay, or a validated test performed in a CLIA- certified laboratory including at least HER2, mismatch repair (MMR)/microsatellite instability (MSI), tumor mutational burden (TMB) testing, NTRK, and RET for predicting rare pan- tumor targeted therapy opportunities. - The arrow sub- bullets below were removed and incorporated into one new bullet as noted above: - Recommend mismatch repair (MMR)/microsatellite instability (MSI) testing for patients with recurrent, progressive, or metastatic cervical carcinoma; and/or NTRK gene fusion testing for patients with cervical sarcoma - Consider comprehensive molecular profiling as determined by an FDA- approved assay, or a validated test performed in a CLIA- certified laboratory. - Consider RET gene fusion testing for patients with locally advanced or metastatic cervical cancer. # Updates in Version 1.2025 of the NCCN Guidelines for Cervical Cancer from Version 4.2024 include:. CERV-B 1 of 4. - Initial Workup;. - Stage I; Non-Fertility Sparing. - New diamond sub-bullet added: Pelvis MRI recommended if considering definitive treatment with a conization, trachelectomy, or Type A hysterectomy.. - 2nd diamond sub-bullet added: "Consider pelvis MRI with contrast to assess...". - 4th diamond sub-bullet revised: "... to evaluate for metastatic disease and pelvic pelvis MRI to assess pelvic residual disease...". - Stage II-IVA. - 1st arrow sub-bullet: "Pelvis MRI with contrast to assess local disease extent (preferred)." This information is in footnote a. - 4th arrow sub-bullet revised: "...and pelvis MRI with contrast to assess pelvic residual disease." This information is in footnote a.. - Footnote a revised: MRI is performed with and without contrast and CT is performed with contrast unless contraindicated. Although contrast is not required for screening chest CT, it may be performed with or without contrast during initial workup for fertility sparing. (Also for CERV-B 2 of 4 and CERV-B 3 of 4). CERV-B 2 of 4. - Follow-up/Surveillance: Pelvic MRI with contrast changed to "pelvis MRI with contrast" throughout this section. The information is in footnote a.. CERV- C Principles of Evaluation and Surgical Staging. CERV- C 1 of 9. - Types of Resection and Appropriateness for Treatment of Cervical Cancer; New bullets added:. - For select patients with Stage IA2-IB1 who desire fertility preservation, a conization with negative margins with negative bilateral pelvic SLN or lymphadenectomy is a reasonable strategy if the patient meets all the following conservative surgery criteria:. - Cone biopsy with negative margins. - No LVSI. - Squamous cell cancer (any grade) or usual type adenocarcinoma (grade 1 or 2).. - Tumor size ≤2 cm. - Depth of invasion ≤10 mm on LEEP/cone. - Negative imaging for locoregional disease (MRI recommended). - The radical vaginal trachelectomy with laparoscopic SLN mapping or lymphadenectomy offers a fertility-sparing option for carefully selected individuals with stage IA2 or stage IB1 lesions (<2 cm diameter). The cervix, 1-2 cm upper vagina, and supporting ligaments are removed as with a type B radical hysterectomy, but the uterine corpus is preserved. In more than 300 subsequent pregnancies currently reported, there is a 10% likelihood of second trimester loss, but 72% of patients carry their gestation to 37 weeks or more. The abdominal radical trachelectomy is a reasonable fertility-sparing strategy. It provides larger resection of parametria than the vaginal approach, is suitable for select stage IB1-IB2 cases and has been utilized in lesions between 2-4 cm in diameter. The operation mimics a type C1 radical hysterectomy.. - Footnote b added: For a description of a type C1 radical hysterectomy, see Table 1 (CERV-C 6 of 9).. # Updates in Version 1.2025 of the NCCN Guidelines for Cervical Cancer from Version 4.2024 include:. CERV-C 2 of 9. Types of Resection and Appropriateness for Treatment of Cervical Cancer; New bullets added:. - First bullet revised: "Radical hysterectomy with bilateral pelvic SLN mapping or lymphadenectomy (with or without SLN mapping) is a the preferred treatment option for FIGO stage IA2, IB1, IB2, and select IB3-IA1 lesions when fertility preservation is not desired. Radical hysterectomy (Type B or C) results in resection of much wider margins compared with a simple Type A hysterectomy, including removal of parts of the cardinal paracervix and uterosacral ligaments and the upper 1-2 cm of the vagina; in addition, pelvic and sometimes para-aortic nodes are removed...". 2nd bullet revised: "...See Discussion for additional details. Studies comparing robotic versus open approach are ongoing.". 3rd bullet revised. Based on a randomized trial comparing simple to radical hysterectomy, select patients with Stage IA2- IB1 disease based on cone biopsy and who meet all the conservative surgery criteria listed below, may be treated with a conization or simple Type A hysterectomy with sentinel node mapping or SLN mapping or bilateral pelvic lymphadenectomy or sentinel node mapping:. - Cone biopsy (preferred). - No LVSI (preferred). - Negative cone margins (preferred). - Squamous cell cancer (any grade) or usual type adenocarcinoma (grade 1 or 2 only) (preferred), or adenosquamous carcinoma. - Tumor size ≤2 cm. - Depth of invasion ≤40 <70 mm on cone. If no conization, MRI must show <50% cervical stromal invasion - Negative imaging for metastatic disease (MRI recommended). New bullet added: Definitive treatment with a conization or simple Type A hysterectomy has not been studied in the more aggressive histologies such as gastric type adenocarcinoma, clear cell, and small cell neuroendocrine carcinoma.. CERV-C 3 of 9. - 2nd bullet revised: For patients who experience treatment-related menopause, ovarian preservation or transposition should be considered when feasible. Ovarian preservation or ovarian transposition outside of pelvic radiation boundaries should be considered when feasible to avoid surgical or radiation induced menopause.. 4th bullet revised: "... If the recurrence is confined to the pelvis (preferable central pelvic), then surgical exploration is carried out. If intraoperative margin and node assessment are appear negative, then resection of pelvic viscera is completed...". New bullet added: In very select cases where there is documented evidence of persistent or recurrent small volume cervical disease (<2 cm) after radiation/chemoradiation and no metastatic disease, a radical hysterectomy instead of pelvic exenteration may be considered. The operation that is most likely to obtain a negative margin should be prioritized.. - Bullet removed: The radical vaginal trachelectomy with laparoscopic lymphadenectomy procedure (with or without SLN mapping) offers a fertility-sparing option for carefully selected individuals with stage IA2 or stage IB1 lesions (<2-cm diameter). The cervix, upper vagina, and supporting ligaments are removed as with a type B radical hysterectomy, but the uterine corpus is preserved. In the more than 300 subsequent pregnancies currently reported, there is a 10% likelihood of second trimester loss, but 72% of patients carry their gestation to 37 weeks or more. The abdominal radical trachelectomy is a reasonable fertility-sparing strategy. It provides larger resection of parametria than the vaginal approach, is suitable for select stage IB1-IB2 cases, and has been utilized in lesions between 2-4 cm in diameter. The operation mimics a type C radical hysterectomy.. # Updates in Version 1.2025 of the NCCN Guidelines for Cervical Cancer from Version 4.2024 include:. CERV- C Principles of Evaluation and Surgical Staging (continued) CERV- C 5 of 9. - Principles of Evaluation and Surgical Staging When SLN Mapping is Used- 1st box revised: "Excision of all-mapped SLN.- Last box removed: Parametrectomy is performed en bloc with a resection of the primary tumor- Footnote i removed: Exceptions made for select cases (CERV-C 1 of 7).. CERV-C 6 of 9 and CERV-C 7 of 9. - Table 1: Resection of Cervical Cancer as Primary Therapy- Comparison of Hysterectomy Types - Column header revised: Extra fascial Simple Hysterectomy (Type A) - Simple Hysterectomy (Type A): - Indication revised, Stage IA1--IB1 meeting conservative surgery criteria - Intent revised: Curative for microinvasion- Modified Radical Hysterectomy (Type B); Indication revised: Stage IA1 with LVSI and IA2 changed to Select IA1 with LVSI--IB1- Radical Hysterectomy (Type C1); Indication revised: Local disease without obvious metastasis, including: Select stage IB1--IB2 IB1--IIA1 Selected stage IB3--IIA1- Comparison of Fertility-Sparing Procedure Types - Table header revised: Comparison of Fertility-Sparing Trachelectomy-Procedure Types - New section for Conization added - Simple Trachelectomy - Indication revised: Gareinoma-in-situ and stage IA1--IB1 meeting conservative surgery criteria - Intent revised: Curative for microinvasion and fertility preserved preserving - Radical Trachelectomy - Indication revised: Stage IA2--IB1 not meeting conservative criteria; Select IB2 - Intent revised: Curative for select stage IA2--IB2 Fertility preserved; Curative and fertility preserving. CERV-C 9 of 9. - New reference added: Schmeler KM, Pareja R, Lopez Blanco A, et al. ConCerv: a prospective trial of conservative surgery for low-risk early-stage cervical cancer. Int J Gynecol Cancer 2021;31:1317-1325.. # Updates in Version 1.2025 of the NCCN Guidelines for Cervical Cancer from Version 4.2024 include:. CERV- D Principles of Radiation Therapy CERV- D 1 of 9 General Principles - 5th bullet revised: "... concurrent platinum- containing chemotherapy with or without immunotherapy is given during the time of EBRT..." General Treatment Information Target Volumes 3rd arrow sub- bullet revised: "...up to the level of the renal vessels (or even more cephalad as directed by involved nodal distribution). For patients with lower 1/3 vaginal involvement, the bilateral groins should be covered as well." New arrow- sub- bullet added: For patients with lower 1/3 vaginal involvement, the bilateral groins should be covered as well. Inguinofemoral node borders for distal vaginal cases: superior border = acetabular roof, lateral border = inguinofemoral vessels to medial sartorius/rectus femoris, posterior = posterior border of vessels, medial = pectineus muscle or 2.5- 3 cm from vessels, anterior = anterior border of sartorius, caudal = top of lesser trochanter of femur.. CERV-D 2 of 9. Treatment Information - External Beam 2nd bullet revised: "IMRT is helpful in minimizing preferred to minimize the dose to the bowel..." 5th bullet revised: New sentence added to the end, "Consider bladder full and empty CT scans to generate utero- cervical- vaginal internal organ motion (internal target volume [ITV]).". CERV-D 3 of 9. - Definitive RT for an Intact Cervix; 1st bullet revised: "...The primary cervical tumor is then boosted, using brachytherapy, with an additional 30-28 to 40 Gy using either image guidance (preferred) or to point A (in low dose-rate [LDR] equivalent dose), for a total point A dose (as recommended in the guidelines) of 80 Gy for small-volume cervical tumors or ≥85 Gy for larger-volume cervical tumors total dose (EBRT+ brachytherapy) to HRCTV D90 (preferred) of ≥85 Gy (EQD2), or Point A. For very small tumors (medically inoperable IA1 or IA2) EQD2 D90 doses of 75-80 Gy may be considered. Grossly involved unresected nodes may be evaluated for boosting with an additional 10 to 15 Gy of highly conformal (and reduced-volume) EBRT. When using image guidance for EBRT, care must be taken to exclude or severely limit the volume of normal tissue included in the high-dose region(s) (see Discussion). Consider bladder full and empty CT scans to generate utero- cervical- vaginal internal organ motion (ITV). Posthysterectomy Adjuvant Radiation Therapy; 1st bullet revised: New sentence added to the end, Consider bladder full and empty CT scans to generate vaginal internal organ motion (ITV) Intraoperative Radiation Therapy: Designated as category 3.. CERV- D 4 of 9 Treatment Information - Brachytherapy; 3rd bullet revised: "...5 mm or 6 Gy X 3 fractions dosed at the vaginal surface- , to upper 3- 4 cm of the vagina.". CERV- D 5 of 9 Dosing Prescription Regimen - Brachytherapy; 4th bullet revised: "...equivalent to 40 Gy to point A (tumor surrogate dose) using LDR brachytherapy to point A or HR- CTV.". # Updates in Version 1.2025 of the NCCN Guidelines for Cervical Cancer from Version 4.2024 include:. CERV- D Principles of Radiation Therapy (continued) CERV- D 6 of 9. - Page title revised: Normal Tissue Cumulative Dose Constraint Guidelines. - Dose Recommendation, Hard Constraint dosing revised . CERV-D 8 of 9. - Normal Tissue Dose Constraint Guidelines for Cervical Cancer - Table header revised: Brachytherapy (Cumulative with EBRT) - The RT dose measurements throughout the table changed from cGy to Gy.. CERV- F Systemic Therapy for Cervical Cancer CERV- F 1 of 3. - Chemoradiation. - Preferred Regimens; New regimens added - Cisplatin + pembrolizumab - category 1: FIGO 2014 Stage III-IVA - category 2B: FIGO 2018 stage III-IVA - Carboplatin + pembrolizumab if cisplatin intolerant - category 1: FIGO 2014 Stage III-IVA - category 2B: FIGO 2018 stage III-IVA. - Revised: Other Recommended Regimens (if single agent cisplatin and carboplatin are unavailable) - First-line Therapy; Preferred Regimens; New regimens added: - Atezolizumab + cisplatin/paclitaxel + bevacizumab (category 1) - Atezolizumab + carboplatin/paclitaxel + bevacizumab (category 1) - Second-line or Subsequent Therapy - Preferred Regimens: Tisotumab vedotin-tftv changed from category 2A to category 1 - Other Recommended: Cemiplimab moved from Preferred Regimens to Other Recommended Regimens - Useful in Certain Circumstances - PD-L1-positive tumors: Tisotumab vedotin-tftv + pembrolizumab added as an option - Neratinib added for HER2 mutant tumors - NTRK gene fusion-positive tumors: Repotrectinib added as an option.. # Updates in Version 1.2025 of the NCCN Guidelines for Cervical Cancer from Version 4.2024 include:. CERV-F 1A of 3. Footnotes revised - Footnote a: An- FDA- approved biosimilar is an appropriate substitute for bevacizumab An FDA- approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. (Also for CERV- F 2 of 3). - Footnote d: Concurrent platinum- containing chemotherapy with EBRT utilizes cisplatin as a single agent (or carboplatin if cisplatin intolerant). Pembrolizumab may be added with CRT as follows: Cisplatin (or carboplatin)/RT and pembrolizumab (FIGO 2014 stage II- IVA: category 1); Cisplatin (or carboplatin)/RT and pembrolizumab (FIGO 2018 stage II- IVA: category 2B) Pembrolizumab may be added with CRT ONLY for patients with FIGO 2014 Stage III- IVA cervical cancer. Efficacy of concurrent platinum- containing chemotherapy with EBRT utilizing cisplatin as a single agent with pembrolizumab was evaluated in KEYNOTE- A18 (NCT04221945), a multicenter, randomized, double- blind, placebo- controlled trial with 596 patients with FIGO 2014 Stage III- IVA cervical cancer who had not previously received definitive surgery, radiation, or systemic therapy. Prescribing information: - Footnote h: Recommended in patients whose tumors express PD- L1 . # Updates in Version 1.2025 of the NCCN Guidelines for Cervical Cancer from Version 4.2024 include:. CERV-F 3 of 3. References added:. - 8 Oaknin A, Gladieff L, Martinez-Garcia J, et al. ENGOT-Cx10-GEICO 68-C-JGOG1084-GOG-3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet 2024;403:31-43. - 18 Vergote I, Gonzalez-Martin A, Fujiwara K, et al. Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer. N Engl J Med 2024;391:44-55. - 22 Vergote I, Van Nieuwenhuysen E, O'Cearbhaill RE, et al. Tisotumab Vedotin in Combination With Carboplatin, Pembrolizumab, or Bevacizumab in Recurrent or Metastatic Cervical Cancer: Results From innovaTV 205/GOG-3024/ENGOT-cx8 Study. J Clin Oncol 2023;41:5536-5549. - 24 Friedman CF, D'Souza A, Belo Roufai D, et al. Targeting HER2-mutant metastatic cervical cancer with neratinib: Final results from the phase 2 SUMMIT basket trial. Gynecol Oncol 2024;181:162-169. - 25 Solomon B, Drilon A, Lin JJ, et al. Repotrectinib in patients with NTRK fusion-positive advanced solid tumors, including non-small cell lung cancer: update from the phase 1/2 TRIDENT-1 trial. Poster presented at the European Society for Medical Oncology Congress, Madrid, Spain, October 20-24, 2023.. References updated. - 8 Lorusso D, et al. Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: A randomized double-blind, phase 3-ENGOT-cx11/GOG-3047/KEYNOTE-A18 study-ESMO Congress 2023-LBA38. Lorusso D, Xiang Y, Hasegawa K. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial. Lancet 2024;403:1341-1350. - 23 Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: DESTINY-PanTumor02 interim results. Presented at: American Society of Clinical Oncology Annual Meeting; June 2-6, 2023; Chicago, IL: Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: DESTINY-PanTumor02 Phase II trial. J Clin Oncol 2024;42:47-58.. # WORKUP. History and physical (H&P) Complete blood count (CBC) (including platelets) Cervical biopsy, pathologic reviewa Cone biopsy as indicatedb Liver function test (LFT)/ renal function studies Imagingc Smoking cessation and counseling intervention, if indicated (See NCCN Guidelines for Smoking Cessation) Consider HIV testingd Consider examination under anesthesia (EUA) cystoscopy/proctoscopye (≥ stage IB3) Consider options for fertility sparing or referral to reproductive endocrinology and infertility (REI) specialist. a Principles of Pathology (CERV- A). b See Discussion for indications for cone biopsy. Principles of Imaging (CERV- B).. Consider HIV testing, especially in younger patients. Patients with cervical cancer and HIV should be referred to an HIV specialist and should be treated for cervical cancer as per these guidelines. Modifications to cancer treatment should not be made solely on the basis of HIV status. For suspicion of bladder/bowel involvement, cystoscopy/proctoscopy with biopsy is required.. Note: All recommendations are category 2A unless otherwise indicated.. # CLINICAL STAGE. PRIMARY TREATMENT (FERTILITY SPARING)h,i. Stage IA2- IB1 (based on cone biopsy and all conservative surgery criteria must be met): - No LVSI - Negative cone margins - Squamous cell (any grade) or usual type adenocarcinoma (grade 1 or 2 only) - Tumor size ≤2 cm - Depth of invasion ≤10 mm on LEEP/cone - Negative imaging for locoregional disease (MRI recommended). Footnotes on CERV-2A. Note: All recommendations are category 2A unless otherwise indicated.. # FOOTNOTES FOR CERV-2. Principles of Imaging (CERV-B).. Fertility- sparing surgery for stage IB has been most validated for tumors . # # FOOTNOTES FOR CERV-3. Principles of Imaging (CERV- B). Principles of Evaluation and Surgical Staging (CERV- C). CKC is the preferred method of diagnostic excision, but LEEP is acceptable, provided adequate margins and proper orientation are obtained. ECC above the excision should be added, except in pregnancy. Principles of Radiation Therapy (CERV- D). Radiation can be an option for patients who are medically inoperable.. # Stage IA2- IB1 cervical carcinoma (All conservative surgery criteria met):- Cone biopsy<sup>j</sup> (preferred)- No LVSI (preferred)- Negative cone margins (preferred)- Squamous cell (any grade) or usual type adenocarcinoma (grade 1 or 2) (preferred), or adenosquamous carcinoma- Tumor size ≤2 cm- Depth of invasion <10 mm on cone.<sup>j</sup> If no conization, MRI<sup>c</sup> must show <50% cervical stromal invasion- Negative imaging for metastatic disease (MRI recommended). PRIMARY TREATMENT (NON-FERTILITY SPARING). Type A hysterectomy + SLN mapping or pelvic lymphadenectomy<sup>g</sup>. # NCCN Guidelines Version 4.2025 Cervical Cancer. CLINICAL STAGE. PRIMARY TREATMENT (NON-FERTILITY SPARING). c Principles of Imaging (CERV- B). g Principles of Evaluation and Surgical Staging (CERV- C). \| For SLN mapping, the best detection rates and mapping results are in tumors . # NCCN Guidelines Version 4.2025 Cervical Cancer. SURGICAL FINDINGS. ADJUVANT TREATMENT. Principles of Imaging (CERV- B). Principles of Radiation Therapy (CERV- D). Concurrent platinum- containing chemotherapy with EBRT utilizes cisplatin as a single agent (or carboplatin if cisplatin intolerant). (See Systemic Therapy for Cervical Cancer [CERV- F]). Risk factors may not be limited to the Sedlis criteria. See Sedlis Criteria (CERV- E). Systemic Therapy for Cervical Cancer (CERV- F).. Note: All recommendations are category 2A unless otherwise indicated.. Surveillance (CERV- 10). # CLINICAL STAGE. PRIMARY TREATMENT. Principles of Imaging (CERV- B). PPrinciples of Radiation Therapy (CERV- D). PInduction chemotherapy (carboplatin/paclitaxel) followed by single agent cisplatin (or carboplatin) and radiation given according to the INTERLACE protocol could be considered. (McCormack M, et al. Lancet 2024;404:1525- 1535). See Systemic Therapy for Cervical Cancer (CERV- F) SSystemic Therapy for Cervical Cancer (CERV- F). tExtended field RT is recommended when para- aortic nodes are involved by imaging or confirmed on pathology. This may also be added in select patients with positive pelvic nodes such as common iliac metastasis. uConcurrent platinum- containing chemotherapy with EBRT utilizes cisplatin as a single agent (or carboplatin if cisplatin intolerant). Pembrolizumab may be added as follows: Cisplatin (or carboplatin)/RT and pembrolizumab (for FIGO 2014 stage IIIA, IIIB, and IVA: Category 1); Cisplatin (or carboplatin)/RT and pembrolizumab (for select FIGO 2018 stage III- IVA: category 2B). Category 2B is for FIGO 2018 stage IIIC purely on nodal metastasis without concomitant tumor characteristics defined in 2014 FIGO Stage IIIA- IIIB. If the FIGO 2018 staging of stage III overlaps with FIGO 2014 IIIA/IIIB staging, category 1 can be applied to cisplatin (or carboplatin) + pembrolizumab. (See Systemic Therapy for Cervical Cancer [CERV- F]). vConsider ablative therapy for 1- 5 metastatic lesions (category 2B) if the primary has been controlled. (Palma DA, et al. Lancet 2019;393:2051- 2058. ). Note: All recommendations are category 2A unless otherwise indicated.. # INCIDENTAL FINDING OF INVASIVE SQUAMOUS OR TREATMENT. # INCIDENTAL FINDING OF INVASIVE SQUAMOUS OR USUAL TYPE ADENOCARCINOMA AFTER SIMPLE HYSTERECTOMY. Principles of Imaging (CERV- B). Principles of Radiation Therapy (CERV- D). Concurrent platinum- containing chemotherapy with EBRT utilizes cisplatin as a single agent (or carboplatin if cisplatin intolerant). (See Systemic Therapy for Cervical Cancer [CERV- F]). x Sedlis Criteria (CERV- E).. Note: All recommendations are category 2A unless otherwise indicated.. # SURVEILLANCE. WORKUP. - Interval H&P - every 3-6 mo for 2 y, - every 6-12 mo for 3-5 y, - then annually based on patient's risk of disease recurrence- Cervical/vaginal cytology screening annuallyz,aa as indicated for the detection of lower genital tract neoplasia- Stage-dependent imaging for follow-upc,bb- Laboratory assessment (CBC, blood urea nitrogen [BUN], creatinine) as indicated based on symptoms or examination findings suspicious for recurrence- Clinical evaluation and management of potential long-term and late effects of treatmentcc (Also see Principles of Gynecologic Survivorship [CERV-G], NCCN Guidelines for Survivorship and NCCN Guidelines for Smoking Cessation). Principles of Imaging (CERV-B).. y Salani R, et al. Gynecol Oncol 2017;146:3- 10. z Regular cytology can be considered for detection of lower genital tract dysplasia and for patients who are immunocompromised, although its value in detection of recurrent cervical cancer is limited. The likelihood of picking up asymptomatic recurrences by cytology alone is low. aa The accuracy of cytology results may be affected in patients who have received pelvic radiation. bb Recurrences should be proven by biopsy before proceeding to treatment planning. cc Patient education should include symptoms of potential recurrence, lifestyle, obesity, exercise, sexual health (including vaginal dilator use and lubricants/moisturizers, local estrogen, and hormone therapy for menopause), smoking cessation, and nutrition counseling.. # #	None	None	None
23314e207fce4897b62906e75e90476c	NCCN临床实践指南	宫颈癌031-060	# NCCN Guidelines Version 4.2025 Cervical Cancer. PRIMARY WORKUP. a Principles of Pathology (CERV- A). g Principles of Evaluation and Surgical Staging (CERV- C). m Principles of Radiation Therapy (CERV- D). s Systemic Therapy for Cervical Cancer (CERV- F). f Principles of Imaging (CERV- B [3 of 4]). 99 Concurrent platinum- containing chemotherapy with EBRT utilizes cisplatin (or carboplatin if cisplatin intolerant) + etoposide. The first two cycles of chemotherapy can be given concurrently with RT (on days 1 and 22). The subsequent two cycles are given after RT.. # NCCN Guidelines Version 4.2025 Cervical Cancer. SMALL CELL NEUROENDOCRINE CARCINOMA OF THE CERVIX (NECC). PRIMARY TREATMENT. ADJUVANT TREATMENT. a Principles of Pathology (CERV- A). b Principles of Imaging (CERV- B). c Principles of Evaluation and Surgical Staging (CERV- C). d Principles of Radiation Therapy (CERV- D). e Systemic Therapy for Cervical Cancer (CERV- F). f Concurrent platinum- containing chemotherapy with EBRT utilizes cisplatin (or carboplatin if cisplatin intolerant) + etoposide. The first two cycles of chemotherapy can be given concurrently with RT (on days 1 and 22). The subsequent two cycles are given after RT.. # Squamous Cell Carcinoma, Adenocarcinoma, or Adenosquamous Carcinoma. Procedure Conization, trachelectomy, Type A hysterectomy, and Type B and C radical hysterectomy. Pathologic assessment:. Uterus. Hysterectomy type (where applicable) . Other tissue/organ involvement (parametrium, vaginal cuff, fallopian tubes, ovaries, peritoneum, omentum, other) . Additional molecular testing and biomarkers. Recommend PD- L1 testing for patients with recurrent, progressive, or metastatic disease . A c 2018 t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t h t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t h t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t. Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF PATHOLOGY. Squamous Cell Carcinoma. General Principles. General Principles- Cervical squamous cell carcinoma (SCC) is a squamous epithelial tumor with stromal invasion and/or exophytic invasion.- It accounts for approximately . Histology. Histology- Squamous cell carcinomas demonstrate infiltrating and angulated epithelial nests, often showing paradoxical maturation, in a background of inflammation and stromal desmoplastic response.- Histologic patterns of SCC include keratinizing (presence of keratin pearls), non- keratinizing, basaloid (nests of basal- type squamous cells), warty (condylomatous), and papillary types.- Non- keratinizing and basaloid patterns are the most commonly noted with HPV- associated tumors, while HPV- independent SCC are usually of the keratinizing type.- Of note, morphology alone is unreliable and utility of p16 IHC and/or molecular HPV typing is recommended for establishing HPV- association.- Almost all HPV- associated SCCs show strong and diffuse p16 overexpression in nuclei and cytoplasm by IHC.. # PRINCIPLES OF PATHOLOGY. Endocervical Adenocarcinoma. General Principles. - Endocervical adenocarcinoma is a gland forming tumor typically originating in the transformation zone, demonstrating stromal invasion and/or expansile type invasion.- Adenocarcinomas of the cervix can be HPV-associated (HR-HPV types 18, 16, and 45 most commonly) or HPV-independent.- Determining the HPV status is recommended as HPV-associated endocervical adenocarcinomas have shown better clinical outcomes compared with HPV-independent adenocarcinomas.- Grossly, endocervical adenocarcinomas may present as ulceration, exophytic masses, or as barrel-shaped cervix when endophytic growth is present.. # PRINCIPLES OF PATHOLOGY. Endocervical Adenocarcinoma (continued). Histologic subtypes. - HPV-associated adenocarcinoma: Include usual type, which accounts for approximately . - 95% of HPV-associated carcinomas will demonstrate block-type p16 expression by IHC. Of note, endometrial carcinomas (high grade endometrioid, serous and clear cell carcinomas) can also express p16; rarely p16 negative cases can occur from methylation-induced activation; and results of p16 were shown to be not as reproducible when performed on older or poorly preserved tissue blocks.. - When available, HR-HPV ISH can be utilized, as it is as sensitive and more specific than p16 IHC.. - While PCR can confirm HPV infection, it has lower sensitivity and specificity, and does not provide ascertainment that HPV is present within the neoplastic cells.. - The Silva system is utilized for evaluating patterns of invasion in HPV-associated endocervical adenocarcinoma, subdividing these tumors into three categories:. - Silva Pattern A – non-destructive invasion; well demarcated rounded glands without solid growth, single stromal cells, desmoplastic stromal response or LVS. These tumors have excellent survival, without lymph node metastasis or recurrence.. - Silva Pattern B – localized (early) destructive stroma invasion, arising from well-demarcated glands; may show small glands or individual cells in a focally desmoplastic stroma with or without LVS, and without solid growth.. - Silva Pattern C – diffuse destructive stromal invasion, solid growth or poorly differentiated component, with or without LVS. - Gastric type makes up approximately . - Mesonephric type demonstrates mesonephric (Wolffian) differentiation and is associated with mesonephric remnants. It typically is located deep in the lateral wall and histologically demonstrates architectural crowding, haphazard infiltration, atypia, mitotic activity, and necrosis. GATA-3 and CD10 IHC stains will be positive in the tumor and associated mesonephric remnants.. - Clear cell carcinomas make up . - Endometrioid carcinoma is quite uncommon, approximating . - Utilizing a panel of immunohistochemical stains (vimentin, ER, p16, and monoclonal carcinoembryonic antigen [CEA]) may be helpful in differentiating between endocervical and endometrial carcinoma. Typically, endometrioid adenocarcinoma will express vimentin and ER, while endocervical adenocarcinoma is positive for mCEA and p16 (when HPV-associated).. # PRINCIPLES OF PATHOLOGY. Adenosquamous Carcinoma. General Principles. General Principles- Epithelial tumor with squamous and glandular differentiation- Accounts for approximately . Histology. Histology- The tumor components (squamous and glandular) should be admixed and be able to be discerned on routine histology- The squamous component typically demonstrates abundant glycogen- rich (clear) cytoplasm, while the gland forming component is often of usual HPV- associated adenocarcinoma. Immunohistochemistry (IHC). Immunohistochemistry (IHC)- IHC for p16 usually shows overexpression in both components- Additional IHC stains such as CK7, CEA, and PAX8 may be utilized to highlight the glandular component, while p63 and p40 highlight the squamous component. # Neuroendocrine Carcinoma of the Cervix (NECC). Histologic description. - Histologic description - Although rare, comprising . Immunohistochemistry (IHC). - Small cell NECC is variably positive for chromogranin, CD56, and synaptophysin. - CD56 and synaptophysin are the most sensitive neuroendocrine markers, but CD56 lacks specificity. - Chromogranin is the most specific neuroendocrine marker, but lacks sensitivity with only about $50\% - 60\%$ of small cell NECC being positive. - Insulinoma-associated protein 1 (INSM1) and synaptophysin are other neuroendocrine markers, with . References. # PRINCIPLES OF PATHOLOGY REFERENCES. 1 Krishnamurti U, Movahedi- Lankarani S, Bell DA, et al. Protocol for the Examination of Specimens from Patients with Primary Carcinoma of the Uterine Cervix. College of American Pathologists 2018. 2 Bratla N, Berek JS, Frodo MC, et al. Revised FIGO Staging for carcinoma of the cervix uteri. Int J Gynecol Obstet 2019;145:129- 135 and Corrigendum to "Revised FIGO Staging for carcinoma of the cervix uteri" [Int J Gynecol Obstet 2019;145:129- 135] Int J Gynecol Obstet 2019;147:279- 280. 3 Minion LE, Tewari KS. Cervical cancer - State of science: From angiogenesis blockade to checkpoint inhibition. Gynecol Oncol 2018;148:609- 621. 4 Chung HC, Schellens JH, Delord J- P, et al. Pembrolizumab treatment of advanced cervical cancer: Updated results from the phase 2 KEYNOTE- 158 study. J Clin Oncol 2018;36; (15_suppl): Abstract 5522. 5 Merino DM, McShane LM, Fabrizio D, et al. Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project. J Immunother Cancer 2020;8:e000147. 6 Stolnicu S, Barsan I, Hoang L, et al. International Endocervical Adenocarcinoma Criteria and Classification (IECC): A New Pathogenetic Classification for Invasive Adenocarcinomas of the Endocervix. Am J Surg Pathol 2018;42:214- 226. 7 Diaz De Vivar A, Roma AA, Park KJ, et al. Invasive endocervical adenocarcinoma: proposal for a new pattern- based classification system with significant clinical implications: a multi- institutional study. Int J Gynecol Pathol 2013;32:592- 601. 8 Roma AA, Mistretta TA, Diaz De Vivar A, et al. New pattern- based personalized risk stratification system for endocervical adenocarcinoma with important clinical implications and surgical outcome. Gynecol Oncol 2016;141:36- 42. 9 Spaans VM, Scheunhage DA, Barzaghi B, et al. Independent validation of the prognostic significance of invasion patterns in endocervical adenocarcinoma: Pattern A predicts excellent survival. Gynecol Oncol 2018;151:196- 201. 10 Rindi G, Klimstra DS, Abedi- Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol 2018;31:1770- 1786. 11 Howitt BE, Kelly P, McCluggage WG. Pathology of neuroendocrine tumours of the female genital tract. Curr Oncol Rep 2017;19:59. 12 Ganesan R, Hirschowitz L, Dawson P, et al. Neuroendocrine carcinoma of the cervix: Review of a series of cases and correlation with outcome. Int J Surg Pathol 2016;24:490- 496. 13 Perunovic B, Sunassee A. Small cell (neuroendocrine/undifferentiated) carcinoma. Pathology Outlines.com website ( 14 Wang HL, Lu DW. Detection of human papillomavirus DNA and expression of p16, Rb, and p53 proteins in small cell carcinomas of the uterine cervix. Am J Surg Pathol 2004;28:901- 908. 15 Masumoto N, Fujii T, Ishikawa M, et al. P16 overexpression and human papillomavirus infection in small cell carcinoma of the uterine cervix. Hum Pathol 2003;34:778- 783.. # PRINCIPLES OF IMAGINGa,1-9. Initial Workup. Stage I. Non- Fertility Sparing. - Pelvis MRI recommended if considering definitive treatment with a conization, trachelectomy, or Type A hysterectomy. Consider pelvis MRI to assess local disease extent (preferred for FIGO stage IB1-IB3). Neck/chest/abdomen/pelvis/groin FDG-PET/CT (preferred) or chest/abdomen/pelvis CT or FDG-PET/MRI for FIGO stage IB1-IB3. For patients who underwent TH with incidental finding of cervical cancer, consider neck/chest/abdomen/pelvis/groin FDG-PET/CT or chest/abdomen/pelvis CT to evaluate for metastatic disease and pelvis MRI to assess pelvic residual disease. Other imaging should be based on symptomatology and clinical concern for metastatic disease. Fertility Sparing Pelvis MRI (preferred) to assess local disease extent and proximity of tumor to internal cervical os; perform pelvic transvaginal ultrasound if MRI is contraindicated. Neck/chest/abdomen/pelvis/groin FDG-PET/CT (preferred) or chest/abdomen/pelvis CT in FIGO stage IB1-IB3. Consider chest CT with or without contrast. Other imaging should be based on symptomatology and clinical concern for metastatic disease.. Stage II-IVA. Pelvis MRI to assess local disease extent (preferred). Neck/chest/abdomen/pelvis/groin FDG- PET/CT (preferred) or chest/abdomen/pelvis CT to evaluate for metastatic disease. Other initial imaging should be based on symptomatology and clinical concern for metastatic disease. For patients who underwent TH with incidental finding of cervical cancer, consider neck/chest/abdomen/pelvis/groin FDG- PET/CT or chest/ abdomen/pelvis CT to evaluate for metastatic disease and pelvis MRI to assess pelvic residual disease. If first post- treatment FDG- PET/CT is indeterminate, then consider repeating in 3 months.. MRI is peed wth and wthot ot and is peed wth ot st unss ontd. hgh ot is nt quird for sring chest CT, it may be performed with or without contrast during initial workup for fertility sparing. b These factors may include abnormal physical exam findings or pelvic, abdominal, or pulmonary symptoms. These factors may include abnormal physical exam findings, bulky pelvic tumor . Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF IMAGINGa,1-9. Follow-up/Surveillance. Stage I. Non- Fertility Sparing. Imaging should be based on symptomatology and clinical concern for recurrent/metastatic disease.b For patients with FIGO stage IB3 or patients who required postoperative adjuvant radiation or chemoradiation due to high- risk factors, a neck/chest/abdomen/pelvis/groin FDG- PET/CT may be performed at 3- 6 months after completion of treatment.. Fertility Sparing Consider pelvis MRI 6 months after surgery and then yearly for 2- 3 years. Other imaging should be based on symptomatology and clinical concern for recurrent/metastatic disease.b. Stage II-IV. Neck/chest/abdomen/pelvis/groin FDG- PET/CT (preferred) or chest/abdomen/pelvis CT within 3- 6 months of completion of therapy. Consider pelvis MRI at 3- 6 months post completion of therapy. Other imaging should be based on symptomatology and clinical concern for recurrent/metastatic disease.b. Stage IVB or Recurrence. Imaging as appropriate (CT, MRI, or FDG- PET/CT) to assess response or determine further therapy.. If first post- treatment FDG- PET/CT is indeterminate, then consider repeating in 3 months.. Suspected Recurrence or Metastasis- Neck/chest/abdomen/pelvis/groin FDG- PET/CT.- Consider pelvis MRI.. # PRINCIPLES OF IMAGING. Small Cell NECC. - Additional Imaging - Neck/chest/abdomen/pelvis/groin FDG-PET/CT + brain MRI (preferred) or - Chest/abdomen/pelvis CT + brain MRI. - Treatment Response Assessment - If primary treatment is chemoradiation, then neck/chest/abdomen/pelvis/groin FDG-PET/CT ± brain MRI (preferred) or chest/abdomen/pelvis CT ± brain MRI - If neoadjuvant chemotherapy is used, consider reassessment to rule out metastatic disease prior to chemoradiation and brachytherapy. - Surveillance - Neck/chest/abdomen/pelvis/groin FDG-PET/CT ± brain MRI (preferred) or - Chest/abdomen/pelvis CT ± brain MRI. # PRINCIPLES OF IMAGING REFERENCES. 1 Salani R, Khanna N, Frimer M, et al. An update on post- treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations. Gynecol Oncol 2017;146:3- 10. 2 Atri M, Zhang Z, Dehadashti F, et al. Uit of PET- CT to evaluate retroperitoneal lymph node metastasis in advanced cervical cancer: Results of ACRIN6671/GOG0233 trial. Gynecol Oncol 2016;142:413- 419. 3 Rajendran JG, Greer BE. Expanding role of positron emission tomography in cancer of the uterine cervix. J Natl Compr Canc Netw 2006;4:463- 469. 4 Lakhman Y, Akin O, Park KJ, et al. Stage IB1 cervical cancer: role of preoperative MR imaging in selection of patients for fertility- sparing radical trachelectomy. Radiology 2013;269:149- 158. 5 Elit L, Reade CJ. Recommendations for follow- up care for gynecologic cancer survivors. Obstet Gynecol 2015;126:1207- 1214. 6 Sala E, Rockall AG, Freeman SJ, et al. The added role of MR imaging in treatment stratification of patients with gynecologic malignancies: what the radiologist needs to know. Radiology 2013;266:717- 740. 7 Balleyguier C, Sala E, Da Cunha T, et al. Staging of uterine cervical cancer with MRI: guidelines of the European Society of Urogenital Radiology. Eur Radiol 2011;21:1102- 1110. 8 Sala E, Micco M, Burger IA, et al. Complementary prognostic value of pelvic MRI and whole- body FDG PET/CT in the pretreatment assessment of patients with cervical cancer. Int J Gynecol Cancer 2015;25:1461- 1467. 9 Bhatla N, Berek JS, Fredes MC, et al. Revised FIGO Staging for carcinoma of the cervix uteri. Int J Gynecol Obstet 2019;145:129- 135 and Corrigendum to "Revised FIGO Staging for carcinoma of the cervix uteri" [Int J Gynecol Obstet 2019;145:129- 135] Int J Gynecol Obstet 2019;147:279- 280.. # NCCN Guidelines Version 4.2025 Cervical Cancer. PRINCIPLES OF EVALUATION AND SURGICAL STAGING<sup>a</sup>. Types of Resection and Appropriateness for Treatment of Cervical Cancer. Treatment of cervical cancer is stratified by stage as delineated in the Guidelines.. Microinvasive disease, defined as FIGO stage IA1 with no LVSI, has less than a . For select patients with Stage IA2- IB1 who desire fertility preservation, a conization with negative margins with negative bilateral pelvic SLN or lymphadenectomy is a reasonable strategy if the patient meets all the following conservative surgery criteria2:. - Cone biopsy with negative margins- No LVSI- Squamous cell cancer (any grade) or usual type adenocarcinoma (grade 1 or 2).- Tumor size ≤2 cm- Depth of invasion ≤10 mm on LEEP/cone- Negative imaging for locoregional disease (MRI recommended). The radical vaginal trachelectomy with laparoscopic SLN mapping or lymphadenectomy offers a fertility- sparing option for carefully selected individuals with stage IA2 or stage IB1 lesions (<2 cm diameter). The cervix, 1- 2 cm upper vagina, and supporting ligaments are removed as with a type B radical hysterectomy, but the uterine corpus is preserved. In more than 300 subsequent pregnancies currently reported, there is a . aRt uteri. Int J Gynecol Obstet 2019;145:129- 135 and Corrigendum to "Revised FIGO Staging for carcinoma of the cervix uteri" [nt J Gynecol Obstet 2019;145:129- 135] Int J Gynecol Obstet 2019;147:279- 280). However, trial data cited within this section utilized the 2009 FIGO staging system. b For a description of a type C1 radical hysterectomy, see Table 1 (CERV- C 6 of 9).. Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF EVALUATION AND SURGICAL STAGING<sup>a</sup>. Types of Resection and Appropriateness for Treatment of Cervical Cancer. - Radical hysterectomy with bilateral pelvic SLN mapping or lymphadenectomy is a treatment option for FIGO stage IA2, IB1, IB2, and select IB3-IIA1 lesions when fertility preservation is not desired. Radical hysterectomy (Type B or C) results in resection of much wider margins compared with a simple Type A hysterectomy, including removal of parts of the paracervix and uterosacral ligaments and the upper 1-2 cm of the vagina; in addition, pelvic and sometimes para-aortic nodes are removed. The Querleu and Morrow classification system<sup>5</sup> is a modern surgical classification that describes degree of resection and nerve preservation in three-dimensional (3D) planes of resection.<sup>6</sup> Procedural details for the most commonly used types of hysterectomy are described in Table 1 (CERV-C 6 of 9).. - The standard and recommended approach for radical hysterectomy is with an open abdominal approach (category 1). A prospective randomized trial<sup>10</sup> demonstrated that minimally invasive radical hysterectomy was associated with lower rates of disease-free survival (DFS) and overall survival than open abdominal radical hysterectomy. Moreover, two recent epidemiologic studies also demonstrated that minimally invasive radical hysterectomy was associated with shorter overall survival than open surgery among patients with stage IA2-IB1 cervical cancer.<sup>11</sup> See Discussion for additional details. Studies comparing robotic versus open approach are ongoing.. - Based on a randomized trial comparing simple to radical hysterectomy,<sup>12</sup> select patients with Stage IA2-IB1 disease who meet all the conservative surgery criteria listed below, may be treated with a simple Type A hysterectomy with SLN mapping or bilateral pelvic lymphadenectomy:. - Cone biopsy (preferred) - No LVSI (preferred) - Negative cone margins (preferred) - Squamous cell (any grade) or usual type adenocarcinoma (grade 1 or 2) (preferred), or adenosquamous carcinoma - Tumor size ≤2 cm - Depth of invasion <10 mm on cone. If no conization, MRI must show <50% cervical stromal invasion - Negative imaging for metastatic disease (MRI recommended). - Definitive treatment with a conization or simple Type A hysterectomy has not been studied in the more aggressive histologies such as gastric type adenocarcinoma, clear cell, and small cell neuroendocrine carcinoma.. # PRINCIPLES OF EVALUATION AND SURGICAL STAGING<sup>a</sup>. Types of Resection and Appropriateness for Treatment of Cervical Cancer<sup>a</sup> - continued- Para- aortic lymphadenectomy for staging is typically done to the level of the inferior mesenteric artery (IMA). The cephalad extent of dissection can be modified based on clinical and radiologic findings.- Ovarian preservation or ovarian transposition outside of pelvic radiation boundaries should be considered when feasible to avoid surgical or radiation induced menopause.- Advanced- stage disease, including FIGO stage IIB and above, is not usually treated with hysterectomy, as delineated in the Guidelines. The majority of advanced- stage disease in the United States is treated with definitive chemoradiation. In some countries, select cases of stage IIB may be treated with upfront radical hysterectomy or neoadjuvant chemotherapy followed by radical hysterectomy.- Recurrent or persistent disease in the central pelvis following radiation therapy may potentially be cured with the pelvic exenteration procedure. Preoperative assessment for exenteration is designed to identify or rule out distant metastasis. If the recurrence is confined to the pelvis (preferable central pelvic), then surgical exploration is carried out. If intraoperative margin and node assessment appear negative, then resection of pelvic viscera is completed. Depending on the location of the tumor, resection may include anterior exenteration, posterior exenteration, or total pelvic exenteration. In cases where the location of tumor allows for adequate margins, the pelvic floor and anal sphincter may be preserved as a supraleator exenteration. Table 2 summarizes the tissues typically removed with differing types of pelvic exenteration (CERV- C & of 9). These are highly complex procedures and should be performed at centers with a high level of expertise for exenteration procedures. Primary pelvic exenteration (without prior pelvic radiation) is restricted to the rare case where pelvic radiation is contraindicated or to patients who received prior pelvic radiation for another indication and then developed a metachronous, locally advanced cervical carcinoma and further radiation therapy is not feasible.- In very select cases where there is documented evidence of persistent or recurrent small volume cervical disease (<2 cm) after radiation/chemoradiation and no metastatic disease, a radical hysterectomy instead of pelvic exenteration may be considered. The operation that is most likely to obtain a negative margin should be prioritized.. Reommendt st 201914519145129- 135 019145129- 135] Int J Gynecol Obstet 2019;147:279- 280). However, trial data cited within this section utilized the 2009 FIGO staging system.. Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF EVALUATION AND SURGICAL STAGING. Sentinel Lymph Node Mapping for Cervical Cancer:. - SLN mapping as part of the surgical management of select stage I cervical cancer is considered in gynecologic oncology practices worldwide. While this technique has been used in tumors up to 4 cm in size, the best detection rates and mapping results are in tumors less than 2 cm.. R 2018;19:1394- 1403).. Note: All recommendations are category 2A unless otherwise indicated.. # NCCN Guidelines Version 4.2025 Cervical Cancer. PRINCIPLES OF EVALUATION AND SURGICAL STAGING WHEN SLN MAPPING IS USED. The key to a successful SLN mapping is adherence to the SLN algorithm, which requires the performance of a side- specific lymphadenectomy in cases of failed mapping and removal of any suspicious or grossly enlarged nodes regardless of mapping (Figure 3).. Adapted with pemisio from Cormie B, Diaz JP, Shih K, t al. tablishing a sertinel ymph node mapping algorith for the trtment of early cervical cancer. Gynecol Oncol 2011;122:275- 280. f Intracervical injection with dye, 99mTc, or both. There is no standard protocol for ultrastaging. Ultrastaging typically includes serial sectioning of the gross lymph node with review of H&E with or without cytokeratin IHC staining. See Principles of Pathology (CERV- A). h Including interiliac/subaortic nodes.. Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF EVALUATION AND SURGICAL STAGING. Cibula D, Abu- Rustum NR, Benedetti- Panici P, et al. New classification system of radical hysterectomy: Emphasis on a three- dimensional anatomic template for parametrial resection. Gynecol Oncol 2011;122:264- 268. The Querleu and Morrow surgical classification system describes the degree of resection and nerve preservation for radical hysterectomy in three- dimensional planes and updates the previously used Piver- Rutledge- Smith classifications. (Querleu D, Morrow CP. Classification of radical hysterectomy. Lancet Oncol 2008;9:297- 303. ). Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF EVALUATION AND SURGICAL STAGING. # PRINCIPLES OF EVALUATION AND SURGICAL STAGING. # PRINCIPLES OF EVALUATION AND SURGICAL STAGING REFERENCES. 1 Teoh D, Musa F, Salani R, et al. Diagnosis and management of adenocarcinoma in situ. A Society of Gynecologic Oncology Evidence- Based Review and Recommendations. Obstet Gynecol 2020;135:869- 878. 2 Schmeler KM, Pareja R, Lopez Blanco A, et al. ConCerv: a prospective trial of conservative surgery for low- risk early- stage cervical cancer. Int J Gynecol Cancer 2021;31:1317- 1325. 3 Plante M, Gregoire J, Renaud MC, Roy M. The vaginal radical trachelectomy: an update of a series of 125 cases and 106 pregnancies. Gynecol Oncol 2011;121:290- 297. 4 Einstein MH, Park KJ, Sonoda Y, et al. Radical vaginal versus abdominal trachelectomy for stage IB1 cervical cancer: a comparison of surgical and pathologic outcomes. Gynecol Oncol 2009;112:73- 77. 5 Querleu D, Morrow CP. Classification of radical hysterectomy. Lancet Oncol 2008;9:297- 303. 6 Cibula D, Abu- Rustum NR, Benedetti- Panici P, et al. New classification system of radical hysterectomy: emphasis on a three- dimensional anatomic template for parametrial resection. Gynecol Oncol 2011;122:264- 268. 7 Piver MS, Rutledge F, Smith JP. Five classes of extended hysterectomy for women with cervical cancer. Obstet Gynecol 1974;44:265- 272. 8 Wethington SL, Sonoda Y, Park KJ, et al. Expanding the indications for radical trachelectomy: a report on 29 patients with stage IB1 tumors measuring 2 to 4 centimeters. Int J Gynecol Cancer 2013;21:1092- 1098. 9 Wethington SL, Cibula D, Duska LR, et al. An international series on abdominal radical trachelectomy: 101 patients and 28 pregnancies. Int J Gynecol Cancer 2012;22:1251- 1257. 10 Ramirez PT, Frumovitz M, Pareja R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med 2018;379:1895- 1904. 11 Melamed A, Margul DJ, Chen L, et al. Survival after minimally invasive radical hysterectomy for early- stage cervical cancer. N Engl J Med 2018;379:1905- 1914. 12 Plante M, Kwon JS, Ferguson S, et al. Simple versus Radical Hysterectomy in Women with Low- Risk Cervical Cancer. N Engl J Med 2024;390:819- 829. 13 Lintner B, Saso S, Tarnai L, et al. Use of abdominal radical trachelectomy to treat cervical cancer greater than 2 cm in diameter. Int J Gynecol Cancer 2013;23:1065- 1070. 14 Bats AS, Mathevet P, Buenerd A, et al. The sentinel node technique detects unexpected drainage pathways and allows nodal ultrastaging in early cervical cancer: insights from the multicenter prospective SENTICOL study. Ann Surg Oncol 2013;20:413- 422. 15 Eiriksson LR, Covens A. Sentinel lymph node mapping in cervical cancer: the future? BJOG 2012;119:129- 133. 16 Cormier B, Diaz JP, Shih K, et al. Establishing a sentinel lymph node mapping algorithm for the treatment of early cervical cancer. Gynecol Oncol 2011;122:275- 280. 17 Altgassen C, Hertel H, Brandstadt A, et al. Multicenter validation study of the sentinel lymph node concept in cervical cancer: AGO Study Group. J Clin Oncol 2008;26:2943- 2951. 18 Frumovitz M, Plante M, Lee PS, et al. Near- infrared fluorescence for detection of sentinel lymph nodes in women with cervical and uterine cancers (FILM): a randomised, phase 3, multicentre, non- inferiority trial. Lancet Oncol 2018;19:1394- 1403. 19 Cibula D, Abu- Rustum NR, Dusek L, et al. Prognostic significance of low volume sentinel lymph node disease in early- stage cervical cancer. Gynecol Oncol 2012;124:496- 501.. # General Principles. The use of CT- based treatment planning and conformal blocking is considered the standard of care for EBRT. MRI is the best imaging modality for determining soft tissue and parametrial involvement in patients with advanced tumors. In patients who are not surgically staged, FDG- PET imaging is useful to help define the nodal volume of coverage, and may be useful postoperatively to confirm removal of abnormal nodes.. - RT is directed at sites of known or suspected tumor involvement. EBRT is directed to the pelvis with or without the para-aortic region. - IMRT technique is preferred to minimize toxicities in definitive treatment of the pelvis with or without para-aortic treatment. Regular use of image-guided radiation therapy (IGRT) with orthogonal imaging and/or routine volumetric imaging (such as cone beam CT) at the time of treatment delivery, is essential to ensure appropriate coverage of targets and sparing of normal tissues.. - Brachytherapy is a critical component of definitive RT for all patients with primary cervical cancer. This is performed using an intracavitary and/or an interstitial approach.. - For the majority of patients who receive EBRT for cervical cancer, concurrent platinum-containing chemotherapy with or without immunotherapy is given during the time of EBRT (See CERV-F 1 of 3).. - Optimal results are achieved when treatment is completed within 8 weeks.. General Treatment Information. Target Volumes. Concepts regarding the gross target volume (GTV), clinical target volume (CTV), planning target volume (PTV), organs at risk (OARs), internal organ motion, and dose- volume histogram (DVH) have been defined for use in conformal radiotherapy, especially for intensity- modulated radiation therapy (IMRT).. - Very careful attention to detail and reproducibility (including consideration of target and normal tissue definitions, patient and internal organ motion, soft tissue deformation, and rigorous dosimetric and physics quality assurance) is required for proper delivery of IMRT and related highly conformal technologies. Routine image guidance, such as cone-beam CT (CBCT), should be used for defining daily internal soft tissue positioning.. - The volume of EBRT should cover the gross disease (if present), parametria, uterosacral ligaments, sufficient vaginal margin from the gross disease (at least 3 cm), presacral nodes, and other nodal volumes at risk. For patients with negative nodes on surgical or radiologic imaging, the radiation volume should include the entirety of the external iliac, internal iliac, obturator, and presacral nodal basins. For patients deemed at higher risk of lymph node involvement (eg, bulkier tumors; suspected or confirmed nodes confined to the low true pelvis), the radiation volume should be increased to cover the common iliacs as well. In patients with documented common iliac and/or para-aortic nodal involvement, extended-field pelvic and para-aortic radiotherapy is recommended, up to the level of the renal vessels (or even more cephalad as directed by involved nodal distribution).. - For patients with lower 1/3 vaginal involvement, the bilateral groins should be covered as well. Inguinofemoral node borders for distal vaginal cases: superior border = acetabular roof, lateral border = inguinofemoral vessels to medial sartorius/rectus femoris, posterior = posterior border of vessels, medial = pectineus muscle or 2.5-3 cm from vessels, anterior = anterior border of sartorius, caudal = top of lesser trochanter of femur.. # PRINCIPLES OF RADIATION THERAPY1. General Treatment Information—Continued Treatment Information - External Beam. - EBRT is delivered using multiple conformal fields or intensity-modulated volumetric techniques, such as IMRT/volumetric-modulated arc therapy (VMAT)/tomotherapy.. - IMRT is preferred to minimize the dose to the bowel and other critical structures in the post-hysterectomy setting and in treating the para-aortic nodes when necessary. These techniques can also be useful when high doses are required to treat gross disease in regional lymph nodes. However, conformal external beam therapies (such as IMRT or stereotactic body radiation therapy [SBRT]) should not be used as routine alternatives to brachytherapy for treatment of central disease in patients with an intact cervix.. - IMRT technique can reduce acute and chronic gastrointestinal and hematologic toxicity.. - A parametrial boost of 5 to 10 Gy can be considered in select cases with bulky parametrial/pelvic sidewall disease after completion of initial whole pelvic radiation.. - IMRT can be planned to deliver a higher dose to gross disease in the lymph nodes, while simultaneously delivering a lower dose to control microscopic disease to the other targets, termed a simultaneous integrated boost (SIB). Using a combination of IMRT with SIB can deliver higher doses to grossly positive nodal disease in a shorter time frame, while sparing normal tissues. In general, an SIB target may be boosted up to approximately 2.10 to 2.3 Gy/fraction, depending on target and OAR volumes. At times, additional external boosts may be necessary. Target doses for nodes can range from 54 to 63 Gy, with strict attention to the contribution from brachytherapy, and respecting normal tissue doses while paying attention to adjacent normal tissue doses. Consider bladder full and empty CT scans to generate utero-cervical-vaginal internal organ motion (internal target volume [ITV]).. - SBRT is an approach that allows for delivery of very high doses of focused EBRT in 1-5 fractions and may be applied to isolated metastatic sites; consideration can be given for limited disease in the reirradiation setting.. Dosing Prescription Regimen - External Beam. - Coverage of microscopic nodal disease requires an EBRT dose of approximately 40-45 Gy (in conventional fractionation of 1.8-2.0 Gy daily possibly with an SIB if IMRT is used), and highly conformal boosts of an additional 10-20 Gy may be considered for limited volumes of gross unresected adenopathy, with consideration of the dose given by brachytherapy. For the majority of patients who receive EBRT for cervical cancer, concurrent platinum-containing chemotherapy is given during the time of EBRT.. # General Treatment Information-Continued Definitive RT for an Intact Cervix. General Treatment Information—ContinuedDefinitive RT for an Intact Cervix<sup>1</sup>- In patients with an intact cervix (ie, those who do not have surgery), the primary tumor and regional lymphatics at risk are typically treated with definitive EBRT to a dose of approximately 45 Gy (40–50 Gy). The volume of the EBRT would depend on the nodal status as determined surgically or radiographically (as previously described). The primary cervical tumor is then boosted, using brachytherapy, with an additional 28 to 40 Gy using either image guidance (preferred) or to point A (in low dose rate [LDR] equivalent dose), total dose (EBRT + brachytherapy) to high risk CTV (HR- CTV) D90 (preferred) of ≥85 Gy (EQD2), or Point A. For very small tumors (medically inoperable IA1 or IA2) EQD2 D90 doses of 75–80 Gy may be considered. Grossly involved unresected nodes may be evaluated for boosting with an additional 10 to 15 Gy of highly conformal (and reduced- volume) EBRT. When using image guidance for EBRT, care must be taken to exclude or severely limit the volume of normal tissue included in the high- dose region(s) (see Discussion). Consider bladder full and empty CT scans to generate utero- cervical- vaginal internal organ motion (ITV).. Posthysterectomy Adjuvant Radiation Therapya. Posthysterectomy Adjuvant Radiation Therapy<sup>a</sup>- Following primary hysterectomy, the presence of one or more pathologic risk factors may warrant the use of adjuvant radiotherapy. At a minimum, the following should be covered: upper 3 to 4 cm of the vaginal cuff, the parametria, and immediately adjacent nodal basins (such as the external and internal iliac, obturator, and presacral nodes). For documented nodal metastasis, the superior border of the radiation field should be appropriately increased (as previously described). A dose of 45 to 50 Gy in standard fractionation with IMRT is generally recommended.<sup>5</sup> Grossly involved unresected nodes may be evaluated for boosting with an additional 10 to 20 Gy of highly conformal (and reduced- volume) EBRT. With higher doses, especially of EBRT, care must be taken to exclude or severely limit the volume of normal tissue included in the high- dose region(s) (see Discussion). Consider bladder full and empty CT scans to generate vaginal internal organ motion (ITV).- Consider Vaginal cuff brachytherapy for positive or close vaginal margins.. Intraoperative Radiation Therapy (category 3). Intraoperative Radiation Therapy (category 3)- IORT is a specialized technique that delivers a single, highly focused dose of radiation to an at- risk tumor bed or isolated unresectable residual disease during an open surgical procedure.<sup>6</sup> It is particularly useful in patients with recurrent disease within a previously radiated volume. During IORT, overlying normal tissue (such as bowel or other viscera) can be manually displaced from the region at risk. IORT is typically delivered with electrons, brachytherapy, or miniaturized x- ray sources using preformed applicators of variable sizes matched to the surgically defined region at risk, which further constrains the area and depth of radiation exposure to avoid surrounding normal structures.. Reirradiation. Reirradiation- Techniques for reirradiation may include IORT, intracavitary or interstitial brachytherapy, SBRT, IMRT, or proton therapy. Such cases are highly customized and depend on the target, proximity to critical organs, previous RT dose, extent of overlap, and time intervals since prior RT. The appropriate dose for each case needs to be individualized.. a Normal Tissue Cumulative Dose Constraints (CERV- D 6 of 9).. Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF RADIATION THERAPY1. General Treatment Information—Continued Treatment Information - Brachytherapy. - Brachytherapy is a critical component of definitive RT for patients with primary cervical cancer. This is usually performed using an intracavitary approach, with an intrauterine tandem and vaginal colposstats. Depending on the patient and tumor anatomy, the vaginal component of brachytherapy in patients with an intact cervix may be delivered using ovoids, ring, or cylinder brachytherapy (combined with the intrauterine tandem). For more advanced disease, or without sufficient regression, interstitial needles may allow increased dose to the target, while minimizing dose to the normal tissues. MRI immediately preceding or during brachytherapy may be helpful in delineating residual tumor geometry. When combined with EBRT, brachytherapy is often initiated towards the latter part of treatment, when sufficient primary tumor regression has been noted to permit satisfactory brachytherapy apparatus geometry. In highly selected, very early disease (ie, stage IA2), brachytherapy alone (without EBRT) may be an option.. In rare cases, patients whose anatomy or tumor geometry renders intracavitary brachytherapy infeasible may be best treated using an interstitial approach; however, such interstitial brachytherapy should only be performed by individuals and at institutions with appropriate experience and expertise, and early referral for timely use of their expertise is critical.. In selected patients who receive post- hysterectomy (especially those with positive or close vaginal mucosal surgical margins), vaginal cylinder brachytherapy may be used as a boost to EBRT. The prescription is typically to the vaginal surface or at 5 mm below the surface. Typical fractionation schemes include 5.5 Gy X 2 fractions dosed at 5 mm or 6 Gy X 3 fractions dosed at the vaginal surface to upper 3–4 cm of the vagina.. - SBRT is not considered an appropriate routine alternative to brachytherapy. - Consider the use of intraprocedural imaging when placing brachytherapy applicators for intact cervical cancer.. # NCCN Guidelines Version 4.2025 Cervical Cancer. PRINCIPLES OF RADIATION THERAPY1. Dosing Prescription Regimen - Brachytherapya. Point A, representing a paracervical reference point, has been the most widely used dosing parameter to date. However, limitations of the point A dosing system include the fact that it does not take into account the 3D shape of tumors, nor individual tumor to normal tissue structure correlations. Traditionally point A doses were based on widely validated dose fractionation for brachytherapy with LDR. The dose at point A assumes an LDR delivery of 40- 70 cGy/h. The traditional LDR point A prescription dose was 70- 80 Gy. Typical point A prescription doses are 5.5 Gy X 5 fractions for early disease and 6 Gy X 5 fractions for large tumors or those demonstrating a poor response. Another reasonable choice that has been well- studied in European trials for intracavity dosing to the HR- CTV is 28 Gy in 4 fractions.. Interstitial brachytherapy is an advanced technique where multiple needles/catheters are inserted in the gross disease/target. Interstitial brachytherapy may be preferred to maximize dose to the target and minimize dose to the OARs for cases where intracavitary brachytherapy is not possible, or anatomy favors interstitial. 3D treatment planning allows for volumetric delineation of targets and OARs on CT and/or MRI with DVHs. Dose and fractionation depend on prior RT dose, target volume, and OAR doses.. There is evidence that image- guided brachytherapy improves outcomes and decreases toxicity. MRI gives the best soft tissue imaging for residual disease and while it is best to have an MRI with the instruments in place, an MRI prior to brachytherapy can help guide therapy. In the absence of MRI, CT can be used but is inferior for determination of residual disease and contouring is less accurate. The goals of care would include an equivalent dose at 2 Gy (EQD2) to the HR- CTV with a D90 of 80- 85 Gy; however, with large disease or poor response dose goals should be HR- CTV D90 ≥87 Gy. Normal tissues should be limited according to published guidelines with 2- cc rectal dose ≤65 to 75 Gy, sigmoid 2- cc dose ≤70 to 75 Gy, and 2- cc bladder dose ≤80 to 90 Gy. If those parameters cannot be achieved, supplemental dosing with interstitial needles should be considered.. For brachytherapy in combination with EBRT, the external dose is delivered at 1.8- 2.0 Gy per daily fraction. Clinicians using high dose rate (HDR) brachytherapy use dosing based on the linear- quadratic model equation to convert nominal HDR dose to a biologically equivalent LDR dose ( The HDR fractionation schedule of 5 fractions delivering 6 Gy nominal dose results in a nominal HDR dose of 30 Gy in 5 fractions, which is generally accepted to be the equivalent to 40 Gy to point A (tumor surrogate dose) using LDR brachytherapy to point A or HR- CTV.. # PRINCIPLES OF RADIATION THERAPY. NORMAL TISSUE CUMULATIVE DOSE CONSTRAINT GUIDELINES FOR CERVICAL CANCER<sup>12-16</sup>. Note: All recommendations are category 2A unless otherwise indicated.. # PRINCIPLES OF RADIATION THERAPY. NORMAL TISSUE DOSE CONSTRAINT GUIDELINES FOR CERVICAL CANCER. Clinicians must balance the risks of normal tissue toxicity with tumor control but suggested dose constraints are provided. Studies indicate that . # PRINCIPLES OF RADIATION THERAPY. NORMAL TISSUE DOSE CONSTRAINT GUIDELINES FOR CERVICAL CANCER<sup>12-16</sup>.	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0d37f0ff4dc147bdb89d170dc43e1c18	NCCN临床实践指南	宫颈癌061-090	# National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 4.2025 Cervical Cancer. PRINCIPLES OF RADIATION THERAPY REFERENCES. 1 Chino J, Anunziata CM, Beriwal S, et al. Radiation Therapy for Cervical Cancer: Executive Summary of an American Society for Radiation Oncology Clinical Practice Guideline. Pract Radiat Oncol. 2020;10:220- 234. 2 Klopp, AH, Yeung AR, Deshmukh S, et al. A phase III randomized trial comparing patient- reported toxicity and quality of life (QOL) during pelvic intensity modulated radiation therapy as compared to conventional radiation therapy. Int J Radiat Oncol Biol Phys 2016;96:S3. 3 Choi CW, Cho CK, Yoo SY, et al. Image- guided stereotactic body radiation therapy in patients with isolated para- aortic lymph node metastases from uterine cervical and corpus cancer. Int J Radiat Oncol Biol Phys 2009;74:147- 153. 4 Higginson DS, Morris DE, Jones EL, et al. Stereotactic body radiotherapy (SBRT): Technological innovation and application in gynecologic oncology. Gynecol Oncol 2011;120:404- 412. 5 Klopp AH, Yeung AR, Deshmukh SW et al. Patient- reported toxicity during pelvic intensity- modulated radiation therapy: NRG Oncology- RTOG 1203. J Clin Oncol 2018;36:2538- 2544. 6 del Carmen MG, McIntyre JF, Goodman A. The role of radiation therapy (IORT) in the treatment of locally advanced gynecologic malignancies. Oncologist 2000;5:18- 25. 7 Pötter R, Tanderup K, Schmid MP, et al; EMBRACE Collaborative Group. MRI- guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE- I): a multicentre prospective cohort study. Lancet Oncol 2021;22:538- 547. 8 Haie- Meder C, Potter R, Van Limbergen E, et al. Recommendations from Gynaecological (GYN) GEC- ESTRO Working Group (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiother Oncol 2005;74:235- 245. 9 Pötter R, Georg P, Dimopoulos JC, et al. Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer. Radiother Oncol 2011;100:116- 123. 10 Pötter R, Haie- Meder C, Van Limbergen E, et al. Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image- based treatment planning in cervix cancer brachytherapy- 3D dose volume parameters and aspects of 3D image- based anatomy, radiation physics, radiobiology. Radiother Oncol 2006;78:67- 77. 11 Lakomy DS, Wu J, Chapman BV, et al. Use of Specific Duodenal Dose Constraints During Treatment Planning Reduces Toxicity After Definitive Paraaortic Radiation Therapy for Cervical Cancer. Pract Radiat Oncol 2022;12:e207- e215. 12 Klopp AH, Yeung AR, Deshmukh S, et al. Patient- Reported Toxicity During Pelvic Intensity- Modulated Radiation Therapy: NRG Oncology- RTOG 1203. J Clin Oncol. 2018 Aug 20;36(24):2538- 2544. Erratum in: J Clin Oncol 2019;37:761. Erratum in: J Clin Oncol 2020;38:1118. 13 Mell LK, Sirak I, Wei L, et al; INTERTECC Study Group. Bone Marrow- sparing Intensity Modulated Radiation Therapy With Concurrent Cisplatin For Stage IB- IVA Cervical Cancer: An International Multicenter Phase II Clinical Trial (INTERTECC- 2). Int J Radiat Oncol Biol Phys 2017;97:536- 545. 14 Pötter R, Tanderup K, Kirisits C, et al; EMBRACE Collaborative Group. The EMBRACE II study: The outcome and prospect of five decades of evolution within the GEC- ESTRO GYN working group and the EMBRACE studies. Clin Transl Radiat Oncol 2018;9:48- 60. 15 Verma J, Sulman EP, Jhingran A, et al. Dosimetric predictors of duodenal toxicity after intensity modulated radiation therapy for treatment of the para- aortic nodes in gynecologic cancer. Int J Radiat Oncol Biol Phys 2014;88:357- 362. 16 Radiation Therapy, Gemcitabine Hydrochloride, and Cisplatin in Treating Patients With Locally Advanced Squamous Cell Cancer of the Vulva. ClinicalTrials.gov identifier: NCT01595061. Posted December 29, 2021. Accessed on September 12, 2023. . # SEDLIS CRITERIA FOR EXTERNAL PELVIC RADIATION AFTER RADICAL HYSTERECTOMY IN NODE-NEGATIVE, MARGIN-NEGATIVE, PARAMETRIA-NEGATIVE CASES<sup>a-c1,2</sup>. Footnotes. Modified wth pssion f B, M t. d til f i r th in p wth stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: a gynecologic oncology study group. Gynecol Oncol 1999;73:177- 183. b Risk factors may not be limited to the Sedlis criteria. Sedis cr w pr s c s a more contemporary tol to model the risk of recurrence and base adjuvant recommendations. Depth of invasion is an important risk factor of recurrence for squamous lesions. Tumor size is an important risk factor for cervical adenocarcinoma, and this risk becomes more pronounced with the presence of LVS1.3. References. 1 Delgado G, Bundy B, Zaino R, et al. Prospective surgical- pathological study of disease- free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 1990;38:352- 357. 2 Rotman M, Sedlis A, Piedmont MR, et al. A phase III randomized trial of postoperative pelvic irradiation in stage IB cervical carcinoma with poor prognostic features: follow- up of a gynecologic oncology group study. Int J Radiat Oncol Biol Phys 2006;65:169- 176. 3 Levinson K, Beavis AL, Purdy C, et al. Beyond sedlis- a novel histology- specific nomogram for predicting cervical cancer recurrence risk: an NRG/GOG ancillary analysis. Gynecol Oncol 2021;162:532- 538.. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 4.2025 Cervical Cancer. Note: All recommendations are category 2A unless otherwise indicated.. # NCCN Guidelines Version 4.2025 Cervical Cancer. SYSTEMIC THERAPY FOR CERVICAL CANCER<sup>a</sup> FOONOTES FOR CERV-F 1 OF 3. An FDA- approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Cisplatin, carboplatin, docetaxel, and paclitaxel may cause drug reactions (See NCCN Guidelines for Ovarian Cancer- - Management of Drug Reactions [O- D]). Cost and toxicity, especially when using extended field RT, should be carefully considered when selecting an appropriate regimen for treatment. Concurrent platinum- containing chemotherapy with EBRT utilizes cisplatin as a single agent (or carboplatin if cisplatin intolerant). Pembrolizumab may be added with CRT as follows: Cisplatin (or carboplatin)/RT and pembrolizumab (FIGO 2014 stage IIIA, IIIB, and IVA: category 1); Cisplatin (or carboplatin)/RT and pembrolizumab (select FIGO 2018 stage III- IVA: category 2B). Category 2B is for FIGO 2018 stage IIIC purely on nodal metastasis without concomitant tumor characteristics defined in 2014 FIGO Stage IIA- IIIB. If the FIGO 2018 staging of stage II overlaps with FIGO 2014 IIA/IIB staging, category 1 can be applied to cisplatin (or carboplatin) + pembrolizumab. Prescribing information: Checkpoint inhibitors and/or monoclonal antibodies included in this regimen may be continued as maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules. NCCN Guidelines for the Management of Immunotherapy- Related Toxicities. Induction chemotherapy (carboplatin/paclitaxel) followed by single agent cisplatin (or carboplatin) and radiation given according to the INTERLACE protocol could be considered. (McCormack M, et al. Lancet 2024;404:1525- 1535) If not used previously, these agents can be used as second- line or subsequent therapy as clinically appropriate. Recommended in patients whose tumors express PD- L1 (CPS ≥1). Atezolizumab and hyaluronidase- tqs injection for subcutaneous injection may be substituted for IV atezolizumab. Atezolizumab and hyaluronidase- tqs has different dosing and administration instructions compared to atezolizumab for intravenous infusion. Additional references for second- line therapy are provided in the Discussion. For the treatment of patients with unresectable or metastatic tumor mutational burden- high (TMB- H) (≥10 mutations/megabase [mut/Mb]) tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. Nivolumab and hyaluronidase- nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase- nvhy has different dosing and administration instructions compared to IV nivolumab. For patients who are PD- L1- positive and have not received prior immuno- oncology (IO) therapy. NTRK- positive tumors that are naive to prior NTRK targeted therapy or have progressed on prior NTRK therapy.. # # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 4.2025 Cervical Cancer. SYSTEMIC THERAPY FOR CERVICAL CANCER REFERENCES. 1 Lorusso D, Xiang Y, Hasegawa K, Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high- risk, locally advanced cervical cancer (ENGOT- cx11/GOG- 3047/KEYNOTE- A18): a randomised, double- blind, phase 3 clinical trial. Lancet 2024;403:1341- 1350. 2 Lorvidhaya V, Chitapanaarux I, Sangruchi S, et al. Concurrent mitomycin C, 5- fluorouracil, and radiotherapy in the treatment of locally advanced carcinoma of the cervix: a randomized trial. Int J Radiat Oncol Biol Phys. 2003;55:1226- 1232. 3 Pattaranutaporn P, Thirapakawong C, Chansilpa Y, et al. Phase II study of concurrent gemcitabine and radiotherapy in locally advanced stage IIIB cervical carcinoma. Gynecol Oncol 2001;81:404- 407. 4 Candelaria M, Garcia- Aria A, Cetina L, et al. Radiosensitizers in cervical cancer. Cisplatin and beyond. Radiat Oncol 2006;1:15. 5 Cerrotta A, Gardan G, Raspagliesi F, et al. Concurrent radiotherapy and weekly paclitaxel for locally advanced or recurrent squamous cell carcinoma of the uterine cervix. A pilot study with intensification of dose. Eur J Gynaecol Oncol 2002;23:115- 119. 6 McCormack M, Eminowicz G, Gallardo D, et al. INTERLACE investigators. Induction chemotherapy followed by standard chemoradiotherapy versus standard chemoradiotherapy alone in patients with locally advanced cervical cancer (GCIG INTERLACE): an international, multicentre, randomised phase 3 trial. Lancet 2024;19;404(10462):1525- 1535. 7 Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N Engl J Med 2021;385:1856- 1867. 8 Tewari KS, Sill MW, Long HJ 3rd, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 2014;370:734- 743. 9 Oaknin A, Gladieff L, Martinez- Garcia J, et al. ENGOT- Cx10- GEICO 68- C- JGOG1084- GOG- 3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open- label, phase 3 trial. Lancet 2024;403:31- 43. 10 Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin- containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2009;27:4649- 4655.. 11 Moore DH, Blessing JA, McQuellon RP, et al. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 2004;22:3113- 3119. 12 Moore RN, Herzog TJ, Lewin S, et al. A comparison of cisplatin/paclitaxel and carboplatin/paclitaxel in stage IVB, recurrent or persistent cervical cancer. Gynecol Oncol 2007;105:299- 303. 13 Kitagawa R, Katsumata N, Shibata T, et al. Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: the open- label randomized phase III trial JCOG0505. J Clin Oncol 2015;33:2129- 2135. 14 Long HJ 3rd, Bundy BN, Grendys EC Jr, et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol 2005;23:4626- 4633. 15 Weiss GR, Green S, Hamnigan EV, et al. A phase II trial of carboplatin for recurrent or metastatic squamous carcinoma of the uterine cervix: a Southwest Oncology Group study. Gynecol Oncol 1990;39:332- 336. 16 Tinker AV, Bhagat K, Swenerton KD, Hoskins PJ. Carboplatin and paclitaxel for advanced and recurrent cervical carcinoma: the British Columbia Cancer Agency experience. Gynecol Oncol 2005;98:54- 58. 17 Marabelle A, Le DT, Ascherto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair- deficient cancer: results from the phase 2 KEYNOTE- 158 study. J Clin Oncol 2020;38:1- 10. 18 Coleman RL, Lorusso D, Gennigens C, et al. Efficacy and safety of isotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG- 3023/ENGOT- cx6): a multicentre, open- label, single- arm, phase 2 study. Lancet Oncol. 2021;22:609- 619. 19 Vergote I, Gonzalez- Martin A, Fujiwara K, et al. Tisotumab Vedotin as Second- or Third- Line Therapy for Recurrent Cervical Cancer. N Engl J Med 2024;391:44- 55. 20 McGuire WP, Blessing JA, Moore D, et al. Paclitaxel has moderate activity in squamous cervix cancer. A Gynecologic Oncology Group study. J Clin Oncol 1996;14:792- 795. 21 Tewari KS, Monk BJ, Vergote I, et al. Survival with Cemiplimab in Recurrent Cervical Cancer. N Engl J Med 2022;386:544- 555.. 22 Naumann RW, Hollebecque A, Meyer T, et al. Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial. J Clin Oncol 2019;37:2825- 2834. 23 Vergote I, Van Nieuwenhuyser E, O'Carabhall RE, et al. Tisotumab Vedotin in Combination With Carboplatin, Pembrolizumab, or Bevacizumab in Recurrent or Metastatic Cervical Cancer: Results From innovaTV 205/GOG- 3024/ENGOT- cx8 Study. J Clin Oncol 2023;41:5536- 5549. 24 Meric- Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2- expressing solid tumors: DESTINYPartumor02 Phase II trial. J Clin Oncol 2024;42:47- 58. 25 Friedman CF, D'Souza A, Bello Roufai D, et al. Targeting HER2- mutant metastatic cervical cancer with neratinib: Final results from the phase 2 SUMMIT basket trial. Gynecol Oncol 2024;181:162- 169. 26 Solomon B, Drilon A, Lin JJ, et al. Repotrectinib in patients with NTRK fusion- positive advanced solid tumors, including non- small cell lung cancer: update from the phase 1/2 TRIDENT- 1 trial. Poster presented at the European Society for Medical Oncology Congress, Madrid, Spain, October 20- 24, 2023. 27 Zivanovic O, Leitao Jr MM, Park KJ, et al. Small cell neuroendocrine carcinoma of the cervix: Analysis of outcome, recurrence pattern and the impact of platinum- based combination chemotherapy. Gynecol Oncol 2009;112:590- 593. 28 Gordhandas S, Schlappe BA, Zhou Q, et al. Small cell neuroendocrine carcinoma of the cervix: Analysis of prognostic factors and patterns of metastasis. Gynecol Oncol 2022;43:101058. 29 Horn L, Mansfield AS, Szczesna A, et al. First- Line Atezolizumab plus Chemotherapy in Extensive- Stage Small- Cell Lung Cancer. N Engl J Med 2018;379:2220- 2229. 30 Paz- Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum- etoposide versus platinum- etoposide in first- line treatment of extensive- stage small- cell lung cancer (CASPIAN): a randomised, controlled, open- label, phase 3 trial. The Lancet 2019;394:1929- 1939. 31 Frumovitz M, Munsell MF, Burzawa JK, et al. Combination therapy with topotecan, paclitaxel, and bevacizumab improves progression- free survival in recurrent small cell neuroendocrine carcinoma of the cervix. Gynecol Oncol 2017;144:46- 50.. # Physical Effects. Physical Effects- Gynecologic cancer treatment typically involves surgery, chemotherapy, hormone therapy, radiation therapy, and/or immunotherapy. These treatments cause acute, short- term, and long- term toxicities.- Surgical approaches may be extensive and pose risks such as adhesion formation, which may cause pain and may contribute to small bowel obstruction, urinary or gastrointestinal complications (eg, incontinence, diarrhea), pelvic floor dysfunction (manifested by a variety of urinary, bowel, and/or sexual effects), and lymphedema.- Chemotherapy agents vary, though commonly used regimens may pose a significant risk of neurotoxicity, cardiac toxicity, development of hematologic cancers, and cognitive dysfunction.- Long- term estrogen deprivation may cause symptoms such as hot flashes, vaginal dryness, and bone loss.- Radiation therapy may cause long- term complications (eg, fibrosis, vulvovaginal atrophy) and may predispose patients to secondary cancers of the subcutaneous tissue, and/or underlying organs that are proximal to the radiation field.- Prior pelvic RT may contribute to bone loss and increase the risk of pelvic fractures. Consider bone density testing and prophylactic use of bisphosphonates, particularly in patients with osteoporosis. Immunotherapy use is emerging, and to date, long- term effects of these treatments are unknown.. Psychosocial Effects. Psychosocial Effects- Psychosocial effects after cancer may be psychological (eg, depression, anxiety, fear of recurrence, altered body image), financial (eg, return to work, insurance concerns), and/or interpersonal (eg, relationships, sexuality, intimacy) in nature.. Clinical Approach. Clinical Approach- All gynecologic cancer survivors should receive regular general medical care that focuses on managing chronic disease, monitoring cardiovascular risk factors, providing recommended vaccinations, and encouraging adoption of a healthy lifestyle.- In order to assess the late and long- term effects of gynecologic cancers, clinicians should comprehensively document the patient's history, conduct a thorough physical examination, and provide any necessary imaging and/or laboratory testing. All patients, whether sexually active or not, should be asked about genitourinary symptoms, including vulvovaginal dryness. Referral to appropriate specialty providers (eg, physical therapy, pelvic floor therapy, sexual therapy, psychotherapy) is recommended. As most treatments for gynecologic cancers will cause sexual dysfunction, early menopause, and infertility, special attention to the resultant medical and psychosocial implications is needed.- Post- radiation use of vaginal dilators and moisturizers is recommended.- For treatment- related menopause, hormone therapy should be considered.- Communication and coordination with all clinicians involved in the care of survivors, including primary care clinicians, is critical. Providing cancer survivors with a summary of their treatment and recommendations for follow- up is recommended.. Additional Guidance. Additional Guidance- NCCN Guidelines for Distress Management- NCCN Guidelines for Smoking Cessation- NCCN Guidelines for Survivorship. # Table 1: International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging of Cancer of the Cervix Uteri (2018). Imaging and pathology can be used, when available, to supplement clinical findings with respect to tumor size and extent, in all stages. Pathological findings supersede imaging and clinical findings. The involvement of vascular/lymphatic spaces should not change the staging. The lateral extent of the lesion is no longer considered. Isolated tumor cells do not change the stage but their presence should be recorded. Adding otion f (imgng) and p (patogy) to indcte the indings that are used to alcat the case to Stge IIC. Example: f imging indcte pelic ymph node metastasis, the stage alation woud be Stage 1r, and if confmed y pathologic indings, it would be Stage 1p. The type of imaging modality or pathology technique used should always be documented.. Reprinted from: Bhatla N, Berek JS, Fredes MC, et al. Revised FIGO Staging for carcinoma of the cervix uteri. Int J Gynecol Obstet 2019;145:129- 135 and Corrigendum to "Revised FIGO Staging for carcinoma of the cervix uteri" [Int J Gynecol Obstet 2019;145:129- 135] Int J Gynecol Obstet 2019;147:279- 280. Copyright 2019, with permission from International Federation of Gynecology and Obstetrics.. # National Comprehensive Cancer Network. NCCN Guidelines Version 4.2025 Cervical Cancer. ABBREVIATIONS. # ABBREVIATIONS. SBRT stereotactic body radiation therapy SCC squamous cell carcinoma SIB simultaneous integrated boost SLN sentinel lymph node. TH total hysterectomy TMB tumor mutational burden TMB- H tumor mutational burden- high TTF1 thyroid transcription factor- 1. VMAT volumetric- modulated arc. # # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. Discussion. This discussion corresponds to the NCCN Guidelines for Cervical Cancer (V4.2024). Last updated on September 24, 2024. Table of Contents. Locoregional Recurrence. MS- 23 Therapy for Metastatic Disease. MS- 24 Systemic Therapy Recommendations. MS- 25 Chemoradiation for Locally Advanced Cervical Cancer. MS- 25 Systemic Therapy for Recurrent or Metastatic Cervical Cancer. MS- 26 First- Line Systemic Therapy Options for Recurrent or Metastatic Disease. MS- 26 Second- line/Subsequent Systemic Therapy Options for Recurrent or Metastatic Cervical Cancer. MS- 29 Principles of Radiation Therapy. MS- 32 Radiation Treatment Planning. MS- 32 Normal Tissue Considerations. MS- 35 Incidental Cervical Cancer. MS- 36 Small Cell Neuroendocrine Carcinoma of the Cervix. MS- 37 Overview. MS- 37 Primary Workup. MS- 37 Principles of Pathology. MS- 38 Systemic Therapy. MS- 38 Cervical Cancer and Pregnancy. MS- 39 Drug Reactions. MS- 39 Gynecologic Survivorship. MS- 40 Best Supportive Care. MS- 40 Summary. MS- 41 References. MS- 42. # National Comprehensive. NCCN Cancer Network. NCCN Guidelines Version 4.2025 Cervical Cancer. Overview. An estimated 13,820 new cases of carcinoma of the uterine cervix (ie, cervical cancer) will be diagnosed in the United States in 2024, and 4360 people are estimated to die of the disease. Although cervical cancer rates are decreasing in the United States following the introduction of screening, incidence remains high among Hispanic/Latino, Black, and Asian populations. The incidence rates of cervical squamous cell carcinoma are highest in Black and Hispanic individuals assigned female at birth (AFAB), while incidence rates of cervical adenocarcinoma are highest among Hispanic and white AFAB individuals. However, cervical cancer is a major world health problem for AFAB individuals. Globally in 2020, there were an estimated 604,127 cervical cancer cases and 341,831 deaths associated with cervical cancer. It is the fourth most common cancer in AFAB individuals worldwide with . Squamous cell carcinoma (SCC), adenocarcinoma (AC), adenosquamous carcinoma (ASC) are the three common histologies of cervical cancer. SCC accounts for approximately . However, AC/ASC of the cervix have increased over the past 3 decades, probably because cervical cytologic screening methods are less effective for AC/ASC as the lesions are located deeper than the ectocervix. The ASC subtype is rare and accounts for approximately . SCC and AC/ASC cervical cancer subtypes although the clinical features and prognosis of disease varies considerably between these subtypes.. Persistent HPV infection is the most important factor in the development of cervical cancer. The incidence of cervical cancer appears to be related to the prevalence of HPV in the population. In countries with a high incidence of cervical cancer, the prevalence of chronic HPV is approximately . In 2020, the World Health Organization (WHO) updated the Female Genital Tumors classification of cervical cancer by subdividing the cervical cancer lesions into HPV- associated and HPV- independent tumors based on the new pathological findings. Among these, the HPV- associated SCC is the most prevalent subtype, with very rare occurrences of the HPV- independent SCC. The HPV- independent AC has a less favorable prognosis as compared to the HPV- associated tumors. The NCCN Cervical Cancer Guidelines Panel acknowledges that while the prior. # versions of the WHO classification discussed these tumors based on morphologic features, the integration of the immunohistochemical and molecular profiles has led to a better classification system that is now adapted in the 2020 WHO Classification of Female Genital Tumors for cervical cancer. Regardless of cancer subtype and HPV infection status, primary treatment with curative intent for patients with cervical cancer typically consists of surgery, chemoradiation, or a combination of these treatments; options vary by cancer stage. By definition, the NCCN Guidelines cannot incorporate all possible clinical variations and are not intended to replace good clinical judgment or individualization of treatments. "Many exceptions to the rule" were discussed among the members of the Cervical Cancer Panel during the process of developing these guidelines.. Guidelines Update Methodology. The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.. Literature Search Criteria. Prior to the update of this version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cervical Cancer, an electronic search of the PubMed database was performed to obtain key literature in cervical cancer published since the previous Guidelines update, using the following search terms: cervical cancer or cervical carcinoma or carcinoma of the cervix. The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes only peer- reviewed biomedical literature.. The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;. Guideline; Randomized Controlled Trial; Meta- Analysis; Systematic Reviews; and Validation Studies.. The data from key PubMed articles as well as articles from additional sources deemed as relevant to these Guidelines as discussed by the Panel during the Guidelines update have been included in this version of the Discussion section. Recommendations for which high- level evidence is lacking are based on the Panel's review of lower- level evidence and expert opinion.. Sensitive/Inclusive Language Usage. NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation. NCCN Guidelines endeavor to use language that is person- first; not stigmatizing; anti- racist, anti- classist, anti- misogynist, anti- ageist, anti- ableist, and anti- weight- biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non- gendered language, instead focusing on organ- specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.. # National Comprehensive. NCCN Cancer Network. NCCN Guidelines Version 4.2025 Cervical Cancer. Diagnosis and Workup. These NCCN Guidelines discuss squamous cell carcinoma, adenosquamous carcinoma and adenocarcinoma of the cervix. The primary workup for small cell neuroendocrine carcinoma is discussed in Small Cell Neuroendocrine Carcinoma of the Cervix (NECC) section. Glassy- cell carcinomas, sarcomas, and other histologic types are not within the scope of these Guidelines.. The earliest stages of cervical carcinoma may be asymptomatic or associated with a watery vaginal discharge and postcoital bleeding or intermittent spotting. Often these early symptoms are not recognized by the patient. Because of the accessibility of the uterine cervix, cervical cytology or Papanicolaou (Pap) smears and cervical biopsies can usually result in an accurate diagnosis. Cone biopsy (ie, conization) is recommended if the cervical biopsy is inadequate to define invasiveness or if accurate assessment of microinvasive disease is required. The shape and depth of the cone biopsy may be tailored to the size, type, and location of the neoplastic lesion. For example, if there is concern for invasive adenocarcinoma versus adenocarcinoma in situ in the cervical canal, the cone biopsy would be designed as a narrow, long cone extending to the internal os in order not to miss possible invasion in the endocervical canal. Length of the cold cone of at least . ( REL_CAPCP.pdf). This CAP protocol was revised in March 2022 and reflects recent updates in AJCC staging (ie, AJCC Cancer Staging Manual, . Workup for these patients with suspicious symptoms includes history and physical examination, complete blood count (CBC, including platelets), and liver and renal function tests. Recommended radiologic imaging includes pelvic MRI, neck/chest/abdomen/pelvis/groin FDG- PET/CT, chest radiograph, CT, or combined PET/CT, and MRI as indicated (eg, to rule out disease high in the endocervix). For detailed imaging recommendations by stage and planned treatment approach, see Principles of Imaging in the NCCN Guidelines for Cervical Cancer. Smoking cessation and counseling, as well as HIV testing (especially in younger patients), are recommended. Cytoscopy and proctoscopy are only recommended if bladder or rectal extension is suspected (ie, for ≥ stage IB3). Options for fertility sparing should be considered, or referral to reproductive endocrinology and infertility (REI) specialist.. Principles of Staging and Surgery. Clinical Staging. The Panel has updated the Guidelines for Cervical Cancer according to the revised 2018 FIGO staging system.38,39 The definitions for lesion size and microinvasion for stage I have been revised. For stage IA, the lateral extent of the lesion no longer affects staging. Stage IB is now divided into 3 subgroups as follows: IB1 includes invasive carcinomas . # not always agree on whether LVSl is present in tissue samples. Some Panel members believe that patients with stage IA1 who have extensive LVSI should be treated using stage IB1 guidelines.38 The staging and treatment recommendations by stage have been revised according to FIGO 2018 in the algorithm, and some of the data cited within this section utilized the previous 2009 FIGO staging system.40,41. Surgical Staging. Pathologic Assessment. Surgical StagingPathologic AssessmentSurgicopathologic factors may be used to guide the extent of surgical staging and treatment decisions. Findings from pathologic assessment of the surgical specimen should be carefully documented according to CAP protocol for cervical carcinoma. Important elements of primary tumor evaluation include tumor site; primary tumor volume (in multiple dimensions); histologic type and grade; stromal invasion including pattern of invasion; surgical margin status; and the presence of LVSI. When evaluating patterns of stromal invasion in endocervical adenocarcinoma, the Silva system is utilized, which subdivides these tumors into three categories (see Principles of Pathology section).42 When evaluating histologic type, according to the 2018 International Endocervical Adenocarcinoma Criteria and Classification (IECC),43 morphologic features (luminal mitotic figures and apoptosis) can be used to distinguish between HPV- associated endocervical adenocarcinomas and HPV- independent adenocarcinomas. Tumors can be further subtyped based on morphologic features. When resected, the number of lymph nodes with isolated tumor cells, micrometastases, and macrometastases should be recorded. When sentinel lymph node (SLN) mapping is performed, SLNs should undergo ultra staging for detection of low- volume metastasis; non- sentinel nodes do not require ultra staging. Other important factors include tumor involvement of tissues/organs such as the parametrium, vaginal cuff, fallopian tubes, ovaries, peritoneum, omentum, and others.. Uterus- 11 was a prospective international multicenter study aimed to evaluate the impact of pre- treatment surgical staging, including removal of bulky lymph nodes, on disease- free survival in patients with locally advanced cervical cancer. A total of 255 patients (surgical arm, . Conservative/Fertility-Sparing Approaches. Fertility- sparing approaches may be considered in highly selected patients who have been thoroughly counseled regarding disease risk as well as prenatal and perinatal issues.45 Consultation with REI experts are suggested.. Microinvasive disease (FIGO stage IA1 with no LVSI) is associated with an extremely low incidence of lymphatic metastasis,46- 49 and conservative treatment with conization is an option for individuals with no evidence of LVSI. The goal of conization is en bloc removal of the ectocervix and endocervical canal; the Panel recommends cold knife conization as the preferred approach to conization. However, loop electrosurgical excision procedure (LEEP) is acceptable if adequate margins, proper orientation, and a non- fragmented specimen without electrosurgical artifact can be obtained.50- 55 Endocervical curettage should be added as clinically indicated except in pregnancy.. Based on ConCerv trial, select patients with stage IA2 and IB1, especially for those with tumors of less than 2 cm in diameter and who meet all the. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. conservative surgery criteria with no evidence of LVSI, may be eligible for conservative surgery with pelvic lymphadenectomy or SLN mapping.41,56,57. The objective of the ConCerv Trial was to prospectively evaluate the feasibility of conservative surgery in women with early- stage, low- risk cervical cancer. The eligibility criteria included: (1) FIGO 2009 stage IA2- IB1 cervical carcinoma; (2) squamous cell (any grade) or adenocarcinoma (grade 1 or 2 only) histology; (3) tumor size . One hundred evaluable patients were enrolled, and the surgery included conization followed by lymph node assessment in 44 women, conization followed by simple hysterectomy with lymph node assessment in 40 women, and inadvertent simple hysterectomy followed by lymphadenectomy in 16 women. Positive lymph nodes were noted in 5 patients. Residual disease in the post- conization hysterectomy specimen was noted in 1/40 patients- that is, an immediate failure rate of . Radical trachelectomy may offer a reasonable fertility- sparing treatment option for patients with stage IA1- IA2 (with LVSI), IB1 (not meeting conservative surgery), and select IB2 cervical cancer with lesions that are 2 to 4 cm.58- 60 In a radical trachelectomy, the cervix, vaginal margins, and supporting ligaments are removed while leaving the main body and fundus of the uterus intact.61 Laparoscopic pelvic lymphadenectomy accompanies the procedure and can be performed with or without SLN mapping (see Lymph Node Mapping and Dissection below). Para- aortic lymphadenectomy can be added for stage 1B1 and select patients with IB2 cervical cancer.62. Due to their aggressive nature, tumors of small cell neuroendocrine histology are considered inappropriate for radical trachelectomy.63 Trachelectomy is also inappropriate for treating gastric type cervical adenocarcinoma and adenoma malignum (minimal deviation adenocarcinoma) due to their diagnostic challenges and potentially aggressive nature.64. Vaginal radical trachelectomy (VRT) may be used for carefully selected patients with lesions of 2 cm diameter or less.65- 67 Abdominal radical trachelectomy (ART) provides a broader resection of the parametria58,67 than the vaginal approach and is commonly used in stage IB1 lesions. Multiple case series have evaluated safety and outcomes with vaginal versus abdominal approaches to radical trachelectomy,65,68- 70 including systematic reviews on VRT71 and ART72 A limited number of studies have specifically examined this approach in patients with tumors between 2 cm and 4 cm in diameter and reported safe oncologic outcomes; however, as expected, more patients in this subgroup will require adjuvant therapy, which may reduce fertility.73- 75. Studies that examined pregnancy in patients who underwent radical trachelectomy have provided differing success rates. One case series of 125 patients with cervical cancer who underwent VRT reported 106 pregnancies among 58 females.66 In a systematic review of 413 females who underwent ART, 113 of those attempted pregnancy and 67 . Non-Fertility-Sparing Approaches. The Querleu and Morrow surgical classification system79,80 describes the degree of resection and nerve preservation for radical hysterectomy in three- dimensional planes and updates the previously used Piver- Rutledge classifications.81 Approaches to hysterectomy include simple/extrafascial. # hysterectomy (Type A), modified radical hysterectomy (Type B), and radical hysterectomy (Type C).82,83. For patients with IA1 disease, cone excision, simple/extrafascial hysterectomy, and modified radical hysterectomy are options. Radical hysterectomy with bilateral pelvic lymphadenectomy (with or without SLN mapping) is the preferred treatment approach for patients with FIGO stage IA2, IB1, IB2, and IIA1 cervical cancers. Radical hysterectomy is preferred over simple hysterectomy due to its wider paracervix margin of resection that also includes aspects of the cardinal and uterosacral ligaments, upper vagina, pelvic nodes, and at times, para- aortic nodes. In the United States, definitive chemoradiation is typically preferred over radical surgery for select patients with FIGO IB3 lesions and the vast majority of FIGO stage IIA2 or greater cervical cancers. Abroad, select FIGO stage IB3- IIB cases may be treated with radical hysterectomy or neoadjuvant chemotherapy, followed by radical hysterectomy.. For recurrent or persistent cervical cancers that are confined to the central pelvis (ie, no distant metastasis), pelvic exenteration may be a potentially curative surgical option.84,85 Discussion of the various approaches to pelvic exenteration are offered by Chi and colleagues,82 and in the Gynecologic Oncology Group (GOG) Surgical Manual.83. Lymph Node Mapping and Dissection. Sentinel Lymph Node Mapping. Based on cumulative published data, SLN biopsy may be useful for decreasing the need for pelvic lymphadenectomy in patients with early- stage cervical cancer and to detect low- volume metastasis.86,87. Prospective studies generally support the feasibility of SLN detection in patients with early- stage cervical cancer and suggest that extensive pelvic lymphadenectomy may be safely avoided in a significant proportion of early- stage cases.86- 97. Meta- analyses of pooled data from SLN mapping studies have generated SLN detection rates of . Study data also highlight limited sensitivity of this approach and potential to miss SLN micrometastases and isolated tumor cells using intraoperative assessment (ie, frozen section or imprint cytology).89,93,95 The sensitivity of this approach appears to be better in patients with tumors equal to or less than 2 cm in diameter.86,88,90,102 Ultra staging of detected SLNs has been shown to provide enhanced detection of micrometastases.91,92. The SENTICOL longitudinal study demonstrated the utility of SLN mapping to uncover unusual lymph drainage patterns.90,103 It also highlighted limited agreement between lymphoscintigraphy and intraoperative SLN mapping.103 Additionally, this study revealed that bilateral SLN detection and biopsy provided a more reliable assessment of sentinel nodal metastases and led to fewer false negatives than unilateral SLN biopsy.87. The SENTICOL- 2 study also demonstrates the benefits of omitting pelvic lymphadenectomy in terms of decreased lymphatic morbidity. The study showed that lymphatic morbidity was significantly lower in the sentinel node resection alone (SN arm) . # if no sentinel nodes are detected on a given side of the pelvis as outlined in the SLN mapping algorithm.. Based on these collective data, the Panel recommends consideration of SLN mapping algorithm and emphasizes that best detection and mapping results are in tumors of less than 2 cm diameter. Adherence to the SLN mapping algorithm is important; surgeons should perform side- specific nodal dissection in any cases of failed mapping and remove all suspicious or grossly enlarged nodes regardless of SLN mapping.. Para-Aortic Lymph Node Assessment. Studies of the incidence and distribution of lymph node metastases in patients with stage IB to IIB cervical cancers suggest that para- aortic lymph node involvement is closely tied to the presence of pelvic lymph node metastases, larger primary tumor size . Analysis of outcomes data from 555 patients who participated in GOG trials (GOG 85, GOG 120, and GOG 165) revealed a more positive prognosis for patients who underwent surgical exclusion of para- aortic lymph node involvement versus those who underwent radiographic determination of para- aortic node involvement.. The ongoing PAROLA trial aims to demonstrate if chemoradiation with tailored EBRT based on surgical staging and pathologic examination of the para- aortic lymph node is associated with improved survival compared with patients staged with radiologic staging only and the accrual is estimated to be completed in 2027. . The Panel recommends para- aortic lymphadenectomy for patients with . Minimally Invasive Surgical Approaches. The standard and historical approach for radical hysterectomy is with an open abdominal approach.. Previous iterations of the Guidelines had indicated that radical hysterectomy could be performed either via open laparotomy or minimally invasive surgery (MIS) laparoscopic approaches, using either conventional or robotic techniques. Data from previous retrospective reviews and prospective observational studies demonstrated oncologic outcomes following conventional laparoscopic radical hysterectomy that were comparable to open abdominal approaches after 3 to 6 years of follow- up.. However, several key contemporary reports have questioned the presumed therapeutic equivalency of open versus MIS approaches. A pivotal prospective randomized trial demonstrated that minimally invasive radical hysterectomy was associated with lower rates of disease- free survival (DFS) and overall survival (OS) than open abdominal radical hysterectomy.. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. Ninety- two percent of participants in both surgical arms had stage IB1 disease. MIS was associated with lower rate of DFS than open surgery (3- year DFS, . Two other epidemiologic studies also demonstrated that minimally invasive radical hysterectomy was associated with shorter OS than open surgery among patients with stage IA2- IB1 cervical cancer.120,121 Melamed et al reported on a SEER- based cohort study that compared females with stage IA2 or IB1 cervical cancer who underwent laparotomy . Another systematic review and meta- analysis of 15 high- quality studies comprising 9499 patients122 confirmed that minimally invasive radical hysterectomy was associated with shorter overall and DFS among women with operable cervical cancer compared with open surgery. Of 9499 patients who underwent radical hysterectomy, . These findings stand in contradiction to the earlier referenced series that had suggested therapeutic equivalency of MIS compared to open approaches along with the MIS- associated potential advantages of decreased hospital stay and more rapid patient recovery.114,115,117,118,123- 126. Given the findings of poorer oncologic outcomes and survival with the MIS techniques compared to open laparotomy, patients should be carefully counseled about the oncologic risks and potential short- term benefits of the different surgical approaches.. Principles of Pathology. Pathologic Assessment. Silva Classification System for HPV-Associated Endocervical Adenocarcinoma. According to the 2018 FIGO criteria38,39 pathologists use tumor size and stromal depth of invasion (DOI) during clinicopathological staging of cervical cancer. During clinicopathological assessment, pathologists calculate DOI (in millimeters) starting from the basement membrane of the originating epithelium.127 Endocervical glands normally vary in size, shape, and distance of extension into the underlying stroma. Because of this architectural complexity determining the DOI in endocervical adenocarcinoma (EAC) is difficult.128,129 Obtaining an accurate DOI. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. measurement is important, as it directly informs treatment decisions. The FIGO staging system does not consider the extent of LVS1, but clinicians also use this information to inform treatment decisions. For instance, patients with stage IA1 cervical cancer (DOl ≤3 mm) whose tumors do not have Lvs1 may be candidates for fertility- sparing conservative treatment (ie, cone biopsy, trachelectomy), as these patients generally have low risk of metastasis and recurrence. Patients with IA2 cervical cancer (DOl >3 mm) may also be candidates for these procedures, but also typically undergo lymphadenectomy with or without SLN mapping due to an increased risk of nodal metastases and recurrence compared to patients with stage IA1 cervical cancer without LvsI. Lymphadenectomy and SLN mapping both may increase morbidity. Therefore, more accurate and reproducible methods of staging EAC are needed to avoid the use of unnecessary procedures in patients who may be at minimal risk of nodal metastases, recurrence, and/or death.. The Silva classification system, which considers the extent of LvsI, stromal invasion, and differentiation, has been proposed to stratify patients more accurately with invasive HPV- associated EAC. A 2013 retrospective study published by Diaz De Vivar et al30 included patients . For tumors that had mixed histopathological characteristics, pathologists assigned the highest classification that they observed in the sample. The mean follow- up time was approximately 4.5 years. Patients with category A tumors did not experience any metastases or recurrences during this . Since 2013, several other groups independently published retrospective studies on use of the Silva classification system. Spaans et al 2018131 classified tumor samples from 82 patients with stage IB- IIA HPV- associated EAC, all of whom previously underwent radical hysterectomy or trachelectomy. The median follow- up time was approximately 10 years. Patients with category A tumors did not experience any metastases, recurrences, or deaths during this time. Of patients with category B tumors, . Stolnicu et al 132 used the Silva classification system to stratify 341 patients with HPV- associated and non- HPV- associated stage I through IV EAC who previously underwent surgical resection (ie, cone biopsy, trachelectomy, hysterectomy) and lymphadenectomy. Pathologists first classified tumor specimens into HPV- associated and non- HPV- associated EAC according to IECC criteria17 and then further classified the tumors by Silva criteria. The authors found that the incidence of metastases in HPV- associated EAC was like that observed by Diaz De Vivar et al.130 They also reported that . # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. were classified as category C, and therefore concluded that the utility of the Silva classification system is limited to patients with HPV- associated EAC.132 Stolnicu et al, have also proposed a binary Silva classification system that groups patients into low risk (patterns A and B without lymphovascular invasion) and high risk (pattern B with lymphovascular invasion and pattern C) categories.133 FIGO (2019 classification) stage IAB1 EACs from 15 international institutions were examined for Silva pattern, presence of LVsI, and other prognostic parameters.. On multivariate analysis, LVsI . Silva pattern and LVsI are important prognostic factors in stage IA1- IB1 endocervical adenocarcinomas and can supplement FIGO staging.. Data from these retrospective studies suggest that the Silva classification system may help stratify patients with invasive, EAC by risk of metastasis, recurrence, and death. Some expert gynecological pathologists are already using the Silva classification system during clinicopathological staging. The system could be particularly helpful for identifying patients who are low risk with stage I disease who may be candidates for conservative, fertility- sparing treatment without compromising short- and long- term patient health outcomes. However, prospective studies are needed to confirm these observations. If data from future prospective studies agree with the data cited above, the Silva classification system could potentially be used in conjunction with, or incorporated into, FIGO/AJCC criteria at the time of diagnostic biopsy. To this end, Roma et . Sedlis Criteria. The "Sedlis Criteria," which are intermediate risk factors used to guide adjuvant treatment decisions, include: 1) greater than one- third stromal invasion; 2) capillary lymphatic space involvement; or 3) cervical tumor diameters more than 4 cm.135 However, potentially important risk factors for recurrence may not be limited to the Sedlis Criteria. Additional risk factors for consideration include tumor histology (eg, adenocarcinoma component)136,137 and close or positive surgical margins.138,139. Sedlis criteria were developed primarily for squamous cell carcinoma. Histology- specific nomograms for squamous and adenocarcinoma lesions may provide a more contemporary tool to model the risk of recurrence and base adjuvant recommendations. In an ancillary analysis of GOG 49, 92, and 14 studies,140 among 715 patients with SCC and 105 with AC, . # LVS1. It is also important to note that the risk factors may not be limited to the Sedlis criteria. These systems remain to be validated for clinical use.. Prognostic and Predictive Biomarkers. Over the years, systemic therapy options for cervical cancer have undergone a paradigm shift with the emergence of biomarkers and the growing number of newer treatment options available with meaningful improvement in survival rates. As the importance of testing for the presence of certain biomarkers in advanced disease is well recognized, the availability of several agents targeting these specific biomarkers have led to improved outcomes in patients. Testing for these biomarkers is critical to guide treatment selection especially for patients with advanced or recurrent disease. While predictive biomarkers indicate how certain patients are likely to respond to treatment, either in terms of efficacy or toxicity and forecasts pharmacodynamic resistance or toxicity and can guide initial treatment decisions by identifying potentially successful drugs and potentially minimizing toxicity, prognostic biomarkers predict the overall survival in certain patients, independent of therapy and can guide treatment decision- making, monitor disease progression, and detect recurrence.141,142. Several biomarker- based immune- oncologic agents have been added to the Guidelines in the management of recurrent/metastatic cervical cancer in recent years (see Systemic Therapy Recommendations) and the NCCN Panel recommends comprehensive molecular profiling as determined by a U.S. Food and Drug Administration (FDA)- approved assay, or a validated test performed in a Clinical Laboratory Improvement Amendments (CLIA)- certified laboratory.. PD-L1. The NCCN Panel recommends programmed death- ligand 1 (PD- L1) testing by an FDA- approved assay, or a validated test performed in a CLIA- certified laboratory for patients with recurrent, progressive, or . The FDA approved pembrolizumab plus chemotherapy, with or without bevacizumab for patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD- L1 (combined positive score [CPS] ≥1) based on Keynote- 826 study.143 The NCCN Panel also recommends the same as a preferred regimen (Category 1) for first- line therapy for recurrent or metastatic disease.. KEYNOTE- 158 is another phase II basket study that evaluates the use of pembrolizumab in multiple cancer types including cervical cancer.144 The interim results from previously treated patients with advanced cervical cancer demonstrated the durable antitumor activity and manageable safety of pembrolizumab monotherapy. Out of 98 patients treated, 82 (83.7%) had PD- L1- positive tumors (CPS ≥1), 77 having previously received one or more lines of chemotherapy for recurrent or metastatic disease. The primary end point, objective response rate (ORR) was 12.2% (95% CI, 6.5%- 20.4%), with three complete and nine partial responses. All 12 responses were in patients with PD- L1- positive tumors, for an ORR of 14.6% (95% CI, 7.8%- 24.2%); 14.3% (95% CI, 7.4%- 24.1%) of these responses were in those who had received one or more lines of chemotherapy for recurrent or metastatic disease. Based on these results, the FDA granted accelerated approval of pembrolizumab for patients with advanced PD- L1- positive cervical cancer who experienced progression during or after chemotherapy. NCCN also recommends pembrolizumab as a preferred regimen for patients who are PD- L1- positive for second- line or subsequent therapy.. Nivolumab, a checkpoint inhibitor, has shown efficacy in patients with recurrent/metastatic cervical cancer who received at least one prior chemotherapy regimen. The Checkmate- 358, phase 1/2, single- arm trial evaluated 19 patients with advanced, pretreated, HPV- associated cervical tumors.145 The ORR was 26.3% (95% CI, 9.1%- 51.2%) and. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. disease control rate was . Based on these results, in the 1.2023 version of the NCCN Guidelines for Cervical Cancer, the Panel moved nivolumab from preferred, second- line or subsequent therapy options to the "useful in certain circumstances" category for PD- L1- positive tumors and continues to recommend nivolumab in the same category in version 2.2024.. Mismatch Repair /Microsatellite Instability. Tumors with mismatch repair deficiency (dMMR) represent approximately . Of 233 patients with MSI- H/dMMR advanced non- colorectal cancer who experienced failure with prior therapy who received pembrolizumab, the objective response rate was . MSI- H/dMMR tumors as a second- line or subsequent therapy for recurrent or metastatic disease.. TMB. Tumor mutational burden (TMB), defined as the total number of somatic mutations per coding area of a tumor genome, is a measure of all non- synonymous coding mutations in a tumor exome and highly mutated tumors can produce many neoantigens, some of which might increase T- cell reactivity. High TMB has been demonstrated to be associated with treatment response to Pembrolizumab.. In a prospective analysis of the multi- cohort, open- label, non- randomized phase 2 KEYNOTE- 158 study,149 the association between antitumor activity and tissue- tumor mutational burden (tTMB) in patients who received at least one dose of pembrolizumab were assessed and tTMB- high status identified a subgroup of patients who could have a robust tumor response to pembrolizumab monotherapy. Out of 790 TMB evaluable, treated patients enrolled by at least 26 weeks before data cutoff, 102 . The NCCN Panel recommends TMB testing by an FDA- approved assay, or a validated test performed in a CLIA- certified laboratory and recommends pembrolizumab as a preferred regimen for the treatment of patients with TMB- H [≥10 mutations/mega base (mut/Mb)] tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options (second- line or subsequent therapy).. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. NTRK Gene Fusion. NTRK gene fusions are found in about . In another primary analysis, the efficacy and safety of larotrectinib was reported in 55 patients enrolled in three clinical studies who had locally advanced or metastatic tumors with NTRK gene fusions and had progressed on standard chemotherapy received previously. The three clinical trials included a phase 1 dose finding study in adults, phase 1- 2 dose- finding study in a pediatric population, and a phase 2, single- arm, basket trial.152 The overall response rate of Larotrectinib in these patients was . HER2. HER2 expression is observed in a wide range of solid tumors and is an established prognostic biomarker for breast, gastric, and colorectal cancers. Cervical cancer has shown HER2 positivity rate of approximately . TheDESTINY- PanTumor02 is an open- label, multicenter, phase 2 trial that evaluated Trastuzumab deruxtecan (T- DXd) on 267 patients with HER2- expressing (IHC . # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. RET Gene Fusion. RET Gene FusionThe rearranged during transfection (RET) gene fusions most commonly occur in thyroid and non- small cell lung cancers and are observed in . HPV Status/p16. HPV Status/p16Approximately . epithelial tumor with squamous and glandular differentiation accounts for approximately . HPV-Independent Adenocarcinoma. HPV- Independent AdenocarcinomaHPV- independent endocervical adenocarcinomas include gastric, clear cell, mesonephric, and endometrioid types. Gastric type makes up approximately . # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. present at an advanced stage. Mesonephric type demonstrates mesonephric (Wolffian) differentiation and is associated with mesonephric remnants. It typically is located deep in the lateral wall and histologically demonstrates architectural crowding, haphazard infiltration, atypia, mitotic activity, and necrosis. GATA- 3 and CD10 IHC stains will be positive in the tumor and associated mesonephric remnants. Clear cell carcinomas make up . Primary Treatment. Note: Recommendations by stage are based on the revised 2018 FIGO staging by Bhatla et al.3 However, trial data cited within this section primarily utilized the previous 2009 FIGO staging system.40. The primary treatment of early- stage cervical cancer is either surgery or RT. Surgery is typically reserved for early- stage disease, fertility- preservation, and smaller lesions, such as stage IA, IB1, IB2, and selected IIA1.163 The Panel agrees that concurrent chemoradiation is generally the primary treatment of choice for stages IB3 to IVA disease based on the results of five randomized clinical trials.164,165 Chemoradiation can also be used for patients who are not candidates for hysterectomy. Although few studies have assessed treatment specifically for . Pelvic RT or chemoradiation will invariably lead to ovarian failure in patients undergoing premenopause.169 To preserve intrinsic hormonal function, ovarian transposition may be considered before pelvic RT for select patients younger than 45 years of age with squamous cell cancers.170,171. Important Phase III Clinical Trials Underpinning Treatment Recommendations. A randomized Italian study compared RT alone versus radical hysterectomy and lymphadenectomy in patients with clinical early- stage disease (stage IB- IIA).172 Adjuvant RT was given to those with parametrial extension, less than 3 cm of uninvolved cervical stroma, positive margins, or positive nodes. Identical outcomes were noted for patients treated with radiation versus surgery, with (or without) postoperative radiation, but higher complication rates were noted for the combined modality approach.. Concurrent chemoradiation, using platinum- containing chemotherapy (cisplatin alone [preferred] or cisplatin/fluorouracil), is the treatment of choice for stages IB3, II, III, and IVA disease based on the results of randomized clinical trials.173- 178 These trials have shown that the use of concurrent chemoradiation results in a . # chemoradiotherapy leads to a . Although chemoradiation is tolerated, acute and long- term side effects have been reported.<sup>182,184,185</sup> Concurrent single- agent cisplatin chemoradiation may be preferred over cisplatin/fluorouracil chemoradiation due to lesser toxicity.<sup>165,186</sup> Concurrent carboplatin (preferred if cisplatin intolerant) or non- platinum chemoradiation regimens are options for patients who may not tolerate cisplatin- containing chemoradiation.<sup>182,187- 192</sup> Carboplatin has been added to the Guidelines as a preferred radiosensitizing agent for patients who are cisplatin intolerant.. Note that when concurrent chemoradiation is used, the chemotherapy is typically given when the external- beam pelvic radiation is administered.<sup>165</sup> The Panel believes that using "systemic consolidation" (ie, adding chemotherapy after chemoradiation) should only be used in clinical trials (eg, OUTBACK [ANZGOG- 0902/GOG 274, NCT01414608] and RTOG 724 [NCT00980954]).<sup>193</sup>. Early-Stage Disease. After careful clinical evaluation and staging, the primary treatment of early- stage cervical cancer is either surgery or RT. The treatment schema is stratified using the FIGO staging system. A fertility- sparing algorithm may be applied for select patients with stage IA, IB1, and certain cases of IB2 disease. Fertility- sparing surgery is generally not recommended for patients with small cell neuroendocrine tumors, gastric type adenocarcinoma, or adenoma malignum (minimal deviation adenocarcinoma) because of its high- risk nature and a paucity of data.. Stage IA1 Disease. Recommended options for stage IA1 disease depend on the results of cone biopsy and whether patients 1) want to preserve their fertility; 2) are medically operable; or 3) have LVSI. The extent of the lymphadenectomy depends on whether pelvic nodal disease and/or LVSI are present and the size of the tumors. SLN mapping can be considered.. Fertility-Sparing. For patients who desire fertility preservation, cone biopsy with or without pelvic lymphadenectomy is recommended.<sup>97,194,195</sup>. The goal of cone biopsy is margins that are negative for invasive disease and high- grade squamous intraepithelial lesion (HSIL). For patients with negative margins after cone biopsy and no findings of LVSI, observation may be an option if fertility preservation is desired. For patients with positive margins after cone biopsy, options include repeat cone biopsy to better evaluate depth of invasion (to rule out stage IA2/IB disease) or a radical trachelectomy. In studies of patients who had positive margins after conization, predictors of residual disease included positive endocervical curettage, combined endocervical margin and endocervical curettage, and volume of disease.<sup>138,196,197</sup> For patients with stage IA1 disease with LVSI, radical trachelectomy and SLN mapping/pelvic lymphadenectomy<sup>70,198- 201</sup> or conization (with negative margins) plus laparoscopic pelvic SLN mapping/lymphadenectomy is a reasonable strategy.. After childbearing is complete, hysterectomy can be considered for patients who have had either radical trachelectomy or a cone biopsy for early- stage disease if they have chronic, persistent HPV infection, they have persistent abnormal Pap tests, or they desire this surgery.. For young (<45 years) patients who are undergoing premenopausal with early- stage squamous cell carcinoma who opt for ovarian preservation (ie, hysterectomy only), the rate of ovarian metastases is low.<sup>202,203</sup>. # Non-Fertility-Sparing. Non- Fertility- SparingFor medically and technically operable patients with stage IA1 disease who do not desire fertility preservation, extrafascial (ie, simple) hysterectomy is commonly recommended for patients without LVSI and with either negative margins after cone biopsy or with positive margins for dysplasia. When medically operable, and if the margins are positive for carcinoma, modified radical hysterectomy is recommended with SLN mapping/pelvic lymphadenectomy (category 2B for node dissection). SLN mapping can be considered. If the margin is positive for dysplasia, extrafascial or modified radical hysterectomy is recommended. Physicians can also consider repeat cone biopsy to better evaluate depth of invasion to rule out stage 1A2/IB1 disease. For patients with positive margins for dysplasia or carcinoma and medically inoperable, Brachytherapy with or without pelvic external beam RT (EBRT) is recommended. If LVSI is present, then modified radical hysterectomy with SLN mapping/pelvic lymphadenectomy is recommended. For patients with negative margins after cone biopsy, observation is recommended for those who are medically inoperable or those who refuse surgery.. Stage IA2 Disease. Stage IA2 DiseaseRecommendations for stage IA2 depend upon whether a patient wishes to preserve their fertility and if the disease is medically operable.. Fertility-Sparing. Fertility- SparingFor patients who wish to preserve their fertility, radical trachelectomy and pelvic lymphadenectomy are recommended. SLN mapping can also be considered. Cone biopsy followed by observation is another option if the margins are negative and pelvic lymphadenectomy is negative. For patients with stage IA2- IB1 with no evidence of LVSI and upon meeting all conservative surgery criteria, conization (with negative margin) and pelvic lymphadenectomy or SNL mapping can be done. The recommended surgical option for stage 1A1- IA2 with evidence of LVSI is radical . Non-Fertility-Sparing. For patients who are medically operable and who do not desire fertility preservation, recommended treatment includes either surgery or RT. The recommended surgical option for stage 1A2- IB1 with no evidence of LVSI and upon meeting conservative surgery criteria is extrafascial hysterectomy with pelvic lymphadenectomy. For patients in stage IA1- IA2 with LVSI, modified radical hysterectomy and bilateral pelvic lymphadenectomy SLN mapping can also be considered.197,204. Pelvic EBRT with brachytherapy (traditionally 70- 80 Gy to total point A dose) is a treatment option for patients who are medically inoperable or who refuse surgery.205 These doses are recommended for most patients based on summation of conventional external- beam fractionation and low dose- rate (40- 70 cGy/h) brachytherapy equivalents. Treatment should be modified based on normal tissue tolerance, fractionation, and size of target volume or on biologic equivalence calculations when using high dose- rate brachytherapy.. Stage IB and IIA Disease. Depending on their stage and disease bulk, patients with stage IB or IIA tumors can be treated with surgery, RT, or concurrent chemoradiation. A combined PET/CT scan can be performed to rule out extra pelvic disease before deciding how to treat these patients. Neck/chest/abdomen/pelvis/groin FDG- PET/CT is preferred to evaluate metastatic disease. A chest/abdomen/pelvis CT or FDG- PET/MRI can also be performed. Pelvic MRI with contrast is preferred to assess local disease extent. The GOG considers that surgical staging is an option for patients with advanced cervical cancer. Radiologic imaging is. # recommended for assessing stage IB3 and IIA2 tumors (see Principles of Imaging in the NCCN Guidelines for Cervical Cancer).. Stage IB1: Fertility-Sparing. For patients who desire fertility preservation, radical trachelectomy and pelvic lymphadenectomy with (or without) para- aortic lymphadenectomy is an option for stage IB1 who do not meet the conservative surgery criteria, and select cases of IB2 disease, but typically only for tumors 2 cm or less in the NCCN Guidelines for Cervical Cancer.58,198- 201,206 SLN mapping can also be considered. Tumors that are 2 to 4 cm must be carefully selected for a fertility- sparing approach as many of these patients may require postoperative adjuvant therapy due to pathologic risk factors (eg, Sedlis Criteria or positive nodes). However, some surgeons suggest that a 2 cm cutoff may be used for vaginal trachelectomy, whereas a 4 cm cutoff may be used for abdominal trachelectomy.207 In one study, oncologic outcomes were similar after 4 years when comparing radical trachelectomy with radical hysterectomy for patients with stage IB1 cervical carcinoma.58 Stage IB1 or IB2 small cell neuroendocrine histology, gastric type adenocarcinoma, and adenoma malignum are not considered suitable for fertility- sparing surgery.. Stage IB and IIA: Non-Fertility-Sparing. The recommended surgical option for stage IB1 (low- risk) with no evidence of LVSI and upon meeting conservative surgery criteria is extrafascial hysterectomy with pelvic lymphadenectomy. For stage IB1 (not meeting conservative surgery criteria, IB2, and IIA1 disease, primary surgery consists of radical hysterectomy plus bilateral pelvic lymphadenectomy (category 1), with (or without) para- aortic lymphadenectomy (category 2B for para- aortic lymphadenectomy).172,208 SLN mapping can also be considered for stages IB1, IB2, and IIA1. Panel members feel that surgery is the most appropriate option for patients with stage IB1, IB2, or IIA1 disease, whereas concurrent chemoradiation is the . For patients with clinical stage IB3 or IIA2 tumors who are treated with definitive radiation, concurrent cisplatin- containing chemotherapy has been shown to significantly improve patient survival. The Panel recommends definitive EBRT with concurrent platinum- containing chemotherapy and brachytherapy (traditionally 75–80 Gy to total point A. dose) (Category 1). Radical hysterectomy with pelvic lymphadenectomy with or without para- aortic lymphadenectomy is under category 2A. The addition of selective completion hysterectomy is a point of disagreement among Panel members. This approach should only be considered in.	None	None	None
06995fe1065f4de7ad8084864ea9846b	NCCN临床实践指南	宫颈癌091-112	# patients whose tumor shows a poor response with evidence of residual disease after chemoradiation . For stage IB3 or IIA2 tumors, the Panel had a major disagreement about recommending adjuvant hysterectomy (category 3) (also known as completion surgery) after primary chemoradiation.173 Adjuvant hysterectomy after RT has been shown to improve pelvic control, but not overall survival, and is associated with increased morbidity.212 A Cochrane review examined whether the addition of hysterectomy to standard non- surgical treatments benefitted patients with locally advanced cervical cancer, finding insufficient data to demonstrate a survival benefit associated with surgery.213 The morbidity is higher after completion surgery, but this may be reduced using a laparoscopic technique.214- 217 Although routine completion hysterectomy is not typically performed, this approach may be considered in patients whose extent of disease or uterine anatomy precludes adequate coverage by brachytherapy.. Advanced Disease. This category has traditionally included patients with stage IIB to IVA disease (ie, locally advanced disease). However, many oncologists now include patients with IB3 and IIA2 disease in the advanced disease category. For patients with more advanced tumors who are undergoing primary chemoradiation, the volume of RT is critical and guided by assessment of nodal involvement in the pelvic and para- aortic nodes. Radiologic imaging studies (neck/chest/abdomen/pelvis/groin FDG- PET/CT (preferred) or chest/abdomen/pelvis CT to evaluate for metastatic disease218 219are recommended for stage IB2 or greater disease, especially for evaluation of nodal or extra pelvic tumor (see Principles of Imaging in the NCCN Guidelines for Cervical Cancer). Pelvic. MRI with contrast is preferred to describe local disease extent and assist in radiation treatment planning. However, needle biopsy of extrauterine abnormality can be considered for questionable imaging findings. Surgical staging (ie, extraperitoneal or laparoscopic lymphadenectomy) is also an option (category 2B) for these patients.220 Surgical staging may also detect microscopic nodal disease that is not discernable with radiologic imaging.221. For patients without nodal disease or with disease limited to the pelvis only through surgical staging, treatment consists of pelvic EBRT with concurrent platinum- containing chemotherapy and brachytherapy (category 1).164,165,174,176- 178,222 Currently, acceptable concurrent platinum- containing regimens include either weekly cisplatin (preferred), carboplatin (preferred if cisplatin intolerant), or cisplatin/fluorouracil, given every 3 to 4 weeks during RT. Pembrolizumab may be added with chemoradiotherapy (CRT) for patients with FIGO 2014 stage III- IVA cervical cancer based on KeyNote A18 trial (See Systemic therapy section). An international phase III randomized trial reported that concurrent cisplatin/gemcitabine and EBRT followed by 2 additional cycles of cisplatin/gemcitabine after RT improved PFS and OS when compared with a standard regimen of concurrent cisplatin with pelvic EBRT.223 However, this trial is controversial because of changes in its statistical design and because the reported superior regimen of concurrent cisplatin/gemcitabine and EBRT has unresolved toxicity issues.223- 226. For patients with para- aortic lymph node positive by surgical staging (FIGO 2018 IIIC2p), further radiologic workup for metastatic disease is recommended. With no distant metastasis, extended- field EBRT with concurrent platinum- based chemotherapy and brachytherapy is recommended. Concurrent platinum- containing chemotherapy with EBRT utilizes cisplatin as a single agent (or carboplatin if cisplatin intolerant).. # Pembrolizumab may be added with chemoradiation for patients with FIGO 2014 stage III- IVA cervical cancer.. Patients with positive adenopathy by CT, MRI and/or FDG- PET/CT with pelvic node positive and para- aortic lymph node negative (by imaging or surgical staging), pelvic EBRT with concurrent chemotherapy and brachytherapy is recommended as category 1. Para- aortic lymph node EBRT can be added to the regimen.. However, for patients with positive para- aortic and pelvic lymph nodes by imaging, imaging workup for metastatic disease is recommended. Extended- field EBRT, concurrent platinum- containing chemotherapy, and brachytherapy are recommended. Patients with positive para- aortic lymph nodes who are positive for distant metastases are treated with systemic chemotherapy with (or without) individualized EBRT.227. Metastatic Disease. For patients who present with distant metastatic disease (ie, stage IVB), primary treatment is often platinum- containing chemotherapy (see Therapy for Metastatic Disease in this Discussion). In these situations, individualized EBRT may be considered for control of pelvic disease and other symptoms.227. Adjuvant Treatment. Adjuvant treatment is indicated after radical hysterectomy depending on surgical findings and disease stage. Observation is appropriate for patients with stage IA2, IB, or IIA1 disease who have negative nodes, negative margins, negative parametria, and no cervical risk factors after radical hysterectomy (Sedlis Criteria). However, adjuvant treatment is indicated after radical hysterectomy if pathologic risk factors are discovered.. Pelvic EBRT is recommended (category 1) with (or without) concurrent platinum- containing chemotherapy (category 2B for chemotherapy) for patients with stage IA2, IB, or IIA1 disease who have negative lymph nodes after surgery but have large primary tumors, deep stromal invasion, and/or LVI.135,226- 231 Recommended radiosensitizing regimens include cisplatin (preferred), carboplatin (preferred if cisplatin intolerant), or capecitabine/mitomycin, gemcitabine or paclitaxel.. Adjuvant pelvic RT alone versus no further therapy was tested in a randomized trial (GOG 92) of selected patients with node- negative stage IB carcinoma of the cervix after hysterectomy and pelvic lymphadenectomy.135 Patients were considered to have "intermediate- risk" disease and were eligible for this trial if they had at least two of the following risk factors (commonly referred to as Sedlis Criteria): 1) greater than one- third stromal invasion; 2) capillary lymphatic space involvement; or 3) cervical tumor diameters more than 4 cm. Patients with positive lymph nodes or involved surgical margins were excluded. At 2 years, the recurrence- free rates were 88% for adjuvant RT versus 79% for the no- adjuvant- treatment group. After long- term follow- up (12 years), an updated analysis confirmed that adjuvant pelvic RT increased PFS; a clear trend towards improved overall survival was noted . Potentially important risk factors for recurrence may not be limited to the Sedlis Criteria" (ie, stromal invasion, LVI, primary tumor size). Additional risk factors for consideration include tumor histology (eg, adenocarcinoma component)136,137 and close or positive surgical margins.138,139. Postoperative pelvic EBRT with concurrent platinum- containing chemotherapy (category 1)175 with (or without) vaginal brachytherapy is recommended for patients with positive pelvic nodes, positive surgical. # margin, and/or positive parametrium; these patients are considered to have "high- risk" disease. Vaginal brachytherapy may be a useful boost for those with positive vaginal mucosal margins. Adjuvant concurrent chemoradiation significantly improves overall survival for patients with high- risk, early- stage disease (those with positive pelvic nodes, parametrial extension, and/or positive margins) who undergo radical hysterectomy and pelvic lymphadenectomy.175 The Intergroup trial 0107/GOG 109 showed a statistically significant benefit of adjuvant pelvic radiation with concurrent cisplatin and fluorouracil in the treatment of patients with stage IA2, IB, or IIA disease who had positive lymph nodes, positive margins, and/or microscopic parametrial involvement found at surgery.175 A study re- evaluated these findings from GOG 109 in a population- based cohort . Depending on the results of primary surgery, imaging may be recommended to determine whether distant metastases are present. In patients who are positive for distant metastases, perform biopsy of suspicious areas as indicated. For patients without distant metastases, recommended treatment is extended- field EBRT (including pelvic and para- aortic lymph nodes) with concurrent platinum- containing chemotherapy and with (or without) brachytherapy. Recommended radiosensitizing regimens include cisplatin (preferred), carboplatin (preferred if cisplatin intolerant), or capecitabine/mitomycin, gemcitabine or paclitaxel. For patients with distant metastases, recommended treatment is systemic chemotherapy with (or without) individualized EBRT.227. Although neoadjuvant chemotherapy followed by surgery has been used in areas where RT is not available, data suggest no improvement in survival when compared with surgery alone for early- stage cervical . Surveillance. The Panel agrees with the new Society of Gynecologic Oncology's (SGOs) recommendations for post- treatment surveillance.240 The recommended surveillance is based on the patient's risk for recurrence and personal preferences. History and physical examinations are recommended every 3 to 6 months for 2 years, every 6 to 12 months for another 3 to 5 years, and then annually. Patients with high- risk disease can be assessed more frequently (eg, every 3 months for the first 2 years) than patients with low- risk disease (eg, every 6 months).. Annual cervical/vaginal cytology tests can be considered as indicated for detection of lower genital tract dysplasia (eg, for those who have had fertility- sparing surgery). Some clinicians have suggested that rigorous cytology follow- up is not warranted because of studies stating that Pap smears did not detect recurrences in patients with stage I or II cervical cancer who were asymptomatic after treatment.240- 242 Noting the inherent differences between these patients and the general screening population, the Panel does not recommend workup of low- grade squamous dysplasia detected during surveillance, but suggests that patients should follow up with a provider with specific expertise in this area. It is important to emphasize good clinical evaluation and a high index of suspicion, because the detection rate of recurrent cervical cancer is low using cervical and vaginal cytology alone.243. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. For patients with stage I disease, follow- up imaging should be based on symptomatology and clinical concern for recurrent/metastatic disease, such as abnormal physical exam finding or new pelvic, abdominal, or pulmonary symptoms. If fertility- sparing treatment was provided, pelvic MRI should be considered 6 months after surgery and yearly for 2 to 3 years. Neck/chest/abdomen/pelvis/groin FDG- PET/CT can be considered if metastasis is suspected.244,245 For patients with stage II disease or greater, neck/chest/abdomen/pelvis/groin FDG- PET/CT (preferred) or chest/abdomen/pelvis CT with contrast should be performed within 3 to 6 months of completing therapy; pelvic MRI is optional. Additional imaging should be guided by symptomatology and clinical concern for recurrent/metastatic disease. Specific indications and recommendations for surveillance imaging are detailed in Principles of Imaging in the NCCN Guidelines for Cervical Cancer.219,240,244,246- 252. Many other tests remain optional based on clinical indications, such as semiannual CBCs, blood urea nitrogen (BUN), and serum creatinine determinations. Patients with persistent or recurrent disease need to be evaluated using additional imaging studies as clinically indicated, biopsy with or without examination under anesthesia (EUA) and surgical exploration in selected cases followed by therapy for relapse (see Therapy for Relapse section).253 Comprehensive molecular profiling as determined by FDA- approved assay or a validated test performed in CLIA certified laboratory can be considered for better selection of systemic therapy. If tissue biopsy of metastatic site is not feasible or tissue is not available, comprehensive genomic profiling via a validated plasma circulating tumor DNA (ctDNA) assay can be considered.. Education of patients regarding symptoms suggestive of recurrence is recommended (eg, vaginal discharge; weight loss; anorexia; pain in the pelvis, hips, back, or legs; persistent coughing). Patients should also be counseled on healthy lifestyle, obesity, nutrition, exercise, sexual health, . Patients who have received RT for cervical cancer may experience vaginal stenosis and dryness and should receive education on important issues regarding sexual health and vaginal health. Providers should inform patients about regular vaginal intercourse and/or vaginal dilator use and on the use of vaginal moisturizers/lubricants (eg, estrogen creams). Anecdotal evidence suggests that vaginal dilators may be used to prevent or treat vaginal stenosis.254 Dilator use can start 2 to 4 weeks after RT is completed and can be performed indefinitely.. Cervical cancer survivors are at risk for second cancers.255 Data suggest that patients who undergo RT for pelvic cancers are at risk for radiation- induced second cancers, especially at radiated sites near the cervix (eg, colon, rectum/anus, urinary bladder); therefore, careful surveillance is appropriate for these patients.256,257. Therapy for Relapse. Recurrences should be proven by biopsy before proceeding to treatment planning for recurrent disease.. Locoregional Recurrence. Patients with a localized recurrence of cervical cancer after initial treatment may be candidates for radical retreatment; options include: 1) RT and/or chemotherapy; or 2) surgery.164,258 After treatment for relapse, long- term, disease- free survival rates of approximately 40% have been reported in some situations.259. For patients who experience locoregional recurrences who have not undergone previous RT or who experience recurrences outside of the. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. previously treated RT field, therapy for relapse includes tumor- directed EBRT and concurrent platinum containing chemotherapy and/or brachytherapy; surgical resection can be considered if feasible. Typically, the chemoradiation for recurrence uses cisplatin as a single agent or carboplatin (if cisplatin intolerant).262,261 However, in those patients who have relapsed soon after completing initial chemoradiation with these regimens, other systemic therapy options might be considered or best supportive care could be offered (see NCCN Guidelines for Palliative Care).. Patients with central pelvic recurrent disease after RT should be evaluated for pelvic exenteration, with (or without) intraoperative RT (IORT), although IORT is category 3.262- 269 Surgical mortality is generally . For patients with noncentral recurrent disease, options include EBRT with (or without) concurrent platinum containing chemotherapy, resection with (or without) IORT (category 3 for IORT), or systemic therapy or best supportive care (see the NCCN Guidelines for Palliative Care), or participation in a clinical trial.. Patients who experience recurrence after second- line definitive therapy, either surgery or RT, have a poor prognosis. They can be treated with . Therapy for Metastatic Disease. Patients who develop distant metastases, either at initial presentation or at relapse, are rarely curable. Comprehensive molecular profiling as determined by FDA- approved assay, or a validated test performed in CLIA certified laboratory can be considered for better selection of systemic therapy. If tissue biopsy of metastatic site is not feasible or tissue is not available, comprehensive genomic profiling via a validated plasma ctDNA assay can be considered to guide appropriate biomarker directed second line therapy. For highly selected patients with isolated distant metastases amendable to local treatment,273 occasional long- term survival has been reported with: 1) surgical resection with (or without) EBRT; 2) local ablative therapies with (or without) EBRT; or 3) EBRT with (or without) chemotherapy. Systemic adjuvant chemotherapy can be considered. For example, patients who may benefit from aggressive local therapy for oligometastatic disease include those with nodal, lung, liver, or bone metastases.274,275 Following local therapy, additional adjuvant chemotherapy can be considered. For most other patients with distant metastases, an appropriate approach is a clinical trial, chemotherapy, or best supportive care (see NCCN Guidelines for Palliative Care).. The palliation of pelvic recurrences in heavily irradiated sites that are not amenable to local pain control techniques or to surgical resection is difficult.276 These sites are generally not responsive to chemotherapy. Adequately palliating the complications of pain and fistulae from these recurrences is clinically challenging ( overview). However, short courses of RT may provide symptomatic relief to patients with bone metastases, painful para- aortic nodes, or supraclavicular adenopathy.227,277,278. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. Chemotherapy is often recommended for patients with extra pelvic metastases or recurrent disease who are not candidates for RT or exenterative surgery. Patients whose disease responds to chemotherapy may have relief from pain and other symptoms. If cisplatin was previously used as a radiosensitizer, combination platinum- based regimens are preferred over single agents in the metastatic disease setting based on several randomized phase III trials (see next paragraph).279,280 However, responses to chemotherapy are often of short duration and survival is rarely increased.. Systemic Therapy Recommendations. Chemoradiation for Locally Advanced Cervical Cancer. Concurrent chemoradiation, using platinum containing chemotherapy (cisplatin alone [preferred]), is the treatment of choice for stages IB3, II, III, and IVA disease based on the results of randomized clinical trials. These trials have shown that the use of concurrent chemoradiation results in a . A multicenter, randomized, double- blind, placebo- controlled trial KEYNOTE- A18 (NCT04221945) evaluated the efficacy of concurrent platinum- containing chemotherapy (CCRT) with EBRT utilizing cisplatin as a single agent with pembrolizumab in 1060 eligible patients with newly diagnosed, previously untreated, high- risk locally advanced cervical. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. cancer (FIGO 2014 stage IB2- IIB with node- positive disease or stage II- IVA). Pembrolizumab . The NCCN Panel has noted for all chemoradiation agents that the cost and toxicity profiles of these radiosensitizing agents should be considered when selecting an appropriate regimen for treatment and have strongly expressed that this is especially critical when these regimens are being used for extended field radiation therapy where toxicities may be more severe.. Systemic Therapy for Recurrent or Metastatic Cervical Cancer. The estimated 5- year survival rate for patients with early- stage cervical cancer is more than . First-Line Systemic Therapy Options for Recurrent or Metastatic Disease. Preferred Regimens. Pembrolizumab Plus Chemotherapy with or without Bevacizumab as First-line Therapy. First- Line Systemic Therapy Options for Recurrent or Metastatic DiseasePreferred RegimensPembrolizumab Plus Chemotherapy with or without Bevacizumab as First- line TherapyPresently, the Guidelines include two immunotherapy- based regimens as preferred, first- line therapy options for the treatment of PD- L1- positive recurrent or metastatic cervical cancer: Pembrolizumab combined with chemotherapy with or without bevacizumab regimens is the preferred, category 1 treatment option based on the results of the Keynote- 826 study.143 In the primary analysis of the phase 3, Keynote- 826 trial, which enrolled 617 patients (548 with PD- L1- positive CPS ≥1 tumors; 317 patients with CPS ≥10) with previously untreated persistent, recurrent, or metastatic cervical cancer, the addition of pembrolizumab to chemotherapy with or without bevacizumab improved PFS and overall survival versus the placebo group (PFS, 10.4 vs. 8.2 months, respectively; HR, 0.65; 95% CI, 0.53- 0.79; . # express PD- L1 . The recently published patient- reported outcomes (PROs) from KEYNOTE- 826 also shows that the addition of pembrolizumab to chemotherapy with or without bevacizumab did not negatively affect health- related quality of life. The exploratory subgroup analyses of patients with persistent, recurrent, or metastatic adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma of the cervix that had not been treated with systemic chemotherapy and was not amenable to curative treatment suggest that adding pembrolizumab to chemotherapy with or without bevacizumab improved OS across all subgroups defined by use of bevacizumab (yes or no), choice of platinum (carboplatin or cisplatin), prior CRT exposure only (yes or no), and histologic type (squamous or nonsquamous) in patients with PD- 1- positive tumors (defined as a CPS . The platinum- based chemotherapy (cisplatin or carboplatin)/paclitaxel with bevacizumab have been extensively investigated in clinical studies and is among the preferred, first- line treatment option for patients with recurrent/metastatic cervical cancer in the NCCN Guidelines (based on GOG 240 trial). The cisplatin/paclitaxel/bevacizumab regimen is category 1 in this disease setting.. A randomized phase III trial (GOG 240) studied the addition of bevacizumab to combination chemotherapy regimens (cisplatin/paclitaxel/bevacizumab or topotecan/paclitaxel/bevacizumab) in 452 patients in the first- line setting of metastatic, persistent, or recurrent cervical cancer. Analysis of pooled data from the two chemotherapy regimens revealed significant improvements in overall survival among patients receiving bevacizumab (16.8 vs. 13.3 months; . systemic review and meta- analysis of data from 19 trials of systemic therapy for patients with recurrent, persistent, or metastatic cervical cancer found a trend towards improved OS for the addition of bevacizumab to cisplatin/paclitaxel or topotecan/paclitaxel when compared with all other non- bevacizumab- containing chemotherapy regimens.. The published data from a phase III randomized trial (JCOG0505) suggested that carboplatin/paclitaxel was non- inferior to cisplatin/paclitaxel in 253 patients with metastatic or recurrent cervical cancer.. A systematic review of the data on cisplatin/paclitaxel and carboplatin/paclitaxel regimens also suggested that lower toxicity carboplatin- based regimens appear to be an equally effective alternative to cisplatin- containing regimens for treating recurrent or metastatic cervical cancer.. Other Recommended Regimens. Cisplatin is generally regarded as the most active agent and is recommended as the preferred first- line single- agent chemotherapy option. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. for recurrent or metastatic cervical cancer; reported response rates are approximately . The Panel recommends single agent cisplatin and carboplatin as other recommended regimens. In previous versions of the Guidelines, cisplatin was placed under "preferred, first- line single- agent" category. However, based on the Panel's clinical judgement, as more effective treatment options are increasingly being available in the first- line setting, platinum- based single- agent chemotherapy has been reserved as alternate options under other recommended regimens in the Guidelines.. The Panel has continued to recommend other platinum- containing combination regimens, such as cisplatin/paclitaxel (category 1), carboplatin/paclitaxel (category 1), topotecan/paclitaxel/bevacizumab (category 1), topotecan/paclitaxel, and cisplatin/topotecan as appropriate alternate options under the other recommended regimens category.279,280,290,304- 306 A randomized phase IlI study (GOG 169) in 264 patients compared cisplatin/paclitaxel versus cisplatin alone for metastatic, recurrent, or persistent cervical cancer. Patients receiving the 2- drug combination had a higher response rate . Another randomized phase III study (GOG 179) in 294 patients investigated cisplatin/topotecan versus cisplatin alone for recurrent or persistent cervical cancer. The topotecan combination regimen was shown to be superior to single- agent cisplatin with respect to overall response rate . A phase III trial (GOG 204) compared 4 cisplatin- doublet regimens (cisplatin/paclitaxel, cisplatin/topotecan, cisplatin/gemcitabine, and cisplatin/vinorelbine) in 513 patients with advanced metastatic or recurrent cancer.306 The trial was closed early based on futility analysis, because it was apparent that the cisplatin/topotecan, cisplatin/gemcitabine, and cisplatin/vinorelbine regimens were not superior to the control arm of cisplatin/paclitaxel. No significant differences in overall survival were seen; however, the trends for response rate, PFS, and overall survival (12.9 vs. 10 months) suggest that cisplatin/paclitaxel is superior to the other regimens. Cisplatin/paclitaxel was associated with less thrombocytopenia and anemia (but with more nausea, vomiting, infection, and alopecia) than the other regimens. While topotecan/paclitaxel was not shown to be superior to cisplatin/paclitaxel, it may be considered as an alternative in patients who are not candidates for cisplatin.290. Based on previous studies, cisplatin/paclitaxel (category 1) and carboplatin/paclitaxel have become the most widely used systemic regimens for metastatic or recurrent cervical cancer. However, for patients who may not be candidates for taxanes, cisplatin/topotecan remains a reasonable alternative regimen.280 In 2019, the Panel voted to remove cisplatin/gemcitabine as a first- line combination therapy option.. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. Non- platinum regimens are also being studied and may be considered in patients who cannot tolerate platinum- based chemotherapy.308. Second-line/Subsequent Systemic Therapy Options for Recurrent or Metastatic Cervical Cancer. The treatment options for patients with disease progression after first- line therapies have mostly been of limited effect with low response rates to second- line and beyond chemotherapies and median PFS of around 3 to 6 months.309,310. Immunotherapy as Preferred, Second-line/Subsequent Therapy. Increasingly available data from several prospective studies have demonstrated the effectiveness of immunotherapies or specific biomarker- based therapies in the setting of disease progression and has significantly transformed the management of cervical cancer. In addition, many biomarker- specific therapies have demonstrated meaningful clinical efficacy and durability regardless of the underlying tumor type leading to an increase in tumor- agnostic regulatory approvals.. Pembrolizumab as a Preferred, Second-line/Subsequent Therapy. Pembrolizumab is an FDA- approved therapy for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy for PD- L1- positive tumors . Tisotumab vedotin- tftv as a Preferred, Second- line/Subsequent TherapyTisotumab vedotin- tftv is an antibody- drug conjugate directed against tissue factor and monomethyl auristatin E, a potent inhibitor of cell division. The tissue factor is aberrantly expressed across multiple solid tumors and is associated with poor clinical outcomes and an increase in metastatic potential. Studies have indicated that tissue factor is highly prevalent in cervical cancer and might have a role in disease progression and poor patient outcome in the clinic.113 The phase 1/2, InnovaTV- 201 trial enrolled 147 patients with pretreated advanced or metastatic solid tumors, including 34 patients with advanced cervical cancer, in the dose expansion phase of the study to evaluate the safety and durability of tisotumab vedotin- tftv.314 The ORR was . # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. ESMO 2023.318 Among the 502 patients that were randomized (TV: 253; chemotherapy: 249); The TV arm had a . Cemiplimab as a Preferred, Second-line/Subsequent Therapy. Cemiplimab is a PD- 1- blocking monoclonal activity shown to have anti- tumor activity against cervical cancer. The phase 3, randomized, Empower- Cervical- 1 clinical trial evaluated the efficacy of cemiplimab or investigator's choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) in patients with recurrent or metastatic cervical cancer who have progressed on prior therapy.319 The trial enrolled 608 patients, who had previously received one or more lines of systemic therapy for recurrence, were randomized to either receive cemiplimab or chemotherapy. The median OS and PFS were significantly longer in the cemiplimab arm than in the control arm (12 vs. 8.5 months; HR, 0.69; . Chemotherapy as Other Recommended, Second- line/Subsequent Therapy The Panel re- evaluated the list of single- agent chemotherapies included as second- line/subsequent therapy options under the other recommended regimens category by re- voting on each of these agents for their efficacy and use based on Panel members' clinical experience and judgement. The Panel agreed to include the following options as second- line/subsequent treatment: bevacizumab, paclitaxel,. # albumin- bound paclitaxel, docetaxel, fluorouracil, gemcitabine, pemetrexed, topotecan, vinorelbine, and irinotecan.. Biomarker-Directed, Useful in Certain Circumstances, Second-line/Subsequent Therapy. The NCCN Guidelines for Cervical Cancer have included a list of biomarkers with their associated targeted treatments as second- line/subsequent therapies under "useful in certain circumstances" options. The Pathology section of the Guidelines provides recommendations for individual biomarkers that should be evaluated for targeted therapy.. Nivolumab for PD-L1-Positive Tumor. Nivolumab, a checkpoint inhibitor, has shown efficacy in patients with recurrent/metastatic cervical cancer who received at least one prior chemotherapy regimen. Based on Checkmate- 358 data (see Prognostic and Predictive Biomarkers section), in the 1.2023 version of the NCCN Guidelines for Cervical Cancer, the Panel moved nivolumab from preferred, second- line or subsequent therapy options to the "useful in certain circumstances" category for PD- L1- positive tumors and continues to recommend nivolumab in the same category in version 2.2024.. Trastuzumab Deruxtecan for HER2-Positive Tumor. Another tumor- agnostic study evaluated the durability and clinically meaningful response of trastuzumab deruxtecan across multiple HER2- expressing (IHC . Based on DESTINY- PanTumor02 (see Prognostic and Predictive. Biomarkers section) Version 2.2024 of the NCCN Guidelines for Cervical Cancer includes fam- trastuzumab deruxtecan- nxki as a category 2A, useful in certain circumstances, second line/subsequent therapy option for HER2- positive tumors (IHC . Selpercatinib for RET- Gene Fusion Tumor. Selpercatinib received tumor- agnostic approval by the FDA for patients with solid tumors with a RET gene fusion that has progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. The NCCN Panel recommends selpercatinib as a biomarker- directed second- line/subsequent therapy under useful in certain circumstances category for RET- gene fusion- positive tumors given its efficacy in tumor- agnostic population. The NCCN Panel also specified that RET gene fusion testing may be considered for patients with locally advanced or metastatic cervical cancer (see Prognostic and Predictive Biomarkers section).. TRK Inhibitors for NTRK-Gene Fusion Tumor. In addition to selpercatinib, other targeted therapy regimens included in the NCCN Guidelines for Cervical Cancer as biomarker- directed second- line/subsequent therapies that have been approved in a tumor- agnostic population are the tropomyosin receptor kinase (TRK) inhibitors, larotrectinib and entrectinib. Larotrectinib targets the TRK proteins that are encoded by the genes NTRK1, NTRK2, and NTRK3. NTRK gene fusions are found in about . # NTRK- gene fusion positive tumors and have changed the category of evidence from category 2B to category 2A based on FDA approval and several clinical trials (see Prognostic and Predictive Biomarkers section).. Pembrolizumab has been added as a preferred regimen for second- line option for treating PD- L1- positive or MSI- H/dMMR cervical tumors (category 2A).143,11,322 Other recommended agents (all category 2B) that have shown responses or prolongation of PFS and may be useful as second- line therapy include bevacizumab,323 albumin- bound paclitaxel (ie, nab- paclitaxel),324 docetaxel,325 fluorouracil,326 gemcitabine,327 ifosfamide,328,329 irinotecan,330 mitomycin,331 pemetrexed,332 topotecan,333,334 and vinorelbine.335. Other Agents. Targeted therapies and biologics have an established role for selected cases of cervical cancer. Pembrolizumab and bevacizumab have been included in the Guidelines for treating recurrent or metastatic disease. The use of these and other targeted or biologic agents remains an active area of investigation.. Principles of Radiation Therapy. Radiation therapy is often used in the management of patients with cervical cancer either 1) as definitive therapy for those with locally advanced disease or for those who are poor surgical candidates; or 2) as adjuvant therapy following radical hysterectomy for those who have one or more pathologic risk factors (eg, positive lymph nodes, parametrial infiltration, positive surgical margins, large tumor size, deep stromal invasion, LVSI).. The algorithm provides general RT dosage recommendations, which should not be interpreted as stand- alone recommendations because RT techniques and clinical judgment are an essential part of developing an appropriate treatment regimen. The ASTRO clinical practice guideline on . Optimum staging of disease to precisely delineate the primary tumor volume and draining lymph nodes, including abdominopelvic radiologic studies (CT, MRI, or combined PET/CT scans), is recommended in patients with stage IB2, IIA2, or advanced stage tumors. Contemporary imaging studies must be correlated with careful assessment of clinical findings to define tumor extent, especially regarding vaginal or parametrial extension.. Radiation Treatment Planning. Technologic advances in imaging, computer treatment planning systems, and linear accelerator technology have enabled the more precise delivery of radiation doses to the pelvis. However, physical accuracy of dose delivery must be matched to a clear understanding of tumor extent, potential pathways of spread, and historical patterns of locoregional recurrence to avoid geographic misses.. CT- based treatment planning with conformal blocking and dosimetry is considered standard care for EBRT. In patients who are not surgically staged, FDG- PET imaging is useful to help define the nodal volume of coverage and may be useful postoperatively to confirm removal of abnormal nodes.337 IMRT technique is preferred to minimize toxicities in definitive treatment of the pelvis with or without para- aortic treatment. Regular use of image- guided radiation therapy (IGRT) with orthogonal. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. imaging and/or routine volumetric imaging (such as cone beam CT) at the time of treatment delivery, is essential to ensure appropriate coverage of targets and sparing of normal tissues. Brachytherapy is a critical component of definitive therapy in patients with cervical cancer who are not candidates for surgery (ie, those with an intact cervix); it may also be used as adjuvant therapy. Brachytherapy is typically combined with EBRT in an integrated treatment plan. MRI imaging immediately preceding brachytherapy may be helpful in delineating residual tumor geometry. Stereotactic body radiotherapy (SBRT) allows delivery of very high doses of focused external beam radiation and may be applied to isolated metastatic sites.62,338. Routine image guidance, such as cone- beam CT (CBCT), may be helpful in defining daily internal soft tissue positioning. Concepts regarding the gross target volume (GTV), clinical target volume (CTV), planning target volume (PTV), organs at risk (OARs) and dose- volume histogram (DVH) have been defined for use in conformal radiotherapy, especially for IMRT.339- 341. Point A, representing a paracervical reference point, has been the most widely used, validated, and reproducible dosing parameter used to date. However, limitations of the Point A dosing system include the fact that it does not consider the three- dimensional shape of tumors, nor individual tumor to normal tissue structure correlations.. Traditionally point A doses were based on widely validated dose fractionation for brachytherapy with low dose rate (LDR). The dose at point A assumes an LDR delivery of 40- 70 cGy/h. The traditional LDR point A prescription dose was 70- 80 Gy. Typical point A prescription doses are 5.5 Gy X 5 fractions for early disease and 6 Gy X 5 fractions for large tumors or those demonstrating a poor response. Another reasonable choice that has been well- studied in European trials for intracavity dosing to the high- risk CTV (HR- CTV) is 28 Gy in 4 fractions.342. Ferrigno et al published a report on the comparative outcome of cervical cancer patients treated with LDR and high dose rate (HDR) brachytherapy.343 In this retrospective analysis, 190 patients were treated with LDR brachytherapy and 118 patients were treated with HDR brachytherapy. . With a median follow- up time of 70 months (LDR) and 33 months (HDR) groups, the OS, DFS, and local control at 5 years were better in the LDR group . Thus, similar outcomes were observed for patients who were stages I and II treated with either HDR or LDR brachytherapy. Although lower overall and disease- free survival and marginally lower local control were observed for patients who were stage III treated with HDR brachytherapy, less late rectal complications were observed in this group. These findings were probably the result of the relatively low HDR brachytherapy dose delivered at Point A.. There are increasing efforts to use and standardize image- based volumetric brachytherapy approaches using MR, CT or ultrasound –. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. international validation efforts with different studies including EMBRACE- I study, which is a benchmark study that represents a positive breakthrough in the treatment of locally advanced cervical cancer.342,344- 349. One such study analyzed the details of brachytherapy practice in cervical cancer patients in the United States between 1996 and 1999 to understand the impact of different practices across different facilities.350 A total of 442 patient records were reviewed in 59 different radiation facilities that were selected from a stratified random sample to obtain data about patients' characteristics including tumor extent, and treatment. Unless otherwise specified, brachytherapy practice was based on the 408 patients who had their brachytherapy or all their treatment at the surveyed facility. A total of . In EMBRACE- I trial, a prospective, observational, multicenter cohort study, cervical cancer patient data from 24 centers in Europe, Asia, and North America with FIGO stage 1B- IVA or stage IVB restricted to para- aortic lymph metastasis below the L1- L2 interspace were prospectively collected.344 The patients were treated with CRT followed by MRI- based image- guided adaptive brachytherapy (IGABT) with primary endpoints . A unified approach to techniques and prescription/fractionation schedules for both EBRT and IGABT is required and RetroEMBRACE and EMBRACE I studies have demonstrated that clinical outcome is related to dose prescription and technique. The EMBRACE II study is an interventional and observational multicenter study which aims to benchmark a high level of local, nodal, and systemic control while limiting morbidity, using an advanced target volume selection and contouring protocol for EBRT and a multi- parametric brachytherapy dose prescription protocol for brachytherapy, and use of advanced EBRT (IMRT and IGRT) and brachytherapy (Intracavitary/Intertitial- IC/IS) techniques.351. For EMBRACE- II, 153 patients were treated with: IMRT/VMAT, daily IGRT, 45 Gy over 25 fractions for the elective CTV, and simultaneously integrated boost for pathologic lymph nodes. Application of IMRT/VMAT, IGRT, and a 45 to Gy dose provides the potential of higher conformality inducing significant reduction of treated volume and the study is currently underway.352 For patients with locally advanced cancers, initial radiation treatment of 40 to 45 Gy to the whole pelvis is often necessary to obtain tumor shrinkage to permit optimal intracavitary placements. With low dose- rate intracavitary systems, total doses from brachytherapy and EBRT to point A of at least 80 Gy are currently recommended for small tumors, with doses of 85 Gy or higher recommended for larger tumors. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. ( oup.pdf).164. For lesions in the lower one third of the vagina, the inguinal lymph nodes must be treated. The use of extended- field radiation to treat occult or macroscopic para- aortic lymph node disease must be carefully planned to ensure an adequate dose (45 Gy for microscopic disease) without exceeding bowel, spinal cord, or renal tolerances.353 General recommendations for radiation volumes and doses are discussed in the algorithm.. Intensity- modulated RT is becoming more widely available; however, issues regarding target definition, patient and target immobilization, tissue deformation, toxicity, and reproducibility remain to be validated.354- 361 Initial phase II hematologic toxicity data from RTOG 418 suggested that limiting the volume of bone marrow treated with IMRT was an important consideration for patients with cervical cancer who were receiving concurrent chemotherapy.362 The reported TIME- C trial (RTOG 1203, NCT01672892) compared post- hysterectomy patients receiving adjuvant IMRT or standard four- field RT to determine whether IMRT reduced acute toxicity. Among the 278 patients with cervical and endometrial cancer included in the analysis, pelvic IMRT was associated with significantly lower scores for gastrointestinal and urinary toxicity than standard RT.363 Dose- escalated IMRT (limiting V55 to below . Phase II Clinical Trial (INTERTECC- 2) evaluated acute hematologic and gastrointestinal (GI) toxicity for patients with locoregionally in which 83 patients met the eligibility criteria and received weekly cisplatin concurrently with once- daily IMRT, followed by intracavitary brachytherapy.365 The primary endpoint was the occurrence of either acute grade . Techniques for re- irradiation may include IORT, intracavitary or interstitial brachytherapy, SBRT, IMRT, or proton therapy.371- 373 Such cases are highly customized and depend on the target, proximity to critical organs, previous RT dose, extent of overlap, and time intervals since prior RT. The appropriate dose for each case needs to be individualized.. Normal Tissue Considerations. Planning for RT in cervical cancer must take into account the potential impact on surrounding critical structures, such as rectum, bladder,. # sigmoid, small bowel, and bone. Acute effects (i.e., diarrhea, bladder irritation, fatigue) occur to some degree in most patients undergoing radiation and are typically magnified by concurrent chemotherapy. However, acute effects can often be managed with medications and supportive care, and they generally resolve soon after completion of radiation. To avoid treatment- related menopause, ovarian transposition can be considered before pelvic RT in select young patients (<45 years with early- stage disease).<sup>169- 171</sup>. After therapy for cervical cancer, late side effects may include potential injury to bladder, rectum, bowel, and pelvic skeletal structures.<sup>374</sup> The risk of major complications (eg, obstruction, fibrosis/necrosis, and fistula) is related to the volume, total dose, dose per fraction, and specific intrinsic radiosensitivity of the normal tissue that is irradiated.<sup>353,375,376</sup> Careful blocking in order to minimize normal tissue exposure while maintaining tumor coverage is critical for optimal outcomes. In addition, patient- related conditions (ie, inflammatory bowel disease, collagen- vascular disease, multiple abdominal/pelvic surgeries, history of pelvic inflammatory disease, diabetes) influence determination of radiation dose and volumes.. For most patients, it is generally accepted that the whole pelvis can tolerate an external- beam radiation dose of 40 to 50 Gy. Gross disease in the parametria or unresected nodes may be treated with tightly contoured external- beam boosts to 60 to 65 Gy. Intracavitary brachytherapy boosts require attention to proper placement of the applicators within the uterus and against the cervix and vaginal apex, as well as appropriate packing to maximally displace the bladder and rectum. SBRT is not considered an appropriate routine alternative to brachytherapy. Normal tissue dose constraint guidelines for cervical cancer are added to the guidelines. Although the suggested dose constraints are provided in the guidelines, the NCCN Panel recommends that the clinicians must balance the risks of normal tissue toxicity with tumor control.. Incidental Cervical Cancer. Invasive cervical carcinoma is sometimes found incidentally after extrafascial hysterectomy. Workup for these patients includes history and physical examination, CBC (including platelets), and liver and renal function tests. Recommended radiologic imaging includes chest radiography, CT, or combined PET/CT; MRI may be performed if indicated to rule out gross residual disease. However, imaging is optional for patients with stage IB1 or smaller tumors.. No definitive data is available to guide the appropriate adjuvant treatment of these patients. Surveillance is recommended for patients with stage IA1 cervical cancer who do not have LVSI. For patients with either stage IA1 with LVSI, stage IA2/IB disease, or positive margins/gross residual disease, the Panel believes that a reasonable treatment schema should be based on the status of the surgical margins. If margins are positive and imaging is negative for nodal disease, then pelvic RT with concurrent platinum- containing chemotherapy with (or without) individualized brachytherapy is recommended. Recommended radiosensitizing regimens include cisplatin (preferred), carboplatin (preferred if patient is cisplatin- intolerant), or cisplatin/fluorouracil.. If margins or imaging is negative in stage IA2 or greater tumors, options include: 1) pelvic RT with brachytherapy, with (or without) concurrent platinum- containing chemotherapy; or 2) if Sedlis Criteria are not met on the hysterectomy specimen, consideration of complete parametrectomy, upper vaginectomy, and pelvic lymphadenectomy with (or without) para- aortic lymph node sampling (category 2B for para- aortic lymph node sampling). Typically, observation is recommended for patients with negative lymph nodes and no residual disease. However, chemoradiation with (or without) vaginal brachytherapy is recommended for subsequent findings of positive nodes, surgical margins, and/or parametrium.. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. For hysterectomy specimens with positive margins, gross residual disease, positive imaging, or primary tumor characteristics meeting Sedlis Criteria, pelvic EBRT with concurrent platinum- containing chemotherapy (with individualized brachytherapy for positive vaginal margins) is recommended.135. Small Cell Neuroendocrine Carcinoma of the Cervix Overview. Neuroendocrine tumors (NETs) are a highly heterogeneous group of neoplasms derived from ubiquitous neuroendocrine cells, mostly from the lungs, the gastrointestinal tract, and the pancreas, but more rarely are found in almost all body tissues including uncommon sites, such as female genital tract.377 The 2014 WHO Classification of neuroendocrine tumors has been updated with adoption of the terms low- grade NET and high- grade neuroendocrine carcinoma (NEC). In the endometrium and cervix, high- grade neuroendocrine neoplasms (NEC) are much more prevalent than low- grade and are more common in the cervix.378. NECC accounts for about . Primary Workup. Primary WorkupSmall cell neuroendocrine cervical cancer is an aggressive type of cervical cancer and most data on treatment regimens for this disease have been adapted from NCCN lung and pulmonary disease- management guidelines ( f and . given that small cell disease is commonplace in those settings. Because this condition is rare in the gynecologic realm and few data are available on small cell cervical cancer, high- level randomized trials are difficult to achieve and some of the primary workup and treatment recommendations are based on cervical cancer guidelines as well.380 FIGO staging system is implemented to describe characteristics and outcomes of patients with small cell neuroendocrine carcinoma of the cervix (small cell NECC) since it is more predictive than the two- tier staging system. Most patients were treated with cisplatin and etoposide.381. Radical hysterectomy with pelvic lymphadenectomy with or without para- aortic lymph node sampling is one of the primary treatment options recommended for NECC tumors confined to the cervix . Metastatic disease workup is the same as stage IVB or recurrent cervical cancer with distant metastasis (see Therapy for Metastatic Disease). For the locally advanced disease (stage IB3- IVA), the preferred primary treatment option is chemoradiation with brachytherapy with or without the addition of chemotherapy. Other treatment options include neoadjuvant chemotherapy followed by chemoradiation and brachytherapy. Based on the treatment response and disease persistence or recurrence, the patient can be further treated with other systemic therapy/best supportive care/pelvic exenteration.. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. Principles of Pathology. NECC is clinically aggressive, with rapid metastasis and a frequently poor clinical outcome. NECC is usually HPV- associated; types 16 and 18 are the most common (18 more often than 16).382 This carcinoma type morphologically resembles neuroendocrine carcinomas of the lung. Small cell NECC is a morphologic diagnosis regardless of IHC staining profile. Most NECCs are diffusely positive for p16 due to the presence of high- risk HPV. However, p16 positivity cannot be used to aid in determining the site of origin; neuroendocrine carcinomas arising at other sites may strongly express p16 due to a non- HPV- related process.. If the tumor demonstrates classic morphologic features of small cell NECC, the diagnosis can be made in the absence of IHC neuroendocrine positivity because of the high variability in the expression levels. Small cell NECC is variably positive for chromogranin, CD56, and synaptophysin by IHC. CD56 and synaptophysin are the most sensitive neuroendocrine markers, but CD56 lacks specificity. Chromogranin is the most specific neuroendocrine marker but lacks sensitivity with only about . Systemic Therapy. NECC, being a rare variant of cervical cancer with a poor prognosis, based on a systematic review, multimodality treatment with radical surgery and neoadjuvant/adjuvant chemotherapy with cisplatin and etoposide with or without radiotherapy is the mainstay of treatment for early- stage disease while chemotherapy with cisplatin and etoposide or topotecan, . The dosing and schedule for chemoradiation and first- line adjuvant therapy are based on NCCN Guidelines for Small Cell Lung Cancer (SCL E). Cisplatin and etoposide combination is one of the most common adjuvant chemotherapy regimens based on literature and tend to have a better prognosis.385 and is the preferred regimen in chemoradiation and first- line therapy for recurrent or metastatic small cell NECC.. Many physicians use carboplatin/paclitaxel because of ease of administration and tolerability, similar to cervical cancer.293,294 The addition of atezolizumab to chemotherapy in the first- line treatment of extensive- stage small- cell lung cancer resulted in significantly longer overall survival and progression- free survival than chemotherapy alone. 386 A double- blind, placebo- controlled, phase 3 trial evaluated atezolizumab plus carboplatin and etoposide in patients with extensive- stage small- cell lung cancer who had not previously received treatment. A total of 201 patients were randomly assigned to receive carboplatin and etoposide with atezolizumab and 202 patients were assigned to receive placebo after carboplatin and etoposide in the induction phase. At a median follow- up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (HR for death, 0.70; . The CASPIAN trial387 assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum- etoposide) in patients with extensive- stage small cell. # National Comprehensive NCCN Guidelines Version 4.2025 NCCN Cancer Network. lung cancer (ES- SCLC) who never received treatment and demonstrated that first- line durvalumab plus platinum- etoposide significantly improved overall survival in patients with ES- SCLC. In this randomized, open- label, phase 3 trial, 268 patients were randomly allocated to the durvalumab plus platinum- etoposide group and 269 to the platinum- etoposide group. Durvalumab plus platinum- etoposide was associated with a significant improvement in overall survival, with HR of 0.73 (95% CI, 0.59- 0.91; . Cervical Cancer and Pregnancy. Cervical cancer is the most frequently diagnosed gynecologic malignancy in pregnant individuals; however, most of these patients have stage I disease. Invasive cervical cancer during pregnancy creates a clinical dilemma and requires multidisciplinary care. Patients must make the difficult decision either to delay treatment until documented fetal maturity or to undergo immediate treatment based on their stage of disease. Patients who delay treatment until fetal maturity should have their children delivered by cesarean section. Radical trachelectomy with preservation of pregnancy has been successfully performed in a few pregnant patients with early- stage cervical cancer. Patients with early- stage disease may prefer to have radical hysterectomy and node dissection instead of RT to avoid radiation fibrosis and to preserve their ovaries. Patients with stage I disease who delay treatment until fetal maturity can undergo cesarean section with concurrent radical hysterectomy and pelvic node dissection. For those choosing RT, traditional RT with (or without) chemotherapy protocols (described previously) may need to be modified.. Drug Reactions. Virtually all drugs have the potential to cause adverse reactions, either during or after infusion. In cervical cancer treatment, drugs that more commonly cause adverse reactions include carboplatin, cisplatin, docetaxel, liposomal doxorubicin, and paclitaxel. Most of these drug reactions are mild infusion reactions (ie, skin reactions, cardiovascular reactions, respiratory or throat tightness), but more severe allergic reactions (ie, life- threatening anaphylaxis) can occur. In addition, patients can have severe infusion reactions and mild allergic reactions. Infusion reactions are more common with paclitaxel. Allergic reactions (ie, true drug allergies) are more common with platinum agents (eg, cisplatin). Management of drug reactions is discussed in the NCCN. # Guidelines for Ovarian Cancer.403 Importantly, patients who experienced severe life- threatening reactions should not receive the implicated agent again unless evaluated by an allergist or specialist in drug desensitization. If a mild allergic reaction previously occurred and it is appropriate to re- administer the drug, a desensitization regimen is recommended even if the symptoms have resolved. Various desensitization regimens have been published and should be followed.404- 406 Patients must be desensitized with each infusion if they have had a previous reaction. Almost all patients can be desensitized.400 To maximize safety, patients should be desensitized in the intensive care unit.400. Gynecologic Survivorship. Treatment for gynecologic cancer typically involves surgery, chemotherapy, hormone therapy, RT, and/or immunotherapy, which may cause acute, short term, and long- term toxicities. Surgical approaches may be extensive and cause adhesions to form, which in turn may cause pain and contribute to the development of small bowel obstruction, urinary or gastrointestinal complications (eg, incontinence, diarrhea), pelvic floor dysfunction (manifested by a variety of urinary, bowel, and/or sexual effects), and lymphedema. Chemotherapy agents vary, though commonly used regimens may pose a significant risk of neurotoxicity, cardiac toxicity, cognitive dysfunction, and the development of hematologic cancers. Long term estrogen deprivation may cause symptoms such as hot flashes, vaginal dryness, and bone loss. RT may cause long- term complications (eg, fibrosis, stenosis, vulvovaginal atrophy) and may predispose patients to subsequent cancers of the skin, subcutaneous tissue, and/or underlying organs that are proximal to the radiation field. Use of immunotherapy agents in gynecologic cancers is emerging, and to date, long term effects of these treatments are unknown.. Following completion of treatment, all gynecologic cancer survivors should receive regular general medical care that focuses on managing chronic . Best Supportive Care. Patients with refractory systemic cancer warrant a comprehensive coordinated approach involving hospice care, pain consultants, and. # emotional and spiritual support, individualized to the situation (see the NCCN Guidelines for Palliative Care).. Summary. Cervical cancer is decreasing in the United States because of the wide use of screening; however, it is increasing in developing countries (~275,000 deaths/year), because screening is not available to many. Effective treatment for cervical cancer (including surgery and concurrent chemoradiation) can yield cures in 80% of patients with early- stage disease (stages I- II) and in 60% of patients with stage III disease. The hope is that immunization against HPV (using vaccines) will prevent persistent infection with the types of HPV against which the vaccine is designed and will therefore prevent specific HPV cancer.<sup>26,27,407</sup>.	None	None	None
06c815b308b242308666a35964390a44	NCCN临床实践指南	遗传／家族高风险评估-乳腺癌，卵巢癌，胰腺癌和前列腺癌001-030	# NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Genetic/Familial High-Risk Assessment:. Breast, Ovarian, Pancreatic, and Prostate. Version 3.2025 — March 6, 2025. NCCN.org. NCCN recognizes the importance of clinical trials and encourages participation when applicable and available. Trials should be designed to maximize inclusiveness and broad representative enrollment.. Continue. # NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. \Mary B.Daly,MD,PhD/Chair Fox Chase Cancer Center. \Tuya Pal, MD/Vice- Chair Vanderbilt- Ingram Cancer Center. Zahraa AlHilli, MD. Case Comprehensive Cancer Center/ University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute. Banu Arun, MD The University of Texas MD Anderson Cancer Center. Saundra S. Buys, MD MD Huntsman Cancer Institute at the University of Utah. Heather H. Cheng, MD, PhD Fred Hutchinson Cancer Center. Jane Churpek, MD, MS University of Wisconsin Carbone Cancer Center. Sarah Colonna, MD, MSCI H Huntsman Cancer Institute at the University of Utah. Susan M. Domchek, MD Abramson Cancer Center at the University of Pennsylvania. Susan Friedman, DVM FORCE: Facing Our Risk of Cancer Empowered. Veda N. Giri, MD Yale Cancer Center/Smilow Cancer Hospital. Michael Goggins, MD Johns Hopkins Kimmel Cancer Center. Andrea Hagemann, MD, MSCI S Siteman Cancer Center at Barnes- Jewish Hospital and Washington University School of Medicine. Ashley Hendrix, MD, MBA St. Jude Children's Research Hospital The University of Tennessee Health Science Center. Dezheng Huo, PhD The UChicago Medicine Comprehensive Cancer Center. Mollie L. Hutton, MS, CGC Roswell Park Comprehensive Cancer Center. Beth Y. Karlan, MD UCLA Jonsson Comprehensive Cancer Center. Nawal Kassem, MD MS Indiana University Melvin and Bren Simon Comprehensive Cancer Center. Seema Khan, MD Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Katia Khoury, MD O'Neal Comprehensive Cancer Center at UAB. Allison W. Kurian, MD, MSc Stanford Cancer Institute. Christine Laronga, MD Moffitt Cancer Center. Julie S. Mak, MS, MSc, CGC UCSF Helen Diller Family Comprehensive Cancer Center. John Mansour, MD UT Southwestern Simmons Comprehensive Cancer Center. Kara N. Maxwell, MD, PhD Abramson Cancer Center at the University of Pennsylvania. Kevin McDonnell, MD PhD City of Hope National Medical Center. Carolyn S. Menendez, MD Duke Cancer Institute. Continue. Sofia D. Merajver, MD, PhD University of Michigan Rogel Cancer Center. Barbara S. Norquist, MD Fred Hutchinson Cancer Center. Kenneth Offit, MD, MPH Memorial Sloan Kettering Cancer Center. Dominique Rash, MD UC San Diego Moores Cancer Center. Gwen Reiser, MS, CGC Fred & Pamela Buffett Cancer Center. Leigha Senter- Jamieson, MS, CGC The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute. Kristen Mahoney Shannon, MS, CGC Mass General Cancer Center. Kala Visvanathan, MD, MHS Johns Hopkins Kimmel Cancer Center. Jeanna Welbom, MD UC Davis Comprehensive Cancer Center. Myra J. Wick, MD, PhD Mayo Clinic Comprehensive Cancer Center. Marie Wood, MD University of Colorado Cancer Center. Matthew B. Yurgelun, MD Dana- Farber/Bingham and Women's Cancer Center. NCCN. Susan Darlow, PhD Zeenat Diwan, MS, PhD Mary Dwyer, MS. Breast surgical oncology Clinical genetics Genetic counseling Gastroenterology Gynecology. Hematology/ Hematology oncology Internal medicine Medical oncology Radiation oncology Patient advocacy Discussion Writing Committee Member. # NCCN Genetic/Familial High-Risk Assessment Panel Members Summary of the Guidelines Updates. Principles of Cancer Risk Assessment and Counseling. Pre- Test Counseling (EVAL- A 1 of 11) Testing Considerations Prior to Testing (EVAL- A 2 of 11) Choice of Multigene Testing (EVAL- A 3 of 11) Evaluating the Source of Genetic Testing Information (EVAL- A 4 of 11) Tumor Genomic Testing: Potential Implications for Germline Testing (EVAL- A 5 of 11) Circulating Tumor DNA (ctDNA) Post- Test Counseling (EVAL- A 6 of 11) Positive Results Negative Results Variants of Uncertain Significance Pedigree: First- , Second- , and Third- Degree Relatives of Proband (EVAL- B). Hereditary Testing Criteria. General Testing Criteria (CRIT- 1) Testing Criteria for High- Penetrance Breast Cancer Susceptibility Genes (CRIT- 2) Testing Criteria for Ovarian Cancer Susceptibility Genes (CRIT- 4) Testing Criteria for Pancreatic Cancer Susceptibility Genes (CRIT- 5) Testing Criteria for Prostate Cancer Susceptibility Genes (CRIT- 6) Testing Criteria for Li- Fraumeni Syndrome (CRIT- 7) Testing Criteria for Cowden Syndrome/PTEN Hamartoma Tumor Syndrome (CRIT- 8). Gene Summary: Risks and Management. Testing Criteria Met (GENE- 1) Cancer Risk Management Based on Genetic Test Results (GENE- A) Autosomal Recessive Risk in Cancer Genes - Multigene Panel Testing (GENE- B). Management/Screening. BRCA Pathogenic/Likely Pathogenic Variant- Positive Management (BRCA- A) Pancreatic Cancer Screening (PANC- A) Li- Fraumeni Syndrome Management (LIFR- A) Cowden Syndrome/PHTS Management (COWD- A). Find an NCCN Member Institution: institutions.. NCCN Categories of Evidence and Consensus: All recommendations are category 2A unless otherwise indicated.. See NCCN Categories of Evidence and Consensus.. Breast, Ovarian, Uterine, and Prostate Cancer Risk Reduction Strategies for Transgender, Non- Binary and Gender Diverse People with Hereditary Cancer Syndromes (TNBGD- 1). Summary of Genes and/or Syndromes Included/ Mentioned in Other NCCN Guidelines (SUMM- 1). Abbreviations (ABBR- 1). For chemoprevention options, see NCCN Guidelines for Breast Cancer Risk Reduction.. The NCCN Guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network (NCCN) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2025.. # Update in Version 3.2025 of the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate from Version 2.2025 include:. MS- 1. - The Discussion section has been updated to reflect the changes in the algorithm.. Updates in Version 2.2025 of the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate from Version 1.2025 include:. New Guideline Name- Prostate added to Guideline name.. CRIT-6. - Testing Criteria for Prostate Cancer Susceptibility Genes - Testing is clinically indicated in the following scenarios: Criteria updated and reorganized. - Testing may be considered in the following scenario, - 1st bullet added: Personal history of prostate cancer ≤55 y not meeting any of the above criteria. Corresponding footnote ee added: Referring to data (Ewing C, et al N Engl J Med 2012;366:141-149; Kote-Jaraj Z, et al Ann Oncol 2015;26:756-761; Witte JS, et al. Cancer Epidemiol Biomarkers Prev 2013;22:675-680) regarding early onset prostate cancer with HOXB13. - New criteria added: - Refer for genetic testing in the following scenario: Biochemical recurrence, For this heterogeneous disease state, refer for genetic testing if: 1) Very high-risk or high-risk disease at diagnosis (see above), 2) family history of cancer criteria met, or if (and at time of) progression to metastatic disease.. GENE-A (all pages). - 3rd column, Prostate cancer added to header.. # NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. Updates in Version 1.2025 of the NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, and Pancreatic from Version 3.2024 include: Global Updates. References updated throughout the guideline.. EVAL-A (1 of 11). - 2nd bullet, 1st sub-bullet added: For principles of genetic testing for patients with cancer (active diagnoses and previous history) when testing is performed outside of specialty genetics setting, see EVAL-A 10 of 11.. EVAL- A (2 of 11). Prior to genetic testing, the following should be taken into consideration:. 4th t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t h t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t. EVAL- A (3 of 11). Choice of multigene testing. 4th t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t h t t t t t t t t t h t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t. EVAL- A (5 of 11). 2nd l, t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. EVAL- A (10 of 11). - New page added: Principles of genetic testing for patients with cancer (active diagnoses and previous history) when testing is performed outside of specialty genetics setting. CRIT-2. Testing Criteria for High- Penetrance Breast Cancer Susceptibility Genes. Header revised: Specifically Genes such as... (Also for CRIT- 4, CRIT- 5). Personal history of breast cancer. bullet revised: Lobular breast cancer with personal or family history of diffuse gastric cancer (NCCN Guidelines for Gastric Cancer NCCN Guidelines for Genetic/Familial High- Risk Assessment: Colorectal. Endometrial, and Gastric). Family history section revised:. Family history of cancer criteria: unaffected; or affected but does not meet above criteria. Individuals affected with breast cancer (not meeting testing criteria listed above) or. Individual unaffected with breast cancer with a first- or second- degree blood relative meeting any of the criteria listed above (except unaffected individuals whose relatives meet criteria only for systemic therapy decision- making).. Individuals affected or unaffected with breast cancer who otherwise do not meet the criteria above but have a probability . CRIT-2A. Footnote n revised: Consideration of the limitations of unknown or limited family structure is indicated in those aged . # Updates in Version 1.2025 of the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic from Version 3.2024 include:. CRIT-3. Testing Criteria for High- Penetrance Breast Cancer Susceptibility Genes. Testing may be considered in the following scenarios 1st bullet revised: Personal history of breast cancer . - Footnote s revised: Kurian A, et al. JAMA 2020;323:995-997 Bedrosian I, et al. J Clin Oncol 2024;42:584-604. - Corresponding footnote t added: Testing includes breast cancer genes plus other inherited cancer genes consistent with family phenotype.. 3rd bullet clarified from, "Individuals affected or unaffected with breast cancer who otherwise do not meet any of the above criteria (CRIT- 2) but with a . 4th bullet added: Personal history of malignant phyllodes tumors. Corresponding footnote u added: See Discussion. There is a low probability...1st bullet revised: Female diagnosed with breast cancer at age . CRIT-4. Testing Criteria for Ovarian Cancer Susceptibility Genes - Footnote x, last sentence revised: Examples include an association between sex com tumors with annular tubules and PJS or Setoli- Leydig tumors, DICER1- related disorders, and small cell carcinoma of the ovary and hypercalcemic type with SMARCA4.. CRIT-6. Testing Criteria for Prostate Cancer Susceptibility Genes - Header revised: Specifically Genes such as... and TP53) - Family history section revised: . CRIT-8A. Testing Diagnostic Criteria for Cowden Syndrome (CS)/PTEN Hamartoma Tumor Syndrome (PHTS) - Major and Minor Criteria clarified as diagnostic criteria and updated to be consistent with Pilarski R, et al. J Natl Cancer Inst 2013;105:1607- 1616. - Footnote \* revised from, "Other cancers associated with PTEN but not in the testing criteria include: colorectal, kidney cancer, and melanoma" to "Melanoma is also associated with PTEN but is not included in the testing criteria.". GENE-1. Genetic Testin, No known famlial P/LP variant revised: Gerline multigene panel testing or if unaffected, attempt if possible, to test family member with highest likelihood of a P/LP variant before testing on unaffected family member While testing an affected family member is most informative, it is also appropriate to test unaffected family members who meet testing criteria.. GENE-A (1 of 11). ATM. Primary Breast Cancer . # Updates in Version 1.2025 of the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic from Version 3.2024 include:. GENE-A (2 of 11). BRCA1. Primary Breast Cancer. Absolute risk revised from . BRCA2. Primary Breast Cancer Absolute risk revised from . GENE-A (3 of 11). CDH1. Primary Breast Cancer Absolute risk revised from . Comments section revised by removing: There is controversy over how to manage gastric cancer risk in individuals with CDH1 P/LP variants in the absence of a family history of gastric cancer. However, one small study found that . GENE-A (4 of 11). CDKN2A. Comments section, 1st sentence revised: Comprehensive skin examination by a dermatologist, supplemented with total body photography and dermoscopy is recommended biannually every 6 mo for individuals. CHEK2. Primary Breast Cancer Absolute risk revised from . Other Cancer Risks. Colorectal cancer removed.. Comment revised: ... The risks for most missense variants are unclear but for some P/LP variants, such as He157Thr, the risk for breast cancer appears to be lower. Additional cancer risk management based on this variant (He157Thr) is not recommended. There is emerging evidence that not all missense P/LP variants are low penetrance. For some P/LP variants, such as He157Thr and Ser428Phe, the risk for breast cancer appears to be lower. Additional cancer risk management based on these variants (He157Thr) is not recommended. Management should be based on best estimates of cancer risk for the specific P/LP variant and family history. There are some data to indicate females with biallelic CHEK2 P/LP variants have a higher risk for invasive breast cancer, are more likely to be diagnosed at . GENE-A (6 of 11). PALB2. Primary Breast Cancer Absolute risk revised from . GENE-A (7 of 11). RAD51C and RAD51D. Primary Breast Cancer Absolute risk revised from . # NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. t 2024 inude:. GENE-A (9 of 11). - Footnote b revised: Screening and risk-reduction management for breast and ovarian cancer is extrapolated from BRCA1/2 data based on risk levels.- Footnote f added: Breast awareness starting at age 18 years. Clinical breast exam, every 6-12 months, starting at age 25 years or 5-10 years before the earliest known breast cancer in the family (whichever comes first). Age . GENE-B. - Bullet added above table: Biallelic P/LP variants in some genes, included on gene panels, may be associated with rare autosomal recessive conditions, such as FA or CMMRD. For these genes, consideration should be given to carrier testing the partner for P/LP variants in the same gene if it would inform reproductive decision-making and/or risk assessment and management.. BRCA Pathogenic/Likely Pathogenic Variant-Positive Management. BRCA-A (2 of 5). - Ovarian/Fallopian Tube/Peritoneal/Uterine Cancers- Surgical risk reduction with bilateral salpingo-oophorectomy, 4th bullet added: If serous tubal intraepithelial carcinoma (STIC lesion) is found, further consultation with a gynecologist oncologist is recommended.. Pancreatic Cancer Screening. PANC-A (1 of 2). - 1st bullet, #2 revised: A family history of exocrine pancreatic cancer in ≥1 first-degree and ≥1 second-degree relatives from the same side of the family, even in the absence of a known P/LP germline variant (many centers would enroll individuals with one affected first-degree relative and one second-degree relative). - Screening table revised:. - Consider pancreatic cancer screening (preferably in the setting of a longitudinal study) for the following:- 3rd bullet added: Individuals with P/LP germline variants in ATM or BRCA2 - Beginning at age 50 years (or 10 years younger than the earliest exocrine pancreatic cancer diagnosis in the family, whichever is earlier).- 4th bullet: ATM and BRCA2 removed from first column and added to second column.. Li-Fraumeni syndrome. - Table 1: Workup and Management Depending on Etiology of TP53 Mutation Found on Genetic Testing extensively revised.. LIFR-A (4 of 6). - Other cancer risks- 7th bullet added: For pancreatic cancer screening recommendations, see PANC-A.. Brest, Oary, Uine, and Pstate Cancer Risk Rdction Sttigie for Transgeder, Non-Binary and Geder Diverse People with Herditary Cancer. Syndromes. TNBGD- 2- Uterine cancer, 1st bullet revised: There are several PVs associated with an increased risk for uterine cancer, including BRCA+ (serous endometrioid- type), PTEN and LS genes.. Summary of Genes and/or Syndromes Included/Mentioned in Other NCCN Guidelines. SUMM- Revisions made throughout.. # NCCN Guidelines Version 3.2025 Breast, Ovarian, Pancreatic, and Prostate Cancer Genetic Assessment. PRINCIPLES OF CANCER RISK ASSESSMENT AND COUNSELING. Risk assessment and discussion of genetic testing involves three related stages:. 1) Pre-test counseling done prior to ordering testing 2) Consideration of the most appropriate tests to order 3) Post-test counseling done when results are disclosed<sup>1-6</sup> - It is recommended that a genetic counselor, clinical geneticist, oncologist, surgeon, oncology nurse, or other health professional with expertise and experience in cancer genetics be involved at each stage whenever possible. - For principles of genetic testing for patients with cancer (active diagnoses and previous history) when testing is performed outside of specialty genetics setting, see EVAL-A 10 of 11. - Testing should be considered in appropriate individuals where it is likely to impact the risk management and/or treatment of the tested individuals and/or their family members who also have increased risk.. Pre- test counseling includes the following elements:. - Evaluate patient's needs and concerns regarding: - Knowledge of genetic testing for cancer risk, including benefits, risks, and limitations - Variant-specific cancer risks - Goals for cancer family risk assessment - Detailed family history including: - Collection of a comprehensive family history - Assessment of family history; close blood relatives include first-, second-, and third-degree relatives on each side of the family, particularly around individuals with a diagnosis of cancer (EVAL-B) - Types of cancer, bilaterality, age at diagnosis, subtype, and pathology report confirmation - Ethnicity (specifically Ashkenazi Jewish ancestry) - Detailed medical and surgical history including: - Documentation of prior genetic testing results for patients and their family members - Personal cancer history (eg, age, histology, laterality) - Pathology reports of primary cancers and/or benign lesions (eg, breast biopsies) - Carcinogen exposure (eg, history of radiation therapy [RT]) - Reproductive history - Hormone or oral contraceptive use - History of risk-reducing surgeries - Smoking, alcohol, or other exposures related to cancer risk - Focused physical exam (conducted by qualified clinician) when indicated: - Cowden syndrome (CS)/PTEN/hamartoma tumor syndrome (PHTS) specific: dermatologic, including oral mucosa, head circumference, and thyroid (enlarged or nodular on palpation) - Generate a differential diagnosis and educate the patient on inheritance patterns, penetrance, variable expressivity, and the possibility of genetic heterogeneity.. Pre- test counseling continued. a For CS/PHTS dermatologic manifestations, see CRIT- 8 and for Peutz- Jeghers syndrome (PJS) dermatologic manifestations, see NCCN Guidelines for Genetic/Familial High- Risk Assessment: Colorectal, Endometrial, and Gastric.. Note: All recommendations are category 2A unless otherwise indicated.. # NCCN Guidelines Version 3.2025 Breast, Ovarian, Pancreatic, and Prostate Cancer Genetic Assessment. PRINCIPLES OF CANCER RISK ASSESSMENT AND COUNSELING. Pre- test counseling includes the following elements (con't):. Prepare for the possible outcomes of testing, including positive (pathogenic/likely pathogenic [P/LP]) (person is a carrier of an alteration in a known cancer- predisposing gene), true negative (person is not a carrier of a known cancer- predisposing gene that has been positively identified in another family member), uninformative negative (person is not a carrier of a known cancer- predisposing gene, and the carrier status of other family members is either also negative or unknown), uncertain variants (person is a carrier of an alteration in a gene that currently has no known significance), and mosaic results (occurrence of 2 or more cell lines with different genetic or chromosomal makeup, within a single individual or tissue).. Obtain written informed consent, and document the informed consent in the patient's medical record.. Discuss plan for results disclosure when appropriate, including the possibility of the patient consenting to Release of Information of test results to a close relative or spouse when results are released in case patient is deceased or incapacitated.. Discuss possible management options if a P/LP variant is identified (enhanced surveillance, risk- reducing agents, and risk- reducing surgery). Discuss that their results may be important to therapeutic decision- making as directed by a qualified health care provider (eg, oncologist).. Advise about possible inherited cancer risk to relatives, and options for risk assessment, testing, and management.. Discuss cost of genetic testing. Provide overview of current legislation regarding genetic discrimination and the privacy of genetic information.b. Prior to genetic testing, the following should be taken into consideration:. The probability of P/LP variant detection associated with these criteria will vary based on family structure, which includes size of the family, age of the family members, early death, adoption, and number of male and female relatives. Individuals with unknown or limited family history/structure, such as fewer than 2 female first- or second- degree relatives having lived beyond age 45 in either lineage, may have an underestimated probability of familial P/LP variant detection. The estimated likelihood of P/LP variant detection may be low in families with a large number of unaffected and/or male relatives.. Patients who have received an allogeneic bone marrow transplant or with active or recent hematologic malignancies should not have molecular genetic testing via blood, saliva, or buccal samples (due to unreliable test results from contamination or due to somatic pathogenic variants [PVs] associated with the hematologic malignancy) until other technologies are available. If available, DNA should be extracted from a fibroblast culture. If this source of DNA is not possible, buccal samples can be considered, subject to the risk of donor DNA contamination or malignant cells from the hematologic malignancy.. If more than one family member is affected with cancers highly associated with a particular inherited cancer susceptibility syndrome, consider initial testing of a family member with youngest age at diagnosis, bilateral disease, multiple primary cancers, or other cancers associated with the syndrome, or most closely related to the proband/patient. If there are no available family members with cancer that is a cardinal feature of the syndrome in question, consider testing first- or second- degree family members affected with other cancers thought to be related to the gene in question (eg, prostate or pancreas with BRCA1/2).. While testing an affected family member is most informative, it is also appropriate to test unaffected family members who meet testing criteria. Limitations of interpreting negative test results in unaffected individuals should be discussed.. In children . Continued. Genetic Information Nondiscrimination Act of 2008 (GINA). Vol. Public Law No.110- 233. Available at: . References on EVAL- A 11 of 11. EVAL- A 2 OF 11. # NCCN Guidelines Version 3.2025 Breast, Ovarian, Pancreatic, and Prostate Cancer Genetic Assessment. Choice of Multigene Testing. The introduction of multigene testing for hereditary forms of cancer has rapidly altered the clinical approach to hereditary cancer testing of patients at increased risk of inherited susceptibility to cancer and their families. Based on nextgeneration sequencing (NGS) technology, these tests simultaneously analyze a set of genes that are associated with a specific family cancer phenotype or multiple phenotypes.. An individual's personal and/or family history may be explained by more than one inherited cancer syndrome; thus, phenotypedirected testing based on personal and family history through a tailoredc multigene panel test is often more efficient and costeffective and increases the yield of detecting a P/LP variant in a gene that will impact medical management for the individual or their family members with increased risk.. There may also be a role for multigene testing in individuals who have tested negative for a single syndrome, but whose personal or family history remains suggestive of an inherited susceptibility.. Some individuals may carry P/LP germline variants in more than one cancer susceptibility gene; thus, consideration of a multigene panel for individuals already known to carry a single P/LP germline variant from phenotype- directed testing may be considered on a case- by- case basis,based on the degree of suspicion for there being additional variants. For individuals of Ashkenazi Jewish descent, complete gene panel analysis including specific AJ founder mutations should be considered based on family history; testing limited to AJ founder testing may be appropriate for families segregating known mutations, or in population screening in which a negative test is followed by more complete testing depending on personal and/or family history.. Because commercially available tests differ in the specific genes analyzed, variant classification, and other factors (eg, methods of DNA/RNA analysis or option to reflex from a narrow to a larger panel; provision of financial assistance for cascade testing of relatives), it is important to consider the indication for testing and expertise of the laboratory when choosing the specific laboratory and test panel.. Multigene testing can include "intermediate" penetrant (moderate- risk) genes. For many of these genes, there are limited data on the degree of cancer risk, and there may currently be no clear guidelines on risk management for carriers of P/LP variants.Not all genes included on available multigene tests will change risk management compared to that based on other risk factors such as family history.. It may be possible to refine risks associated with both moderate and high penetrance genes, taking into account the influence of gene/gene or gene/environment interactions. In addition, certain P/LP variants in a gene may pose higher or lower risk than other P/LP variants in that same gene. This information should be taken into consideration when assigning risks and management recommendations for individuals and their relatives who also have increased risk.. PLP variants in many breast, ovarian, pancreatic, and prostate cancer susceptibility genes involved in DNA repair may be associated with rare autosomal recessive conditions, thus posing risks to offspring if the partner is also a carrier.. As more genes are tested, there is an increased likelihood of finding VUS, mosaicism, and clonal hematopoiesis of indeterminate potential (CHIP). When a P/LP variant with clinical implications for the patient and/ or their family members is found on tumor genomic testing, germline confirmatory testing should be recommended.. There are significant limitations in interpretation of polygenic risk scores (PRS). PRs should not be used for clinical management at this time and use is recommended in the context of a clinical trial, ideally including diverse populations. See Discussion.. Tailored is defined as a disease- focused multigene panel of clinically actionable cancer susceptibility genes, in contrast to large multigene panels of uncertain or unknown clinical relevance. d Research is evolving, and individuals with P/LP variants in cancer susceptibility genes should be encouraged to participate in clinical trials or genetic registries. Individuals with P/LP variants are also encouraged to recontact their genetics providers every few years for updates.. Continued References on EVAL- A 11 of 11. # PRINCIPLES OF CANCER RISK ASSESSMENT AND COUNSELING. Evaluating the Source of Genetic Testing Information. Prior to using any germline findings for medical management, it is important to establish whether the reported findings were obtained from a laboratory that is certified by the College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA) to issue a report of germline findings directly to ordering health care providers. Some states (eg. New York) may have additional reporting requirements.. Confirmatory germline testing through an appropriately certified laboratory is clinically indicated when a potential P/LP variant is identified through various data sources as noted below:. Commercial entities providing ancestry (and sometimes health) information typically do so through microarray- based single nucleotide polymorphism (SNP) testing that has not been validated for clinical use. Third- party software applications can be used by consumers to obtain an interpretation of the raw data provided by these companies. Raw data and third- party software are not able to provide information that is appropriate for medical management, as these services are not subject to quality- control processes and recent research suggests that the error rate . Commercial laboratories utilizing consumer- initiated or direct- to- consumer (DTC) marketing of DNA sequence- based cancer predisposition tests vary substantially in providing information necessary to make informed decisions regarding results and may vary in accuracy in their variant interpretation.. Research: Patients may have participated in research studies that included germline genomic analysis. In such cases, it is clinically indicated to review the patient's findings with a genetics professional and/or the reporting laboratory to establish whether the original report was generated by an appropriately certified laboratory, or whether confirmatory testing is clinically indicated.. # NCCN Guidelines Version 3.2025 Breast, Ovarian, Pancreatic, and Prostate Cancer Genetic Assessment. PRINCIPLES OF CANCER RISK ASSESSMENT AND COUNSELING. Tumor Genomic Testing: Potential Implications for Germline Testing - Testing may provide information suggesting a potential germline finding. P/LP variants reported in the tumor may be of somatic or germline origin. - Because tumor genomic testing is designed to address treatment actionability, not germline status, a variant that may be considered as P/LP in the germline may not be reported at all, or reported as normal in the tumor if it lacks clinical implications. - The filtering of raw sequencing data may differ between tumor and germline testing labs so that variants reported out with one analysis may not be reported with the other. - Somatic P/LP variants seen in tumor specimens are common in some genes with germline implications (eg, TP53, STK11, PTEN) and may not indicate the need for germline testing unless the clinical/family history is consistent with a P/LP variant in the germline. - Tumor- only sequencing may not detect about . # PRINCIPLES OF CANCER RISK ASSESSMENT AND COUNSELING. Post-Test Counseling. When the testing provider/facility does not include pre- test counseling or have all of the resources or expertise for facilitating follow- up testing, management, or family testing, referral to a genetics provider is recommended. In particular, referral to a genetics provider is recommended for the following test results:. P/LP variant identified. Negative results but tumor profiling, personal history, or family history remain suggestive of inherited condition Any VUS result that warrants further evaluation or for which a patient or provider considers using to guide management (EVAL- A 9 of 11) A mosaic/possibly mosaic result or clonal hematopoiesis Discrepant interpretation of variants, including discordant results across laboratories Interpretation of PRS, if they are being considered for use in clinical management, recognizing that the clinical value of PRS has not yet been established Interpretation of P/LP variants for patients tested through DTC or consumer- initiated models. Post- test counseling includes the following elements:. Discussion of results and associated medical risks Interpretation of results in context of personal and family history of cancer Discussion of recommended medical management options including discussion of therapeutic implications by a qualified health care provider if positive Discussion of the importance of notifying family members and offering materials/resources for informing and testing family members who also have increased risk Discussion of available resources such as high- risk clinics, disease- specific support groups, and research studies. # Positive results:. Some medical centers include services that are specialized in cancer screening, risk reduction, and treatment for individuals with a P/LP variant associated with increased risk for cancer. Where available, consider referring patients to these services, either on a consultative basis or for coordination of ongoing care. In patients being treated for cancer, identification of a P/LP variant may affect options and recommendations for treatment of their disease. A P/LP variant in certain genes is also a component of eligibility for some clinical trials. Specific circumstances are addressed in the NCCN Treatment Guidelines for breast, ovarian, and other cancers.. Many patients who have been diagnosed with cancer and have a P/LP variant are at increased risk for additional primary cancers in the future. Management of those risks may be appropriate after treatment of the current cancer or may be combined with treatment for a current cancer.. Multiple sources, including these NCCN Guidelines, provide estimated lifetime risks of cancer associated with specific P/LP variants. A discussion of risk should include:. \langle \zeta \rangle. Risk estimates are influenced by the numbers of individuals with these mutations: the more individuals, the more precise the estimates are (ie, the confidence interval is narrower).. Individuals with a P/LP variant should be informed of the importance of this information for their blood relatives. Knowledge of the P/LP variant may affect risk assessment and recommendations for genetic testing, early detection, and/or cancer risk reduction in those relatives. Where relationships allow, individuals should be encouraged to communicate this information to their blood relatives. A medical provider can assist by providing patients with information for relatives written in simple language and a copy of their genetic test results.. Over time, patients with a P/LP variant benefit from re- consultation with a medical provider who is familiar with inherited risk for cancer. This reconsultation is important for:. Increasing adherence with screening guidelines, which is known to decrease over time. Re- evaluating personal choices about risk- reducing surgeries, based on changing life stage and circumstances. Ensuring patients are following up- to- date guidelines. Discussing additional genetic testing options. Reviewing improved risk models as appropriate. The frequency of follow- up depends on many factors, such as age, reproductive planning, comorbidities, risk- reducing surgeries, and other risk factors.. For patients of reproductive age, advise about options for prenatal diagnosis and assisted reproduction, including pre- implantation genetic testing and donor gametes. Discussion should include known risks, limitations, and benefits of these technologies. See Discussion for details.. Biallelic P/LP variants in some genes, included on gene panels, may be associated with rare autosomal recessive conditions, such as Fanconi anemia (FA) or constitutional mismatch repair (MMR) deficiency (CMMRD) (GENE- B). Thus, for these genes, consideration should be given to carrier testing the partner for P/LP variants in the same gene if it would inform reproductive decision- making and/or risk assessment and management.. Some P/LP variants found in blood, saliva, or buccal samples, most notably in TP53, warrant consideration of testing of non- blood samples to try to distinguish between germline, constitutional mosaicism, and somatic findings.. Continued References on EVAL- A 11 of 11. # NCCN Guidelines Version 3.2025 Breast, Ovarian, Pancreatic, and Prostate Cancer Genetic Assessment. PRINCIPLES OF CANCER RISK ASSESSMENT AND COUNSELING. Negative results:. - These results reduce concern for cancer risk. However, the individual may still have increased cancer risk based on personal and family history. Also, other family members may have a P/LP variant that the tested individual did not inherit. Although negative results of genetic testing are generally reassuring, other reasons that a patient can test negative include: 1) A gene P/LP variant may exist in the gene that was not recognized due to limitations in technology. 2) P/LP variants exist in genes that were not evaluated by this testing. 3) Family members may harbor a P/LP variant that the patient may not have inherited. Other family members may be appropriate candidates for testing, both to assess their own cancer risk as well as to clarify the overall contribution of known P/LP variants to the family history. If another family member tests positive for a P/LP variant, this might lower concern for the individuals who tested negative. The determination of a "true negative" result depends on the specific family history of cancer, the specific P/LP variant found, and the relationship to the family member(s) who tested positive. When an individual has tested negative, it may still be appropriate to consider increased screening and risk reduction measures for cancer based on family history. See appropriate screening based on family history in the guidelines as outlined in Summary of Genes and/or Syndromes Included/Mentioned in Other NCCN Guidelines (SUMM-1). Some medical centers include specialized high-risk clinics to offer this type of family history-based screening. Over time an individual who tested negative may be a candidate for additional genetic testing due to additional family history, as new genes are identified to be associated with cancer risk or technology advances.. # NCCN Guidelines Version 3.2025 Breast, Ovarian, Pancreatic, and Prostate Cancer Genetic Assessment. PRINCIPLES OF CANCER RISK ASSESSMENT AND COUNSELING. Variants of uncertain significance (VUS). - VUS are alterations in the genetic code for which the impact on protein function is uncertain.- VUS are common, particularly with the use of large multigene panels. The more genes that are included on a genetic testing panel, the more likely a VUS will be identified.20- VUS are more commonly found during genetic testing of Asian and Black individuals compared with non-Hispanic white individuals.20- In VUS that are reclassified, approximately $80\% - 90\%$ are reclassified as likely benign or benign and $10\% - 20\%$ as P/LP.21,22- There are discordant variant interpretations across labs,23 requiring careful counseling and skilled interpretation. Resources are available to review the available data supporting pathogenic consequences of specific variants and identify discrepant results (eg, cangene-canvaruk.org/canvig-uk).- VUS should not be used to alter medical management. In the event additional discussion is needed for classification and management, additional genetic expertise is recommended. Screening and risk reduction strategies should be recommended on the basis of personal and family history.- RNA studies (when appropriate) may be a consideration to further define functional impact of variants. Testing family members for a VUS should not be done for clinical purposes, unless there are data to support discrepancy in interpretation of results. Consider a referral to research studies that aim to define the functional impact of variants such as variant reclassification programs through clinical labs or registries.. # NCCN Guidelines Version 3.2025 Breast, Ovarian, Pancreatic, and Prostate Cancer Genetic Assessment. PRINCIPLES OF CANCER RISK ASSESSMENT AND COUNSELING. Principles of genetic testing for patients with cancer (active diagnoses and previous history) when testing is performed outside of specialty genetics setting (often referred to as "point of care" testing). There are clinical situations in which germline genetic testing is critical to therapeutic decision- making but comprehensive risk assessment and genetic counseling are not feasible. In these situations, the treating clinician (eg, oncologist, surgeon) may order germline genetic testing. They should be aware that there may be feasibility and cost limits on the type and number of genetic tests ordered for each individual patient. To maximize the value of the testing experience they should ensure that they include in their discussion with the patient the following points:. Pre- test. Documentation. \langle \hat{\mathbf{u}}\rangle. Understanding of the germline genetic test ordered and preparedness to counsel patients about any possible result outcomes, including future cancer risks. There are many testing options and the choice of which multigene panel test to order can be complicated, eg, when the personal and/or family history may suggest more than one cancer syndrome (EVAL- A 3 of 11) . Post- test. Discussion of result including interpretation of result in the context of the patient's diagnosis, impact on future cancer risk and management if applicable, impact on reproductive plans if applicable, and impact on family members if applicable. Referral to clinical genetics services should be offered in the following situations:. \langle \hat{\mathbf{u}}\rangle. \langle \hat{\mathbf{u}}\rangle. Patients should be given a physical and/or electronic copy of their germline genetic test results, as this is often not available to patients through electronic medical record (EMR) portals, if the testing was sent to an outside laboratory. This document is an important reference for the patient and their relatives in the future.. For patients who test positive or need other genetics follow- up, consider revisiting this information over time, such as when initial treatment is completed and patient is entering a phase of maintenance or surveillance. This is a time when patients may have more ability to follow up on long- term implications of their genetic testing, such as increased screening for other cancers and informing family members.. It is expected for the ordering clinician to communicate a change in the status of a VUS to the patient, especially if it is an upgrade to pathogenic.. # NCCN Guidelines Version 3.2025 Breast, Ovarian, Pancreatic, and Prostate Cancer Genetic Assessment. PRINCIPLES OF CANCER RISK ASSESSMENT AND COUNSELING REFERENCES. 1 Robson ME, Bradbury AR, Arun B, et al. American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol 2015;33:3660- 3667. 2 Berliner JL, Fay AM, Cummings SA, Burnett B. Tillmanns T. NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. J Genet Couns 2013;22:155- 163. 3 American College of Obstetricians and Gynecologists; ACOG Committee on Practice Bulletins- - Gynecology; ACOG Committee on Genetics; Society of Gynecologic Oncologists. ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. Obstet Gynecol 2009;113:957- 966. 4 Lancaster JM, Powell CB, Chen LM, Richardson DL; SGO Clinical Practice Committee. Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 2015;136:3- 7. 5 Konstantinopoulos PA, Norquist B, Laccetti C, et al. Germline and somatic tumor testing in epithelial ovarian cancer: ASCO Guideline. J Clin Oncol 2020;38:1222- 1245. 6 Weitzel JN, Blazer KR, Macdonald DJ, Culver JO, Offit K. Genetics, genomics, and cancer risk assessment: State of the art and future directions in the era of personalized medicine. CA Cancer J Clin 2011;61:327- 359. 7 Committee on Bioethics; Committee on Genetics, and American College of Medical Genetics and; Genomic Social; Ethical; Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Pediatrics 2013;131:620- 622. 8 Tandy- Connor S, Guiltinan J, Krempey K, et al. False- positive results released by direct- to- consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care. Genet Med 2018;20:1515- 1521. 9 Kilbride MK, Bradbury AR. Evaluating web- based direct- to- consumer genetic tests for cancer susceptibility. JCO Precis Oncol 2020 Mar 5;4:PO.19.00317. 10 Direct- to- Consumer Tests: devices/in- vitro- diagnostics/direct- consumer- tests. 11 Green R, Berg J, Grody W, et al. ACGG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 2013;15:565- 574. 12 Terraf P, Pareja F, Brown DN, et al. Comprehensive assessment of germline pathogenic variant detection in tumor- only sequencing. Ann Oncol 2022;33:426- 433. 13 Mandelker D, Donoghue M, Talukdar S, et al. Germline- focused analysis of tumour- only sequencing: recommendations from the ESMO Precision Medicine Working Group. Ann Oncol 2019;30:1231- 1231. 14 Kuzbari Z, Bandlamudi C, Loveday C, et al. Germline- focused analysis of tumour- detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations. Ann Oncol 2023;34:215- 227. 15 Duffy MJ, Diamandis EP, Crown J. Circulating tumor DNA (ctDNA) as a pan- cancer screening test: is it finally on the horizon? Clin Chem Lab Med 2021;59:1353- 1361. 16 Offit K, Sharkey C, Green D, et al. Regulation of laboratory- developed tests in preventive oncology: Emerging needs and opportunities. J Clin Oncol 2023;41:11- 21. 17 Hackshaw A, Clarke C, Hartman A- R. Now genomic technologies for multi- cancer early detection: Rethinking the scope of cancer screening. Cancer Cell 2022;40:109- 113. 18 Raoof S, Lee R, Jajoo K, et al. Multicancer early detection technologies: A review informed by past cancer screening studies. Cancer Epidemiol Biomarkers Prev 2022;31:1139- 1145. 19 Offit K, Levran O, Mullaney B, et al. Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J Natl Cancer Inst 2003;95:1548- 1551. 20 Kurian AW, Ward KC, Abrahams P, et al. Time trends in receipt of germline genetic testing and results for women diagnosed with breast cancer or ovarian cancer, 2012- 2019. J Clin Oncol 2021;39:1631- 1640. 21 Esterling L, Wijayatunge R, Brown K, et al. Impact of a cancer gene variant reclassification program over a 20- year period. JCO Precis Oncol 2020; 4:PO.20.0020. 22 Mersch J, Brown N, Pirzadeh- Miller S, et al. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA 2018;320:1266- 1274. 23 Balmaña J, Digiovanni L, Gaddam P, et al. Conflicting interpretation of genetic variants and cancer risk by commercial laboratories as assessed by the prospective registry of multiplex testing. J Clin Oncol 2016;34:4071- 4078.. # PEDIGREE: FIRST-, SECOND-, AND THIRD-DEGREE RELATIVES OF PROBAND<sup>a</sup>. Common Pedigree Symbols (EVAL- B 2 of 3). # # AMAB = assigned male at birth. # GENERAL TESTING CRITERIA. Testing is clinically indicated in the following scenarios:. Individuals with any blood relative with a known P/LP variant in a cancer susceptibility gene Individuals meeting the criteria below but who tested negative with previous limited testing (eg, single gene and/or absent deletion duplication analysis) and are interested in pursuing multigene testing A P/LP variant identified on tumor genomic testing that has clinical implications if also identified in the germline To aid in systemic therapy and surgical decision- makingb Individual who meets Li- Fraumeni syndrome (LFS) testing criteria (CRIT- 7) or CS/PHTS testing criteria (CRIT- 8) or Lynch syndrome (LS) NCCN Guidelines for Genetic/Familial High- Risk Assessment: Colorectal, Endometrial, and Gastric For personal or family history of > Breast cancer Testing Criteria for High- Penetrance Breast Cancer Susceptibility Genes (CRIT- 2) > Ovarian cancer Testing Criteria for Ovarian Cancer Susceptibility Genes (CRIT- 4) > Pancreatic cancer Testing Criteria for Pancreatic Cancer Susceptibility Genes (CRIT- 5) > Prostate cancer Testing Criteria for Prostate Cancer Susceptibility Genes (CRIT- 6) > Colorectal cancer NCCN Guidelines for Genetic/Familial High- Risk Assessment: Colorectal, Endometrial, and Gastric. Testing may be considered in the following scenario (with appropriate pre- test education and access to post- test management): An individual of Ashkenazi Jewish ancestry without additional risk factors Personal history of serous endometrial cancer. For a list of NCCN Guidelines that include content focused on inherited cancer conditions, including criteria for testing and/or cancer risk management based on a genetic test result, see Summary of Genes and/or Syndromes Included/Mentioned in Other NCCN Guidelines (SUMM- 1).. # FOOTNOTES FOR CRIT-1. a For further details regarding the nuances of genetic counseling and testing, see ELAl- A. b Eg, PARP inhibitors for ovarian cancer, prostate cancer, pancreatic cancer, and metastatic HER2- negative breast cancer; platinum therapy for prostate cancer and pancreatic cancer; and risk- reducing surgery. See the relevant NCCN Treatment Guidelines for further details. c Testing for three founder P/LP variants of BRCA1/2 may be offered to individuals as early as age 18–25 years, who have one grandparent identified as of Ashkenazi Jewish ancestry, irrespective of cancer history in the family, as part of longitudinal studies. For those without access to longitudinal research studies, testing may be provided if there is access to pre- test education along with post- test counseling, additional genetic testing if indicated, and high- risk management. Testing should not be offered outside of a medical framework or clinical trial. d In addition to the BRCA1 and BRCA2 PV in those of Ashkenazi ancestry, there are other ancestries that demonstrate “Founder mutations.” In these circumstances, the decision to test will depend on the prevalence of the PV in the local population, family history, clinical features, and age of cancer diagnosis. Some additional examples where ancestry may, along with personal and/or family history, contribute to decisions about genetic testing include the following associations: BRCA1 PV in those of Polish ancestry; BRCA2 PV in those of Icelandic ancestry; BRCA1 and BRCA2 PV in those of French Canadian ancestry; numerous BRCA1 and BRCA2 PV in those of Spanish, Mexican, and Central and South American ancestry; BRCA1 and BRCA2 PV in those of Bahamian ancestry; and BRCA1 and BRCA2 PV in those of Hungarian ancestry. The TP53 PV c.1010G>A (p.Arg337His) is seen in a subset of those of Brazilian ancestry, and CDKN2A founder c.225_243del (p.Ala76fs) in those of Dutch ancestry. While emerging data derived from populations of Asian, African, and Middle Eastern origin have documented recurring mutations in BRCA1 and BRCA2 and other genes, population allele frequency data are not yet available to inform testing individuals based solely on ancestry in the absence of personal and/or family history. The same is true for founder mutations in lower penetrance genes (eg, CHEK2 c.1100delC in those of northern European ancestry), where family and personal history inform decisions for testing. See Discussion. e This is a rare subtype of uterine cancer for which there is evolving evidence of an association with BRCA1/PLP variants.. # TESTING CRITERIA FOR HIGH-PENETRANCE BREAST CANCER SUSCEPTIBILITY GENES (Genes such as BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, and TP53. See GENE-A)a,f,g,h,i. Continued on CRIT-3. Footnotes on CRIT- 2A. # TESTING CRITERIA FOR HIGH-PENETRANCE BREAST CANCER SUSCEPTIBILITY GENES. a For further details regarding the nuances of genetic counseling and testing, see EVAL- A.. Testing for PVs in other genes should take into consideration factors such as patient preferences, turnaround time, and insurance restrictions to particular labs (and thus particular panels). The prevalence of VUS increases with testing of additional genes. Individuals should have pre- test education on the challenges in managing PVs in genes associated with specific syndromes (eg, CDH1 and TP53 given their expanding clinical phenotypes) in the absence of a family history typical of such syndromes (does not apply for de novo PVs). Patients should also have pre- test education regarding the uncertain clinical utility of identifying certain PVs (eg, monoallelic MUTYH).. e e t t h For the purposes of these guidelines, invasive and ductal carcinoma in situ breast cancers should be included.. For personal or family history of ovarian cancer, see CRIT- 4; for pancreatic cancer, see CRIT- 5; for prostate cancer, see CRIT- 6. Robson M, et al. N Engl J Med 2017;377:523- 533; Litton JK, et al. N Engl J Med 2018;379:753- 763.. As indicated in the criteria, testing is recommended for all triple- negative breast cancers, and these indications are specifically for PARP inhibitor eligibility. The definition of high- risk disease is that used in the phase III OlympiA trial, which compared adjuvant olaparib to placebo among BRCA1/BRCA2 carriers with high- risk disease (Tutt ANJ, et al. Engl J Med 2021;384:2394- 2405). The definition includes:. - Triple-negative breast cancer treated with either:. - adjuvant chemotherapy with axillary node-positive disease or an invasive primary tumor . - Hormone receptor-positive disease treated with either:. - adjuvant chemotherapy with . - The CPS + EG scoring system is based on a combination of clinical and pathologic stage, estrogen receptor status, and histologic grade. See Neoadjuvant Therapy Outcomes Calculator (Jeruss JS, et al. J Clin Oncol 2008;26:246-252; Mittendorf EA, et al. J Clin Oncol 2011;29:1956-1962). See NCCN Guidelines for Breast Cancer for further details.. - Weitzel JN, et al. Breast Cancer Res Treat 2021;188:759-768. - Consideration of the limitations of unknown or limited family structure is indicated in those aged . Metastatic proste cancer is biopsy- proven and/or with radographic evidence and includes distant metastasis and regional bed or nodes. It is not a biochemical recurrence only. Prostate cancer- specific mortality should be a surrogate for metastatic disease for family history purposes.. This may be extended to an affected third- degree relative if related through two male relatives (eg, paternal grandfather's mother or sister). If the affected first- degree relative underwent genetic testing and is negative for detectable P/LP variants and there is no other family history of cancer, there is a low probability that any finding will have documented clinical utility.. The approximate . # TESTING CRITERIA FOR HIGH-PENETRANCE BREAST CANCER SUSCEPTIBILITY GENES (continued). # TESTING CRITERIA FOR OVARIAN CANCER SUSCEPTIBILITY GENES<sup>a</sup> (Genes such as ATM, BRCA1, BRCA2, BRIP1, LS genes [MLH1, MSH2, MSH6, EPCAM], PALB2, RAD51C, and RAD51D; see <sup>a</sup>GENE- A)<sup>w</sup>. Testing is clinically indicated in the following scenarios:. See General Testing Criteria on CRIT- 1.. Personal history of epithelial ovarian cancer<sup>x</sup> (including fallopian tube cancer or peritoneal cancer) at any age. Family history of cancer only. An individual unaffected with ovarian cancer with a first- or second- degree blood relative with epithelial ovarian cancer,<sup>x</sup> (including fallopian tube cancer or peritoneal cancer) at any age<sup>9</sup> An individual unaffected with ovarian cancer who otherwise does not meet the criteria above but has a probability . a For further details regarding the nuances of genetic counseling and testing, see EVAL- A.. This may be extended to an afected third- degre relative if related through two male reatives (g, patenal grandfather's mother or sister) If the affcted first- degre relative underwent genetic testing and is negative for detectable P/LP variants and there is no other family history of cancer, there is a low probability that any finding will have documented clinical utility.. The approximate . For personal or family history of breast cancer, see CRIT- 2; for pancreatic cancer, see CRIT- 5; for prostate cancer, see CRIT- 6. The listed genes differ in their levels of risk. See <sup>a</sup>GENE- A for specific risks.. BRCA- related ovarian cancers are associated with epithelial, non- mucinous histology. LS can be associated with both non- mucinous and mucinous epithelial tumors. Be atttive for cical evidence of LS (see CC Guidelines for Gentic/amil High- Risk Asssment: Colorectal, Endometrial, and Gastric) Specific types of nonepithelial ovarian cancers and tumors can also be associated with other rare syndromes. Examples include an association between sex- cord tumors with annular tubules and PJS or Sertoli- Leydig tumors, DICER1- related disorders, and small cell carcinoma of the ovary and hypercalcemic type with SMARCA4.. Note: All recommendations are category 2A unless otherwise indicated.. # TESTING CRITERIA FOR PANCREATIC CANCER SUSCEPTIBILITY GENES (Genes such as ATM, BRCA1, BRCA2, CDKN2A, LS genes [MLH1, MSH2, MSH6, EPCAM], PALB2, STK11, and TP53) (GENE-A). Testing is clinically indicated in the following scenarios:. See General Testing Criteria on CRIT- 1.. Exocrine pancreatic cancers - All individuals diagnosed with exocrine pancreatic cancer - First- degree relatives of individuals diagnosed with exocrine pancreatic cancer. Neuroendocrine pancreatic tumors - NCCN Guidelines for Neuroendocrine and Adrenal Tumors. a For further details regarding the nuances of genetic counseling and testing, see EVAL- A. - For personal or family history of breast cancer, see CRIT- 2; for ovarian cancer, see CRIT- 4; for prostate cancer, see CRIT- 6. - Pancreatic cancer risk is higher in individuals of Ashkenazi Jewish ancestry. Genetic testing of Ashkenazi Jewish patients with pancreatic cancer may have a higher yield of P/LP variants than of non- Ashkenazi Jewish patients. See Discussion. a Testing of first- degree relatives should only be done if it is impossible to test the individual who has pancreatic cancer. Some second- degree relatives may meet testing criteria based on additional family history. Approximately . # TESTING CRITERIA FOR PROSTATE CANCER SUSCEPTIBILITY GENES (Genes such as ATM, BRCA1, BRCA2, CHEK2, HOXB13,bb and TP53) (GENE-A)a,cc,dd. Testing is clinically indicated in the following scenarios:. Testing may be considered in the following scenario:. - Personal history of prostate cancer ≤55 y<sup>ee</sup> not meeting any of the above criteria- Personal history of prostate cancer with intermediate-risk prostate cancer with intraductal/cribriform histology (see Initial Risk Stratification and Staging Workup in NCCN Guidelines for Prostate Cancer) at any age. Refer for genetic testing in the following scenario:. - Biochemical recurrence- For this heterogeneous disease state, refer for genetic testing if: 1) Very high-risk or high-risk disease at diagnosis (see above), 2) family history of cancer criteria met, or if (and at time of) progression to metastatic disease. Footnotes on CRIT-6A.	None	None	None
7b110e102bbc4acdb2161c44c49d4327	NCCN临床实践指南	遗传／家族高风险评估-乳腺癌，卵巢癌，胰腺癌和前列腺癌031-060	# FOOTNOTES FOR CRIT-6. For further details regarding the nuances of genetic counseling and testing, see EVAL- A. Close blood relatives include first- , second- , and third- degree relatives on the same side of the family (EVAL- B). Metastatic proste cancer is biopsy- proven and/or with radographic evidence and incudes distant metastasis and regional bed or nodes. It is not a biochemical recurrence only. Prostate cancer- specific mortality should be a surrogate for metastatic disease for family history purposes. This may be extended to an affected third- degree relative if related through two male relatives (eg, patenal grandfather's mother or sister). If the affected first- degree relative underwent genetic testing and is negative for detectable P/LP variants and there is no other family history of cancer, there is a low probability that any finding will have documented clinical utility. bb NCCN Guidelines for Prostate Cancer. cc For personal or family history of breast cancer, see CRIT- 2; for ovarian cancer, see CRIT- 4; for pancreatic cancer, see CRIT- 5. dd e f i t t 2013;22:675- 680) regarding early onset prostate cancer with HOXB13.. # TESTING CRITERIA FOR LI-FRAUMENI SYNDROME<sup>a</sup>. Testing is clinically indicated in the following scenarios:. See General Testing Criteria on CRIT- 1.. Individual from a family with a known TP53<sup>ff</sup> P/LP variant Classic LFS criteria:99. Individual from a family with a known TP53<sup>ff</sup> P/LP variant- Classic LFS criteria:<sup>99</sup>- Combination of an individual diagnosed at age <45 years with a sarcoma<sup>hh</sup> AND A first- degree relative diagnosed at age <45 years with cancer AND An additional first- or second- degree relative in the same lineage with cancer diagnosed at age <45 years, or a sarcoma at any age- Chompret criteria:<sup>ii</sup>- Individual with a tumor from LFS tumor spectrum (eg, soft tissue sarcoma, osteosarcoma, central nervous system [CNS] tumor, breast cancer, adrenocortical carcinoma [ACC]), diagnosed <46 years of age, AND at least one first- or second- degree relative diagnosed with any of the aforementioned cancers (other than breast cancer if the proband has breast cancer) at age <56 years or with multiple primaries at any age OR- Individual with multiple tumors (except multiple breast tumors), two of which belong to LFS tumor spectrum with the initial cancer occurring at age <46 years OR- Individual with ACC, or choroid plexus carcinoma or rhabdomyosarcoma of embryonal anaplastic subtype, at any age of onset, regardless of family history OR- Breast cancer diagnosed at age <31 years- Personal or family history of pediatric hypodiploid acute lymphoblastic leukemia- In individuals with cancer with a P/LP TP53 variant identified on tumor- only genomic testing, germline testing should be considered for:<sup>jj,kk,II</sup>1. Those meeting one or more of the other LFS testing criteria above after reevaluation of personal and family history2. Those diagnosed at age <30 years with any cancer3. Those with clinical scenario not meeting these criteria but warranting germline evaluation per clinician discretion. Other cancers associated with LFS but not in the testing criteria include: melanoma, colorectal, gastric, and prostate.. a For further details regarding the nuances of genetic counseling and testing see EVAL- A. When this gene is included as part of a multigene panel, an individual does not need to meet these testing criteria if testing criteria on other testing criteria pages are met. 99 Li FP, et al. Cancer Res 1988;48:5358- 5362. hh In contrast to other types of sarcoma, germline TP53 P/LP variants are rare in those with Ewing sarcoma, gastrointestinal stromal tumor (GIST), desmoid tumor, or angiosarcoma.. Chompret A, et al. J Med Genet 2001;38:43- 47; Bougeard G, et al. J Clin Oncol 2015;33:2345- 2352. jj For testing in the pediatric setting, see Frebourg T, et al. Eur J Hum Genet 2020;28:1379- 1386. kk This should prompt a careful evaluation of personal and family history of the individual to determine the yield of germline sequencing. Somatic TP53 P/LP variants are common in many tumor types in absence of a germline P/LP variant. l Mandelker D, et al. Ann Oncol 2019;30:1221- 1231.. # TESTING CRITERIA FOR COWDEN SYNDROME (CS)/PTEN HAMARTOMA TUMOR SYNDROME (PHTS). See major and minor criteria on CRIT-8A.. a For further details regarding the nuances of genetic counseling and testing, see EVALA. When this gene is included as part of a multigene panel, an individual does not need to meet these testing criteria if testing criteria on other testing criteria pages are met. mm These are testing criteria; clinical diagnostic criteria can be found on CRIT- 8A. nn If two criteria involve the same structure/organ/tissue, both may be included as criteria. oo Current evidence does not support testing for succinate dehydrogenase (SDH) gene P/LP variants in patients with PHTS (Bayley J- P. Am J Hum Genet 2011;88:674- 675). pp Pilarski R, et al. J Natl Cancer Inst 2013;105:1607- 1616. See COWD- A. qq If an individual has two or more major criteria, such as breast cancer and nonmedullary thyroid cancer, but does not have macrocephaly, one of the major criteria may be included as one of the three minor criteria to meet testing criteria. rr This should prompt a careful evaluation of personal and family history of the individual to determine the yield of germline sequencing. Somatic PTEN P/LP variants are common in many tumor types in absence of germline P/LP variant.. # DIAGNOSTIC CRITERIA FOR COWDEN SYNDROME (CS)/PTEN HAMARTOMA TUMOR SYNDROME (PHTS). Major criteria:. - Breast cancer- Endometrial cancer (epithelial)- Follicular thyroid cancer- . Minor criteria. \ Melanoma is also associated with PTEN but is not included in the testing criteria.. REVISED CLINICAL DIAGNOSTIC CRITERIA FOR PTEN HAMARTOMA TUMOR SYNDROME. Operational diagnosis in a family where one individual meets revised PTEN hamartoma tumor syndrome clinical diagnostic criteria or has a PTEN P/LP variant:. 1. Any two major criteria with or without minor criteria; or2. One major and two minor criteria; or3. Three minor criteria.. a For further details regarding the nuances of genetic counseling and testing, see EVAL- A. pp Pilarski R, et al. J Natl Cancer Inst 2013;105:1607- 1616. See COWD- A. ss Multiple polyp types are often seen in patients with PHTS, and less commonly may include adenomas, hyperplastic polyps, and other histologies. t Roche AF, et al. Pediatrics 1987;79:706- 712. u The litr aalable on mctous sions i t adate to acutely spit the mber r xt f mctous ons requred to be a major criterion for CS/PHTS. Clinical judgment should be used. v Insufficent evidence exists in the literature to include fibrocystic disease of the breast, fibromas, and uterine fibroids as diagnostic criteria.. # NCCN Guidelines Version 3.2025 Gene Summary: Risks and Management. # NCCN Guidelines Version 3.2025 Gene Summary: Risks and Management. Footnotes on GENE-A 9 of 11 References on GENE-A 10 of 11 and GENE-A 11 of 11. # NCCN Guidelines Version 3.2025 Gene Summary: Risks and Management. Footnotes on GENE-A 9 of 11 References on GENE-A 10 of 11 and GENE-A 11 of 11 Continued. # NCCN Guidelines Version 3.2025 Gene Summary: Risks and Management. # NCCN Guidelines Version 3.2025 Gene Summary: Risks and Management. Note: All recommendations are category 2A unless otherwise indicated.. Footnotes on GENE-A 9 of 11 References on GENE-A 10 of 11 and GENE-A 11 of 11 Continued. # NCCN Guidelines Version 3.2025 Gene Summary: Risks and Management. Note: All recommendations are category 2A unless otherwise indicated.. Footnotes on GENE-A 9 of 11 References on GENE-A 10 of 11 and GENE-A 11 of 11 Continued. # NCCN Guidelines Version 3.2025 Gene Summary: Risks and Management. CANCER RISK MANAGEMENT BASED ON GENETIC TEST RESULTS<sup>a,1,2</sup>. Footnotes on GENE-A 9 of 11 References on GENE-A 10 of 11 and GENE-A 11 of 11. # NCCN Guidelines Version 3.2025 Gene Summary: Risks and Management. CANCER RISK MANAGEMENT BASED ON GENETIC TEST RESULTSa,1,2. Footnotes on GENE-A 9 of 11 References on GENE-A 10 of 11 and GENE-A 11 of 11 Continued. # NCCN Guidelines Version 3.2025 Gene Summary: Risks and Management. CANCER RISK MANAGEMENT BASED ON GENETIC TEST RESULTSa,1,2. Footnotes on GENE-A 9 of 11 References on GENE-A 10 of 11 and GENE-A 11 of 11. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 3.2025 Gene Summary: Risks and Management. FOOTNOTES FOR GENE TABLES. The following genes and others are found on some of the panels, but there is insufficient evidence to make any recommendations for breast MRI, RRSO, or RRM for FANCC, MRE11, MUTYH heterozygotes, NBN, RAD50, RECL, RINT1, SLX4, SMARCA4, or XRCC2. There is emerging evidence of an increased risk for breast cancer for NTHL1 biallelic P/LP variant carriers (Weatherill CB, et al. Clin Genet 2023;103:231- 235; Grolleman JE, et al. Cancer Cell 2019;35:256- 266; Salo- Mullen EE, et al. JCO Precis Oncol 2021;5: Beck SH, et al. Fam Cancer 2022;21:453- 462); however, there are not yet enough data to support increased breast cancer surveillance. There is emerging evidence of an increased risk for breast cancer for RAD51B P/LP variant carriers (Setton J, et al. NPJ Breast Cancer 2021;7:135) and breast screening may be considered.. Screening and risk- reduction management for breast and ovarian cancer is extrapolated from BRCA1/2 data based on risk levels.. May be modied based on famly history (typicall beginning screening 5- 10 years earier than the youngest diagnosis in the family but not later than stated in the table) or specific gene P/LP variant.. For patients with P/LP variants who are treated for breast cancer and have not had bilateral mastectomy, screening should continue as described. The use of MRI in these patients depends on a number of risk factors, including family history, age, breast density, and patient preference. Breast awareness starting at age 18 years. Clinical breast exam, every 6- 12 months, starting at age 25 years or 5- 10 years before the earliest known breast cancer in the family (whichever comes first). Age . This estimate is based on . Risk varies depending on age at diagnosis of first breast cancer, ER status, and/or family history. See Discussion.. Risk and benefits of premature surgical menopause versus risk of cancer and family history should all be carefully considered, and the Panel recommends patients seek expert care.. For CHEK2 carriers, the risk of CBC is higher if the primary breast cancer was ER- positive (Yadav S, et al. J Clin Oncol 2023;41:1703- 1713; Hanson H, et al. Genet Med 2023;25:100870).. For PALB2 carriers, the risk of CBC is not significantly elevated except if the primary breast cancer was ER- negative (Yadav S, et al. J Clin Oncol 2023;41:1703- 1713). For risk associated with other LFS- associated cancers, see de Andrade KC, et al. Lancet Oncol 2021;22:1787- 1798.. Strength of Evidence of Association with Cancer. - Very strong: Prospective cohort studies in a population-based setting have demonstrated risk.- Strong: Traditional case-control studies or more than three case-control studies including those with cases ascertained by commercial laboratories or those without controls from the same population. Traditional case-control study: A retrospective study that compares patients with a disease or specific outcome (cases) with patients without the disease or outcome (controls).- Limited: Small sample size or case series.- None. Population risk (per SEER registry data). Breast cancer: . # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 3.2025 Gene Summary: Risks and Management. REFERENCES FOR GENE TABLES. 1 Tung N, Domchek SM, Stadler Z, et al. Counselling framework for moderate- penetrance cancer- susceptibility mutations. Nat Rev Clin Oncol 2017;13:581- 588. 2 Domchek SM, Robson ME. 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J Clin Oncol 2017;35:2240- 2250. 31 Nyberg T, Frost D, Barnowdale B, et al. Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Eur Urol 2020;77:24- 35. 32 Roberts ME, Ranola JMO, Marshall ML, et al. Comparison of CDH1 penetrance estimates in clinically ascertained families vs families ascertained for multiple gastric cancers. JAMA Oncol 2019;5:1325- 1331. 33 Ryan CE, Fasaye GA, Gallanis AF, et al. Germline CDH1 variants and lifetime cancer risk [Published online June 14, 2024]. JAMA. doi: 10.1001/jama.2024.10852. 34 Xicola RM, Li S, Rodriguez N, et al. Clinical features and cancer risk in families with pathogenic CDH1 variants irrespective of clinical criteria. J Med Genet 2019;56:838- 843. 35 Weber- Lasselle N, Hauke J, Ramser J, et al. BRIP1 loss- of- function mutations confer high risk for familial ovarian cancer, but not familial breast cancer. Breast Cancer Res 2018;20:7. 36 Hu C, Hart S, Gnanoolvu R, et al. A population- based study of genes previously implicated in breast cancer. N Engl J Med 2021;384:440- 451. 37 Morra A, Mavaddat N, Muranen TA, et al. The impact of coding germline variants on contralateral breast cancer risk and survival. Am J Hum Genet 2023;110:475- 486. 38 Bishop DT, Demenais F, Goldstein AM, et al. Geographical variation in the penetrance of CDKN2A 36 mutations for melanoma. J Natl Cancer Inst 2002;94:894- 903. 39 Begg CB, Orlow I, Hummer AJ, et al. Lifetime risk of melanoma in CDKN2A mutation carriers in a population- based sample. J Natl Cancer Inst 2005;97:1507- 1515. 40 Hanson H, Astiazaran- Symonds E, Amendola LM, et al. Management of individuals with germline pathogenic/likely pathogenic variants in CHEK2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2023.. # National Comprehensive NCCN Cancer Network. NCCN Guidelines Version 3.2025 Gene Summary: Risks and Management. REFERENCES FOR GENE TABLES. 41 Goldberg M, Bell K, Aronson M, et al. Association between the Lynch syndrome gene MSH2 and breast cancer susceptibility in a Canadian familial cancer registry. J Med Genet 2017;54:742- 746. 42 Harkness EF, Barrow E, Newton K, et al. Lynch syndrome caused by mlh1 mutations is associated with an increased risk of breast cancer: a cohort study. J Med Genet 2015;52:553- 556. 43 Latham A, Srinivasan P, Kemel Y, et al. Microsatellite instability as associated with the presence of Lynch syndrome pan- cancer. J Clin Oncol 2019;37:286- 295. Erratum in: J Clin Oncol 2019;37:942. 44 Uusitalo E, Rantanen M, Kallionpaa RA, et al. Distinctive cancer associations in patients with neurofibromatosis type 1. J Clin Oncol 2016;34:1978- 1986. 45 Seminog OO, Goldacre MJ. Age- specific risk of breast cancer in women with neurofibromatosis type 1. Br J Cancer 2015;112:1546- 1548. 46 Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 2011;305:2304- 2310. 47 Engel C, Loeffler M, Steinke V, et al. Risks of less common cancers in proven mutation carriers with Lynch syndrome. J Clin Oncol 2012;30:4409- 4415. 48 Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 2011;305:2304- 2310. 49 Moller P, Seppala TT, Bernstein I, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut 2018;67:1306- 1316. 50 Dominguez- Valentin M, Sampson JR, Seppala TT, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the prospective Lynch syndrome database. Genet Med 2020;22:15- 25. 51 Pilarski R. Cowden syndrome: A critical review of the clinical literature. J Genet Couns 2009;18:13- 27. 52 Pilarski R, Burt R, Kohlman W, et al. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst 2013;105:1607- 1616. 53 Bubien V, Bonnet F, Brouste V, et al. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet 2013;50:255- 263. 54 Tan MH, Mester JL, Ngeow J, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res 2012;18:400- 407. 55 Hendricks L, Hoogerbrugge N, Venselaar H, et al. Genotype- phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort. Eur J Med Genet 2022;65:104632. 56 Walsh S, Carter M, Tubridy N, McDermott EW, Lhermitte- Duclos and Cowden diseases: breast cancer as an unusual initial presentation of these overlapping conditions. BMJ Case Rep 2011;2011:bcr0820114700. 57 Schrager CA, Schneider D, Gruener AC, et al. Clinical and pathological features of breast disease in Cowden's syndrome: an underrecognized syndrome with an increased risk of breast cancer. Hum Pathol 1998;29:47- 53.. 58 Lukomska A, Menkiszak J, Gronwald J, et al. Recurrent mutations in BRCA1, BRCA2, RAD51C, PALB2 and CHEK2 in Polish patients with ovarian cancer. Cancers 2021;13:849. 59 Song H, Dicks E, Tyrer J, et al. Population- based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high grade versus ovarian cancer. J Med Genet 2021;58:305- 313. 60 Tischkowitz M, Balmaña J, Foulkes WD, et al. Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2021;23:1416- 1423. 61 Hanson H, Kulkarni A, Long L, et al. UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2. J Med Genet 2023;60:417- 429. 62 Yang X, Song H, Leslie G, et al. Ovarian and breast cancer risks associated with pathogenic variants in RAD51C and RAD51D. J Natl Cancer Inst 2020;112:1242- 1250. 63 Ramin C, Withrow DR, Davis Lynn BC, et al. Risk of contralateral breast cancer according to first breast cancer characteristics among women in the USA, 1992- 2016. Breast Cancer Res 2021;23:24. 64 Song H, Dicks E, Ramus SJ, et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol 642015;33:2901- 2907. 65 Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum of cancers in the Peutz- Jeghers syndrome. Clin Cancer Res 2006;12:3209- 3215. 66 Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial 60Peutz- Jeghers syndrome. Gastroenterology 2000;119:1447- 1453. 67 Mai PL, Best AF, Peters JA, et al. Risks of first and subsequent cancers among TP53 mutation carriers in the national cancer institute Li- Fraumeni syndrome cohort. Cancer 2016;122:3673- 3681. 68 de Andrade KC, Khincha PP, Hatton JN, et al. Cancer incidence, patterns, and genotype- phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study. Lancet Oncol 2021;22:1787- 1798. 69 Siegel A, Bremer R, Klein WMP, et al. Uptake and timing of bilateral and contralateral risk- reducing mastectomy in women with Li- Fraumeni syndrome. Breast Cancer Res Treat 2022;191:159- 167. 70 Packwood K, Martland G, Sommerlad M, et al. Breast cancer in patients with germline TP53 pathogenic variants have typical tumour characteristics: the Cohort study of TP53 carrier early onset breast cancer (COPE study). J Pathol Clin Res 2019;3:189- 198. 71 Gun Y, Wan Q, Ouyang T, et al. Risk of ipsilateral breast tumor recurrence and contralateral breast cancer in patients with and without TP53 variant in a large series of breast cancer patients. The Breast 2022;65:55- 60.. # NCCN Guidelines Version 3.2025 Gene Summary: Risks and Management. AUTOSOMAL RECESSIVE RISK IN CANCER GENES - MULTIGENE PANEL TESTING. Biallelic P/LP variants in some genes, included on gene panels, may be associated with rare autosomal recessive conditions, such as FA or CMMRD. For these genes, consideration should be given to carrier testing the partner for P/LP variants in the same gene if it would inform reproductive decision- making and/or risk assessment and management.. # NCCN Guidelines Version 3.2025 BRCA-Pathogenic/Likely Pathogenic Variant - Positive Management. a Females should be familiar with their breasts and promptly report changes to their health care provider. Periodic, consistent breast self examination (BSE) may facilitate breast self awareness. Premenopausal individuals may find BSE most informative when performed at the end of menses. b Randomized trials comparing clinical breast exam versus no screening have not been performed. Rationale for recommending clinical breast exam every 6- 12 mo is the concern for interval breast cancers. c The appropriateness of imaging modalities and scheduling is still under study. Lowry KP, et al. Cancer 2012;118:2021- 2030. d Lehman CD, et al. J Natl Cancer Inst 2016;108.. e The criteria for high- quality breast MRI include a dedicated breast coil, the ability to perform biopsy under MRI guidance, radiologists experienced in breast MRI, and regional availability. Breast MRI is preferably performed on days 7- 15 of a menstrual cycle for premenopausal patients. FDA Drug Safety Communication: FDA identifies no harmful effects to date with brain retention of gadolinium- based contrast agents for MRIs; review to continue. f Breast MRI is preferred due to the theoretical risk of radiation exposure in P/LP variant carriers. g Because of lack of screening, males diagnosed with breast cancer have historically presented with advanced stage disease. There are limited data describing the performance of breast screening for males at inherited risk; however, recent studies suggest that the detection rate is similar or better than for females at population risk. Gao Y, et al. Radiology 2019;293:282- 291; Li S, et al. J Clin Oncol 2022;40:1529- 1541. h In males, breast cancer risk in BRCA1 carriers is lower than that in BRCA2 carriers.. Continued. # NCCN Guidelines Version 3.2025 BRCA-Pathogenic/Likely Pathogenic Variant - Positive Management. # NCCN Guidelines Version 3.2025 BRCA-Pathogenic/Likely Pathogenic Variant - Positive Management. Clinical trials are in progress. See Discussion.. Note: All recommendations are category 2A unless otherwise indicated.. # # NCCN Guidelines Version 3.2025 BRCA-Pathogenic/Likely Pathogenic Variant - Positive Management. BRCA PATHOGENIC/LIKELY PATHOGENIC VARIANT-POSITIVE MANAGEMENT. Ovarian/Fallopian Tube/Peritoneal/Uterine Cancers References. Kobayashi M, Kitahara Y, Hasegawa Y, Tsukui Y, Hiraishi H, Iwase A. Effect of salpingectomy on ovarian reserve: A systematic review and meta- analysis. J Obstet Gynaecol Res 2022;48:1513- 1522. 2Vignarajan CP, Malhotra N, Singh N. Ovarian reserve and assisted reproductive technique outcomes after laparoscopic proximal tubal occlusion or salpingectomy in women with hydrosalpinx undergoing in vitro fertilization: A randomized controlled trial. J Minim Invasive Gynecol 2019;26:1070- 1075. 3Narod SA, Risch H, Mosleh R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 1998;339:424- 428. 4AlHilli MM, Pederson HJ. Controversies in hereditary cancer management. Obstet Gynecol 2021;137:941- 955. 5Huber D, Seitz S, Kast K, Emons G, Ortmann O. Use of oral contraceptives in BRCA mutation carriers and risk for ovarian and breast cancer: a systematic review. Arch Gynecol Obstet 2020;301:875- 884. Erratum in: Arch Gynecol Obstet. 2022;305:1627. 6Wheeler LJ, Desanto K, Teal SB, Sheeder J, Guntupalli SR. Intrauterine device use and ovarian cancer risk: A systematic review and meta- analysis. Obstet Gynecol 2019;134:791- 800. 7Balayla J, Gil Y, Lasry A, Mitric C. Ever- use of the intra- uterine device and the risk of ovarian cancer. J Obstet Gynaecol 2021;41:848- 853. 8Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA 2017;317:2402- 2416. 9Hickey M, Trainer A, Braat S, Davey MA, Krejany E, Wark J. What Happens After Menopause? (WHAM): protocol for a prospective, multicentre, age- matched cohort trial of risk- reducing bilateral salpingo- oophorectomy in high- risk premenopausal women. BMJ Open 2017;7:e018758; 10 Steenbeek MP, Harmsen MG, Hoogerbrugge N, et al. Association of salpingectomy with delayed oophorectomy versus salpingo- oophorectomy with quality of life in BRCA1/2 pathogenic variant carriers: A nonrandomized controlled trial. JAMA Oncol 2021;7:1203- 1212. 11Gordhandas S, Norguist BM, Pennington KP, Yung RL, Laya MB, Swisher EM. Hormone replacement therapy after risk reducing salpingo- oophorectomy in patients with BRCA1 or BRCA2 mutations; a systematic review of risks and benefits. Gynecol Oncol 2019;153:192- 200. 12"The 2022 Hormone Therapy Position Statement of The North American Menopause Society" Advisory Panel. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause 2022;29:767- 794. 13ACOG Committee Opinion No. 774: Opportunistic Salpingectomy as a Strategy for Epithelial Ovarian Cancer Prevention. Obstet Gynecol 2019;133:e279- e284; SGO statement: clinical- practice- statement- salpingectomy- for- ovarian- cancer- prevention 14Gaba F, Goyal S, Marks D, et al; PROTECTOR team. Surgical decision making in premenopausal BRCA carriers considering risk- reducing early salpingectomy or salpingo- oophorectomy: a qualitative study. J Med Genet 2022;59:122- 132. 15Hanley GE, Pearce CL, Talhouk A, et al. Outcomes from opportunistic salpingectomy for ovarian cancer prevention. JAMA Netw Open 2022; 5:1- 10. 16Falconer H, Yin L, Gronberg H, Altman D. Ovarian cancer risk after salpingectomy: a nationwide population- based study. J Natl Cancer Inst 2015;107:dju410. 17de Jonge MM, de Kroon CD, Jenner DJ, et al. Endometrial cancer risk in women with germline BRCA1 or BRCA2 mutations: Multicenter cohort study. J Natl Cancer Inst 2021;113:1203- 1211. 18Marchetti C, De Felice F, Boccia S, et al. Hormone replacement therapy after prophylactic risk- reducing salpingo- oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers: A meta- analysis. Crit Rev Oncol Hematol 2018;132:111- 115. 19Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321- 333. 20Kuittinen T, Tulokas S, Rahkola- Soisalo P, et al. Pelvic organ prolapse after hysterectomy: A 10- year national follow- up study. Acta Obstet Gynecol Scand 2023;102:556- 566. 21Tulokas S, Mentula M, Harkki P, et al. Stress urinary incontinence after hysterectomy: a 10- year national follow- up study. Arch Gynecol Obstet 2022;305:1089- 1097. 22Manyonda I, S Talaulikar V, Pirhadi R, Onwude J. Progestogens are the problem in hormone replacement therapy: Time to reappraise their use. Post Reprod Health 2020;26:26- 31. 23Hoffman SR, Governor S, Daniels K, et al. Comparative safety of conjugated estrogens/bazedoxifene versus estrogen/progestin combination hormone therapy among women in the United States: a multidatabase cohort study. Menopause 2023;30:824- 830.. # NCCN Guidelines Version 3.2025 Pancreatic Cancer Screening. PANCREATIC CANCER SCREENING. - Emerging data have examined the efficacy of pancreatic cancer screening in select individuals at increased risk for exocrine pancreatic cancer. To date, most such studies have restricted pancreatic cancer screening to individuals with: 1. A known P/LP germline variant in a pancreatic cancer susceptibility gene (ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, EPCAM, PALB2, STK11, and TP53; see GENE-A) and a family history of pancreatic cancer (first-degree or second-degree relative) from the same side of the family as the germline P/LP variant; or 2. A family history of exocrine pancreatic cancer in ≥1 first-degree and ≥1 second-degree relatives from the same side of the family, even in the absence of a known P/LP germline variant; or 3. Some groups have recommended pancreas surveillance for P/LP variant carriers in the absence of a family history.. - For individuals considering pancreatic cancer screening, the Panel recommends that screening be performed in experienced high-volume centers. The Panel recommends that such screening only take place after an in-depth discussion about the potential limitations to screening, including cost, the high incidence of benign or indeterminate pancreatic abnormalities, and uncertainties about the potential benefits of pancreatic cancer screening.. - Consider screening using annual contrast-enhanced MRI/magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic ultrasound (EUS), with consideration of shorter screening intervals, based on clinical judgment, for individuals found to have potentially concerning abnormalities on screening. Studies have typically started screening with contrast-enhanced MRCP and/or EUS in individuals at increased risk for pancreatic cancer. The Panel emphasizes that most small cystic lesions found on screening will not warrant biopsy, surgical resection, or any other intervention.. a Abe T, et al. J Clin Oncol 2019;37:1070- 1080.. Note: All recommendations are category 2A unless otherwise indicated.. # PANCREATIC CANCER SCREENING. Hereditary Pancreatitis Genes. For individuals with P/LP variants in PRSS1 or other hereditary pancreatitis genes AND a clinical phenotype consistent with hereditary pancreatitis<sup>b</sup> - Consider pancreatic cancer screening 20 years after onset of pancreatitis, or at age 40 years, whichever is earlier.. # LI-FRAUMENI SYNDROME. Establishing a Diagnosis and Management Plan for Patients with a P/LP TP53 Variant Found on Germline Genetic Testing. Introduction. The presence of a TP53 P/LP variant on a germline genetic test may indicate a diagnosis of LFS. However, it is important to recognize that somatic TP53 variants frequently confound germline testing results, especially when testing is performed in older adults and/or patients with cancer.. Late post- zygotic aberrant clonal expansions containing a TP53 P/LP variant, limited to the hematologic compartment or to a tumor, may be detected in the blood or saliva through germline testing, particularly using NGS technology. The phenomenon of aberrant clonal expansion is well described and is most often due to CHIP, which can be demonstrated in healthy populations at increasing frequency with increasing age. If CHIP is misinterpreted as LFS, unwarranted clinical interventions may be advised (eg, LFS screening and prevention). Further, the finding of CHIP itself may portend adverse clinical outcomes, such as an increased risk of future development of hematologic neoplasia and increased non- hematologic mortality.. Careful examination of the patient's complete blood count (CBC) and peripheral blood smear may be warranted in all cases reporting the discovery of a TP53 P/LP variant, and testing of non- hematopoietic ancillary tissues and/or offspring may help to delineate bona fide mosaic involvement of different germ layers or other diagnoses (see Table 1).. Considerations Prior to Providing an LFS Diagnosis in a Patient Found to Have a TP53 P/LP Variant on a Germline Genetic Test. Does the personal and/or family history meet LFS criteria (CRIT- 7)? - Yes: Review Tissue Source Considerations and Test Metrics; and if no concerns, provide LFS diagnosis and manage accordingly; see LIFR- A 4 of 6 if LFS diagnosis - No: Review Tissue Source Considerations and Test Metrics; Consider testing of additional tissue sources and/or close relatives to delineate among possibilities in Table 1.. # NCCN Guidelines Version 3.2025 Li-Fraumeni Syndrome Management. LI-FRAUMENI SYNDROME: ADULT SURVEILLANCE. Tissue Source Considerations: Was the tissue source used for germline genetic testing a reliable germline tissue for the patient?. Blood and/or saliva. Personal history of a hematologic malignancy with active blood involvement and/or prior allogeneic hematopoietic cell transplantation: Blood and/or saliva is an unsuitable source of DNA for germline testing for these patients. DNA from cultured skin fibroblasts, hair follicles, or other non- hematopoietic origin tissue(s) is required to confirm germline origin. Blood or saliva may be used for germline genetic testing in patients with a prior or well- controlled hematologic malignancy and no evidence of active disease.. Personal history of CBC abnormalities at the time of sample collection: Peripheral blood smear review and evaluation by a hematologist is warranted to rule out an undiagnosed hematologic disorder, such as clonal cytopenia of undetermined significance or overt hematologic neoplasm. Testing of cultured skin fibroblasts, hair follicles, or other non- hematopoietic origin tissue(s) or offspring may be warranted to delineate the diagnosis (see Table 1).. Age . Test Metrics: Is the TP53 variant allele fraction . Tissue source:. Blood or saliva: Rule out a tissue source issue per "Tissue Source Considerations" Cultured skin fibroblasts: A low variant allele fraction variant in this tissue source can be due to: . Tumor somatic interference:. Somatic TP53 variants restricted to a tumor can be detected in the peripheral blood or saliva on a germline test due to blood/saliva contamination with ctDNA and/or circulating tumor cells. Patients with a high volume of tumor burden, especially metastatic disease, and/or tumors involving the blood (eg, hematologic neoplasms, especially acute leukemias, myelodysplastic syndrome, and chronic lymphocytic leukemia) are at higher risk for tumor somatic interference. DNA from cultured skin fibroblasts, hair follicles, or other non- hematopoietic origin/non- tumor contaminated tissue(s) is required to confirm germline origin.. Technical limitations:. Standard NGS tests utilized by most commercial germline genetic testing companies are not quantitative. Thus, a VAF . When a TP53 PV is identified for the first time in a family at an allele frequency near . Note: All recommendations are category 2A unless otherwise indicated.. # NCCN Guidelines Version 3.2025 Li-Fraumeni Syndrome Management. LI-FRAUMENI SYNDROME: ADULT SURVEILLANCE. See footnotes on next page. # NCCN Guidelines Version 3.2025 Li-Fraumeni Syndrome Management. LI-FRAUMENI SYNDROME: ADULT SURVEILLANCE. FOOTNOTES FOR TABLE 1. aDesit t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t e. # NCCN Guidelines Version 3.2025 Li-Fraumeni Syndrome Management. Females should be familiar with their breasts and promptly report changes to their health care provider. Periodic, consistent BSE may facilitate breast self awareness. Premenopausal individuals may find BSE most informative when performed at the end of menses. 9 Or at the age of the earliest diagnosed breast cancer in the family, if . Or mammogram, if MRI is unavailable. Breast MRI is preferred because of concerns regarding the risk of radiation exposure in P/LP variant carriers.. J Whole body MRI is not uniformly available. If whole body MRI is not available, then individuals with LFS are encouraged to participate in clinical trials or consider alternate comprehensive imaging methods. Other components of screening are being evaluated in protocols, including biochemical screening and regular blood screening for hematologic malignancies. FDA Drug Safety Communication: FDA identifies no harmful effects to date with brain retention of gadolinium- based contrast agents for MRIs; review to continue. Ballinger M, Best A, Mai P, et al. Baseline surveillance in Li- Fraumeni syndrome using whole- body magnetic resonance imaging: a meta- analysis. JAMA Oncol 2017;3:1634- 1639. Screening through whole body MRI has been broadly demonstrated to be feasible and of potential utility in the early detection of cancer among classic LFS families, though it also results in the detection of false- positive findings and possible cancer overdiagnosis. Furthermore, screening utility has not been evaluated among those with a germline TP53 P/LP variant without a classic family history of LFS, who are increasingly identified through multigene panel tests.. Continued. # NCCN Guidelines Version 3.2025 Li-Fraumeni Syndrome Management. Pediatric Surveillance (LIFR-A 6 of 6).	None	None	None
ec530a42becb4fc8b2934d441a5eb099	NCCN临床实践指南	遗传／家族高风险评估-乳腺癌，卵巢癌，胰腺癌和前列腺癌061-090	# NCCN Guidelines Version 3.2025 Li-Fraumeni Syndrome Management. iWhole body MRl is not unifomly available. If whole body MRl is not available, then individuals with LFS are encouraged to participate in clinical trials or consider alteate omphie g mths. ther co f sring ig vated in procs, indg chmical sng d rgul blood screening for hmiogic malgnices. FDA Drug Safety Commnction: DA idtifies no hamful effct to date with brain etention of gadolinium- based contrast agents for MRIs; review to continue. Ballinger M, Best A, Mai P, et al. Baseline surveillance in Li- Fraumeni syndrome using whole- body magnetic resonance imaging: a meta- analysis. JAMA Oncol 2017;3:1634- 1639. Screenin hgh wlo y d e a t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t h wth a gerline TP53 P/LP variant without a classic family history of LFS, who are increasingly identified through multigene panel tests.. # NCCN Guidelines Version 3.2025 Cowden Syndrome/PTEN Hamartoma Tumor Syndrome Management. F t t t. Premenopausal individuals may find BSE most informative when performed at the end of menses. b The appropriateness of imaging modalities and scheduling is stil under study. The criteria for high- qualit brast MRl include a dedcat brst co, the abilit to pefom biopsy under MRl guidance by xpered radiogists in brast MRl, and regional availaility. Breast MRl is preferably perfomed on days 7- 15 of a menstrual cycle for premenopausal females. FDA Drug Safety Communication: FDA identifies no harmful effects to date with brain retention of gadolinium- based contrast agents for MRIs; review to continue.. Note: All recommendations are category 2A unless otherwise indicated.. # NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. There are limited data regarding the lifetime risk of endometrial cancer in CS/PHTS. Surveillance screening and surgical intervention should be on an individual basis. Oophorectomy is not indicated for CS/PHTS alone.. Note: All recommendations are category 2A unless otherwise indicated.. # NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. BREAST, OVARIAN, UTERINE, AND PROSTATE CANCER RISK REDUCTION STRATEGIES FOR TRANSGENDER, NON- BINARY, AND GENDER DIVERSE PEOPLE WITH HEREDITARY CANCER SYNDROMES. General. The following section introduces special considerations for risk reduction strategies for individuals who are transgender, non- binary, and gender diverse and is anchored in the following principles.. The terms "transgender," "non- binary," and "gender diverse" include a wide variety of physical and psychological states referring to individuals whose gender identity differs from the biologic sex at birth (sometimes referred to as "sex assigned at birth"). Many of these individuals pursue gender- affirming hormonal and/or surgical treatments at some point in their lives, which may impact their cancer risks and risk reduction options.. Our focus is on hereditary increased cancer risks due to the presence of a germline P/LP in a cancer- related gene. These risks may be altered by gender- affirming treatments and should be considered in risk reduction strategies.. There are several variables associated with magnitude of cancer risk in transgender, non- binary, and gender diverse people who have a hereditary predisposition to cancer:. \Delta. There are no prospective data on appropriate cancer risk reduction and/or screening options for transgender, non- binary, or gender diverse individuals who are at average or high risk, regardless of average risk or increased risk. Recommendations for risk reduction must be made on a case- by- case basis depending on all of the variables involved.. Strategies for Risk Assessment and Care of Individuals Who Are Transgender, Non-binary, and Gender Diverse. One way to approach risk reduction choices is to focus on those organs at risk based on biologic sex at birth.. Female organs at risk: . # NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. BREAST, OVARIAN, UTERINE, AND PROSTATE CANCER RISK REDUCTION STRATEGIES FOR TRANSGENDER, NON- BINARY, AND GENDER DIVERSE PEOPLE WITH HEREDITARY CANCER SYNDROMES. Ovarian Cancer: Risk Reduction Principles and Strategies. There are several PVs associated with an increased risk for ovarian cancer, including BRCA1, BRCA2, ATM, BRIP1, PALB2, RAD51C, RAD51D, and LS genes. There is no known effective screening for ovarian cancer. It is not known what effect gender- affirming hormones have on ovarian or fallopian tube tissue. RSO is recommended for individuals with one or both intact ovaries and fallopian tubes, as it is for cisgender women- - see GENE- A for RRSO recommendations and age at the time of surgery for the specific PV found. RSO may be a consideration at an earlier age than recommended to alleviate gender dysphoria in conjunction with appropriate health care professionals. Individuals considering RRSO before natural menopause should be counseled about the adverse events, including loss of fertility, menopausal symptoms, cardiovascular disease, and bone loss associated with premature menopause. There are no data on the effect of medical ovarian suppression on ovarian cancer risk.. Uterine Cancer: Risk Reduction Principles and Strategies. There are several PVs associated with an increased risk for uterine cancer, including PTEN and LS genes. It is not known what effect gender- affirming testosterone therapy has on uterine tissue. However, as androgens are partially aromatized to estrogen, this may increase circulating estrogen levels and pose a risk to the uterus. Screening with transvaginal ultrasound with or without random endometrial biopsies is done in some settings but its benefit is unclear. Hysterectomy may be a consideration at an earlier age than recommended to alleviate gender dysphoria in conjunction with appropriate health care professionals. See GENE- A and NCCN Guidelines for Genetic/Familial High- Risk Assessment: Colorectal, Endometrial, and Gastric for PV- specific hysterectomy recommendations and recommended age at the time of surgery. All individuals with an intact uterus should be counseled about the early warning signs of uterine cancer. There are no data on the effect of medical ovarian suppression on uterine cancer risk.. Prostate Cancer: Risk Reduction Principles and Strategies. There are several PVs associated with an increased risk for prostate cancer, including BRCA1, BRCA2, and possibly ATM. It is not known what effect gender- affirming estrogen or anti- androgens have on the risk of prostate cancer, although some studies have reported diffuse atrophy and basal cell hyperplasia in prostate tissue among individuals on hormone therapy. Theoretically these changes may make the prostate gland less prone to develop cancer, but there are no data to support this. Gender- affirming hormone therapy has also been shown to alter PSA levels, thus reducing their efficacy as a screening tool. The Panel still advises PSA screening as per the NCCN Guidelines for Prostate Cancer Early Detection. See GENE- A and NCCN Guidelines for Prostate Cancer for PV- specific screening recommendations.. # National NCCN Guidelines Version 3.2025 Comprehensive Genetic/Familial High-Risk Assessment: NCCN Network Breast, Ovarian, Pancreatic, and Prostate. BREAST, OVARIAN, UTERINE, AND PROSTATE CANCER RISK REDUCTION STRATEGIES FOR TRANSGENDER, NON-BINARY, AND GENDER DIVERSE PEOPLE WITH HEREDITARY CANCER SYNDROMES. Breast Cancer: Risk Reduction Principles and Strategies:. There are several PVs associated with an increased risk for breast cancer, including BRCA1, BRCA2, ATM, BARD1, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53. Risk reducing strategies may differ by biologic sex at birth.. Level of risk differs by gene and may guide risk reduction decisions (see GENE- A for more details).. For transgender male and/or non- binary individuals with a P/LP in a breast cancer gene who have had reduction mammoplasty with retention of breast tissue, or no surgery, breast screening may begin at an earlier age and may include mammography and breast MRI. See GENE- A for gene- specific screening recommendations, including age to begin screening.. Female sex at birth. It is unclear if the use of gender- affirming hormone therapy with testosterone alters the risk of breast cancer in individuals with a hereditary susceptibility to breast cancer, although long- term testosterone in cisgender females has been shown to reduce breast glandular tissue and increase connective tissue. - Gender- affirming breast surgery, known as "top surgery," typically involves reduction mammoplasty with retention of some breast tissue and the nipple areolar complex.. Individuals with a known P/LP in a breast cancer gene may want to consider RRM in which . For transgender male individuals with a P/LP in a breast cancer gene who have had reduction mammoplasty with retention of some breast tissue, or no breast surgery, breast cancer screening may begin at an earlier age and may include mammography and breast MRI. See GENE- A for gene- specific screening recommendations, including age to begin screening. This approach is also supported by the ACR guidelines.. The term "breast cancer" may be associated with femininity; thus, the term "chest cancer," instead of breast cancer, may be preferred in individuals who identify as men.. Male sex at birth. Gender- affirming hormone therapy with estrogens and anti- androgens in transgender women increases breast tissue, which includes the formation of ducts, lobules, and acini, similar to that in cisgender women, and this should not be described as gynecomastia. Breast changes occur within 6 months after starting therapy and result in increased breast density. In situ and invasive breast cancers have been reported in this population. Anecdotally, these breast tumors tend to occur at an earlier age than the average population. Breast cancer risk in individuals who are biologically male at birth, even with breast cancer P/LP variants, is low, and while estrogen and anti- androgens may increase breast cancer risk, they are not contraindicated in individuals taking female- promoting (gender- affirming) hormones.. While there are limited data on the benefit of radiographic screening of breast tissue with mammography and/or breast MRI in transgender women at increased hereditary risk who are taking gender- affirming hormone therapy, there are case reports of breast cancer detection in this setting and NCCN supports the rationale for breast cancer screening of cisgender males at increased hereditary risk. This area clearly represents a major research gap in the care of transgender women who have a hereditary risk for breast cancer. Taking into account that the risk for breast cancer has been shown to be elevated in transgender women compared to cisgender men, breast screening modalities for transgender women at increased hereditary risk should be decided on a case- by- case basis, and may be based on age, family history, the duration of use of gender- affirming hormone therapy and/or the amount of breast tissue present; digital mammography and tomosynthesis rather than MRI is recommended by radiology guidelines. For those who have chosen implant reconstruction, MRI without contrast can be performed to assess implant integrity; however, this would not detect cancer.. # NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. BREAST, OVARIAN, UTERINE, AND PROSTATE CANCER RISK REDUCTION STRATEGIES FOR TRANSGENDER, NON- BINARY, AND GENDER DIVERSE PEOPLE WITH HEREDITARY CANCER SYNDROMES. Additional Considerations. Transgender, non- binary, and gender diverse individuals encounter many challenges to health care, including stigmatization, denial of services, discrimination, abuse, and possible higher rates of mortality due to lack of access to appropriate preventive care. Individuals pursuing gender- affirming care should be followed at centers of excellence with access to a multidisciplinary team that understands their unique needs and provides a safe and welcoming environment. The team should include surgeons, primary care specialists, oncologists, radiologists, pathologists, endocrinologists, pediatricians, psychologists, genetic counselors, and social workers, allof whom are trained in the appropriate care of the transgender population and can address medical, psychologic, and social care needs. There is a need for formal education in the care of transgender, non- binary, and gender diverse individuals at every level of the health care system, with a particular focus in breast/chest cancer screening. There is a need for research regarding the impact of gender- affirming hormones and puberty- blocking agents and how they interact with hereditary susceptibility to cancer syndromes as well as optimal prevention strategies for these populations. Most electronic health data, including SEER data, census data, and even EMRs do not incorporate gender identity, thus hindering the collection of health data in these populations and denying appropriate screening invitations to these individuals. A National Registry on the health outcomes of transgender, non- binary, and gender diverse populations is needed to fill the many gaps in the magnitude and management of risks associated with gender- affirming treatment in the setting of hereditary cancer susceptibilities. As in all research involving human participants, care must be taken to preserve the privacy and protection of this population.. References:. Corman V, Potorak J, Manto F, et al. Breast cancer in a male- to- female transsexual patient with a BRCA2 mutation. Endocr Relat Cancer 2016;23:391- 397. de Blok CJM, Klaver M, Wiepjes CM, et al. Breast development in transwomen after 1 year of cross- sex hormone therapy: Results of a prospective multicenter study. J Clin Endocrinol Metab 2018;103:532- 538. De Blok CJM, Wiepjes CM, Nota NM, et al. Breast cancer risk in transgender people receiving hormone treatment: Nationwide cohort study in the Netherlands. BMJ 2019;365:11652. Hodan R, Rodgers- Fouche L, Chittenden A, et al; Collaborative Group of the Americas on Inherited Gastrointestinal Cancer. Cancer surveillance for transgender and gender diverse patients with Lynch syndrome: a practice resource of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer. Fam Cancer 2023;22:437- 448. Lourenco AP, Niell BL, Cronin B, et al. ACR Appropriateness Criteria Transgender Breast Cancer Screening 2021;18:S502- S515. Parikh U, Mausner E, Chhor CM, et al. Breast imaging in transgender patients: What the radiologist should know. Radiographics 2020;40:13- 27. Sieberg R, Soriano K, Zurbier R. A rare case of breast cancer in a transgender woman. Radiol Case Rep 2021;16:3285- 3288. Skop M, Lorentz J, Jassi M, et al. "Guy's Don't Have Breasts": The lived experience of men who have BRCA gene mutations and are at risk for male breast cancer. Am J Mens Health 2018;12:961- 972. Sonnenblick EB, Lebron- Zapata L, Yang R, et al. Breast imaging for transgender individuals: assessment of current practice and needs. J Am Coll Radiol 2022;19:221- 231. Sutherland N, Espinel W, Grotzke M, Colonna S. Unanswered questions: Hereditary breast and gynecological cancer risk assessment in transgender adolescents and young adults. J Genet Couns 2020;29:625- 633.. # # # # # National Comprehensive Cancer Network. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. ABBREVIATIONS. # NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. # Discussion. This discussion corresponds to the NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. Last updated: March 6, 2025.. Table of Contents. Overview. MS- 2 Literature Search Criteria and Guidelines Update Methodology. MS- 3 Sensitive/Inclusive Language Usage. MS- 3 Genetic Risk Assessment and Counseling. MS- 3 Evaluating the Source of Genetic Testing Information. MS- 5 Tumor Genomic Testing. MS- 6 Multigene Testing. MS- 6 Pre- and Post- Test Counseling. MS- 8 High- Penetrance Breast and/or Ovarian Cancer Susceptibility Genes. MS- 11 BRCA- Related Breast/Ovarian Cancer Syndrome. MS- 12 Breast Cancer Risk. MS- 12 Ovarian Cancer Risk. MS- 14 Prostate Cancer Risk. MS- 15 Pancreatic Cancer Risk. MS- 15 Other Cancer and Health Risks. MS- 15 Risk Management. MS- 17 Other P/LP Variants Associated with Breast, Ovarian, Pancreatic, and Prostate Cancers. MS- 26 ATM. MS- 27 BARD1. MS- 28 BRIP1. MS- 29 CDH1. MS- 29. CHEK2. MS- 29 MLH1, MSH2, MSH6, PMS2, and EPCAM. MS- 31 NF1. MS- 31 PALB2. MS- 32 RAD51C and RAD51D. MS- 33 STK11. MS- 34 Emerging Evidence. MS- 34 NCCN Genetic Testing Criteria. MS- 34 Testing Criteria Related to Prostate Cancer. MS- 35 Systemic Therapy Decision- Making. MS- 35 Founder Mutations. MS- 36 Breast Cancer Population Testing. MS- 36 Probability Models. MS- 38 Li- Fraumeni Syndrome. MS- 39 Risk Assessment, Counseling, and Management. MS- 41 Cowden Syndrome/PTEN Hamartoma Tumor Syndrome. MS- 42 Risk Assessment, Counseling, and Management. MS- 45 Hereditary Pancreatic Cancer. MS- 48 Pancreas Screening. MS- 48 Cancer Risk Reduction Strategies for Transgender, Non- Binary, and Gender Diverse People with Hereditary Cancer Syndromes. MS- 50 References. MS- 54. # NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. Overview. All cancers develop as a result of pathogenic or likely pathogenic (P/LP) variants in certain genes, such as those involved in the regulation of cell growth and/or DNA repair,1,2 although not all of these P/LP variants are inherited from a parent. For example, sporadic P/LP variants can occur in somatic/tumor cells only, and de novo P/LP variants can occur for the first time in a germ cell (ie, egg or sperm) or in the fertilized egg itself during early embryogenesis. However, family studies have long documented an increased risk for several forms of cancer among first- degree relatives (ie, parents, siblings, children) and second- degree relatives (ie, grandparents, aunts or uncles, grandchildren, nieces or nephews) of affected individuals. These individuals may have an increased susceptibility to cancer as the result of . Hereditary cancers are often characterized by P/LP variants associated with increased risk for certain cancers and transmission to offspring through the mother and/or father.3,4 They often have an early age of onset and exhibit an autosomal dominant inheritance pattern (ie, occur when the individual has a P/LP variant in only one copy of a gene). Familial cancers share some but not all features of hereditary cancers. For example, although familial breast cancers occur in a given family more frequently than in the general population, they generally do not exhibit the inheritance patterns or onset age consistent with hereditary cancers. Familial cancers may be associated with chance clustering of sporadic cancer cases within families, genetic variation in lower penetrance genes, a shared environment, or combinations of these factors.5- 8. An individual suspected of being at risk for hereditary cancer should be offered genetic counseling.9,10 This is consistent with recommendations . The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High- Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate were developed with an acute awareness of the preliminary nature of much of our knowledge regarding the clinical application of the rapidly emerging field of molecular genetics, and with an appreciation for the need for flexibility when applying these guidelines to individual families. Furthermore, it should be emphasized that these Guidelines were not developed as a substitute for professional genetic counseling. Rather, they are intended to: 1) serve as a resource for health care providers to identify individuals who may benefit from cancer risk assessment and genetic counseling and testing; 2) guide decisions related to genetic testing; and 3) facilitate a multidisciplinary approach in the comprehensive care of individuals at increased risk for hereditary breast, ovarian, pancreatic, and prostate cancer. The current NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate focus primarily on assessment of P/LP variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer, including BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53, and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants. Where possible, P/LP. # variants in more recently identified genes have been addressed to the extent possible given the limited information available. Recommendations regarding P/LP variants associated with pancreatic cancer, and pancreas screening for individuals harboring such variants, were added to the NCCN Guidelines in the 2020 update. Additionally, these Guidelines are now the primary NCCN source for testing criteria for those with or at risk for prostate cancer, as of 2024.. A glossary of genetic terms is included in Table 1 for reference.. Literature Search Criteria and Guidelines Update Methodology. Prior to the update of this version of the NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate, an electronic search of the PubMed database was performed to obtain key literature using the following search terms: (hereditary breast cancer) OR (familial breast cancer) OR (hereditary ovarian cancer) OR (familial ovarian cancer) OR (Li- Fraumeni syndrome) OR (tp53 breast cancer) OR (Cowden syndrome) OR (pten hamartoma tumor syndrome) OR (pten breast cancer) OR (brca breast cancer) OR (brca ovarian cancer) OR (brip1 ovarian cancer) OR (cdh1 breast cancer) OR (palb2 breast cancer) OR (stk11 breast cancer) OR (rad51c ovarian cancer) OR (rad51d ovarian cancer) OR (hereditary pancreas cancer) OR (hereditary pancreatic cancer) OR (familial pancreas cancer) OR (familial pancreatic cancer) OR (brca pancreas cancer) OR (brca pancreatic cancer) OR (cdkn2a pancreas cancer) OR (cdkn2a pancreatic cancer) OR (cancer genetic testing) OR (cancer genetic counseling). The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes peer- reviewed biomedical literature.. The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types:. Practice Guidelines; Randomized Controlled Trial; Meta- Analysis; Systematic Reviews; Multicenter Study; and Validation Studies. The data from key PubMed articles as well as articles from additional sources deemed as relevant to these guidelines as discussed by the Panel during the Guidelines update have been included in this version of the Discussion section. Recommendations for which high- level evidence is lacking are based on the Panel's review of lower- level evidence and expert opinion.. Sensitive/Inclusive Language Usage. NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation. NCCN Guidelines endeavor to use language that is person- first; not stigmatizing; anti- racist, anti- classist, anti- misogynist, anti- ageist, anti- ableist, and anti- weight- biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non- gendered language, instead focusing on organ- specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.. Genetic Risk Assessment and Counseling. Cancer genetic risk assessment and genetic counseling is a multi- step process involving the identification and counseling of individuals at risk for familial or hereditary cancer. The purpose of cancer genetic counseling is. # to educate individuals about the genetic, biological, and environmental factors related to a cancer diagnosis and/or risk for disease to help derive personal meaning from cancer genetic information, and to empower them to make educated, informed decisions about genetic testing, cancer screening, and cancer prevention. Many patients undergoing genetic testing do not receive proper counseling.13 Further, testing rates are inadequate among some populations with higher risk, such as African American individuals.14,15 A genetic counselor, clinical geneticist, oncologist, surgeon, oncology nurse, or other health professional with expertise and experience in cancer genetics should be involved in every stage of the process.9. Testing is clinically indicated in individuals for whom there is a personal or family history suggesting genetic cancer susceptibility and for whom results will aid in risk management and treatment. The selection of genes for which testing is indicated is based on the personal and familial characteristics that determine the individual's prior probability of being a carrier of a P/LP variant, and on the psychosocial degree of readiness of the person to receive genetic test results. Genetic risk assessment is a dynamic process and can change if additional relatives are diagnosed with cancer. The genetic testing strategy is greatly facilitated when a P/LP variant has already been identified in another family member. In that case, the genetic testing laboratory can limit the search for P/LP variants in additional family members to the same location in the gene. However, if there is reason to suspect more than one P/LP variant in the family, then broader testing may be considered.. For the majority of families in whom presence of a P/LP variant is unknown, it is best to consider testing an affected family member first, especially a family member with early- onset disease, bilateral disease, or multiple primaries, because that individual has the highest likelihood of a positive test result. The testing of the unaffected individual (or of . Individuals who have received allogeneic hematopoietic cell transplantation (HCT) should not have molecular genetic testing performed on blood samples. In such cases, DNA of the individual being tested should be extracted from a fibroblast culture, if available. If this is not possible, buccal cells or saliva may be considered as an alternative source for DNA; however, a study has reported that over time, buccal epithelial cells are replaced by donor- derived cells in allogeneic HCT recipients.17,18 Therefore, genetic testing using saliva or buccal swab samples may be limited given this known risk of contamination or malignant cells from the hematologic malignancy. Fibroblasts are also indicated when testing individuals with active or recent hematologic malignancies.19. # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. A counseling dilemma is posed by the finding of a variant of uncertain significance (VUS), a genetic alteration that may actually represent a benign polymorphism unrelated to an increased cancer risk or may indicate an increased cancer risk. Retrospective analyses have estimated that . Carriers of a P/LP variant should be encouraged to participate in clinical trials or genetic registries. Carriers should be encouraged to recontact their genetics providers every few years for updates, as laboratories may issue amended reports as the knowledge base surrounding hereditary cancer risk expands.. Evaluating the Source of Genetic Testing Information. Reports regarding germline findings that may impact medical management should come from laboratories that are certified by the College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA), with some U.S. states (eg, New York) having additional reporting requirements. Direct- to- consumer (DTC) services and tumor profiling both provide genetic test results. The testing typically used by companies providing ancestry information directly to consumers is microarray- based single nucleotide polymorphism (SNP) testing that has not been validated for clinical use. These companies do not provide comprehensive genetic analysis that includes gross deletion or duplication analysis. Third- party services are available to assist patients with interpreting their raw data, but these services are not government- regulated. In addition to the errors inherent in working with raw uncurated data from DTC labs, other limitations of these services include inadequate informed consent process, uncertain clinical validity and utility, and lack of medical oversight.27 Currently available tests also only provide limited founder P/LP variant results without the benefit of family history. An analysis of concordance between DTC testing results and results from confirmatory testing for 49 patients showed a false- positive rate of . # management based solely on DTC testing results are not recommended.28 Testing offered through DTC services may have other limitations as well that could impact informed decision- making and interpretation of test results.29 These limitations include use of terms that are not clearly defined for consumers (eg, "clinical grade, "medical grade," "diagnostic grade"); unclear procedures for processing and receiving results and for variant reclassification; inadequate genetic counseling; and unclear use of consumers' health information.29. Incidental germline findings discovered through other sources (eg, participation in a research study) should be reviewed by a genetics professional.30 Confirmatory testing in these cases may be clinically indicated, especially if the reporting laboratory is not appropriately certified.. Tumor Genomic Testing. Tumor profiling can be considered complementary to germline testing. However, the absence of a P/LP variant for a given gene from tumor profiling does not rule out the possibility of a germline P/LP variant in that gene. Tumor genomic testing tends to be designed to address treatment actionability and prognosis.31 Therefore, a variant interpreted as P/LP in the germline may be interpreted as normal or as a VUS in the tumor, if that variant has no clear clinical implications. In addition, the sensitivity of most tumor testing is lower (particularly for intermediate- sized deletions and duplications) than that for most dedicated germline tests, sometimes due to filtering out of germline findings reported in tumor sequencing results. In a study of 21,333 patients with cancer who underwent both tumor and germline testing at an NCCN Member Institution, tumor- only sequencing missed . Circulating tumor DNA (ctDNA) assays may be used by some labs. ctDNA has the potential to identify both somatic and germline variants.33 However, since the primary intent of tumor testing is to inform treatment decision- making, ctDNA assays are not validated for reporting or interpretation of germline variants. The sensitivity, false- positive rates, and positive predictive value of ctDNA tests for early- stage disease, which are needed to derive clinical utility and to determine clinical validity, are also not fully defined.34,35 The psychological impact of ctDNA testing also remains unknown. For these reasons, ctDNA should not be used, outside of the clinical trial setting, to replace well- established methods of cancer screening (eg, mammography). If a germline variant that could impact medical management is detected with a ctDNA assay, then confirmatory testing with a CLIA- approved assay intended for detection and interpretation of germline results is recommended.. Multigene Testing. Next- generation sequencing (NGS) allows for the sequencing of multiple genes simultaneously. This is referred to as multigene testing. Multigene testing can detect P/LP variants not found in single- gene testing.36- 38 Since more than one gene can explain an inherited cancer syndrome, phenotype- directed testing based on personal and family history through a multigene panel test is often more efficient and/or cost- effective.39- 41 Multigene testing may also be considered for those who tested negative for one particular syndrome, but whose personal and family history is suggestive of an inherited susceptibility.39,42 It is now common practice to order multigene panel tests that include genes beyond the original indication for which testing is warranted. Phenotype needs to be considered when ordering multigene panel tests, to ensure that the relevant genes are included.43. There are several issues to consider regarding multigene testing. First, commercially available tests may differ significantly on a number of. # National Comprehensive Cancer Network. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. factors, such as number of genes analyzed, turnaround time, insurance coverage, laboratory expertise, variant reclassification protocol, methods of DNA/RNA analysis, and availability of financial assistance for cascade testing of relatives, among others. Therefore, the specific laboratory and multigene test should be chosen carefully.59 In addition, P/LP variants identified for more than one gene add complexity that may lead to difficulty in making risk management recommendations.42 A management plan based on genetic test results should only be developed for identified P/LP variants that are clinically actionable.. A major dilemma regarding multigene testing is that there are limited data and a lack of clear guidelines regarding degree of cancer risk associated with some of the genes assessed, and how to communicate and manage risk for carriers of these genes.44- 48 This issue is compounded by the low incidence rates of hereditary disease, leading to a difficulty in conducting adequately powered studies.44 Multigene tests include moderate- penetrance genes, and they often also include low- penetrance genes for which there are little available data regarding degree of cancer risk and guidelines for risk management.39,49 Analysis from a prospective, multicenter cohort study including 2984 patients with cancer unselected based on cancer type, disease stage, family history of cancer, age of diagnosis, and ethnicity showed that, with use of an 80- gene panel test, a P/LP variant was found in . Multigene tests also increase the likelihood of detecting a VUS.37- 39,45- 55- 57 An analysis of germline genetic testing results through 2019 for 200,000 patients with breast cancer and 15,000 patients with ovarian cancer diagnosed between 2013 and 2017 showed that VUS rates increased from 2013 to 2017 for both the patients diagnosed with breast cancer . There is also an increase in the chance of finding genotypically distinct cell lines (ie, genetic mosaicism) with NGS.60,61 Clones of non- cancerous cells (ie, aberrant clonal expansion) containing a P/LP TP53 variant have been found in healthy adults undergoing multigene testing. This phenomenon can often be attributed to clonal hematopoiesis, a condition in which a hematopoietic stem cell begins making blood cells with the same acquired P/LP variant.19 When there is no evidence of a hematologic malignancy, then it is referred to as clonal hematopoiesis of indeterminate potential (CHIP). Age- related CHIP is associated with increased risk of hematologic. # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. malignancies,62,63 but may also lead to unnecessary clinical intervention. Ancillary testing of non- lymphoid non- cancerous tissue can be used to help determine the true presence of a germline variant.19. Polygonic risk scores (PRS) are now sometimes included in some genetic test reports. PRS are groups of SNPs associated with a specific disorder or disease, such as cancer. Studies evaluating the validity of PRS to refine risks in those with hereditary cancer have been conducted primarily with breast and prostate cancers. Two studies identified PRS that were strongly associated with estrogen receptor (ER)- negative breast cancer in carriers of a BRCA1 P/LP variant, overall breast cancer in carriers of a BRCA2 P/LP variant, and high- grade serous ovarian cancer in carriers of both BRCA1 and BRCA2 P/LP variants.64,65 Two studies of male carriers of a BRCA1/2 P/LP variant identified PRS associated with breast cancer risk and prostate cancer risk.66,67 Studies have also evaluated the potential clinical utility of incorporating PRS into a risk- stratified approach for screening for prostate cancer68 and for identifying age of onset of aggressive prostate cancer.69 Studies of PRS have largely been done with those of European ancestry.70,71 Studies with larger samples from diverse populations are needed. Given that the clinical value of PRS has not yet been established, these should not be used to inform clinical management at this time.. Pre- and Post-Test Counseling. For individuals potentially meeting established criteria for . # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. The presentation of testing information is most effective when tailored to the age and education of the person undergoing counseling, and that individual's personal exposure to the disease, level of risk, and social environment.7 Information could be delivered in person or over the phone.74,75 Telehealth (ie, real- time two- way videoconference) is also increasingly utilized as a feasible alternative for in- person genetic counseling.75 Remote options (eg, telephone, telehealth) have the potential to help improve genetic testing rates in areas with inadequate access.75. Post- test counseling includes disclosure of results, a discussion of the associated medical risks, an assessment of the impact of the results on the emotional state of the individual, a discussion of the impact of the results on the comprehensive care of the individual (including discussion of therapeutic implications by a qualified health care professional), and how and where the patient will be screened for cancer risk.9 Counseling should include making the individual aware of any available resources, such as disease- specific support groups, high- risk clinics, advocacy groups, and research studies.76 The counselor should discuss the importance of genetic counseling and testing for relatives who also may be at increased risk.. Since some P/LP variants are associated with rare autosomal recessive conditions (eg, Fanconi anemia is associated with BRCA2, BRIP1, and PALB2 variants), the proband should be advised regarding possible inherited cancer risk to relatives and their own options for risk assessment and management. Testing of a partner of a carrier of a P/LP variant may also be considered to inform reproductive decision- making.77 See Autosomal Recessive Risk in Cancer Genes - Multigene Panel Testing in the algorithm for a full list of the P/LP variants covered in these Guidelines that are associated with autosomal recessive conditions.. Pre- and post- test genetic counseling with involvement of an expert in cancer genetics is recommended. However, the Panel acknowledges that most genetic testing is conducted by providers with limited expertise in genetics and often without pre- test genetic counseling.78- 80 Shortages in genetics health providers, expansion of testing indications, aggressive marketing, and increased accessibility of testing due to plummeting costs inclusive of DTC models for testing provide the impetus for the Panel to identify scenarios in which referral to a genetics health provider should be considered. These scenarios are as follows: identification of a P/LP variant; negative results despite tumor profiling, personal history, or family history suggestive of inherited condition; VUS result that warrants further evaluation or for which a patient or provider considers using to guide management; mosaic/possibly mosaic result or clonal hematopoiesis (CH; discrepant interpretation of variants (eg, discordant results across laboratories); interpretation of PRS; and detection of P/LP variants from DTC testing.. Many patients who have been diagnosed with cancer and have a P/LP variant are at increased risk for additional primary cancers in the future. Management of those risks may be appropriate after treatment of the current cancer or may be combined with treatment for a current cancer. For example, a patient with breast cancer and a pathogenic variant (PV) in BRCA1 or BRCA2 may consider bilateral blastectomies to treat their current cancer and also to reduce the risk of a future primary breast cancer. These patients may also consider oophorectomy for treatment of hormone receptor- positive breast cancer and also for reducing ovarian cancer risk.. Best practices for communicating an individual's personal risk relative to published estimated lifetime risks of cancer include the following: 1) presenting risk estimates as a range rather than as a single estimate (eg, 30%- 40%); 2) presenting absolute risk versus relative risk terminology; 3). # acknowledging the margin of error associated with risk estimates and how these are impacted by number of individuals with a P/LP variant; and 4) acknowledging that risk estimates can change over time. Specifically, patients who are older will have lower remaining lifetime risks. Over time, patients with a P/LP variant benefit from re- consultation with a medical provider who is familiar with inherited risk for cancer. This re- consultation is important for the following reasons: 1) increases adherence with screening guidelines, since screening behaviors may decrease over time; 2) allows the patient to re- evaluate personal choices about risk- reducing surgeries, based on changing life stage and circumstances; and 3) provides opportunities to "check in" with the patient about following up- to- date risk management guidelines, discuss additional or emerging genetic testing options, and review improved risk models. Cancer risk estimates can change based on larger case- control studies. Similarly, recommendations for screening and risk reduction can change based on new technologies and data. The frequency of follow- up with the patient will depend on factors such as age, reproductive planning, comorbidities, risk- reducing surgeries, and others as applicable.. Counseling may be warranted for those with negative or indeterminate results, as reasons for a negative result include the following scenarios: P/LP variant exists in a gene variant that was not recognized due to limitations in technology; P/LP variant exists in a gene variant that was not evaluated; and potential presence of a P/LP variant in a family member that was not detected in the individual. The determination of a "true negative" result depends on the specific family history of cancer, the specific P/LP variant found, and the relationship to any family members who test positive. When an individual has tested negative, it may still be appropriate to consider increased screening and risk reduction measures for cancer, based on family history. Over time, this individual may be a candidate for additional genetic testing due to additional family history or . Additional information and the full list of elements that should be included in pre- and post- test genetic counseling can be found in the Principles of Cancer Risk Assessment and Counseling in the algorithm.. For the 2024 update, the Panel added guiding principles of genetic testing for patients with cancer (ie, those with active diagnosis and a previous cancer history) for whom testing is performed outside of a specialty genetics setting (ie, "point of care" testing). These principles include essential pre- and post- test areas of discussion. For the full list of these principles, see the Principles of Cancer Risk Assessment and Counseling in the algorithm.. Reproductive Options. The outcomes of genetic testing can have a profound impact on family planning decisions for individuals of reproductive age who are found to be carriers of a P/LP variant. Counseling for reproductive options such as prenatal diagnosis and assisted reproduction using preimplantation genetic testing (PGT) and donor gametes may therefore be warranted for couples expressing concern over their future offspring's carrier status of a P/LP variant. Such counseling should include a comprehensive discussion of reproductive options; extent of cancer risk balanced with cancer worry; degree of protection for breast, ovarian, and uterine cancer; management of menopausal symptoms; hormone replacement therapy (HRT); related medical or surgical history; and consideration of a gestational carrier.. Prenatal diagnosis involves postimplantation genetic analysis of an early embryo, utilizing chorionic villi or amniotic fluid cell samples; genetic testing is typically conducted between week 12 and week 16 of gestation, and testing results may potentially lead to a couple's decision to terminate the pregnancy.82,83 PGT has emerged as an alternative method of genetic. # testing in early embryos. PGT involves the testing of 1 or 2 cells from embryos in very early stages of development (ie, 6- 8 cells) after in vitro fertilization (IVF). This procedure allows for the selection of unaffected embryos to be transferred to the uterus,82,83 and may therefore offer the advantage of avoiding potential termination of pregnancy. The PGT process requires the use of IVF regardless of the fertility status of the couple (ie, also applies to couples without infertility issues), and IVF may not always lead to a successful pregnancy. Lastly, the technology or expertise may not be readily available in a couple's geographic location. If eggs/embryos are cryopreserved, pregnancy may be achieved with uterus in place, with or without fallopian tubes or ovaries.. Various factors, both medical and personal, must be weighed in the decision to utilize prenatal diagnosis or PGT. Medical considerations may include factors such as the age of onset of the hereditary cancer, penetrance, severity or associated morbidity and mortality of the cancer, and availability of effective cancer risk reduction methods or effective treatments.82,83 For example, results from two systematic reviews have suggested that carrying a P/LP BRCA1/2 variant may be associated with diminished ovarian reserve.84,85 Although the use of prenatal diagnosis or PGT is relatively well established for severe hereditary disorders with very high penetrance and/or early onset (eg, Fanconi anemia), its use in conditions associated with lower penetrance and/or later onset (eg, hereditary breast or ovarian cancer syndrome) remains somewhat controversial from both an ethical and regulatory standpoint. Personal considerations for the decision to utilize prenatal diagnosis or PGT may include individual ethical beliefs, value systems, cultural and religious beliefs, and social and economic factors. Successful births have been reported with the use of PGT and IVF in carriers of a BRCA1/2 P/LP variant,86,87 but data in the published literature are still very limited. In addition, data pertaining to long- term safety or outcomes of PGT and assisted reproduction in carriers of a P/LP variant are not yet available.. High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes. Specific patterns of hereditary breast and ovarian cancers have been found to be linked to P/LP variants in the BRCA1/2 genes.88,89 In addition, two very rare hereditary cancer syndromes exhibiting an increased risk for breast cancer are Li- Fraumeni syndrome (LFS) and Cowden syndrome, which are related to germline P/LP variants in the TP53 and PTEN genes, respectively.90,91 PALB2, STK11, and CDH1 are also considered high penetrance breast cancer susceptibility genes.92- 99 These hereditary syndromes share several features beyond elevation of breast cancer risk. These syndromes arise from germline P/LP variants that are not within sex- linked genes; hence, the variants can be inherited from either parent. The syndromes are associated with breast cancer onset at an early age and development of other types of cancer, and exhibit an autosomal dominant inheritance pattern (see Table 1). Offspring of an individual with one of these hereditary syndromes have a . Prior to 2020, the NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast and Ovarian (Breast, Ovarian, Pancreatic, and Prostate as of 2024) focused largely on testing criteria for BRCA1/2 and appropriate risk management for carriers of a BRCA1 or BRCA2 P/LP variant. Sections on LFS and Cowden syndrome/PTEN hamartoma tumor syndrome (PHTS) were also included. Based on strong evidence that. # genes beyond BRCA1/2, TP53, and PTEN confer markedly increased risk of breast and/or ovarian cancers, these Guidelines have been expanded; see the sections below on other P/LP variants associated with breast/ovarian cancer.. BRCA-Related Breast/Ovarian Cancer Syndrome. Both the BRCA1 and BRCA2 genes encode for proteins involved in tumor suppression. BRCA1/2 P/LP variants can be highly penetrant (for definition, see Table 1), although the probability of cancer development in carriers of BRCA1/2 P/LP variants is variable, even within families with the same variant.100- 102 At present, it is unclear whether penetrance is related only to the specific P/LP variant identified in a family or whether additional factors, either genetic or environmental, affect disease expression. Epigenetic modification can also influence disease penetrance for a P/LP variant.103 It is generally accepted, however, that carriers of BRCA1/2 P/LP variants have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies.. Breast Cancer Risk. Estimates of penetrance for lifetime risk for primary breast cancer range from . While the evidence is mixed, we do not currently have evidence to support that BRCA- associated breast cancers are more aggressive and/or have poorer outcomes. A meta- analysis including 13 studies showed that carriers of a BRCA1 P/LP variant with breast cancer had worse overall survival (OS) compared to those without a BRCA1 or BRCA2 P/LP variant (hazard ratio [HR], 1.50; . BRCA1/2 P/LP variants are associated with early- onset primary breast cancer. In a sample of 21,401 families who met German Consortium for Hereditary Breast and Ovarian Cancer testing criteria for BRCA1/2 P/LP. # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. variants, a P/LP variant was detected in . Some histopathologic features have been reported to occur more frequently in breast cancers of individuals with a germline BRCA1/2 P/LP variant. For example, several studies have shown that BRCA1- related breast cancer is more likely to be characterized as ER- /PR- negative and HER2- negative (ie, "triple negative").94,115- 121 Studies have reported BRCA1 P/LP variants in . Among patients with triple- negative disease, carriers of a P/LP BRCA variant were diagnosed at a younger age compared with non- carriers.123,134 In a study of a large cohort of patients with triple- negative breast cancer (N = 403), the median age of diagnosis among carriers of a P/LP BRCA1 variant (n = 65) was 39 years.122 Patients in this population- based study were unselected for family history or age. Among the group of patients with early- onset (age at diagnosis . # carriers of a P/LP BRCA1 variant (HR, 0.49; 95% CI, 0.35–0.69) and carriers of a P/LP BRCA2 variant (HR, 0.60; 95% CI, 0.41–0.89), compared to non- carriers.. Carriers of a P/LP BRCA1/2 variant who were assigned male at birth (AMAB) also have a greater risk for cancer susceptibility.. Ovarian Cancer Risk. Increased risks for cancers of the ovary, fallopian tube, and peritoneum are observed in carriers of a P/LP BRCA1/2 variant.. Several studies have reported more favorable survival outcomes among carriers of a P/LP BRCA1/2 variant in patients with ovarian cancer compared with patients who are non- carriers.. The histology of ovarian cancers in carriers of a P/LP BRCA1/2 variant is more likely to be characterized as serous adenocarcinoma and high grade compared with ovarian cancers in non- carriers, although endometrioid and clear cell ovarian cancers also have been reported in the former population.. In studies of carriers of a P/LP BRCA1/2 variant who underwent risk- reducing salpingo- oophorectomy (RRSO) for occult gynecologic neoplasia, both invasive carcinoma and intraepithelial lesions were identified in 4.5% to 9% of cases based on rigorous pathologic examinations of the ovaries and fallopian tubes.. # variant compared with non- carriers undergoing RRSO,. Prostate Cancer Risk. Germline BRCA1/2 P/LP variants are associated with increased risk for prostate cancer.. Pancreatic Cancer Risk. Prior to more widespread testing of individuals with pancreatic cancer for germline variants in cancer predisposition genes, studies showed that BRCA1/2 P/LP variant rates in pancreatic cancer cases ranged from . More information on genes associated with pancreatic cancer can be found below, under Hereditary Pancreatic Cancer.. Other Cancer and Health Risks. Some studies have suggested an increased risk specifically of serous uterine cancer in carriers of a P/LP BRCA1/2 variant.. # increased risk for serous and/or serous- like endometrial cancer.212 A Dutch cohort study including 5980 carriers of a P/LP BRCA1/2 variant showed a 2- to 3- fold increased risk for endometrial cancer, with the highest risks for serous- like (HR, 10.48; . A meta- analysis including five studies of patients with uterine serous cancer and Ashkenazi Jewish ancestry showed that BRCA1/2 P/LP variant prevalence was greater in those with uterine serous cancer than in controls (also of Ashkenazi Jewish ancestry) (OR, 5.4; . The absolute risk of uterine cancer in carriers of a P/LP BRCA1/2 variant appears low overall, despite some evidence of increased risk. However, genetic testing, including for a P/LP BRCA1 variant, may be considered for patients diagnosed with serous endometrial cancer.. Studies that investigated associations between BRCA2 P/LP variant and cutaneous melanoma have drawn inconsistent conclusions, though there . In cases where both partners carry a P/LP BRCA2 variant, there may be a high risk for the offspring to develop Fanconi anemia, a rare autosomal recessive condition.77 A review of 27 patients with Fanconi anemia with biallelic P/LP variants in BRCA2 (FA- D1) showed a . # Risk Management. Risk ManagementRecommendations for the medical management of BRCA- related cancers are based on an appreciation of the early onset and increased risk for associated cancers. An individual from a family with a known BRCA1/2 P/LP variant who tests negative for the familial variant should be followed according to the recommendations for the general population for breast cancer (eg, the NCCN Guidelines for Breast Cancer Screening and Diagnosis [available at www.NCCN.org]).. Breast Cancer Risk Management. Screening. Mammography has served as the standard screening modality for detection of breast cancer during the last few decades. There are currently no data indicating that mammography on its own reduces mortality in females with genetically increased risk for breast cancer.226 Also, falsenegative mammography results are common and have been correlated with factors such as presence of a BRCA1/2 P/LP variant and high breast tissue density,227- 230 both of which may occur more frequently among younger females. Rapidly growing or aggressive breast tumors- - also more common among younger females - - have also been associated with decreased sensitivity of mammographic screening methods.227,231. Prospective studies on comparative surveillance modalities in females at high risk for familial breast cancer (ie, confirmed or suspected BRCA1/2 P/LP variant based on family history) have consistently reported higher sensitivity of MRI screening . 2009) that evaluated the performance of annual MRI and mammography in females (aged 25-65 years; . All of these studies discussed above evaluated a screening strategy that was conducted on an annual basis, and many of the studies included individuals without known BRCA1/2 P/LP variant status. A study of 1219 carriers of a P/LP BRCA1 variant and 732 carriers of a P/LP BRCA2 variant showed that the increased sensitivity of mammography in addition to MRI was greater for carriers of a P/LP BRCA2 variant .	None	None	None
4d6ee95c248340428ff8a69a94ed8d0d	NCCN临床实践指南	遗传／家族高风险评估-乳腺癌，卵巢癌，胰腺癌和前列腺癌091-126	# NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. BRCA1 variant (HR, 0.20; 95% CI, 0.10–0.43; . The optimal surveillance approach in individuals assigned female at birth (AFAB) who are at high risk for familial breast cancer remains uncertain, especially for those between the ages of 25 and 30 years. While some studies have reported an association between radiation exposure from mammography and increased risk for breast cancer in carriers of a P/LP BRCA1/2 variant,243,244 current data are insufficient to support risks of radiation. Nevertheless, one of the potential benefits of incorporating MRI modalities into surveillance strategies may include minimizing the radiation risks associated with mammography, in addition to the higher sensitivity of MRI screening in detecting tumors. The use of MRI, however, may potentially be associated with higher false- positive results and higher costs relative to mammography. The combined use of digital mammography (two- dimensional, 2D) in conjunction with digital breast tomosynthesis (DBT) appears to improve cancer detection and reduce false- positive call back rates.245- 254 Tomosynthesis allows acquisition of three- dimensional (3D) data using a moving x- ray and digital detector. These data are reconstructed using computer algorithms to generate thin sections of images. The combined use of 2D and DBT results in double the radiation exposure compared with mammography alone. However, this increase in radiation dose falls below dose limits of radiation set by the U.S. Food and Drug Administration (FDA) for standard mammography. The radiation dose can be minimized by newer tomosynthesis techniques that create a synthetic 2D image, which may obviate the need for a conventional digital image.246,255,256 In carriers of a BRCA1/2 P/LP variant who are . The appropriate imaging modalities and surveillance intervals are still under investigation. In a report based on a computer simulation model that evaluated different annual screening strategies in carriers of a P/LP BRCA1/2 variant, a screening approach that included annual MRI starting at 25 years of age combined with alternating digital mammography/MRI starting at 30 years of age was shown to be the most effective strategy when radiation risks, life expectancy, and false- positive rates were considered.260 Future prospective trials are needed to evaluate the different surveillance strategies in individuals at high risk for familial breast cancer. For an individual AFAB who is a carrier of a BRCA1/2 P/LP variant, training in breast awareness with regular monthly practice should begin at 18 years of age, and clinical breast examinations should be conducted every 6 to 12 months, beginning at 25 years of age. Between the ages of 25 and 29 years, these individuals should have annual breast MRI screening with contrast (to be performed on days 7 to 15 of menstrual cycle for premenopausal individuals) or annual mammograms only if MRI is not available. The age to begin screening can be individualized if the family history includes a breast diagnosis prior to 30 years of age.232,234,237,261,262 Breast MRI screening is preferred over mammogram in the 25- to 29- year age group. High- quality breast MRI screening should consist of the following: dedicated breast coil, ability to perform biopsy under MRI guidance, experienced radiologists in breast MRI, and regional availability. Between 30 and 75 years of age, annual mammogram and breast MRI with contrast should both be done. After 75 years of age, management should be considered on an individual basis. In females treated for breast cancer who have not had bilateral mastectomy,. # mammography and breast MRI screening with contrast should continue as recommended based on age. Emerging evidence suggests that abbreviated- protocol breast MRI is a screening strategy that warrants further investigation in carriers of a BRCA1/2 P/LP variant.. Carriers of a BRCA1/2 P/LP variant who were AMAB should have an annual clinical breast examination and undergo training in breast self- examination with regular monthly practice starting at 35 years of age. A 12- year longitudinal observational study evaluated the outcomes of mammography screening in 1869 males who were at increased risk of developing breast cancer (ie, personal or family history of breast cancer and/or germline P/LP variant associated with breast cancer, mostly BRCA1 and BRCA2).. Bilateral Total Mastectomy. Two meta- analyses show that prophylactic bilateral mastectomy reduces the risk for breast cancer.. It is important that the potential psychosocial effects of RRM are addressed. A 2018 Cochrane review including 20 studies that evaluated psychosocial effects of RRM showed that patients are generally satisfied with their decision, with reported decreases in worry about breast cancer, but negative impacts on body image and sexuality have also been reported. Additional research is needed to further evaluate the psychosocial impact of RRM.. The NCCN Guidelines Panel supports discussion of the option of RRM for individuals AFAB on a case- by- case basis. Counseling for this risk- reducing surgery should include discussion of extent of cancer risk reduction/protection, risks associated with surgeries, breast reconstructive options, and management of menopausal symptoms. Since risk of breast cancer remains increased with age in carriers of a BRCA1/2 P/LP variant,. # NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. Chemoprevention. ChemopreventionThe use of selective ER modulators (ie, tamoxifen, raloxifene) has been shown to reduce the risk for invasive breast cancer in individuals considered at high risk of developing breast cancer, especially ER- positive disease.. The aromatase inhibitors (Als) exemestane and anastrozole have been demonstrated to be effective in preventing breast cancer in postmenopausal individuals considered to be at high risk of developing breast cancer.. Studies on the effect of oral contraceptive use on breast cancer risk among carriers of a P/LP BRCA1/2 variant have reported conflicting data. In one case- control study, use of oral contraceptives was associated with a modest but statistically significant increase in breast cancer risk among carriers of a P/LP BRCA1 variant (OR, 1.20; . # oral contraceptives before 1975 (OR, 1.42; . To summarize, findings from case- control studies are inconsistent regarding the effect of oral contraceptive use on the association of P/LP BRCA1 or BRCA2 variant and breast cancer risk. Oral contraceptive use for . Differences in the study design used by these case- control studies make it difficult to compare outcomes between studies, and likely account for the conflicting results. The design of these studies might have differed with regard to factors such as the criteria for defining the "control" population for the study (eg, non- BRCA1/2 carriers vs. P/LP variant carriers without a cancer diagnosis), consideration of family history of breast or ovarian cancer, baseline demographics of the population studied (eg, nationality, ethnicity, geographic region, age groups), age of onset of breast cancer, and formulations or duration of oral contraceptives used.. Ovarian/Uterine Cancer Risk Management. Bilateral Salpingo-Oophorectomy. Carriers of a confirmed BRCA1/2 P/LP variant are at increased risk for both breast and ovarian cancers (including fallopian tube cancer and primary peritoneal cancer).147,148 Although the risk for ovarian cancer is generally considered to be lower than the risk for breast cancer in carriers of a P/LP BRCA1/2 variant,308- 310 the absence of reliable methods of early detection and the poor prognosis associated with advanced ovarian cancer have lent support for the performance of bilateral RRSO after completion of childbearing.. A 2014 observational prospective study of 5783 females carrying a P/LP BRCA1/2 variant showed that ovarian cancer is more prevalent in individuals carrying a BRCA1 (4.2%) P/LP variant than those carrying a BRCA2 (0.6%) P/LP variant.311 In carriers of a P/LP BRCA1 variant, prevalence of ovarian, fallopian tube, and peritoneal cancers found during. # risk- reducing surgery was . The effectiveness of RRSO in reducing the risk for ovarian cancer in carriers of a BRCA1/2 P/LP variant has been demonstrated in a number of studies. For example, results of a meta- analysis involving 10 studies of carriers of a BRCA1/2 P/LP variant showed an approximately . A . RRSO may provide an opportunity for gynecologic cancer detection in carriers of a P/LP BRCA1/2 variant. An analysis of 966 RRSO procedures showed that invasive or intraepithelial ovarian, tubal, or peritoneal. # National Comprehensive Cancer Network®. NICN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. neoplasms were detected in . In early studies, RRSO was reported to reduce the risk for breast cancer in carriers of a P/LP BRCA1/2 variant.269,313,318,319,325- 328 In the case- control international study by Eisen et al, a . Results of a prospective cohort study suggested that RRSO may be associated with a greater reduction in breast cancer risk for carriers of a P/LP BRCA2 variant compared with carriers of a BRCA1 P/LP variant.314 Another retrospective analysis including 676 females with stage I or II breast cancer and a P/LP BRCA1/2 variant showed that oophorectomy was associated with decreased risk of mortality from breast cancer in . The reduction in breast cancer risk following RRSO was questioned in a prospective cohort study from the Netherlands . Results from one of the earlier studies showed that greater reductions in breast cancer risk were observed in females carrying a P/LP BRCA1 variant who had an RRSO at . # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. 50 years of age is not associated with a substantial decrease in breast cancer risk.318 A 2017 study showed that oophorectomy was not significantly associated with decreased risk of breast cancer in carriers of a P/LP BRCA1/2 variant . A large case series published in 2021 addressed the permanent exposure hypothesis that has potentially dampened the strength of the conclusions drawn from previous studies on the association between RRSO and breast cancer risk reduction.335 Specifically, some of these earlier studies assumed that this association remains constant each year following RRSO. This study, which included 876 families with a known BRCA1 or BRCA2 P/LP variant, showed that RRSO reduced risk of breast cancer within 5 years following the surgery (HR, 0.28; . To summarize, studies suggest a benefit of RRSO on breast cancer risk, but the magnitude of the effect based on age remains uncertain.. Two systematic reviews showed that HRT does not negate the reduction in breast cancer risk associated with the surgery.336,337 One of these reviews showed that breast cancer risk tended to be lower in females who received estrogen only, compared to estrogen plus progesterone (OR, 0.62; . Salpingectomy (surgical removal of the fallopian tube with delayed oophorectomy) reduces the risk of ovarian cancer in the general population and is an option for premenopausal patients with hereditary cancer risk who are not yet ready for oophorectomy in the context of a clinical trial.340- 342 Salpingectomy is currently not proven to improve outcomes and continues to be a procedure still under investigation. CA- 125 and pelvic ultrasound are recommended for preoperative planning. Continuation of combination oral contraceptives or hormonal intrauterine device (IUD) for continued ovarian cancer risk reduction while ovaries remain in place may be considered. Clinical trials of interval salpingectomy with delayed oophorectomy are ongoing (eg, NCT02321228, NCT01907789, NCT04294927).. Some studies suggest a link between BRCA P/LP variants and development of serous uterine cancer (primarily with BRCA1),211 although the overall risk for uterine cancer was not increased when controlling for tamoxifen use.207,208,212 Individuals who undergo hysterectomy at the time of RRSO are candidates for estrogen- alone HRT, which is associated with a decreased risk of breast cancer, compared to combined estrogen and progesterone, which is required when the uterus is left in situ.336,337,343 Risk of pelvic floor dysfunction or urinary incontinence after hysterectomy is influenced by factors other than hysterectomy alone. Long- term follow- up studies indicate that the risks are . # may discuss the risks and benefits of concurrent hysterectomy, but more data are needed to determine the magnitude of the association between BRCA variants and development of serous uterine cancer.. HRT is generally not contraindicated and thus should be discussed with premenopausal patients who do not have a personal history of breast cancer.346 HRT recommendations should be tailored depending on each patient's personal history of breast cancer and/or breast cancer risk reduction strategies. In patients for whom the uterus is left in place at time of RRsO, there are several hormone replacement options. There is evidence that levonorgestrel IUD is associated with lower risk of breast cancer compared to risk of breast cancer from orally administered progestin.347 However, combination estrogen/progestin HRT continues to be an option after RRsO, though counseling should include bleeding precautions and uterine cancer risk awareness. Combined estrogen with a selective ER modulator (eg, bazedoxifene) is also an option.348. The NCCN Guidelines Panel recommends RRsO for carriers of a known BRCA1/2 P/LP variant, typically between 35 and 40 years of age for carriers of a BRCA1 P/LP variant. Since ovarian cancer onset tends to be later in carriers of a BRCA2 P/LP variant, it is reasonable to delay RRsO for management of ovarian cancer risk until between 40 and 45 years of age, unless age at diagnosis in the family warrants earlier age for consideration of this prophylactic surgery.311 Peritoneal washings should be performed at surgery, and pathologic assessment should include fine sectioning of the ovaries and fallopian tubes.173,174 The protocol published by CAP (2009) can be consulted for details on specimen evaluation.349 See the NCCN Guidelines for Ovarian Cancer for treatment of findings (available at www.NCCN.org). If STIC lesion is found, then further consultation with a gynecologic oncologist is recommended.. The decision to undergo RRsO is a complex one and should be made ideally in consultation with a gynecologic oncologist, especially when the . Chemoprevention. With respect to the evidence regarding the effect of oral contraceptives on cancer risks in carriers of a known BRCA1/2 P/LP variant, case- control studies have demonstrated that oral contraceptives reduced the risk for ovarian cancer by . # Screening. ScreeningStudies assessing whether ovarian cancer screening procedures are sufficiently sensitive or specific have yielded mixed results. The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), which assessed multimodality screening with transvaginal ultrasound (TVUS) and CA- 125 versus either TVUS alone or no screening, showed that multimodality screening is more effective at detecting early- stage cancer; however, after a median of 11 years of follow- up, a significant mortality reduction was not observed.355,356 In phase II of the UK Familial Ovarian Cancer Screening Study (UK FOcSS), 4348 females with an estimated lifetime ovarian cancer risk . Risk Management for Other Cancers. Risk Management for Other CancersScreening for prostate cancer starting at 40 years of age is recommended for carriers of a P/LP BRCA2 variant and should be considered for carriers of a P/LP BRCA1 variant.181 See the NCCN Guidelines for Prostate Cancer Early Detection (available at www.NCCN.org). General melanoma risk management is also indicated, such as annual full body skin exam and minimizing ultraviolet (UV) exposure. There are no specific screening guidelines for melanoma, though more information can be found at the website for the Skin Cancer Foundation (www.skincancer.org). Information on pancreas screening can be found below under Hereditary Pancreatic Cancer.. Other P/LP Variants Associated with Breast, Ovarian, Pancreatic, and Prostate Cancers. Other P/LP Variants Associated with Breast, Ovarian, Pancreatic, and Prostate CancersPrior to 2020, the NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate focused largely on testing criteria for BRCA1/2, PTEN, and TP53 and appropriate risk management for carriers of these P/LP variants. There is now strong evidence that genes beyond BRCA1/2 confer markedly increased risk of breast and/or ovarian cancers. These genes include ATM, BARD1, BRIP1, CDH1, CHEK2, MSH2, MSH6, MLH1, PMS2, EPCAM, NF1, PALB2, RAD51C, RAD51D, and STK11. The Panel's recommendations for cancer risk management intervention for carriers of P/LP variants associated with breast and/or ovarian cancer risk are based on absolute lifetime risk estimates. Cancer risk management intervention may be recommended when a carrier's absolute risk exceeds that of the average- risk population (ie, . # evidence, while limited conclusions can be drawn from case series or studies with small samples.361. The age at which breast screening is recommended may be impacted by the presence of risk factors such as family history of breast cancer, especially early- onset breast cancer.47 In those with a family history of early- onset breast cancer, breast screening may begin 5 to 10 years earlier than the youngest breast cancer diagnosis in the family. In individuals AFAB treated for breast cancer who have not had bilateral mastectomy, breast screening should continue as recommended based on age. Currently there is insufficient evidence to recommend RRM in carriers of moderately penetrant P/LP variants,47 though this option may be considered and discussed in the presence of a family history of breast cancer. Breast awareness in carriers of a moderately penetrant P/LP variant is recommended starting at age 18 years. Clinical breast examinations should be conducted every 6 to 12 months, beginning at 25 years of age (or 5- 10 years before the earliest known breast cancer in the family [whichever comes first]). After 75 years of age, management should be considered on an individual basis. Absolute risk estimates for breast cancer provided in the NCCN Guidelines for Genetic/Familial High- Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate are for primary breast cancer unless otherwise noted. With the exception of BRCA2, risk of hereditary contralateral breast cancer decreases once the patient is postmenopausal and is equivalent to sporadic breast cancer risk > 65 years of age.107. RRSO may be considered when risk of developing ovarian cancer exceeds that of the average- risk population. The Panel uses a threshold of . The P/LP variants described below may be included concurrently in panel testing (see Multigene Testing above). Lower penetrance genes that may be included as part of multigene testing but for which there is currently insufficient evidence of an association with breast and/or ovarian cancer include: FANCC, MRE11A, MUTYH heterozygotes, NBN, RECQL4, RAD50, RINT1, SLX4, SMARCA4, and XRCC2. Risk management recommendations for these genes should take into account family history and other clinical factors.. Information regarding testing criteria and risk management for LFS (associated with germline TP53 P/LP variant) and Cowden syndrome/PHTS (associated with germline PTEN P/LP variant) can be found in their respective sections, below.. ATM. P/LP variants in the ATM gene may increase the risk for breast cancer. A meta- analysis including 19 studies showed that the cumulative lifetime risk for primary breast cancer in individuals with an ATM P/LP variant is . # National Comprehensive Cancer Network. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. lifetime risk of developing primary breast cancer in females who carry an ATM P/LP variant in the range of . The association between specific types of ATM genetic variants and breast cancer susceptibility is less clear,371- 374 with some evidence showing that certain missense P/LP variants may act in a dominantnegative fashion to increase cancer risk, relative to truncating P/LP variants.371,372 A meta- analysis including five studies showed that carriers of an ATM P/LP variant have a . The 2022 comparative modeling analysis by Lowry et al showed that beginning annual MRI screening at age 30 to 35 years may reduce breast cancer mortality by . Large studies of patients with ovarian cancer have shown that there may be a slightly increased risk for ovarian cancer in carriers of an ATM P/LP variant,163,368,376,377 but there is currently insufficient evidence to recommend RRSO in these carriers.361 Given the association between ATM and development of the autosomal recessive condition ataxia telangiectasia, counseling for carriers of ATM P/LP variants should include a discussion of reproductive options.. There is emerging evidence that ATM P/LP variants are associated with increased risk for prostate cancer.180,141,187,380 Prostate cancer screening may be considered at age 40 years (see the NCCN Guidelines for Prostate Cancer Early Detection, available at www.nccn.org).. ATM P/LP variants have been found in patients with pancreatic cancer, with a lifetime risk of about . BARD1. A modest association between breast cancer and P/LP variants in the BARD1 gene has been found in case- control studies with a prevalence rate of . # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. associations between a BARD1 P/LP variant and increased risk of triple- negative breast cancer (0.42%; OR, 9.29; 95% CI, 4.58–18.85 and 0.41%; OR, 3.18; 95% CI, 1.16–7.42, respectively).<sup>129,130</sup> The Panel recommends annual mammogram for carriers of a P/LP BARD1 variant beginning at 40 years of age, with consideration of annual breast MRI. Age at which to initiate MRI in carriers with a P/LP BARD1 variant depends on a number of risk factors, including family history, age, breast density, and patient preference. RRM is not recommended in carriers of a BARD1 P/LP variant, but this procedure may be considered based on family history.. BRIP1. Panel testing of germline DNA in patients with ovarian cancer has shown that the prevalence rate of P/LP variants in BRIP1, a Fanconi anemia gene, is about . Regarding breast cancer, a case- control study including 10,901 patients with triple- negative breast cancer showed that BRIP1 was prevalent in . CDH1. Germline P/LP variants in CDH1 are associated with hereditary diffuse gastric cancer and lobular breast cancer, and studies have reported a cumulative lifetime risk for breast cancer of . CHEK2. Another breast cancer susceptibility gene that has been identified is CHEK2. Panel testing of germline DNA in large samples of patients with primary breast cancer has shown that the prevalence rate of a CHEK2 P/LP variant is about . # variants have been reported to occur with a higher frequency in Northern and Eastern European countries compared with North America.392- 395 The cumulative lifetime risk for primary breast cancer in females with CHEK2 P/LP variants range from approximately . Studies investigating the association between primary breast cancer risk and specific CHEK2 variants have primarily been based on the truncating variant 1100delC. An analysis from the Copenhagen General Population Study . Ten- year cumulative risk of developing contralateral breast cancer in carriers of a CHEK2 P/LP variant is . The 2022 comparative modeling analysis by Lowry et al showed that beginning annual MRI screening at age 30 to 35 years may reduce breast cancer mortality by . There is emerging evidence that CHEK2 P/LP variants are associated with increased risk for prostate cancer.180,198,402,406 Prostate cancer screening. # may be considered at age 40 years (see the NCCN Guidelines for Prostate Cancer Early Detection, available at www.nccn.org).. Data regarding increased risks for thyroid, kidney, and pancreatic cancers in carriers of a P/LP CHEK2 variant are inconclusive at this time.402. MLH1, MSH2, MSH6, PMS2, and EPCAM. Lynch syndrome results from a germline P/LP variant in 1 of 4 DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2).407 Additionally, deletions in the EPCAM gene, which lead to hypermethylation of the MSH2 promoter and subsequent MSH2 silencing, cause Lynch syndrome.408,409 Females with Lynch syndrome are at heightened risk for endometrial cancer.410- 413 With a lifetime risk of up to . TVUS and serum CA- 125 testing to screen for ovarian cancer in postmenopausal individuals has not been shown to be sufficiently sensitive or specific to warrant a routine recommendation.418- 420 Since there is no effective screening for ovarian cancer, individuals should be educated on the symptoms that may be associated with the development of ovarian cancer, such as pelvic or abdominal pain, bloating, increased abdominal girth, difficulty eating, early satiety, or increased urinary frequency or urgency. Symptoms that persist for several weeks and are a change from baseline should prompt physician evaluation. BSO may reduce the incidence of ovarian cancer.419,421- 425 The decision and timing of BSO as an option should be individualized based on whether childbearing is complete, menopausal status, comorbidities, family history, patient preference, and Lynch syndrome gene, as risks for ovarian cancer vary by mutated gene. Estrogen replacement after premenopausal oophorectomy . While studies have found that . Patients of reproductive age should be advised regarding their options for prenatal diagnosis and assisted reproduction, including PGT. This discussion should include known risks, limitations, and benefits of these technologies. If both partners are a carrier of a P/LP variant in the same MMR or EPCAM gene, then they should also be advised about the risk for constitutional MMR deficiency (CMMRD) syndrome, a rare recessive syndrome.431 More information regarding Lynch syndrome can be found in the NCCN Guidelines for Genetic/Familial High- Risk Assessment: Colorectal, Endometrial, and Gastric (available at www.NCCN.org).. NF1. Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary cancer syndrome that is caused by an NF1 P/LP variant. NF1 is a neurocutaneous syndrome characterized by cafe- au- lait spots and axillary/inguinal freckling, associated with non- cancerous tumors of the nerve tissues. Individuals with NF1 have an increased risk for malignant peripheral nerve sheath tumors, other central nervous system (CNS) tumors, and gastrointestinal stromal tumors.432- 436 A population- based study in Finland of 1404 patients with NF1 showed an estimated lifetime cancer risk of . # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. 2.06- 4.31; . Given the increased risk for early- onset breast cancer in carriers of these P/LP variants, annual breast screening with mammography should begin at 30 years of age.436,438 Screening with breast MRI could also be considered. The presence of neurofibromas in the breast may lead to false- positive MRI results, but more data are needed to determine the sensitivity and specificity of breast MRI in individuals with NF1. A prospective study of patients with NF1 from the United Kingdom . PALB2. PALB2 (partner and localizer of BRCA2) is a Fanconi anemia gene. PALB2 P/LP variants are associated with increased risk for breast cancer, with studies of patients with breast cancer showing that . Ten- year cumulative risk of developing contralateral breast cancer in carriers of a PALB2 P/LP variant is . # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. wide CI.107 The risk of contralateral breast cancer in carriers of a PALB2 P/LP variant is only elevated in ER- negative disease. The risk of metachronous contralateral breast cancer in women . The Panel recommends annual mammogram for carriers of a PALB2 P/LP variant AFAB beginning at 30 years of age. Breast MRI screening may also be considered. RRM for carriers of a PALB2 P/LP variant may be considered. For individuals AMAB, breast cancer screening similar to that for carriers of a BRCA1 P/LP variant is reasonable.. Some studies suggest an association between PALB2 and increased ovarian cancer risk.163,443- 446 The most robust data to date showing an association between PALB2 and increased ovarian cancer risk come from the international study, which included 524 families with a known P/LP PALB2 variant.93 This study showed a . PALB2 is associated with Fanconi anemia, inherited in an autosomal recessive manner.449 Therefore, counseling for carriers of PALB2 P/LP variants should include a discussion of reproductive options.. RAD51C and RAD51D. Genes in the RAD51 protein family are involved in homologous recombination and DNA repair. RAD51C and RAD51D have been shown to be associated with increased risk for ovarian cancer. Panel testing of germline DNA in females with ovarian cancer has shown that the prevalence rate of the RAD51C or RAD51D P/LP variant is about . The Panel recommends RRSO in carriers of RAD51C and RAD51D P/LP variants starting at 45 to 50 years of age. A discussion about risk- reducing surgery may be initiated earlier if there is a family history of early- onset ovarian cancer. As with BRIP1 P/LP variants, large prospective trials are needed to make a firm age recommendation regarding when a discussion about RRSO should begin in carriers of RAD51C and RAD51D P/LP variants.361. Regarding breast cancer, studies have shown prevalence rates of . # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. beginning at 40 years of age, with consideration of annual breast MRI. There are no data on the benefit of RRM for carriers of a P/LP ATM variant, but this procedure may be considered based on family history. RAD51C is associated with Fanconi anemia, inherited in an autosomal recessive manner. Therefore, counseling for carriers of a RAD51C P/LP variant should include a discussion of reproductive options.. STK11. Germline STK11 P/LP variants are associated with Peutz- Jeghers syndrome (PJS), an autosomal dominant disorder characterized by gastrointestinal polyps, mucocutaneous pigmentation, and elevated risk for gastrointestinal cancers as well as breast and non- epithelial ovarian cancers, such as Sertoli- Leydig tumors. Breast cancer risk in females with PJS is . Emerging Evidence. A systematic review of 21 papers including 47 patients with biallelic P/LP variants in NTHL1 showed that . In a study including 3422 patients with breast or ovarian cancer who underwent tumor and germline sequencing, a RAD51B P/LP variant was . NCCN Genetic Testing Criteria. The NCCN genetic testing criteria for high- penetrance breast, ovarian, pancreatic, and prostate cancer are organized into three sections: 1) testing is clinically indicated; 2) testing may be considered; and 3) there is a low probability of testing results having documented clinical utility (ie, finding of high- penetrance genes). The testing criteria listed are for cancer susceptibility genes with strong or moderate evidence of actionability for breast, ovarian, pancreatic, and prostate cancer (eg, BRCA1/2, CDH1, PALB2, PTEN, STK11, and TP53 for breast cancer; additionally, testing criteria for LFS and Cowden syndrome continue to be contained in their own dedicated sections; see below). Included genes may change with emerging clinical data. Further, the personal and/or family history criteria included may suggest the possibility of additional syndromes and would necessitate additional unlisted genes to be evaluated.. The NCCN Panel recommends that individuals from a family with a known P/LP variant in a breast, ovarian, pancreatic, and/or prostate cancer susceptibility gene be tested for the known variant. However, multigene panel testing is often indicated in these individuals if the family history suggests a different syndrome in addition to the known variant. In individuals from a family without a known P/LP variant, germline multigene testing is recommended for those individuals who meet the testing criteria described in the Hereditary Testing Criteria section in the algorithm. Multigene testing may be considered for individuals who meet testing criteria and who previously underwent single- gene and/or absent deletion duplication analysis but tested negative. Both first- and second- degree relatives of individuals who meet these testing criteria are also eligible for testing, except for second- degree relatives of individuals with pancreatic cancer or prostate cancer, for whom prior probability of a high- penetrance. # cancer susceptibility gene is low in the absence of additional family history of cancer; only first- degree relatives of these affected individuals should be offered testing, unless indicated based on additional family history.. Testing Criteria Related to Prostate Cancer. Approximately . There is also emerging evidence of other genes and increased risk for prostate cancer (eg, ATM, CHEK2).180,181,187,378- 380,402 HOXB13 P/LP variants have been found in . Testing criteria related to prostate cancer include diagnosis of metastatic prostate cancer, as well as diagnosis of prostate cancer in an individual with Ashkenazi Jewish ancestry or suspicious family history (ie, breast cancer diagnosed at an early age or in a male blood relative, ovarian cancer, pancreatic cancer, metastatic or high- or very- high- risk prostate . Prostate tumors with intraductal or cribriform histology may have increased prevalence of somatic MMR gene alterations.463 In addition, limited data suggest that germline homologous DNA repair gene mutations may be more common in prostate tumors of ductal or intraductal origin.464 Studies examining the association between carrying a germline BRCA2 P/LP variant and intraductal histology have been conflicting.465,466 By definition, intraductal carcinoma includes cribriform proliferation of malignant cells, as long as they remain confined to a preexisting gland that is surrounded by basal cells. These features are seen frequently with an adjacent invasive cribriform component and would be missed without the use of basal cell markers. Genetic testing may be considered in individuals diagnosed with intermediate- risk prostate cancer with intraductal/cribriform histology.. Systemic Therapy Decision-Making. Some of the NCCN treatment guidelines for BRCA- related cancers (Breast, Ovarian, Pancreatic Adenocarcinoma, Prostate, available at www.NCCN.org) recommend treatment with PARP inhibitors for patients with germline or somatic BRCA1/2 P/LP variants, as PARP inhibitors have been demonstrated to be active in these patients. These agents include olaparib467,468 and talazoparib469 for HER2- negative metastatic disease and as adjuvant treatment for high- risk HER2- negative breast cancer (olaparib only); niraparib,470 olaparib,471,472 and rucaparib473,474 for chemotherapy- refractory ovarian cancer; olaparib475 and rucaparib476 for metastatic castration- resistant prostate cancer that has progressed following previous treatment; and olaparib and rucaparib as maintenance therapy options for metastatic pancreatic cancer.477,478 Even though the. # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. focus of these Guidelines continues to be on management of breast, ovarian, pancreatic, and/or prostate cancer risk in individuals with associated hereditary syndromes, the Guidelines now identify intent to aid in systemic therapy and surgical decision- making as a scenario in which germline testing is clinically indicated. If a P/LP variant is detected through tumor profiling that has clinical implications if identified in the germline, then germline testing for this variant is indicated.. Founder Mutations. The rate of the three founder P/LP variants in those of Ashkenazi Jewish ancestry is . In addition to the BRCA1 and BRCA2 PVs in those of Ashkenazi ancestry, there are other ancestries in which founder mutations have been identified. In these circumstances, the decision to test will depend on the prevalence of the PV in the local population, family history, clinical features, and age of cancer diagnosis. Examples where ancestry may, along with personal and/or family history, contribute to decisions about genetic testing include the following associations: numerous BRCA1 and BRCA2 PV in those of Spanish, Mexican, Central American, and South American descent<sup>484- 486</sup>; BRCA1 PV and Polish ancestry<sup>487,488</sup>; BRCA1 and BRCA2 PV and Bahamian ancestry<sup>489</sup>; BRCA2 PV and Icelandic ancestry<sup>486</sup>; BRCA1 and BRCA2 PV in those of French Canadian ancestry<sup>486</sup>; and BRCA1 and BRCA2 PV and Hungarian ancestry<sup>486</sup> While emerging data derived from populations of Asian, Middle Eastern, and African origin have documented recurring mutations in BRCA1 and BRCA2 genes,<sup>490- 492</sup> population allele frequency data are not yet available to inform testing individuals based solely on ancestry in the absence of personal and/or family history. Other founder mutations that are not BRCA1 and BRCA2 include the TP53 PV p.1010G>A (p.Arg337His) PV, which has been observed in a subset of those of Brazilian ancestry,<sup>493</sup> and CDKN2A founder c.225_243del (p.Ala76fs) in those of Dutch ancestry.<sup>494</sup>. Breast Cancer Population Testing. The rapid advent of multigene testing and recent availability of PARP inhibitors for patients with breast cancer who carry a BRCA1/2 or PALB2 P/LP variant highlights the need for evolving and up- to- date recommendations for genetic testing criteria for patients with breast cancer. In 2019, the American Society of Breast Surgeons (ASBrS). # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. published a consensus statement recommending genetic testing for all patients with breast cancer.495 This recommendation was based on studies showing that criteria in testing guidelines miss some patients with breast cancer who harbor a P/LP variant496,497 and that population- based multigene testing is more cost- effective than testing based on personal and family history criteria.41,498 However, only . In 2024, a joint ASCO- SSO panel published guidance regarding germline testing in patients with breast cancer, in which all patients with newly diagnosed disease at age ≤65 years should be offered BRCA1/2 testing.500 This recommendation was based on a systematic review of 6 studies regarding prevalence of BRCA1/2 mutations in patients with breast cancer, as well as age cutoffs for BRCA1/2 testing. A registry study including 3907 women diagnosed with breast cancer analyzed sensitivity and specificity of various age threshold criteria for genetic testing, including 9 breast cancer predisposition genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53).501 A threshold of age ≤65 years had a sensitivity value of . To summarize, the aim of the ASCO- SSO age cut- off recommendation was to optimize sensitivity for detection of BRCA1/2.500 Use of a ≤65- year threshold is associated with good sensitivity both for BRCA1/2 and for other breast cancer predisposition genes. An analysis of postmenopausal patients with breast cancer from the Women's Health Initiative showed a BRCA1/2 prevalence of . Additional tailoring of testing criteria in patients with breast cancer could be done based on histopathology or the presence of multiple primary breast cancers. An analysis of females >65 years (N = 26,707) from population- based case- control studies showed that . The NCCN Panel continues to endorse a risk- stratified approach for patients with breast cancer. For patients diagnosed with breast cancer at age ≤65 years who do not meet other testing criteria, testing may be considered, including breast cancer genes plus other inherited cancer. # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. genes consistent with family phenotype. The Panel continues to not endorse universal testing of all patients with breast cancer due to limitations of this approach, such as low specificity, shortages in trained genetics health professionals to provide appropriate pre- and post- test genetic counseling, and lack of evidence to support risk management for genes included in many multigene panels. Though all patients with breast cancer should be evaluated to determine the appropriateness of germline genetic testing, testing should ultimately be based on patient characteristics, such as those specified in the Testing Criteria for High- Penetrance Breast Cancer Susceptibility Genes in the algorithm.499 It is estimated that the age ≤65 years threshold will lead to a recommendation of testing 80% of women with breast cancer. Therefore, the Panel developed minimal standards of genetic testing to take into account the increased demand for testing with a shortage of resources. For the full list of these principles, see the Principles of Cancer Risk Assessment and Counseling in the algorithm.. Probability Models. Decision models developed to estimate the likelihood that a BRCA1/2 P/LP variant is present include BRCAPRO,508,509 Penn II,510 and the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA).508 Validated clinical and family history- based models that incorporate PRS are also emerging as precision risk estimation tools.511- 513 A lifetime risk for breast cancer of 20% to 25% or greater as assessed by models based largely on family history has been used in some guidelines to identify females as being at high risk for breast cancer. For example, this risk threshold was used in updates to the American Cancer Society (ACS) guidelines on breast screening, which incorporate MRI.261,514 Penn II has been validated in families with ≥2 cases of breast and/or ovarian cancer.510,515 Therefore, caution should be taken in applying this model to individuals with only one case of breast or ovarian cancer. In addition, this model was developed specifically to . If an individual does not meet the criteria for testing for high- penetrance breast and/or ovarian cancer susceptibility genes that are described above, then testing may be considered in those who are determined to have a 2.5% to 5% probability of harboring a BRCA1/2 P/LP variant, based on probability models validated for BRCA1/2 (eg, Tyrer- Cuzick, BRCAPRO, BOADICEA). However, the Panel cautions that model estimates vary substantially, and different thresholds may be applied if other genes are utilized in a specific model. If genes other than BRCA1/2 are to be included in models that evaluate the threshold for testing, then penetrance, clinical actionability, and phenotypic features of cancers associated with these genes should be taken into account. Models that take these parameters into account to determine eligibility and appropriateness of multigene testing should be developed and validated. Subgroup analyses of 1075 carriers of a BRCA1/2 P/LP variant from the Breast Cancer Prospective Family Study Cohort showed that BRCAPRO underpredicted breast cancer risk, but BOADICEA was well- validated.516 In 2020, the web- based CanRisk tool was developed to apply BOADICEA for clinical use and is now available. Further development and testing is needed to increase acceptability of the tool by clinicians.517 Besides BRCA1/2, BOADICEA also includes PAL3/2, CHEK2, and ATM. In 2022, BOADICEA was expanded to also take into account associations between BARD1, RAD51C, and RAD51D with breast cancer risk.518 PREMMplus has also been developed at an NCCN Member Institution to evaluate the likelihood of a germline mutation in a number of P/LP variants (APC, BRCA1, BRCA2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, TP53, ATM, BRIP1, CDKN2A, CHEK2, PALB2, PTEN, RAD51C, and RAD51D).519. # Li-Fraumeni Syndrome. Li- Fraumeni SyndromeLFS is a rare hereditary cancer syndrome that is frequently associated with germline . Given the broad tumor types seen in LFS families, a number of different sets of criteria have been used to help identify individuals who have a high . Classic LFS criteria include, based on a study by Li and Fraumeni involving 24 LFS kindreds, a member of a kindred with a known . Other groups have broadened the classic LFS criteria to facilitate identification of individuals with LFS. For example, criteria for . # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. criteria set forth by Chompret et al. the Panel recommends adopting the 2015 Revised Chompret Criteria, including testing individuals with choroid plexus carcinoma or rhabdomyosarcoma of embryonal anaplastic subtype diagnosed at any age and regardless of family history (for inclusion in criterion 3), based on reports of considerable incidence of TP53 P/LP variants found in patients with these rare forms of cancer.522,530,544- 546 The Panel supports the broader age cut- offs proposed by Tinat et al, based on a study in a large number of families, which detected germline TP53 P/LP variants in affected individuals with later tumor onsets.544,546 These age cut- offs are: 1) individuals diagnosed with LFS spectrum cancer . Patients with early- onset breast cancer (age of diagnosis . Lastly, when TP53 is included on multigene germline panels, the NCCN testing criteria for LFS are often not met. It has been argued that a spectrum of heritable TP53- related cancer syndromes exist.559 One study described families with TP53 P/LP variants falling into a spectrum from classic LFS to attenuated families who do not meet criteria. These definitions will help future LFS research describe the populations being studied, but at this time LFS management is recommended for all individuals with P/LP TP53 variants regardless of the presentation in the family.560. If a TP53 P/LP variant is found in blood, saliva, or buccal samples, especially in individuals whose personal or family history does not meet LFS criteria, this warrants consideration of testing of an alternative tissue, usually cultured skin fibroblasts, and close relatives to try to distinguish between germline, constitutional mosaicism, and somatic findings, such as CH or tumor contamination of peripheral blood. For patients who have a personal history of cancer, the Panel also recommends looking for signs of tumor somatic interference and technical limitations.. A table describing workup and management depending on etiology of TP53 P/LP variant found on genetic testing was added to the Guidelines for the 2024 update. The intent of this new table was to expand on potentially mosaic TP53 findings. Prior to publication of this table, the Guidelines did not sufficiently point out the possibility of post- zygotic (somatic or constitutional) mosaicism (PZM) versus abnormal clonal expansions (ACE; including CHIP and clonal cytopenia of undetermined significance [CCUS]) and did not provide adequate guidance regarding how to care for these patients. A review of 84 TP53- positive probands. # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. identified through multigene testing on blood or saliva from 2012 to 2019 showed constitutional mosaicism in . Risk Assessment, Counseling, and Management. Discussions with patients about LFS management should address the limitations of screening for the many cancers associated with this syndrome. It is also important to address the psychosocial and quality- of- life aspects of this syndrome. Given the complexity of LFS management and that LFS is rare, individuals with LFS should be followed at centers with expertise in management of this syndrome. Personal and family history of cancer should be taken into consideration for screening (ie, specific screenings, 5 to 10 years before earliest diagnosis). It is also important for patients' primary care providers and/or pediatricians to be informed about patients' diagnoses of LFS. Patients should be advised about the risk to relatives, and genetic counseling for relatives is recommended.564 For the 2024 Guidelines update, the Panel added a section on pediatric surveillance in LFS.. Breast screening in adults with LFS includes clinical examination, breast imaging (MRI and mammogram, as indicated), and breast awareness. Although there are no data regarding risk reduction surgery, individuals with LFS who were AFAB have increased breast cancer risk that warrants consideration of RRM. Given the high risk of contralateral breast cancer in LFS, the option of contralateral RRM should be discussed with patients . Use of a screening protocol that includes MRI may improve early cancer detection in individuals with LFS.564,565 Whole- body MRI for screening of cancers associated with LFS continues to be evaluated in multiple international trials. Use of whole- body MRI is appealing due to its wide anatomic coverage, lack of radiation, and the potential to reduce the number of imaging studies that a patient undergoes.567 A meta- analysis including 578 individuals with TP53 P/LP variants across 13 prospective cohorts showed that baseline whole- body MRI identified cancer in . # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. clinicians to develop an alternative screening program based on available cancer screening approaches. The Panel also acknowledges that whole- body MRI screening of all individuals with LFS may result in false positives and overdiagnosis.568,571 Further, the utility of whole- body MRI has not been evaluated in individuals with a TP53 P/LP variant who do not have a classic family history of LFS, a group that is increasingly being identified through multigene testing. The brain may be examined as part of whole body MRI or as a separate exam.. In addition to whole body MRI, the Panel recommends additional screening modalities for certain cancers. Individuals AFAB should begin breast cancer screening with annual clinical breast exam and breast MRI at age 20 and the addition of annual mammogram at age 30. The Panel recommends colonoscopy and upper endoscopy every 2 to 5 years starting at . Many of the other cancers associated with germline TP53 P/LP variants do not lend themselves to early detection. Thus, additional recommendations for adults with LFS are general and include comprehensive physical examinations (including neurologic examination) every 6 to 12 months, especially when there is a high index of suspicion for second malignancies in cancer survivors and rare cancers. Clinicians should address screening limitations for other cancers associated with LFS. Screening methods for other LFS- associated cancers include periodic colonoscopy and upper endoscopy, dermatologic examination, and PSA. Education regarding signs and symptoms of cancer is important. Cancer screening in LFS should take into account prior treatment with radiation therapy.. Individuals with a TP53 P/LP variant are at increased risk of second malignant neoplasms.545,572 Radiosensitivity in individuals with a TP53. P/LP variant is not significantly different than in the general population,573,574 but carriers seem to be more susceptible to radioresistance.526,574,575 Though use of therapeutic RT should generally be avoided in individuals with a TP53 P/LP variant, clinical decision- making should take into account the availability of other curative treatment options.. There is little evidence regarding care of TP53 P/LP variant carriers with PZM or hypomorphic variants. Until there are more data on these carriers, they should be cared for as LFS, as opposed to patients with TP53 CH, which should not be managed as LFS. Instead, given TP53 mutation is considered a high- risk clinical feature in CH, patients with TP53 CH may be referred to hematology expertise.576,577. Cowden Syndrome/PTEN Hamartoma Tumor Syndrome. The spectrum of disorders resulting from germline P/LP variants in PTEN578 are referred to as PHTS. The spectrum of PHTS includes Cowden syndrome, Bannayan- Riley- Ruvalcaba syndrome (BRRS), adult Lhermitte- Duclos disease (LDD), Proteus- like syndrome,90,579,580 and autism spectrum disorders with macrocephaly.90,580,581 Cowden syndrome is rare, with an incidence of 1 in 200,000, although it is likely to be underestimated due to difficulties associated with making a clinical diagnosis of the disease.582,583 Cowden syndrome is an autosomal dominant disorder, and most cases are associated with germline PTEN P/LP variants, though one study found that germline KULLIN methylation may also be associated with this syndrome.584 The frequency of germline PTEN P/LP variant in Cowden syndrome cases is high, at approximately 80%.585. Hamartomas (benign tumors resulting from an overgrowth of normal tissue) are a common manifestation of the PHTS syndromes. Cowden syndrome is associated with multiple hamartomatous and/or cancerous. # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. lesions in various organs and tissues, including the skin, mucous membranes, breast, thyroid, endometrium, and brain.90,586 However, it has been suggested that patients with other PHTS diagnoses associated with PTEN P/LP variants should be assumed to have Cowden syndrome- associated cancer risks.. The lifetime risk for breast cancer for females diagnosed with Cowden syndrome/PHTS has been estimated at . Thyroid disease, including benign multinodular goiter, adenomatous nodules, and follicular adenomas, has been reported to occur in approximately . Macrocephaly (defined as head circumference . As in many other hereditary cancer syndromes, affected individuals are more likely to develop bilateral and multifocal cancer in paired organs.585 Although not well defined, females with Cowden syndrome/PHTS may have a . In addition, brain tumors and vascular malformations affecting any organ are occasionally seen in individuals with Cowden syndrome/PHTS, although the risks for developing these conditions are not well defined.90,587 It is important to note, however, that most of the data on the frequencies of the clinical features of Cowden syndrome/PHTS are from compilations of case reports of relatively young individuals who may have subsequently developed additional signs of the disease (ie, new cancerous lesions), and these data are also likely to be confounded by selection bias.90 Furthermore, a considerable number of these studies were published prior to the establishment in 1996 of the International. # Cowden Consortium operational diagnostic criteria for the syndrome, which were based on published data and the expert opinion of individuals representing a group of centers mainly in North America and Europe.90,606. Benign skin lesions are experienced by most to all patients with Cowden syndrome/PHTS.580,586,595 Skin lesions associated with Cowden syndrome/PHTS include trichilemmomas (ie, benign tumors derived from the outer root sheath epithelium of a hair follicle), oral papillomas, mucocutaneous neuromas (hamartoma of the peripheral nerve sheath), palmoplantar keratoses, penile pigmentation, lipomas and vascular anomalies, and fibromas.587,595,607 Trichilemmomas associated with Cowden syndrome/PHTS tend to appear on the face, particularly the eyes, mouth, nose, and forehead.587 Most individuals with Cowden syndrome/PHTS exhibit characteristic mucocutaneous lesions by their twenties, and such lesions have been reported to occur in . It was previously estimated that about half of individuals with Cowden syndrome/PHTS have gastrointestinal polyps.610 However, this was almost . Several studies have projected lifetime estimates of cancer risk that are significantly higher than previously estimated. In a study of patients meeting diagnostic criteria for Cowden syndrome/PHTS . # National Comprehensive Cancer Network. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. endometrial cancer, . The BRRS variant of Cowden syndrome/PHTS has been characterized by the presence of multiple lipomas, gastrointestinal hamartomatous polyps, macrocephaly, hemangiomas, developmental delay, and pigmented . Risk Assessment, Counseling, and Management. The assessment of individuals suspected of having Cowden syndrome/PHTS incorporates both a history of the benign and malignant conditions associated with the syndrome and a targeted physical examination, including the skin and oral mucosa, breast, thyroid gland, and head circumference (see Testing Criteria for Cowden Syndrome/PTEN Hamartoma Tumor Syndrome in the algorithm). The NCCN Guidelines Panel has established a list of criteria to help indicate which individuals are candidates for testing for PTEN P/LP variants (see Testing Criteria for Cowden Syndrome/PTEN Hamartoma Tumor Syndrome in the algorithm). These criteria are used to assess the need for further risk assessment and genetic testing. When PTEN is included on multigene panels, these testing criteria do not need to be met. Clinical diagnostic criteria have also been developed to help identify clinical features associated with Cowden syndrome/PHTS (see Diagnostic Criteria for Cowden Syndrome/PTEN Hamartoma Tumor Syndrome in the algorithm, and discussed below under Diagnostic Criteria). Patients who meet clinical diagnostic criteria for Cowden syndrome/PHTS as described in this section are candidates for testing for PTEN P/LP variants.. Testing Criteria. Testing criteria for Cowden syndrome/PHTS are grouped into three general categories. A patient is considered for testing for PTEN P/LP variants based on whether they meet certain criteria or combinations of criteria from these three categories. The first criteria category includes. # individuals meeting diagnostic criteria for Cowden syndrome617: a personal history of BRRS, adult LDD, autism spectrum disorder with macrocephaly, or . The next category of criteria represents "major" features associated with Cowden syndrome/PHTS and are described in the Guidelines (see Testing Criteria for Cowden Syndrome/PTEN Hamartoma Tumor Syndrome in the algorithm).580,583,589,597,617 With respect to decisions related to the presence of mucocutaneous lesions, the Panel did not consider the available literature to be adequate to accurately specify the number or extent of these lesions required for the condition to be defined as a major criterion for Cowden syndrome/PHTS, and clinical judgment is needed when evaluating such lesions. An individual exhibiting . The final category of criteria represents features with a "minor" association with Cowden syndrome/PHTS.580,583,593,617 These criteria are described in the Guidelines (see Testing Criteria for Cowden Syndrome/PTEN. Hamartoma Tumor Syndrome in the algorithm). An individual would need to exhibit . Lastly, an individual who has a first- degree relative diagnosed with Cowden syndrome/PHTS or BRRS for whom testing has not been performed would also meet the threshold for PTEN testing if the individual meets at least one major criterion or . Diagnostic Criteria. The frequency of PTEN P/LP variant in individuals meeting International Cowden Consortium diagnostic criteria for Cowden syndrome has previously been estimated at about . # of PHTS (see Diagnostic Criteria for Cowden Syndrome/PTEN Hamartoma Tumor Syndrome in the algorithm).. Screening Recommendations. Cancer is the major health risk associated with Cowden syndrome/PHTS. Therefore, the NCCN Panel has outlined guidelines for prevention and early detection screening of commonly associated cancers with Cowden syndrome/PHTS. Current medical management recommendations for Cowden syndrome/PHTS include annual physical examinations, starting at 18 years of age (or 5 years before the youngest age of diagnosis of a component cancer in the family).. The recommendations for individuals with Cowden syndrome/PHTS who were AFAB focus on primary and secondary prevention options for breast cancer since this is the most commonly associated cancer in individuals with Cowden syndrome/PHTS based on the available literature. Individuals AFAB should begin regular monthly breast self- examinations at 18 years of age and have a semiannual clinical breast examination beginning at 25 years of age or 5 to 10 years earlier than the earliest known breast cancer in the family (whichever comes first). Individuals AFAB should also have an annual mammogram and breast MRI screening with and without contrast starting at 30 years of age, or 10 years earlier than the earliest known breast cancer in the family (whichever comes first). After 75 years of age, management should be considered on an individual basis. In patients treated for breast cancer who were AFAB and who have not had bilateral mastectomy, mammography and breast MRI screening with contrast should continue as recommended based on age. A single- center retrospective study including 65 females diagnosed with PHTS showed that the yield of breast cancer screening (MRI and mammography) is comparable in this population, compared to other carriers of high- penetrance breast cancer susceptibility genes (eg, BRCA1/2).621. Although there are no data regarding risk reduction surgery in individuals with Cowden syndrome who were AFAB, the option of RRM and hysterectomy should be discussed. Oophorectomy is not indicated for Cowden syndrome since ovarian cancer risk is not elevated in these patients. Counseling for risk- reducing surgeries may include discussion of extent of cancer risk reduction/protection, risks associated with surgeries, and reproductive options. It is also important to address the psychosocial and quality- of- life aspects of undergoing risk- reducing surgical procedures.. Given that Cowden syndrome is rare, there are no data on screening for endometrial cancer in these patients, though consideration of screening can begin as early as age 35. The Panel recommends patient education regarding the symptoms of endometrial cancer including the necessity of a prompt response to symptoms such as abnormal bleeding. Prompt reporting promotes early detection of endometrial cancer. The evaluation of these symptoms should include an endometrial biopsy. Though endometrial cancer screening does not have proven benefit in individuals with Cowden syndrome, endometrial biopsy is highly sensitive and specific as a diagnostic procedure. Therefore, screening through endometrial biopsy every 1 to 2 years may be considered.. Routine TVUS to screen for endometrial cancer in postmenopausal individuals has not been shown to be sufficiently sensitive or specific to warrant a positive recommendation but may be considered at the clinician's discretion. However, TVUS is not recommended as a screening tool in premenopausal individuals due to the wide range of endometrial strip thickness throughout the normal menstrual cycle.. Individuals with Cowden syndrome/PHTS have approximately at least a . # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. testing may also undergo annual thyroid ultrasound, since this is a noninvasive procedure. Colonoscopy is recommended starting at 35 years of age, or earlier if symptomatic. If a close relative was diagnosed with colon cancer before 40 years of age, then colonoscopy screening should begin 5 to 10 years before the age of the earliest known diagnosis. Colonoscopy should be performed every 5 years or more frequently in cases where the patient is symptomatic or polyps are found. To screen for renal cell carcinoma, renal ultrasound should be considered every 1 to 2 years beginning at 40 years of age. Annual dermatologic examination is recommended. If there are symptoms in children, then assessment of psychomotor abilities should be considered, as well as a brain MRI. Education regarding the signs and symptoms of cancer is important; patients should also be advised about the risk to relatives, and genetic counseling is recommended for relatives as indicated.. No published data exist on the use of prenatal diagnostics/genetic testing for PTEN P/LP variants in families with Cowden syndrome. For a general discussion on the topic of reproductive options and counseling considerations, see the Discussion section above on Reproductive Options under Genetic Risk Assessment and Counseling.. Hereditary Pancreatic Cancer. Pancreatic cancer is thought to have a familial or hereditary component in approximately . EPCAM).93,198,200,202,205,381,382,625,627,629- 639 BRCA2 and CDKN2A are generally the most prevalent, with rates in families at moderate to high risk ranging from . Given the considerable rate of predisposing P/LP variants in patients with pancreatic cancer, as well as the fact that typical clinical factors (eg, young age of onset, family history of cancer) are poorly predictive for identifying carriers of a P/LP variant, universal genetic testing for these individuals is warranted. Given the elevated rates of P/LP variants in pancreatic cancer and that pancreatic cancer risk increases when there is a family history,640- 642 testing of first- degree relatives of patients may be beneficial. However, testing the patient is preferred. Testing of second- degree relatives is generally not recommended but may be considered in select cases. Given that mortality rates for this cancer are high,643,644 it may be beneficial to family members to test patients near the time of diagnosis, since the option to test the patient may not be available for very long. Family history of pancreatic cancer with unknown histology is often presumed to be exocrine. Detecting a germline P/LP variant can potentially aid in treatment decision- making, particularly regarding systemic therapy options (see Systemic Therapy Decision- Making above).. Pancreas Screening. Evidence to support screening for pancreatic cancer comes from studies including those who harbor an associated germline P/LP variant and/or those who have a particularly strong family history of pancreatic cancer (at. # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. least one first- degree relative and at least one second- degree relative on the same side of the family). The multicenter CAPS5 prospective cohort study, which included 1461 individuals considered high risk (ie, P/LP carriers of CDKN2A, STK11, ATM, BRCA1, BRCA2, MSH2, MLH1, MSH6, EPCAM, or PALB2; or family history of . The considerable rate of resectable asymptomatic lesions found from routine screening of individuals at high risk demonstrates the potential for downstaging (ie, identification of lesions at an earlier stage). There is also the potential for impact on mortality rates, though long- term studies are needed in this area. Lesions detected through routine screening may not always require resection (eg, sporadic branch- duct intraductal papillary mucinous neoplasms). Although there is much more experience with evaluating and managing pancreatic cysts and other pancreatic imaging abnormalities, determination of the overall risk/benefits of pancreatic surveillance requires further study. Results of surveillance of individuals at high risk performed in tertiary care/high- volume centers under clinical trial settings may not be the same as those performed in routine clinical practice. Data are beginning to better define which screen- detected lesions in individuals at high risk should be considered to be at particularly high risk for neoplastic progression (eg, those with a solid pancreatic mass, those with pancreatic duct abnormalities, those with growing pancreatic cysts650), but further data are needed to better define the. # threshold for surgical intervention in individuals at high risk undergoing pancreatic cancer screening.. With the exception of CDKN2A, STK11, ATM, and BRCA2 pancreas cancer screening in individuals who have a P/LP variant associated with increased risk of exocrine pancreatic cancer (ie, BRCA1, MSH2, MLH1, MSH6, EPCAM, PALB2, TP53) is not recommended unless there is additional family history of pancreatic cancer (at least 1 first- or second- degree relative).651 If family history criteria are met, then pancreas screening may be considered at age 50, or 10 years younger than the earliest pancreatic cancer diagnosis in the family, whichever is earlier.651 The International Cancer of the Pancreas Screening Consortium recommendations for pancreas screening in individuals with increased risk for hereditary pancreatic cancer do not include carriers of a TP53 P/LP variant in this group,651 as there are very limited data on pancreatic cancer screening in these carriers. However, the NCCN Guidelines Panel recommends that pancreatic cancer screening be considered in carriers of a TP53 P/LP variant, if there is additional family history of pancreatic cancer (at least 1 first- or second- degree relative), as there is some evidence of a modestly increased risk of pancreatic cancer in these carriers.202,205. For carriers of a CDKN2A, STK11, ATM, or BRCA2 P/LP variant, no additional family history is needed to warrant screening. For carriers of an ATM, or BRCA2 P/LP variant, screening may be considered at age 50, or 10 years younger than the earliest pancreatic cancer diagnosis in the family, whichever is earlier.652 For carriers of a CDKN2A P/LP variant, screening may be considered at age 40, or 10 years younger than the earliest pancreatic cancer diagnosis in the family, whichever is earlier.651 For carriers of a STK11 P/LP variant, screening may be considered beginning at ages 30 to 35 years, or 10 years younger than the earliest pancreatic cancer diagnosis in the family, whichever is earlier.422,651. Hereditary pancreatitis is defined by the presence of a causative P/LP variant such as PRSS1 or SPINK1, or a suspicious family history of chronic pancreatitis (two first- degree relatives or three second- degree relatives across . When screening is recommended, it may be done with contrast- enhanced MRI/magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic ultrasound (EUS).648,650,651 MRI and EUS have been shown to be superior in detection of subcentimeter pancreatic cysts, compared to CT.650 Screening at a high- volume center of expertise is recommended, preferably in the context of a longitudinal research study. In those for whom screening shows potentially concerning features that suggest progression, shorter screening intervals may be indicated.. Cancer Risk Reduction Strategies for Transgender, Non-Binary, and Gender Diverse People with Hereditary Cancer Syndromes. Risk reduction strategies for ovarian cancer (including ovarian, fallopian tube, and peritoneal cancer), uterine cancer, prostate cancer, and breast cancer for transgender, non- binary, and gender diverse people who have. # National Comprehensive Cancer Network®. NCCN Guidelines Version 3.2025 Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. a hereditary predisposition to cancer were added to these Guidelines in 2023. This addition is part of an ongoing NCCN initiative that began in 2020, which states that the Guidelines recommendations should fully address the needs of individuals of all sexual orientations and gender identities. The terms transgender, non- binary, and gender diverse include a wide variety of physical and psychological states referring to individuals whose gender identity differs from the biological sex assigned at birth. According to a recent Gallup poll, transgender individuals represent . Transgender, nonbinary, and gender diverse people encounter many challenges to health care, including stigmatization, discrimination, abuse, and possible higher rates of mortality due to lack of access to appropriate preventive care and guidance.658 In addition, these individuals face health inequities associated with cancer. Most electronic health data, including SEER data, census data, and electronic health records (EHR) do not incorporate gender identity, thus hindering the collection of health data in these populations and denying appropriate screening invitations to these individuals.. Transgender women may have lower prostate cancer incidence relative to cisgender men.659,660 A retrospective cohort study including 95,460 transgender women in the United States showed that gender- affirming hormone therapy was associated with lower incidence of prostate cancer (OR, 0.60; . (HR, 0.67; . Many transgender individuals pursue gender- affirming hormonal and/or surgical treatments at some point in their lives, which may impact their cancer risks, though management of their risk is challenging as a result of limited data on the impact of these treatments on cancer risk in transgender individuals. A retrospective cohort study conducted in the Netherlands showed that estrogen therapy may be associated with increased risk of breast cancer in transgender women, compared to cisgender men (SIR, 46.7; . # (SIR, 0.3; 95% CI, 0.2- 0.4). Testosterone, a gender- affirming hormone therapy that may be used by transgender men, has been shown to reduce breast glandular tissue and increase connective tissue in these individuals.. There are no prospective data on appropriate prevention and/or screening options for transgender, nonbinary, or gender diverse individuals, regardless of whether they are at average risk or hereditary risk. Therefore, recommendations for risk reduction must be made on a case- by- case basis depending on variables involved, which include age, family history, presence of a PV in relevant genes, and duration of use of gender- affirming hormone therapy. One way to approach risk reduction choices is to focus on those organs at risk based on biologic sex at birth. Specifically, organs at risk in those AFAB include the ovaries and uterus, while organs at risk in those AMAB include the prostate. Breast cancer risk should be considered elevated regardless of whether AMAB or AFAB. See the NCCN Guidelines for a complete list of cancer risk reduction strategies for transgender individuals with a hereditary risk for these cancers.. Individuals pursuing gender- affirming care should be followed at centers of excellence with access to a multidisciplinary team that understands their unique needs and provides a safe and welcoming environment. The team should include surgeons, primary care specialists, oncologists, radiologists, pathologists, endocrinologists, pediatricians, psychologists, genetic counselors, and social workers, all of whom are trained in the appropriate care of the transgender population and can address medical, psychologic, and social care needs. There is a need for formal education in the care of transgender, nonbinary, and gender diverse individuals at every level of the health care system. There is also a need for research regarding the impact of gender- affirming hormones and puberty- blocking agents and how they interact with hereditary susceptibility to cancer syndromes so that optimal prevention strategies for these populations may . # Table 1. Glossary of Relevant Genetic Terms (from the National Cancer Institute [NCI]). Autosomal dominant. Autosomal dominant dominant inheritance refers to genetic conditions that occur when a P/LP variant is present in one copy of a given gene (ie, the person is heterozygous).. Autosomal recessive. Autosomal recessiveAutosomal recessive inheritance refers to genetic conditions that occur only when P/LP variants are present in both copies of a given gene (ie, the person is homozygous for a P/LP variant, or carries two different variants of the same gene, a state referred to as compound heterozygosity).. de novo mutation. de novo mutationAn alteration in a gene that is present for the first time in one family member as a result of a P/LP variant in a germ cell (egg or sperm) of one of the parents, or a P/LP variant that arises in the fertilized egg itself during early embryogenesis. Also called new P/LP variant.. Familial. A phenotype or trait that occurs with greater frequency in a given family than in the general population; familial traits may have a genetic and/or nongenetic etiology.. Family history. Family historyThe genetic relationships within a family combined with the medical history of individual family members. When represented in diagram form using standardized symbols and terminology, it is usually referred to as a pedigree or family tree.. Founder effect. A P/LP variant observed with high frequency in a population founded by a small ancestral group that was once geographically or culturally isolated, in which one or more of the founders was a carrier of the mutant gene.. Germline. GermlineThe cells from which eggs or sperm (ie, gametes) are derived.. KindredAn extended family.. Pedigree. A graphic illustration of family history.. Penetrance. PenetranceA characteristic of a genotype; it refers to the likelihood that a clinical condition will occur when a particular genotype is present.. Proband. ProbandThe individual through whom a family with a genetic disorder is ascertained. In males this is called a propositus, and in females it is called a proposita.. Sporadic cancer. Sporadic cancerThis term has two meanings. It is sometimes used to differentiate cancers occurring in people who do not have a germline P/LP variant that confers increased susceptibility to cancer from cancers occurring in people who are known to carry a variant. Cancer developing in people who do not carry a high- risk P/LP variant is referred to as sporadic cancer. The distinction is not absolute, because genetic background may influence the likelihood of cancer even in the absence of a specific predisposing variant. Alternatively, sporadic is also sometimes used to describe cancer occurring in individuals without a family history of cancer..	None	None	None
1f4a9af6d691461ab011fa71939fe95c	2018+ACOG实践简报	妊娠期遗传性易栓症（No.197）	# ACOG PRACTICE BULLETIN Clinical Management Guidelines for Obstetrician–Gynecologists NUMBER 197 (Replaces Practice Bulletin Number 138, September 2013) Committee on Practice Bulletins–Obstetrics. This Practice Bulletin was developed by the American College of Obstetricians and Gynecologists Committee on Practice Bulletins—Obstetrics with the assistance of Torri D. Metz, MD, and Neil S. Silverman, MD. # Inherited Thrombophilias in Pregnancy Inherited thrombophilias are associated with an increased risk of venous thromboembolism and have been linked to adverse outcomes in pregnancy. However, there is limited evidence to guide screening for and management of these conditions in pregnancy. The purpose of this document is to review common thrombophilias and their association with maternal venous thromboembolism risk and adverse pregnancy outcomes, indications for screening to detect these conditions, and management options in pregnancy. This Practice Bulletin has been revised to provide additional information on recommendations for candidates for thrombophilia evaluation, updated consensus guidelines regarding the need for prophylaxis in women with an inherited thrombophilia during pregnancy and the postpartum period, and discussion of new published consensus guidelines from the Society for Obstetric Anesthesia and Perinatology addressing thromboprophylaxis and neuraxial anesthetic considerations in the obstetric population. # Background # The Hemostatic Paradox of Pregnancy Pregnancy poses a particularly complex hemostatic challenge. Successful pregnancy requires the avoidance of hemorrhage during implantation and endovascular cytotrophoblast remodeling of maternal spiral arteries. Maintaining hemostatic balance during pregnancy requires alterations in local uterine and systemic clotting, as well as anticoagulant and fibrinolytic proteins. The decidual layer of the uterus plays a crucial role in the prevention of hemorrhage during implantation, placentation, and the third stage of labor (1, 2). Confirmation of the crucial role that the decidua plays in hemostasis is demonstrated by hemorrhage associated with obstetric conditions marked by absent or impaired decidua (eg, ectopic pregnancy and placenta accreta). Conversely, decidual tissue factor also can promote the intense hypofibrinogenemia and disseminated intravascular coagulation observed in decidual hemorrhage (ie, placental abruption). Normal pregnancy physiology is marked by increased clotting potential, decreased anticoagulant activity, and decreased fibrinolysis (3–5). The thrombotic potential of pregnancy is exacerbated by venous stasis in the lower extremities due to compression of the inferior vena cava and pelvic veins by the enlarging uterus, a hormone-mediated increase in venous capacitance, insulin resistance, and hyperlipidemia. These factors contribute to the fact that venous thromboembolism (VTE) complicates approximately $0 . 5 { - } 2 . 0 $ per 1,000 pregnancies, and contributes to $9 . 2 \%$ of pregnancy-related deaths in the United States (6–12). Women who are pregnant or in the postpartum period have a fourfold to fivefold increased risk of thromboembolism compared with nonpregnant women (13, 14). The risk of recurrent VTE is increased threefold to fourfold (relative risk [RR], 3.5; $9 5 \%$ CI 1.6–7.8) in pregnant women compared with nonpregnant women, with a recurrence rate of $1 0 . 9 \%$ per patient–year during pregnancy (15). Inherited thrombophilias are associated with increased risk of VTE (Table 1), which makes detection of these mutations a logical target for prevention of the morbidity and mortality of VTE in the peripartum period. However, it is controversial whether there is an association between inherited thrombophilias and uteroplacental thrombosis that leads to adverse pregnancy outcomes such as fetal loss, preeclampsia, fetal growth restriction, and placental abruption (16). Copyright $\circledcirc$ by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. This possible association has resulted in increased screening for thrombophilias in pregnancy, including detection in extended carrier panels frequently obtained before or during pregnancy, despite the fact that empiric treatment of identified thrombophilia carriers during pregnancy has not been confirmed to confer any discrete benefit regarding pregnancy outcomes, other than thromboembolism prevention in at-risk women. # Prevalence of Common Inherited Thrombophilias Factor V Leiden The prevalence of the factor $\mathrm { v }$ Leiden mutation in European populations is approximately $5 \%$ (17, 18). In a survey of 4,047 American men and women participating in two longitudinal prospective studies, carrier Table 1. Risk of Venous Thromboembolism With Different Inherited Thrombophilias <table><tr><td></td><td>Prevalence in General Population (%)</td><td>VTE Risk Per Pregnancy (No History)(%)</td><td>VTE Risk Per Pregnancy (Previous VTE) (%)</td><td>Percentage of AII VTE</td><td></td></tr><tr><td>Factor V Leiden</td><td>1-15</td><td>0.5-3.1</td><td>10</td><td>40</td><td>References 1-4, 11, 12</td></tr><tr><td>heterozygote Factor V Leiden</td><td><1</td><td>2.2-14.0</td><td>17</td><td>2</td><td>1-4, 11, 12</td></tr><tr><td>homozygote Prothrombin gene heterozygote</td><td>2-5</td><td>0.4-2.6</td><td>>10</td><td>17</td><td>1-4, 11, 12</td></tr><tr><td>Prothrombin gene homozygote</td><td><1</td><td>2-4</td><td>>17</td><td>0.5</td><td>1-4, 11, 12</td></tr><tr><td>Factor V Leiden/ prothrombin double</td><td>0.01</td><td>4-8.2</td><td>>20</td><td>1-3</td><td>1-4, 12</td></tr><tr><td>heterozygote Antithrombin deficiency</td><td>0.02</td><td>0.2-11.6</td><td>40</td><td>1</td><td>1, 5, 6, 11, 12</td></tr><tr><td>Protein C deficiency</td><td>0.2-0.4</td><td>0.1-1.7</td><td>4-17</td><td>14</td><td>1, 5, 7, 11, 12</td></tr><tr><td>Protein S deficiency</td><td>0.03-0.13</td><td>0.3-6.6</td><td>0-22</td><td>3</td><td>1, 8-12</td></tr></table> Abbreviation: VTE, venous thromboembolism. 1. Franco RF, Reitsma PH. Genetic risk factors of venous thrombosis. Hum Genet 2001;109:369–84. 2. Gerhardt A, Scharf RE, Beckmann MW, Struve S, Bender HG, Pillny M, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000;342:374–80. 3. Zotz RB, Gerhardt A, Scharf RE. Inherited thrombophilia and gestational venous thromboembolism. Best Pract Res Clin Haematol 2003;16:243–59. 4. Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen. Thromb Haemost 1995;73:151–61. 5. Friederich PW, Sanson BJ, Simioni P, Zanardi S, Huisman MV, Kindt I, et al. Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: implications for prophylaxis [published erratum appears in Ann Intern Med 1997;127:1138]. Ann Intern Med 1996;125:955–60. 6. Vossen CY, Preston FE, Conard J, Fontcuberta J, Makris M, van der Meer FJ, et al. Hereditary thrombophilia and fetal loss: a prospective follow-up study. J Thromb Haemost 2004;2:592–6. 7. Paidas MJ, Ku DH, Lee MJ, Manish S, Thurston A, Lockwood CJ, et al. Protein Z, protein S levels are lower in patients with thrombophilia and subsequent pregnancy complications. J Thromb Haemost 2005;3:497–501. 8. Dykes AC, Walker ID, McMahon AD, Islam SI, Tait RC. A study of Protein S antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state. Br J Haematol 2001;113:636–41. 9. Goodwin AJ, Rosendaal FR, Kottke-Marchant K, Bovill EG. A review of the technical, diagnostic, and epidemiologic considerations for protein S assays. Arch Pathol Lab Med 2002;126:1349–66. 10. Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines. Chest 2012;141:e691S–736S. 11. Gerhardt A, Scharf RE, Greer IA, Zotz RB. Hereditary risk factors for thrombophilia and probability of venous thromboembolism during pregnancy and the puerperium. Blood 2016;128:2343–9. 12. Rheaume M, Weber F, Durand M, Mahone M. Pregnancy-related venous thromboembolism risk in asymptomatic women with antithrombin deficiency: a systematic review. Obstet Gynecol 2016;127:649–56. ![](images/0a94e2d74f04a584c11ed47192e80ac08858617a6d4812ec05b3492975ac1174.jpg) Copyright $\circledcirc$ by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. frequencies of factor $\mathrm { v }$ Leiden mutation in different racial and ethnic groups were as follows: Caucasians $( 5 . 2 7 \%$ ; $9 5 \%$ CI $4 . 4 2 \substack { - 6 . 2 2 \% } )$ , Hispanic Americans $( 2 . 2 1 \% )$ , African Americans $( 1 . 2 3 \% )$ , Asian Americans $( 0 . 4 5 \% )$ , and Native Americans $( 1 . 2 5 \% )$ (17). The mutation renders factor $\mathrm { v }$ Leiden refractory to proteolysis by activated protein C. Women who are heterozygous for factor V Leiden have been observed to account for approximately $40 \%$ of cases of VTE during pregnancy. Although the risk of VTE among pregnant women who are heterozygous for factor V Leiden without a personal history of VTE or an affected first-degree relative with a thrombotic episode before age 50 years is increased above the baseline pregnancy risk, it is estimated to be no more than 5–12/1,000 deliveries (19–21). In contrast, this risk increases to up to $10 \%$ among pregnant women heterozygous for the factor V Leiden mutation with a personal history of VTE (20–22). A woman who is heterozygous for factor V Leiden with only an affected firstdegree relative but with no personal history of VTE only has a slightly higher risk of VTE during pregnancy (15/ 1,000 deliveries) than that conferred by her thrombophilia alone (20, 21). Pregnant women who are homozygous for factor V Leiden without a personal history of VTE or an affected first-degree relative have a $1- 2 \%$ risk for VTE, whereas those with such a history have a $17 \%$ risk (20). # Prothrombin G20210A The prothrombin G20210A mutation is a point mutation that results in elevated circulating prothrombin levels (18). The prothrombin G20210A mutation is present in approximately $3 \%$ of the European population, and it has been reported to account for $17 \%$ of cases of VTE in pregnancy (19). In a systematic review, North Americans were noted to have a prevalence of prothrombin gene mutation of $3 . 6 \%$ in Caucasians, $3 . 5 \%$ in Hispanics, $0 { - } 1 . 7 \%$ in African Americans, and $0 { - } 0 . 6 \%$ in American Indians (23). The carrier rate in this study was $0 \%$ for Asians living in Japan, Singapore, China, Oman, South Korea, and India (23). As with factor V Leiden, a personal history of VTE increases the risk of VTE in pregnancy for carriers of the prothrombin gene mutation. Without such a history, heterozygous carriers of the prothrombin G20210A mutation have a less than $1 \%$ risk of VTE during pregnancy. For a carrier with a personal history of VTE, the risk increases to at least $10 \%$ (19, 21). Also, as with factor V Leiden, heterozygous prothrombin gene mutation carriers without a personal history of VTE have only a slight increase in risk during pregnancy if an affected first-degree relative exists (21). Pregnant women who are homozygous for the prothrombin G20210A mutation without a personal or positive family history have a $2 \mathrm {- } 3 \%$ increased risk of VTE in pregnancy. The combination of factor V Leiden and prothrombin G20210A mutations has synergistic hypercoagulable effects. Although present in only 1 per 10,000 patients, women who are heterozygous for factor V Leiden and prothrombin G20210A mutations have a $4- 5 \%$ risk of VTE even without a personal or positive family history (19, 20). ![](images/33931b63ed4f7d99d2b4f48b5f2560f31ed8612e9036b40548df705907cc6a17.jpg) # Protein C Deficiency Protein C deficiency has been linked to more than 160 distinct mutations that produce a highly variable phenotype (18). Levels of protein C vary even among individuals with known familial mutations (24), which results in a lack of clarity regarding an appropriate lower limit of normal for protein C levels. The prevalence of protein C deficiency is dependent on the cutoff used. In one study, protein C levels of $3 1 - 5 1 \%$ were found in $0 . 2 \%$ of blood donors; all of these individuals were heterozygous for protein C gene mutations (25). However, many laboratories consider a result of less than $65 \%$ to be abnormal (26). Protein C levels of $5 5 \mathrm { - } 6 5 \%$ were found in $1 . 5 \%$ of blood donors consistent with either heterozygosity for a gene mutation or low normal results (25). Consultation with a hematologist may be helpful in interpreting an abnormal protein C result. The risk of VTE in pregnancy among typical protein C deficient patients with a personal or family history of VTE has been reported to be $2 \mathrm {- } 8 \%$ (27–29). In pooled estimates, the absolute risk of pregnancy-related VTE in women with protein C deficiency and no family history is $0 . 7 \%$ $9 5 \%$ CI $0 . 3 \mathrm { - } 1 . 5 \% )$ ) (21). The absolute risk increases to an estimated $1 . 7 \%$ $5 \% \mathrm { ~ C ~ I ~ } 0 . 4 { - 8 . 9 \% } )$ in familial studies with a confirmed proband with protein C deficiency and symptomatic VTE (21). Differences in the prevalence of protein C deficiency by racial or ethnic group are not delineated. Although rare, newborns who are homozygous for protein C deficiency may develop neonatal purpura fulminans, a rare life-threatening condition characterized by disseminated intravascular coagulation and hemorrhagic skin necrosis, and will require lifetime anticoagulation therapy (30). # Protein S Deficiency Protein S deficiency generally has two causes, a silenced gene or a mutation that results in reduced free protein S antigen levels and activity (18). The prevalence of protein S deficiency in the general population remains unknown. Among patients with a history of VTE in the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis case–control study, $0 . 9 \%$ had protein S deficiency below the level thought to be associated with VTE (31). Detection of protein S deficiency using activity assays alone is subject to substantial variability because of fluctuating levels of protein S binding protein in pregnancy (32). Therefore, screening in nonpregnant women is more reliable, and planned testing should be deferred until remote from a recent birth Copyright $\circledcirc$ by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. or miscarriage to allow for return to normal protein S levels. Among those with a positive family history and documented protein S deficiency, the risk of VTE in pregnancy has been reported to be $5 - 7 \%$ (29, 33). As with protein C deficiency, homozygous protein S deficiency may result in neonatal purpura fulminans (30). # Antithrombin Deficiency Antithrombin deficiency is highly thrombogenic but rare. The more than 250 associated mutations can decrease gene transcription, leading to reductions in antigen level and activity, or alter structure and function, leading to normal antigen levels but decreased activity (18). The very rare homozygous state is associated with little or no antithrombin activity. The prevalence of heterozygous antithrombin deficiency is approximately 1 per 2,500 members of the general population. Differences in the prevalence of antithrombin deficiency by racial or ethnic group are not known. In nonpregnant patients, the risk of VTE among antithrombindeficient patients is increased more than 25-fold. Hemostatic changes of pregnancy, including a decrease in antithrombin levels, may increase the thrombogenic potential of inherited antithrombin deficiency (28, 33). However, the absolute risk is lower in the absence of a positive personal or family history of thromboembolism (20). Similarly, the degree of risk is dependent on the antithrombin level. More severe deficiencies are associated with higher risk of VTE (20). Among women with no prior VTE and a mild antithrombin deficiency (activity between $70 \%$ and $8 5 \%$ ), the risk of thromboembolism in pregnancy ranges from $0 . 2 \%$ to $0 . 4 \%$ . In contrast, among pregnant women with known familial thrombophilia, a history of thromboembolism, and severe antithrombin deficiency (less than $60 \%$ activity), the risk may be as high as $40 \%$ (20). A systematic review of the effect of asymptomatic (with a family history but no personal history of thrombosis) antithrombin deficiency on the risk of VTE in women who are pregnant or in the postpartum period, pooled results from four case–control studies resulting in an estimated odds ratio of 6.09 $9 5 \%$ CI, 1.58–23.43) for thrombosis (34). The pooled estimate is based on 265 cases of thrombosis and 591 controls. In the same systematic review, three cohort studies were identified; however, these could not be pooled because of recurrent pregnancies among the same women. In the cohort studies, the overall incidence of VTE was $1 1 . 6 \%$ $9 5 \%$ CI, $6 . 3 \mathrm { - } 1 9 . 0 \% )$ among asymptomatic antithrombin-deficient patients during pregnancy or the postpartum period, which supports the classification of antithrombin deficiency as a high-risk thrombophilia. A separate Bayesian meta-analysis similarly found an absolute risk of VTE of $7 . 3 \%$ antepartum $9 5 \%$ credible interval $1 . 8 \%$ $1 5 . 6 \% )$ ) and $1 1 . 1 \%$ postpartum $9 5 \%$ credible interval $3 . 7 \% - 2 1 . 0 \% )$ in women with antithrombin deficiency (29). # Methylenetetrahydrofolate Reductase Mutations There is insufficient evidence to support assessment of methylenetetrahydrofolate reductase (MTHFR) polymorphisms or measurement of fasting homocysteine levels in the evaluation of a thrombophilic etiology for VTE. Homozygosity for the MTHFR gene mutation is the most common cause of hyperhomocysteinemia. Homozygosity for the MTHFR C677T and A1298C polymorphisms is present in $1 0 { - } 1 6 \%$ and $4- 6 \%$ of all Europeans, respectively (35). However, MTHFR mutations by themselves do not appear to convey an increased risk of VTE in either nonpregnant (36) or pregnant women (37). Although hyperhomocysteinemia was previously reported to be a modest risk factor of VTE (38, 39), data indicate that elevated homocysteine levels are a weak risk factor of VTE (40). This observation may reflect the folate-replete diet of developed nations, including folate supplementation of flour in the United States. Moreover, intervention studies with vitamin B supplementation in nonpregnant patients show no reduction in VTE (41, 42). # Other Thrombophilias A variety of other thrombophilias have been described, including alternative mutations in the factor $\mathrm { v }$ gene, a promoter mutation in the PAI-1 gene, protein $\textsf { Z }$ deficiency, and activity-enhancing mutations in various clotting factor genes. Although they appear to exert little independent risk of VTE, they may exacerbate risk among patients with the aforementioned mutations. However, there is insufficient evidence to recommend testing for these thrombophilias even in the setting of diagnosed VTE. # Inherited Thrombophilias and Adverse Pregnancy Outcomes A definitive causal link cannot be made between inherited thrombophilias and adverse pregnancy outcomes. Most of the available studies are small case– control and cohort studies assembled in heterogeneous populations, are frequently contradictory, and display potential reporting biases (43–45). Larger prospective cohort studies completed by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network and Stillbirth Collaborative Research Network demonstrate no or weak associations between inherited thrombophilias and adverse pregnancy outcomes (46–48). # Fetal Loss There are inconsistent associations between any inherited thrombophilias and recurrent pregnancy loss or stillbirth. Whereas meta-analyses and a retrospective cohort study Copyright $\circledcirc$ by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. ![](images/23627f0fb528d23ca8df44cd797ba91ba5b538482e3fcb6c9fbd523023f6616f.jpg) have revealed an association between inherited thrombophilias and first-trimester pregnancy loss (49–54), prospective cohort studies have found no association between inherited thrombophilias and fetal loss. The Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network tested low-risk women with a singleton pregnancy less than 14 weeks of gestation and found no increase in the incidence of fetal loss among women heterozygous for factor V Leiden (46). Similar findings of no increased risk of fetal loss were noted for maternal carriers of the prothrombin G20210A gene mutation (47). Recent meta-analyses demonstrated no benefit of treatment with a prophylactic dose of low-molecular-weight heparin to improve the rates of live birth in women with an inherited thrombophilia and a history of pregnancy loss when compared with no treatment or aspirin alone (55, 56). A Cochrane review also concluded that there is insufficient evidence to support the use of anticoagulants (aspirin or low-molecular-weight heparin) in women with recurrent pregnancy loss and an inherited thrombophilia, and advocated for randomized controlled trials to address this question (57). Regarding fetal death later in pregnancy, the Stillbirth Collaborative Research Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development conducted a secondary analysis of their prospective population-based case–control study, which demonstrated no association between stillbirth and either prothrombin or MTHFR mutations (48). There was, however, a weak association between maternal homozygous factor V Leiden mutation and stillbirth, with 2/405 women with antepartum stillbirths who were homozygous for factor V. The authors concluded that there is insufficient evidence to screen for inherited thrombophilia in the setting of stillbirth. # Preeclampsia There is insufficient evidence to conclude that inherited thrombophilias are associated with an increased occurrence of preeclampsia. Some clinical studies have reported a link between factor $\mathrm { v }$ Leiden and preeclampsia, severe preeclampsia, and preeclampsia before 37 weeks of gestation (58, 59). However, multiple other case–control studies have failed to demonstrate an association between factor V Leiden mutation and preeclampsia (46,60–63). Meta-analyses yield conflicting results dependent upon the type of studies analyzed. Two meta-analyses of case– control studies found an association between factor V Leiden mutation and preeclampsia. One meta-analysis that included 31 studies with 7,522 patients found an association between factor $\mathrm { v }$ Leiden mutation and preeclampsia (pooled odds ratio [OR], 1.81; $9 5 \%$ CI, 1.14–2.87) (64). Another metaanalysis similarly found an association with preeclampsia when including 37 studies with 5,048 preeclampsia patients (pooled OR, 1.60; $9 5 \%$ CI, 1.28–2.00) (65). In both of these meta-analyses women who were heterozygous and homozygous for the gene mutations were analyzed together. In contrast, a 2016 systematic review and metaanalysis of 10 prospective cohort studies with 21,833 patients to evaluate the association between either factor V Leiden or prothrombin gene mutation and preeclampsia found no association between factor $\mathrm { v }$ Leiden and preeclampsia (pooled OR, 1.23; $9 5 \%$ CI, 0.89–1.70) (66). Similarly, a recent prospective cohort study of 7,343 unselected women failed to demonstrate an association between heterozygosity for factor V Leiden or prothrombin gene mutation and a composite adverse outcome of preeclampsia, pregnancy loss, placental abruption or small for gestational age (less than 10th percentile) (45). Multiple studies also have failed to establish a link between prothrombin G20210A mutation and either preeclampsia or severe preeclampsia (46, 47, 62, 64, 67, 68). However, a 2014 meta-analysis did find an association between prothrombin gene mutation and preeclampsia (pooled OR, 1.81; $9 5 \%$ CI, 1.25–2.63), which is in contrast to the findings of another 2014 study in an unselected population in which no association was noted (45, 65). Although several meta-analyses have suggested an association between protein C and protein S deficiency and preeclampsia, the conclusions are based on a small number of studies with small numbers of participants (69). # Fetal Growth Restriction Multiple case–control, cohort, and systematic review studies have failed to detect a significant association between factor V Leiden and fetal growth restriction less than the 10th percentile or less than the 5th percentile (58, 62, 70). A similar lack of association was noted between prothrombin G20210A mutation and fetal growth restriction (47, 71, 72). A case–control study among 493 newborns with fetal growth restriction and 472 matched controls found no association between fetal growth restriction and factor V Leiden, prothrombin G20210A mutation, or MTHFR mutations (73). # Placental Abruption Overall, there is insufficient evidence to establish a link between thrombophilias and placental abruption. Prospective cohort analyses of factor V Leiden, prothrombin G20210A, and pregnancy outcome found no association with placental abruption (46, 47). However, a meta-analysis of case–control studies reported an association between placental abruption and both homozygosity and heterozygosity for the factor V Leiden mutation and a link between prothrombin G20210A mutation heterozygosity and placental abruption (69). The Hordaland Homocysteine Study found an association between placental abruption and hyperhomocysteinemia greater than 15 micromol/L (74), but minimal association Copyright $\circledcirc$ by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. ![](images/f9d3d9d669f16234378f52bddb048ed39d6b4e4ddb3ba0996e209698238d27cc.jpg) between homozygosity for the MTHFR C677T polymorphism and placental abruption (75). # Anticoagulation for Prevention of Adverse Pregnancy Outcomes There is insufficient evidence to recommend anticoagulation as an intervention to prevent adverse pregnancy outcomes among women with inherited thrombophilias. Prior studies focus predominantly on anticoagulation as a strategy for prevention of placenta-mediated adverse outcomes. A recent meta-analysis of individual patientlevel data from eight randomized trials assessed the effect of low-molecular-weight heparin on prevention of adverse pregnancy outcomes. Of the women included in the meta-analysis, $42 \%$ (403/963) had a thrombophilia (76). Eligible women were those who were currently pregnant and had a history of adverse pregnancy outcomes. Overall, low-molecular-weight heparin did not reduce the rate of recurrent placenta-mediated pregnancy complications including small for gestational age (less than 5th percentile), pregnancy loss at or after 20 weeks of gestation, early onset (less than 34 weeks of gestation) preeclampsia or preeclampsia with severe features, or placental abruption leading to delivery when compared with placebo. Two randomized trials included in this meta-analysis enrolled only women with a thrombophilia (77, 78). In the Thrombophilia in Pregnancy Prophylaxis trial there was no reduction in adverse pregnancy outcome with low-molecular-weight heparin compared with placebo (risk difference, $1 . 8 \%$ ; $9 5 \%$ CI, $1 0 . 6 \%$ to $7 . 1 \%$ in intention-to-treat analysis) (77). However, in another randomized controlled trial there was a reduction in risk of adverse pregnancy outcome when administering lowmolecular-weight heparin versus placebo among women with a thrombophilia and a history of delivery before 34 weeks of gestation with hypertensive disease, or smallfor-gestational-age infants, or both (risk difference, $8 . 7 \%$ ; $9 5 \%$ CI, $1 . 9 \mathrm { - } 1 5 . 5 \% \rangle$ (78). Given the inconsistency in findings, and lack of effect in the meta-analysis, anticoagulation is not recommended for prevention of adverse pregnancy outcomes. Further research may delineate subgroups of women with a thrombophilia in which anticoagulation may be beneficial. # Clinical Considerations and Recommendations Who are candidates for thrombophilia evaluation? Screening for inherited thrombophilias is useful only when results will affect management decisions, and it is not useful in situations in which treatment is indicated for other risk factors (79). Targeted assessment for inherited thrombophilia may be considered in the following clinical scenarios: A personal history of VTE, with or without a recurrent risk factor, and no prior thrombophilia testing. In a population-based study, the recurrence risk of VTE in untreated pregnant women differed based on whether the prior embolism was associated with a recurrent (eg, pregnancy, estrogen containing contraceptives) or nonrecurrent (eg, fractures, surgery, prolonged immobilization) risk factor ( $4 . 5 \%$ versus $2 . 7 \%$ ; RR, 1.71; $9 5 \%$ CI, 1.0–2.8) (21). Inherited thrombophilia increases this risk to varying degrees dependent on the type of thrombophilia (Table 1). A first-degree relative (eg, parent or sibling) with a history of high-risk inherited thrombophilia. In this setting, targeted testing for the known thrombophilia can be considered if testing will influence management. In other situations, thrombophilia testing is not routinely recommended. Specifically, screening for inherited thrombophilias is not recommended for women with a history of fetal loss or adverse pregnancy outcomes including abruption, preeclampsia, or fetal growth restriction because there is insufficient clinical evidence that antepartum prophylaxis with unfractionated heparin or low-molecular-weight-heparin prevents recurrence in these patients, and a causal association has not been established (57). Although testing for inherited thrombophilias is not recommended, testing for the acquired antibodies present in antiphospholipid syndrome should be considered in the setting of recurrent pregnancy loss or stillbirth (80). # What laboratory tests are recommended for thrombophilia screening among women with personal histories of venous thromboembolism and no prior thrombophilia testing? Among women with personal histories of VTE, recommended screening tests for inherited thrombophilias should include factor V Leiden mutation; prothrombin G20210A mutation; and antithrombin, protein S, and protein C deficiencies (Table 2). Thrombophilia screening also includes testing for acquired thrombophilia with antiphospholipid antibodies (80). Whenever possible, laboratory testing should be performed remote (after 6 weeks) from the thrombotic event and while the patient is not pregnant and not taking anticoagulation or hormonal therapy. Ideally, protein S deficiency should be assessed initially by performing a functional assay remote from Copyright $\circledcirc$ by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. pregnancy. A value less than $5 5 \%$ should be followed up by assessing free protein S levels. In the nonpregnant state, a free protein S antigen value less than $55 \%$ is consistent with protein S deficiency. In pregnancy, it is unclear what protein S activity value is diagnostic, but free protein S cutoffs of less than $30 \%$ and less than $24 \%$ may be used in the second and third trimesters, respectively (4). Because of the lack of association between either heterozygosity or homozygosity for the MTHFR C677T polymorphism and any negative pregnancy outcomes, including any increased risk of VTE (43, 81), screening with either MTHFR mutation analyses or fasting homocysteine levels is not recommended. # In which patients should anticoagulants be considered to prevent venous thromboembolism? All patients with inherited thrombophilias should undergo individualized risk assessment, which may modify management decisions regarding VTE prevention. Risk assessment algorithms exist to evaluate whether women who are pregnant or in the postpartum period with inherited thrombophilias could benefit from anticoagulants to prevent VTE (82, 83). The decision to use anticoagulants in women with inherited thrombophilias is influenced by personal history of VTE, severity of inherited thrombophilia (Table 3), family history of VTE, and additional risk factors such as cesarean delivery, obesity, and prolonged immobility (21, 82, 83). There is poor consensus among existing guidelines as to what should be classified as a “high-risk” or “lowrisk” thrombophilia (21, 82, 83). Overall recommendations are limited by the quality of existing evidence with a high reliance on case–control studies. In an effort to provide clinical guidance in the setting of contradictory national guidelines, a group of experts formed an Anticoagulation Forum and produced a consensus statement regarding the need for prophylaxis in women with an inherited thrombophilia during pregnancy and the postpartum period (84). These authors recommended prophylaxis if the risk of VTE was $3 \%$ or greater. Notably, this threshold was determined by consensus opinion, and significantly affected the recommendations. The degree of acceptable risk likely differs for individual patients and requires a discussion of the risks and benefits of anticoagulation in each unique clinical scenario. A 2017 meta-analysis of 36 studies found that the absolute risk of VTE exceeded $3 \%$ only for women with antithrombin, protein C, and protein S deficiencies, or homozygosity for factor V Leiden (29). The absolute risk of thromboembolism in women who are homozygous for the prothrombin gene mutation could not be assessed with the available studies. Notably all women with antithrombin, protein C, and protein S deficiency included in this meta-analysis also had a family history of VTE, which is an additional risk factor for VTE. Existing guidelines vary regarding the classification of antithrombin, protein C, and protein S deficiency as low-risk or high-risk thrombophilias. Family history of thromboembolism increases the risk of thromboembolism in pregnancy and may have contributed to the observed increased absolute risk of thromboembolism in this meta-analysis. Table 2. How to Test for Inherited Thrombophilias <table><tr><td></td><td>Testing Method</td><td>Is Testing Reliable During Pregnancy?</td><td>Is Testing Reliable During Acute Thrombosis?</td><td>Is Testing Reliable With Anti- coagulation?</td></tr><tr><td>Thrombophilia Factor V Leiden mutation</td><td>Activated protein C resistance assay (second</td><td>Yes</td><td>Yes</td><td>No</td></tr><tr><td></td><td>generation) If abnormal: DNA analysis</td><td>Yes</td><td>Yes</td><td>Yes</td></tr><tr><td>Prothrombin G20210A mutation</td><td>DNA analysis</td><td>Yes</td><td>Yes</td><td>Yes</td></tr><tr><td>Protein C deficiency</td><td>Protein C activity (<65%)</td><td>Yes</td><td>No</td><td>No</td></tr><tr><td>Protein S deficiency</td><td>Functional assay (<55%)</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Antithrombin deficiency</td><td>Antithrombin activity (<60%)</td><td>Yes</td><td>No</td><td>No</td></tr></table> \If screening in pregnancy is necessary, cutoff values for free protein S antigen levels in the second and third trimesters have been identified at less than $3 0 \%$ and less than $2 4 \%$ , respectively. Copyright $\circledcirc$ by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. ![](images/93dc434a33a4706855e787c7483d60c69cf5bd72c4173f50b5ebb54e8f70f517.jpg) Table 3. Recommended Thromboprophylaxis for Pregnancies Complicated by Inherited Thrombophilias\* <table><tr><td>Clinical Scenario</td><td>Antepartum Management</td><td>Postpartum Management</td></tr><tr><td>Low-risk thrombophiliat without previous VTE</td><td>Surveillance without anticoagulation therapy</td><td>Surveillance without anticoagulation therapy or postpartum prophylactic anticoagulation therapy if the patient has additional risks factorst</td></tr><tr><td>Low-risk thrombophiliat with a family history (first-degree relative) of VTE</td><td>Surveillance without anticoagulation therapy or prophylactic LMWH/UFH</td><td>Postpartum prophylactic anticoagulation therapy or intermediate-dose LMWH/UFH</td></tr><tr><td>Low-risk thrombophiliat with a single previous episode of VTE-Not receiving long-term anticoagulation therapy</td><td>Prophylactic_ or intermediate- dose LMWH/UFH</td><td>Postpartum prophylactic anticoagulation therapy or intermediate-dose LMWH/UFH</td></tr><tr><td>High-risk thrombophilias without previous VTE</td><td>Prophylactic_ or intermediate- dose LMWH/UFH</td><td>Postpartum prophylactic anticoagulation therapy or intermediate-dose LMWH/UFH</td></tr><tr><td>High-risk thrombophilia§ with a single previous episode of VTE or an affected dose, or adjusted-dose first-degree relative-Not receiving long-termanticoagulation therapy</td><td>Prophylactic,intermediate- LMWH/UFH</td><td>Postpartum prophylactic anticoagulation therapy, or intermediate or adjusted-dose LMWH/ UFH for 6 weeks (therapy level should be equal to the selected antepartum</td></tr><tr><td>Thrombophilia with two or more episodes of VTE-Not receiving long- term anticoagulation therapy</td><td>Intermediate-dose or adjusted-dose LMWH/UFH</td><td>treatment) Postpartum anticoagulation therapy with intermediate-dose or adjusted- dose LMWH/UFH for6weeks (therapy level should be equal to the selected</td></tr><tr><td>Thrombophilia with two_or more episodes of VTE-Receiving long-term anticoagulation therapy</td><td>Adjusted-dose LMWH/UFH</td><td>antepartum treatment) Resumption of long-term anticoagulation therapy. Oral anticoagulants may be considered postpartum based upon planned duration of therapy, lactation,and patient preference.</td></tr></table> Abbreviations: LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; VTE, venous thromboembolism. \Postpartum treatment levels should be equal to antepartum treatment. †Low-risk thrombophilia: factor V Leiden heterozygous; prothrombin G20210A heterozygous; protein C or protein S deficiency. z First-degree relative with a history of a thrombotic episode or other major thrombotic risk factors (eg, obesity, prolonged immobility, cesarean delivery). §High-risk thrombophilias include factor V Leiden homozygosity, prothrombin gene G20210A mutation homozygosity, heterozygosity for factor V Leiden and prothrombin G20210A mutation, or antithrombin deficiency. Even in the absence of other risk factors, women who are known to be homozygous for the factor V Leiden mutation or prothrombin gene mutation should receive pharmacologic prophylaxis during pregnancy and the postpartum period given the high risk of VTE (21). Similarly, based on National Partnership for Maternal Safety recommendations, women with antithrombin deficiency and women who are heterozygous for factor V and the prothrombin gene mutation are considered high risk of VTE and should receive pharmacologic prophylaxis in the absence of other risk factors (83). Decision-making regarding the need for pharmacologic prophylaxis for other lower risk thrombophilias (factor V Leiden heterozygous, prothrombin G20210A heterozygous, protein C or S deficiency) is based on the presence or absence of other risk factors and can be made in a multidisciplinary fashion with involvement of maternal–fetal medicine subspecialists or hematologists. Treatment recommendations are listed in Table 3. ![](images/6de3b4089eb3283edd6bce54fe767d1ce4b4b1c4702c17a4372c29d7af3cb654.jpg) Women deemed to require pharmacologic prophylaxis during pregnancy will typically continue anticoagulation for at least 6 weeks postpartum (82). Women with recurrent VTE events or other indications for life-long full anticoagulation should receive adjusted-dose low-molecularweight heparin throughout pregnancy with transition back to maintenance anticoagulation postpartum (21). Copyright $\circledcirc$ by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. # What anticoagulant regimens are available for pregnant women? Neither low-molecular-weight heparin nor unfractionated heparin cross the placenta, and both can be used in pregnancy. Vitamin K antagonists should be avoided in pregnancy with the possible exception of prevention of thromboembolism in women with a mechanical heart valve (85–87). Low-molecularweight heparin is preferred over unfractionated heparin given its longer half-life, more predictable dose response, and improved maternal safety profile (21, 88, 89). Dosage is based on the severity of thrombophilia (Table 3) and may be influenced by the presence of other risk factors for VTE (obesity, cesarean delivery, family history, history of VTE). Prophylactic, intermediate, and adjusted-dose (therapeutic) anticoagulant regimens are in Table 4. In addition, antithrombin concentrates can be used in antithrombin-deficient patients who are refractory to standard anticoagulant therapy or as part of a multidisciplinary plan for prophylaxis or treatment of VTE (90, 91). The increased risk of VTE in pregnancy is present from the first trimester (92, 93). Therefore, initiation of anticoagulant regimens should occur upon confirmation of a viable pregnancy, or as early in pregnancy as possible (82). Maternal weight will be used to calculate a dose of low-molecular-weight heparin in adjusted-dose regimens. However, there is insufficient evidence to recommend changing the dose based on weight when using prophylactic regimens. Similarly, routine assessment of anti-Xa levels in the setting of prophylactic anticoagulation is not recommended (21), and decisions regarding prophylactic dosage can be made on a case-by-case basis. For women requiring adjusted-dose anticoagulation, an initial dose can be calculated based on maternal weight (Table 4) with a goal anti-Xa level of $0 . 6 { - } 1 . 0$ units/mL 4 hours after injection (21). The need to perform routine anti-Xa levels is controversial even in the setting of adjusted-dose therapy. Because dose adjustment during pregnancy has not been shown to increase the safety or efficacy of low-molecular-weight heparin, serial assessment of anti-Xa levels is largely unnecessary (21) but can be considered on a case-by-case basis. If using unfractionated heparin to achieve therapeutic anticoagulation, mid-interval activated partial thromboplastin time (aPTT) levels should be checked in order to ensure therapeutic dosage (21). Consultation with a maternal– fetal medicine subspecialist or hematologist may be helpful in tailoring the anticoagulation plan. Almost all women who require antepartum anticoagulation will be continued on therapy postpartum (Table 3). Some women who require anticoagulation beyond 6 weeks postpartum will be transitioned to warfarin after delivery. Unfractionated heparin, lowmolecular-weight heparin, and warfarin are compatible with breastfeeding (94–96). Oral direct thrombin inhibitors (dabigatran) and antiXa inhibitors (rivaroxaban, apixaban) should be avoided in pregnancy and lactation because there are insufficient data to evaluate safety for the woman, fetus, and breastfeeding neonate (84). # What is appropriate peripartum management for thrombophilic patients? The presence of a thrombophilia alone is not an indication for induction outside of standard obstetric indications. However, induction of labor at term can be used for timing of discontinuation of anticoagulation to facilitate neuraxial anesthesia if desired. The plan for delivery should take into account a discussion with the patient about avoiding an unwanted coagulation effect during delivery and options for analgesia or anesthesia before delivery. The Society for Obstetric Anesthesia and Perinatology (SOAP) has published consensus guidelines addressing thromboprophylaxis and neuraxial anesthetic considerations specifically in the obstetric population (97). In addition to making specific management recommendations, they recommend that every unit have a protocol for when pregnant women and women in the postpartum period should have anticoagulant medications held and when women receiving thromboprophylaxis are eligible for neuraxial anesthesia. In general, adjusted-dose low-molecular-weight heparin should be held for 24 hours, and prophylactic lowmolecular-weight heparin for 12 hours before induction of labor to facilitate neuraxial anesthesia placement (97). Alternatively, consideration can be given to substituting a comparable dose of unfractionated heparin as delivery approaches because its shorter half-life may improve the likelihood that the patient will be a candidate for neuraxial anesthesia during labor and delivery. However, similar to the interval from last dose for prophylactic low-molecular-weight heparin, SOAP guidelines recommend a 12-hour interval from last dose of unfractionated heparin if the dose is more than 7,500 units, in addition to laboratory testing to verify normal aPTT (97). Ultimately, the goal is to optimize appropriate anticoagulation for the patient while still allowing neuraxial anesthesia when desired. The use of sequential compression devices should be considered for patients with a known thrombophilia intrapartum and until they are fully ambulatory postpartum (83). All women undergoing cesarean delivery should have sequential Copyright $\circledcirc$ by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. ![](images/2c9a50a015b93ca3831de5892458a50352f6b9bd99bb27e1fbe74da6fe58a54b.jpg) Table 4. Anticoagulation Regimen Definitions <table><tr><td> Anticoagulation Regimen</td><td> Anticoagulation Dosage</td></tr><tr><td>Prophylactic LMWH</td><td>Enoxaparin, 40 mg SC once daily Dalteparin, 5,0o0 units SC once daily Tinzaparin, 4,500 units SC once daily</td></tr><tr><td>Intermediate-dose LMWH</td><td>Nadroparin 2,850 units SC once daily Enoxaparin 40 mg SC every 12 hours</td></tr><tr><td>Adjusted-dose (therapeutic) LMWHt</td><td>Dalteparin 5,000 units SC every 12 hours Enoxaparin,1mg/kg every 12 hours Dalteparin, 200 units/kg once daily Tinzaparin,175 units/kg once daily</td></tr><tr><td>Prophylactic UFH</td><td>Dalteparin, 100 units/kg every 12 hours Target an anti-Xa level in the therapeutic range of O.6-1.0 units/ mL 4 hours after last injection for twice-daily regimen; slightly higher doses may be needed for a once-daily regimen. UFH,5,000-7,500 units SC every 12 hours in first trimester</td></tr><tr><td>Adjusted-dose (therapeutic) UFHt</td><td>UFH,7,500-10,000 units SC every 12 hours in the second trimester UFH,10,0o0 units SC every 12 hours in the third trimester,unless the aPTT is elevated</td></tr><tr><td>Postpartum anticoagulation</td><td>UFH, 10,000 units or more SC every 12 hours in doses adjusted to target aPTT in the therapeutic range (1.5-2.5 X control) 6 hours after injection Prophylactic, intermediate, or adjusted dose LMWH for 6-8</td></tr><tr><td>Surveillance</td><td>weeks as indicated. Oral anticoagulants may be considered postpartum based upon planned duration of therapy, lactation, and patient preference.</td></tr><tr><td></td><td>Clinical vigilance and appropriate objective investigation of women with symptoms_suspicious of deep vein thrombosis or pulmonary embolism. VTE risk assessment should be performed prepregnancy or early in pregnancy and repeated if complications develop,particularly those necessitating hospitalization/</td></tr></table> Abbreviations: aPTT, activated partial thromboplastin time; INR, international normalized ratio; LMWH, low-molecular-weight heparin; SC, subcutaneously; UFH, unfractionated heparin; VTE, venous thromboembolism. \* Although at extremes of body weight, modification of dose may be required. †Also referred to as weight-adjusted, full treatment dose. compression devices at a minimum, with consideration for pharmacologic prophylaxis depending on the type of thrombophilia and other risk factors (Table 3). Patients receiving anticoagulants should be instructed to withhold their injections at the onset of labor. Patients receiving unfractionated heparin or lowmolecular-weight heparin who require rapid reversal of the anticoagulant effect for delivery can be treated with protamine sulfate (98). Dosing of protamine sulfate is dependent on the route of administration and whether the patient is receiving unfractionated heparin or low-molecular-weight heparin and the route these medications are being administered (98). Only partial neutralization of low-molecular-weight heparin can be achieved with protamine sulfate. # What is the appropriate management of thrombophilic patients who require postpartum anticoagulation therapy? Postpartum doses of unfractionated heparin or lowmolecular-weight heparin should be equal to antepartum therapy. The optimal time to restart anticoagulation therapy postpartum is unclear. A reasonable approach to minimize bleeding complications is to restart unfractionated heparin or low-molecular-weight heparin no Copyright $\circledcirc$ by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. ![](images/020ef5c8bf24bc24f1f14dc7b68beae4a0a0b1b8a54cbbc20c786530e94c4138.jpg) sooner than 4–6 hours after vaginal delivery or 6–12 hours after cesarean delivery. Timing of reinitiation of anticoagulation should be made in conjunction with anesthesiology for women who used neuraxial anesthesia during delivery (99). To avoid paradoxical thrombosis and skin necrosis from the early anti-protein C effect of warfarin, women who will be treated with warfarin should be bridged with adjusted-dose low-molecular-weight heparin or unfractionated heparin until an international normalized ratio in the therapeutic range (2.0–3.0) is achieved for 2 consecutive days. Warfarin can be started concurrently with adjusted-dose heparin compounds in the postpartum period. Initial dose of warfarin is $5 ~ \mathrm { m g }$ daily for 2 days, with subsequent doses determined by monitoring the international normalized ratio. Warfarin, low-molecularweight heparin, and unfractionated heparin do not accumulate in breast milk and do not induce an anticoagulant effect in the infant; therefore, these anticoagulants may be used in women who breastfeed (94–96). # What postpartum contraceptive options are appropriate for women with thrombophilias? The risk of VTE among women with an inherited thrombophilia is increased with the use of estrogencontaining oral contraceptives. The relative risk of an initial thromboembolic event is increased above baseline for factor V Leiden heterozygotes (RR, 2.47–15.04), prothrombin gene mutation heterozygotes (RR, 3.60–8.63), factor $\mathrm { v }$ Leiden and prothrombin gene heterozygotes (RR, 3.79–76.47), protein C deficiency (RR, 1.7–23.9), protein S deficiency (RR, 1.4–17.1), and antithrombin deficiency (RR, 1.4–115.8) (79). However, the absolute annualized risk of thromboembolism with a thrombophilia and estrogen-containing contraceptive use remains low with estimates ranging from $0 . 1 \%$ to $7 . 1 \%$ (79). The relative risks of thromboembolism with high-risk thrombophilias such as homozygosity for factor $\mathrm { v }$ Leiden or homozygosity for prothrombin gene mutation are unknown (79). Alternative methods of contraception such as intrauterine devices (including those containing progestin), progestin-only pills or implants, and barrier methods should be considered for women with known inherited thrombophilias. However, screening all women for thrombophilias before initiating combination contraception is not recommended given a low absolute risk of thromboembolism even with a thrombophilia, and the large number of women (nearly half a million assuming baseline incidence of fatal embolism of 6 per 100,000) who would need to be screened in order to prevent one death from embolism (100, 101). # Summary of Recommendations # The following recommendations are based on limited or inconsistent scientific evidence (Level B): Screening for inherited thrombophilias is not recommended for women with a history of fetal loss or adverse pregnancy outcomes including abruption, preeclampsia, or fetal growth restriction because there is insufficient clinical evidence that antepartum prophylaxis with unfractionated heparin or low-molecular-weight heparin prevents recurrence in these patients. Because of the lack of association between either heterozygosity or homozygosity for the MTHFR C677T polymorphism and any negative pregnancy outcomes, including any increased risk of VTE, screening with either MTHFR mutation analyses or fasting homocysteine levels is not recommended. Warfarin, low-molecular-weight heparin, and unfractionated heparin do not accumulate in breast milk and do not induce an anticoagulant effect in the infant; therefore, these anticoagulants may be used in women who breastfeed. # The following recommendations are based primarily on consensus and expert opinion (Level C): Among women with personal histories of VTE, recommended screening tests for inherited thrombophilias should include factor V Leiden mutation; prothrombin G20210A mutation; and antithrombin, protein S, and protein C deficiencies. All patients with inherited thrombophilias should undergo individualized risk assessment, which may modify management decisions regarding VTE prevention. # For More Information The American College of Obstetricians and Gynecologists has identified additional resources on topics related to this document that may be helpful for ob-gyns, other health care providers, and patients. You may view these resources at www.acog.org/More-Info/ThrombophiliasInPregnancy. These resources are for information only and are not meant to be comprehensive. Referral to these resources does not imply the American College of Obstetricians and Gynecologists’ endorsement of the organization, the organization’s website, or the content of the resource. The resources may change without notice. Copyright $\circledcirc$ by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. 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May mothers given warfarin breast-feed their infants? Br Med J 1977;1:1564–5. (Level III) 96. Richter C, Sitzmann J, Lang P, Weitzel H, Huch A, Huch R. Excretion of low molecular weight heparin in human milk. Br J Clin Pharmacol 2001;52:708–10. (Level III) 97. Leffert L, Butwick A, Carvalho B, Arendt K, Bates SM, Friedman A, et al. The Society for Obstetric Anesthesia and Perinatology consensus statement on the anesthetic management of pregnant and postpartum women receiving thromboprophylaxis or higher dose anticoagulants. Members of the SOAP VTE Taskforce. Anesth Analg 2017. (Level III) 98. Holst J, Lindblad B, Bergqvist D, Garre K, Nielsen H, Hedner U, et al. Protamine neutralization of intravenous and subcutaneous low-molecular-weight heparin (tinzaparin, Logiparin). An experimental investigation in healthy volunteers. Blood Coagul Fibrinolysis 1994;5:795–803. (Level II-3) 99. Thromboembolism in pregnancy. Practice Bulletin No. 196. American College of Obstetricians and Gynecologists. Obstet Gynecol 2018;132:e1–17. (Level III) 100. Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med 1997;127:895–903. (Level III) 101. Comp PC, Zacur HA. Contraceptive choices in women with coagulation disorders. Am J Obstet Gynecol 1993; 168:1990–3. (Level III) Copyright $\circledcirc$ by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. ![](images/ef992da8d65a707ff6fdda942479df428df61dd09c465c385ec5bde711b5e527.jpg) The MEDLINE database, the Cochrane Library, and the American College of Obstetricians and Gynecologists’ own internal resources and documents were used to conduct a literature search to locate relevant articles published between January 1985 to March 2018. The search was restricted to articles published in the English language. Priority was given to articles reporting results of original research, although review articles and commentaries also were consulted. Abstracts of research presented at symposia and scientific conferences were not considered adequate for inclusion in this document. Guidelines published by organizations or institutions such as the National Institutes of Health and the American College of Obstetricians and Gynecologists were reviewed, and additional studies were located by reviewing bibliographies of identified articles. When reliable research was not available, expert opinions from obstetrician–gynecologists were used. Studies were reviewed and evaluated for quality according to the method outlined by the U.S. Preventive Services Task Force: I Evidence obtained from at least one properly designed randomized controlled trial. II-1 Evidence obtained from well-designed controlled trials without randomization. II-2 Evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group. II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments also could be regarded as this type of evidence. III Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. Published online on June 25, 2018. Copyright 2018 by the American College of Obstetricians and Gynecologists. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, posted on the Internet, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior written permission from the publisher. Requests for authorization to make photocopies should be directed to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400. American College of Obstetricians and Gynecologists 409 12th Street, SW, PO Box 96920, Washington, DC 20090-6920 Inherited thrombophilias in pregnancy. ACOG Practice Bulletin No. 197. American College of Obstetricians and Gynecologists. Obstet Gynecol 2018;132:e18–34. Based on the highest level of evidence found in the data, recommendations are provided and graded according to the following categories: Level A—Recommendations are based on good and consistent scientific evidence. Level B—Recommendations are based on limited or inconsistent scientific evidence. Level C—Recommendations are based primarily on consensus and expert opinion. Copyright $\circledcirc$ by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. 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1d33f80ac931432dab013d5117088f17	2019+NICE指南	异位妊娠和流产的诊断和初始管理（NG.126）	# 宫外孕和流产:诊断和初始治疗 NICE指南发布日期:2019年4月17日好的.org.uk/guidance/ng126 # 你的责任本指南中的建议代表了NICE的观点，是在仔细考虑现有证据后得出的。在进行判断时，专业人员和从业者预计会充分考虑本指南以及患者或使用其服务的人员的个人需求、偏好和价值观。不强制适用这些建议，并且该指南不凌驾于与个人及其家人、照顾者或监护人协商后做出适合个人情况的决定的责任之上。当个人专业人员和使用服务的人希望使用该指南时，当地医疗保健委托人和提供者有责任使该指南得到应用。他们应该在资金和发展服务的本地和国家优先事项的背景下这样做，并根据自己的职责，尽职尽责地去消除非法歧视，推进机会平等和减少健康不平等的需要。本指南中的任何内容都不应以不符合这些职责的方式解释。委员和提供者有责任促进环境可持续的健康和护理系统，应尽可能评估和减少实施NICE建议对环境的影响。 # 内容 # 概述.. 4 它是为了谁？.. 4 建议... 5 1.1支持和信息提供. .5 1.2 早期妊娠评估服务.. .6 1.3异位妊娠的症状和体征以及初步评估.. ..7 1.4活宫内妊娠和输卵管异位妊娠的诊断. .10 1.5流产管理. .15 1.6输卵管异位妊娠的治疗. ..18 1.7抗D恒河猴预防. .22 本指南中使用的术语. .23 研究建议... .24 1早期妊娠评估单位.. ..24 2超声确定宫内妊娠存活率. ..25 3 黄体酮/孕激素治疗先兆流产. ..25 4流产管理. ..26 5 宫外孕的期待治疗、内科治疗或手术治疗的比较. .26 理由和影响. .28 利用超声诊断输卵管异位妊娠. .28 输卵管异位妊娠的治疗. .29 背景.... ..30 寻找更多信息和资源. .31 更新信息.. .32 本指南取代了CG154。本指南是QS69 的基础。 # 概述本指南涵盖了对妊娠早期(即妊娠晚期长达13 周)出现疼痛和出血等并发症的女性进行异位妊娠和流产的诊断和管理。它旨在改善早期妊娠损失的诊断方法，并为妇女提供支持，以限制她们失去怀孕的心理影响。 # 它是为了谁？医疗保健专业人员委员· 妊娠早期(妊娠完成后13 周内)出现并发症的女性、她们的家人和护理人员· # 建议人们有权参与讨论并就他们的护理做出明智的决定，正如您的护理中所述。使用NICE指南做出决策解释了我们如何使用单词来显示我们的建议的强度(或确定性)，并提供有关处方药物(包括标签外使用)、专业指南、标准和法律(包括同意和精神能力)以及维护的信息。 # 1.1 支持和信息提供 1.1.1 以尊严和尊重对待所有患有早期妊娠并发症的女性。请注意，女性会以不同的方式对并发症或怀孕的失败做出反应。考虑到女性的个人情况和情绪反应，以敏感的方式为所有女性提供信息和支持。有关提供信息的更多指导，请参阅 NICE关于成人NHS 服务中患者经验的指南。[2012] 1.1.2 在任何环境中为患有早期妊娠并发症的女性提供护理的医疗保健专业人员都应意识到，早期妊娠并发症会给一些女性及其伴侣带来重大困扰。为这些女性提供护理的医疗保健专业人员应接受如何敏感沟通和打破坏消息的培训。还应培训在提供早期妊娠护理的环境中工作的接待员等非临床工作人员如何与经历早期妊娠并发症的女性进行敏感沟通。有关支持的更多指南，请参阅NICE产前和产后心理健康指南。[2012年，2019年修订] 1.1.3 在女性的护理过程中，以多种形式向女性和(经她同意)她的伴侣提供特定的循证信息。这应包括(根据适当情况): 如果现有症状恶化或出现新症状，何时以及如何寻求帮助，包括24小时联系电话号码· 在她等待超声波扫描期间会发生什么· 在她的护理过程中要期待什么(包括期待管理)，例如潜在的疼痛和/或出血的持续时间和程度，以及可能的副作用。·这些信息应该根据她接受的护理进行定制有关术后护理的信息(对于接受手术的女性)·恢复期要期待什么一例如，什么时候可以恢复性活动和/或尝试再次怀孕，如果她再次怀孕怎么办？这些信息应该根据她得到的护理进行定制· 关于她治疗可能对未来生育能力影响的信息·在哪里可以访问支持和咨询服务，包括支持组织的小单、网页地址和帮助线号码。·确保在女性护理过程中有足够的时间与女性讨论这些问题，并在需要更多时间时安排额外的预约。[2012] 1.1.4 早期怀孕后，向妇女提供随访预约的选择，由她选择的医疗保健专业人员负责。[2012] # 1.2 早期妊娠评估服务 1.2.1 应组织区域服务，以便为患有早期妊娠并发症的女性每周7天提供早期妊娠评估服务，并进行扫描和管理决策。[2012] 1.2.2 早期妊娠评估服务应：由有能力诊断和护理患有妊娠早期疼痛和/或出血的女性的医疗保健专业人员提供专门的服务·提供超声检查并评估血清人绒毛膜促性腺激素 (hCG)水平和·由医疗保健专业人员配备敏感沟通和打破坏消息方面的培训。[2012]· 1.2.3 早期妊娠评估服务应接受女性的自我转诊反复流产或既往有过宫外或葡萄胎妊娠的人。尽管指南范围中没有包括对反复流产妇女的额外护理，但指南制定小组认识到，允许这些妇女自行接受早期妊娠评估服务是常见的临床实践，并希望这种情况仍然存在。所有其他患有疼痛和/或出血的女性在转诊至早期妊娠评估服务之前均应由医疗保健专业人员(例如全科医生、事故和紧急情况[A&E]医生、助产士或护士)进行评估。[2012] 1.2.4 确保建立一个系统，以便在24小时内因临床情况需要就诊的女性参加当地的早期妊娠评估服务。如果服务不可用，且临床症状需要进一步评估，请将妇女转诊至最近的提供专科临床评估和超声扫描的无障碍设施(例如妇科病房或 A&E 服务，并获得专科妇科支持)。[2012] 1.3 异位妊娠的症状和体征以及初步评估 1.3.1 将血流动力学不稳定的女性或对疼痛或出血程度有重大担忧的女性直接转诊至A&E。[2012] 请注意，异位妊娠的不典型表现很常见。[2012] 1.3.3 请注意，宫外孕可能会出现多种症状。即使症状不太常见，但可能仍然很严重。宫外孕的症状包括：常见症状：· 腹痛或盆腔疼痛- 闭经或漏诊期- 阴道出血伴或不伴血栓其他报告的症 # 状:- 乳房压痛- 胃肠道症状- 宫外孕和流产:诊断和初始治疗 (NG126) 头晕、晕厥或晕厥肩尖疼痛--尿路症状组织传代直肠压力或排便时疼痛。[2012]- 1.3.4 请注意，宫外孕在医疗保健专业人员检查时可能会出现多种症状。宫外孕的症状包括：更常见的迹象：骨盆压痛附件压痛腹部压痛其他报告的症状:-颈椎活动压痛-反跳痛或腹膜征象苍白--腹胀增大子宫--心动过速(每分钟超过 100 次)或低血压(低于 100/60 mmHg)-休克或塌陷-直立性低血压。[2012]- 1.3.5 在对育龄妇女进行临床评估时，请注意：他们可能是怀孕了，即使症状是非特异性的，也考虑进行妊娠测试·异位妊娠的症状和体征可能类似于其他疾病的常见症状和体征一例如胃肠道疾病或尿路感染。[2012]· 1.3.6所有参与育龄妇女护理的医疗保健专业人员都应获得妊娠测试。[2012] 1.3.7 立即咨询早期妊娠评估服务(如果无法提供早期妊娠评估服务，则请咨询临产妇科服务)以进一步评估妊娠测试呈阳性且检查时有以下情况的女性: 疼痛和腹部压痛或骨盆压痛或·宫颈活动度压痛。[2012]· 1.3.8 排除宫外孕的可能性，即使没有危险因素(例如以前的宫外孕)，因为大约三分之一的宫外孕女性不会有已知的危险因素。[2012] 1.3.9 请参阅早期妊娠评估服务(如果无法提供早期妊娠评估服务，请参阅院外妇科服务)患有出血或其他早期妊娠并发症症状和体征的女性，这些女性有：疼痛或·妊娠6周或以上或妊娠不确定。·这种转诊的紧急性取决于临床情况。[2012] 1.3.10对妊娠小于6 周、出血但不出现疼痛且没有危险因素(例如既往宫外孕)的女性进行期待管理。建议这些女性: 如果继续出血或出现疼痛，请返回· 7-10天后重复尿妊娠试验，如果呈阳性则返回·妊娠试验呈阴性意味着妊娠流产[2012年，2019年修订]。· 1.3.11 将出现症状和体征恶化且可能提示宫外孕的妇女转诊至早期妊娠评估服务(如果无法提供早期妊娠评估服务，则请提供意外妇科服务)进行进一步评估。应立即还是24小时内见到她的决定将取决于临床情况。[2012] 1.3.12如果女性被转诊至早期妊娠评估服务中心(如果无法获得早期妊娠评估服务，则请转诊至不经批准的妇科服务中心)，请解释转诊的原因以及到达那里时她可以期待什么。[2012] # 1.4 活宫内妊娠和输卵管异位妊娠的诊断 1.4.1 为参加早期妊娠评估服务(或未参加早期妊娠评估服务的外周妇科服务)的妇女提供经阴道超声扫描，以确定妊娠位置以及是否存在胎儿极和心跳。[2012] 1.4.2 对于子宫增大或其他盆腔病变(例如肌瘤或卵巢囊肿)的女性，考虑进行经腹超声扫描。[2012] 1.4.3 如果女性无法接受经阴道超声扫描，请提供经腹部超声扫描并解释这种扫描方法的局限性。[2012] # 超声诊断宫内妊娠活检 1.4.4 告诉女性，使用1次超声扫描诊断流产不能保证 $100 \%$ 准确，并且诊断可能不正确的可能性很小，特别是在胎龄很早的情况下。[2012] 1.4.5 在进行超声波扫描以确定宫内妊娠的活力时，首先看是否存在胎儿心跳。如果没有有心跳但有胎儿极，测量牙冠-牙缝长度。如果胎儿极不可见，仅测量平均孕囊直径。[2012] 1.4.6 如果经阴道超声扫描的牙冠-牙缝长度小于7.0毫米并且没有明显的心跳，则至少进行第二次扫描诊断前第7天后7天。在做出诊断之前可能需要进一步扫描。[2012] 1.4.7 如果经阴道超声扫描的牙冠-牙缝长度为7.0毫米或更长并且没有明显的心跳：寻求关于怀孕和/或存活能力的第二次意见·在做出诊断之前，在第一次扫描后至少7天进行第二次扫描。[2012]· 1.4.8如果使用经腹部超声扫描测量牙冠-牙缝长度时没有明显的心跳: 记录牙冠长度和牙冠长度的大小·在做出诊断之前，在第一次扫描后至少14天进行第二次扫描。[2012]· 1.4.9 如果经阴道超声扫描的平均孕囊直径小于25.0毫米，并且没有可见的胎儿极，则在诊断前至少7天后进行第二次扫描。在做出诊断之前可能需要进一步扫描。[2012] 1.4.10如果使用阴道超声扫描的平均孕囊直径为25.0毫米或更多并且没有可见的胎儿极：寻求关于怀孕和/或存活能力的第二次意见·在做出诊断之前，在第一次扫描后至少7天进行第二次扫描。[2012]· 1.4.11如果没有可见的胎儿极，并且使用经腹超声扫描测量平均孕囊直径：记录平均孕囊直径的大小并· 在做出诊断之前，在第一次扫描后至少14天进行第二次扫描。[2012]· 1.4.12不要仅用末次月经的胎龄来判断是否应可见胎心跳。[2012] 1.4.13告知女性，由于月经周期的变异性，她们最后一次月经的日期可能无法准确表示胎龄。[2012] 1.4.14告知女性在等待重复扫描时要期待什么，并且等待重复扫描对怀孕的结果没有不利影响。[2012] 1.4.15 给女性一个24小时联系电话号码，以便她们可以与有照顾早孕并发症女性经验的人交谈，了解她们的需求并可以提供适当护理的建议。有关应提供的更多信息的详细信息，另请参阅建议1.1.3。[2012] 1.4.16在超声波扫描诊断完全流产时，在之前没有扫描证实宫内妊娠的情况下，始终意识到胎次不明的可能性。建议这些女性返回进行随访(例如hCG 水平、超声扫描)，直到获得明确的诊断。(另请参阅有关未知地点妊娠的建议1.4.23至1.4.32)[2012年，2019年修订] 超声扫描诊断输卵管异位妊娠 1.4.17在怀孕早期进行阴道超声检查时，寻找这些表明存在输卵管异位妊娠的迹象：附件肿块，分开移动到卵巢[1]，包括含有卵黄囊的妊娠囊或·附件肿块，分别移动到卵巢[1]，包括妊娠囊和胎儿极(有或没有胎心跳)。[2019]· 1.4.18在怀孕早期进行阴道超声扫描时，寻找这些表明输卵管异位妊娠可能性较高的迹象:附件肿块，分别移动到卵巢[1]，有空的妊娠囊(有时称为"输卵管环"或"基格尔征")或·复杂的不均匀附件肿块，分开到达卵巢·如果存在这些特征，则在诊断前考虑扫描中的其他宫内和附件特征、女性的临床表现和血清 hCG 水平。[2019] 1.4.19在怀孕早期进行阴道超声扫描时，寻找这些表明可能发生宫外孕的迹象: 空腹子宫或· 子宫腔内积液(有时称为假性囊肿[2])。·如果存在这些特征，则在诊断前考虑扫描中的其他宫内和附件特征、女性的临床表现和血清 hCG 水平。(另请参阅有关未知地点妊娠的建议1.4.23至1.4.32)。[2019] 1.4.20怀孕早期进行经腹或经阴道超声扫描时，寻找腹膜腔或道格拉斯袋中中等至大量游离液体，这些液体可能代表血腹膜。如果存在这种情况，请在诊断前考虑扫描中的其他宫内和附件特征、女性的临床表现和 hCG 水平。[2019] 1.4.21怀孕早期进行经腹或经阴道超声扫描时，扫描子宫和附件，看看是否存在异位妊娠。[2019] 1.4.22所有超声扫描均应由适当合格的具有诊断宫外孕培训和经验的医疗保健专业人员进行或直接监督和审查。[2012年，2019年修订] 要了解委员会为何提出 2019 年关于使用超声扫描诊断输卵管异位妊娠的建议，以及它们可能如何影响实践，请参阅理由和影响。妊娠地点不明女性人绒毛膜促性腺激素测量 1.4.23 请注意，妊娠地点未知的女性可能会发生宫外孕，直到确定位置为止。[2012] 1.4.24不要使用血清hCG 测量来确定妊娠位置。[2012] 1.4.25对于妊娠地点未知的女性，比血清 hCG 结果更重视临床症状，如果她的任何症状发生变化，则检查该女性的病情，无论之前的结果和评估如何。[2012] 1.4.26仅使用血清 hCG 测量来评估滋养层增殖，以帮助确定后续治疗。[2012] 1.4.27 尽可能接近相隔 48 小时(但不早)的2次血清 hCG 测量，以确定未知地点妊娠的后续管理。仅在经过高级医疗保健专业人员审查后才进行进一步测量。[2012] 1.4.28 无论血清hCG水平如何，请向妊娠地点未知的女性提供书面信息，说明如果她们出现任何新的或恶化的症状，包括有关如何获得紧急护理的详细信息一天24小时。如果出现新症状或现有症状恶化，建议妇女返回。[2012] 1.4.29对于 48 小时后血清 hCG 水平升高超过 $63 \%$ 的女性：告诉她她很可能正在发生宫内妊娠(尽管不能排除宫外孕的可能性)。·为她提供经阴道超声扫描，以确定7至14天后的妊娠位置。对于血清hCG水平大于或等于 $1 5 0 0 ~ \mathrm { I U / L }$ 的女性，考虑进行早期扫描。·如果宫内妊娠存活得到证实，请为她提供常规产前护理。-请参阅NICE关于无并发症妊娠产前护理的指南。如果没有确认宫内妊娠可行，请转介她立即接受高级妇科医生的临床审查。[2012]- 1.4.30对于 48 小时后血清 hCG 水平降低超过 $50 \%$ 的女性: 告诉她怀孕不太可能继续，但尚未证实这一点，并且· 向她提供有关她在哪里可以获得支持和咨询服务的口头和书面信息。有关应提供的更多信息的详细信息，另请参阅建议1.1.3· 要求她在第二次血清hCG 检测后14天进行尿妊娠试验，并解释：·如果测试呈阴性，则无需进一步采取行动-如果检测呈阳性，应在24小时内返回早期妊娠评估服务处进行临床审查。[2012]- 1.4.31对于血清 hCG 水平降低低于 $50 \%$ 或升高低于 $63 \%$ 的女性，请在 24小时内转介其接受早期妊娠评估服务的临床审查。[2012年，2019年修订] 1.4.32对于妊娠地点未知的女性，在使用连续血清 hCG 测量时，不要使用血清孕酮测量作为辅助手段来诊断可行的宫内妊娠或宫外孕。[2012] # 1.5 流产管理 # 流产威胁 1.5.1建议一名患有阴道出血且已确诊宫内妊娠并出现胎心跳的女性: 如果她的出血情况恶化或持续超过14天，她应返回进行进一步评估· 如果出血停止，她应该开始或继续常规产前护理。[2012]· # 期待管理 1.5.2 对确诊流产的女性使用7至14天的期待管理作为一线管理策略。如果出现以下情况，请探索除期待管理之外的管理选项：女性出血的风险增加(例如，她处于妊娠早期晚期)或· 她以前有过与怀孕相关的不良和/或创伤经历(例如死产、流产或产前出血)或· 她患出血的风险会增加(例如，如果她患有凝血病或无法输血)或· 有感染的证据。[2012]· 1.5.3如果女性无法接受期待管理，则为确诊为流产的女性提供医疗管理。[2012] 1.5.4 解释预期管理涉及什么，并且大多数女性将不需要进一步的治疗。还为女性提供有关进一步治疗方案的口头和书面信息。[2012] 1.5.5 向所有接受口服流产期待管理的女性提供有关整个流程中预计的事情、疼痛缓解建议以及在紧急情况下在哪里和何时获得帮助的书面信息。有关应提供的更多信息的详细信息，另请参阅建议1.1.3。[2012] 1.5.6 如果出血和疼痛的缓解表明流产在期待治疗的7至14天内已完成，建议女性在3周后进行尿妊娠测试，如果尿妊娠测试呈阳性，则返回接受个性化护理。[2012] 1.5.7 如果在期待治疗期间出现出血和疼痛后，提供重复扫描：尚未开始(表明流产过程尚未开始)或持续存在和/或不断增加(表明流产不完全)。· 与女性讨论所有治疗方案(持续期待管理、医疗管理和手术管理)，以便让她做出明智的选择。[2012] 1.5.8 检查一名女性在首次随访预约后至少14天内反对对流产进行持续期待管理的情况。[2012] # 医疗管理 1.5.9 请勿将米非司酮作为遗漏或不完全流产的治疗方法。[2012] 1.5.10提供阴道米索前列醇[3]用于遗漏或不完全流产的医疗治疗。如果这是女性的喜好，口服给药是一种可以接受的替代方案。[2012] 1.5.11对于流产漏诊的女性，使用单剂量800 微克米索前列醇[3]。[2012] 1.5.12建议女性，如果治疗后24小时出血尚未开始，应联系医疗保健专业人员，以确定持续的个性化护理。[2012] 1.5.13 对于流产不完全的女性，使用单剂量 600 微克米索前列醇[3]。(800 微克可作为替代方案，允许对遗漏和不完全流产的治疗方案进行比对)。[2012] 1.5.14根据需要，为所有接受流产疼痛缓解和止吐药医疗管理的女性提供帮助。[2012] 1.5.15 告知接受医疗管理的流产女性整个过程中的期望，包括出血的长度和程度以及治疗的潜在副作用，包括疼痛、腹泻和呕吐。[2012] 1.5.16建议女性在医疗管理流产后3周进行尿妊娠试验，除非她们出现症状恶化，在这种情况下建议她们返回负责提供医疗管理的医疗保健专业人员。[2012] 1.5.17 建议尿妊娠试验呈阳性的女性在3周后返回接受医疗保健专业人员的检查，以确保没有葡萄胎或宫外孕。[2012] # 手术治疗 1.5.18如果临床上合适的情况，为接受流产的女性提供以下选择:在门诊或诊所环境中或在全身麻醉下手术室进行局部麻醉下的手动真空抽吸。[2012]· 1.5.19向所有接受流产手术治疗的女性提供有关可用治疗方案以及手术期间和手术后预期的口头和书面信息。有关应提供的更多信息的详细信息，另请参阅建议1.1.3。[2012] # 1.6 输卵管异位妊娠的治疗 1.6.1 向所有患有宫外孕的女性口头提供书面信息:治疗方案以及治疗期间和治疗后预期的·如果需要，他们如何联系医疗保健专业人员在治疗后寻求建议，以及这将是谁·紧急情况下何时何地寻求帮助。·有关应提供的更多信息的详细信息，另请参阅建议1.1.3。[2012年，2019年修订] 1.6.2 告知宫外孕的女性，如果她们有任何早期担忧，她们可以在未来的怀孕中自行接受早期妊娠评估服务。[2012] # 期待管理 1.6.3 为以下女性提供期待管理: 临床稳定且无痛且· 输卵管异位妊娠小于35毫米，经阴道超声扫描未见心跳，并且· 血清 hCG 水平为1，000IU/L或更低，并且能够返回进行随访。[2019]· 1.6.4 将期待管理视为以下女性的选择: 临床稳定且无痛且· 输卵管异位妊娠小于35毫米，经阴道超声扫描未见心跳，并且·血清 hCG 水平高于1，000IU/L且低于1，500 IU/L，并且能够返回进行随访。[2019]· 1.6.5 对于接受预期输卵管异位妊娠治疗的女性，在最初测试后第2、4和7天重复hCG水平，并且：如果hCG 水平在第2、4和7天较之前的值下降 $15 \%$ 或更多，则每周重复一次，直到获得阴性结果(小于 $2 0 \ \mathrm { I U } / \mathrm { L } )$ 或· 如果hCG 水平没有下降 $15 \%$ ，请保持不变或较之前的值上升，检查女性的临床状况并寻求高级建议以帮助决定进一步的治疗。[2019]· 1.6.6建议女性，根据有限的证据，期待或医疗管理后似乎没有差异：自然终止异位妊娠的发生率· 宫外孕和流产:诊断和初始治疗 (NG126) 输卵管破裂的风险· 需要额外治疗，但如果病情恶化可能需要紧急入院· 健康状况、抑郁或焦虑评分。[2019]· 1.6.7 建议女性，宫外孕解决所需的时间和未来的生育结果可能与预期或医疗管理相同。[2019] 要了解委员会为何制定2019 年关于期待管理的建议以及它们可能如何影响实践，请参阅理性和影响。 # 医疗和外科管理 1.6.8 为以下女性提供全身甲氨蝶呤[4]: 没有明显的疼痛并且· 具有未破裂的输卵管异位妊娠，附件质量小于35毫米，无明显心跳，并且· 血清 hCG 水平低于1，500 IU/升且· 没有宫内妊娠(超声波扫描证实)，并且能够返回进行随访。·只有当明确诊断为宫外孕并且排除可行的宫内妊娠时，才应在首次就诊时提供甲氨蝶呤。在女性无法接受甲氨蝶呤治疗的情况下进行手术。[2012年，2019年修订] 1.6.9 将手术作为一线治疗，用于甲氨蝶呤[4]治疗后无法返回随访或有任何以下情况的女性：宫外孕和剧烈疼痛·宫附件肿块≥35mm的异位妊娠·超声波扫描可见胎儿心跳的异位妊娠·宫外孕且血清 hCG 水平为5，000 IU/升或更高。[2012]· 1.6.10为宫外孕且血清hCG水平至少为1，500IU/L且低于5，000IU/L、能够返回进行随访且符合以下所有标准的女性选择甲氨蝶呤[4]或手术治疗：无明显疼痛· 宫附件肿块小于 $3 5 ~ \mathsf { m m }$ 且无明显心跳的未破裂宫外孕· 无宫内妊娠(超声波扫描证实)。·建议选择甲氨蝶呤的女性，他们需要进一步干预的机会会增加，如果病情恶化，可能需要紧急入院。[2012] 1.6.11对于患有甲氨蝶呤的宫外孕女性，在治疗后第一周(4 天和7天)进行2 次血清hCG 测量，然后每周测量1次血清hCG，直至获得阴性结果。如果hCG 水平稳定或上升，请重新评估女性的病情以进一步治疗。[2012] # 进行腹腔镜检查 1.6.12当宫外孕女性需要手术治疗时，应尽可能通过腹腔镜进行手术，同时考虑到妇女的病情和手术的复杂性。[2012] 1.6.13为异位妊娠妇女提供护理的外科医生应该有能力进行腹腔镜手术。[2012] 1.6.14专员和管理人员应确保腹腔镜手术设备可用。[2012] # 输卵管切除术和输卵管切开术 1.6.15为因宫外孕而接受手术的女性提供输卵管切除术，除非她们有其他不孕症的危险因素。[2012] 1.6.16对于有对侧管损伤等不孕危险因素的女性，考虑将输卵管切开术作为输卵管切除术的替代方案。[2012] 1.6.17告知接受输卵管切开术的女性，多达五分之一的女性可能需要进一步治疗。该治疗可能包括甲氨蝶呤和/或输卵管切除术。[2012] 1.6.18对于接受输卵管切开术的女性，请在以下处进行1次血清 hCG 测量:手术后7天，每周测量1次血清hCG，直至获得阴性结果。[2012] 1.6.19建议接受输卵管切除术的女性在3周后进行尿妊娠测试。如果检测呈阳性，建议女性返回进行进一步评估。[2012] # 1.7 抗D恒河猴预防 '.1 为所有接受过异位妊娠或流产手术的恒河猴阴性女性提供 250 IU (50 微克)剂量的抗D恒河猴预防。[2012] 1.7.2 不要向以下女性提供抗D 恒河猴预防:仅因宫外孕或流产或有威胁流产而接受医疗管理或·完全流产或·怀孕地点不明。[2012]· 1.7.3不要使用 Kleihauer 检验来量化胎儿-母体出血。[2012] # 本指南中使用的术语早期妊娠妊娠早期(即妊娠晚期最多 13 周)。 # 期待管理当不进行药物或手术治疗时，采用一种管理方法，也称为"等待并观察"。目的是看看病情是否会自然解决。 # 地点不明的怀孕当女性妊娠试验呈阳性，但经阴道超声扫描未发现宫内或宫外妊娠时。 # 研究建议指南委员会根据其对证据的审查，提出了以下研究建议，以在未来改善NICE指南和患者护理。指南制定小组的全套研究建议详见全文指南。 # 1早期妊娠评估单位应对国家早期妊娠评估单位服务提供进行评估，以确定影响结果的因素。因素应包括是否在专用单位提供护理、人员配置和专用服务的开放时间。结果应包括 process(服务)结果和妊娠相关结果。收集的数据应用于分析早期妊娠评估单位与其他护理模式相比的成本效益。 # 为什么这很重要英国早孕评估单位的首份报告于20多年前发表，推动了早孕问题管理中心的快速发展。如今，英国和威尔士估计有 150个早孕评估单位(早孕单位协会，2012年)。然而，各中心在获得服务和提供护理的水平方面存在相当大的变化。此外，对于早期妊娠评估单位与专科单位以外提供的服务相比，在改善身心健康方面的有效性，几乎没有很好的质量研究。对早孕评估服务的全国审计将有助于弥补信息的缺乏。这样的审计应该沿着国家剖腹产科哨兵审计的路线进行，这是一项针对服务配置和结果的横断面全国调查。记录的数据将包括服务地点、开放时间和相关医疗保健专业人员。结果将包括出勤时间、住院时间、入院率、治疗时间和女性经验。在审计期间，获得其中一些信息将涉及早期妊娠服务对女性进行比目前更正式的随访。评估应结构化以允许不同护理模式之间的比较。收集的比较结果数据将用于分析早期妊娠评估单位与其他护理模式相比的成本效益。 # 2超声确定宫内妊娠存活率超声检查的时间和频率如何影响早期妊娠并发症的诊断和结果，包括女性的经验和成本效益？ # 为什么这很重要超声波频率用于改善早期妊娠并发症的诊断和结果背后的基本原理解决了与未知部位妊娠和活力不确定的宫内妊娠相关的问题。妊娠早期扫描的时间和频率的证据基础有限，扫描次数由各个单位根据能力和需求进行组织。一些医疗保健专业人员选择在扫描之间等待5天，而另一些专业人员则会等待10至14天。这些决策是由资源可用性和临床考虑驱动的，但特别是不同策略对成本和女性经验的影响尚不清楚。文献表明，目前尚无明确共识，但普遍一致认为，到14天时诊断就会明确。为了确定最合适的扫描时间，可以将14天后扫描的功效与7天后扫描的功效进行比较，以诊断宫外孕或活力。 # 3黄体酮I孕激素治疗先兆流产黄体酮或孕激素有效治疗受威胁的流产吗？ # 为什么这很重要大约 $20 \%$ 的妊娠在妊娠早期流产，许多女性在怀孕早期会经历一些出血和/或疼痛，但不会引起流产。在许多国家，患有出血和/或疼痛的女性将接受黄体酮或孕激素治疗，以尝试降低流产风险。这种治疗有效性的证据尚无定论，但对多项小型研究的荟萃分析数据表明孕激素优于安慰剂。然而，在怀孕期间开任何治疗处方都有理论上的风险，对于许多从业者来说，这将是实践中的一次重大变化。缺乏强有力的证据使得这是一个优先研究领域。应对接受孕激素/孕激素或安慰剂治疗的女性进行一项非常大规模的多中心随机对照试验。该试验的规模应足够大，足以检测长期结果的差异。该人群是患有疼痛和出血以及妊娠6至12周之间自发性、确诊、可行、单胎宫内妊娠的女性。将给予黄体酮/孕激素或安慰剂从出血开始到第13周结束。妊娠期持续到妊娠早期结束之后可能是主要结局。还应测量活产以及妊娠结局、出生时妊娠和先天性异常的存在。 # 4流产管理对于确诊流产的女性，管理策略(直观、医疗和手术)的类型是否会影响女性的经历，包括心理和情感结果？ # 为什么这很重要在过去的二十年中，英国对流产的管理发生了许多变化，特别是从住院患者转向门诊或日间病例护理以及引入医疗和期待管理作为手术的替代方案。尽管发生了这些变化，但对于这些不同方法与女性的forwardlook性的影响，特别是它们的心理和情感影响缺乏研究。流产对大多数女性来说很痛苦，管理类型本身可能会影响女性的咨询需求，从而导致NHS 的成本。因此，它是研究的重要领域。文献中的缺陷可以通过对具有不同管理策略(直肠、医疗或外科)和各种临床环境(例如早期妊娠评估单位、妇科病房或妇科急诊室)的女性进行比较研究来解决。收集的数据可以是定量的(使用经过验证的心理健康问卷)和定性的(特别关注女性对特定护理类型和环境的体验)。 # 5 宫外孕的期待治疗、内科治疗或手术治疗的比较对于宫外孕的女性，这种干预类型是否会影响女性的经历，包括心理和情感结果？ # 为什么这很重要目前没有证据探讨异位妊娠不同治疗方法的心理影响。然而，这种情况对情绪的影响可能很大，在某些情况下会导致创伤后应激障碍。应进行定性比较研究以评估如何减少这种影响。这将有助于最大限度地提高女性的宫外孕和流产:诊断和初始治疗 (NG126) # 理由和影响这些部分简要解释了委员会提出建议的原因以及这些建议可能如何影响实践。它们链接到证据的详细信息和委员会讨论的完整描述。 # 利用超声诊断输卵管异位妊娠建议1.4.17至1.4.20 # 委员会为何提出建议有充分的证据表明，在超声检查时，伴有妊娠早期特征的附件肿块(含有卵黄囊或胎儿极的妊娠囊，伴或不伴心跳)是异位妊娠的可靠指标。其他特征如复杂的不均匀的附件肿块、妊娠囊空的附件肿块、子宫空、子宫腔内积液或游离腹腔液可能提示宫外孕，但证据表明它们本身不足以诊断宫外孕。委员会利用他们的知识和经验建议，应使用其他扫描特征、临床表现和血清人绒毛膜促性腺激素(hCG)水平来确认或排除异位妊娠的诊断。 # 这些建议可能如何影响实践这些建议不会改变进行的超声扫描量，但将规范NHS的实践。通过定义应用于指示是否存在宫外孕或怀疑是否存在宫外孕的特征(然后可以进一步研究)，应改进宫外孕的诊断，从而降低女性的风险。证据和委员会讨论的完整细节见证据综述A:输卵管异位妊娠超声特征的诊断准确性。返回建议宫外孕和流产:诊断和初始治疗 (NG126) # 输卵管异位妊娠的治疗 # 期待管理建议1.6.3至1.6.7 # 委员会为何提出建议证据表明，在自然终止的宫外孕次数、额外治疗的需要、输卵管破裂的发生率或预期治疗与医疗管理之间对健康相关生活质量的影响方面，没有显着差异，因此委员会建议，可以向临床稳定的宫外孕次数小且hCG 水平低的女性提供预期治疗，并应考虑对临床稳定的宫外孕次数小且 hCG 水平略高的女性作为医疗管理的替代方案。没有证据表明宫外孕的时间自然结束或对未来生育力的影响，但委员会根据他们的专业知识和经验同意，与医疗管理相比，这些结果可能与预期管理相同。 # 这些建议可能如何影响实践这些建议将规范异位妊娠的管理，并在临床上适当的情况下为女性提供期待的管理。因此，更多的女性可能会对宫外孕有期待的管理。这可能通过减少药物使用和治疗相关副作用来节省成本。需要当地协议来评估、监测和跟踪女性选择期待管理。证据和委员会讨论的完整细节见证据审查B:输卵管异位妊娠的期待与医疗管理。返回建议 # 背景宫外孕和流产对许多女性的生活质量产生不利影响。大约 $20 \%$ 的怀孕会出现流产，流产会造成相当大的痛苦。英国每年早孕人数超过50，000人。宫外孕率为每1，000次妊娠11例，孕产妇死亡率为每1，000次估计宫外孕的0.2例。这些死亡中约三分之二与不合格的护理有关。不容易获得医疗帮助的女性(例如最近成为移民、寻求庇护者、难民或难以阅读或说英语的女性)尤其容易受到影响。因此，改善早期妊娠丢失的诊断和治疗至关重要，以降低相关心理发病率并避免宫外孕女性不必要的死亡。 # 寻找更多信息和资源您可以在我们的有关异位妊娠和流产的交互流程图中看到NICE关于异位妊娠和流产的所有内容。要了解NICE对本指南相关主题的评价，请参阅我们的怀孕问题网页。有关证据和指南委员会讨论2019年建议的完整详细信息，请参阅证据审查。有关2012年建议的证据和指南委员会讨论的详细信息，请参阅完整版本。您还可以找到有关指南如何制定的信息，包括委员会的详细信息。 NICE 已经生产了工具和资源来帮助您将本指南付诸实践。有关将NICE指南付诸实践的一般帮助和建议，请参阅帮助您将指导付诸实践的资源。 # 更新信息 2019年4月:我们回顾了证据，并就使用超声波诊断输卵管异位妊娠和对异位妊娠进行期待治疗提出了新建议。这些建议是标记的[2019]。我们还在没有进行证据审查的情况下做出了一些改变: 建议1.1.2已将有关产前和产后健康的 NICE 指南添加了附加链接。· 建议1.1.3已更新，使获得同意的措辞符合其他NICE 指南。· 建议1.3.10已更新，附加信息涵盖了更广泛的因素，以便不遗漏潜在的宫外孕。· 第1.4节和第1.6节的标题已更新，以澄清它仅与输卵管异位妊娠有关。· 建议1.4.16 已更新，以refrain未知地点怀孕的可能性，并增加了对未知地点怀孕建议的交叉参考。建议1.4.22已更新为当前超声波实践的反流。· 建议1.6.1已更新，包括有关宫外孕部分流产的建议。· 建议1.4.31已更新，以明确血清hCG 水平下降低于 $50 \%$ 。· 建议1.6.7已更改为当前的反流实践和甲氨蝶呤处方指南。·这些建议是标记的[2012年，2019 年修订]。标记为[2012]的建议最后一次证据审查是在2012年。在某些情况下，措辞发生了微小的变化，使语言和风格达到最新水平，但没有改变含义。国际标准书号:9781-4731-3380-8 宫外孕和流产:诊断和初始治疗 (NG126) # 认证	None	None	None
56f3b7954e8643fa8e1c9d27afa6fe50	2023+JSGO指南	子宫体肿瘤的治疗	# Japan Society of Gynecologic Oncology 2023 guidelines for treatment of uterine body neoplasm Received: Oct 25, 2024 Accepted: Apr 22, 2025 Published online: Apr 30, 2025 # Correspondence to # Yoichi Kobayashi Department of Obstetrics and Gynecology, Faculty of Medicine, Kyorin University, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. Email: yoichi@ks.kyorin-u.ac.jp $\circledcirc$ 2025. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https:// creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. # ORCID iDs Tohru Morisada https://orcid.org/0000-0002-4223-1291 Yoichi Kobayashi $\textcircled{1}$ https://orcid.org/0000-0002-8474-0625 Satoru Nagase $\textcircled{1}$ https://orcid.org/0000-0001-5212-1128 Tsukasa Baba $\textcircled { 1 0 }$ https://orcid.org/0000-0003-0066-3747 Hideki Tokunaga $\textcircled{1}$ https://orcid.org/0000-0002-1622-3810 Hidemichi Watari $\textcircled{1}$ https://orcid.org/0000-0002-4189-6187 Munetaka Takekuma $\textcircled{1}$ https://orcid.org/0000-0002-0807-1845 Yasuhisa Terao $\textcircled{1}$ https://orcid.org/0000-0002-9126-3361 Yoshito Terai $\textcircled { 1 0 }$ https://orcid.org/0000-0002-5581-8518 Tohru Morisada $\textcircled{1}$ , 1 Yoichi Kobayashi $\circledcirc$ , 1 Satoru Nagase $\textcircled{1}$ ,2 Tsukasa Baba $\textcircled{1}$ , 3 Hideki Tokunaga $\circledcirc$ ,4 Hidemichi Watari $\circledcirc$ ,5 Munetaka Takekuma , 6 Yasuhisa Terao $\circledcirc$ , 7 Yoshito Terai $\textcircled{1}$ , 8 Hiroaki Kajiyama $\textcircled{1}$ , 9 Mikiko Asai-Sato $\textcircled{1}$ 10 , Kazuhiro Takehara $\textcircled{1}$ , 11 Tsutomu Tabata $\textcircled{1}$ , 12 Kenichi Harano $\textcircled{1}$ ,13 Yasuyuki Hirashima $\textcircled{1}$ ,6 Mayu Yunokawa $\textcircled{1}$ ,14 Aikou Okamoto $\textcircled{1}$ ,15 Mikio Mikami $\textcircled{1}$ 16,17 1 Department of Obstetrics and Gynecology, School of Medicine, Kyorin University, Tokyo, Japan 2 Department of Obstetrics and Gynecology, Faculty of Medicine, Yamagata University, Yamagata, Japan 3 Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, Morioka, Japan 4 Division of Obstetrics and Gynecology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan 5 Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine and Faculty of Medicine, Sapporo, Japan 6 Department of Gynecology, Shizuoka Cancer Center, Shizuoka, Japan 7 Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan 8 Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Japan 9 Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan $^ { 1 0 } { \sf S t }$ . Luke's International Hospital Branch Clinic, St. Luke's MediLocus, Tokyo, Japan 11Department of Gynecologic Oncology, NHO Shikoku Cancer Center, Matsuyama, Japan 12Department of Obstetrics and Gynecology, Tokyo Women's Medical University, Tokyo, Japan 13Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan 14Department of Gynecology and Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan 15Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan 16Faculty of Medical Sciences, Shonan University of Medical Sciences, Yokohama, Japan 17Department of Gynecology, Chigasaki Central Hospital, Chigasaki, Japan # ABSTRACT The Japan Society of Gynecologic Oncology (JSGO) guideline for the treatment of uterine body neoplasm are revised from the 2018 guideline. This guideline aimed to provide standardized care for uterine body neoplasm, indicate appropriate current treatment methods for uterine body neoplasm, minimize variances in treatment methods among institutions, improve disease prognosis and treatment safety, reduce the economic and psychosomatic burden on patients by promoting the performance of appropriate treatment, and enhance mutual understanding between patients and healthcare professionals. The guidelines were prepared through the consensus of the JSGO guideline committee, based on a careful review of evidence from the literature searches and the medical health insurance system and actual clinical practice situations in Japan. The main features of the 2023 revision are as follows: 1) The Guidelines Formulation Committee members were asked to understand Minds' medical guideline development method in advance. 2) The clinical question (CQ) was changed to Patient, Intervention, Comparison, Outcome format as much as possible. 3) Introduced the "body of evidence," which summarizes the results of research reports collected for the CQs by outcome and study design, and the strength of evidence for each body of evidence was rated from levels A to D. 4) Introduction of systematic reviews in some CQs. 5) The strength Hiroaki Kajiyama https://orcid.org/0000-0003-0493-1825 Mikiko Asai-Sato https://orcid.org/0000-0002-7811-947X Kazuhiro Takehara $\textcircled{1}$ https://orcid.org/0000-0001-8808-3338 Tsutomu Tabata $\textcircled{1}$ https://orcid.org/0000-0003-0243-8180 Kenichi Harano $\textcircled { 1 0 }$ https://orcid.org/0000-0002-0833-3489 Yasuyuki Hirashima $\textcircled { 1 0 }$ https://orcid.org/0000-0003-0269-9313 Mayu Yunokawa $\textcircled{1}$ https://orcid.org/0000-0001-7354-6977 Aikou Okamoto $\textcircled{1}$ https://orcid.org/0000-0002-5079-0464 Mikio Mikami $\textcircled{1}$ https://orcid.org/0000-0002-7496-3518 # Participating contributors list Members of the Guidelines Formulation Committee (alphabetical order) Kazunari Fujino, Satoe Fujiwara, Keiko Furusawa, Masayuki Futagami, Kenichi Harano, Yuji Ikeda, Kazuhiko Ino, Haruko Iwase, Hiroaki Kajiyama, Yosuke Konno, Kenzo Kudo, Sakura Kudo, Shiho Kuji, Hiroko Machida, Kouji Matsumoto, Junji Matsuoka, Takashi Mitamura, Mayuyo Mori, Taisuke Mori, Toshinari Muramatsu, Isao Murakami, Akitoshi Nakashima, Satoshi Nagamata, Takashi Nagai, Takayuki Nagasawa, Keiichiro Nakamura, Tadaaki Nishikawa, Hidetaka Nomura, Hiroyuki Nomura, Kaoru Niimi, Yoshitake Oishi, Takashi Ota, Shinya Sato, Manabu Seino, Shogo Shigeta, Sirou Suzuki, Munetaka Takekuma, Masataka Takenaka, Yasuhisa Terao, Yoshito Terai, Takafumi Toita, Hideki Tokunaga, Naotake Tsuda, Kiyomi Toyma, Hirokazu Usui, Miho Watanabe, Hidemichi Watari, Hideaki Yahata, Ken Yamaguchi, Wataru Yamagami, Eiko Yamamoto, Hiroshi Yoshida. Members of the Guidelines Evaluation Committee (alphabetical order) Daisuke Aoki, Kaoru Abiko, Mitsuya Ishikawa, Yutaka Ueda, Kimio Ushijima, Kouta Umemura, Yasuhiko Ebina, Katsutoshi Oda, Masanori Ono, Takashi Onda, Tetsuko Kato, Yuuko Kaneyasu, Hiroaki Kobayashi, Yuuko Sasajima, Mikiko Sato, Ayumi Shikama, Nobuyuki Susumu, Kiyoshi Takamatsu, Kazuhiro Takehara, Hiroshi Tanabe, Michihiro Tanigawa, Fumio Nagashima, Kaei Nasu, Hirotaka Nishi, Yoshiko Nishigaya, Kiyoshi Hasegawa, Kosei Hasegawa, Junzo Hamanishi, Akira Hirasawa, of evidence, the balance of benefits and harms, value and hope for patients, and clinical applicability were considered while drafting recommendations. Herein, we present the English version of the JSGO guidelines 2023 for the treatment of uterine body neoplasm. Keywords: Clinical Practice Guideline; Endometrial Cancer; Treatment; Gestational Trophoblastic Disease; Sarcoma # Synopsis The Japanese guidelines for the treatment of uterine body neoplasm 2023 aim to provide a standard of care for endometrial cancer, improve disease prognosis and treatment safety, reduce the economic and physical burden on patients, and promote mutual understanding between patients and health care professionals. # INTRODUCTION More than 17,000 women are diagnosed with endometrial cancer annually, and approximately 2,600 women in Japan die from the disease [1]. The first edition of the Guidelines for the Treatment of Uterine Body Neoplasm was published in 2006, with subsequent revisions in 2009 [2], 2013 [3], and 2018 [4], and the fifth edition was published in 2023. The method of preparation and description style have been revised, including other guidelines published by the Japanese Society of Gynecologic Oncology (JSGO). The general changes in the guideline include: transition from a textbook-style review to a Patient, Intervention, Comparison, Outcome-style clinical question (CQ) format; more uniform method of literature collection; inclusion of a diverse committee that includes the general public, patients, and professionals; evaluation of the total body of evidence, focusing on outcomes and the certainty of the evidence, and the adoption of recommendations that consider patient values and the social context in which guidelines are used. The 2023 edition of the guidelines for treatment of uterine body neoplasm is prepared in accordance with the “Minds Medical Practice Guideline Formulation Manual 2020 ver. 3.0.” This manual was published by Medical Information Distribution Service (Minds), an Evidence-Based Medicine promotion project that aims to improve the quality of medical care by supporting decision-making by patients and medical professionals through the dissemination of high-quality medical guidelines. Given that surgery is commonly chosen as the initial treatment for several histological types of uterine body neoplasms, including carcinosarcoma, and for stage III and part of stage IV, as well as the early stage, the CQs on initial treatment, which were divided into several chapters in the previous edition, are summarized in Chapter 2. CQs on unresectable, advanced cancer and recurrent cancers are now summarized in Chapter 4. The new version includes 9 chapters with the following contents and 8 algorithms. Chapter 1: Overview of the guidelines Chapter 2: Initial treatment for endometrial cancer Chapter 3: Postoperative adjuvant treatment for endometrial cancer Chapter 4: Treatment of unresectable advanced/recurrent cancer Chapter 5: Post-treatment surveillance Chapter 6: Fertility-sparing treatment Takuma Fujii, Hiroyuki Fujiwara, Hisashi Masuyama, Takeshi Motohara, Hidekazu Yamada, Mayu Yunokawa, Yoshio Yoshida, Tomoko Morita, Miwa Seshita. # Conflict of Interest No potential conflict of interest relevant to this article was reported. # Author Contributions Conceptualization: N.S., B.T., T.H., A.M., T.K., T.T., H.K., H.Y., Y.M., O.A., M.M., K.Y.; Data curation: M.T., N.S., B.T., T.H., W.H., T.M., T.Y.1 , T.Y.2 , K.H.; Formal analysis: M.T., W.H., T.M., T.Y.1 , T.Y.2 , K.H., A.M., T.K., H.K., H.Y., Y.M., K.Y.; Funding acquisition: T.T., K.Y.; Investigation: M.T., W.H., T.M., T.Y.1 , T.Y.2 , K.H., O.A., M.M., K.Y.; Supervision: N.S., B.T., T.H., O.A., M.M., K.Y.; Validation: M.T., N.S., B.T., A.M., T.K., T.T., H.K., H.Y., Y.M., O.A., M.M., K.Y.; Writing - original draft: M.T., K.Y.; Writing - review & editing: M.T., N.S., B.T., T.H., W.H., T.M., T.Y.1 , T.Y.2 , K.H., A.M., T.K., T.T., H.K., H.Y., Y.M., O.A., M.M., K.Y. T.Y.1 , Yasuhisa Terao; T.Y.2 , Yoshito Terai. Chapter 7: Treatment for uterine sarcoma Chapter 8: Treatment for trophoblastic disease Chapter 9: Document collections, including literature search terms A consensus for each recommendation was achieved through voting by the members of the committee and external evaluation board. # CHAPTER 1: OVERVIEW OF THE GUIDELINES # 1. How to use the guidelines This guideline provides a criterion for selecting an effective therapeutic approach for uterine body neoplasms in Japan and outlines the rationale supporting this approach based on current knowledge. However, it does not exclude other treatment methods that are not described in this document. The guidelines aim to: 1) Establish appropriate treatment methods for endometrial cancer, sarcoma, and trophoblastic disease 2) Reduce disparities in treatment approaches among institutions 3) Improve treatment safety and patient prognosis 4) Reduce physical, psychological, and economic burdens on patients by providing appropriate treatment 5) Foster mutual understanding between patients and health care professionals # 2. Intended audience These guidelines are intended for healthcare professionals, such as doctors, nurses, and pharmacists involved in the care of patients with endometrial cancer, sarcoma, and trophoblastic diseases. Furthermore, these guidelines aim to enhance the understanding of the general public, including patients and their families, regarding the treatment approaches for atypical endometrial hyperplasia (AEH), endometrial cancer, sarcoma, and trophoblastic disease. # 3. Diseases addressed by this guideline This guideline addresses AEH, endometrial carcinomas, carcinosarcomas and sarcomas, and trophoblastic diseases and their recurrences. # 4. Notes on using this guideline 1) Each item comprises of a CQ, recommendation, purpose, and commentary. References for the content are listed at the end of each CQ, and search formulas for collecting literature are available on the JSGO website (https://jsgo.or.jp/guideline/index.html). 2) For the CQs where $7 5 \%$ consensus was not achieved, the discussion and rationale behind the final recommendation were presented as "Discussion points at voting." 3) Because of the potential challenges associated with the administration of certain antineoplastic drugs under the Japanese medical care insurance system, the guidelines emphasize adherence to the recommendations of the Committee on Clinical Practice Guidelines for the Use of Anticancer Agents of the Japan Society of Clinical Oncology (JSCO). 4) Given the limited treatment options available for uterine cancer, it is not easy to make a comparative evaluation of the medical and economic aspects. Therefore, the 2023 edition basically does not evaluate the economic burden on individual patients or the healthcare system. # 5. Committee members The Guidelines Formulation Committee and Evaluation Committee included radiologists, medical oncologists, pathologists, and palliative care physicians in addition to gynecologic oncologists. Additionally, the Formulation Committee included nurses, pharmacists, patients, and the general public, who participated as external committee members from the initial stage of CQs setting. # 6. Literature retrieval This revision requested the Japan Medical Library Association (JMLA) to prepare literature search terms for a systematic database searches. The specific literature retrieval method is as follows: 1) The Formulation Committee selected an article using keywords related to the $\mathrm { C Q } ,$ and then the JMLA prepared relevant search terms and conducted a comprehensive literature search. If the initial search yielded a large number of articles, keywords were changed or added after review by the Formulation Committee and the JMLA. The Formulation Committee examined the retrieved articles and shortlisted 20 key articles. 2) Articles in PubMed, the Japan Medical Abstract Society, and the Cochrane Library were searched for articles published between January 2017 and December 2021. Articles published before 2016 that were cited in previous guideline editions and are needed for recommendations were used as references. Articles published after January 2022 were examined separately, and some were used as references. # 7. Level of evidence and grade of recommendations 1) We referred to the Minds Medical Practice Guideline Formulation Manual 2020 ver. 3.0 to determine the evidence levels for the recommendation grades [5]. The outcomes were set for each CQ. The body of evidence was assessed by considering the study designs, bias risk, and indirectness of the studies selected for each outcome (Table S1). 2) Levels of evidence in these guidelines are determined based on the factors prescribing a body of evidence that differ from the previous “levels of evidence,” which were based on study design, such as “randomized phase III.” Level of evidence might be “B (moderate),” not “A (strong),” depending on the quality of the clinical trial although evidence arises from a randomized phase III trial. 3) The “strength of recommendation” (Table S2) was evaluated by the Guideline Formulation Committee by considering the level of evidence, the balance of benefits and harms, patient values and preferences, and reimbursement status for the relevant treatment method in Japan. 4) For CQ06, CQ11, and CQ33, the Guideline Formulation Committee members conducted a systematic review for each CQ outcome. For CQs where quantitative evaluation (metaanalysis) was not possible, qualitative systematic reviews were conducted to evaluate the logic and certainty of the context. 5) The recommendation text, strength of the recommendations, and level of evidence were discussed and finalized at the seventh meeting of the Subcommittee for the Revision of Guidelines for the Treatment of Uterine Body Neoplasms. The consensus rate on these decisions was determined by voting. 6) For recommendations that failed to achieve $7 5 \%$ consensus, the content of the recommendation was reviewed, the “strength of recommendation” and “level of evidence” were modified, or the content of the recommendation was modified and voted again. 7) Opinions and points of discussion for the re-voted recommendations or those with a lower consensus threshold are described in re-voted CQs as “Discussion points at voting.” 8) The recommendations in CQ02-04, CQ06-08, CQ13-17, CQ23-29, CQ32, and CQ33, and those that achieved initial consensus within the Formulation Committee, were subjected to a final vote by the external committee. Therefore, the consensus for these CQs is the sum of the votes by both core and external committee members. # 8. Procedure for guideline creation The Guidelines Formulation Committee and Evaluation Committee were independently established within the Committee for Treatment Guidelines for Cervical Cancer established by the Guidelines Committee of the JSGO to create these guidelines. The Chair of the Guidelines Committee is concurrently the chair of the Committee for Treatment Guidelines for Cervical Cancer and the chair of the Guidelines Formulation Committee. After 8 meetings of the Guidelines Formulation Committee, a consensus meeting, and a period of public comments, guidelines were revised between June 2021 and April 2023. # 9. Tips for activation of use and disclosure of information 1) Algorithms were developed to enhance the practical utility to the audience. 2) These guidelines are published as a pamphlet and available on the JSGO, JSCO, and Minds websites to facilitate widespread use. 3) The results of systematic reviews and meta-analyses in CQ15 [6] and CQ29 [7] have been published in internationally cited journals. # 10. Responsibility for treatment The JSGO assumes responsibility for the content of the guidelines. However, the final decision on using the guideline recommendations for individual treatment is at the discretion of the user. Responsibility for treatment outcomes should be attributed to the person directly in charge of the treatment. # 11. Monitoring and revision 1) A monitoring team has been established within the Guideline Development Committee. 2) The monitoring Team will continue to collect and accumulate newly reported evidence after the completion of these guidelines. 3) The monitoring Team will collect relevant information on cases of clinical inconvenience in the use of this guideline. 4) The next revision is scheduled for 2028. 5) If it is deemed necessary to change the strength or content of a recommendation or to establish a new CQ during the interim period, the monitoring team and guideline committee chair, and vice-chair will form a new drafting committee to prepare a revised draft or a new draft recommendation. 6) The revised or newly recommended draft will be published on the website of the JSGO after approval by the Board of Directors of the Society following a consensus meeting and review of public comments. 7) Some CQs will be measured as process indicators or actual status indicators, and the implementation rate will be analyzed to evaluate the guideline recommendations using the tumor registry database of the Japanese Society of Obstetrics and Gynecology and through joint research with the National Cancer Center. # 12. Funding The development of these guidelines was solely funded by the JSGO. No external funding or support was received. # 13. Conflicts of interest The Board of the Society Conflict of Interest Committee confirmed the status of conflicts of interest disclosures of Guidelines Formulation Committee and Evaluation Committee members and their affiliates for 2020 and 2021. A total of 26 and 48 members of the Guideline Formulation Committee, respectively, and 19 and 27 members of the Evaluation Committee, respectively, reported conflicts of interest in 2020 and 2021. No member was judged to have a conflicts of interest that exceeded the socially acceptable range. # 14. Summary of recommendations Each chapter comprises the CQs, recommendations, background, objectives, explanations, and references. This article summarizes the guidelines in a question-and-answer format. Recommendations from each chapter are listed in their respective chapter titles. # 15. Algorithms The guidelines contain the following 8 algorithms and one panel: 1) Initial treatment for endometrial cancer considered to be stage I or II preoperatively (Fig. 1). 2) Initial treatment for the patients diagnosed with endometrial cancer after hysterectomy and for cases with an intermediate or high risk of postoperative recurrence despite a presumed low risk preoperatively (Fig. 2). 3) Initial treatment for endometrial cancer considered to be stage III or IV preoperatively (Fig. 3). 4) Postoperative adjuvant treatment for endometrial cancer (Fig. 4). 5) Treatment of recurrent endometrial cancer (Fig. 5). 6) Fertility-sparing therapy for AEH and endometrioid carcinoma (corresponding to G1) (Fig. 6). 7) Treatment for uterine sarcoma (Fig. 7). 8) Treatment for choriocarcinoma (Fig. 8). 9) Classification of postoperative risk of recurrence of endometrial cancer (Fig. 9). ![](images/2ad35105049e36aec62a81cc0871ad1d6a689feb3b711356bcb2e82c82594e17.jpg) Fig. 1. Initial treatment for endometrial cancer considered to be stage I or II preoperatively. CQ, clinical question. ![](images/c376f11fa985bec4353cae7757ad43f6f5c187bac34b4fa74b980c21c2babc4a.jpg) Fig. 2. Initial treatment for the patients diagnosed with endometrial cancer after hysterectomy and for cases with an intermediate or high risk of postoperative recurrence despite a presumed low risk preoperatively. CQ, clinical question. \In the 2022 National Comprehensive Cancer Network guidelines, observation is possible for patients with a tumor of ${ \mathrm { < } } 2 \ \mathsf { c m }$ , lymph-vascular space invasion negative, and a presumed low recurrence risk (CQ16). ![](images/154d388be0b72c4b2e54d270030750b126dd39dcb4b65dee80391e0d13e1bf08.jpg) Fig. 3. Initial treatment for endometrial cancer considered to be stage III or IV preoperatively. CQ, clinical question. \If the general condition is not worse, this refers to all patients in stage III and patients who can undergo hysterectomy and cytoreductive surgery in stage IV (CQ11). ![](images/6303261cd7f5942da7e5d821a216a619b0ed99c32860abd71bca75f73caf42b0.jpg) Fig. 4. Postoperative adjuvant treatment for endometrial cancer. CQ, clinical question. ![](images/06c544976f1b1dc66e88e34a62f1a5784958cdcab3eb8da6d3931307b872ffd1.jpg) Fig. 5. Treatment of recurrent endometrial cancer. CQ, clinical question. \Resection should also be considered for cases with a few small lung metastases (CQ20). ![](images/b3d4f1f05552b81bfb0954beafa1cebecd93de8a89bbc0ba10b0f24766f50715.jpg) Fig. 6. Fertility-sparing therapy for AEH and endometrioid carcinoma (corresponding to G1). AEH, atypical endometrial hyperplasia; CT, computed tomography; CQ, clinical question; MRI, magnetic resonance imaging. ![](images/bb50c63a9a9262ceb9f191ddd5a729f8cbade3bbbf458413bcb2e5b751c791dd.jpg) Fig. 7. Treatment for uterine sarcoma. CQ, clinical question; HGESS, high-grade endometrial stromal sarcoma; LGESS, low-grade endometrial stromal sarcoma; LMS, leiomyosarcoma; UUS, undifferentiated uterine sarcoma. ![](images/8a27b288e1d429a076567be78f8c6fd7cfa369a3edef4a897b00a94ce343529e.jpg) Fig. 8. Treatment for choriocarcinoma. AcD, actinomycin-D; CQ, clinical question; FIGO, International Federation of Gynecology and Obstetrics; GTN, gestational trophoblastic neoplasia; hCG, human chorionic gonadotropin; MTX, methotrexate. ![](images/45e3d42f42bdf21f195ef2882ebd25c2bfea8fb4e5f3f1e251b3cc66395f9b0c.jpg) Fig. 9. Classification of postoperative risk of recurrence of endometrial cancer. LVSI, lymph-vascular space invasion. \Adnexa, uterine serosa, vagina, cardinal ligament, lymph node, bladder, rectum, intraperitoneal and distant metastasis. # CHAPTER 2: INITIAL TREATMENT FOR ENDOMETRIAL CANCER CQ01: Is total hysterectomy recommended as initial surgical therapy? # Recommendations 1. Total hysterectomy (extrafascial) or extended simple hysterectomy is recommended for patients presumed to have no vaginal or parametrial involvement. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $100 \%$ . 2. Modified radical hysterectomy or radical hysterectomy for complete resection is suggested for patients with presumed vaginal or parametrial involvement. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $1 0 0 \%$ . # CQ02: Is omission of pelvic lymphadenectomy recommended for patients preoperatively estimated to be at low risk of recurrence? # Recommendation 1. The omission of pelvic lymphadenectomy is suggested in patients with endometri carcinoma G1 or G2 that is presumed to be stage IA preoperatively. Strength of recommendation: 2 (↑) level of evidence: C; consensus: $9 1 \%$ . CQ03: Is pelvic and para-aortic lymphadenectomy recommended for patients who are preoperatively estimated to be at an intermediate or high-risk of recurrence? # Recommendations 1. Pelvic lymphadenectomy is recommended. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $100 \%$ . 2. In addition to pelvic lymphadenectomy, para-aortic lymphadenectomy down to the renal vein is suggested. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $8 2 \%$ . Discussion points at voting: The consensus for recommendation 2 was $7 6 \%$ . Although there was a concern that para-aortic lymph node dissection could be easily omitted, there was also an opinion that the standard treatment group in the JCOG1412 trial was pelvic lymph node dissection, and the therapeutic significance of para-aortic lymph node dissection remains unclear. # CQ04: Is omission of pelvic lymph node dissection recommended when sentinel nodes are negative? # Recommendation 1. In medical institutes that are skilled in the technique of sentinel node biopsy and have the cooperation of pathologists for intraoperative diagnosis, the omission of pelvic lymph node dissection is suggested as a clinical trial. Strength of recommendation; 2 (↑); level of evidence: B; consensus: $9 1 \%$ . # CQ05: Is omentectomy recommended for patients without gross evidence of omental metastases? # Recommendation 1. Omentectomy is suggested as a staging surgical technique if the patient is considered to have a special histological subtypes or endometrial carcinoma G3, or an extrauterine lesion is found intraoperatively. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $8 1 \%$ . Discussion points at voting: Initially, the recommendation included the words "deep muscle invasion" and "positive peritoneal cytology," which received $3 8 \%$ consensus. There was no mention of "positive peritoneal cytology," and the recommendation did not match some of the explanatory content. After correction, the consensus was $8 1 \%$ . # CQ06: Is ovarian preservation recommended for patients with preoperative stage I or II disease without gross ovarian metastases? Systematic review # Recommendations 1. In principle, ovarian preservation is not recommended for initial treatment. Strength of recommendation:1 (↓↓); level of evidence: A; consensus: $8 6 \%$ . 2. In young patients with endometrial carcinoma G1 and preoperatively estimated stage IA, if there is a strong desire for ovarian preservation, ovarian preservation is suggested after fully explaining the risks. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $9 5 \%$ . Discussion points at voting: Recommendation 2 was initially “Stage I, G1, young patients with shallow myometrial invasion are suggested for ovarian preservation after fully explaining the risks associated with ovarian preservation. Strength of recommendation 2 (↑) evidence level $\mathrm { C } ^ { \mathfrak { N } }$ with a consensus rate of $7 1 \%$ . The committee members asked about the principles of salpingo-oophorectomy and whether to propose ovarian preservation even for patients who did not wish to undergo ovarian preservation. The consensus was $9 5 \%$ . # CQ07: Is omission of pelvic lymphadenectomy recommended for surgery on elderly patients? # Recommendation 1. In elderly patients, perform an elderly functional assessment first. The omission of lymph node dissection is not suggested in operable patients who are presumed to be at intermediate or high risk of recurrence. Strength of recommendation: 2 (↓); level of evidence: C; consensus: $9 1 \%$ . # CQ08: Is it recommended to wait for weight loss before surgery in a severely obese patient? # Recommendations 1. In patients with advanced-stage disease, special histologies, or endometrial carcinoma G3, wait for surgery for weight loss is not recommended. Strength of recommendation: 1 (↓↓); level of evidence: C; consensus: $1 0 0 \%$ . 2. In patients with endometrial carcinoma G1 or equivalent and preoperative stage IA, wait for surgery for weight loss is suggested under the principle that the procedure should be performed at a facility with multidisciplinary cooperation. Strength of recommendation: 2 (↑); level of evidence: D; consensus: $9 1 \%$ . CQ09: Are magnetic resonance imaging (MRI), computed tomography (CT), or positron emission tomography/CT (PET/CT) recommended for treatmentdecision making? # Recommendations 1. MRI is recommended to evaluate local extensions such as myometrial invasion and cervical stromal invasion. Strength of recommendation: 1 (↑↑); level of evidence: A; consensus: $100 \%$ . 2. Evaluation of lymph node metastasis and distant metastasis by CT and MRI is recommended. Strength of recommendation: 1 (↑↑); level of evidence: A; consensus: $100 \%$ . 3. Evaluation by PET/CT is suggested when it is difficult to evaluate lymph node and distant metastasis by CT or MRI. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $9 4 \%$ . # CQ10: Is endoscopic (laparoscopic/robotic) surgery recommended for initial treatment? # Recommendations 1. Endoscopic surgery is recommended for patients presumed to be in stage I. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $9 4 \%$ . 2. Endoscopic surgery is suggested for patients presumed to be in stage II. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $8 8 \%$ . 3. Endoscopic surgery is not suggested in patients with advanced-stage disease. Strength of recommendation: 2 (↓); level of evidence: C; consensus: $8 8 \%$ . # CQ11: Is surgical treatment recommended for patients considered preoperatively stage IV? # Recommendation 1. Surgical intervention is suggested if total hysterectomy plus maximal tumor reduction is feasible. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $8 8 \%$ . CQ12: Is definitive radiation therapy recommended as the initial therapy for patients with resectable tumors, but surgical resection is not indicated owing to medical reasons? Recommendation 1. Definitive radiation therapy is suggested. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $9 4 \%$ . # CHAPTER 3: POSTOPERATIVE ADJUVANT TREATMENT FOR ENDOMETRIAL CANCER CQ13: Is postoperative chemotherapy recommended for patients who have undergone complete surgical resection during initial surgery? # Recommendations 1. Chemotherapy with adriamycin (doxorubicin hydrochloride) and cisplatin (AP regimen) is recommended for high-risk patients. Strength of recommendation: 1 (↑↑); level of evidence: A; consensus: $8 6 \%$ . 2. Chemotherapy with paclitaxel and carboplatin (TC regimen) is suggested for highrisk patients. Strength of recommendation: 2 (↑); level of evidence: B; consensus: $8 2 \%$ . 3. Regimens for high-risk patients are also suggested for intermediate-risk patients. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $9 5 \%$ . 4. Postoperative chemotherapy is not recommended for patients at low risk of recurrence. Strength of recommendation: 1 (↓↓); level of evidence: C; consensus: $9 5 \%$ . 5. For postoperative chemotherapy for carcinosarcoma, a 2-agent combination including ifosfamide, platinum, and paclitaxel is suggested. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $9 1 \%$ . 6. Progesterone therapy is not recommended as a postoperative adjuvant therapy. Strength of recommendation: 1 (↓↓); level of evidence: B; consensus: $9 5 \%$ . Discussion points at voting: Although the consensus rate for both recommendations was more than $7 5 \%$ , the AP regimen is used in only $1 0 \%$ of clinical settings, whereas the TC regimen is more commonly adopted. This disparity prompted discussion on whether the recommendations for AP and TC should be the same. # CQ14: Is postoperative radiation therapy recommended for patients who have undergone complete surgical resection during initial surgery? Recommendation 1. Postoperative radiation therapy is suggested as an option to reduce pelvic recurrence. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $9 5 \%$ . CQ15: Is postoperative adjuvant therapy recommended in patients with a low risk of recurrence and positive peritoneal cytology? Systematic review Recommendation 1. Adjuvant therapy is not suggested. Strength of recommendation: 2 (↓); level of evidence: C; consensus: $8 6 \%$ . Discussion points at voting: Although the consensus among the core members of the Formulation Committee was $9 4 \%$ , the consensus among the external committee members was $60 \%$ , making this the only CQ with a notable discrepancy between the Formulation Committee members and the general public. This disparity may reflect patient anxiety about not receiving adjuvant chemotherapy. Although a recommendation was made after a systematic review, evidence supporting the recommendation was deemed insufficient, resulting in “level of evidence C.” # CQ16: Is additional treatment recommended for patients diagnosed with endometrial cancer after hysterectomy? # Recommendations 1. Additional treatment, including staging surgery is recommended if the patient is suspected to recurrent intermediate- or high-risk cases. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $9 1 \%$ . 2. If the patient can be presumed to be in the low-risk cases for recurrence, additional treatment is not recommended and careful follow-up is suggested. Strength of recommendation: 2 (↓); level of evidence: C; consensus: $1 0 0 \%$ . # CQ17: Is additional treatment recommended for patients initially presumed to have low-risk for recurrence but later found to have intermediate- or highrisk for recurrence after surgery? Recommendations 1. Additional treatment is recommended after metastasis examination by imaging. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $8 6 \%$ . 2. Staging surgery is suggested to determine the exact surgical stage. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $9 5 \%$ . # CHAPTER 4: TREATMENT OF UNRESECTABLE ADVANCED/RECURRENT CANCER CQ18: Is preoperative treatment recommended for advanced cancer that is expected to be difficult to resect or have residual disease? # Recommendation 1. Preoperative chemotherapy for patients with advanced-stage disease with invasion to the surrounding organs presenting challenges in surgical resection or those with distant metastases and the possibility of residual disease is suggested. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $9 4 \%$ . CQ19: Is radiation therapy recommended for vaginal stump recurrence? # Recommendations 1. Radiotherapy is recommended. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $100 \%$ . 2. Surgery is suggested instead of radiotherapy. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $8 8 \%$ . Discussion points at voting: The consensus for recommendation 2 was $8 8 \%$ , but there was a suggestion that the option of drug therapy (including hormonal therapy) should be added for vaginal stump recurrence. # CQ20: Is surgical treatment recommended in patients with recurrent sites other than the vaginal stump? Recommendation 1. Surgical treatment is suggested if complete resection of the recurrent site is feasible. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $1 0 0 \%$ . # CQ21: Is chemotherapy recommended for advanced or recurrent cancers that are unresectable or have residual disease? # Recommendations 1. TC or AP regimen is recommended for advanced disease. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $9 4 \%$ . 2. For recurrent disease A. TC regimen is recommended for patients who have not received prior platinum containing chemotherapy. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $100 \%$ . B. Lenvatinib plus pembrolizumab is recommended for patients who have received prior platinum-containing chemotherapy. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $8 1 \%$ . C. Monotherapy with pembrolizumab suggested for patients with a history of platinum-containing chemotherapy and microsatellite instability (MSI)-high, deficient mismatch repair, or tumor mutational burden-high. Strength of recommendation: 2 (↑); level of evidence: B; consensus: $8 8 \%$ . 3. Regimens, including ifosfamide, platinum, and paclitaxel is suggested for chemotherapy in patients with advanced or recurrent carcinosarcoma. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $100 \%$ . 4. Progestin therapy is suggested for patients with endometrioid carcinoma G1 or estrogen receptor/progesterone receptor positive. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $9 4 \%$ . Discussion points at voting: The consensus rate was $3 5 \%$ on “strength of recommendation 2 (↑)” for recommendation 2B. Many committee members recommended “strength of recommendation 1 (↑↑)” for the lenvatinib plus pembrolizumab regimen considering the availability of evidence, increased clinical use, and guideline endorsements from the United States and Europe. A consensus rate of $8 1 \%$ was reached for “strength of recommendation 1 (↑↑)” after re-voting, though some suggested adjusting the recommendation based on MSI test results. Initially, recommendation 2-dimensional (2D) suggested AP regimen, TC regimen, monotherapy, and best supportive care for patients with a history of platinum therapy and for those where LP therapy is not appropriate. (strength of recommendation 2 (↑), level of evidence C). Recommendation 2D was deleted because it only describes obvious cases, and the definition of cases in which the LP regimen is not appropriate is ambiguous. However, some have expressed concerns that the significance of platinum-free therapy in endometrial cancer is inconclusive and that the removal of platinum rechallenge from the recommendation may cause confusion in the field. # CQ22: Is radiation therapy recommended for patients with advanced or recurrent cancers that are unresectable or have residual disease? # Recommendation 1. Radiotherapy is suggested for advanced or recurrent cancer with unresectable or residual disease for the purpose of local control or palliation. Strength of recommendation: 2(↑); level of evidence: C; consensus: $100 \%$ . # CQ23: Is oncogene panel testing using next-generation sequencing, etc. recommended for patients with recurrent cancer? Recommendation 1. A cancer gene panel test is suggested for patients with recurrent cancer who have completed or are about to complete standard treatment. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $9 5 \%$ . # CHAPTER 5: POST-TREATMENT SURVEILLANCE CQ24: Is periodic surveillance recommended after definitive treatment? # Recommendations 1. The suggested intervals of surveillance are every 3–6 months for 1–3 years, and every 6–12 months for 4–5 years. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $8 6 \%$ . 2. Careful interviews to confirm the symptoms and pelvic examinations are recommended to diagnose pelvic recurrence. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $9 1 \%$ . 3. Vaginal stump cytology, serum tumor markers, ultrasonography, and imaging such as chest radiography and CT are suggested as appropriate, considering the risk of recurrence in each case. Strength of recommendation: 2(↑); level of evidence C; consensus: $1 0 0 \%$ . 4. CT, MRI, and PET/CT evaluations are recommended to search for the lesion when recurrence is suspected. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $100 \%$ . # CQ25: Is hormone replacement therapy (HRT) recommended after treatment for endometrial cancer? # CQ26: What factors should be considered when providing lifestyle guidance after endometrial cancer treatment? # Recommendations 1. Risk assessment of lifestyle-related diseases is recommended. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $9 5 \%$ . 2. Lifestyle modification guidance for patients with lifestyle-related diseases is suggested. Strength of recommendation 2 (↑), level of evidence: B; consensus $9 5 \%$ . 3. Lower gastrointestinal endoscopic surveillance is recommended for patients with endometrial cancer diagnosed with Lynch syndrome. Strength of recommendation: 1 (↑↑); level of evidence; B; consensus: $100 \%$ . 4. Genetic counseling is suggested for blood relatives of patients with endometrial cancer diagnosed with Lynch syndrome. Strength of recommendation: 2 (↑); level of evidence: B; consensus: $100 \%$ . # CHAPTER 6: FERTILITY-SPARING THERAPY CQ27: Is fertility-sparing therapy recommended for young patients with AEH or endometrial cancer? # Recommendation 1. Progesterone therapy is suggested for patients with AEH or endometrioid adenocarcinoma G1 limited to the endometrium. Strength of recommendation: 2 (↑↑); level of evidence: C; consensus: $8 6 \%$ . Discussion points at voting: The consensus rate was $7 1 \%$ for the initial recommendation "progesterone therapy is recommended for patients with AEH or G1 confined to the endometrium, strength of recommendation 1 (↑↑), level of evidence C". The committee members expressed concerns regarding the strength and suggested incorporating the need for confirmatory full curettage. The committee re-voted to include full curettage in the recommendation and lower the strength of recommendation to 2 (↑), resulting in a consensus rate of $8 6 \%$ . # CQ28: What are suitable follow-up periods and examinations after fertility preservation therapy? Recommendation Endometrial histology and transvaginal ultrasonography are suggested every 3–6 months. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $9 5 \%$ . # CQ29: Is conservative treatment recommended for patients with residual lesions or intrauterine recurrence after fertility preservation therapy? Systematic review # Recommendation 1. Conservative treatment is not recommended for patients with residual lesions. Strength of recommendation: 1 (↓↓); level of evidence: B; consensus: $8 6 \%$ . 2. Repeat progesterone therapy is suggested under close supervision in patients with intrauterine recurrence and a strong desire for fertility preservation. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $1 0 0 \%$ . Discussion points at voting: Recommendation 1 initially stated that conservative therapy is not recommended (strength of recommendation 1 [↓↓] evidence level B), with a consensus rate of $5 0 \%$ . Committee members noted inconsistencies between the recommendation and the commentary, which included positive statements for conservative therapy. Additionally, the recommendation is too strong, and differentiating between lesion remnants and intrauterine recurrence was necessary. Based on these discussions, the CQ was revised to "Is conservative treatment recommended for patients with residual lesions or intrauterine recurrence after fertility preservation therapy?" and the consensus rate was $8 6 \%$ . # CQ30: Is assisted reproductive technology (ART) recommended for patients after fertility preservation therapy? Recommendation 1. ART is suggested for conception. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $1 0 0 \%$ . # CHAPTER 7: TREATMENT OF UTERINE SARCOMA CQ31: What surgical techniques are recommended for uterine sarcoma? # Recommendations 1. Total abdominal hysterectomy and bilateral salpingo-oophorectomy are recommended. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $8 8 \%$ . 2. Tumor reduction surgery with the aim of complete extraction is suggested. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $100 \%$ . 3. Lymph node dissection is not suggested for leiomyosarcoma and low-grade endometrial stromal sarcoma (ESS) without findings of lymph node metastasis. Strength of recommendation: 2 (↓); level of evidence: B; consensus: $7 5 \%$ . # CQ32: Is additional surgery recommended for patients diagnosed with uterine sarcoma postoperatively? # Recommendation 1. Additional surgeries to complete the total hysterectomy and bilateral salpingooophorectomy are suggested. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $1 0 0 \%$ . Discussion points at voting: Initially, recommendation 2 stated that “ovarian preservation for premenopausal early-stage leiomyosarcoma” (strength of recommendation 2 [↑], level of evidence C). However, there were concerns regarding whether “premenopausal” is appropriate and whether ovarian preservation should be considered for patients after enucleation, a procedure typically performed for benign disease. The deletion of recommendation 2 was initially supported by $6 9 \%$ consensus, with some discussion on modifying its wording. Ultimately, the committee reached a $100 \%$ consensus to delete the recommendation. # CQ33: What postoperative adjuvant therapy is recommended for patients with uterine sarcomas who have undergone complete surgical removal during the initial surgery? # Recommendations 1. Postoperative adjuvant therapy is not suggested for stage I leiomyosarcoma. Strength of recommendation: 2 (↓); level of evidence: B; consensus: $9 5 \%$ . 2. Chemotherapy is suggested for postoperative adjuvant treatment of leiomyosarcoma, undifferentiated uterine sarcoma, and high-grade ESS. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $8 6 \%$ . 3. Hormone therapy is suggested when postoperative adjuvant therapy is indicated for low-grade ESS. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $9 5 \%$ . # CQ34: Is chemotherapy recommended for unresectable advanced or recurrent cases of uterine sarcoma? # Recommendations 1. Chemotherapy is suggested based on the systemic condition of patients. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $9 4 \%$ . 2. Doxorubicin monotherapy is recommended as chemotherapy. Strength of recommendation: 1 (↑↑); level of evidence: A; consensus: $9 4 \%$ . 3. Pazopanib, trabectedin, and eribulin are suggested in the second-line and subsequent treatments. Strength of recommendation: 2 (↑); level of evidence: B; consensus: $9 4 \%$ . 4. Hormone therapy is suggested for low-grade ESS. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $100 \%$ . # CHAPTER 8: TREATMENT OF TROPHOBLASTIC DISEASE CQ35: What chemotherapy is recommended for an invasive mole, clinically invasive mole, or post-molar persistent human chorionic gonadotropin (hCG)? Recommendation 1. Monotherapy with methotrexate or actinomycin D is recommended. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $100 \%$ . # CQ36: What chemotherapy is recommended for choriocarcinoma? # Recommendation 1. Multidrug regimen, including methotrexate, actinomycin D, and etoposide is recommended. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $100 \%$ . # CQ37: Is treatment other than chemotherapy recommended for choriocarcinoma? # Recommendations 1. Surgical treatment for uterine lesions refractory to chemotherapy or metastatic lesions is suggested with careful consideration of the indications. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $8 1 \%$ . 2. Surgical treatment is suggested for uterine lesions with difficulty in bleeding control or brain metastases with urgent bleeding and symptoms of cerebral hypertension. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $1 0 0 \%$ . 3. Radiotherapy is suggested for brain metastases after careful consideration of the indications. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $8 1 \%$ . # CQ38: What treatments are recommended for patients with placental site trophoblastic tumor or epithelioid trophoblastic tumor? # Recommendations 1. Total hysterectomy is suggested for patients with lesions confined to the uterus. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $1 0 0 \%$ . 2. Combination of surgical treatment including total hysterectomy and chemotherapy including platinum-based agents are suggested for patients with extrauterine lesions. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $9 4 \%$ . # CQ39: What is the recommended treatment for patients with persistently low-positive hCG? # Recommendations 1. Detection of the lesion and confirmation of real hCG are recommended. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $100 \%$ . 2. Treatment as a trophoblastic tumor is recommended if the lesion is confirmed or if the hCG tends to increase. Strength of recommendation: 1 (↑↑); level of evidence: B; consensus: $100 \%$ . 3. If low levels of real hCG do not disappear after follow-up without lesions, chemotherapy and evaluation of efficacy are suggested. Strength of recommendation: 2 (↑); level of evidence: C; consensus: $8 6 \%$ . Discussion points at voting: Initially, Recommendation 2: "If the lesion is confirmed or if the hCG tends to increase, treatment is recommended based on the clinical diagnosis as a trophoblastic disease. Strength of recommendation 1 (↑↑), level of evidence B," Recommendation 3: "If low levels of real hCG do not disappear, it is suggested that chemotherapy be given to determine whether it is effective. Strength of recommendation 2 (↑), level of evidence C." The agreement rates were $6 9 \%$ and $1 9 \%$ , respectively. The consensus for recommendation 2 was $1 0 0 \%$ as a result of discussion with some modifications. Regarding recommendation 3, there were opinions that chemotherapy for all patients with persistent low-levels of hCG might be overtreatment and that easy followup should be avoided. After discussion, the recommendation was changed to the current recommendation, and the consensus rate was $8 6 \%$ . # ACKNOWLEDGEMENTS The authors thank the Japan Society of Obstetrics and Gynecology, Japan Association of Obstetricians and Gynecologists, Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy, Japanese Gynecologic Oncology Group, Japanese Society for Radiation Oncology, and Japanese Society of Pathology for their comments and contributions throughout the project. Furthermore, the authors acknowledge the clerical and technical assistance provided by Ms. Toshie Yasuda of the JSGO and Ms. Yuriko Adachi of Kanehara Co., Ltd. The authors would like to thank Editage for language editing. # SUPPLEMENTARY MATERIALS # Table S1 Certainty ratings for outcomes to determine grades of recommendation # Table S2 Strength of recommendation # REFERENCES 1. Cancer Information Service, National Cancer Center. Uterine body [Internet]. Tokyo: Cancer Information Service, National Cancer Center; 2024 [cited 2024 Jul 1]. Available from: https://ganjoho.jp/reg_stat/ statistics/stat/cancer/18_corpus_uteri.html#anchor1. 2. Nagase S, Katabuchi H, Hiura M, Sakuragi N, Aoki Y, Kigawa J, et al. Evidence-based guidelines for treatment of uterine body neoplasm in Japan: Japan Society of Gynecologic Oncology (JSGO) 2009 edition. Int J Clin Oncol 2010;15:531-42. PUBMED \| CROSSREF 3. Ebina Y, Katabuchi H, Mikami M, Nagase S, Yaegashi N, Udagawa Y, et al. Japan Society of Gynecologic Oncology guidelines 2013 for the treatment of uterine body neoplasms. Int J Clin Oncol 2016;21:419-34. PUBMED \| CROSSREF 4. Yamagami W, Mikami M, Nagase S, Tabata T, Kobayashi Y, Kaneuchi M, et al. Japan Society of Gynecologic Oncology 2018 guidelines for treatment of uterine body neoplasms. J Gynecol Oncol 2020;31:e18. PUBMED \| CROSSREF 5. Minds Manual Developing Committee. Minds medical practice guideline formulation manual 2020 ver. 3.0 [Internet]. Tokyo: Council for Quality Health Care; 2021 [cited 2021 Dec 20]. Available from: https:// minds.jcqhc.or.jp/docs/methods/cpg-development/minds-manual/pdf/all_manual_.pdf. 6. Shigeta S, Konno Y, Terai Y, Morisada T, Tokunaga H, Baba T, et al. A qualitative systematic review of the significance of adjuvant therapy in patients with low-risk endometrial cancer presenting positive peritoneal cytology: a relevant study to the guideline update for endometrial cancer by the Japan society of gynecologic oncology guideline committee. Jpn J Clin Oncol 2024;54:217-20. PUBMED \| CROSSREF 7. Murakami I, Machida H, Morisada T, Terao Y, Tabata T, Mikami M, et al. Effects of a fertility-sparing retreatment for recurrent atypical endometrial hyperplasia and endometrial cancer: a systematic literature review. J Gynecol Oncol 2023;34:e49. PUBMED \| CROSSREF	None	None	None
9cb2205684784fe6bb4cf24057f324e9	2025+ASRI指南	复发性妊娠丢失的治疗	# 2025 American Society for Reproductive Immunology Guidelines for the Treatment of Recurrent Pregnancy Losses: Practice Recommendations From the ASRI Clinical Reproductive Immunology Fellowship Marcelo Borges Cavalcantel $\textcircled { 1 0 }$ Conor Harrity² $\textcircled{1}$ \|Thanh Luu3 $\textcircled { 1 0 }$ Joy Fatunbi3 $\textcircled { 1 0 }$ IKoji Nakagawa4 $\textcircled{1}$ 1 Yuan Zhang $\textcircled { 1 0 }$ Tao Zhang6 $\textcircled{1}$ Hallah Alanazi7 $\textcircled { 1 0 }$ 1LiWu8 $\textcircled { 1 0 }$ 1Sungki Lee9 $\textcircled { 1 0 }$ Ricardo Barini10 $\textcircled{1}$ 1 Joanne Kwak-Kim³ $\textcircled{1}$ lPostgraduate Program in Medical Sciences, University of Fortaleza (UNIFOR),Fortaleza,Brazil $1 \ ^ { 2 } \mathrm { R C S I }$ University of Medicine and Health Sciences,Dublin, Ieladepce Northicagcipatu丨e Reproductielesasi Universityeia 7VFandeprctiocrnt'saltsialgulalCiybi Hospitalof USTC,DivisionofLifeSciencesandMedicine,UniversityofcienceandTechnologyofChina,Hefei,China $1 ~ ^ { 9 }$ Department of Obstetrics and Gynecologyiialbtedi Campinas,Sao Paulo,Brazil Correspondence: Joanne Kwak-Kim (Joanne.kwakkim@rosalindfranklin.edu) Received: 4 December 2024丨Revised: 24 April 2025丨Accepted:12 May 2025 ywords: guidelines limmunotherapy \|recurrent miscarriage 丨recurrent pregnancyloss丨recurent spontaneous abortic # ABSTRACT Various immunomodulatory treatments have been applied to women with recurrent pregnancy losses since a significant proportion of them havecellularand autoimmune abnormalities.However,immunomodulatory treatments are often considered controversial for their eficacies.Often,theyare provided tounselected patients without investigating potential etiologies by healthcare providers without appropriate reproductive immunology training andqualifications.To eliminate theseconcerns, the American Society for Reproductive Immunology (ASRI) established the Clinical Reproductive Immunology Felowship and has beencertifying reproductive immunologists.The approach to RPL from a reproductive immunology perspective requires a detailedunderstanding of underlying immunopathology,advanced knowledgeof clinical and basic science andtranslational research,and thecapabilityto evaluate theavailable evidence.The immunotherapy guideline development group,composedof clinical reproductive immunology fellows,ASRI,reviewedthecurrentlyavailable data and developed the clinical guidelines for immunotherapy. # 1Introduction Recurrent pregnancy loss (RPL) is defined as two or more spontaneous abortions [1].It affects $1 \%$ to $5 \%$ of couples trying to conceive [2,3].Recent studies suggest that the contemporary reproductive profile,characterized by advanced maternal age,increased rates of obesity, exposure to environmental contaminants,and other lifestyle or health related factors,contribute to pregnancy losses in up to half of all couples experiencing pregnancy losses. Genetic abnormalities,endocrinopathies,uterine malformations,cervical incompetence,and antiphospholipid syndrome (APS)are among the most commonly reported causes of RPL[4].However, natural killer(NK) cell dysfunction and aberrant Thl/Th2 ratios have been identified in over $7 3 \%$ of women with unexplained RPL (uRPL) [5]. The maternal immune response during pregnancy is a dynamic physiological event.Briefly, pregnancy can be divided into three distinct immunological stages: two predominantly inflammatory phases (first and third trimester) and one anti-inflammatory phase (second trimester) [6,7].An imbalance in the maternal immune response is related to poor pregnancy outcomes.Women with reproductive failures,such as RPL and repeated implantation failures (RIF),and obstetrical complications,including preeclampsia and preterm labor,have various cellular and autoimmune abnormalities,whether or not associated with autoimmune diseases [8]. Importantly, preconception control of autoimmune abnormalities and disease activity has been shown to improve pregnancy outcomes [8, 9]. Previous studies have observed that women with positive autoantibodies,such as antithyroid antibodies (ATA)，antinuclear antibodies(ANA),and antiphospholipid antibodies (aPL) have a higher risk of pregnancy losses,even when there is no diagnosed autoimmune disease [1O-l4]. Additionally, abnormal cellular immune responses involving both systemic and uterine immune effectors have been associated with an increased risk of reproductive failures.Elevated concentrations of NK cells in both peripheral blood and endometrium,as well as increased peripheral blood NK (pbNK) cytotoxicity, have been observed in women with uRPL [15-17]. An exaggerated inflammatory maternal immune response during the first trimester of pregnancy, characterized byan imbalance between T helper(Th)1and Th2 responses,is also frequently observed in patients with uRPL and RIF[18].Recently, endometrial biomarkers have been reported to offer a valuable tool for assessing immune abnormalities at the maternal/fetal interface and help guide immunotherapeutic strategies for women with uRPL and RIF [19,20]. Over the past few decades, various immunotherapeutic strategies have been proposed for the treatment of women with uRPL [21- 23].Advanced understanding of immune mechanisms involved in embryo implantation,along with improvement of diagnostic biomarkers have enabled more accurate selection of patients who may benefit from targeted immunotherapies.Immunotherapeutic interventions for women at risk of reproductive failure have been reported to improve reproductive outcomes significantly [23].However, standardized guidelines for immunotherapy based on immunological risk factors are currently lacking, largely due to limitations in the quality and consistency of available evidence. The American Society for Reproductive Immunology (ASRI) has acknowledged the current gaps in clinical guidance and is committed to addressing them,while taking current limitations into account.To this end,the ASRI established the Board of Reproductive Immunology, composed of certified Reproductive Immunologists,and developed immunotherapy guidelines.The primary objectives of these guidelines are: (1) to systematically review the current data supporting each immunotherapeutic intervesion;(2) to outline the potential benefits and risks associated with each therapy;and(3) to provide practical recommendations that reflect current clinical practice patterns. # 2l Materials and Methods The guideline was developed by the Clinical Reproductive Immunology Fellowship of the ASRI(CRIF/ASRI) in an effort to standardize current immunotherapy. This document was developed in accordance with Appraisal of Guidelines for Research and Evaluation Instrument II (AGREE II) [24]. Initially,an online questionnaire was sent to the members of CRIF/ASRI to identify which immunotherapies are routinely prescribed in cases of RPL.Then,the literature review and the first draft of recommendations were developed by the Immunotherapy Guideline Development Group (IGDG). The final practice guidelines and recommendations were approved by the CRIF/ASRI (Appendix 1). The impact of the following immunotherapies was evaluated for live birth rate (LBR)and miscarriage rate (MR): (1) corticosteroids; (2) intravenous immunoglobulin,(3) lymphocyte immunotherapy,(4) intravenous lipids emulsion,(5) vitamin D,(6)calcineurin inhibitors,(7) granulocyte-colony stimulating factor,(8) tumor necrosis factor antagonists,(9) heparin and acetylsalicylic acid (ASA), (l0) hydroxychloroquine (HCQ),and (11) human chorionic gonadotropin (hCG). The search terms applied were “recurrent miscarriage” or “recurrent pregnancy loss”or“recurrent spontaneous abortion”AND“corticosteroids”or“prednisone”or“prednisolone" or“intravenous immunoglobulin”or“IVIG”or“lymphocyte immunotherapy”or“intravenous lipid emulsion”or“lipid emulsion”or“intralipid”or“vitamin $\mathbf { D } ^ { \prime \prime }$ or“calcineurin inhibitors” or“tacrolimus”or“cyclosporine”or“granulocyte-colony stimulating factor”or“G-CSF”or“tumor necrosis factor antagonists” or“heparin”or“acetylsalicylic acid”or“hydroxychloroquine” or“human chorionic gonadotropin”or“hCG.”Additionally, CRIF/ASRI contacted subject matter experts to identify relevant systematic reviews and meta-analyses (SRMA) or randomized controlled trials (RCTs). The IGDG searched titles and abstracts of SRMAs and RCTs published in English in the main databases (PubMed/Medline, EMBASE,and Cochrane Library).SRMAs were selected when the included studies met the following criteria: (1) the definition of RPL as at least two or more spontaneous abortions;(2) patients with uRPL or with the presence of aberrant immune profile; (3) immunotherapy;(4) immunotherapy given before and/or during pregnancy and (5) randomized or non-randomized controlled trials.RCTs that had similar inclusion criteria were selected.In the absence of well-designed studies,quasi-experimental studies were evaluated as long as they described the same inclusion criteria.The guidelines and recommendations were developed using the GRADE certainty ratings (Appendices 2 and 3).A summary of immunotherapies proposed for recurrent pregnancy loss and the recommendations are developed (Table 1). # 3 Corticosteroids # 3.1 Background Corticosteroids,including glucocorticoids (GCT) and mineralocorticoids,are a group of hormones synthesized by the adrenal glands or derived synthetically. Cortisone was the first GCT introduced into clinical practice in l949 for the treatment of rheumatoid arthritis (RA)[25]. Currently, GCTs are widely prescribed for various medical conditions,especially for chronic inflammatory and autoimmune diseases [26]. GCTs exert an anti-inflammatory effect through various cellular and molecular mechanisms [26]. GCTs inhibit T lymphocyte activation,proliferation,and survival and block the production of inflammatory cytokines, promoting Th2 immunity at physiological concentrations. GCTs are capable of reducing the number of B lymphocytes and decreasing the release ofcytokines and inflammatory mediators by macrophages [26]. The main GCTs used in pregnancy are prednisolone,prednisone, dexamethasone,and betamethasone [27].GCTs are prescribed in the perinatal period for pregnant women at risk of premature birth to accelerate fetal lung maturation and,consequently, reduce morbidity and mortality of preterm infants.In early pregnancy, GCTs are often indicated for the prevention of RPL and the treatment of fetal abnormalities,such as congenital adrenal hyperplasia [27].GCT treatment for the prevention of uRPL was first proposed in l965 [28].Since then,studies have evaluated the benefit of GCT in improving pregnancy outcomes in women with RPL.A recent review of the quality of SRMA on the benefit of GCT on the LBR in patients with RPL showed a controversial conclusion [23]. GCT treatment to reduce MR in women with RPL has been justified since it controls the systemic and uterine immune response.GCTs promote Thl/Th2 immune balance in women with RPL, improving pregnancy outcomes [29]. Additionally, GCTs control the uterine immune responses and reduces the number of endometrial NK cells [30].Autoimmune diseases often have a negative impact on female reproductive capacity, increasing the risk of infertility and obstetric complications,such as pregnancy losses [31]. GCTs are drugs widely used in the treatment of autoimmune diseases, such as systemic lupus erythematosus (SLE) [9,31],and improved reproductive outcomes have been observed with strict control of autoimmune disease activity before and during pregnancy [31]. Thus,GCTs are able to reduce the MR of patients diagnosed with autoimmune diseases indirectly. Immunotherapy with GCTs has been proposed for patients with uRPL,as well as patients with altered immune biomarkers (ANA and endometrial NK cells). # 3.2 Evidence In the last two decades,a total of three SRMA that evaluated the impact of GCTs on LBR in women with RPL have been published (Table S1).All three studies demonstrated increased LBR with prednisone treatment compared to controls [32-34]. In these SRMAs,except for the study of Mekinian et al. [34], there was no significant heterogeneity in the study population.Notably, studies by Dan et al.[33] and Ma et al.included the studies of women with uRPL and immune abnormalities such as increased uNK cell levels and ANA positivity.Dan et al.[33] observed that the use of prednisone or prednisolone in doses ranging from 5 to $2 0 ~ \mathrm { m g }$ daily in the periconception period raised LBR in patients with uRPL (RR 1.58, $9 5 \%$ CI 1.23-2.02; $p = 0 . 0 0 0 3$ $I ^ { 2 } = 0$ ; 2 RCTs, $n = 1 7 6 { \mathrm { , } }$ ),especially when patients had immunological disorders, such as high concentration of uNK cells [33].Ma et al.also reported an increase in LBR of patients with uRPL,including women with immune abnormalities (women with $\mathrm { u N K } > 5 \%$ or ANA positivity)(OR 2.45, CI; 1.11-5.44, $n = 1 4 2 ; p = 0 . 0 3 ; I ^ { 2 } = 0 \% )$ Therefore,prednisone treatment in women with RPL and auto and cellular immune abnormalities significantly improved the LBR.Contrarily,Mekinian et al.[34] observed an increase in LBR of patients with uRPL when they were treated with prednisolone (RR 7.99, $9 5 \%$ CI 5.01-12.73; $p < 0 . 0 0 0 0 1$ $I ^ { 2 } = 7 1 \%$ ; 4RCTs, $n =$ 400)[32,34].In this SRMA,only1 out of 4 studies had a study population with immune etiology $\mathrm { ( u N K > 5 \% ) }$ ),andotherstudies did not have any evidence of immune abnormalities.This analysis has a moderate to severe risk of bias due to the heterogeneity of the study population.Again,prednisone $5 { - } 2 0 ~ \mathrm { m g }$ daily was used with different combinations of aspirin, heparin,and progesterone [32-34]. In a recent study by Li et al.,investigating women with uRPL or infertility with autoantibody positivity but not meeting any classification criteria for autoimmune diseases,GCT improved the clinical pregnancy rate (CPR: RR 2.19, $9 5 \%$ CI 1.64-2.92; $p$ $< 0 . 0 0 0 0 1$ $I ^ { 2 } = 3 9 \%$ ）and LBR (RR1.92, $9 5 \%$ CI 1.17-3.16, $p =$ 0.009, $I ^ { 2 } = 6 4 \%$ ); however,only one out of 6 studies investigated women with RPLs.In general, GCT started before pregnancy had significantly improved reproductive outcomes in infertile women with autoimmune abnormalities (LBR: RR 2.30, $9 5 \%$ CI 1.58-3.34, $p < 0 . 0 0 0 1$ $I ^ { 2 } = 0 \mathrm { \Omega }$ [35]. # 3.3\| Safety and Possible Side Effects Data on the safety of systemic use of GCTs during pregnancy are drawn from studies that evaluated their long-term use for treating autoimmune diseases [36-38]. Despite a low level of evidence, it appears that the use of systemic GCTs in pregnancy independently increases the risks of preterm delivery,low birth weight, and preeclampsia.However, the risk of miscarriage with the use of GCTs is often confused with the risk of pregnancy loss due to other immunosuppressants for underlying rheumatological diseases.The risk of gestational diabetes mellitus does not appear to be increased with prolonged use of GCTs in pregnancy [36- 38].Additionally, no increased risk of teratogenicity was observed with the use of oral or intravenous GCTs during pregnancy. The use of prednisone in therapeutic doses does not appear to represent a major teratogenic risk in humans, including orofacial clefts [38,39].However, one study has reported a slight increase in cleft palate in animal and human studies [4O]. The recent metaanalysis revealed no association between maternal corticosteroid exposure during the first trimester and offspring congenital heart defects [41]. TABLE 1l Summary of immunotherapies proposed for recurrent pregnancy loss and the recommendations. <table><tr><td> Immunotherapy</td><td>Recommendation</td></tr><tr><td>Corticosteroids</td><td>There is moderate evidence that GCTs improve pregnancy outcomes in RPL with altered immune biomarkers without diagnosed autoimmune disease,including expanded uNK cells ≥ 5% and positive ANA.</td></tr><tr><td></td><td>GCTs are strongly recommended to improve pregnancy outcomes of women with uRPL with auto- and cellular-immune abnormalities (such as uNK cells ≥5%, positive ANA,and other autoantibodies).</td></tr><tr><td></td><td>GCTs are conditionally recommended to improve pregnancy outcomes of women with uRPL without clear evidence of immune abnormalities.</td></tr><tr><td></td><td>GCTs are recommended at a dose of 10 to 20 mg of prednisone or prednisolone,initiated in the preconception period and maintained throughout the first trimester of pregnancy.</td></tr><tr><td>IVIG</td><td>IVIG treatment for RPL has moderate evidence to improve the live birth rate,particularly initiated prior to pregnancy,in women with a high number of RPL and immune abnormalities (Cellular immune responses,such as increased pbNK cell levels or cytotoxicity,abnormal Thl/Th2 immunity, and aberrantautoimmunity).</td></tr><tr><td></td><td>IVIG is recommended at a dose of 40o mg/Kg,IV,every one to three weeks,initiated in the preconception period, and maintained throughout pregnancy.</td></tr><tr><td>LIT</td><td>LIT is banned in the United States by the FDA.</td></tr><tr><td></td><td>-In countries without the restriction ofLIT,LIT is conditionally recommended for women with uRPL.</td></tr><tr><td></td><td>：LIT has low to moderate evidence to increase LBR in women with uRPL.</td></tr><tr><td></td><td>It is strongly recommended that patients should be selected using standardized biomarkers,such as anti-paternal leukocyte antibody,and that seroconversion is confirmed after LIT.</td></tr><tr><td>ILE</td><td>Strict infectious disease guidelines for the preparation of LIT should be followed.</td></tr><tr><td></td><td>There is low evidence that ILE improves LBR of women with RPL. ILE may increase LBR in women with uRPL without embryological factors,particularly those with</td></tr><tr><td>Vitamin D</td><td>positive immune markers (increased pbNK cytotoxicity or elevated Thl cytokines). However,despite promising results,there is a lack of high-quality RCTs to confirm these findings.</td></tr><tr><td></td><td>Women with RPL are at an increased risk of having low vitamin D levels.Particularly,Africans, American Africans,South Asians,and those living in northern latitudes are high-risk populations for vitamin D deficiency.</td></tr><tr><td></td><td> There is moderate evidence that vitamin D deficiency is associated with RPL.</td></tr><tr><td></td><td>There is low evidence that vitamin D supplementation increases the LBR of women with RPL. A preconception assessment of serum 25(OH)D is strongly recommended.Supplementation ofvitamin</td></tr><tr><td>CNI (tacrolimus</td><td>D3 2000-40o0 IU/day is recommended to achieve at least a preconception serum 25(OH)D level higher than 30 ng/mL (≥ 75 nmol/L). There is low-level evidence (concerning a small number of studies) that tacrolimus and cyclosporine</td></tr><tr><td>and cyclosporine)</td><td>treatment improve LBR in women with RPL and immune abnormalities such as increased Thl/Th2 cell ratios,endometrial CD56+,and CD57+ NK cell expansion,and other markers.</td></tr><tr><td></td><td>More clinical studies are needed with standardized approaches targeting patients with immune abnormalities.</td></tr><tr><td>G-CSF</td><td> There is conflicting evidence for rhG-CSF as a treatment for uRPL.</td></tr><tr><td></td><td>- New RCTs are needed to evaluate possble effects on improving reproductive outcomes.</td></tr><tr><td>Anti-TNF</td><td>There is conflicting data for using anti-TNF as a monotherapy for RPL.</td></tr><tr><td></td><td> New RCTs are needed to evaluate possible effects on improving reproductive outcomes.</td></tr><tr><td>Heparin/ASA</td><td>The combination of heparin (UFH or LMWH) plus aspirin during pregnancy may increase the LBR in RPL women with persistent aPL when compared with aspirin treatment alone.However,the observed beneficial effect of heparin was driven by one large study in which LMWH plus aspirin was compared</td></tr></table> TABLE 1\| (Continued) <table><tr><td>Immunotherapy</td><td>Recommendation</td></tr><tr><td></td><td>- There is conflicting data for heparin treatment for uRPL with or without thrombophilia (excluding APS).</td></tr><tr><td rowspan="4"></td><td>-Prophylactic-dose heparin (LMWH)and aspirin are recommended for patients with obstetrical APS.</td></tr><tr><td>- A therapeutic dose of heparin is recommended throughout pregnancy and postpartum for pregnant women with thrombotic APS.</td></tr><tr><td>- Further research is needed to clarify the optimal dosage,duration,and patient selection for LMWH and aspirin therapy in RPL.</td></tr><tr><td>- There is low-level evidence for HCQ treatment for women with uRPL. HCQ treatment can be considered for uRPL women with autoimmunity (autoimmune diseases, such</td></tr><tr><td rowspan="4">hCG</td><td>as APS, SLE, and RA, or positive antiphospholipid antibodies and ANA) or placental inflammatory diseases,such as chronic intervillositis of unknown etiology/chronic histiocytic intervillositis,those who failed first-line treatment,and have contraindications/limitations for the standard treatment. -HCQ is recommended at 100 to 20o mg, twice daily,and maintained throughout pregnancy and often</td></tr><tr><td>postpartum as well.</td></tr><tr><td>- There is a low level of evidence that the injection of hCG prevents pregnancy loss.</td></tr><tr><td>- There remains a lack of high-quality evidence to determine which population would benefit from the hCG treatment.</td></tr></table> Abbreviatios:pd;dceylid;e;,d Amstratic intraeolo; RCT natural killer. # 3.4\| Recommendation - There is moderate evidence that GCTs improve pregnancy outcomes in RPL with altered immune biomarkers without diagnosed autoimmune disease,including expanded uNK cells $\geq 5 \%$ and positive ANA. ：GCTs are strongly recommended to improve pregnancy outcomes of women with uRPL with auto- and cellular immune abnormalities (such as uNK cells $\ge 5 \%$ ，positive ANA,and other positive autoantibodies). - GCTs are conditionally recommended to improve pregnancy outcomes of women with uRPL without clear evidence of immune abnormalities. - GCTs are recommended at a dose of 5 to $2 0 ~ \mathrm { m g }$ of prednisone or prednisolone,initiated in the periconception period and maintained throughout the first trimester of pregnancy. # 4l Intravenous Immunoglobulin # 4.1 Background Intravenousimmunoglobulin (IVIG）isa blood derivative extracted from the purified plasma of thousands of donors. Originally, IVIG was developed to treat primary immunodeficiency, being prescribed for the first time in the early 1950s 42]. Currently, the improvement in IVIG formulation techniques allows for greater safety and efficacy in treating immunodeficiencies, neuroinflammatory disorders,autoimmune diseases,chronic inflammatory conditions,infections,infection-related disorders, and alloimmune processes [42-44]. Particularly, IVIG has been utilized for fetal and neonatal alloimmune thrombocytopenia (NAIT),APS,and immune thrombocytopenic purpura (ITP). IVIG modulates both the innate and adaptive immune cellular response.It aims to replenish IgG antibodies that passively neutralize or opsonize infectious pathogens but can also elicit an active immune response via activation of various immune cells, conferring protection against diverse diseases [45].In addition to the above,the IVIG mechanism of action includes the Fc and F(ab')2 receptor-mediated effects,modulation of cytokine production,repressing complement-mediated damage,and regulation of autoreactive B-cell clones by anti-idiotype antibodies [46]. The off-label use of IVIG has been prescribed for the treatment of reproductive failures,especially in association with immune conditions, such as RPL,RIF,second and third-trimester pregnancy losses with cellular and autoimmune disorders [47,48],and APS refractory to thromboprophylaxis therapy [47, 48]. Subsequently, several studies (RCT and non-RCT) have had conflicting results regarding the effectiveness of IVIG for RPL [23,49]. # 4.2Evidence The 20l4 Cochrane SRMA [50] found that overall, there was no significant beneficial effect of IVIG over placebo in improving the LBR after RPL.Live birth after 2O weeks of gestation was the only primary outcome measured,and it did not include the placebocontrolled trials ofIVIG in RPL[51, 52]. This SRMA suggested that IVIG had no significant impact on LBR. Still, sensitivity analyses showed that IVIG significantly increases LBR when initiated prior to conception and when there were serological signs of autoimmunity [53]. The SRMA by Hutton et al. found that the treatment effect of IVIG was significant in secondary RPL but not in primary RPL [54]. In addition, in RCTs of IVIG in RPL where infusions were started before conception, the outcome in the treated patients was significantly better than in those who received a placebo.Whereas no treatment effect could be found in RCTs starting infusions after conception [54]. Recently, Yamada et al.found that women with a higher order previous miscarriages $\geq 4$ RPL) benefited from IVIG (LBR, OR 2.6, $9 5 \%$ CI 1.15-5.86; $p$ $= 0 . 0 3$ ,and ongoing pregnancy rate at 22 weeks of gestation, OR 3.07, $9 5 \%$ CI 1.35-6·97; $p = 0 . 0 0 9 $ [55]. The meta-analysis of IVIG in women with RPL and RIF with abnormal NK cell levels and activity revealed that IVIG treatment significantly increased LBR in women with RPL than controls (RR 2.31, $9 5 \%$ CI 1.66-3.21; $p < 0 . 0 0 0 0 1$ ， $I ^ { 2 } = 2 9 \%$ [56]. In a study of RPL with expansion of pbNK cells level or cytotoxicity, orincreased Thl/Th2 or Thl7/Treg ratios,IVIG significantly increased LBR both in quasi-experimental studies (OR 8.64, $9 5 \%$ CI 4.36-17.15; $p < 0 . 0 0 0 0 1 _ { . }$ ）and cohort studies(OR 50.44, $9 5 \%$ CI 15.28-166.58; $p < 0 . 0 0 0 0 1 _ { . }$ ) in comparison to the control group [57].Habets et al. reported that women with elevated NK cells $( > 1 2 \% )$ have significantly increased LBR with IVIG treatment compared to controls (RR 2.32, $9 5 \%$ CI 1.77-3.02; $p < 0 . 0 0 0 1$ $I ^ { 2 }$ $= 0$ ). When patients were selected without NK cell evaluation, IVIG also increased the success rate; however, there was a severe risk for bias due to the significant heterogeneity of the studies [58] (Table S2). Several meta-analyses of randomized clinical trials of IVIG therapy for uRPL failed to prove its effectiveness,but numerous studies have shown that IVIG treatment of women with RPL reduces NK-cell-related parameters [59, 60] and significantly increased the live birth rate.In addition,patients with RPL who are positive for at least one autoantibody had a better cumulative LBR after IVF/ICSI treatment when a combination of IVIG and prednisone was used from the start of the next IVF/ICSI cycle [54, 61]. Yamada et al. performed a high-quality RCT supporting the recommendation for IVIG for patients with higher-order miscarriages. They found that IVIG given in repeated doses $( 4 0 0 \mathrm { m g / k g ) }$ for five consecutive days very early in pregnancy to women with four or more unexplained pregnancy losses increased the LBR significantly(OR 2.60, $9 5 \% \mathrm { C I }$ 1.15-5.86; $p = 0 . 0 3 ,$ ）[55].Therefore,IVIG treatment for women with identifiable immunological risk factors,such as abnormal cellular and autoimmunity, significantly increases the live birth rate of women with reproductive failiures,while empirical IVIG treatment for women with uRPL and implantation failure is inefficient. The high number of pregnancy losses $\left( \geq 4 \right)$ and preconception treatment should also be considered [55]. # 4.3\| Safety and Possible Side Effects Side effects of IVIG are rare but can include headaches,vasovagal reaction,and mild infusion reactions consisting of myalgia, malaise,fatigue,and skin erythema [49]. Substantial increased risk of side effects,especially severe headache,was experienced using a protocol with four weekly infusions of IVIG [49]. Notably, patients with IgA deficiency need additional screening for antiIgA antibodies.Low IgA IVIG or subcutaneous immunoglobulin (SCIG) is often indicated to prevent anaphylactic reactions in women with low IgA with anti-IgA antibodies. # 4.4\| Recommendation - IVIG treatment for RPL has moderate evidence to improve the LBR,particularly initiated prior to pregnancy,in women with a high number of RPL and immune abnormalities (cellular immune responses,such as increased pbNK cell levels or cytotoxicity,abnormal Thl/Th2 immunity,and aberrant autoimmunity). - IVIG is recommended at a dose of 200 to $4 0 0 ~ \mathrm { m g / k g }$ every one to three weeks,initiated in the periconception periodand maintained throughout pregnancy. # 5l Lymphocyte Immunotherapy # 5.1 Background Lymphocyte immunotherapy(LIT）is classified as an active immunotherapy. LIT consists of concentrated lymphocytes prepared from the peripheral blood of the partner or a third party to promote maternal immunomodulation.LIT has been reported to have immune modulatory effects, such as T-cell suppression, decreasing maternal IL-2 receptor expression,reduction in IL-6 level,inhibition of Thl cytokines,suppression of pbNK cytotoxicity, increasing progesterone-induced blocking factor, balancing the Thl/Th2 and Th17/Treg ( $\scriptstyle \mathrm { C D 4 + }$ $\mathrm { C D } 2 5 +$ ）immune responses [62-70]. Leukocyte transfusion for the treatment of RPL was first proposed by Taylor and Faulk [7l]. Subsequently, the treatment protocols for couples with RPL were developed, including administering lymphocyte concentrates intravenously,subcutaneously,or intradermally[21,22].The first RCT evaluating the LIT for uRPL was published by Mowbray et al.in l985[22].The authors observed an increase in the LBR(RR 2.08, $9 5 \%$ CI 1.21-3.58; $p = 0 . 0 0 7 ,$ inthe treated group (LIT with partner's blood) compared to the control (LIT with own blood) [22].However, in 1999, Ober et al. reported that LIT did not increase LBR in women with uRPL (OR 0.6, $9 5 \%$ CI 0.33-1.12; $p = 0 . 1 0 8 ^ { \cdot }$ ）[72].Numerous criticisms of Ober's study have been reported due to concerns for methodologies, particularly for the LIT preparation protocol [50,73-75].In 2001, the Food and Drug Administration (FDA),USA,recommended that the use of LIT should be limited to research protocols due to the Stem Cell Therapeutics and Research Act of 2Oo5 in the United States.Although FDA restrictions exist in the United States,LIT has been utilized continuously in other countries. # 5.2Evidence Twenty-two RCTs published between 1985 and 20l3 were conducted on four continents that evaluated the use of LITin treating couples with RPL.LIT increased the LBR in $6 8 \%$ of these RCTs (n $= 1 5 / 2 2 \AA$ ,while in the remaining studies,there was no difference between the treated group and the control group [23]. Over the past 23 years, six SRMAs that compiled the results of these RCTs have been published [23]. Four of six SRMAs observed a positive impact of LIT on the LBR of couples with RPL (Table S3). ORs ranged from 1.45( $9 5 \%$ CI 1.05-2.01; 8 RCTs) to 3.74（ $9 5 \%$ CI 3.07-4.57; 18 RCTs) [23]. The most recent SRMA that evaluated the effectiveness of LIT in treating women with uRPL demonstrated an increase in the LBR despite moderate heterogeneity in the study population (RR 1.45, $9 5 \%$ CI 1.05-2.01; $p = 0 . 0 0 3$ $I ^ { 2 } = 6 7 \%$ ).Sensitivity analysis, including studies with a low risk of bias,confirmed the increased LBR without significant heterogeneity (RR 1.97, $9 5 \%$ CI 1.53-2.53; $p = 0 . 4 0 ; I ^ { 2 } = 2 \% ,$ [76]. Various factors may interfere with the efficacy of LIT.A short interval between collecting the partner's blood and injecting LIT to the patient,a concentration of lymphocytes around 1oo million per dose,and the intradermal administration route before and during pregnancy are factors related to higher LIT eficacy 65, 77].Women with five or more previous pregnancy losses,with thrombophilia or associated autoimmune diseases,hada reduced success rate with LIT[77-79].The efficacy of LIT was reduced if seroconversion was not induced after LIT; however, there was a moderate risk of bias due to significant heterogeneity of the study population (RR 12.12, $9 5 \% \mathrm { C I } 1 . 8 2 – 8 0 . 6 2 ; I ^ { 2 } = 5 6 \% )$ [76]. Contrarily, increased mixed lymphocyte reaction blocking factor(MLR-Bf) a level was associated with an increased LBR [80]. # 5.3丨 Safety and Possible Side Effects LIT is an active immunotherapy using prepared peripheral blood lymphocytes from the partner or third party.LIT potentially has risks of local and systemic complications in the short and long term.In 1994,the Recurrent Miscarriage Immunotherapy Trialists Group observed that the prevalence of systemic side effects $2 . 1 \%$ [24/1149] vs. $0 . 5 \%$ [2/410], $p = 0 . 0 5 1 ,$ and obstetric/neonatal complications ( $3 \%$ [36/1149] vs. $4 \%$ [18/410], $p = 0 . 2 1 1 \AA$ )in patients undergoing LIT were similar to those of controls [78]. Kling et al. described the local and systemic side effects detected in 2587 patients treated with LIT. The most frequent reactions observed at the vaccination site (up to 4 weeks after injection) were redness $( 9 2 \% )$ ,itching $( 9 1 \% )$ ,swelling $( 6 6 \% )$ ,and burning sensation $( 3 0 \% )$ ： The duration of these local reactions was between 5 and 15 days.Fatigue $( 1 . 9 \% )$ ,"influenza”like symptoms $( 1 . 8 \% )$ ,headache $( 1 . 2 \% )$ , elevated temperature $( 1 . 0 4 \% )$ ,and dizziness $( 0 . 9 6 \% )$ were the most frequent systemic reactions [8l].HIV transmission was reported in five Chinese women who received LIT due to multiple failures in the laboratory process,such as delays in HIV detection in blood donors and the reuse of blood tubes during lymphocyte preparation [82]. # 5.4l Recommendation - LIT is banned in the United States by the FDA. - In countries without the restriction of LIT,LIT is conditionally recommended for women with uRPL. - LIT has low to moderate evidence to increase LBR in women with uRPL. - It is strongly recommended that patients be selected using standardized biomarkers,such as anti-paternal leukocyte antibody,and that seroconversion is confirmed after LIT. - Strict infectious disease guidelines for the preparation of LIT should be followed. # 6\|Intravenous Lipids Emulsion # 6.1 Background Intravenous lipid emulsion (ILE) is indicated to provide nutritional support for seriously ill patients.The immunomodulatory effect of ILE was reported in studies demonstratingan increased risk of bacteremia in neonates who received lipid-based parenteral nutrition [83,84],increased infectious complications in surgical patients who received ILE [85],and lower rates of graft versus host disease in bone marrow transplantation patients using soybean oil-based parenteral nutrition [86]. ILE can inhibit pbNK cell cytotoxicity by stimulating peroxisome proliferator-activated receptor c (PPARC) [87-90] and prevent the action of pro-inflammatory mediators produced by Thl cells [91,92]. Contrarily, fatty acids can induce G-protein-coupled receptors (GPCR) and CDl receptor [93,94] mediated activation of cAMP pathway, which triggers the nuclear factor kappa-lightchain-enhancer of activated B cells (NFkB) pathway [95]. # 6.2Evidence Several reviews have assessed the impact of ILE on MR for patients with poor reproductive outcomes and implantation failure,but only one SRMA analyzed the impact of ILE on a defined RPL population.A meta-analysis by Kumar etal.,which analyzed selected RPL cases,including 2 cohort and1RCT studies demonstrated a significant reduction in MR(OR 0.24, $9 5 \%$ CI 0.15-0.39; $p < 0 . 0 0 0 1$ $I ^ { 2 } = 8 6 \%$ ）with a significant improvement in subsequent LBR (OR 2.67, $9 5 \%$ CI 1.79-3.98; $p < 0 . 0 0 0 1$ $I ^ { 2 } = { }$ $5 3 \%$ ) in the ILE patients [96](Table S4).Inclusion criteria were $\geq 3$ miscarriages,with either unexplained etiology [88], $\mathrm { C D 5 6 + }$ pbNK cell levels $> 1 2 \%$ [97],or elevated Thl:Th2 cytokine ratios [98]. Adecrease in pbNK cell cytotoxicity and lymphokine-activated killer activity was reported after ILE administration [99],along with a reduction in pro-inflammatory cytokines from Thl cells [91,92,100],which may contribute to this effect. ILE has been shown to suppress pbNK cytotoxicity with equal efficacy as IVIG by both in vitro [1Ol] and in vivo assays [1O2].A single RCT compared ILE with IVIG in RPL patients reported a statistically insignificant difference in pregnancy success rates between the groups (92.1 vs. $8 8 . 2 \%$ $p = 0 . 4 1 5$ [87]. # 6.3\| Safety and Possible Side Effects The major benefits of ILE over alternative treatments,such as IVIG,are reduced patient risks, fewer adverse side effects [103],and less cost,making it an affordable choice.Minor symptoms such as headache,nausea,vomiting,sweating，or flushing may occur during the infusion,but anaphylaxis is the most serious concern.Therefore,ILE should be avoided in patients with allergies to soya oil,eggs,or peanuts.Other contraindications are disturbances of normal fat metabolism, including pathologic hyperlipemia, lipoid nephrosis,and acute pancreatitis with hyperlipidemia.Pregnancy outcomes have been assessed following ILE therapy,demonstrating a low rate of adverse events,with no adverse maternal outcomes [87,104]. # 6.4I Recommendation - There is low evidence that ILE improves LBR of women with RPL. ：ILE may increase LBR in women with uRPL without embrological factors, particularly those with positive immune markers (increased pbNK cytotoxicity or elevated Thl cytokines). However, despite promising results,there is a lack of highquality RCTs to confirm these findings. # 7I Vitamin D # 7.1 Background Vitamin D3,knownas cholecalciferol,is a fat-soluble secosteroid. It is hydroxylated in the liver to 25-hydroxyvitamin D3 (25[OH]D) and then further hydroxylated in the kidney to produce the active hormone,calcitriol (1,25-dihydroxy vitamin D3) [1o5]. The vitamin D-activating enzyme CYP27Bl is expressed in the maternal decidua and the fetal trophoblast during early pregnancy [106]. The placenta accumulates $2 5 ( \mathrm { O H } ) \mathrm { D }$ and its active form,1,25- dihydroxy vitamin D,exerting effects on trophoblast invasion, spiral artery remodeling,and immune cell function [107-109]. Vitamin D promotes successful pregnancy through several immunomodulatory functions at the maternal-fetal interface [1l0].In patients with APS,vitamin D inhibits complement activation and thus prevents preterm birth [lll]. In addition, it suppresses anti- $\cdot \beta 2$ glycoprotein expression and, therefore,decreases the risk of thrombosis and antiphospholipid antibody (aPL)- induced tissue factor expression [ll2].In autoimmune thyroiditis, vitamin D may exert anti-inflammatory and immunomodulatory functions [ll3].An inverse relationship exists between vitamin D and thyroid stimulating hormone (TSH),and thyroid peroxidase antibody levels in women with autoimmune thyroid disease [1l4, 115]. Vitamin D downregulates peripheral blood Thl,B,and NK cells and proinflammatory cytokines such as IL-2, TNF- $\alpha$ ,and $\mathrm { I F N } { - \gamma }$ and upregulates IL-4, IL-10,vascular endothelial growth factor, and granulocyte colony-stimulating factor [ll6]; [1l7]. Vitamin D increases Treg cell function and reduces the number of Thl7 cells,which secrete IL-17[ll8].Vitamin D inhibits pbNK cell cytotoxicity and modulates the secretion of cytokines and Toll-like receptor 4 expression [ll6,ll9].Vitamin D alters glucose/insulin metabolism, increasing the expression of endometrial proteins such as glycodelin and insulin-like-growth factor binding protein1,altering endometrial glucose levels to promote a successful pregnancy [120]. These multiple actions of vitamin D make it an effective immunomodulator for treating RPL. # 7.2Evidence An SRMA(14 studies,l4l2 cases,and 16l6 controls) showed that RPL patients had lower vitamin D levels during pregnancy than controls (SMD $- 1 . 4 8$ $9 5 \%$ CI $- 2 . 0 1 \mathrm { - } - 0 . 9 4$ $p < 0 . 0 0 1 _ { \cdot } ^ { \cdot }$ ,and pregnant women with vitamin D deficiency had a higher risk of developing RPL than pregnant women with normal vitamin D (OR 4.02, $9 5 \%$ CI 2.23-7.25; $p < 0 . 0 0 1 ,$ [121] (Table S5).Inanother SRMA consisting of 6 studies $\mathit { T } n = 6 3 3 8 $ ),the combined analysis of women with vitamin D deficiency and insufficiency found an association with miscarriage(OR 1.6, $9 5 \%$ CI 1.11-2.30; $p { = } 0 . 0 1 ; I ^ { 2 }$ $= 3 5 \%$ )[122] (Table S5). In an RCT involving 8O patients with uRPL,the incidence of miscarriage in the vitamin D supplementation and control groups was $1 2 . 8 \%$ and $3 4 . 2 \%$ ,respectively (OR 3.53, $9 5 \%$ CI 1.12-11.2; $p =$ 0.03)[l23].Another RCT by Rafiee et al.with 44 non-pregnant women with a history of RPL and vitamin D deficiency showed that vitamin D supplementation decreased the frequency of Thl7 cells in addition to reducing the Thl7/Treg ratio in the peripheral blood of RPL patients compared to the control group [67].An RCT by Sablok et al. involving 180 women showed that $4 4 \%$ in the control group and $2 0 . 3 \%$ in the vitamin D supplementation group developed preterm labor,preeclampsia,or gestational diabetes. Newborns of mothers in the control group had lower birth weight $( 2 . 4 \pm 0 . 3 8 \mathrm { { k g } ) }$ compared with the vitamin D supplementation group $( 2 . 6 \pm 0 . 3 3 \mathrm { k g } )$ [124]. Contrarily, the RCT by Ibrahim et al. with 40 pregnant RPL women supplemented with alfacalcidiol did not show statistically significant MR compared to controls [125]. The two meta-analyses have shown a strong association between vitamin D deficiency and RPL (Table S5).RCTs of vitamin D supplementation in RPL have shown a reduced incidence of MR, decreased frequency of Thl7 and Thl7/Treg ratio,and a lower incidence of preterm labor,preeclampsia,gestational diabetes, and low birthweight infants.However, these RCTs had small sample sizes with heterogeneity, thus requiring further studies. International health organizations recommend supplementing with 200 to 20oo IU of vitamin D daily for a minimum 25(OH)D level ranging from 12 to $3 0 ~ \mathrm { n g / m L }$ (30 to $7 5 \ \mathrm { n m o l / L }$ ). Supplementation with vitamin D l50o to 200o IU/day appears safe in pregnancy,with 4ooo IU/day being the most effective in optimizing serum $2 5 ( \mathrm { O H } ) \mathrm { D }$ concentrations in mothers and their infants [126,127].Potential toxicity may occur if the vitamin D level exceeds $1 0 0 ~ \mathrm { { n g / m L } }$ # 7.3\| Safety and Side Effects When taken following suggested dietary intakes,using supplementary vitamin D is generally not linked to any significant negative effects.Clinically,vitamin D intoxication can lead to hypercalcemia.Hypercalcemia can be associated with muscle pain,nausea,vomiting，weakness,fatigue,weight loss，soft tissue calcification,or tachycardia [124,128]. These symptoms usually do not occur until serum $2 5 ( \mathrm { O H } ) \mathrm { D }$ concentrations exceed $1 5 0 ~ \mathrm { { n g / m L } }$ $( 3 7 5 \mathrm { n m o l / L } )$ ,which may result from daily vitamin D intakes of more than 20,000 IU $( 5 0 0 \mu \mathrm { g } )$ [128, 129]. # 7.4\| Recommendation - Women with RPL are at an increased risk of having low vitaminD levels. - There is moderate evidence that vitamin D deficiency is associated with RPL. - There is low evidence that vitamin D supplementation increases the LBR of women with RPL. - A pre-conceptional assessment of serum $2 5 ( \mathrm { O H } ) \mathrm { D }$ is strongly recommended.Supplementation of vitamin D3 2ooo-4000 IU/day is recommended to achieve at least a preconception serum 25(OH)D level higher than $3 0 ~ \mathrm { n g / m L }$ $\left( \ge 7 5 \mathrm { n m o l / L } \right)$ # 8丨Calcineurin Inhibitors # 8.1 Background Thl and Th2 cells play important roles in immune responses, such as immune rejection or tolerance.There is a general agreement that pregnancy is associated with Th2 dominance, and Thl immune response is associated with embryonic rejection [7].A transferred embryo during IVF/ET may fail to implant due to the same immunological reaction involved in allograft rejection. Therefore,immunosuppressive agents might improve the implantation of embryos in the maternal decidua if Th1/Th2 disturbance is a major contributory factor for the failure [130]. Calcineurin inhibitors (CNIs） are immunosuppressive drugs that are frequently used to prevent organ rejection following transplantation.CNIs are also prescribed for the treatment of rheumatic diseases and severe atopic dermatitis.The two main CNIs are cyclosporine and tacrolimus.The use of CNIs to treat reproductive failures was first proposed in 2Ol5 [131,132]. # 8.2Evidence A recent SRMA of CNIs for Women with RPL or RIF aimed to evaluate both efficacy and safety [l3o] (Table S6).From this review, CNIs (3 studies for cyclosporine and one study for tacrolimus) increased LBR(OR 2.68, $9 5 \%$ CI 1.82-3.97; $p <$ 0.00001; $I ^ { 2 } \ : = \ : 2 3 \%$ ）and decreased the MR(OR 0.37, $9 5 \%$ CI 0.25-0.54; $p \ : < \ : 0 . 0 0 0 0 1$ ， $I ^ { 2 } = 0 \mathrm { \large : }$ )，when compared to controls [130].Except for one study, three studies included women with immune abnormalities such as elevated Thl/Th2 cell ratios,high endometrial $\mathrm { C D 5 6 + }$ ,and $\mathrm { C D 5 7 + }$ cells,or high IL33/ST-2 levels. Studies by Nakagawa et al. included women with increased Thl/Th2 ratios $\mathrm { ( C D 4 ^ { + } I F N - } \gamma ^ { + } / \mathrm { \ C D 4 ^ { + } I L - } 4 ^ { + }$ ratios, cut-off value $\geq$ ll.8) for the tacrolimus treatment,and the dose was adjusted based on Thl/Th2 ratios [133,134]. # 8.3\| Safety and Possible Side Effects The safety of using CNIs during pregnancy has been established through clinical experience in treating pregnant women with solid organ transplants or rheumatic diseases using these medications [36,l35]. Cyclosporine and tacrolimus are not classified as teratogenic agents; however, the FDA categorized them as category C drugs,indicating that human risk cannot be definitively excluded [36].Nonetheless,cyclosporine and tacrolimus are deemed safe for use during pregnancy when administered at standard therapeutic doses.Although there are minor differences in their structure and metabolism,cyclosporine and tacrolimus exhibit similar mechanisms of action [135]. The doses of CNIs recommended for patients with reproductive failures are lower than those typically prescribed for transplant recipients.Cyclosporine and tacrolimus share a similar profile of adverse effects [l35]. These side effects,which can manifest in both the short and long term,are dose-dependent and generally diminish over time or upon discontinuation of the medication.Common adverse effects,occurring in more than $1 0 \%$ of patients undergoing kidney or liver transplantation at standard dosages,include headache,diarrhea,nausea, vomiting,abdominal pain,renal dysfunction,hyperglycemia,and hypertension. Less frequently observed adverse events comprise rash,acne, weakness,myalgia,eye irritation,neurotoxicity, hepatotoxicity, metabolic disturbances (such as hyperlipidemia,hyperkalemia, hyperuricemia,and hypomagnesemia),increased susceptibility to infections (bacterial, viral,and fungal),and other neurological symptoms [36,l35]. Cautious use of calcineurin inhibitors, such as tacrolimus,is recommended,with monthly monitoring of glucose levels and renal function.A recent SRMA revealed that women with reproductive failure who were treated with CNIs exhibited side effects and obstetric and neonatal complications comparable to those observed in the control group [130]. # 8.4 Recommendation - There is low-level evidence (concerning a small number of studies) that tacrolimus and cyclosporine treatment improve LBR in women with RPL and immune abnormalities such as increased Thl/Th2 cell ratios,endometrial $\mathrm { C D 5 6 + }$ ,and $\mathrm { C D 5 7 + }$ NK cell expansion,and other markers. -More clinical studiesare needed with standardized approaches targeting patients with immune abnormalities. # 9I Granulocyte-Colony Stimulating Factor # 9.1 Background Granulocyte colony-stimulating factor(G-CSF) is a protein produced by immune cells (such as monocytes,macrophages,and neutrophils), fibroblasts,stromal,and endothelial cells [136]. G-CSF participates in the inflammatory response,regulated by inflammatory cytokines (such as $\mathrm { I L - } 1 \beta$ and TNF- $\alpha$ ）and lipopolysaccharide (LPS).Recombinant human G-CSF (rhGCSF) is an FDA-approved drug indicated for neutropenic patients due to its ability to mobilize stem cells, hematopoietic precursors, and progenitor cells.G-CSF also has anti-inflammatory and angiogenic properties [l36]. The off-label use of rhG-CSF is also studied in inflammatory, infectious,and immune diseases, such as acute or chronic liver failure,pulmonary fibrosis,and Parkinson's disease [137-139]. Physiologically，G-CSF plays an important role in embryo implantation through endometrial decidualization,regulation of trophoblasticdevelopment,placentalmetabolism，and angiogenesis.Studies suggest that G-CSF has an endometrial immunomodulatory effect,as it increases $\mathrm { C D 4 + }$ and $\mathrm { C D 8 + }$ T cell levels,stimulates secretion of Th2 cytokines,activates Tregs, and recruits dendritic cells.Animal studies revealed that rG-CSF had contradictory effects on reproductive outcomes [l36]. In female rats,rG-CSF treatment had an anti-abortion effect,while in female rabbits,rG-CSF administration was associated with a higher MR [140,14l]. The use of rhG-CSF has been proposed for treating unresponsive thin endometrium resistant to standard therapies [142].Scarpelli and Sbracia first evaluated the effect of rhG-CSF immunotherapy in women with uRPL,reporting that rhG-CSF increased the LBR $( 8 2 . 8 \%$ [29/35] vs. $4 8 . 5 \%$ [16/33], OR 5.1, $9 5 \%$ CI 1.5-18.4; $p = 0 . 0 0 6 1 _ { . }$ [143]. # 9.2 Evidence Mu et al.published an SRMA evaluating the rhG-CSF effect for uRPL,which included 5 RCTs and 1 cohort study (CS) [144] (Table S7). There were insignificant changes in LBR of women with uRPL when treated with rhG-CSF (RR1.35, $9 5 \%$ CI 0.99- 1.84; 4 RCTs and 1 CS, $6 2 . 5 \%$ [172/275] vs. $4 6 . 3 \%$ [138/298]，n $= 5 7 3$ ). This systematic review showed moderate heterogeneity $( I ^ { 2 } = 6 6 \%$ ).The studies included in this SRMA used different treatment protocols,starting points of immunotherapy(ovulatory or non-ovulatory period),route of administration (intrauterine or subcutaneous),and dose [l44]. Subgroup analysis observed that the best outcomes occurred when rhG-CSF was started in the ovulatory period and administered subcutaneously [144]. The recent RCT,including l5O women with uRPL,revealed no difference between treated and non-treated groups [l45]. In this study,subcutaneous application of rhG-CSF was started with a positive pregnancy test,which may affect the success rate [145,146]. Contrarily,a recent retrospective study by Sun et al. observed an increase in LBR in patients with uRPL treated with a combination of rhG-CSF1milligram $( 1 0 0 , 0 0 0 \mathrm { I U } ) / \mathrm { K g } / \mathrm { d a y }$ subcutaneously from the 6th day following ovulation until either the onset of menstruation or the conclusion of the 9th week of pregnancy and aspirin compared to a control group without any treatment ( $( 8 1 . 8 \%$ [54/66]) vs. $6 1 . 5 \%$ [40/65], OR 2.81 $9 5 \%$ CI 1.26-6.26; $p = 0 . 0 1 0 ^ { \cdot }$ [147]. Four of six published studies observed increased LBR in women with uRPL treated with rhG-CSF. These studies evaluated a limited number of patients with different management protocols (treatment period,route of administration,and dose) and high heterogeneity of participants.More robust studies are needed to corroborate the beneficial effect of rhG-CSF treatment. # 9.3\| Safety and Possible Side Effects Side effects commonly reported by non-pregnant women using rhG-CSF are bone or muscle pain,headaches,tiredness and weakness (fatigue)，bruising，bleeding gums or nosebleeds, diarrhea,feeling or being sick,high temperature (fever),breathlessness and looking pale,hair thinning,and sore mouth.High numbers of white blood cells and allergic reactions are adverse reactions that occur rarely (fewer than $1 \%$ [148]. Maternal side effects and obstetrical and neonatal complications with the use of rhG-CSF are still poorly investigated.In the recent meta-analysis,the occurrence of maternal adverse effects and neonatal complications was similar between the rhG-CSF and control groups ( $2 6 . 5 \%$ [65/245] vs. $2 2 . 0 \%$ [59/268], OR 1.13, $9 5 \%$ CI 0.89-1.43; $p = 0 . 2 3 $ ). Leukocytosis,skin rash,bone and muscle pain, headaches,and weakness were the most frequently reported side effects [144]. # 9.4l Recommendation - There is conflicting evidence for rhG-CSF as a treatment for uRPL. -New RCTs are needed to evaluate possible effects on improving reproductive outcomes. # 10\| Tumor Necrosis Factor Antagonists # 10.1 Background TNF- $\alpha$ is an important cytokine playing a role in embryo implantation.It is secreted by various immune cells and signals by binding to its receptors,TNFRl and TNFR2 [149]. Since the balance of Thl/Th2 and Tl7/Treg cytokines has been implicated in uRPL and RIF,there is a potential rationale for the use of antiTNF drugs to balance cytokine milieu and increase reproductive outcomes [6,150].Anti-TNF drugs can be divided into two groups: (1) monoclonal antibodies,such as adalimumab (ADA),and (2) TNF- $\alpha$ receptor fusion protein, such as etanercept.Both agents act by reducing the effect of TNF- $\mathbf { \nabla } \cdot \alpha$ on embryo implantation, thereby reducing the risk of pregnancy loss [150]. # 10.2Evidence There is one RCT but no SRMA on the use of anti-TNF during pregnancy regarding uRPL or implantation failure.Winger et al. reported an increase in pregnancy rates with TNF- $\cdot \alpha$ antagonists associated with or without IVIG in women undergoing IVF cycles [l5l]. The same group also published an article comparing patients with and without adalimumab and showed that the rate of birth defects was similar for both groups [152].The recent RCT by Fu et al. included 188 women with refractory innate immune RPL;95 received $2 5 ~ \mathrm { m g }$ of etanercept weekly, and 93 were on placebo. The placebo group had $7 2 \%$ LBR,and the treated group had $8 9 \%$ LBR (OR 3.30, $9 5 \%$ CI 1.49-7.32; $p = 0 . 0 1$ )[153]. # 10.3\| Safety and Possible Side Effects Recently,many articles have been published reporting the use of anti-TNF drugs during pregnancy for inflammatory bowel disease,assessing the safety of those during pregnancy and also with long-term follow-up of children exposed to these drugs in utero [154]. One observational cohort study, including live births in 221/257 $( 8 8 . 5 \% )$ with ADA exposure and 198/225 $( 8 8 \% )$ without ADA [l55], found ADA use in pregnancy was not associated with an increased risk for any of the adverse outcomes [155]. If anti-TNF treatment is indicated,patients should be screened for asymptomatic tuberculosis or an existing subclinical infection before use.Also,the use of anti-TNF drugs should be cautious where a high number of cases of multidrug-resistant tuberculosis occur. # 10.4\| Recommendation - There is conflicting data for using anti-TNF as a monotherapy for RPL. - New RCTs are needed to evaluate possible efects on improving reproductive outcomes. # 1l\| Heparin and ASA # 11.1」Background Heparin is the most widely used anticoagulant worldwide [156]. There are various therapeutic forms of heparin,such as unfractionated heparin(UFH),low molecular weight heparin (LMWH), and synthetic heparins such as fondaparinux.The mechanism of heparin involves inhibiting thrombin (factor IIa) and factor Xa,which are key players in the coagulation cascade [l56]. The difference in therapeutic forms of heparin involves different ratios of anti-Xa to anti-Ia activity [l56]. Heparin has both anticoagulative and anti-inflammatory effects; it is now widely used to treat various thrombophilic disorders,such as acquired APS and inherited thrombophilia,such as Factor V Leiden (FVL) and prothrombin gene mutation (PGM). Heparin can be used alone or with other agents,such as ASA.ASA,also known as aspirin,prevents the formation of thromboxane A2 and inhibits platelet aggregation [156]. In general,pregnancy is a pro-thrombophilic state that is associated with a 4.29-fold increase in thrombotic events [157], which includes venous thromboembolism (VTE) and pulmonary embolism (PE).These thrombotic pathologies increase both maternal morbidity and mortality. In addition to pregnancy, if there is a predilection for thrombophilia,this further increases the risk of thrombotic events both in the antepartum and postpartum state [158].Currently, it encompasses both acquired, such as APS inherited thrombophilias (FVL heterozygous/homozygous, PGM heterozygous/homozygous,and compound heterozygous FVL and PGM), with ORs of thrombosis 15.8, 6.4/46.7, 4.3/13.4, and 26.6,respectively [159,160]. The role of thrombophilia in RPL can be explained partly by thrombosis of the microvasculature in the placenta and inhibition of extravillous trophoblast differentiation [16l].In APS,aPL directly inhibits trophoblast proliferation and differentiation, which can lead to defective placentation [162] and early pregnancy loss [163,l64]. It has been suggested that aPLs stimulated human endometrial endothelial cells to produce chemokines and angiogenic factors,contributing to impaired placentation and vascular transformation.Additional complications have been associated with thromboses,including fetal growth restriction, placental abruption,preeclampsia,and RPL [l65].However, the data revolving around RPL and thrombophilia are controversial. The recent SRMA demonstrated a link between inherited thrombophilia and RPL.In this analysis including 89 studiesand 30,254 individuals, women with FVL mutation (OR 2.44, $9 5 \%$ CI 1.96- 3.03; $p < 0 . 0 0 0 0 1$ $I ^ { 2 } = 7 0 \%$ ),PGM (OR 2.08, $9 5 \%$ CI 1.61-2.68; $p$ $< 0 . 0 0 0 0 1$ $I ^ { 2 } = 4 2 \%$ ),or deficiency of protein S (OR 3.45, $9 5 \%$ CI 1.15-10.35; $p < 0 . 0 3 ; I ^ { 2 } = 5 9 \% )$ had higher risks of developing RPL [166] (Table S8). # 11.2Evidence The Cochrane review by Hamulyak et al.assessed the effects of aspirin,heparin,or both in improving pregnancy outcomes for women with persistent aPL and RPL [l67].The review included nine RCTs and two quasi-RCTs: (1) Aspirin versus placebo: One trial with 40 women showed uncertain evidence (very low) regarding the effect of aspirin on live birth compared to placebo (RR 0.94, $9 5 \%$ CI 0.71-1.25);(2) heparin plus aspirin versus aspirin alone: SRMA of five studies (l295 women) revealed that heparin plus aspirin may increase the number of live births (RR 1.27, $9 5 \%$ CI1.09-l.49) and reduce the risk of pregnancy loss (RR 0.48, $9 5 \%$ CI 0.32-0.71) compared to aspirin alone (low evidence).Subgroup analyses comparing LMWH plus aspirin versus aspirin alone and UFH plus aspirin versus aspirin alone showed significant increases in LBR (RR 1.20, $9 5 \%$ CI 1.04-1.38, and RR 1.74, $9 5 \%$ CI 1.28-2.35,respectively,low evidence);(3) LMWH versus aspirin: one study comparing LMWH with aspirin showed a higher LBR with LMWH $( 8 6 . 3 \% )$ compared to aspirin $( 7 2 . 1 \% )$ (RR 1.20, $9 5 \%$ CI 1.00-1.43) [168]; (4) LMWH plus aspirin versus UFH plus aspirin: two studies suggested a lower risk of pregnancy loss with LMWH plus aspirin compared to UFH plus aspirin (RR 0.53, $9 5 \%$ CI 0.28- 0.99) [169,17O]. However, there was no clear difference in LBR between these two groups (RR 1.44, $9 5 \%$ CI 0.80-2.62) [169,170]. Overall, the review highlighted the potential benefits of heparin plus aspirin, particularly LMWH,in improving LBR and reducing pregnancy loss in women with persistent aPL and RPL. The evidence regarding the efficacy of anticoagulation treatment in women with inherited thrombophilia was inconclusive due to the small sample sizes of relevant studies.A meta-analysis was performed with3 RCTs,including women with RPL treated with LMWH.This meta-analysis showed no differences in LBR,MR, gestational age,or birth weight but an increase in the risk of preeclampsia [17l]. The first clinical trial included women with a negative thrombophilia workup starting enoxaparin after an established pregnancy at 5 weeks or later with no improvement $\left( n \ = \ 2 5 8 \right)$ [172].The second clinical trial showed improved outcomes in women with anticoagulation treatment started after an established pregnancy and a negative thrombophilia workup $( n = 1 5 0 )$ [173].The third clinical trial included 294 women with a negative thrombophilia workup,and enoxaparin and aspirin were started at the confirmation of pregnancy, showing no improvement in LBR between groups [174]. An additional meta-analysis was performed by Skeith et al. that included 8 trials (483 patients). Inclusion criteria were RCTs, pregnant women with inherited thrombophilia and a prior late $\mathrm { > } 1 0$ weeks) or RPLs( $\left. > 2 \right.$ losses, $< 1 0$ weeks),and randomized into LMWH or no LMWH [175]. There was no significant difference in LBR in LMWH compared to controls (RR 0.81, $9 5 \%$ CI 0.55-1.19; $p = 0 . 2 8 )$ [175].This study was echoed by De Jong et al.,who evaluated 9 studies,including l228 women with two unexplained miscarriages,with or without inherited thrombophilia,and with/without the use of LMWH and LDA [176]. The RR for live birth was 0.94 ( $9 5 \%$ CI 0.80-1.ll) in women who received aspirin compared to placebo,1.08 ( $9 5 \%$ CI 0.93-1.26) in women who received LMWH compared to aspirin,and 1.01 $9 5 \%$ CI 0.87-1.l6) in women who received LMWH and aspirin compared to no-treatment.The authors concluded that there is no benefit in using anticoagulation for RPL. Similarly, the ALIFE2 multicenter international study ( $n = 3 2 6$ ）investigating women with thrombophilia and RPL demonstrated no difference in LBR between the enoxaparin treatment group (started at 7 weeks of gestation) and controls [177]. There have been other SRMAs that support the use of enoxaparin and RPL.Jacobson et al. performed a meta-analysis that included 24 published studies showing lower rates of pregnancy loss in women with enoxaparin compared to controls (RR 0.58, $9 5 \%$ CI 0.34-0.96) and enoxaparin $^ +$ aspirin versus aspirin alone (RR 0.42, $9 5 \%$ CI 0.32-0.56); however, there was a high level of heterogeneity $\left( I ^ { 2 } > 6 0 \right) ,$ [178]. Two additional meta-analyses have been subsequently published.The first analysis included women with a history of RPL who were either prescribed LMWH(enoxaparin, tinzaparin,or dalteparin） alone versus those without LMWH intervention(placebo,folic acid,or no treatment)(total 8 studies). The results showed that there is a significant increase in LBR (RR 1.10, $9 5 \%$ CI 1.03-1.38; $p = 0 . 0 2$ ）anda decreased risk of miscarriages (RR 0.62, $9 5 \%$ CI 0.43-0.91; $p = 0 . 0 1 { \mathrm { , } }$ [179].The third SRMA included 5 RCTs,categorizing patients into 2 or 3 miscarriages with the use of enoxaparin.The study reported that LMWH reduced the miscarriage risk of women having $\geq 3$ miscarriages ( $\mathrm { R R } 0 . 4 6 , 9 5 \% \mathrm { C I } 0 . 3 5 \mathrm { - } 0 . 6 .$ 1) but notin women having $\geq 2$ miscarriages (RR 0.70, $9 5 \%$ CI 0.57-0.86). There was also no appreciable difference in LBR (RR 1.19, $9 5 \%$ CI 0.99-1.43) [180]. # 11.3丨 Safety and Possible Side Effects Heparin and aspirin have well-documented safety profiles when used appropriately and are considered safe for pregnant women.Adverse reactions are rare and mild, including bleeding (hematoma,epistaxis, bleeding of gums,vaginal bleeding, hematuria,or any other form of bleeding),heparin-induced thrombocytopenia,skin reaction to the injection site,and allergic reactions,if present,are mild and self-limiting.Heparins do not cross the placenta and are considered safe for the fetus. # 11.4\| Recommendation - The combination of heparin (UFH or LMWH) plus aspirin during pregnancy may increase the LBR in RPL women with persistent aPL when compared with aspirin treatment alone. However, the observed beneficial effect of heparin was driven by one large study in which LMWH plus aspirin was compared with aspirin alone [167]. - There is conflicting data for heparin treatment for uRPL with or without thrombophilia (excluding APS). - Prophylactic-dose heparin (LMWH) and aspirin are recommended for patients with obstetrical APS. - A therapeutic dose of heparin is recommended throughout pregnancy and postpartum for pregnant women with thrombotic APS. - Further research is needed to clarify the optimal dosage, duration,and patient selection for LMWHand aspirin therapy in RPL. # 12IHydroxychloroquine (HCQ) # 12.1Background HCQ,a quinacrine-derived molecule,is an antimalarial agent first described in 1955.It has an anti-inflammatory and immunomodulatory effect through a complex mechanism of action that increases intracellular pH within intracellular vacuole and alters intracellular molecular processes,such as protein degradation by acidic hydrolases in the lysosome, assembly of macromolecules in the endosomes,and posttranslation modification of proteins in the Golgi apparatus [181]. HCQ affects phagocytosis,proteolysis,antigen presentation,and chemotaxis. It decreases the production of pro-inflammatory cytokines and prostaglandins,inhibits matrix metalloproteinases, and blocks T- and B-cell receptors and toll-like receptor signaling [182].Additionally， HCQ has lipid-lowering，anticoagulant, and antidiabetic effects that may reduce cardiovascular risk in autoimmune diseases [l83].At a dosage ranging from 200 to $4 0 0 \mathrm { m g / d a y } ,$ it has been widely utilized as an anti-inflammatory medication for autoimmune diseases,such as SLE and RA. It was frequently utilized for thromboprophylaxis following total hip replacement in the l97Os at a higher dosage (600- $1 2 0 0 ~ \mathrm { m g / d a y } )$ before the routine usage of LMWH[183].Recent studies have shown that HCQ partially reverses aPL-induced inhibition of trophoblast migration and restores diminished trophoblast fusion and function [l83].For these reasons,it has been utilized for inflammatory conditions associated with adverse perinatal outcomes such as SLE,APS,RPL,and placental inflammatory diseases,such as chronic intervillositis ofunknown etiology/chronic histiocytic intervillositis [184]. # 12.2 Evidence In an RCT, 30o women with RPL were included, including 150 women with HCQ and 150 with placebo treatment.It showed significant positive results favoring the HCQ intervention over the control group [185].Possible therapeutic benefits of HCQ were also demonstrated in recent studies for pregnancies with APS [186-189]. Using HCQ $2 0 0 { - } 4 0 0 \ \mathrm { \ m g }$ daily in 30 patients with APS.1O with a history of RPL,10 with fetal death $> 1 0$ weeks gestation,and 5 with severe preterm delivery, HCQ was reported to reduce pregnancy losses from $8 1 \%$ to $1 9 \%$ $( p < 0 . 0 5 )$ [184]. In 2ol7, the follow-up study demonstrated a reduction in pregnancy loss from $7 6 \%$ to $1 4 \%$ $( p < 0 . 0 0 1 )$ when comparing index pregnancies to subsequent pregnancies with the HCQ [190]. No significant changes in maternal or neonatal complications were reported in these studies.Similarly, the study by Ye et al. demonstrated a significant reduction in pregnancy loss from $2 2 . 7 \%$ to $1 1 . 1 \%$ $( p = 0 . 0 1 2 )$ with the addition of twice-daily HCQ and prednisone to the conventional therapy of aspirin and LMWH for APS patients [191]. The recommended dose is $1 0 0 { - } 2 0 0 ~ \mathrm { m g }$ orally twice a day. HCQ has a relatively long half-life,achieving clearance in 4O-6o days.Due to significant tissue sequestration, an immunomodulatory therapeutic benefit is seen only after several weeks to months. # 12.3\| Safety and Possible Side Effects HCQ has a long track record of safety in pregnant women. In the literature,studies have suggested no HCQ-related adverse effects on the fetus [192-196] except one meta-analysis that showed an increased rate of spontaneous abortion when HCQ was administered in the first weeks of pregnancy [197]. They linked the significant increase in the spontaneous abortion rate in that meta-analysis to the presence of confounders inherent in the included studies.However, the underlying conditions were not excluded when the meta-analysis was made.Therefore, the result was potentially biased,and further analysis is needed. HCQ has good oral absorption,long plasma elimination time, and slow renal clearance.It crosses the placental barrier,and the umbilical cord blood concentration is similar to maternal blood. Several studies found that there was no clinical ocular toxicity in pregnant women,and it has a good risk-to-benefit balance in treating immunological impairment and chronic endothelial dysfunction in pregnant women [198].HCQ is well-tolerated. The most common side effects are gastrointestinal symptoms (nausea, vomiting,or diarrhea).However, more serious complications, including HCQ-associated myopathy and retinopathy, have also been reported [199]. In a large chloroquine/HCQ-exposed pregnancy cohort study including 288 patients,no increased risk of prematurity,low birth weight,or major congenital malformations was reported [200]. # 12.4\| Recommendation -There is low-level evidence for HCQ treatment for women with uRPL. - HCQ treatment can be considered for uRPL women with autoimmunity (autoimmune diseases,such as APS,SLE, and RA,or positive aPL and ANA）or placental inflammatory diseases,such as chronic intervillositis of unknown etiology/chronic histiocytic intervillositis,those who failed first-line treatment,and have contraindications/limitations for the standard treatment. - HCQ is recommended at 1 $0 0 \ - 2 0 0 \ \mathrm { ~ m g }$ ，twice daily，and maintained throughout pregnancy and often postpartum as well. # 13\| Human Chorionic Gonadotropin # 13.1Background hCG is a glycoprotein hormone synthesized during pregnancy, initially transcribed by a four-cell stage embryo.It serves as an embryonic signal,interacting with the endometrium prior to embryo implantation.Following attachment to the endometrium, syncytiotrophoblast cells abundantly produce hCG [2Ol]. Accumulated evidence highlights the significant roles of hCG in embryo implantation and supporting the early stage of pregnancy by stimulating the corpus luteum to secrete progesterone, promoting decidualization,vascular remodeling,and angiogenesis,modulating maternal immune tolerance and facilitating trophoblast invasion.As a result of these critical functions, hCG supplementation through either injection or intrauterine infusion has emerged as a potential therapeutic approach for addressing pregnancy losses and implantation failure. # 13.2Evidence In a Cochrane systematic review conducted in 2Olo, three RCTs involving 3l2 participants who had fetal heartbeat confirmed by ultrasound before recruitment were included to evaluate the efficacy and safety of hCG in treating threatened miscarriage. No statistically significant difference in MR was observed between the hCG and control groups who received a placebo or were on bed rest (RR 0.66, $9 5 \%$ CI 0.42-1.05; $p = 0 . 3 4$ $I ^ { 2 } = 7 \%$ [202].However,when comparing hCG administration with bed rest alone,a significant reduction in the risk of miscarriage was noted (RR 0.47, $9 5 \%$ CI 0.27-0.82; $p \ = \ 0 . 4 8$ ：， $I ^ { 2 } = 0 \%$ ） Nevertheless,this result should be interpreted cautiously because one study had poor methodological quality. Another Cochrane SRMA conducted in 20l3 aimed to assess the efficacy and safety of prophylactic hCG in women with a history of uRPL [203]. This meta-analysis included five studies involving 596 women and demonstrated a statistically significant reduction in the MR with hCG injection among Women with uPRL (RR 0.51, $9 5 \%$ CI $0 . 3 2 \mathrm { - } 0 . 8 1$ $p = 0 . 1 6 ; I ^ { 2 } = 3 9 \% )$ . However, when two studies of poor methodological quality were removed, the statistically significant benefit was no longer observed (RR 0.74, $9 5 \%$ CI 0.44-1.23; $p =$ 0.80; $I ^ { 2 } = 0 \%$ ). It underscores the uncertainty surrounding this issue and highlights the need for further research before making firm recommendations (Table S9). The trials in the Cochrane database were not matched for factors such as the number of miscarriages,abortus status,maternal age,and so forth.Additionally, the limited number of studies available for inclusion restricts the ability of these reviews to draw definitive conclusions regarding the eficacy and safety of hCG in preventing pregnancy loss.Well-designed RCTs with adequate power and methodology are needed to determine whether hCG has an evidence-based role in preventing miscarriage and improving pregnancy outcomes for women with RPL. It is important to note that the dosage and source of hCG (purified urinary hCG and recombinant hCG)and timing of administration varied significantly among these studies,which could potentially confound the results.Furthermore,none of these studies administered hCG based on endometrial or peripheral molecular or cellular immune indications,making it challenging to identify subpopulations that might benefit from this treatment.Additionally, the crucial role of embryonic chromosomes in embryo implantation and pregnancy maintenance was not considered in these studies. The use of intrauterine hCG infusion is primarily employed for infertile patients undergoing IVF-assisted reproductive treatment [204].Several RCTand meta-analyses have been conducted [205], with the majority focusing on women undergoing their first IVF-ET cycle [206],while limited studies addressing RIF [207] and minimal exploration in RPL.Despite multiple clinical trials attempting to validate the efficacy of intrauterine hCG infusion on IVF-ET outcomes,the findings remain controversial.A metaanalysis,which included eight RCTs with a total of 3o87 women undergoing IVF or ICSI cycles,revealed no significant difference in the LBR (RR1.13, $9 5 \%$ CI 0.84-1.53; $p = 0 . 0 0 0 8$ $I ^ { 2 } = 8 6 \%$ and MR (RR 1.00, $9 5 \%$ CI 0.74-1.34; $p { = } 0 . 7 7$ $I ^ { 2 } = 0 \%$ )between women who received intrauterine hCG infusion and those who did not [208]. # 13.3\| Safety and Possible Side Effects No adverse effects of hCG were reported on either the mother or the baby. None of these studies reported any adverse effects, including no increased risk of congenital defects. # 13.4\| Recommendation - There is a low level of evidence that the injection of hCG prevents pregnancy loss. - There remains a lack of high-quality evidence to determine which population would benefit from the hCG treatment. # Disclosure The American Society for Reproductive Immunology (ASRI),an independent,professional,medical,and scientific society,is committed to upholding the highest professional standards and does not guarantee, warrant,or endorse any commercial product or service.The guidelines and recommendations are intended to guide the particular practice patterns.It is not intended to dictate a particular pattern of patient care.The health care providers should make the ultimate determination regarding the application of recommendations in the guideline, considering each case,and adherence to the recommendations in the guideline is voluntary. Guidelines and recommendations are intended to promote favorable and desired outcomes but cannot guarantee any specific outcome.These guidelines developed by ASRI are subject to periodic revision as warranted by the evolution of medical knowledge, technology,and practice.ASRI recommendations are not intended to dictate payment or insurance decisions. They cannot adequately convey all the uncertainties and distinctions of patient care. # Data Availability Statement Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. # References 1.A.M. Kolte,L.A. Bernardi, O.B. Christiansen, et al.,“Terminology forPregnancy Loss Prior to Viability:A Consensus Statement From the ESHRE Early Pregnancy Special Interest Group,”Human Reproduction 30,no.3(2015):495-498. 2.E.Dimitriadis,E.Menkhorst, S. Saito,W.H. Kutteh,and J.J. 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Khalaf,“The Effect of Intrauterine HCG Injection on IVF Outcome: A Systematic Review and Meta-Analysis,”Reproductive Biomedicine Online 33,no.3(2016): 350-359. # Supporting Information Additional supporting information can be found online in the Supporting Information section. Appendix1: Clinical Reproductive Immunology Group (CRIG)(Fellows CRI who reviewed and approved the final version of the manuscript). Appendix2: GRADE certainty ratings.Appendix3: Recommendations Table S1:Characteristics of systematic reviews and meta-analyses (from 2000 to 2O23) that evaluated the use of corticosteroids in the treatment of RPL.Table S2:Characteristics of systematic reviews and meta-analyses (from 20oO to 2O23) that evaluated the use of IVIG in the treatment of RPL.Table S3:Characteristics of systematic reviews and meta-analyses (from 2OoO to 2O23) that evaluated the use of LITin the treatment of RPL. Table S4: Characteristics of systematic reviews and meta-analyses that evaluated the use ofILE in the treatment ofRPL.TableS5:Characteristics of systematic reviews and meta-analyses that evaluated the relationship between vitamin D and RPL.Table S6:Characteristics of systematic reviews and meta-analyses that evaluated the use of CNIs in the treatment ofRPL.Table S7:Characteristics of systematic reviews and meta-analyses that evaluated the use of G-CSF in the treatment of RPL.Table S8: Characteristics of systematic reviews and meta-analyses that evaluated the use of anticoagulation in the treatment of RPL and the association between thrombophilias and RPL.Table S9:Characteristics of systematic reviews and meta-analyses evaluating the use of hCG in the treatment of RPL	None	None	None
de019da054dc46bf9ebeef2e9752dea5	2025+CNGOF临床实践指南	妊娠早期RhD同种异体免疫的预防	# Prevention of RhD alloimmunization in the first trimester of pregnancy: Clinical practice guidelines of the French College of Obstetricians and Gynecologists Paul Maurice1 丨 Solene Vigoureux²丨 Charles Garabedian³丨 Jeanne Sibiude4\| Nicolas Sananés5 1National Reference Center for Perinatal Hemobiology, Armand Trousseau Hospital, AP-HP.Sorbonne Université, Paris,France 2Obstetrics and Gynecology Department, CHU Nantes,Nantes, France 3Department of Obstetrics, Jeanne de Flandre Hospital, CHU Lille, France 4Obstetrics and Gynecology Department, Armand Trousseau Hospital, AP-HP. Sorbonne Université,Paris,France 5Obstetrics and Gynecology Department, American Hospital of Paris, Neuillysur-Seine, France # Correspondence Nicolas Sananés,American Hospital of Paris,55 Boulevard du Chäteau,92200 Neuilly-sur-Seine, France. Email: nicolas.sananes@ahparis.org # Abstract The French College of Obstetricians and Gynecologists has decided to update its clinical practices guidelines for preventing RhD alloimmunization in the first trimester of pregnancy. The quality of evidence of the literature was assessed following the GRADE methodology with questions formulated in the Patients, Intervention, Comparison, Outcome (PlCO) format and outcomes defined a priori and classified according to their importance. An extensive bibliographic search was performed using Pubmed, Cochrane, EMBASE,and Google Scholar databases.The quality of evidence was assessed (high, moderate,low, very low)and a recommendation was formulated: strong,weak, or no recommendation. The recommendations were reviewed in two rounds by members of the scientific board of the French College of Obstetricians and Gynecologists (Delphi survey) in order to select the consensus recommendations. The three recommendations from the PlCO questions were agreed upon through the use of the Delphi method. It is not recommended to administer RhD immune globulin before 12weeks of gestation to reduce the risk of alloimmunization in the event of induced or spontaneous abortion in RhD-negative patients when the progenitor is RhD-positive or unknown (weak recommendation, very low-quality evidence). It is not recommended to administer RhD immune globulin before 12weeks of gestation to reduce the risk of alloimmunization in the event of bleeding (weak recommendation, very low-quality evidence). The quality and quantity of literature data are insufficient to determine whether injection of RhD immune globulin can reduce the risk of alloimmunization in ectopic pregnancy, so no recommendation could be made. # KEYWORDS alloimmunization, bleeding,ectopic pregnancy,first trimester, guidelines, induced abortion, prevention, RhD,spontaneous abortion # 1—INTRODUCTION The theoretical risk of alloimmunization in the first trimester of pregnancy is challenging to quantify. RhD immunization occurs when the maternal immune system encounters the D antigen present on fetal red blood cells that have entered the maternal circulation.The D antigen is theorized to be present on fetal red blood cells from 7.5weeks of gestation.1 The gestational age at which fetal red blood cells can be identified in the mother's blood and are likely to elicit an immune response is currently unknown. This is due to the fact that the studies that have investigated this phenomenon are outdated,lackinga precise method for determining the gestational age,and based on tests with limited accuracy for quantifying the number of fetal red blood cells present in the mother's circulation. In 2005,the French College of Obstetricians and Gynecologists (CNGOF) published recommendations pertaining to the prevention of RhD alloimmunization during pregnancy,including the first trimester. Situations involving induced or spontaneous abortion (with surgical or medical treatment),bleeding,or ectopic pregnancy were deemed to pose a moderate risk of fetal red blood cell passage during the first trimester.² This justified the prevention of RhD alloimmunization through the administration of anti-RhD immune globulin. However,at the time these recommendations were established, there were few published studies that specifically evaluated the benefits and efficacy of preventing alloimmunization in the first trimester.Furthermore,the epidemiologic and theoretical data that informed these recommendations were heterogeneous and dated (while the techniques for quantifying fetal red blood cells in maternal blood have since evolved),and were subject to bias,resulting in a very low quality of evidence. Moreover, in the meantime,a number of national and international learned societies,including the International Federation of Gynecology and Obstetrics (FlGO) have published guidelines recommending that alloimmunization should not be systematically prevented in the first trimester.3-15 Thus,while there is a broad consensus on the need to systematically prevent RhD alloimmunization during pregnancy at 28 weeks of gestation and during eventsat risk for fetomaternal hemorrhage in the second and third trimesters,the recommendations of the various learned societies on immunoprophylaxis are heterogeneous when it comes to events at risk during the first trimester (Table 1). Finally,a recent prospective observational study of good methodological quality published in 202316 examined the passage of fetal red blood cells during surgical or medical abortion,and concluded that these procedures do not increase the concentration of fetal red blood cells in the maternal blood and are therefore not associated with an additional risk of alloimmunization. For these reasons, the CNGOF has decided to update its recommendations for preventing RhD alloimmunization in the first trimester of pregnancy.These recommendations are intended to assist health care professionals in their daily clinical practice when counseling or caring for patients in the first trimester of pregnancy who are considered,rightly or wrongly,to be at risk for alloimmunization.They concern gynecologists and obstetricians,but also midwives and general practitioners.The topic of these Recommendations for Clinical Practice (RCPs) was proposed by the CNGOF Scientific Committee to the CNGOF Bureau and Board of Directors,which approved it. # 2\|METHODS As a first step, the workgroup coordinators defined the questions to be addressed and identified the workgroup members responsible for each question.The questions were formulated according to the Patients, Intervention,Comparison,Outcome (PlCO) format. Thus,in a given population (P), the outcome of a treatment (l) is assessed in relation to a reference treatment (C),or even the absence of treatment,on the basis of an a priori assessment criteria (O),such as a clinical or paraclinical outcome.The formulation of a question in the PlCO format implies a classification of the importance of the evaluation criteria: crucial,important, not very important.An extensive bibliographic search was performed using Medline, Cochrane, EMBASE and Google Scholar databases.To be included in the analysis,publications had to be considered important by the expert group and published in English or French. The GRADE methodology was used to develop these recommendations.After analyzing the literature,this method makes it possible to determine the quality of the evidence and thus provide an estimate of the confidence we can have in the effect observed for a given intervention and,ultimately,in the strength of the recommendation. The quality of the evidence is classified into four categories: · High: Future research is unlikely to change our confidence in the effect estimate. ·Moderate: Future research is likely to change the confidence in the effect estimate and may change the effect estimate itself. ·Low: Future research is very likely to affect confidence in the effect estimate and is likely to change the estimate of the effect itself. · Very low: The estimate of the effect is very uncertain. The quality of evidence is analyzed for each assessment criterion,and an overall quality of evidence is then defined based on the quality of evidence for the predefined criteria,with priority given to those that are most important.The final wording of recommendations,when the data in the literature allows,is always binary:either positive or negative and either strong or weak. The strength of the recommendation is determined based on five key factors and validated by expert voting using the GRADE methodology: · Estimation of effect. · Overall quality of the evidence: the higher the quality,the stronger the recommendation. Sometimes the strength of the recommendation is not related to the quality of the evidence.In such cases, the working group would provide a rationale. <table><tr><td colspan="2">FIGO VTLEY TABLE 1 Learned societies recommendations on first trimester RhD alloimmunization prevention.</td></tr><tr><td> American College of Obstetricians</td><td>Not necessary for both medical and surgical treatment in case of induced or spontaneous abortion before 12 WG</td></tr><tr><td>and Gynecologists (ACOG)- 202412</td><td></td></tr><tr><td>Society of Obstetricians and Gynecologists of Canada-202413</td><td>Not necessary for both medical and surgical treatment in case of induced abortion before 12 WG</td></tr><tr><td>National Abortion Federation-202414</td><td> Not necessary for both medical and surgical treatment in case of induced abortion before 12 WG</td></tr><tr><td>Society for Maternal-Fetal Medicine (SMFM)-202415</td><td>Necessary for both medical and surgical treatment in case of induced or spontaneous abortion regardless of gestational age</td></tr><tr><td>Royal College of Obstetricians and Gynecologists-20225</td><td> Not necessary for both medical and surgical treatment in case of induced abortion before 12 WG</td></tr><tr><td>Society of Family Planning-20224 World Health Organization-2022³</td><td>Not necessary for both medical and surgical treatment in case of induced or spontaneous abortion before 12 WG</td></tr><tr><td>International Federation of Gynecology and Obstetrics and</td><td>Not necessary for both medical and surgical treatment in case of induced abortion before 12 WG Not necessry before 10 WG in case of induced or spontaneous abortion without surgical treatment</td></tr><tr><td>international Confederation of Midwives guidelines (FIGO/</td><td>Necessary in case of:</td></tr><tr><td>ICM)-20216</td><td>· Induced or spontaneous abortion with surgical treatment</td></tr><tr><td rowspan="6">Royal Australian and New Zealand College of Obstetricians and · Bleeding before 12 WG Gynecologists-20217 · Induced abortion with medical treatment before 10 WG Necessary in case of:</td><td>· Molar pregnancy · Ectopic pregnancy</td></tr><tr><td>·Chorionicvilus biopsy</td></tr><tr><td> Not necessary in case of:</td></tr></table> ·Balance between desirable and undesirable effects: the more favorable the balance,the stronger the recommendation. ·Values and preferences: the more uncertain or highly variable these are, the weaker the recommendation.These values and preferences should be obtained from the stakeholders (patient, physician,decision maker) as much as possible. ·Cost: the higher the cost or use of resources,the lower the recommendation. The recommendations formulated by the working group,along with their rationale and tables,were sent to 24 obstetriciangynecologists of the CNGOF Scientific Advisory Board,who rated each recommendation on a scale of 1 (strongly disagree) to 9 (strongly agree).Two rounds of Delphi were organized.Only experts who answered more than one question in the first round were invited to participate in the second round.Of the experts contacted, 20 $8 3 . 3 \%$ ,20/24) responded in the first round and all( $100 \%$ ,20/20) responded in the second round. Arecommendation was considered validated if it received at least $7 5 \%$ of the responses in the same section,with a median greater than or equal to 7.The recommendation that did not meet the consensus of the reviewers in the first evaluation, together with the reason for the lack of consensus,was analyzed by the working group,then modified and returned to the same group of reviewers, together with a specific argument explaining the modification of the recommendation in question.At the time of this second evaluation,in order to validate the recommendation,at least $7 5 \%$ of the responses had to be in the same section,with a median greater than or equal to 7.If this was not the case,no recommendation would be made and the proposal would be considered rejected. These RCPs were publicly presented at the CNGOF Annual Congress,Pari(s) Santé Femme,in Paris on June 13,2024.They have already been published in French language.17 We decided to address the following three PlCO questions with a five-person working group: Question 1: In a patient who is RhD negative,when the progenitor is RhD positive or unknown,in case of induced or spontaneous abortion before 12weeks of gestation,does the injection of RhD immune globulin reduce the risk of alloimmunization? Question 2: In a patient who is RhD negative,when the progenitor is RhD positive or unknown,in case of bleeding in an ongoing pregnancy before 12weeks of gestation,does the injection of RhD immune globulin reduce the risk of alloimmunization? Question 3: In a patient who is RhD negative,when the progenitor is RhD positive or unknown,in case of ectopic pregnancy,does the injection of RhD immune globulin reduce the risk of alloimmunization? # 3\|RECOMMENDATIONS After summarizing the work of the experts and applying the GRADE methodology, three recommendations were formalized. All recommendations were submitted to the expert group for evaluation using the GRADE method. After a first round of scoring, agreement was reached on $6 6 . 6 \%$ (2/3)of the recommendations. In the second round of scoring,agreement was reached on the third recommendation,which had been modified following comments made in the first round.For three questions, the quality of the evidence was rated as very low,and two weak recommendations were given.The quality and quantity of the data in the literature were considered insufficient to make a recommendation on the third question. # 3.1丨Question 1 In a patient who is RhD negative,when the progenitor is RhD positive or unknown,in case of induced or spontaneous abortion before 12weeks of gestation,does the injection of RhD immune globulin reduce the risk of alloimmunization?(Table S1). R1-It is not recommended to administer RhD immune globulin before 12weeks of gestation in order to reduce the risk of alloimmunization in the event of induced or spontaneous abortion in RhD-negative patients when the progenitor is RhD-positive or unknown <table><tr><td>Weak recommendation Very low-quality evidence</td></tr><tr><td>Delphi: n=20; median 8; 80.0% agreed at first round.</td></tr></table> # Argumentation # Benefit of RhD immune globulin Few studies have evaluated the efficacy of RhD immune globulin in preventing alloimmunization in the first trimester.A single randomized controlled interventional trial published in 1972 compared administration of RhD immune globulin with no administration of RhD immune globulin.18 In this previous study of spontaneous abortions,a total of 19 patients (14 with surgical treatment) received prophylaxis (RhD immune globulin $\mu \sigma ^ { \sf I M }$ within 72 h) compared with 38 patients (34 with surgical treatment) in the control group.Gestational ages,which were not reported in detail, ranged from eight to 24weeks of gestation.There were no cases of immunization in this study,but the number of patients involved was small and there was a potential lack of power.There are two other interventional studies,including spontaneous abortion with surgical treatment, that compared administration of RhD immune globulin with no administration.19,20 However, these studies contain numerous biases that severely limit the reliability of the results: recruitment bias (RHD phenotype of progenitor not systematically known),selection bias (lack of randomization or randomization not detailed),and detection bias (diagnostic method for alloimmunization not optimal). # Population-based study of the effect of prophylaxis A population-based study published in 2018 compared the prevalence of alloimmunization among pregnant women in Canada and the Netherlands.21 These countries have different practices: systematic administration of RhD immune globulin in Canada for spontaneous or induced abortion versus no administration in the Netherlands for spontaneous abortion before 1Oweeks of gestation (WG) or induced abortion before 7WG.The study was based on public health data.The primary endpoint was the prevalence of immunization, that is,the presence of clinically significant perinatal antibodies at a significant titer (whatever the type of antibody) when screening for irregular antibodies at the beginning of pregnancy in the entire population of pregnant women.The calculated estimated prevalencewas4.21/1000( $9 5 \%$ Cl: 4.12-4.30) in Canada and 4.03/1000 $9 5 \%$ Cl: 3.93-4.12) in the Netherlands.A sensitivity analysis taking into account a compliance with the national health policy of $80 \%$ and $90 \%$ ,respectively confirmed these results.This study is subject to several biases,in particular the fact that the populations of the two countries are not strictly comparable.In addition,this type of study cannot formally establish a causal relationship.However, this population-based study suggests that systematic prophylaxis does not influence the prevalence of alloimmunization. # Passage of fetal red blood cells into the maternal circulation before12 WG A recent multicenter prospective observational study,published in 2023,examined the passage of fetal red blood cells into the maternal circulation in patients who underwent medical or surgical abortion at multiple centers in the USA before 12 WG between 2019 and 2022.16 Fetal red blood cells (FRBC) were detected and quantified by flow cytometry before and after the procedure.Because the cytometry protocol was modified during the study, three groups were defined: a medical abortion group with a first cytometry protocol including 113 patients,a medical abortion group with a second cytometry protocol including 2O6 patients,and a surgical abortion group with the second protocol including 187 patients.Of the 506 women,three had preprocedure FRBC concentrations above the threshold of 125 FRBC/5 million adult red blood cells (ARBC),which is considered the risk threshold forimmunization according to the literature.2 Only one of these three women (medical abortion group with first cytometry protocol) still had a high post-procedural FRBC level $( 0 . 2 \%$ [ $9 5 \%$ Cl: $0 \% { - } 0 . 9 3 \% ]$ ). None of the 5O6 women had an elevated post-procedural FRBC concentration if they did not have an elevated preprocedural FRBC concentration $(0 \%$ $1 9 5 \%$ Cl: $0 \% { - } 0 . 5 9 \% ]$ ).The increase in post-procedural concentration was a median of O FRBC/5 million ARBC (maximum 35.6) for the entire population and a median of O.5 FRBC/5 million ARBC(maximum 28.5) for the group using the first cytometry protocol. The only factors significantly associated with the level of postprocedural concentration were the preprocedural concentration and the patient's blood group: taking patients with blood group O as a reference,having group AB was significantly associated with a higher postprocedural concentration of FRBC.This can be explained by the fact that in the case of group O,there is a greater clearance of FRBC.On the other hand,group Aor B were not significantly associated with a different concentration.Given that the majority of patients in the population were group O $( 5 4 \% )$ ,this may have minimized the results on the concentrations,but the extent of this bias appears to be limited,as group A or B patients $(43 \% )$ had concentrations that were not significantly different from those of group O patients.No details were provided on the time at which the post-procedure samples were obtained, but the stability of repeat samples taken from six patients up to $7 2 \mathrm { h }$ may suggest that this time did not really influence the results. Thus,even if the threshold of FRBC at risk of immunization used in this study is controversial because it is not consensual or formally established,these results show that an abortion before 12weeks' gestation,by medical or surgical method, does not increase the concentration of FRBC in the blood of the patients and is therefore not associated with an additional risk of alloimmunization compared to a normally progressing pregnancy in the first trimester.To be noted that only patients in whom a FRBC concentration above the risk threshold was found were the ones with already preprocedural elevated FRBC.This can probably be extrapolated to the situation of spontaneous abortion. It should be noted that while these guidelines were being prepared for publication in French, the American Society for Maternal-Fetal Medicine (SMFM) issued a statement recommending administration of RhD immune globulin in the event of a spontaneous or induced abortion.14 The reasons given are that RhD alloimmunization is a particularly serious pathology and that there are insufficient data in the literature to show that prevention with RhD immune globulin is of no benefit. Indeed, there is no reliable evidence for the lack of benefit of prophylaxis in these circumstances,but on the other hand, there is no reliable evidence for the need to prevent alloimmunization in the first trimester either,and no evidence foran increased risk of alloimmunization duringabortion.Therefore,it does not necessarily seem legitimate to expose a potentially large number of women to a blood-derived product for which there is no proven benefit.Regarding the interpretation of the observational study on the passage of fetal red blood cells duringabortion,16 the authors,like us,point out that the risk threshold for alloimmunization is controversial,but this study shows anyway that the fact of having an abortion might not increase the concentration of fetal red blood cels in the blood of patients.During this period, two other additional recommendations were issued in which the administration of RhD immune globulin was not recommended for induced and spontaneous abortions before 12 WG.13.14 Recently, the American College of Obstetricians and Gynecologists suggested the possibility of not administering RhD immune globulin in these situations and, consequently, not testing for RhD. 12 Risks associated with RhD immune globulin administration The risks associated with RhD immune globulin are low(viraland prion risks associated with injection of a blood-derived product, hypersensitivity or allergies). It is a product of human origin,obtained primarily from healthy, hyperimmunized and compensated North American donors.23 Since 2O05,only Rhophylac has been marketed in France in two doses, $2 0 0 \mu \ g$ and $3 0 0 \mu \ g$ ,depending on the indication.There is a theoretical risk associated with prions,as well as a viral risk,which is low because of the treatments used to eliminate viruses,but the risk is not zero,particularly with regard to viruses that have not yet ben identified.23.24 There is alsoa risk of alergy and hypersensitivity.A few cases of serious allergic reactions to other brands of RhD immune globulin have been reported in theliterature.25-27 No allergic reactions have been reported in antenatal and postnatal efficacy studies of Rhophylac.24 Therefore, the risks associated with RhD immune globulin are very low but potentially serious. # Population potentially concerned by RhD immune globulin administration A total of 234253 induced abortions were performed in 2022 in France.28 The exact number of spontaneous abortions in France in the first trimester is not known,but has been calculated at 176280.29 The proportion of RhD-negative individuals in the French population is approximately $1 5 \%$ .30 The administration of RhD immune globulin in France for these two indications therefore affects approximately 61580 patients per year. Overall, there is no evidence in the literature that RhD immune globulin administration reduces the risk of alloimmunization in cases of spontaneous or induced abortion before 12 WG.A population-based study suggests that routine prophylaxis in the first trimester of pregnancy has no effect on the prevalence of alloimmunization in pregnant women.21 In addition,a prospective multicenter observational study published in 2O23 showed that medical or surgical abortion before 12 WG does not appear to increase the concentration of fetal red blood cells in maternal blood and therefore would not be associated with an increased risk of aloimmunization.16 Finally, the risk of RhD immune globulin is not zero and the potentially affected population is large. # 3.2丨Question 2 In a patient who is RhD negative,when the progenitor is RhD positive or unknown,in case of bleeding in an ongoing pregnancy before 12 WG,does the injection of RhD immune globulin reduce the risk of alloimmunization? (Table S2). R2-It is not recommended to administer RhD immune globulin before 12weeks of gestation in order to reduce the risk of alloimmunization in case of bleeding in an ongoing pregnancy in RhDnegative patients when the progenitor is RhD-positive or unknown <table><tr><td>Weak recommendation</td></tr><tr><td>Very low-quality evidence</td></tr><tr><td>Delphi: n=20; median 8; 80.0% agreed at first round</td></tr></table> # Argumentation Risk of alloimmunization and benefit of RhD immune globulin There are very few studies in the literature evaluating the risk of alloimmunization and the benefit of RhD immune globulin in case of first trimester bleeding.These studies provide a very low level of evidence because they are purely observational,reporting clinical cases or case series.Some studies have a case-control design,but sometimes the controls are not even pregnant women.For example,a 20o3 study compared 24 cases (RhD negative pregnant women who were not immunized at the beginning of pregnancy and were immunized at the end) with 24 controls (RhD negative pregnant women who were not immunized at the end of pregnancy),all of whom had bleeding during pregnancy. This study showed that there was no association between alloimmunization and bleeding during pregnancy before the 2Oth week of pregnancy.31 In addition,these studies are old,the most recent being published 2Oyears ago,and methods for detecting alloimmunization have evolved since then.Finally, these studies focus on the risk factors for alloimmunization rather than the benefit of prophylaxis with RhD immune globulin injection and refer to highly heterogeneous patient populations,not only in the first trimester of pregnancy.32 # Passage of fetal red blood cells into the maternal circulation before 12WG A recent multicenter, prospective,observational study published in 2023 examined the passage of fetal red blood cells into the maternal circulation in patients who underwent medical or surgical abortion before 12 WG at multiple centers in the USA between 2019 and 2022.16 Fetal red blood cels were detected and quantified by flow cytometry before and after the procedure.Of the 506 women, three had a preabortion FRBC concentration above the threshold of 125 FRBC/5 million ARBC,which is considered the risk threshold for immunization according to literature data.22 None of the three women had a history of prior bleeding.In addition,the level of FRBC was not significantly increased after the procedure in cases of bleeding (RR 1.06 $1 9 5 \%$ Cl: 0.84-1.36], $_ { P = 0 . 6 2 }$ ). It should be noted that no high FRBC concentration was found in any of the 5O6 women after the procedure when it was not present before the procedure $(0 \%$ $1 9 5 \%$ Cl: $0 \% { - } 0 . 5 9 \% ]$ ).This study, focusing on the effect of abortion (medical or surgical) on FRBC passage in maternal blood, suggests that abortion before 12 WG is not associated with an increased risk of alloimmunization.This result is likely to be extrapolated to bleeding before 12 WG. # Risks associated with RhD immune globulin administration The risks associated with RhD immune globulin are low (viral and prion risks associated with injection of a blood-derived product, hypersensitivity orallergies).It is a product of human origin,obtained primarily from healthy,hyperimmunized and compensated North American donors.23 Since 2005,only Rhophylac has been marketed in France in two doses, $2 0 0 \mu \ g$ and $3 0 0 \mu \ g$ ,depending on the indication.There is a theoretical risk associated with prions,as wellas a viral risk,which is low because of the treatments used to eliminate viruses, but the risk is not zero,particularly with regard to viruses that have not yetbeen identified.23.24 There is alsoariskof alergy and hypersensitivity.A few cases of serious allergic reactions to other brands of RhD immune globulin have been reported in the literature.25-27 No allergic reactions have been reported in antenatal and postnatal efficacy studies of Rhophylac.24 Therefore, the risks associated with RhD immune globulin are very low but potentially serious. # Population potentially concerned by RhD immune globulin administration Approximately $20 \% - 2 5 \%$ of pregnant women will experience bleeding in the first trimester and will go to their doctor or gynecologic emergency room for diagnosis and management.34 The proportion of RhD negative individuals in the French population is approximately $1 5 \%$ 30 The administration of RhD immune globulin for first-trimester bleeding therefore potentially affects approximately 30000 women per year in France. Overall, there is no evidence in the literature to support the efficacy of RhD immune globulin administration to prevent alloimmunization in the setting of first-trimester bleeding in an ongoing pregnancy. Moreover,a recent multicenter prospective observational study shows that the risk of alloimmunization is low in cases of abortion before 12 WG and that there is no association between bleedingand an increased risk of alloimmunization.Finally, the risk of RhD immune globulin is not zero and the potentially affected population is large. # 3.3\|Question 3 In a patient who is RhD negative,when the progenitor is RhD positive or unknown,in case of ectopic pregnancy,does the injection of RhD immune globulin reduce the risk of alloimmunization? (Table S3). R3-The current literature does not provide sufficient data to determine whether the administration of RhD immune globulin can effectively reduce the risk of alloimmunization in case of ectopic pregnancy <table><tr><td>No recommendation Very low-quality evidence</td></tr><tr><td>Delphi: n=20; median 7; 50.0% agreed at first round; n=20; median 8.5;80.0% agreed at second round</td></tr></table> # Argumentation # Previous recommendations of the CNGOF In 2005,the CNGOF published recommendations for the prevention of RhD alloimmunization during pregnancy including the first trimester.² The following circumstances were considered to be at moderate risk of fetal red blood cell passage in the first trimester: spontaneous or induced abortion,bleeding,and ectopic pregnancy.29 This provided justification for the prevention of alloimmunization through the administration of RhD immune globulin injections. However,at the time these recommendations were formulated, there were few studies in the existing literature specifically designed to evaluate the benefits and efficacy of preventing alloimmunization in the first trimester.Furthermore,the epidemiologicand theoretical data on which these recommendations were based were heterogeneous,outdated (whereas techniques for quantifying fetal red blood cells in maternal blood have since evolved),and subject to certain biases,resulting in a very low quality of evidence.In addition, none of the data specifically addressed the risk of alloimmunization in ectopic pregnancy. # Benefit of RhD immune globulin The review of the literature reveals that no study has specifically evaluated the interest of RhD immune globulin in preventing alloimmunization in ectopic pregnancy. Passage of fetal red blood cels into the maternal circulation in case of ectopic pregnancy A single comparative study,published in 1972,examined the passage of fetal red blood cells into maternal blood in case of ectopic pregnancy.33 This single-center South African study compared women who had undergone surgery for a ruptured tubal pregnancy with a control group of non-pregnant women. The primary endpoint was a Kleihauer test result of at least 5 FRBC/15000O ARBC in the blood sample obtained within $^ { 2 4 \mathrm { h } }$ of surgery. This criterion was met in nine out of 38 $( 2 3 . 7 \% )$ patients in the operated group,but not in the control group (O out of 40).The presence of intraperitoneal fetal red blood cells was a secondary criterion observed in 16 of the 21 cases of operated patients for whom this examination was available,representing a proportion of $7 6 . 2 \%$ . In the control group, $1 2 . 5 \%$ (5/40) of cases demonstrated the presence of 1 to 2 FRBC per 150000 ARBC.The authors assumed two potential mechanisms by which fetal red blood cells may gain access to the maternal circulation: through the fallopian tube wall and by absorption through the peritoneum.This study was subject to a number of biases,including a lack of randomization,a control group of non-pregnant patients,and lack of information on the characteristics of the groups.Furthermore,the potential for false-positive results of the Kleihauer test due to hemoglobinopathy or the presence of F cells,which can be observed in early pregnancy,34 was not considered.Therefore,the study does not provide sufficient evidence to determine the risk of aloimmunization in ectopic pregnancy. Moreover,a recent prospective observational study of good methodological quality, published in 2023,16 examined the passage of fetal red blood cells during surgical or medical abortion.The study concluded that these procedures did not increase the concentration of fetal red blood cells in the maternal blood and thus were not associated with an additional risk of alloimmunization.The results of this study call for a re-evaluation of the value of alloimmunization prophylaxis in the first trimester. However,it is not possible to extrapolate these results to ectopic pregnancy because the underlying pathophysiology is different (i.e.,a reduction in the tightness and fragility of the fallopian tube wall and the potential externalization of pregnancy material into the peritoneal cavity). Risks associated with RhD immune globulin administration The risks associated with the injection of RhD immune globulin are minimal.These include the possibility of infection with prions and other unidentified viruses and the rare occurrence of serious allergic reactions.24,26 Population potentially concerned by RhD immune globulin administration In France,approximately 16ooO patients are treated for ectopic pregnancy each year.35 Given that $1 5 \%$ of the population is RhD negative,a total of 24OO patients should potentially receive this prophylaxis.35 Overall,a recent prospective observational study of good methodological quality indicates that medical or surgical abortion is not associated with an additional risk of alloimmunization.16 This study calls for a general reconsideration of the value of preventing alloimmunization in the first trimester. However, these reassuring results cannot be extrapolated to ectopic pregnancy,and there are no studies of good methodological quality specifically addressing the question of alloimmunization after ectopic pregnancy.Therefore, it is not possible to make a recommendation based on the current data in the literature regarding the value of RhD immune globulin injection to reduce the risk of alloimmunization in the setting of ectopic pregnancy. # 4 CONCLUSION Although the quality of evidence from the literature is very low, it is recommended that RhD immune globulin not be administered in case of induced or spontaneous abortion or bleeding before 12weeks of gestation to reduce the risk of alloimmunization.However, the quality and quantity of literature data was insufficient to determine whether injection of RhD immune globulin can reduce the risk of alloimmunization in ectopic pregnancy and no recommendation can be made. # AUTHOR CONTRIBUTIONS All authors contributed to the conception of the guidelines,draft of the work or reviewed it critically for important intellectual content. They approved the final the version to be published and agree to be accountable for all aspects of the work. # ACKNOWLEDGMENTS The authors thank the Interassociative group on childbirth (ClANE) and its user representative: France Artzner.The authors also thank the review group of those guidelines:A Agostini, J Belaisch-Allart, JL Brun,N Chabbert-Buffet,P Collinet,B Courbiere,V Debarge,X Fritel, C Huissoud,G Kayem,G Legendre,P Rozenberg,G Robin,C Rousset-Jablonski, L Salomon,T Schmitz,MV Senat,L Sentilhes,C Vayssiere,EVerspyck. # CONFLICT OF INTEREST STATEMENT SV,JS and NS: None.PM: Remuneration by CSL Behring for one training mission,remuneration by Janssen for three advisory boards,subinvestigator in two clinical trials promoted by Janssen. CG: has been memberof advisory boards for Bioserenityand Organon,participated in symposiums for Ferring and General Electrics in the last 3years. # DATA AVAILABILITY STATEMENT Data sharing is not applicable to this article as no new data were created or analyzed in this study. # REFERENCES 1．Bergstrom H, Nilsson L-A,Nilsson L, Ryttinger L.Demonstration of Rh antigens ina 38-day-old fetus.AmJObstet Gynecol.1967;99:130- 133. doi:10.1016/S0002-9378(16)34502-1 2． College National des Gynécologues et Obstétriciens Francais. Recommendations for clinical practice.Prevention in maternofetal Rh immunization (December 2Oo5).Gynecol Obstet Fertil. 2006;34(4):360-365. doi:10.1016/j.gy0bfe.2006.02.007 3.World Health Organization.Abortion care guideline 2022. Accessed October 3,2024. https://iris.who.int/bitstream/handle/ 10665/349316/9789240039483-eng.pdf?sequence $^ { = 1 }$ 4. 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2642d505c86f42b1868f4e5020049edf	2025+ESUR指南	宫颈癌、子宫内膜癌和卵巢癌患者保留生育能力治疗前的磁共振成像	# European Society of Urogenital Radiology (ESUR) guidelines on MR imaging prior to fertility-sparing treatments in patients with cervical, endometrial, and ovarian cancers Benedetta Gui1 , Luca Russo ${ } ^ { 1 , 2 ^ { \ast } } \oplus _ { \prime }$ Nishat Bharwani3,4, Teresa Margarida Cunha5 , Carlos Nicolau6 , Carlos Carnelli7 , Francesco Fanfani8,9, Denis Querleu8 , Pamela Causa Andrieu10, Yulia Lakhman11, Stefania Rizzo12, Evis Sala1,2, Stephanie Nougaret13,14 and Lucia Manganaro15 # Abstract Objective To establish standardised MRI protocols and structured reporting guidelines for optimal patient selection in fertility-sparing treatments for gynaecological cancers. Methods The European Society of Urogenital Radiology (ESUR) Female Pelvis Working Group utilised the RAND-UCLA Appropriateness Method to develop these guidelines. A multidisciplinary panel composed of ten radiologists and two gynaecological oncologists conducted a comprehensive review of clinical and imaging literature (until 28th February 2025) and evaluated MRI protocols through a structured survey consisting of 104 questions across five sections covering MR imaging preparation, equipment specifications, protocols, and reporting standards. Recommendations achieving $\geq 8 0 \%$ consensus were designated as “RECOMMENDED”, with those below this threshold marked as “SUGGESTED” or “NOT RECOMMENDED”. Results Consensus was reached on MRI technical requirements, including sequence selection, imaging planes, and contrast timing. Disease-specific structured reporting templates were developed with standardised criteria for cervical, endometrial and ovarian cancers. Conclusions These evidence-based guidelines provide a standardised framework for MRI acquisition and reporting to support optimal patient selection for fertility-sparing treatments. By harmonising imaging protocols and structured reporting, we aim to enhance diagnostic accuracy and clinical decision-making. These guidelines represent a key step toward developing comprehensive recommendations for fertility preservation, with future validation and adaptation ensuring their applicability across diverse clinical settings. # Key Points Question Fertility-sparing treatments in gynaecological cancers require adherence to strict selection criteria based on tumour stage, size, and histological subtype. Findings MRI is essential for accurately assessing eligibility criteria in cervical and endometrial cancers, and characterising adnexal masses using standardised reporting criteria. Clinical relevance MRI is valuable for the preoperative evaluation of patients considered for fertility-sparing treatments in gynaecologic cancers. Key parameters include precise tumour measurements, depth of invasion, and local tumour extent through optimised protocols combining anatomical and functional sequences. Keywords Magnetic resonance imaging, Fertility preservation, Uterine cervical neoplasms, Endometrial neoplasms, Ovarian neoplasms # Introduction Gynaecologic cancers have a significant impact on premenopausal women, with age-specific (18–45 years) incidence rates for cervical, endometrial and ovarian cancers of $3 . 2 \%$ , $1 . 8 \%$ , and $2 . 4 \%$ , respectively, in 2022 [1, 2]. Impact of these cancers on reproductive-aged women underscores the critical need to preserve fertility without compromising oncologic outcomes, emphasising the importance of timely referral to specialists for fertility preservation counselling after cancer diagnosis [3, 4]. Incorporation of imaging information in the fertilitysparing (FS) decision process has recently been defined by the European Society of Gynaecological Oncology (ESGO), the European Society of Human Reproduction and Embryology (ESHRE), and the European Society for Gynaecological Endoscopy (ESGE) for cervical cancer (CC) and ovarian cancer (OC) [5]. Consensus guidelines for endometrial cancer (EC) are also available [5]. These guidelines establish specific staging criteria and eligibility thresholds for fertility preservation. Among imaging techniques, while ultrasound provides initial assessment and CT evaluates distant spread, MRI offers superior soft tissue contrast and multiplanar capabilities [6–9] crucial for assessing the local extent of disease, guiding management and surgical planning [10, 11]. Recognising the importance of consistency in imaging practices, the European Society of Urogenital Radiology (ESUR) developed this manuscript through a consensus process among radiologists and gynaecologists with the aim of standardising imaging protocols, including imaging planes and contrast timing, along with structured reporting templates incorporating selection criteria. # Discussion # Methods To develop these guidelines, we employed the RANDUCLA Appropriateness Method (RAM), similar to the previous ESUR guidelines for EC and CC [8, 12]. The following steps were applied: team design, literature search, questionnaire development and distribution, data analysis and panel discussion, data reporting. The details of these steps are provided in the Electronic supplementary material (ESM). # Results The final panel composition is reported in the ESM. The panel’s recommendations are summarised in Table 1. # Patient preparation The panel recommends fasting and the use of spasmolytic agents $2 0 \mathrm { m g }$ scopolamine-N-butyl bromide $\mathrm { i m / i v }$ or $1 \mathrm { m g }$ glucagon iv) to reduce bowel peristalsis. Intravaginal ultrasound gel $( 5 0 \mathrm { m L } )$ is optional for visualisation of small exocervical tumours [13]. Vaginal opacification is not recommended for EC and OC due to lack of added diagnostic value. Rectal opacification is not recommended for all gynaecologic cancers. # Acquisition protocol 1.5- or 3-T scanners are recommended. The acquisition protocol employs multiparametric MRI, incorporating conventional morphologic sequences, diffusion-weighted imaging (DWI), and dynamic contrast-enhanced (DCE) imaging. For patients with contraindications to contrast agents, a non-contrast MRI protocol remains the best alternative. Considering the small size of tumours, MR technologists should consult the radiologist to supervise them in challenging cases (e.g., unusual shape or location). Axial T1WI (with and without fat saturation) and T2WI (without fat saturation) of the pelvis are recommended in CC and EC. For CC, at least two planes, including high-resolution (HR; small FOV and slice thickness $\leq 4 \mathrm { m m }$ ) oblique axial (perpendicular to the cervical canal) and sagittal T2WI, are recommended. DWI in the same oblique axial plane as T2WI is recommended. Sagittal DWI (with the same orientation as sagittal T2WI) is suggested. The use of contrast agent is recommended, with multiphase acquisition in the sagittal plane. Axial T2WI from the pubic symphysis to renal hila is recommended, while axial DWI is suggested. For patients classified as FIGO stage IB1, with tumours $\leq 2 \mathrm { c m }$ , pelvic MRI may suffice without further abdominal sequences, given the very low risk of para-aortic lymph node (LN) metastases [5, 14]. The acquisition protocol for EC does not differ significantly from ESUR guidelines for EC staging [12]. In addition to the oblique axial DWI (perpendicular to the endometrial cavity), a sagittal DWI is suggested. DCE is recommended in a multiphase approach, including at least a sagittal arterial phase [15–17] and a delayed oblique axial phase at around $2 { : } 3 0 \mathrm { m i n }$ [18, 19]. Axial T2WI from the pubic symphysis to the renal hila is recommended, and axial DWI is suggested. Table 1 List of panel recommendations <table><tr><td colspan="2">Patient preparation</td></tr><tr><td></td><td> Item</td></tr><tr><td>Recommended</td><td>Field strength 1.5Tor 3T</td></tr><tr><td>Recommended</td><td>Fasting</td></tr><tr><td>Recommended</td><td> Use of spasmolytic agent</td></tr><tr><td>Optional (cervical cancer)</td><td>Vaginal gel</td></tr><tr><td>Not recommended (endometrial and</td><td></td></tr><tr><td>ovarian cancers)</td><td></td></tr><tr><td>Not recommended</td><td>Scheduling according to menstrual cycle</td></tr><tr><td>Not recommended</td><td>Rectal gel</td></tr></table> Acquisition protocol <table><tr><td></td><td>Sequence</td><td>Location</td></tr><tr><td>Cervical cancer</td><td></td><td></td></tr><tr><td>Recommended</td><td>Sagittal T2-WI ST≤4mm</td><td>Uterus</td></tr><tr><td>Recommended</td><td>Axial oblique T2-WI</td><td>Cervical canal—perpendicular to</td></tr><tr><td>Recommended</td><td>ST≤4 mm, small FOV Axial oblique DWI</td><td>cervical long axis Cervical canal—perpendicular to</td></tr><tr><td>Suggested</td><td>ST same as axial oblique T2-Wl, min. 2 b-values (low b= 0-50 s/mm², high b= 800-1000 s/mm2) Sagittal DWI ST same as sagittal T2-Wl, min.2 b-values (low b= 0-50 s/mm²,</td><td>cervical long axis Uterus</td></tr><tr><td>Recommended</td><td>high b= 600-1000 s/mm²) Sagittal T1FS w/ gadolinium (multiphase)</td><td>Uterus</td></tr><tr><td>Recommended</td><td>Axial T1-Wl (with and without FS)</td><td>Pelvis</td></tr><tr><td>Recommended</td><td>Axial T2-WI</td><td>Pubic symphysis-renal hila</td></tr><tr><td>Suggested</td><td>Axial DWI ST same as axial T2-Wl, min.2 b-values (low b= 0-50 s/mm², high</td><td>Pubic symphysis-renal hila</td></tr><tr><td>Endometrial cancer</td><td>b= 800-1000 s/mm2)</td><td></td></tr><tr><td>Recommended</td><td>Sagittal T2-WI ST≤4mm</td><td>Uterus</td></tr><tr><td>Recommended</td><td>Axial oblique T2-WI ST≤4 mm, small FOV</td><td>Uterine corpus—perpendicular to</td></tr><tr><td>Recommended</td><td>Axial oblique DWI ST same as axial oblique T2-Wl, min.</td><td>endometrial cavity Uterine corpus—perpendicular to endometrial cavity</td></tr><tr><td>Suggested</td><td>2 b-values (low b= 0-50 s/mm², high b= 800-1000 s/mm²) Sagittal DWI ST≤4 mm,min.2 b-values (low b= 0-50 s/mm², high</td><td>Uterus</td></tr><tr><td>Recommended</td><td>b= 600-1000 s/mm²) T1-WI FS w/ gadolinium—sagittal multiphase (including arterial</td><td>Uterus</td></tr><tr><td></td><td>phase (25-40 s) + late axial oblique (2:30 min))</td><td></td></tr><tr><td>Recommended Recommended</td><td>Axial T1-Wl (with and without FS) Axial T2-WI</td><td>Pelvis Pubic symphysis-renal hila</td></tr></table> Table 1 continued <table><tr><td colspan="3">Acquisition protocol</td></tr><tr><td></td><td> Sequence</td><td>Location</td></tr><tr><td>Suggested</td><td>Axial DWI ST same as axial T2-W, min.2 b-values (low b=0-50s/mm²,high</td><td>Pubic symphysis-renal hila</td></tr><tr><td></td><td>b= 800-1000 s/mm2)</td><td></td></tr><tr><td>Ovarian cancer According to O-RADS MRl protocol</td><td></td><td></td></tr><tr><td></td><td>Sagittal T2-WI</td><td>From hip to hip</td></tr><tr><td></td><td>Axial T1-WI (with and without FS)</td><td>Pubic symphysis-kidneys</td></tr><tr><td></td><td>Axial T2-WI</td><td>Pubic symphysis-kidneys</td></tr><tr><td></td><td>Axial DWI</td><td>Pubic symphysis-kidneys</td></tr><tr><td></td><td>Axial T2-WI thin (≤ 3 mm)</td><td>To include adnexal lesion</td></tr><tr><td></td><td>Axial DCE</td><td>To include adnexal lesion</td></tr><tr><td></td><td>Axial T1-WI FS post-gadolinium</td><td>Same as axial T1-WI</td></tr></table> DCE dynamic contrast enhanced, DWI diffusion-weighted imaging, WI weighted imaging For OC MRI protocol adhering to the O-RADS MRI guidelines is recommended due to its focus on characterising sonographically indeterminate adnexal masses. Following O-RADS MRI, axial T2WI, T1WI (with and without fat saturation) and DWI from the kidneys to the pubic symphysis are recommended. Axial DCE and T1WI post-gadolinium to allow subtraction are also recommended. HR axial T2 (slice thickness $\leq 3 \mathrm { { m m } }$ ) is suggested to facilitate lesion interpretation. lymphadenectomy or, as alternative, NACT followed by conisation or simple trachelectomy. Conisation is a cone-shaped removal of the cervix, including the exocervix and endocervical canal. Simple trachelectomy consists of cylindrical-shaped removal of the cervix with the creation of an isthmic-vaginal anastomosis suturing the cuff of the vagina with the lower part of the uterine body. Radical trachelectomy consists of cylindrical-shaped removal of the cervix and the vaginal fornices and en-bloc parametrial/paracervical resection. # Cervical cancer (CC) Indications and types of treatment CC continues to be a significant global cause of cancerrelated illness and death among women [2]. Advances in early detection and treatment have greatly improved the outcomes. However, there is an increasing number of cases diagnosed during reproductive age with patients desiring to preserve their fertility. According to recent ESGO-ESHRE-ESGE guidelines [5], FS surgery can be considered in patients with stage IA1-IB2. Tumours $\leq 2 \mathrm { c m }$ in diameter are more amenable to FS approaches. However, patients with stage IB2 (tumour diameter $2 . 1 { - } 4 \thinspace \mathrm { c m } \rangle$ ) can be treated with neoadjuvant chemotherapy (NACT) followed by conisation or simple trachelectomy. Additional indications are outlined in Table 2. The surgical approach is stage-related: (1) for stage IA1 without lymphovascular space invasion (LVSI), conisation; (2) for stage IA1 with LVSI, conisation and sentinel node mapping; (3) for stage IA2 and IB1, conisation or simple trachelectomy plus sentinel node mapping and pelvic lymphadenectomy; (4) for stage IB2, radical trachelectomy plus sentinel node mapping and pelvic # Role of imaging and MRI technique Pelvic MRI and expert sonography are mandatory imaging tests [5]. MRI is the preferred imaging modality and should be evaluated and reported by dedicated radiologists [5]. Oblique axial T2WI and DWI planes are important for evaluating tumour dimension and extension into the cervical stroma (CS) and excluding parametrial invasion (PI). Sagittal T2WI and DWI planes are fundamental for evaluating tumour location and growth (endocervical or exophytic). Sagittal DWI plane can reduce the distortion caused by the rectal-gas susceptibility artefacts. Sagittal DCE could help in detecting small lesions that may be undetectable on T2WI because post-contrast imaging demonstrated increased tumour conspicuity and margins delineation (sensitivity $8 7 \%$ and specificity $1 0 0 \%$ in 40 patients) [20, 21]. Flat exocervical tumours are better detected and evaluated in the sagittal plane and post-contrast imaging evaluation could help in assessing tumour presence and extension. <table><tr><td>Type of cancer</td><td>FIGO stage</td><td> Histology</td><td>LN metastasis exclusion by</td><td>Other distant metastases exclusion by</td><td>Guidelines</td></tr><tr><td>Cervical cancer</td><td>IA1-IB2</td><td>HPV-associated usual-type adenocarcinomas</td><td>Suitable for FS:squamous cellcarcinoma orMRl and surgery,through sentinel lymph node mapping with or without pelvic lymphadenectomy</td><td>CT or PET-CT could be performed to ESGO-ESHRE-ES exclude any distant metastatic disease</td><td>guidelines (202</td></tr><tr><td>Endometrial cancer</td><td>IA G1-G2 without MI IA G1 with minimal MI (1-2 mm)</td><td>Suitable for FS: Endometrioid adenocarcinoma Not eligible for FS: Non-endometrioid or poorly differentiated endometrioid adenocarcinoma</td><td>MRI or CT</td><td>MRI or CT Adnexal involvement should be ruled out by pelvic MRl or guidelines (202 transvaginal US</td><td>ESGO-ESHRE-ES</td></tr><tr><td>Ovarian cancer</td><td>Borderline and all stage germ cell ovarian tumours, Granulosa cell tumours, stage IA and IC1-3</td><td>contraindication for FS treatment Sertoli-Leydig cell well and moderately differentiated tumours，</td><td>Imaging. LN staging by pelvic and para-aortic lymphadenectomy,in high-grade epithelial histological types</td><td>Peritoneal disease: surgical exploration,including omental and</td><td>ESGO-ESHRE-ES</td></tr></table> Table 3 Summary of the imaging findings for cervical cancer prior to fertility-sparing treatment <table><tr><td colspan="3">for cervical cancer prior to fertility-sparing treatment</td></tr><tr><td>Description</td><td>Importance</td><td>Key MRl sequences</td></tr><tr><td>Maximum diameter (on any plane)</td><td>It affects treatment eligibility and type. Cranio-caudal dimension is clinically difficult to evaluate.</td><td>HR oblique axial ano sagittal T2Wl and DWI</td></tr><tr><td>Exophytic:with outward localisation and without extension into the endocervical canal. or</td><td>It may influence surgical approach.</td><td>Sagittal T2Wl and DWI</td></tr><tr><td>Endophytic:with inward extension along the endocervical canal. or Combination of both patterns</td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td>Distance between the tumour cranial≥ 1 cm is considered a favourableSagittal T2Wl and</td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td>marginand the internal os</td><td>criterion.</td><td>DWI</td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td><5mm can also be accepted.</td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td></tr><tr><td></td></table> ![](images/c9a32449af7e05f94c528b15c9db45d9bf39e996ecd01c54c107e02ea03f7c93.jpg) Tumour-to-internal os distance ![](images/47abb840128264e3c5a126ff5a49ce3403ee3cc51fce3be73730b7749106404d.jpg) ![](images/65d306c0ec05a84af11fbede8d867b1c62f9f1f80af38ab7466004bb9131b2d0.jpg) Cervical stromal invasion (CSI) Present if the intermediate SI tumour invades the low-SI of the CS. Deep CSI is defined when the tumour involves external outer third of the cervical stroma ![](images/315815eb17d5b935012ca2770159ce53b469028bd904df319c04a9c3a56616fa.jpg) Extra-cervical extension - Parametrial invasion (PI) $\mathsf { C S l } < 1 0 \mathsf { m m }$ is favourable oncologic criteria. Deep CSI imaging can be accepted in selected cases following ESGO-ESGE-ESHRE guidelines. Oblique axial T2WI and DWI. Fused imaging\* is useful. ![](images/8d63f9c97a5f98ecfd27f07a6704afc6220de636e9cd75079022f73a0d28ad76.jpg) Full-thickness cervical stromal invasion with tumour-to-parametrium nodular or spiculated borders or vessel encasement Oblique axial T2WI and DWI. Fused imaging is useful. Table 3 continued <table><tr><td>Anatomic tumour findings</td><td>Description</td><td>Importance</td><td>Key MRl sequences</td></tr><tr><td>- Lymph node involvement (LNI)</td><td>Short axis > 8 mm, round shape, irregular margins and intranodal necrosis</td><td></td><td>Pelvic axial T1- and T2WI and axial oblique DWI. Upper abdomen axial T2WI (and DWI if acquired).</td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td>- Distant metastases</td><td>PET-CT or CT performed to rule out distant metastases</td><td></td><td>Pelvic axial T1- and T2WI of the pelvis. Upper abdomen axial T2WI (and DWI</td></tr></table> # Recommendations for imaging interpretation and reporting (Table 3) Tumour size Accurate measurement of tumour size is crucial in determining stage and feasibility of FS treatment. A favourable criterion is a maximum diameter of $2 \mathrm { c m }$ . In selected cases, the largest diameter between 2.1 and $4 \mathrm { c m }$ can be accepted [5, 22–24]. Maximum tumour diameter should be reported. MRI has high accuracy in measuring tumour dimension, within $5 \mathrm { m m }$ in surgical dimension, in $7 0 { - } 9 0 \%$ of cases [25, 26]. Prior procedures (biopsy or conisation) can overestimate tumour size due to oedema and inflammation [7]. Combined evaluation of T2WI and DWI may help differentiate these conditions and delineate the tumour. Tumour growth Pattern of tumour growth should be described for treatment selection. Tumour can show exophytic growth, with outward localisation and without endocervical extension, or endophytic growth, with inward extension within the endocervical canal; a combination of both patterns of growth can be present [7, 10, 11]. Tumour-to-internal os (IO) distance Tumour cranial extent of $\geq 1 \mathrm { c m }$ from the IO on MRI is considered a favourable criterion. This optimises local tumour control and improves obstetric outcomes. Tumour cranial extent between 5 and $1 0 \mathrm { m m }$ from the IO (or with involvement) is accepted in selected cases [5]. Tumour-to-IO distance should be measured from the tumour cranial margin to the IO on the sagittal plane (Fig. 1). MRI has demonstrated excellent accuracy for determining tumour’s proximity to the IO (reported pooled sensitivity of $8 6 \%$ and specificity of $9 7 \%$ ) [27]. The addition of DWI and DCE-MRI has been reported to improve conspicuity of tumour margins [7, 16]. Cervical length should be assessed on sagittal T2WI and measured from the internal to the external os (ideally $> 2 . 5 \mathrm { c m } \rangle$ . This information is critical in patients with prior cone biopsy/other excisional surgery or with the possibility of an extra cone biopsy due to potential future complications such as cervical incompetence and preterm delivery. Cervical stromal invasion (CSI) $\mathrm { C S I } \le 1 0 \mathrm { m m }$ at histology on biopsy or conisation is a favourable oncological criterion. In fact, deep CSI and shorter “tumour-free distance” (shortest distance between the tumour margin and the stromal external border) are associated with greater recurrence risk [28]. However, evidence of deep CSI at imaging is considered an acceptable criterion in selected cases [5]. At MRI, CSI is seen as an intermediateSI tumour invading the low-SI CS. In FS setting, outer half CSI is defined when the tumour invades more than $5 0 \%$ of the CS thickness [7, 11]. Oedema and inflammation from previous procedures may lead to false-positive findings on T2WI, but careful combined evaluation with DWI helps in the correct diagnosis. MRI has shown excellent sensitivity $( 8 7 \% )$ and specificity $( 9 1 \% )$ for the CSI diagnosis [27]. The added value of DCE for CSI has been reported, showing early focal enhancement in contrast to the outer hypo-enhancing CS [7]. ![](images/a3a12142df1c159f90df7b29be4a2a2990aa347e3d21d63e7ccfcd28e19c76d6.jpg) Fig. 1 36-year-old patient with cervical squamous cell carcinoma. Sagittal T2WI (A), DWI $b$ -800 (B) ADC map (C) showing a 2-cm flat tumour of the posterior lip of the exocervix. The lesion shows intermediate SI on T2WI (A, E) and marked impeded diffusion (B, C, F). Tumour maximum size is the anterior-to-posterior diameter (line in A). Tumour-to-internal os distance measured on sagittal images between the internal os (above) and the cranial margin of the tumour (below) (dotted line in B). On early post-contrast fat-suppressed T1WI, the tumour demonstrates hypervascularity compared to cervical stroma (D). On oblique axial T2WI (E) and DWI $b$ -1000 (F), the tumour appears confined to the right posterior lip of the exocervix, without CSI, PI or vaginal invasion. CSI, cervical stromal invasion; PI, parametrial invasion; SI, signal intensity; WI, weighted images pLNI assessment is based on morphologic criteria, including short axis $\left( > 8 \mathrm { m m } \right)$ , round shape, irregular margins, necrosis with good specificity $( 8 9 \% )$ but limited sensitivity $( 5 1 \% )$ due to the challenges in depicting micrometastases [27, 32]. Follow-up Follow-up is the same as for any patient with CC. MRI is mandatory at 6 and 12 months and then as clinically needed; expert sonography is an option [5]. Extra-cervical tumour extension PI, pelvic lymph node invasion (pLNI), or distant metastases are absolute contraindications to FS treatment. MRI is better than clinical examination for the evaluation of PI with reported high accuracy $( 9 4 \% )$ [8, 29]. The presence of an intact CS ring around the tumour excludes PI with high negative predictive value $( 9 4 - 1 0 0 \% )$ [7, 30, 31]. PI is detected when full-thickness CSI is seen, along with tumour-to-parametrium nodular or spiculated borders or vessel encasement. After conisation, the appearances of the cervix can differ depending on the depth of the procedures showing a portio defect with scar on the vaginal portion and an asymmetry between the anterior and posterior lip (Fig. 2). After trachelectomy, the appearance of the uterus is completely different due to the absence of the cervix with an isthmic-vaginal anastomosis (Fig. 3). Some surgeryrelated artefacts can be present, better depicted on T1WI using gradient-recalled echo sequences. ![](images/809419935aa4959ced3388e0213546d70027e15b8eee6419b42907e19e8cb2fa.jpg) Fig. 2 Illustration (A), sagittal T2WI and post-contrast fat-suppressed T1WI showing cervix appearance after conisation. Conisation is a cone-shaped resection of the part of the cervix below the vaginal fornices (portio) of variable deepness (yellow triangle in A). On sagittal T2WI (B) and post-contrast T1WI (C), there is a shortening of the cervical canal, more distinct on the posterior lip (arrow in B and C) ![](images/2e7ddbbf9c8fc22f9eb9db6756b9ceb941431d7a5c31c0078bf7b17ba572652b.jpg) Fig. 3 Illustration (A), sagittal T2WI (B) and post-contrast sagittal T1WI (C) showing appearance of the uterus after trachelectomy. Cervix is resected with anastomosis between the uterine body at the level of the isthmus and the upper vagina (arrowhead in B and C) Recurrences typically occur at the conisation margins or anastomosis site and share the signal characteristics of the primary tumour, intermediate-to-high SI on T2WI with restricted diffusion. PET-CT can be considered in cases of recurrence suspicion [5]. countries [2]. Remarkably, up to $7 \%$ of cases occur in patients younger than 45 years [33]. According to ESGOESHRE-ESGE guidelines [34], FS treatment can be considered in stage IA G1 without myometrial invasion (MI) and in selected cases for stage IA G2 without MI and stage IA G1 with minimal MI $\left( < 3 \mathrm { m m } \right)$ . More indications are detailed in Table 2. # Endometrial cancer (EC) Indications and types of treatment EC is the fifth most common cancer in women worldwide and the most common gynaecologic cancer in developed Hysteroscopic resection is the gold standard for the surgical approach. Hormonal therapy could be administered orally, by intra-uterine device or with a combination of both. Patients should be followed by subsequent hysteroscopic endometrial biopsy every 6 months. After completion of their family, a hysterectomy should be performed [34]. Table 4 Summary of the imaging findings for endometrial cancer prior to fertility-sparing treatment <table><tr><td colspan="2">SumalyOrtneiagingmaingsTolendometnlalCanicerpnoltoTertilty-spanng teatiient Anatomic tumour findings Description</td><td colspan="2">Importance Key MRl sequences</td></tr><tr><td>Myometrial invasion (Ml)</td><td>Excluded if uninterrupted low-Sl rim of JZ on T2WI. Integrity of SEE (if seen) or</td><td>FS treatment can be considered in stage IA G1-2</td><td>Oblique axial and sagittal T2WI, DWI and DCE</td></tr><tr><td>Cervical stromal invasion (CSl)</td><td>endometrium-JZ interface demarcated tumour-CS interface ：On T2Wl: between the</td><td>without Ml or stage IA G1 with minimal MI (1-2 mm) Excluded in the presence of a sharplyPresence of CSl excludes FS treatment</td><td>Oblique axia land sagittal T2WI, DWI and DCE (pay attention to oblique axial</td></tr><tr><td></td><td>intermediate-to-high Sl tumour and hypointense stroma On DCE: between the hypo- enhancing tumours and the regular stromal enhancement</td><td></td><td>and sagittal DWI)</td></tr><tr><td>Extra-uterine disease - Synchronous ovarian cancer (sOC) or ovarian metastases (OMs)</td><td>Any type of suspicious adnexa massUnfavourable oncologic should be excluded. Signs of unilateral or bilateral involvement and of intra- or extra-capsular</td><td>criteria that should be discussed case by case</td><td>Pelvic axial T1- and T2WI. On sagittal and oblique axial DWI look for suspicious lesions</td></tr><tr><td>- Lymph node involvement (LNI)</td><td>suspicious spread should be described Short axis > 8mm, round shape, irregular margins and intranodal necrosis</td><td>Oncologic criteria that exclude FS treatment</td><td>Pelvic axial T1- and T2WI and axial oblique DWI. Upper abdomen axial</td></tr><tr><td>- Distant metastases</td><td>PET-CT or CT can be performed to rule out distant metastases.</td><td>Oncologic criteria that exclude FS treatment</td><td>T2WI (and DWI if acquired). Pelvic axial T1- and T2WI of the pelvis. Upper abdomen axial T2WI (and DWI if</td></tr></table> # Role of imaging and MRI technique Imaging is mandatory for oncological selection criteria, and MRI should be evaluated by a dedicated gynaecological radiologist; pre-operative assessment of MI should be performed using transvaginal US by a specialised sonographer [34]. Sagittal and oblique axial T2WI and DWI planes are crucial to identify tumours, evaluate the presence of MI and/or extension to the CS. Sagittal DCE and oblique axial delayed contrast-enhanced images are useful for evaluation of MI [7, 35]. ![](images/6908ea29f2226ab44fe422bf64162a39b71dca2214c4104442973dbb3732457e.jpg) Fig. 4 Endometrial cancer patient candidate for fertility-sparing treatment. Endometrial irregular thickening, showing intermediate-to-high SI on T2WI (A, B), marked diffusion restriction (C) and low SI on post-contrast $( 2 { : } 3 0 \mathsf { m i n }$ after contrast injection) fat-suppressed T1WI compared to the myometrium (D). On oblique axial images, tumour-myometrium interface is smooth on T2WI (B) with sharply demarcated tumour margins on high-b-value DWI and post-contrast T1WI (arrows in C and D), suggesting the absence of MI. On early post-contrast sagittal T1WI (25–40 s after contrast injection), SEE is seen as a thin subendometrial hypervascular rim, confirming myometrial integrity (arrowhead in E). The delayed phase at $4 { - } 8 \mathsf { m i n }$ (F) shows the typical enhancement of the endocervical canal and endocervix (dotted arrow in F). MI, myometrial invasion; ${ \mathrm { S E E } } ,$ subendometrial enhancement; SI, signal intensity; WI, weighted images # Recommendation for imaging interpretation and reporting (Table 4) Myometrial invasion On MRI tumour appears slightly more hypointense or isointense compared to the endometrium and hyperintense compared to the myometrium on T2WI and high- $^ { b }$ -value DWI, and hypointense on ADC map [7, 36]. On DCE, tumour shows homogenous enhancement, which is slower and less intense than the adjacent myometrium with maximum contrast between tumour and myometrium at about 90–120 s after IV contrast administration [19]. Key imaging findings to exclude MI are the presence of an uninterrupted low-SI rim of the junctional zone (JZ) on T2WI and an uninterrupted rim between the endometrium and $J Z$ on DCE, due to the early subendometrial enhancement (SEE)—a thin layer of early enhancement of inner JZ—acquired within the first $2 0 { - } 6 0 s$ (Fig. 4). However, the SEE is reported in only $1 0 { - } 3 0 \%$ of cases. If SEE is absent, the inner myometrium/ JZ should be smooth and sharply demarcated [7, 37–39]. Even though the above-mentioned findings, in some instances, it is challenging to detect minimal MI, and correlation between imaging and pathology findings would help clinicians to manage patients. Similarly, on imaging, we only detect macroscopic disease, but we cannot evaluate for microscopic disease [7, 37–39]. There is no specific data regarding the performance of MRI for evaluation of initial MI [34]. A recent metaanalysis including 18 articles with low risk of bias and 1548 patients, reported the pooled sensitivity $( 8 1 . 1 \% )$ and specificity $( 8 3 . 8 \% )$ for deep MI assessment, with moderate heterogeneity for both sensitivity (TVS: $I ^ { 2 } = 4 2 \%$ $[ 0 - 6 7 \% ]$ , MRI: $\dot { I } ^ { 2 } = 4 8 \%$ $\left[ 1 0 - 7 0 \% \right] .$ ) and specificity (TVS: $I ^ { 2 } = 7 0 \%$ $[ 5 1 - 8 1 \% ]$ , MRI: $I ^ { 2 } = 6 8 \%$ $\left[ 4 8 - 8 0 \% \right] ,$ ) [40]. Diagnosis can be challenging in the presence of concomitant leiomyomas and/or adenomyosis, myometrial thinning in the uterine cornua and with tumour showing the same degree of myometrial enhancement or early irregular peritumoural enhancement disrupting the SEE [3, 41]. # Cervical stroma invasion CSI should be assessed as associated with a higher risk of LN metastases and worse prognosis [34]. CS is hypointense on T2WI with continuous enhancement of the cervical epithelium and stroma, better observed $1 . 5 { - } 4 \operatorname* { m i n }$ after IV contrast administration. CSI is suspected when the intermediate-to-high SI tumour disrupts the hypointense CS on T2WI. On post-contrast imaging, hypo-enhancing tumour disrupts the regular CS enhancement [7, 36]. # Extra-uterine disease/synchronous or metastatic The presence of synchronous ovarian cancer (sOC) or metastases (OMs), LNI or distant metastases are considered absolute contraindications to FS treatment. ![](images/d403005630198c2fbda76a5ee12aa0969a3762582a55a51f69d8b1d04b9d945b.jpg) Fig. 5 A 35-year-old patient with an incidental ovarian lesion noted during infertility work-up. A Initial TVUS shows an unilocular right ovarian solid-cystic mass with internal papillary projections and a scant Doppler signal (arrow), O-RADS US 4. B, C Further evaluation with MRI shows that the papillary projections have intermediate-to-high signal on T2WI (straight arrow) and less enhancement than the external myometrium (asterisk), reflected as an intermediate-risk curve on time-intensity curve analysis (O-RADS MRI 4). A crescent of preserved ovarian parenchyma was observed around the periphery of the lesion (arrowheads in B). The radiological suspicion was an ovarian epithelial neoplasm, including a borderline subtype. The patient underwent a cystectomy with a frozen section that confirmed the histology Overall, $1 0 \%$ of EC cases present with sOC or OMs and detection of adnexal masses is critical [42]. MRI should be used to rule out adnexal involvement [34]. Both oblique axial and sagittal DWI are very useful for detecting suspicious lesions, looking for high SI on high- $^ { b }$ -value DWI and low SI on ADC map within the ovaries. The distinction between sOC and OMs can be challenging, but signs of unilateral/bilateral involvement and intra/extracapsular suspicious spread should be described [34]. LNI is rare in early-stage EC and can occur in pelvic and para-aortic regions [43]. MRI or CT is recommended for detecting pelvic or para-aortic LNs and distant metastases [34]. Assessment criteria are the same as for CC [5]. Follow-up Clinical examination and US are recommended at every 3-month follow-up visit alongside hysteroscopy and biopsies following the guidelines [34]. MRI is considered on a case-by-case basis [34]. The MRI protocol for follow-up is the same as for staging. In the post-treatment scenario, it can be challenging to distinguish between post-treatment findings and residual/ recurrent tumour, and imaging-pathology correlation can aid patient management [34]. # Ovarian cancer (OC) Indications and types of treatment According to ESGO-ESHRE-ESGE guidelines, if OC is detected at an early stage and the patient desires future pregnancy, FS management can be considered in some cases alongside adequate counselling [5]. Further details on indications can be found in Table 2. The potential for fertility preservation is related to the lack of disseminated disease, and therefore, comprehensive surgical exploration is crucial to identify any occult advanced disease. # Role of imaging and MRI technique Imaging plays a critical role in planning FS surgery for OC, serving first to accurately assess tumour extent and provide radiological staging, and subsequently to guide the surgical approach [44]. MRI plays an important role in the characterisation of sonographically inconclusive adnexal masses $( 2 0 - 3 0 \%$ of cases) and stratify their risk (reported accuracy of $9 2 \%$ ) [45–48]. MRI also enhances the delineation of the lesion and normal ovarian parenchyma, which facilitates surgical planning in cystectomy cases and helps assess ovarian parenchymal preservation for future fertility treatment [49] (Fig. 5). MRI protocol for assessing an adnexal lesion follows O-RADS MRI guidelines [46]. Recommendations for imaging interpretation and reporting Imaging features suggesting a benign aetiology include purely cystic, endometriotic, or fatty lesions with thin, smooth walls. Where solid components are noted, benign features are consistent with fibrous tissue (homogeneously low SI on T2WI and DWI) or tissue showing slow, gradual enhancement without a shoulder or plateau (low-risk time-intensity curve) [50]. Borderline ovarian tumours have histological features of malignancy but no stromal invasion and tend to affect younger patients carrying a better prognosis [51]. The most common subtype is serous, which typically shows papillary projections with internal branching [52]. Stage I epithelial ovarian tumours may be considered for fertility preservation if confined to a single ovary (FIGO stage IA). Bilateral ovarian involvement (FIGO stage IB) precludes FS approaches. Malignant germ cell tumours include dysgerminomas and immature teratomas, which are most prevalent in young patients. They are generally diagnosed with stage I disease, confined to the ovary, and therefore eligible for fertility preservation [53]. On MRI, dysgerminomas manifest as large, solid and homogeneous masses with high T2WI SI, fibrovascular septa and uniform enhancement [54]. Malignant immature teratomas typically have scattered small fat foci within prominent solid tissue and small irregular calcifications [55]. ![](images/c0e1f80a74ee842fdaca29146dd438b2ea1236e97736eda357952f0f281c1188.jpg) Fig. 6 Structured report template prior to fertility-sparing treatments should include this information Sex-cord stromal tumours present as solid masses, usually with low SI on T1WI and T2WI but can become increasingly heterogeneous according to the cellular content and potential features such as haemorrhage or fibrosis [56, 57]. # Follow-up # Structured report The panellists recommend using a structured report incorporating the selection criteria for CC, EC and OC prior to FS surgery. While these criteria may differ slightly across institutions, radiologists must be familiar with the guidelines at their centres and tailor structured reports accordingly. Figure 6 outlines the proposed structured MRI reports for cervical, endometrial, and ovarian cancers. pre-surgical markers are missing). PET-CT is only indicated in cases of suspicious recurrence [34]. # Future directions Further research is needed to validate these guidelines, assess their clinical impact, and ensure reproducibility. Evaluating adherence across institutions will help determine feasibility, while standardisation across MRI vendors and further experimental validation of imaging criteria should be explored. Additionally, future research should investigate cost-effectiveness analyses, protocols reproducibility and its accuracy in applying imaging-based selection criteria for FS treatments. The ESUR female pelvic working group has produced the first practice guidelines for FS imaging in patients with cervical, endometrial and ovarian cancer. These guidelines emphasise the role of MRI, focusing on the importance of protocol acquisition and reporting with detailed disease evaluation. FS treatments require the highest-quality imaging and reporting to guide clinicians in selecting patients and optimising treatment strategies. Follow-up is recommended every 3–4 months for 2 years, every 6 months for another 3–5 years, and then annually for at least 10 years. Follow-up consists of physical examination and ultrasound performed by an experienced operator. Pelvic and abdominal MRI (no ionising radiation; CT to be performed if MRI unavailable) should be performed at 6 months and then annually until the fifth year. Measurement of CA125 concentration or other tumour markers according to pathological subtype (is only recommended when initially elevated or when # Abbreviations # Conclusions ADC Apparent diffusion coefficient CC Cervical cancer CS Cervical stroma CSI Cervical stromal invasion DCE Dynamic contrast-enhanced DWI Diffusion-weighted imaging EC Endometrial cancer ESGE European Society for Gynaecological Endoscopy ESGO European Society of Gynaecological Oncology ESHRE European Society of Human Reproduction and Embryology ESUR European Society of Urogenital Radiology FIGO International Federation of Gynaecology and Obstetrics FS Fertility-sparing HR High resolution JZ Junctional zone LNI Lymph node involvement LVSI Lymphovascular space invasion MI Myometrial invasion NACT Neoadjuvant chemotherapy OC Ovarian cancer OM Ovarian metastasis O-RADS Ovarian-Adnexal Reporting and Data System PI Parametrial invasion RAND- Research and Development Corporation-University of California, UCLA Los Angeles (Appropriateness Method) SI Signal intensity sOC Synchronous ovarian cancer WI Weighted imaging # Supplementary information The online version contains supplementary material available at https://doi. org/10.1007/s00330-025-11625-x. # Funding S.N. is supported by a European Research Council starting grant (MROMICS101077710). # Compliance with ethical standards # Guarantor The scientific guarantor of this publication is Dr. Benedetta Gui. # Conflict of interest The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article. # Statistics and biometry No complex statistical methods were necessary for this paper. Informed consent Not applicable. # Ethical approval Institutional Review Board approval was not required for this special report. Study subjects or cohorts overlap Not applicable. # Methodology ● Recommendations # Author details 1 Dipartimento Diagnostica per Immagini e Radioterapia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. 2 Dipartimento Universitario di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy. 3 Department of Radiology, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK. 4 Department of Surgery and Cancer, Imperial College, London, UK. 5 Department of Radiology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal. 6 Department of Radiology, Hospital Clínic de Barcelona, Barcelona, Spain. 7 Departamento de Radiología, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay. 8 Dipartimento per la Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. 9 Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy. 10Department of Radiology, Mayo Clinic, Rochester, USA. 11Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, USA. 12Department of Radiology, Ente Ospedaliero Cantonale (EOC), Università della Svizzera Italiana (USI), Lugano, Switzerland. 13INSERM, PINKCC lab, Montpellier Cancer Research Institute, University of Montpellier, Montpellier, France. 14Department of Radiology, University of Montpellier, Montpellier, France. 15Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome, Italy. Received: 29 December 2024 Revised: 17 March 2025 Accepted: 13 April 2025 Published online:13 May 2025 # References 1. Taylan E, Oktay K (2019) Fertility preservation in gynecologic cancers. Gynecol Oncol 155:522–529 2. 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Cheng M, Causa Andrieu P, Kim TH et al (2023) Fat-containing adnexal masses on MRI: solid tissue volume and fat distribution as a guide for O-RADS Score assignment. Abdom Radiol (NY) 48:358–366 56. Horta M, Cunha TM (2015) Sex cord-stromal tumours of the ovary: a comprehensive review and update for radiologists. Diagn Interv Radiol 21:277–286 57. Javadi S, Ganeshan DM, Jensen CT, Iyer RB, Bhosale PR (2021) Comprehensive review of imaging features of sex cord-stromal tumours of the ovary. Abdom Radiol (NY) 46:1519–1529 # Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	None	None	None
529847a9bdf24ba38002bd3e3cb05d94	2025+FIGO立场声明	产后宫内节育器	# FIGO position statement on postpartum intrauterine devices (PPIUD) # Anita Makins $^ { 1 , 2 } \oplus$ \| Azra Ahsan2,3,4 Marium Waqas3,4\| Asha Kasliwal2,5 for the FlGO Committee on Contraception 1Nuffield Department of Women's and Reproductive Health,University of Oxford,Oxford,UK 2FIGO Committee on Contraception, London, UK 3Association for Mothers and Newborns (AMAN), Karachi, Pakistan 4National Committee for Maternal and Neonatal Health (NCMNH), Karachi, Pakistan 5Manchester University NHS Foundation Trust,Manchester, UK Correspondence Anita Makins,Nuffield Department of Women's and Reproductive Health, University of Oxford,Oxford, UK. Email: anita.makins@wrh.ox.ac.uk # Abstract Postpartum contraception is a critical intervention to address the unmet need for family planning, which affects over 218 million women globally, predominantly in low- and middle-income countries (LMICs). Immediate postpartum family planning(PPFP) offers a unique opportunity to provide contraception during a crucial health-seeking encounter, particularly given the rise in institutional births worldwide.Short inter-pregnancy intervals are associated with increased maternal and neonatal morbidity and mortality, making timely postpartum contraception essential. The postpartum intrauterine device (PPlUD),a long-acting reversible contraceptive (LARC), is a highly cost-effective, non-hormonal method with a low failure rate. It can be safely inserted immediately after vaginal or cesarean delivery, offering women a reliable and accessible option. However, successful implementation of PPlUD services requires overcoming barriers such as fragmented health services, provider bias, sociocultural misconceptions, and supply chain challenges. FlGO advocates for integrating PPFP, including PPIUD, into routine maternity care and emphasizes task sharing, community engagement, and comprehensive counseling as critical strategies. By incorporating postpartum contraception into standard maternal care, particularly in LMiCs, health systems can improve maternal and child health outcomes,advance Sustainable Development Goals (SDGs), and empower women to make informed reproductive choices. # KEYWORDS contraceptive counseling, healthcare integration, immediate postpartum contraception, long-acting reversible contraceptives (LARCs), postpartum family planning (PPFP), postpartum intrauterine device (PPIUD), task sharing, unmet contraceptive need # 1\|THE IMPORTANCEOFPOSTPARTUM CONTRACEPTION It is estimated that there are more than 218 million women with an unmet need for contraception and that the vast majority are living in low- and middle-income countries (LMICs).1 WHO defines the unmet need for family planning as“those women who are fecund and sexually active but are not using any method of contraception,and report not wantingany more children or wanting to delay the next child".2.3 In many parts of the world,access to health is limited.Therefore,it is imperative thatthe benefit of each health-seeking encounter is maximized through integrated services.Traditionally,contraception has been offered to women when they attend their 6-week postnatal check,a universally implemented follow-up for women after birth.Similarly,many women were told to go to their local family planning or sexual health clinic. In reality, this extra step is frequently hard to achieve as women are busy with their families and newborn, tending to neglect their own health. Unsurprisingly, there is therefore a documented high unmet need for contraception during the postpartum period.4 Globally, the percentage of births attended by skilled health personnel increased from $64 \%$ in 2001-2007 to $84 \%$ in 2015-2021.In sub-Saharan Africa,over the same period,the indicator rose from $43 \%$ to $64 \%$ .In other regions,namely Europe,North America,and Central Asia,near-universal or universal coverage was recorded over the period of interest.5 The fact that institutional birth rates have increased globally means there is now an invaluable opportunity to provide contraception to women before they leave the maternity unit.This is particularly valuable in countries where access to health care is limited. Short inter-pregnancy intervals exacerbate maternal morbidity and mortality and result in worse neonatal and childhood outcomes. Birth spacing of less than 24months has been associated with increased rates of miscarriage,planned abortion,maternal mortality, pre-term labor,small for gestational age infants,and increases in malnutrition and mortality in children under the age of 5years.6,7 Reducing the unmet need for contraception is one of the 17 Sustainable Development Goals (SDGs)-target 3.7,and advances would also impact targets 3.1 (maternal mortality)and 3.2 (reduce deaths of newborns and under-5s). Contraception alone is postulated to have the potential to reduce maternal mortality by $30 \%$ 9. Contraceptive choices for postpartum women have been largely restricted to temporary methods.This proves to be problematic when supply chains are broken,as was the case during the COVID-19 pandemic.With the threat of unstable funding for contraceptive methods in LMlCs,as well as the possibility of new pandemics affecting international trade and the continuous demand for contraception, there is a need to refocus and motivate eligible couples for LARCs such as the PPIUD,with significantly lower failure rates.10,11 Therefore,counseling on immediate postpartum family planning (PPFP)and subsequent access to LARCs,such as the PPlUD,offer women the opportunity to take a more reliable break from childbearing than short-acting methods.This allows them to look after their own health and that of their children,as wellas consider further education and/or supporting the family financially if they choose to. This in turn would help to break the cycle of poverty. # 2丨THEPOSTPARTUM INTRAUTERINE DEVICE (PPIUD) The PPlUD is a LARC that contains no hormones and is extremely cost-effective.It has been available internationally for many years,with many doctors,nurses,and midwives around the world being comfortable with inserting and removing the device. However, experience with insertion in the immediate postpartum period is less widespread and globalized.Its insertion into the postpartum uterus by hand was first described in the 196Os,12 but the method went out offavoras very high expulsion rates were reported.In the recent past, three large studies have examined insertion using the Kelly forceps methodology, reporting expulsion rates similar to those observed with interval insertion of the method.Jhpiego launched a multi-country initiative between 2010 and 2013,13 as did FIGO between 2013 and $2 0 2 0 ^ { 1 4 , 1 5 }$ and between 2012 and 2022 in 52 health facilities across Pakistan.16 # 3\|THE METHODOLOGY BEHIND PROVISION OF PPIUD After in-depth non-coercive counseling,a woman who chooses the PPIUD method can have it inserted immediately after birth,once the infant and placenta are delivered.This is often described asa “postplacental" insertion and allows fora “one-stop"approach,negating the need for any repeat examination or postnatal visit.For those women who decide to take up the method after birth,or if the maternity unit is unable to provide the service immediatelyat birth,the PPIUD can also be inserted any other time up until $4 8 \mathrm { h }$ after delivery,before discharge from the health facility.For vaginal deliveries, the insertion technique uses the $3 2 \mathrm { - c m }$ long curved Kelly placental forceps.This technique has been welldescribed in the literature17-22 and ensures a high fundal placement when compared to using the inserter's hand or other instruments,such as the Rampley sponge holding forceps,which is much shorter. Insertion after $4 8 \mathrm { h }$ is not recommended owing to the known higher risk of complications.23 If a woman is havinga cesarean delivery, the PPlUD can also be inserted through the surgical incision to the uterus once the infant and placenta have been removed and any bleeding is under control.The method can involve removing the intrauterine contraceptive device from the inserterand introducing it in the fundus of the uterus by hand, or it can be introduced using the inserter. Either method is acceptable as long as it is positioned at the fundus of the uterus and lies longitudinally,with the threads in the cavity and stretched out towards the internal cervical os.While closing the uterine incision,it is important to ensure that the IUD thread is not entrapped in the sutures. FIGO has published guidance on the insertion of PPlUDs after both vaginal delivery and intra-cesarean,including videos on the FlGO website demonstrating the technique: https://www.figo.org/ what-we-do/figo-projects/ppiud-project/ppfp-counselling-andppiud-insertion-training-videos. # 4\|BARRIERS AND SOLUTIONS TO IMPLEMENTATION OF PPIUD SERVICES # 4.1丨Fragmented services Setting up a PPFP and PPlUD service can be difficult in some contexts because they tend to span a variety of departments, including maternity services,sexual health,and primary care. Coordinating action between these departments，particularly in high-income country settings where services become super specialized,can be difficult. Coordination and agreement among all stakeholders from the outset are key to ensuring a functional service. 24,25 # 4.2丨 The importance of task sharing Insertion of the PPlUD is a task that has been traditionally performed by doctors.Limiting its postpartum insertion to doctors only will limit its accessibility to those women who have a normal birth and never see a doctor during their care.These are the majority of women.Task sharing is therefore an invaluable tool to increase access to postpartum contraception and PPlUD services.Many studies document huge increases in the accessibility of PPlUD when task sharing to nurses and midwives occurs in both Africa and Asia.14,26,27 Task sharing has also been found to be safe with no concerns regarding an increase in complications when insertions are performed by properly trained non-medical staff.14 # 4.3丨 Community engagement Community engagement is key to ensuring a successful program. In many parts of the world,there are deeply engrained misconceptions, myths,and misunderstandings regarding postpartum contraception and the IUD in particular.This can come both from the women and the providers.It is imperative that from the outset the local community is engaged in the service and that providers ofall levelsare trained in counseling,enabling them to explain the pros and cons of the method and dispel any myths.28-30 # 5丨FIGO RECOMMENDATIONS 1.Postpartum contraception services should be provided in maternity services as part of continuity of care for the woman and to improve maternal and reproductive health outcomes. Healthcare providers should be encouraged to integrate PPFP into their practice and ensure their teams are trained in providing these services.Prioritizing PPFP as part of standard postpartum care,rather than referring patients to exclusive family planning clinics,is essential for optimizing access to postpartum contraceptive options.Immediate PPFP is crucial to meet unmet needs and unintended pregnancies,and reduce health risks associated with closely spaced pregnancies. There isa move to integrate family planning services into Emergency Obstetric and Newborn Care (EmONC).This would ensure that EmONC services offer contraception as part of routine maternity care. 2.When commencing postpartum contraception services,it is imperative that myths and misconceptions are addressed on both the provider's and the woman's side. Provider-related bias and sociocultural beliefs of the woman and her family impact hugely on the uptake of PPlUD.Studies have highlighted barriers such as insufficient knowledge,myths, religious beliefs,provider biases,preference for short-acting methods,spousal pressure,and fear of side effects and complications.Furthermore,healthcare providers'personal beliefs, shaped by cultural or religious values or inadequate training, may hinder comprehensive PPFP services.It is recommended that specific targeted interventions involving the community and healthcare providers should be developed alongside the provision of services. 3．Counseling on contraception should be offered throughout the antepartum, early intrapartum,and immediate postpartum periods,with balanced,coercion-free discussions over multiple encounters to ensure women have the time and information needed to make an informed choice. This approach allows women to consult with her family and make decisions before labor begins.For those arriving in labor without prior antenatal care,early labor presents an opportunity to counsel the woman and her family members, especially male partners who are often present and may be involved in decision-making. Contraception counseling should also be offered immediately postpartum for those women who report late in labor,when women may be more receptive to the discussion.To facilitate this,counseling in antenatal clinics as well as round-the-clock counseling should be available in delivery rooms,with additional family planning counselors hired if necessary. However, regular supervision and monitoring of the counselors is required to sustain quality. In high-volume settings,pre-recorded videos can serve as effective counseling tools when individualized sessions are not feasible. These can be played in waiting rooms and corridors.Similarly, leaflets containing key information on each method can be useful. 4.Maternity services should offer PPIUD as a key option among the array of PPFP methods.PPlUD is highly cost-effective, long-acting (remaining effective for 10-12years),reversible, has a very low failure rate,and is non-hormonal (no interference with breastfeeding). The hormone-based levonorgestrel-releasing intrauterine system can also be offered during the postpartum period.It falls in Medical Eligibility Criteria for Contraceptive Use (MEC) category 2 for breastfeeding women,remains effective for 8years,and may be particularly suitable for women with a history of heavy periods or anemia.A key barrier to accessing implants and intrauterine systems in LMlCs is the high cost driven by patent laws,making these effective contraceptive methods unaffordable for many. To address this inequity in access to modern contraception,efforts should focus on making these options affordable and accessible to women in LMlCs who need them most. 5．Counseling specific to PPlUD needs to provide comprehensive information on the device's efficacy,benefits,potential side effects,and complications. Counseling should include detailed discussions on common concerns,such as menstrual irregularities,missing threads, signs of expulsion,and pain.Since PPlUD threads are not trimmed at insertion,women should be advised that threads may protrude as the uterus contracts but that this is incredibly rare.Were it to occur,they should be instructed to gently push the threads back into the vagina and report to their provider. Clinicians should be aware that because bleeding and discomfort are common postpartum and after IUD insertion, acceptance of the device may be higher immediatelyafter childbirth than with interval insertion. 6．If the PPlUD is chosen, it should be administered at or immediately after birth (within 48h)and before hospital discharge. If a PPlUD is not inserted within $4 8 \mathsf { h }$ of delivery, it should be delayed until 4-6weeks postpartum.If women are unable to receive their preferred contraceptive method before discharge frommaternity services,they should be offered effective bridging contraception to ensure continuous protection. 7.APPlUD can be safely inserted during cesarean delivery,immediately after the infant and the placenta have been delivered.Care should be taken to place the PPlUD at the fundus,to straighten the threads towards the cervical os,and not to inadvertently include the threads in the closure of the uterine incision. With $2 1 . 1 \%$ of women worldwide having a cesarean delivery-ranging from $5 \%$ in sub-Saharan Africa to $4 2 . 8 \%$ in Latin America and the Caribbean-the option to insert a PPlUD during cesarean delivery is an effective strategy.31 The PPlUD can be placed immediatelyafterdelivering the infantand placentaand before closing the uterus,with studies showing comparable effectiveness and expulsion rates to insertion after vaginal delivery.After insertion,care should be taken to not inadvertently include the IUD threads into closure of the incision. Given the high rates of emergency cesarean deliveries,PPIUD insertion should also be integrated into EmONC services.If the woman has consented in advance and there are no contraindications,such as prolonged rupture of membranes or evidence of chorioamnionitis,this is deemed safe. # 8．APPlUD can be safely inserted after vaginal delivery using either long 33-cm Kelly forceps or a purpose-built device. Proper placement high in the uterine cavity at the fundus is essential to minimize expulsion. When correctly positioned, evidence suggests that expulsion rates are comparable to those of interval insertions $( 3 \% )$ .It is not recommended to insert the device using the $2 4 \mathrm { - c m }$ tissue or sponge forceps as it is not long enough and does not reach the uterine fundus, increasing the risk of expulsion. It has been noted that there is a better chance of thread visibility after insertion using the purpose-built device. However，given the longer threads,a follow up visit is required at 2weeks to trim these threads.The purpose-built device is also prohibitively expensive for many countries providing the service free at the point of care. 9.PPlUD insertion is contraindicated in the presence of infection (chorioamnionitis) or prolonged rupture of membranes $( { > } 1 8 \mathsf { h } )$ due to the risk of infection. In addition,if there is a history of prolonged labor,particularly when managed by traditional birth attendants,insertion of a PPlUD is not advised given that the risk of infection is high.In the case of an ongoing postpartum hemorrhage (PPH),this should be dealt with first and the IUD inserted only once the PPH is under control and mitigating action has been taken successfully. Clinicians should also bear in mind the standard contraindications to insertion of the copper coil at any time,including any allergy to copper,Wilson's disease,a grossly distorted uterine cavity,malignant trophoblastic disease,pelvic tuberculosis,and cancers of the genital tract (cervical or endometrial). # 10．PPlUD insertions are associated with very low complication rates,with minimal risk of infection and very few cases of perforation reported. However, misperceptions among healthcare providers and patients can lead to unnecessary removal due to mistaken concerns of infection.In a large study of 146318 PPIUD insertions in Pakistan,only two cases of uterine perforation were reported.There were none reported in the FIGO series of 37383 across six countries. Nevertheless,comprehensive training of providers and appropriate patient selection are essential to ensure safe and effective PPlUD insertion. To minimize the risk of perforation,it is recommended that healthcare providers carefully trace the entire cervix before insertion to avoid accidental perforation,especially of the posterior vaginal fornix. # 11.Routine post-insertion check-ups are not required for IUDs in a healthcare facility. For IUDs placed in the first $4 8 \mathrm { h }$ postpartum,it is recommended that the woman self-checks for the threads per vagina at 4-6weeks.If they are not present,she should use another form of bridging contraception and go and see a clinician for further investigation. Although self-checking is suficient,many units routinely organize a follow-up with a clinician 4-6weeks after insertion to check that the threads are visible and that the IUD is in situ. For IUDs,especially with longer threads,women can be advised to attend an earlier follow-up and not to pull on any threads that may become visible outside the vagina.Instead, they should consult their provider for trimming. # 12.Missing strings or lost threads can occur in up to $30 \%$ of PPIUD cases and are more common in women who had it inserted during a cesarean delivery. This rate often decreases once menstruation resumes. Missing threads are generally not a cause for concern.Patients should be reassured but advised to use bridging contraception until a transvaginal sonography (TVS) can be organized to ensure the device is still in utero.If the device is not visible on TVS,an abdominal radiograph may be necessary. For cases involving migrated devices, laparoscopy or laparotomy may berequired.If the device is found in utero,retrieval of the threads is only necessary if the woman wants the device to be removed.This can be performed using a Cytobrush or plastic thread retriever and,if unsuccessful,a hysteroscopy can be considered.Metallic thread retrievers and artery forceps should only be used by senior clinicians as the risk of inadvertently perforating the uterus may be high. # 13．Task sharing is strongly recommended as an effective approach to expand access to PPlUD services. With proper training and empowerment,mid-level providers areequally skilled in delivering safe PPlUD services.This is particularly beneficial in facilities where women primarily interact with midwives during delivery. Limiting insertion to doctors only will reduce access to this highly efficacious method. 14.To ensure the continuous availability of contraceptives,a robust supply chain system should be established, guaranteeing that contraceptives are accessible in labor rooms and operation theaters 24h a day. Currently,healthcare providers lack clarity on how to secure asustainable supply of contraceptive commodities for their facilities.Addressing this gap should be a government priority. 15.To sustain the provision of PPFP, including PPIUD services, both pre-service and on-the-job training should be provided for all healthcare providers. Nursing and medical curricula should be updated to incorporate PPFP concepts into pre-service education,practical training, and examinations.Regular training on the labor ward using hands on mannequins of the postpartum uterus and Kelly forceps or the purpose-built device should be developed and run cyclically so that there is continuous learning. # 6丨CONCLUDING STATEMENT PPFP isa key intervention for the reduction of maternal and neonatal morbidity and mortality,by reducing the unmet need for contraception in the postpartum period.It is essential that appropriate balanced non-coercive contraception counseling services are provided in the antepartum,early intrapartum,and immediate postpartum periods forall women.PPlUD isa highly cost-effective,efficacious LARC that should be made available in maternity services to all women who choose it. The recent FlGO and ICM (International Confederation of Midwives) joint statement on contraception supports the recommendations.32 # 6.1丨FIGO's commitments ·To advocate for access to contraception throughout a woman's reproductive years and in particular during the immediate postpartum period. · To facilitate and provide training materials to help clinicians and ministries of health to provide access to contraception during the immediate postpartum period,regarding PPlUD in particular. # AUTHOR CONTRIBUTIONS AM and AA devised the concept,planned and wrote the article with strong support from MW with regards to the literature review.AK reviewed the article.AM,AA and AK are members and chair of the FlGO Committee of Contraception,and this article was written as part of their involvement with the committee. # FUNDING INFORMATION There was no funding source for the preparation of this paper. # CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest. # DATA AVAILABILITY STATEMENT Data sharing is not applicable to this article as no new data were created or analyzed in this study. # MEMBERS OF THE FIGO COMMITTEEON CONTRACEPTION,2023-2025 Asha Kasliwal (Chair),Azra Ahsan (Vice Chair),Aparna Sridhar (Past Chair),Cuauhtemoc C.Gonzälez,Wai-cheung Lam，Silvia Bonsergent,Felix Momat，Helena K.Kallner,Sara Ooi (WATOG Representative),Nomi Fuchs-Montgomery (Associate Member); Anita Makins (Associate Member)，Monica Kerrigan (Associate Member), lan Askew (Associate Member). # ORCID Anita Makins $\textcircled{1}$ https://orcid.org/0000-0002-8259-0897 # REFERENCES 1．Sully EA,Biddlecom A, Darroch JE,et al.Adding it up: Investing in Sexual and Reproductive Health 2O19.Guttmacher Institute; 2020. 2.World Health Organization. Unmet need for Family Planning 2015. https://www.who.int/reproductivehealth/topics/family_planning/ unmet_need_fp/en/ 3．United Nations Department of Economic and Social Affairs Population Division.World Contraceptive Use 2014. https://www. un.org/en/development/desa/population/publications/dataset/ contraception/wcu2014/Metadata/WCU2014_UNMET_NEED_ metadata.pdf 4.Vernon R.Meeting the family planning needs of postpartum women. Stud Fam Plan. 2009;40(3):235-245. doi:10.1111/j.1728-4465.2009. 00206.x 5．Talon PY, Saizonou J,Kpozehouen A,Zannou RF,Ouendo EM. Trends in the utilisation of skilled birth attendance among pregnant women in Benin,from 2001 to 2017-2018,and projections to 2030.BMC Public Health.2023;23(1):874.doi:10.1186/ s12889-023-15460-x 6. Rutstein SO.Effects of preceding birth intervals on neonatal,infant and under-five years mortality and nutritional status in developing countries:evidence from the demographic and health surveys.Int J Gynaecol Obstet.2005;89(Suppl 1):S7-S24. 7.Kozuki N,Lee AC,Silveira MF,et al.The associations of birth intervals with small-for-gestational-age,preterm,and neonatal and infant mortality:a meta-analysis.BMC Public Health.2013;13(Suppl 3):S3. doi:10.1186/1471-2458-13-S3-S3 8.United Nations Department of Economic and Social Affairs Sustainable Development. Sustainable Development Goal 3.2015 Accessed March 09, 2022. https://sdgs.un.org/goals/goal3 9．Arulkumaran S,Hediger V,Manzoor A,May J,Group MHW.Saving Mothers' Lives: Transforming Strategy Into Action: Report of the Maternal Health Working Group 2012: Global Health Policy Summit. 2012. 10．Makins A,Arulkumaran S,Contraception F, Family Planning C.The negative impact of COVID-19 on contraception and sexual and reproductive health: could immediate postpartum LARCs be the solution? Int JGynaecol Obstet.2020;150(2):141-143.doi:10.1002/ ijgo.13237 11. Naik PT, Radhakrishnan SD,Murugan RB,etal. Impact of COVID-19 pandemic on postpartum contraception services in women delivering ata tertiary care centre in South India.IntJ Reprod Contracept Obstet Gynecol.2021;10(12):4392-4396.doi:10.18203/2320-1770. ijrcog20214444 12. Echeverry G.Family planning in the immediate postpartum period. Stud Fam Plan. 1973;4(2):33-35. doi:10.2307/1964827 13．PfitzerA,Mackenzie D,Blanchard H,etal.A facility birth can be the time to start family planning: postpartum intrauterine device experiences from six countries.Int JGynaecol Obstet.2015;130:S54-S61. 14．MakinsA,Taghinejadi N,Sethi M,etal.FlGO postpartum intrauterine device initiative: complication rates across six countries. Int J Gynaecol Obstet.2018;143(Suppl1):20-27. 15.de Caestecker L, Banks L, BellE,Sethi M,Arulkumaran S.Planning and implementation of a FlGO postpartum intrauterine device initiative in six countries.Int JGynaecol Obstet.2018;143:4-12. 16．Ahsan A,Ali A.Acceptability,continuation and complication rate of postpartum insertion of intrauterine contraceptive device among Pakistani women.JPak Med Assoc.2023;73(5):966-972. 17.Lopez LM,Bernholc A,Hubacher D,Stuart G,Van Vliet HA. Immediate postpartum insertion of intrauterine device for contraception. Cochrane Database Syst Rev.2015;2015(6):CD003036. doi:10.1002/14651858.CD003036.pub3 18.Kapp N， Curtis KM. Intrauterine device insertion during the postpartum period:a systematic review. Contraception. 2009;80(4):327-336. 19. Salem RM. New attention to the IUD: expanding women's contraceptive options to meet their needs.Popul Rep B.2006;7:1-26. 20． Celen S,Moroy P, Sucak A,Aktulay A,Danisman N. Clinical outcomes of early postplacental insertion of intrauterine contraceptive devices. Contraception.2004;69(4):279-282. 21．Chi IC,Wilkens L,Rogers S.Expulsions in immediate postpartum insertions of Lippes loop D and copper T IUDs and their counterpart Delta devices-an epidemiological analysis.Contraception. 1985;32(2):119-134. 22. Araujo VB,Ortiz L, Smith J. Postpartum IUD in Paraguay: a case series of 3000 cases. Contraception.2012;86:13-186. 23．World Health Organization.Medical eligibility criteria for contraceptive use.2015 https://www.who.int/publications/i/item/97892 41549158 24. Cooper M,Johnstone A,McCabe K,et al. Feasibility and acceptability of providing immediate postpartum intrauterine contraception (PPlUC)in a public maternity service.EurJContracept Reprod Health Care.2018;23:76. 25. Cooper M,Cameron S. Successful implementation of immediate postpartum intrauterine contraception services in Edinburgh and framework for wider dissemination.Int J Gynaecol Obstet. 2018;143:56-61. 26. Bhadra B,Burman SK,Purandare CN,Divakar H,Sequeira T, Bhardwaj A.The impact of using nurses to perform postpartum intrauterine device insertions in Kalyani Hospital,India.IntJGynaecol Obstet.2018;143(Suppl1):33-37. 27. Muganyizi PS,Kimario G,Ponsian P, Howard K,Sethi M,Makins A.Clinical outcomes of postpartum intrauterine devices inserted by midwives in Tanzania.Int J Gynaecol Obstet.2018;143(Suppl 1):38-42. 28. Thapa K,Dhital R,Rajbhandari S,etal.Factors affecting the behavior outcomes on post-partum intrauterine contraceptive device uptake and continuation in Nepal: a qualitative study. BMC Pregnancy Childbirth. 2019;19(1):148.doi:10.1186/s12884-019-2310-y 29. Thapa K,Dhital R,Rajbhandari S,et al. Improving post-partum family planning services provided by female community health volunteers in Nepal: a mixed methods study.BMC Health Serv Res. 2020;20(1):123. 30. Makins A,Taghinejadi N,Sethi M,et al.Factors influencing the likelihood of acceptance of postpartum intrauterine devices across four countries: India,Nepal, Sri Lanka,and Tanzania.Int JGynaecol Obstet.2018;143(Suppl1):13-19. 31. Betran AP, Ye J,Moller AB,Souza JP,Zhang J.Trends and projections of caesarean section rates: global and regional estimates.BMJ Glob Health.2021;6(6):e005671. 32.Koch M,Nayiga H, Yates A,et al.FlGO and ICM joint statement on contraception: 2024.Int JGynaecol Obstet.2024;167(3):972-975. # SUPPORTING INFORMATION Additional supporting information can be found online in the Supporting Information section at the end of this article. How to cite this article: Makins A,Ahsan A,Waqas M, Kasliwal A,.FlGO position statement on postpartum intrauterine devices (PPIUD). Int JGynecol Obstet.2025;00:1- 6. doi:10.1002/ijgo.70146	None	None	None
6309a41a2bce465489932ec1c520eaf8	2025+RCOG指南	妊娠和乳腺癌（No.12）	# Pregnancy and Breast Cancer Green-top Guideline No. 12 Anne Armstrong丨Ashu Gandhi丨 Suzanne Frank丨David Williams丨 Samantha Nimalasena丨on behalfofthe Royal College of Obstetricians and Gynaecologists Correspondence: Royal Collge of Obstetricians and Gynaecologists (clinicaleffectiveness@rcog.org.uk) Accepted: 17 June 2025 Funding:Allooveloptdedeledei guidelivelosdt exeptiotoOafepdetet for expensesforatendingGuidelines Commitee metings.Pleaseseemoreinformationon travelxpenserulesontheRCOG website. # KEY RECOMMENDATIONS · Anysuspicious breastlesionorlump which is present for more than 7days should beinvestigatedbyaspecialistunit.Good Practice Point (GPP)] · Suspicious breast lesions should be investigated by ultrasonography with mammography reserved for investigation of extent of a known cancer. [Grade B] · Breast surgerycan be performed throughout pregnancy with appropriate fetal monitoring prior to and following surgery. [Grade C] · Chemotherapy is contraindicated during the first rimester of pregnancy but can be administered during the second and third trimesters. [Grade B] · Choose the treatment strategy according to local guidelines for a non-pregnant woman according to the pathology and tumour characteristics wherever possible. [GPP] · Dosing ofchemotherapyshould be based on the woman's actual weight,not the pre-pregnancy weight.The woman should be reweighed and doses recalculated at each cycle of treatment. [GPP] ·Where posible theadministrationof HER2-directed therapyshouldbe delayeduntilafterbirth.IfHER2-directed therapy is required forthe managementoflife-threatening metastaticdisease individualised monitoringof the womanand fetus is recommended. [Grade B] · Methylprednisolone or hydrocortisone should be used in place of dexamethasone. [GPP] · Granulocyte-colony stimulating factor should be used as indicated in line with standard protocols.[Grade C] ·Where a delay in radiotherapy is not expected toadversely impact maternal outcome,it is recommended that adjuvant breast or chest wal radiotherapy is postponed until after the birth of the baby. [Grade B] ·Adjuvant radiotherapycanbeconsidered inspecific circumstances (i..,if risk from omision ordelayoutweighs harm to thefetus)provided thatthis isachievable withinsafelimitsofradiation exposure tothefetus(i.e.,belowthedeterministic threshold). Referral to a specialist centre with suitable expertise should be considered. [Grade D] · In the metastatic seting,pallative radiotherapy may be indicated forlocal control ofsymptomatic diseaseor to preserve function (e.g., metastatic spinal cord compression). [Grade D] · Women with breast cancer during pregnancy can be reasured that their breast cancer can be treated during pregnancy without long-term harm to their unborn child. [Grade A] · Iatrogenic preterm birth should be avoided unless there are clear maternal or fetal indications.[Grade A] · Women receiving chemotherapy should be advised not to breastfeed. [Grade B] · Women ofchildbearing potential withanewdiagnosis ofbreastcancershould becounseled,atdiagnosis,about thepotential impact of systemic therapy on their future fertility. [Grade B] . Women of reproductive age who are being considered for medical treatment for breast cancer that may cause premature ovarian insufficiency should be ofered oocyte or embryo cryopreservation as appropriate.[Grade C] · Premenopausal womenundergoing (neo)adjuvantchemotherapy for breast cancer and who are interested in fertility preservation should be ofered temporary ovarian suppresson with a gonadotrophin-releasing hormone agonist during their chemotherapy. [Grade A] ·Women with a history ofearly breast cancer who wish tobecome pregnant should be advised that pregnancydoes not increase their risk of breast cancer recurrence.[Grade B] # 1 \|Purpose and Scope The purpose of this guideline is to describe the diagnosis,management and treatment of breast cancer during and immediately after pregnancy. It also provides advice on future fertility considerations after a breast cancer diagnosis. This guideline is for healthcare professionals who care for women, non-binary and trans people who experience pregnancy associated breast cancer (PABC).Within this document we use the terms woman and women's health.However, it is important to acknowledge that it is not only women for whom it is necessary to access women's health and reproductive services in order to maintain their gynaecological health and reproductive wellbeing. Gynaecological and obstetric services and delivery of care must therefore be appropriate,inclusive and sensitive to the needs of those individuals whose gender identity does not align with the sex they were assigned at birth. # 2 \| Introduction and Background Breast cancer is the most common cancer in the UK,accounting for $1 5 \%$ of all new cancer cases (20l7-19) [1]. There are around 56800 new breast cancer cases in the UK every year (2o17-19) [1]. Of these, $9 \%$ occur in women at or under 44years of age [1]. Survival rates have improved significantly in recent decades.In women diagnosed under the age of 39years, $8 5 \%$ are alive more than 5years after their diagnosis [1] leading many women to now consider pregnancy as an option after cancer. A new breast cancer diagnosis complicates about 1 in 3000 pregnancies [2].With advancing maternal age at pregnancy [3] it is likely that the incidence of breast cancer during pregnancy will increase. Clinical care of people who are pregnant with breast cancer should follow the principles of care for all pregnant women with medical disorders: the clinician's duty of care is first towards the woman and then to the fetus.This principle was outlined in the 2021 MBRRACE report which states that clinicians should ‘Treat women who may become pregnant,are pregnant,or who have recently been pregnant the same as a non-pregnant person unless there is a very clear reason not to' [4]. For pregnant women with breast cancer a care plan should first be established by surgeons and oncologists,as if the woman was not pregnant. This plan can then be adapted with a multidisciplinary team (MDT) that should also include obstetricians, fetal and neonatal specialists.This team should balance potential treatment for the woman and her fetus with potential compromise for pregnancy outcome.These treatment options must be discussed with the woman. As breast cancer during pregnancy is relatively rare and heterogeneous in its presentation,recommendations for care are guided by international registries rather than clinical trials. Treatment decisions are therefore limited to the best available evidence,which is often not definitive.In the absence of evidence of harm or safety in pregnancy,MDTs may need to consider treatment which is in the best interest for the woman. Pregnancy is not,however,an exception to the principle that an informed patient has the right to refuse treatment,even treatment needed to maintain life and a pregnant woman's informed decision to refuse recommended medical or surgical interventions for breast cancer should be respected [5]. # 3丨 Identification and Assessment of the Evidence The Cochrane Library (including the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects [DARE] and the Cochrane Central Register of Controlled Trials [CENTRAL]),EMBASE,Trip,MEDLINE and International HTA database were searched for relevant papers. Databases were searched using the relevant Medical Subject Headings (MeSH) terms,including all subheadings and synonyms,and this was combined witha keyword search.Search terms included:‘pregnancy,‘breast cancer',‘inflammatory breast neoplasm',‘pregnancy complications’ and ‘breastfeeding'.The search was limited to studies on humans and papers in the English language and included all relevant studies 2010 until December 2O23.Relevant guidelines were also searched for using the same criteria in the ECRI Guidelines Trust (replaces National Guideline Clearinghouse),Guidelines International Network and the National Institute for Health and Care Excellence (NICE) Evidence Search. This guideline was developed using the methodology described in the Royal College of Obstetricians and Gynaecologists (RCOG) handbook Developing a Green-top Guideline: Guidance for developers.Where possible,recommendations are based on available evidence.Areas lacking evidence are highlighted and annotated as ‘good practice points'.Further information about the assessment of evidence and the grading of recommendations may be found in Appendix A. # 4\|How Should Women Who Have Breast Cancer Diagnosed During Pregnancy Be Cared for? # 4.1\| Prognosis of Breast Cancer Diagnosed During Pregnancy and Postpartum Historically, the prognosis of women diagnosed with breast cancer during pregnancy or up to 12 months postpartum has been reported as being worse than non-pregnant women of childbearing potential diagnosed outside of this timeframe [6,7].However, previous studies addressing PABC outcomes have conflated two separate but clearly related cohorts of women-those diagnosed with breast cancer while pregnant (a breast cancer that occurs during pregnancy, PrBC) and those diagnosed in the months postpartum (postpartum breast cancer;PPBC).There is increasing evidence that breast cancer prognosis differs between these two groups [8] and that if outcomes of the two groups are combined this distinction may be lost [9]. [Evidence level $^ { 2 + ] }$ # 4.1.1 l Breast Cancer Diagnosed During Pregnancy Three meta-analyses [lO-l2] and a retrospective national registry review [l3] meta-analysis have described a worse prognosis in women with PABC than their non-pregnant counterparts.However, these meta-analyses either included studies from the 196Os and 7Os when diagnosis and treatment were radically different,had inconsistent definitions of PABC,and/ or were poorly age and staged matched.Therefore,the applicability to modern day practice of the findings from these reports is limited. Low expression of oestrogen receptors (ER) and increased expression of human epidermal growth factor-2 (HER2) have been reported in women with PABC,with both factors known to be associated with a relatively worse prognosis [14-16].A large nationwide study, published in 2o21,comparing histopathological profiles of 74l women with PrBC with age matched non-PrBC women,confirmed that women with PrBC have tumours with a more aggressive phenotype than non-pregnant counterparts [17],a finding also noted in other national databases [18,19]. However,when matched for tumour stage the outcome for women with PrBC is similar to non-pregnant controls [20-22]. [Evidence level $^ { 2 + }$ 一 By using diagnostic and treatment pathways for women with PrBC which are as close as possible to women with non-PrBC, similar outcomes can be achieved [20,21,23,24].[Evidence level $^ { 2 + }$ 一 # 4.1.2丨 Breast Cancer Diagnosed in the Postpartum Period Historically breast cancers diagnosed during pregnancy or in the first few postpartum years following birth have been combined under the heading of PABC [25].Definitions of the length of the postpartum period have varied from 6 to 60 months [12]. Data published in 2021/22 suggest that breast cancer diagnosed during pregnancy has differing tumour biology and clinical outcomes when compared with breast cancer diagnosed in the postpartum period,and that this distinction can last for 5-loyears following birth [8,26-28].Therefore, there are calls to consider PrBC as a distinct entity from breast cancer diagnosed in the 5-10years following birth (PPBC) [8,29]. Compared with women diagnosed with breast cancer during pregnancy or nulliparous women,PPBC is associated with worse survival rates and more than double the risk of metastatic disease [15,25,28],findings that persist despite correcting for clinical and pathological factors [3o]. Compared with women with PrBC, those with PPBC are noted to have higher rates of lymph node positivity and higher grade disease [25]. In a cohort of women with oestrogen receptor-positive $\left( \mathrm { E R + } \right)$ PPBC metastasis-free survival was similar to that seen in oestrogen receptor-negative (ER-) nulliparous women [3o].[Evidence level 2-] The pathogenesis for this worsened prognosis is currently the topic of much investigation but is thought to be linked to the shift of mammary gland epithelium,froma state of proliferation and differentiation (in preparation for lactation),to involution (following cessation of,or in the absence of,lactation).Involutional changes specific to the immediate postpartum breast and seen again on cessation of lactation are noted to share numerous stromal attributes with putative pro-malignant states [29,31,32]. Furthermore,pro-malignant cytokines and altered immune infiltration may persist for several years following birth [27,33, 34], which may explain the relatively worse clinical outcomes seen in women with PPBC compared with PrBC or controls. # 4.2\| What Is the Optimal Care of Women With Breast Cancer Diagnosed During Pregnancy? 4.2.1 \| Diagnosis and Radiological Investigations <table><tr><td>Recommendation Any suspicious</td><td>Evidence level</td><td>Strength GPP</td><td>Rationale for the recommendation Rapid assessment</td></tr><tr><td>breast lesion or lump which is present for more than 7days should be urgently referred to a specialist unit with the patient seen and diagnosed within the national “Faster Diagnosis</td><td>4</td><td></td><td>of breast lumps will lead to most favourable clinical outcomes</td></tr><tr><td>Standard" 28 day timeframe Suspicious breast lesions should be investigated by ultrasonography to allow a targeted biopsy. Mammography should be reserved for investigation of</td><td>2++</td><td>B</td><td>Ultrasound assessment with targeted biopsy where indicated will permit rapid differentiation between benign and malignant lesions</td></tr><tr><td>cancer Suspicious breast lesions (clinically or on imaging) should be investigated by image guided core biopsy and not solely fine needle</td><td>2++</td><td>B</td><td>Core biopsy is more accurate, informative and can help treatment planning if malignant</td></tr><tr><td>aspirate cytology Suspicious axillary lesions (clinically or on imaging) should be investigated by image guided core biopsy or fine needle aspirate</td><td>2++</td><td>B</td><td>Preoperative axillary staging is essential for treatment planning</td></tr><tr><td>cytology Non-contrast or diffusion-weighted imaging magnetic resonance imaging (MRI) scans are safe during pregnancy and can be used when</td><td>2+</td><td>B</td><td>MRI scanning may contribute to surgical planning and staging information</td></tr><tr><td>indicated Contrast enhanced MRI scanning should be avoided with the exception of situations where the benefits will clearly outweigh the risks</td><td>2-</td><td>C</td><td>Contrast enhanced MRI scanning may contribute to surgical planning and staging information</td></tr></table> <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Positron emission tomography- computed tomography (PET-CT) can be used with caution if the MDT feels that information gained may change management and providing this information cannot be obtained by non- ionising imaging modalities</td><td>3</td><td>C</td><td>Case reports and national registry data show that in appropriately chosen patients PET CT may result in changes in management</td></tr></table> Pregnant women with breast symptoms persisting over 7days, such as a breast lump,skin distortion or nipple discharge not clearly because of pregnancy-related galactorrhoea should be referred to a diagnostic breast clinic for urgent assessment. Blocked milk ducts are a common problem encountered by lactating women and can present as a breast lump [35]. Any lump perceived to be a blocked milk duct that does not resolve within 7days should be referred for urgent assessment.[Evidence level 4] Diagnostic assessment of symptoms will include clinical evaluation with imaging and biopsy as indicated.Breast density and nodularity increase during pregnancy which can complicate clinical examination [36]. 4.2.1.1 \| Ultrasound Scanning. Breast ultrasound has the highest sensitivity for the diagnosis of PrBC and is the first line imaging examination in pregnant and lactating women [37]. [Evidence level 2+] 4.2.1.2\| Mammography. Mammography is not used routinely in women below the age of 40 as it has reduced sensitivity and specificity in this age group [38].This is further affected bypregnancy-induced changes within the breast. However, it may be indicated in people who are pregnant in the presence of suspected false negative ultrasound scan or suggestion of malignancy on the ultrasound scan [37].Fetal radiation exposure during two-view mammography is between O.0ol and 0.01 milligray (mGy),well below the 50 mGy limit of acceptable fetal exposure [36,39].Lead apron shielding will further reduce fetal exposure by $5 0 \%$ [39]. Once an underlying malignancy is proven, mammography with percutaneous biopsy will characterise tumour extent and presence or absence of associated malignant microcalcification [39]. This will be essential for surgical planning [40]. [Evidence level $^ { 2 + }$ 一 4.2.1.3丨 Digital Breast Tomosynthesis. Digital breast tomosynthesis acquires a series of images by passage of the X-ray tube across a limited arc above the breast.Multiple exposures are obtained and reconstructed to produce a set of parallel image planes through the whole breast, typically with $1 \mathrm { m m }$ spacing [4l]. Although digital breast tomosynthesis incurs a very slightly higher radiation dose to the fetus [42,43], it offers superior sensitivity and specificity in the dense breast tissue of pregnant women,and therefore is considered to provide clinically useful information in this setting with minimal risk to the fetus [37]. [Evidence level $^ { 2 + }$ 4.2.1.4丨 Percutaneous Core Biopsy. Imaging suspicion of the presence of a breast malignancy should be followed by image-guided biopsy of the lesion [44,45] as the development of fistulae in this scenario is rare [36,46]. Concerns regarding development of a milk fistula following percutaneous core biopsy are largely theoretical.Ultrasound guided core needle biopsy is sensitive and specific in diagnosing potential axillary lymph node metastasis [47].[Evidence level $^ { 2 + ] }$ 4.2.1.5丨 Magnetic Resonance Imaging. Non-contrast MRI scanning is considered to be safe throughout pregnancy with no specific precautions or contraindications [48-50]. Available evidence indicates no acoustic injuries to the fetus, no evidence of teratogenesis or tissue heating with 3Tesla MRI scanning [51, 52].A study examined long-term safety of MRI scanning in the first trimester and found no increased harm to the fetus or in early childhood [53].[Evidence level 2+] Contrast-enhanced MRI is contraindicated during pregnancy as chelated gadolinium is known to cross the placenta and enter the fetal circulation where it may theoretically dissociate into the non-chelated form,which is neurotoxic.While several small retrospective studies in women have not shown adverse fetal effects,animal studies show fetal malformation and death following supraclinical doses [54].A large study examined outcomes in children exposed to gadolinium in utero with follow-up to a median of 2.4years.Exposure to gadolinium during MRI scanning at any stage of pregnancy was not associated with an increase in congenital anomalies [53].A small increase in rheumatological,inflammatory or infiltrative skin conditions was noted in gadolinium-exposedinfants,together with an increased relative risk for stillbirth or neonatal death (adjusted relative risk [RR] 3.70; $9 5 \%$ CI 1.55-8.85),although the study was not powered to definitively establish this association [53].[Evidence level 2-] European guidelines state that use of gadolinium-enhanced MRI scanning should only be used if “there is strong clinical indication”and then“at the lowest dose to achieve a diagnostic result”[55].American guidance is similar,advising that gadolinium use should be limited to situations where the benefits would clearly outweigh the risks [56].However, the use of diffusion-weighted imaging sequences will often add diagnostic accuracy to allow an avoidance of contrast imaging [57, 58]. [Evidence level 4] 4.2.1.6丨 CT Scanning. CT scanning is uncommonly used for the diagnosis and management of early breast cancer. However,its use may potentially be considered in the presence of suspected metastatic disease.In practice, this can generally be achieved by modern MRI techniques.The radiation dose to the fetus is critical in deciding the appropriateness of CT scans in the pregnant woman. Scanning of the head,chest or abdomen/pelvis results in markedly differing fetal radiation doses; below 0.005-0.05, 0.001-0.66 and 8-25mGy respectively [59]. [Evidence level 3] Shielding of the abdomen with lead aprons does not substantially reduce fetal exposure to ionising radiation [60-62]. CT scanning of the abdomen/pelvis in pregnancy should be avoided if possible but if it is considered necessary for the clinical management of the pregnant woman, discussing the benefit of the information to be derived versus the risks with the mother is important; there may be a very low chance of complications [59].[Evidence level 3] Iodinated contrast material is known to cross the placenta, but animal studies have not shown any teratogenic effects [63].Human studies have not shown any negative effect of contrast material on fetal thyroid gland development [64, 65]. Notwithstanding any concrete proof of fetal harm from iodinated contrast material, it is recommended that contrast be used where potential benefits outweigh risks [59].[Evidence level 3] 4.2.1.7丨 PositronEmissionTomography-Computed Tomography. A PET-CT scan is an important modality that is increasingly used in clinical practice to aid the staging of early and advanced breast cancer [66].Historically, hesitation regarding the use of PET-CT as a staging tool in women with PrBC have centred on concerns of fetal exposure to l8Fludeoxyglucose-DG (l&FDG) as a result of accumulation within maternal tissue and by traversing the placenta. Comprehensive testing has,however,shown that the actual levels of fetal exposure from 18FDG is very low. Following maternal administration of a typical PET-CT dose of $2 5 0 \mathrm { M B q }$ ,fetal exposure is between 10 and $2 0 \mathrm { m G y }$ [67], significantly below the $1 0 0 \mathrm { m G }$ ylevelaccepted to have deterministic effects;adoption oflow dose,long axial field of view protocols may reduce fetal exposure further.The maternal urinary bladder is the primary contributor to fetal radiation dose and good maternal hydration with encouragement of early voiding(or catherisation) can help minimise radiation exposure. Micturition 1 hour post administration reduces fetal exposure by up to $4 5 \%$ ,compared with emptying the bladder at 2.5 hours [68].Data from the French national registry have shown that PET-CT investigation changed management strategies in 38 of 63 patients $( 6 0 . 3 \% )$ with pregnancy-associated cancer (46 had PABC) [69]. The International Atomic Energy Agency states that pregnancy is not a contraindication to nuclear medicine procedures provided there is clinical justification for the procedure and alternative imaging using non-ionising radiation has been explored [70].[Evidence level 4] 4.2.2\| Surgery: Approach and Considerations <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Women diagnosed with breast cancer during pregnancy should be under the care of a dedicated MDT which has</td><td>4</td><td>GPP</td><td>Care of women with breast cancer by specialist MDTs has been shown to improve outcomes</td></tr><tr><td>the expertise and experience to manage all aspects of maternal and fetal health</td><td></td><td></td><td></td></tr></table> <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Breast surgery can be performed throughout pregnancy with appropriate fetal monitoring prior to and following surgery</td><td>2+</td><td>C</td><td>Any decision to delay surgery until the second trimester should be balanced against the risk of leaving the cancer in situ,</td></tr><tr><td>Breast surgical choices should be the same as for non- pregnant women, with the exception that reconstructive procedures, where required, should be performed postpartum</td><td></td><td></td><td>surgery should be guided by tumour biology and the woman's choice</td></tr><tr><td>be performed with 99mTc-labelled radiocolloid, injected on the day of surgery. Isosulfan blue, Patent Blue or methylene blue dye</td><td></td><td></td><td>component of treatment planning. Blue dye may cause allergic/ anaphylactic reactions</td></tr></table> Care is best facilitated bya specialised PrBC MDT which,in addition to the oncology team members,also includes an obstetrician,an obstetric physician (where available),an anaesthetist and,where necessary,a neonatologist [71-74].[Evidence level 4] 4.2.2.1 \| Timing of Surgery. Surgery can be performed in any trimester of pregnancy.There are no established teratogenic effects of modern anaesthetic agents in any trimester,including the first [75,76].A large observational study across NHS hospitals of 47628 non-obstetric surgeries in 6486 280 pregnancies found that pregnant women who underwent non-obstetric surgery had a slight excess of spontaneous miscarriage compared with non-pregnant women (RR 1.13; $9 5 \%$ CI 1.09-1.17), but it was not possible to separate risks of surgery and anaesthesia from the effects of the underlying condition [77]. Surgical outcomes do not differ between pregnant and non-pregnant women undergoing breast surgery [78]. [Evidence level $^ { 2 + }$ For an individual diagnosed with cancer in pregnancy,any decision to delay surgery until the second trimester should be balanced against the risk of leaving the cancer in situ,as wellas any consequent delays to chemotherapy—which is contraindicated in the first trimester. 4.2.2.2\| Perioperative Care. Breastcancer， surgery and pregnancy itself are all risk factors for thrombosis.Thromboprophylaxis with low-molecular-weight heparin or equivalent In the third trimester,positioning ofthe woman on the operating table in the left lateral tilt position will reduce aortocaval compression by the gravid uterus,allowing maintenance of cardiac preload and output [8o]. Fetal heart-rate monitoring perioperatively should be guided by obstetricians [81].[Evidence level 4] 4.2.2.3丨 Choice of Surgical Operation. Surgical recommendations for women with PrBC (mastectomy versus breast conserving surgery) follow the same principles to those available to all women and are guided by clinical stage, tumour biology, trimester and the individual preferences of the woman [82, 83]. [Evidence level $^ { 1 + + ] }$ （204 For breast cancers requiring localisation to permit breast conserving surgery, localisation techniques should follow the same principles as in non-pregnant women [84].[Evidence level $^ { 1 + + ] }$ For early stage breast cancer, breast conserving surgery with a wide local excision followed by radiotherapy is as effective as mastectomy, provided the margins of the resected specimen are free of tumour [85].[Evidence level $^ { 1 + ] }$ However,radiotherapy is challenging to deliver during pregnancy (see Section 4.2.4).Women diagnosed during the first and second trimesters who are considering breast conserving surgery and who are unlikely to require chemotherapy should have early input from a clinical oncologist.This is to advise on the possibility of radiotherapy during pregnancy,and the implications of any delay to radiotherapy if this is not given during pregnancy. Some women may choose to undergo a mastectomy to avoid these issues.For the vast majority of women diagnosed in pregnancy (neo)adjuvant chemotherapy will be indicated and radiotherapy can be safely delayed until postpartum.[Evidence level 4] 4.2.2.4 \| Axillary Staging. Women with PrBC should undergo the same diagnostic assessment of the axillary lymph nodes as non-pregnant women.Abnormal appearing lymph nodes (using established criteria from The Royal College of Radiologists [86]) should be subject to ultrasound guided biopsy and those women with biopsy-proven axillary metastases should, similar to non-pregnant women,receive a recommendation for axillary node clearance [87]. [Evidence level $^ { 1 + + ] }$ Sentinel node surgery has been extensively studied in pregnancy and is now the standard of care for women with clinically node-negative (cNo) PrBC [81,88]. In pregnancy, the sentinel node should be identified using 99mTc-labelled radiocolloid. Measurement of radiation exposure to the fetus (approximately $4 . 3 \mathrm { m G y } )$ indicates that levels are well below the safety threshold $( 5 0 \mathrm { m G y } )$ for adverse effects on the fetus [89]. Fetal exposure can be further minimised by deploying same day radioactive tracer injection,thereby reducing time between injection and surgery.Accuracy of,and local recurrence rates following,sentinel node surgery in PrBC are similar to those seen in non-pregnant women [9o]. Patent Blue,isosulfan blue and methylene blue use is not recommended because of concerns regarding maternal allergy or anaphylaxis [91-93].[Evidence level $^ { 2 + + ] }$ 4.2.2.5丨 Breast Reconstruction. There are very limited data upon which to base recommendations regarding immediate breast reconstruction in women with PrBC who undergo mastectomy. The three available publications are single institution case series describing outcomes in a total of 24 women [94-96]. Each describes tissue expander reconstruction with successful aesthetic,maternal and fetal outcomes. Operative time is increased when immediate reconstruction is undertaken [95]. Wound complications following breast surgery in pregnant women are not well reported. One study examining this parameter reported complications in five of 25 cases $( 2 0 \% )$ following mastectomy [97]. Such complications following reconstruction can be expected to be higher and could potentially delay commencement of systemic therapy for the pregnant woman. Personalised decision making is clearly important.People who are pregnant contemplating immediate reconstruction following mastectomy should be fully informed of the lack of data available to provide evidence-based recommendations.Furthermore, physical changes in the breasts during the shift from pregnant to postpartum state may significantly exaggerate any asymmetry between the reconstruction and contralateral breast, leading to poorer long term cosmetic outcomes.[Evidence level 4] # 4.2.3 l Systemic Therapy During Pregnancy When discussing the potential impact of any medication administered during pregnancy it is important to discuss this within the context of a background incidence of major congenital malformations $( 2 \% - 3 \% )$ ，miscarriage $( 1 0 \% - 2 0 \% )$ and stillbirth $( 0 . 5 \% )$ , irrespective of any drug or chemical exposure [98]. Evidence-based data exist on the use of systemic anti-cancer therapy (SACT) during pregnancy. [Evidence level $^ { 2 + + ] }$ 4.2.3.1 \| Chemotherapy. <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Chemotherapy is contraindicated during the first trimester of pregnancy but can be administered during the second and third trimesters Chemotherapy should not be given beyond 35 weeks of pregnancy, or within 2weeks of anticipated birth if this is earlier, with</td><td>2++ 4</td><td>B GPP</td><td>Chemotherapy administered during the first trimester is associated with a significantly increased risk of fetal malformation Chemotherapy has a myelosuppressive effect on both the woman and fetus and therefore adequate time for bone marrow recovery prior to</td></tr></table> <table><tr><td>Recommendation Choose the</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation The majority of</td></tr><tr><td>treatment strategy according to local guidelines for a non-pregnant woman according to the pathology</td><td>4</td><td>GPP</td><td>chemotherapy agents used in the management of breast cancer can be safely given adjuvantly</td></tr><tr><td>and tumour characteristics wherever possible</td><td></td><td></td><td>or neoadjuvantly in the second and third trimesters of pregnancy and the regime which offers the best maternal outcome should be used These agents are</td></tr><tr><td>Anthracyclines, cyclophosphamide, taxanes and carboplatin are the preferred chemotherapy agents in the treatment of pregnant women</td><td>2++</td><td>B</td><td>considered as optimal in the treatment of breast cancer, especially in stage I-III disease, and have been demonstrated to be safe to administer during pregnancy Pharmacokinetics of chemotherapeutic agents are altered in pregnancy. Dosing on pre-pregnancy</td></tr></table> 4.2.3.1.1 丨 Timing of Chemotherapy. In the first trimester fromimplantation to organogenesis,chemotherapy is contraindicated owing to the teratogenic effects [99-103]. The period of organogenesis is characterised by the growth and differentiation of tissues into organs and is the stage of development most susceptible to teratogenic agents.Data from the International Network on Cancer, Infertility and Pregnancy (INCIP) database confirmed the risks from chemotherapy exposure prior to l2 weeks of pregnancy,with major malformations seen in $2 1 . 7 \%$ （ $9 5 \%$ CI 7.5-43.7; odds ratio, 9.24 $[ 9 5 \%$ CI, 3.13-27.30]) of exposed pregnancies $\left( n = 2 9 \right)$ ）[104]. Chemotherapy administered after 12weeks of pregnancy was associated with a major congenital malformation rate of $3 . 0 \%$ 0 $9 5 \%$ CI 1.9-4.6), similar to the expected rates in the general population.[Evidence level $^ { 2 + }$ Pregnant women with breast cancer should follow the treatment plan for non-pregnant women as far as is possible,while taking into account gestational age at diagnosis and the expected date of birth.However,at times a more tailored approach may be needed [1o5]. [Evidence level 4] Chemotherapy should be discontinued 2-3weeks prior to birth to allow sufficient time for both maternal and fetal bone marrowrecovery to minimise the risk of complications postpartum [106].In general this means no chemotherapy after 35weeks of pregnancy although weekly chemotherapy regimens,which are less myelosuppressive,could be cautiously continued for another week or two if this would allow completion of the chemotherapy course.[Evidence level4] 4.2.3.1.2丨 Choice of Regime. The choice of chemotherapy regime should be selected,as far as possible,according to tumour biology and tumour stage,based on local practice in non-pregnant women.The standard (neo)adjuvant breast cancer chemotherapy regimes consist of an anthracycline/cyclophosphamide doublet in combination or in sequence with a taxane, with or without a platinum agent [87].[Evidence level 1+] The majority of data on the use of chemotherapy in women and people who are pregnant with breast cancer involves the use of anthracycline (doxorubicin or epirubcin) and cyclophosphamide containing regimes. There are a number of studies reporting that anthracycline-based chemotherapy does not increase rates of fetal harm [20,107,108].[Evidence level 2+] Taxanes (docetaxel and paclitaxel) have less reported use in pregnancy than anthracycline/cyclophosphamide combinations,although the body of evidence supporting their safety in the second and third trimesters is increasing,with studies failing to highlight any major concerns regarding perinatal outcomes [1o8-111]. Taxane based chemotherapy is now considered as safe to administer during the second and third trimesters of pregnancy [106]. Weekly paclitaxel has equivalent efficacy to three-weeklydocetaxel in the population of non-pregnant women with breast cancer [112], and may be the preferable taxane regimen in pregnancy as it is less myelosuppressive,with a lower risk of complications should unexpected early birth occur.Nab-paclitaxel is a nano-particle albumin-bound formulation of paclitaxel that is predominantly used in women who have had hypersensitivity reactions to taxanes.While there are currently no data regarding the use of this agent in pregnancy, the drug is essentially an alternative formulation of paclitaxel,and there is no reason to suspect it could not be used in pregnant women where indicated.[Evidence level $^ { 2 + ] }$ In recent years carboplatin has been added to the regimes in the neoadjuvant treatment of triple negative breast cancer (TNBC) (tumours that lack receptors for oestrogen,progesterone and HER2),with demonstrated improvements in pathological complete response rate [ll3,1l4].Carboplatin is the backbone of many treatment regimes for gynaecological cancers and therefore much of the evidence regarding its safety in pregnancy can be extrapolated from that cohort [115,1l6],where carboplatin is deemed safe.As with paclitaxel the benefit of reduced myelosuppression would make the use of weekly carboplatin preferential over three-weekly carboplatin.[Evidence level 2+] 5-Fluorouracil has also been demonstrated to be safe to administer during the second and third trimesters of pregnancy [117], but is no longer felt to add any additional disease-free survival advantage [l18] when added into anthracycline/cyclophosphamide regimes and therefore should be omitted in early breast cancer. Capecitabine, the oral prodrug of 5-fluorouracil,is still extensively used in the treatment of advanced disease and,although there are very little data regarding its use in pregnancy, could be considered for the treatment of advanced disease.[Evidence level 4] Older regimes such as cyclophosphamide/methotrexate/fluorouracil (CMF） have inferior efficacy compared with anthracycline/taxane combinations.CMF should be avoided in pregnancy as there is a risk of prolonged fetal exposure with methotrexate owing to amniotic fluid accumulation of the drug [119]. [Evidence level 4] 4.2.3.1.3丨 Dosing. Chemotherapy is usually dosed on body surface area or body weight,with the exception of carboplatin that is dosed on renal function,either calculated or measured. Pharmacokinetic profiles of drugs differ between pregnant and non-pregnant women,and there is limited evidence from human studies and animal preclinical models that the pharmacokinetics of chemotherapy agents are also altered in the pregnancy. These differences are mostly because of the altered physiology of pregnancy,with haemodynamic changes and an increase in plasma volume and glomerular filtration rate, together with hormonal changes to hepatic function,and changes in albumin concentrations affecting protein-bound drugs such as taxanes. These changes may result in decreased plasma exposure to chemotherapy drugs [120,121]. There is,however, insufficient evidence to make altered dosing recommendations in the context of pregnancy. Available outcome data do not show a worse outcome for pregnant compared with non-pregnant women and the same drug doses should be used. Chemotherapy dosing in pregnant women,as for non-pregnant women, should therefore be based on the woman's actual weight at each cycle to account for pregnancy-related weight changes [81, 88,122]. Dosing based on pre-pregnancy weight is likely to lead to under dosing with potentially reduced efficacy. [Evidence level 4] The use of dose dense (dd) (where the interval between successive treatments is reduced compared with a standard regimen) chemotherapy regimens is increasing in the treatment of early breast cancer,particularly for women with a higher risk of recurrence [123,124].This involves reducing the interval between chemotherapy regimes with the use of granulocyte-colony stimulating factor (G-CSF) support,and could be a useful strategy to ensure completion of chemotherapy prior to birth.A cohort of ten women undergoing dd chemotherapy for breast cancer experienced an increased risk of fetal or maternal toxicity [lo8].[Evidence level 2-] Intensified dd regimens (using a higher dose over a shorter period of time) is not a common approach in non-pregnant women, is associated with higher rates of toxicity,and is not recommended in pregnancy. While maternal drug exposure is relevant for breast cancer related outcomes,transplacental drug transfer is relevant for fetal outcomes,but few studies exist.In a preclinical model of nonhuman primates,involving simultaneous collection of fetal and maternal plasma samples [12o], transplacental transfer of anthracyclines and taxanes demonstrated marked variability but, when a drug was detected,levels were low. Transfer of carboplatin was greater (at $5 7 \%$ of maternal levels) [l20],although the clinical impact of this remains uncertain [ll5]. It does appear that the fetus may be relatively protected from exposure to some chemotherapy agents because the placenta acts as a protective barrier. However,even when drugs are not efficiently transferred across the placenta,fetal development can be indirectly affected by drug effects on placental function.Exposure to chemotherapy in utero may be associated with fetal growth restriction (FGR),as shown in a cohort study of 1l70 women treated over a 20-year period in all cancer subtypes,where 50o had received chemotherapy [125]. The highest rates of FGR were with platinum-based chemotherapy exposure (OR 3.12; $9 5 \%$ CI 1.45-6.7). Breast cancer specific studies,involving the use of anthracyclines and alkylating-based chemotherapy,with or withouta taxane,identified only an association of chemotherapy with low birthweight [23,126] but not with the incidence of small-for-gestational-age infants [23,122, 126]. Data from INCIP confirmed FGR is common after chemotherapy in pregnancy, with duration of chemotherapy having a negative impact on growth [127].[Evidence level $^ { 2 + ] }$ Because of potential adverse effects on fetal growth,women undergoing chemotherapy should receive additional monitoring for fetal growth.[Evidence level 4] 4.2.3.2\| Endocrine Therapy. <table><tr><td>Recommendation</td><td>Evidence Level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Defer the administration of endocrine therapy until after birth</td><td>2-</td><td>B</td><td>Fetal malformations have been reported following tamoxifen and aromatase inhibitor</td></tr></table> Tamoxifen is indicated in the treatment of $\mathrm { E R + }$ breast cancer for both early and advanced disease [87]. Fetotoxicity has been reported in some animal studies.A literature review of 167 pregnancies reported anomalous fetal development in $1 2 . 6 \%$ ,which exceeds the baseline rate of fetal anomalies in the general population of around $4 \%$ [128]. The reported malformations were varied including facial malformations and anomalies in the infant female external genitalia,and were not confined to first trimester exposure.There is also a theoretical concern of potential malignancies in female offspringin later life as has been observed following exposure to diethylstilboestrol in utero [128],although the small numbers mean that a definitive causal relationship has not been established.The UK Teratology Information Service (UKTIS)advise that there is insufficient evidence to support the use of tamoxifen in pregnancy. [Evidence level $^ { 2 + ] }$ 4.2.3.3\| Targeted Therapies. <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Where possible the administration of HER2- directed therapy should be</td><td>2+</td><td>B</td><td>Trastuzumab administration is associated with a</td></tr><tr><td>delayed until after birth. If HER2-directed therapy is required for the management</td><td></td><td></td><td>significant risk of oligohydramnios</td></tr><tr><td>of life-threatening metastatic disease individualised monitoring of the woman and</td><td></td><td></td><td>and anhydramnios and consequently fetal toxicity</td></tr></table> <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Inadvertent trastuzumab exposure during the first trimester is not an indication for termination If HER2-directed therapy is required for the management</td><td>2</td><td>B</td><td>The risk of fetal harm with short duration of exposure in the first trimester is low</td></tr><tr><td>of life-threatening metastatic disease, twice-weekly fetal scans to assess amniotic fluid volume and fetal wellbeing with umbilical artery Doppler</td><td></td><td></td><td>To maximise clinical benefit in a life- threatening situation, while minimising the risk of fetal harm, additional</td></tr></table> 4.2.3.3.1 丨 Trastuzumab. Trastuzumab is a monoclonal antibody(MAB) directed against the HER2 receptor that is indicated in HER2 positive disease,both in early breast cancer to reduce the risk of recurrence [87] and in advanced breast cancer to prolong survival [129].[Evidence level $1 +$ 一 Oligohydramnios (OR 17.68; $9 5 \%$ CI 12.26-25.52; $p { < } 0 . 0 1 \dot$ ）， congenital respiratory disorders (OR 9.98; $9 5 \%$ CI 2.28-34.67; $p { < } 0 . 0 1 )$ and neonatal kidney failure (OR 9.15; $9 5 \%$ CI 4.62- 18.12; $p { < } 0 . 0 1$ )were reported in a case-control study of 328 individuals exposed to anti-HER2 agents during pregnancy and registered in the WHO international pharmacovigilance database [l3o].Neonatal deaths have been reported because of renal and respiratory failure [l3l,132]. Gestation of exposure may be relevant,with a smaller study documenting oligohydramnios and anhydramnios in 17 of 24 $( 7 0 . 8 \% )$ cases through second and third trimester exposure,but only 1 of 6 $( 1 6 . 7 \% )$ cases through first trimester exposure [l27]. In the Herceptin Adjuvant (HERA) trial which investigated the use of adjuvant trastuzumab,16 pregnancies occurred during and up to 3 months after trastuzumab exposure [l33],with no cases of oligohydramnios or anhydramnios reported,but $2 5 \%$ of the pregnancies ended in spontaneous miscarriage,numerically higher than the general population risk of around $1 5 \%$ [134].The risk of oligo/anhydramnios is potentially linked to duration of trastuzumab exposure,although statistical significance has not been proven [132]. There is some evidence that oligohydramnios induced by trastuzumab is reversible upon discontinuation of treatment [132]. [Evidence level 3] The effects of trastuzumab on amniotic fluid production and renal development are likely to be attributable to blockade of feto-renal epidermal growth factor receptors and downregulation of vascular endothelial growth factor expression.MABs are transported across the placenta by active transport in a linear fashion as pregnancy progresses,with the largest amount transferred during the third trimester. The placental Fc receptor responsible for this is not effective until the l4th week of pregnancy. Despite the fact that treatment with trastuzumab is associated with cardiotoxicity in adults this has not been reported in infants exposed in utero [l31].[Evidence level 2+] A study describing 5l pregnant women case-matched with nonpregnant HER2 positive women found that the pregnant women had poorer breast cancer survival with statistically significant earlier recurrence [l35]，perhaps owing to delayed HER2- directed therapy. More reassuring data came from a much larger study of 2749 (non-pregnant) women with early breast cancer that found delays in initiation of trastuzumab of less than 6 months after diagnosis did not appear to worsen prognosis [136]. [Evidence level $^ { 2 + ] }$ Treatment with trastuzumab is not recommended in pregnancy and should be delayed until postpartum wherever possible. However,short duration of therapy (less than one trimester) could be considered, with careful monitoring for complications, in women who present with imminently life-threatening metastatic disease in pregnancy.Furthermore,available data suggest that women who accidentally become pregnant while receiving, or soon after completion of HER2-directed treatment,can be reassured that inadvertent exposure to limited cycles of trastuzumab is not a reason for a pregnancy termination.[Evidence level 3] More recently,the therapeutic options for the treatment of HER2 positive breast cancer have been expanded with pertuzumab,a MAB directed against a different subdomain of the HER2 receptor, trastuzumab-based antibody-drug conjugates (ADCs),and small molecule inhibitors that hinder tyrosine kinase activity. Fetal toxicity has also been reported following maternal exposure during pregnancy to the ADC,trastuzumab emantansine (cardiovascular malformations; two of 20 cases $[ 1 0 \% ]$ ),andthe tyrosine kinase inhibitor,lapatinib (intrauterine growth retardation; eight of 18 cases $\left[ 4 4 . 4 \% \right] .$ )[130]. 4.2.3.3.2\| Other Targeted Therapies. There are numerous other targeted therapies employed in the treatment of breast cancer including: mechanistic target of rapamycin (mTOR） inhibitors；cyclin-dependent kinase (CDK）4 and 6 inhibitors; poly-ADP ribose polymerase(PARP) inhibitors;and immunotherapy.These agents are usually used in addition to endocrine therapy or chemotherapy.There are little or no data to support the use of these newer targeted agents in the treatment of PABC,and their use is not currently recommended.[Evidence level 4] 4.2.3.4\| Bone-Modifying Therapy. <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Consider bone-modifying treatment to pregnant women with metastatic disease only where the maternal need outweighs the risk to the fetus, for example, uncontrolled</td><td>2-</td><td>B</td><td>There is only a small body of evidence supporting the safe use of bisphosphonates</td></tr></table> <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Where exposure to bisphosphonates has occurred, either prior to or during pregnancy, fetal growth and skeletal development should be monitored. Mother and infant should also be monitored for</td><td>3</td><td>D</td><td>Limited clinical data but low birthweight and hypocalcaemia have been reported following exposure</td></tr></table> Bisphosphonates and denosumab are routinely used in the treatment of women with secondary breast cancer,to reduce the risk of skeletal-related events from bone metastases [129,137],and in the management of hypercalcaemia of malignancy.Bisphosphonates (zoledronic acid and sodium clodronate),when delivered as adjuvant therapy,have also produced improvements in survival in women with early breast cancer [138]. [Evidence level $^ { 1 + ] }$ Preclinical animal studies have demonstrated the potential for fetal and maternal toxicity arising from bisphosphonate administration in pregnancy [l39,140]. The majority of the data regarding bisphosphonates in pregnancy in humans relates to alendronic acid exposure and includes instances where bisphosphonates were taken prior to conception owing to the long halflife of these agents.Bisphosphonate exposure has not resulted in any major fetal malformations [14l-l43]; however, there have been possible associations with increased risk of spontaneous miscarriage,decreased infant birthweight,and earlier gestational age at birth [l42]. Bisphosphonates are known to cause hypocalcaemia which can affect the contractility of the uterus [81] and there are reports of neonatal hypocalcaemia following in utero exposure [l44]. UKTIS advise that there are currently insuficient data to support the use of bisphosphonates in pregnancy [144]. [Evidence level 2-] For the management of imminently life-threatening hypercalcaemia the available data,predominantly gleaned from the management of hyperparathyroidism in pregnancy,indicates that bisphosphonates can safely be administered in this situation [145].[Evidence level 3] In postmenopausal women with early breast cancer, bisphosphonates reduce the risk of breast cancer recurrence and can, therefore,be given with adjuvant endocrine therapy in conjunction with ovarian function suppression in premenopausal women.After administration bisphosphonates remain in bone for a long period of time,potentially years,which is an important consideration for those women planning a pregnancy following treatment.During this time they are slowly released from bone and excreted by the kidneys.UKTIS advise that, where exposure to bisphosphonates has occurred,either prior to or during pregnancy,monitoring of fetal growth,skeletal development and neonatal calcium levels may be warranted.[Evidence level 4] Denosumab is a MAB that is only used in metastatic breast cancer.However,there are no data regarding the use of denosumab in pregnancy and it cannot be recommended. 4.2.3.5\| Supportive Therapy. <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Seek pharmacist/ Medicines Information (MI) centre/UKTIS/ UK Medicines Information (UKMi) drugs in pregnancy special advisory service for advice on any other medication indicated that is not covered by this guideline</td><td>4</td><td>GPP</td><td>A variety of supportive medications may be required for the symptomatic management of SACT-associated toxicity which are beyond the scope of this guideline</td></tr></table> <table><tr><td>Recommendation</td><td>Evidence level</td><td></td><td>Rationale for the</td><td>centre/UKTIS/ UK Medicines Information</td></tr><tr><td>Antiemetics including 5-HT3 antagonists, cyclizine, prochlorperazine,</td><td>2+</td><td>Strength C</td><td>recommendation Optimal management of anticipated or actual treatment-related toxicity is essential to improve patient</td><td>which are beyond th (UKMi) drugs in scope of this guidelir pregnancy special advisory service for advice on any other medication indicated that is</td></tr><tr><td>metoclopramide, domperidone and olanzapine may be used as indicated in line with standard protocols</td><td></td><td></td><td>tolerability and adherence. These agents have been demonstrated as safe to use during pregnancy</td><td>not covered by this guideline</td></tr><tr><td>Aprepitant may be used in line with standard protocols where</td><td>3</td><td>C</td><td>Optimal management of anticipated or actual treatment-related toxicity is</td><td>Determining which supportive therapy to prescribe du pregnancy involves careful consideration of risks to the and the woman,both from the supportive medication itself also the likelihood and consequences of treatment-related t</td></tr><tr><td></td><td></td><td></td><td></td><td>ities should standard supportive medications be withheld.</td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td> essential to improve patient</td><td></td></tr><tr><td> (NKi1)anininisis</td><td></td><td></td><td></td><td>also worth considering that systemic therapy is only indic</td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td> indicated</td><td></td><td></td><td></td><td>from the second trimester onwards,that many of these sup</td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td>demonstrated as safe to</td><td>ive treatments will only be indicated for short courses with</td></tr><tr><td> Methylprednisolone</td><td>4</td><td></td><td> use during pregnancy</td><td>cycle of chemotherapy and not for continuous dosing, thus</td></tr><tr><td> or hydrocortisone</td><td></td><td>GPP</td><td></td><td>imising fetal exposure.</td></tr><tr><td> should be used</td><td></td><td></td><td>Corticosteroids reduce</td><td></td></tr><tr><td> in place of</td><td></td><td></td><td> chemotherapy-induced</td><td></td></tr><tr><td>dexamethasone</td><td></td><td></td><td> nausea and vomiting</td><td>4.2.3.5.1 丨 Antiemetics. For women undergoing che</td></tr><tr><td></td><td></td><td></td><td>(CINV) and treatment</td><td>therapy the recommended antiemetic prophylaxis will de</td></tr><tr><td></td><td></td><td></td><td>associated hypersensitivity</td><td>on the emetogenicity of the regime with 5-HT3 antagonists</td></tr><tr><td></td><td></td><td></td><td> reactions. Corticosteroids</td><td>ticosteroids and NK1 antagonists being routinely employe</td></tr><tr><td></td><td></td><td></td><td> generally have been</td><td></td></tr><tr><td></td><td></td><td></td><td>demonstrated as safe to use</td><td>prevent both acute and delayed chemotherapy-induced na</td></tr><tr><td></td><td></td><td></td><td>during pregnancy. These</td><td>and vomiting (CINV). Olanzapine is also now recomme)</td></tr><tr><td></td><td></td><td></td><td> specific agents are more</td><td>for the prevention of CINV for highly emetogenic regimes [</td></tr><tr><td></td><td></td><td></td><td>extensively metabolised</td><td>although this has not been widely adopted as routine practi</td></tr><tr><td></td><td></td><td></td><td> in the placenta than </td><td>the UK.Agents such as metoclopramide,domperidone,cycl</td></tr><tr><td>G-CSF should be</td><td>2+</td><td></td><td>dexamethasone, thus</td><td>and prochlorperazine are generally reserved for breakthre</td></tr><tr><td></td><td></td><td>C</td><td>minimising fetal exposure</td><td>nausea and vomiting.</td></tr><tr><td> used as indicated in</td><td></td><td></td><td>Prevention of febrile</td><td></td></tr><tr><td> line with standard</td><td></td><td></td><td>neutropenia(FN) is</td><td>4.2.3.5.2\| 5-HT3 Antagonists. Ondansetron is the 5</td></tr><tr><td>protocols</td><td></td><td></td><td> paramount to minimise</td><td>antagonist that has been most extensively evaluated in</td></tr><tr><td></td><td></td><td></td><td> maternal toxicity and</td><td>nancy and is routinely used in the treatment of hyperer</td></tr><tr><td></td><td></td><td></td><td>intensity.G-Cs hasten</td><td> gravidarum that has failed to respond to first line therapy. T</td></tr><tr><td></td><td></td><td></td><td>demonstrated as safe to</td><td>are some reports of malformations following fetal exposu</td></tr><tr><td></td><td></td><td></td><td> use during pregnancy</td><td>ondansetron during the first trimester [147, 148]. Howev largeretrospective analysis of 1970 women receiving onda</td></tr><tr><td> H2 renitor may</td><td>2+</td><td></td><td></td><td>tron during pregnancy did not identify a significantly incre</td></tr><tr><td> be used where</td><td></td><td></td><td>Preventionyptretegty</td><td>risk of any adverse fetal outcome [149]. This finding was</td></tr><tr><td> required to prevent</td><td></td><td></td><td> reactions is imperative</td><td>roborated further by a large case-control study [150] and a</td></tr><tr><td> administration</td><td></td><td></td><td> to minimise maternal</td><td></td></tr><tr><td>associated</td><td></td><td></td><td> toxicity and optimise</td><td>arate cohort study [151] of birth defects following ondanse</td></tr><tr><td>hypersensitivity</td><td></td><td></td><td>treatment intensity. H2</td><td>exposure,with neither study showing an increase in the m</td></tr><tr><td>reactions</td><td></td><td></td><td>antagonists have been demonstrated as safe to</td><td> ity of birth defects. Both of these studies [150,152] did sug</td></tr><tr><td></td><td></td><td></td><td></td><td>a small increased risk (O.03% absolute increase) of oral</td></tr><tr><td></td><td>2+</td><td></td><td> use during pregnancy</td><td> palate following use in the first trimester [152], with a gr</td></tr><tr><td> Antihistamines may</td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td>C</td><td></td><td>risk associated with intravenous administration compared</td></tr><tr><td></td><td></td><td></td><td>Antihistamines have been</td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td>be administered</td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td>demonstratedassafe to</td><td></td></tr><tr><td></td><td></td><td></td><td></td><td>oral formulation [153]. Subsequent data from almost 1.9]</td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td> use during pregnancy</td><td></td></tr><tr><td></td><td></td><td></td><td></td><td> pregnancies,of which almost 24ooo women had at least</td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td> where required</td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr><tr><td></td><td></td></table> ondansetron injection and after adjusting for potential confounding,showed no excess cleft palate risk with ondansetron dosing [l51].Regardless of any first trimester risk,ondansetron use in the second trimester and beyond,as a means to prevent chemotherapy-induced emesis,is considered safe.[Evidence level $^ { 2 + + ] }$ There are fewer data on the use of granisetron and the longer acting 5-HT3 antagonist palonosetron in pregnancy. Anecdotally these agents have been used for the prevention of CINV in people who are pregnant with breast cancer,and preclinical animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development,parturition or postnatal development [154,155]. In ex vivo modelling studies granisetron did not appear to cross the placenta [156]. 5-HT3 antagonists,preferably ondansetron,should be administered to pregnant women undergoing treatment for breast cancer where indicated according to the emetogenicity of the SACT regime. 4.2.3.5.3丨 Corticosteroids. The corticosteroid of choice in chemotherapy regimes for the prevention of CINV is usually dexamethasone,whereas hydrocortisone is often used to prevent or treat administration associated hypersensitivity reactions.Methylprednisolone or hydrocortisone are the steroids of choice for the management of treatment-related adverse effects in breast cancer in pregnancy,as they are extensively metabolised in the placenta thus minimising fetal exposure [157].Both are widely available as oral and injectable preparations and therefore it would seem prudent to use these agents instead of dexamethasone; $4 \mathrm { m g }$ methylprednisolone or $2 0 \mathrm { m g }$ hydrocortisone are considered equivalent to $0 . 7 5 \mathrm { m g }$ dexamethasone [158]. [Evidence level 4] Animal studies and an early human study suggested an association between exposure to corticosteroids,predominantly in the first trimester,and cleft lip malformations,but this finding is not corroborated by the majority of pregnancy exposure data in humans [159]. Steroids are widely used throughout pregnancy for the management of a range of conditions.Corticosteroids,preferably methylprednisolone or hydrocortisone,should be used in the prevention of CINV and the prevention and management of acute hypersensitivity reactions in women with breast cancer receiving SACT.This is consistent with the advice of UKTIS that, where use of systemic corticosteroids is clinically indicated, treatment should not be withheld on account of pregnancy [159]. [Evidencelevel 4] Screening for glucocorticoid-induced diabetes should be considered in all patients commencing steroids in line with national guidelines [l6o]. The use of steroids may exacerbate gestational diabetes which should be managed in accordance with the NICE guideline [NG3] [161]. 4.2.3.5.4 \| Neurokinin-1 Receptor Antagonists. There has been little published evidence regarding the use of NK1 antagonists during pregnancy,aprepitant being the agent that has most use in pregnancy. No fetal adverse effects have been observed in animal studies [162], however, the supraphysiological dosing above the exposure level in humans could not be attained in animal studies.Expert consensus advocates their use for the prevention of CINV [1l9] and aprepitant can be considered for pregnant women where necessary. [Evidence level 3] 4.2.3.5.5 丨 Olanzapine. Of-label use of the atypical antipsychotic olanzapine for the prevention of CINV is relatively new, with no data concerning its use for this indication in pregnancy. There is,however,experience regarding the use of olanzapine in pregnancy for psychiatric indications.A retrospective study of over 13oo women taking olanzapine during pregnancy found no increased incidence of fetal malformations [163]. Newborns exposed to prolonged olanzapine and other atypical antipsychotics during the third trimester have been reported to show withdrawal symptoms and other central nervous system (CNs) disorders and monitoring is recommended following birth [l64]. Olanzapine use may also predispose the woman to gestational diabetes, therefore a glucose tolerance testing is advised [164,165]. Olanzapine would only be indicated for short courses at low doses for CINV prevention and, therefore, may be considered for pregnant women following the failure of other antiemetics. [Evidence level 4] 4.2.3.5.6 丨 Other Antiemetics. Cyclizine and prochlorperazine are recommended as first-line agents in the management of hyperemesis gravidarum,with metoclopramide and domperidone reserved as second line because of their potential to cause extrapyramidal adverse effects in the woman [166]. These antiemetics have been extensively studied in pregnancy,are considered as safe to administer during pregnancy [167] and should be used for the management of breakthrough nausea and vomiting in the pregnant woman with breast cancer. [Evidence level 3] 4.2.3.5.7 \| Granulocyte-Colony Stimulating Factors. The use of G-CSF is recommended to reduce the risk of FN for all chemotherapy regimes where the risk of FN is high ( $2 0 \%$ or higher) [l68,169],and in less myelosuppressive regimens in women who are at high risk of FN complications owing to co-morbidities.G-CSF is also used as secondary prevention in women who have previously experienced an episode of FN as a common strategy to maintain dose intensity.[Evidence level $^ { 1 + + ] }$ G-CSF is known to cross the placenta, but no adverse effects are seen in animals with clinically relevant dosing [170]. Two studies,which reviewed the data from the Severe Chronic Neutropenia Internal Registry, reported the safe use of G-CSF in pregnancy outside of a cancer diagnosis [171,172]. There are also small numbers of women included in retrospective studies treated with G-CSF in combination with chemotherapy for various cancers,predominantly breast cancer and lymphomas,where G-CSF has not been associated with fetal harm [173].Furthermore,G-CSF has been studied,as part of a randomised placebo-controlled trial of 150 women,as a potential agent to prevent unexplained recurrent miscarriage.Although the proposed benefits of G-CSF in preventing miscarriage were not proven, there were no significant differences in pregnancy outcome or fetal harm between the G-CSF treated and placebo treated groups [174]. G-CSF should be used in pregnancy for the same indications as in a non-pregnant woman with breast cancer.[Evidence level 2+] 4.2.3.5.8 \| H2 Antagonists. H2 antagonists are often recommended as premedication to reduce risk of hypersensitivity reactions,for example prior to the administration of paclitaxel. Following a UK national shortage of ranitidine in 2o2o,alternative H2 antagonists including cimetidine,famotidine and nizatidine have been used in premedication regimes. The UKTIS advises that the use of H2 antagonists in pregnancy appears to be safe with data from more than 46oo pregnancy exposures, albeit with the majority of this data relating to ranitidine administration.Increased risk of childhood asthma following maternal exposure to H2 antagonists has been reported; however,further research has been recommended as present data are not reliable [175]. [Evidence level $^ { 2 + ] }$ Where H2 antagonists are deemed necessary, especially for the premedication of women with known hypersensitivity reactions to SACT, they can be administered in pregnancy. 4.2.3.5.9丨 Antihistamines. Chlorphenamine is recommended as premedication to reduce the risk of associated hypersensitivity reactions,for example prior to the administration of paclitaxel.It may also be administered in the event of a hypersensitivity reaction to any agent.The available data do not indicate that chlorphenamine use in pregnancy is associated with increased rates of congenital malformation [176].Chlorphenamine could be administered for the prevention and treatment of hypersensitivity reactions with SACT in pregnant women undergoing treatment for breast cancer in line with standard treatment protocols.[Evidence level $^ { 2 + }$ 一 Antihistamines may be used in the management of treatmentrelated toxicity where the woman's preference is often for a non-sedating antihistamine.Both cetirizine and loratidine are widely used during pregnancy for the symptomatic relief of allergic conditions [177].[Evidence level 2+] The available evidence regarding the use of fexofenadine has not demonstrated cause for concern,but data are very limited and fexofenadine use should be reserved for cases where other antihistamines have proven ineffective.[Evidence level 4] <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Where a delay in radiotherapy is not expected to adversely impact maternal outcome,</td><td>2++</td><td>B</td><td>There are well-recognised risks associated with fetal exposure to</td></tr><tr><td>it is recommended that adjuvant breast or chest wall radiotherapy is postponed</td><td></td><td></td><td>radiation (data from animal studies, case</td></tr><tr><td>until after the birth of the baby</td><td></td><td></td><td>reports,and survivors of nuclear incidents). The available information on long-term consequences</td></tr></table> 4.2.4l Therapeutic Radiation During Pregnancy <table><tr><td>Recommendation Adjuvant radiotherapy</td><td>Evidence levelStrength</td><td>Rationale for the</td></tr><tr><td>can be considered in specific circumstances (i.e. if risk from omission or delay outweighs harm to the fetus) provided that this is achievable within safe limits ofradiation exposure to the fetus (i.e. below the deterministic</td><td>3 D</td><td>recommendation Successful radiotherapy of breast cancers during pregnancy and birth of healthy children has been reported in case reports/series. Radiotherapy of people who are pregnant with</td></tr><tr><td>threshold). Referral to a specialist centre with suitable expertise should be considered The option of mastectomy versus breast conserving surgery may be considered, if the former will allow omission of, or avoid, unacceptable delay in If the woman is unexpectedly discovered to be pregnant during radiotherapy, they should be informed of the individual risks,so that they can make an informed choice regarding continuation of radiotherapy</td><td>4 GPP 4 D</td><td>breast cancer is possible with fetal doses below the deterministic threshold Randomised studies have shown equivalent outcomes for breast cancer recurrence and survival with breast conserving surgery and radiotherapy versus mastectomy There are well-recognised risks associated with fetal exposure to</td></tr><tr><td>the pregnancy In the metastatic setting, palliative radiotherapy may be indicated for local control of symptomatic disease or to preserve function (e.g. metastatic spinal cord compression)</td><td>4 D</td><td>animal studies, case reports, and survivors of nuclear incidents). The possible effects of radiation include fetal death in the first 2 weeks post conception, congenital malformations up to 8 weeks, and the highest risk of neurodevelopmental delay between 8 and 15 wees of pregnancy. The available information on long term consequences of in utero exposure to radiotherapy is limited Careful discussion is required between the clinical oncologist and the woman regarding the risks and benefits of radiotherapy, with consideration given to the overall prognosis of the woman and the likelihood of the</td></tr></table> It is well-established that the human embryo and fetus are sensitive to ionising radiation at doses greater than O.1 gray (Gy) (equivalent to more than 1000 chest X-rays) [178,179]. This is derived from animal studies,and data from survivors of nuclear incidents such as occurred at Chernobyl. The risks are uncertain between 0.05 and 0.1 Gy and deemed negligible when below 0.05 Gy [180]. [Evidence level $^ { 2 + + ] }$ Significant potential harmful effects of ionising radiation can be summarised into four main categories: pregnancy loss (miscarriage,stillbirth); malformation; growth disturbance; and carcinogenic effects [18l]. The effect of exposure to radiation (for the same given dose) highly depends on the gestational age; the greatest risk for a lethal effect is in the preimplantation stage, whereas the risk of malformations is highest during organogenesis (weeks 3-8) and CNS damage most likely between 8 and 16 weeks of pregnancy [181,182]. [Evidence level $2 + + ]$ Broadly,radiation effects are expressed as being either deterministic or stochastic.Deterministic effects have a cause and effect relationship,such that below a certain threshold the effect will not occur.However,once the threshold has been crossed, the effect of significance will increase linearly with dose.Stochastic effects represent the radiation effects that may occur by chance (i.e.,no threshold dose) [183].[Evidence level $^ { 2 + + ] }$ Successful radiotherapy for breast cancers during pregnancy and birth of healthy offspring have been reported,but information on long-term sequelae of in utero exposure to radiotherapy is limited [88].Advanced radiotherapy techniques may be less effective at minimising radiation dose to healthy maternal and fetal tissue.This is because of the low dose exposure to normal tissues outside the breast, generated by intensity-modulated radiotherapy or volumetric-modulated arc therapy.Therefore,conventional radiotherapy techniques are favoured.Additionally, imaging during radiotherapy is used to verify treatment position and can result in additional dose to the fetus [182]. Orthogonal kilovoltage instead of CT (megavoltage) imaging is preferred as this uses lower beam energies and provides the lowest additional peripheral dose [182,183].[Evidence level 2+] During breast irradiation,the most critical factors determining the fetal dose are the field size and distance from the radiation field.Radiotherapy delivery during pregnancy requires input from the physicist to determine fetal dose and to achieve adequate shielding (a total of 4-5 half value layers.A half value layer is defined as the thickness of the material required to attenuate the radiation beam by half). This can reduce the dose to the fetus by $5 0 \% - 7 5 \%$ [182]. Commercial planning systems are very precise in estimating dose within the treatment volume,but underestimate the peripheral dose.Therefore,additional measures such as the use of dedicated software,a phantom model and/or in vivo dosimetry using thermo-luminescent dosimeters (TLD) to monitor actual fetal exposure should be used [182]. [Evidence level 3] It is important for a physicist to calculate the fetal radiation dose,and modifications to the treatment plan such as changing the field size,angle,and radiation energy should be considered where possible.Treatment plan documentation should include estimation of the fetal dose.The principle is that fetal dose should be“as lowas reasonably achievable”as the effects of radiation are linearly cumulative.In practice,even though the fetus is excluded from the direct radiation field,exposure occurs via radiation leaking from the accelerator and collimator scatter. Planning treatment requires a close discussion between radiation oncologists,medical physicists,and dosimetrists.Maternal and fetal consequences of treatment with and without radiation should be carefully discussed with the woman to enable informed consent.[Evidence level 3] Fetal exposure increases exponentially with gestational stage as the distance between the radiation field edge and uterine fundus narrows.Therefore, it is important to evaluate the expected change in fundal height during radiotherapy while calculating the fetal dose [184]. In the first l2 weeks of a singleton gestation, the uterine fundus remains within the pelvis,and by 20weeks reaches the umbilicus.Therefore,there is a theoretical window in the first,or early part of the second trimester for breast radiotherapy to be delivered safely.For example, when giving breast or chest wall radiotherapy during early pregnancy, the fetus will be exposed to $0 . 1 \% - 0 . 3 \%$ of the total dose (0.05-0.15 Gy with a prescription dose of 50 Gy equivalent) [180]. Hypofractionated radiotherapy (e.g.,26Gy in five fractions as per FAST-FORWARD trial) [185] has been shown to be noninferior to the standard $4 0 \mathrm { G y }$ in 15 fractions schedule,and is therefore applicable in these women.Towards the latter stages of pregnancy, the dose to the fetus could exceed 2Gy.Hershman et al. [186] showed that it is safe to delay adjuvant radiotherapy for up to l2 weeks following breast conserving surgery, without impacting on overall or cancer-specific mortality.Therefore in the last trimester, it is reasonable to delay radiotherapy until after birth [180].[Evidence level 4] More recently, there has been interest on the role of proton therapy in reducing the out of field dose compared with traditional photon therapy,for which there is evidence of benefit in the management of CNS tumours.Furthermore,with the use of pencil beam scanning,a 3o-fold decrease in dose to the fetus has been demonstrated compared with photon therapy with all shielding in place.An additional benefit of proton therapy in this respect is that no shielding is necessary when using pristine pencil beams [186,187].This is an area of research which can be used to model this more specifically in women with breast cancer. 4.2.5\| Termination of Pregnancy <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Women diagnosed with breast cancer during pregnancy should have all treatment options discussed and the</td><td>4</td><td>GPP</td><td>All treatment options must be fully discussed with the woman. Women should be</td></tr><tr><td>implications of terminating or continuing with their pregnancy to allow informed decision making</td><td></td><td></td><td>supported in their decision making</td></tr></table> It is important that women diagnosed with breast cancer during their pregnancy make informed decisions about all available options and are supported in their decision making.The decision to continue or end a pregnancy must be a personal one.Women should be reassured that the prognosis for women diagnosed with breast cancer during pregnancy is similar to that of a nonpregnant women (see Section 4.1),and that termination does not appear to improve outcomes [188]. [Evidence level 3] Furthermore,for women with early breast cancer, surgery can be performed throughout pregnancy and chemotherapy from the second trimester.Where treatments cannot be given during pregnancy, such as trastuzumab and pertuzumab, the implications (or otherwise) of any delay in therapy should be discussed to allow informed decision making. The diagnosis of metastatic breast cancer during pregnancy is uncommon.Treatments that may be urgently needed, such as radiotherapy for imminent spinal cord compression,can be challenging to deliver during pregnancy.As with early breast cancer, all treatment options and their implications should be discussed, including the impact of not administering the treatment on the woman's prognosis against the risk of fetal complications if generally contraindication treatments are administered.The option of termination (or preterm birth) to allow for optimal oncological treatment should also be part of these discussions. 4.2.6l Care During Pregnancy <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for recommendation</td></tr><tr><td>Women with PrBC can be reassured that their breast cancer can be treated during pregnancy without long-term harm to</td><td>1+</td><td>A</td><td>A prospective assessment of children born to women with PrBC showed normal infant development until 36 months</td></tr><tr><td>their unborn child Women with PrBC should have monitoring to identify FGR from 28+0 weeks of gestation and</td><td>2+</td><td>B</td><td>An international multicentre prospective assessment of children born to women with PrBC showed increased risk of FGR</td></tr><tr><td>thereafter according to clinical need Iatrogenic preterm birth should be avoided unless there are clear maternal or fetal indications</td><td>1+</td><td>A</td><td>An international multicentre prospective assessment of children born to women with PrBC showed that impaired cognitive development was</td></tr></table> <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for recommendation</td></tr><tr><td>In the absence of established lymphoedema, in</td><td>2+</td><td>C</td><td>There is no evidence that medical procedures on the surgical side increase</td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td>women who have had any previous</td><td></td><td></td><td> the risk of lymphoedema</td></tr><tr><td> axillary surgery</td><td></td><td></td><td></td></tr><tr><td>medical procedures</td><td></td><td></td><td></td></tr><tr><td>(including blood</td><td></td><td></td><td></td></tr><tr><td> tests, cannulation</td><td></td><td></td><td></td></tr><tr><td>and blood pressure</td><td></td><td></td><td></td></tr><tr><td>measurements) can</td><td></td><td></td><td></td></tr><tr><td>be performed on the</td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td> side of surgery if the</td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td> contralateral arm is</td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td> unsuitable for use</td><td></td><td></td><td></td></tr></table> Women with PABC tend to be older and preterm births occur more commonly (OR 4.84; $9 5 \%$ CI 4.05-5.79) [122]. The risk of spontaneous preterm rupture of membranes was also increased and may have contributed to preterm birth (OR 1.79, $9 5 \%$ CI 1.06-3.05) [122].Another cohort of 122 women with PABC showed that babies were more likely to be born of low birthweight (aOR 8.88; $9 5 \%$ CI 5.87-13.43) and preterm (aOR 12.93, $9 5 \%$ CI 8.97-18.64) [189]. Preterm birth was usually by induction of labour (aOR 4.40; $9 5 \%$ CI 2.63-7.38) or by caesarean (aOR 2.46; $9 5 \%$ CI1.57-3.86) compared with women without cancer [189].In this study,the indication for preterm birth was unclear. In a separate study, birthweight was below the 10th centile in 28/127 $( 2 2 \% )$ children from women with breast cancer compared with 19/125 $( 1 5 \% )$ of children from a control group [19o]. Reassuringly, gestational hypertension and diabetes were no more common in women with PABC [189]. [Evidence level 2-] Women who have had previous axillary lymph node surgery have a risk of subsequent lymphoedema.For women who do not have established lymphoedema there is not good evidence that medical procedures (including blood tests,cannulation and blood pressure testing) increase the risk of lymphoedema development [87].Where the non-affected arm is unsuitable for use,medical procedures can be performed on the affected side. [Evidence level 2+] Breast cancer,chemotherapy and pregnancy itself are all risk factors for venous thrombosis.Thromboprophylaxis with lowmolecular-weight heparin or equivalent should be administered in accordance with RCOG Green-top Guideline No.37a [79]. [Evidence level $^ { 2 + + ] }$ Both pregnancy and immunosuppression from chemotherapy are deemed clinical risk factors for adverse outcomes from influenza and COvID-19,and immunisation is advised for the affected individual and their household contacts in accordance with the recommendations from the UK Health Security Agency Green Book [191]. [Evidence level $^ { 2 + + ] }$ PrBC,with or without treatment,has shown no negative effects on infant cardiac or cognitive development in infants aged 18 and 36 months [19o]. Only preterm birth,independently of cancer treatment, was correlated with impaired cognitive development [19o]. [Evidence level 2+] # 4.2.7丨 Timing of Birth 4.2.8\| Metastatic Breast Cancer Diagnosed During Pregnancy <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>A date for birth should be jointly planned by the MDT and the woman. This date should be kept under review and adjusted according to maternal and fetal wellbeing</td><td>4</td><td>GPP</td><td>Pragmatic clinical management. The MDT should include, for example,a breast oncologist and surgeon, obstetrician/ obstetric physician/</td></tr><tr><td>Women with breast cancer should aim to give birth at term (after 37+0 weeks)</td><td>2+</td><td>B</td><td>This gives the best outcome for the fetus without compromising maternal wellbeing</td></tr><tr><td>If preterm birth is indicated, corticosteroids for fetal lung maturation can be given as usual in addition to previously administered steroids</td><td></td><td></td><td>This is a standard of care and additional steroids would not be considered harmful</td></tr><tr><td>planned a minimum of 2-3 weeks after the last dose of chemotherapy to reduce the risk of fetal and maternal myelosuppression</td><td></td><td></td><td>effect on both the woman and fetus and therefore adequate time for bone marrow recovery prior to birth is advisable</td></tr></table> The timing of birth for women with breast cancer must balance maternal benefits from optimal treatment following birth, with fetal toxicity from maternal treatment and neonatal harm from prematurity. Preterm birth causes short and long term neonatal morbidity directly correlated with gestational age at birth [190,192],and birth after 37weeks of pregnancy should be the aim where possible.Judicious treatment of breast cancer during the second and third trimesters usually makes this aim achievable (see Section 4.2.3). The decision for timing of birth ina woman with breast cancer must therefore consider multiple issues across different disciplines and exemplifies the need for a MDT, which should include a breast oncologist and surgeon, obstetrician/obstetric physician and neonatologist. [Evidence level 4] Once a treatment plan during pregnancy has been implemented, an interval of 2-3weeks between chemotherapy and planned birth is recommended to reduce the risk of peripartum haematological toxicity for woman and neonate [lo6] (see Section 4.2.3). [Evidence level 4] <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>For women with metastatic breast cancer requiring palliative care,</td><td>4</td><td>GPP</td><td>The pregnant woman is the clinician's primary patient and a decision on timing of childbirth</td></tr><tr><td>late preterm birth (34-37 weeks) may be discussed</td><td></td><td></td><td>should be in her best medical interest, while</td></tr><tr><td></td><td></td><td></td><td>also considering the long term benefits of continued pregnancy for the healthy</td></tr></table> Most breast cancers diagnosed in pregnancy are localised to the breast and women will receive treatment intended to be curative.The diagnosis of metastatic breast cancer during pregnancy is rare.The aim of treatment in metastatic breast cancer is to prolong survival,maintain quality-of-life and to palliate symptoms.Median overall survival for a woman with newly-diagnosed metastatic breast cancer ranges from around 15 months for triple negative breast cancer to around 4years for ER+/HER2 negative and HER2 positive cohorts [193].For a pregnant woman with newly-diagnosed metastatic disease the stage of the pregnancy, the urgency of the indication for treatment for the maternal cancer,and modality of that treatment are important considerations,as well as the woman's desire to continue with,or to consider termination of, her pregnancy.A multidisciplinary approach is needed to plan and discuss all treatment options and their implications for both the woman and the fetus.Overall,although metastatic breast cancer is incurable and available data suggest that pregnancy itself does not appear to adversely influence breast cancer prognosis (see Section 4.1), some treatments are challenging to give in pregnancy,or at certain trimesters in pregnancy (see Section 4).As with early breast cancer, the optimal treatment for the woman should be determined, followed by consideration of what adaptations can be made to that therapeutic plan because of the pregnancy. Where the woman's health is of immediate concern, therapies that are normally advised against in pregnancy may need to be considered.These include consideration of short duration HER2-targeted therapy to maximise response rates in HER2 positive cancer,use of bisphosphonates in malignant hypercalcaemia,and radiotherapy to manage impending cord compression or fracture and brain metastases.[Evidence level 4] 4.3\| Long-Term Paediatric Outcomes After a Maternal Diagnosis of Breast Cancer During Pregnancy <table><tr><td>Recommendation Women undergoing</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>treatment for breast cancer during pregnancy should be reassured that paediatric outcomes after maternal treatment automated auditory</td><td>2+</td><td>B</td><td>Case-control studies have shown that exposure in utero to maternal cancer and its treatment does not impair development in childhood</td></tr><tr><td>for cancer in pregnancy are good Newborns exposed to platinum agents in utero should undergo the</td><td>4</td><td>GPP</td><td>Children exposed to platinum agents risk ototoxicity which may not be identified by otoacoustic emission</td></tr></table> Optimal fetal development is multifactorial. For women diagnosed with breast cancer during their pregnancy,factors such as diagnostic tests,cancer therapies,maternal illnesses and higher levels of maternal stress [194] all have the potential to impact on outcomes of children born to women with a diagnosis of breast cancer during their pregnancy [195]. A multicentre case-control study compared 129 children of women who were diagnosed with cancer during pregnancy with matched children of women without cancer [19o].The children were prospectively assessed for general and cardiac health measures,development using Bayley Scales of Infant Development and neurological function at 18,36 months and subsequently every 3years.The study found that,with a median follow-up of 22 months,prenatal exposure to maternal cancer,with or without treatment, did not impact general development,cardiac or cognitive function.Consistent with studies of children born to women without cancer [196,197], prematurity across both exposed and control groups,did correlate with a worse cognitive outcome. Six-year follow-up of the cohort identified that children prenatally exposed to maternal cancer had lower verbal IQ and visuospatial long-term memory scores, and higher diastolic blood pressures than matched controls [198]. Verbal IQ was more affected in children whose mothers had died,highlighting the need for additional support for these children.At 9years of age cognitive and behavioural outcomes of the children exposed to cancer in utero did not differ from normal population ranges [l99]. There was no difference in Full-Scale Intelligence Quotient (FSIQ) with exposure to chemotherapy nor type of chemotherapy.FSIQ continued to be adversely affected by preterm birth,maternal death and was also by maternal education level.A systematic review, published in 2020,of 17 studies exploring the impact of prenatal exposure to chemotherapy found no major consequences on the long term neurodevelopmental outcome of children after prenatal exposure to chemotherapy [2oo].Despite the reassurances these studies provide, there remains a paucity of data and more research is needed.[Evidence level $^ { 2 + }$ 一 The platinum agent carboplatin is increasingly used as part of chemotherapy regimens for women diagnosed with triple negative breast cancer. Children treated with platinum agents, particularly cisplatin or high doses of carboplatin (more than $1 5 0 0 \mathrm { m g / m } ^ { 2 } ,$ ）are at risk of ototoxicity [20l].A registry study of childhood hearing loss after in utero exposure to platinum agents identified hearing loss in three of 16 children exposed to cisplatin and one of 13 exposed to carboplatin; 264 children exposed to other chemotherapy drugs experienced no ototoxicity [202]. Of note,the three cisplatin-exposed children passed standard newborn audiometry testing,and diagnosis required auditory brainstem response testing.[Evidence level 3] # 5丨Future Fertility Considerations 5.1\| Impact of Systemic Therapy for Breast Cancer on Fertility <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Women of childbearing potential with a</td><td>2++</td><td>B</td><td>Chemotherapy reduces ovarian reserve, whereas endocrine therapy</td></tr><tr><td>new diagnosis of breast cancer should</td><td></td><td></td><td>indirectly impairs fertility need to make informed</td></tr><tr><td>be counselled, at diagnosis, about the potential impact of systemic therapy on</td><td></td><td></td><td>because of the time on treatment. Women with breast cancer</td></tr></table> In women, germ cells are non-proliferative.Chemotherapy reduces ovarian reserve by destroying the primordial and growing follicles within the ovary,accelerating the aging process. The degree of gonadotoxicity seen is dependent on the type of chemotherapy used,the dose and duration of chemotherapy, and the age and pretreatment fertility of the woman [203]. Quantification of the actual risk to fertility with chemotherapy is difficult; most data come from published studies using surrogate markers,such as amenorrhoea and ovarian reserve assessments,rather than the standard definition of delay in conceiving after lyear of regular,unprotected intercourse. This makes counselling women about their exact fertility risk with a given regimen extremely challenging.Nevertheless, it is clear that all the standard (neo)adjuvant chemotherapy agents used in breast cancer are known to have an impact on fertility. Alkylating agents, such as cyclophosphamide,are a standard component of most regimens.Cyclophosphamide is one of the most studied agents in relation to fertility and carries a high risk of amenorrhoea,with six cycles of CMF or 5-fluorouracil/ epirubicin/cyclophosphamide (FEC) causing an intermediate risk $2 0 \% - 8 0 \%$ risk of permanent amenorrhoea in a women aged 30-39),and a lower risk (less than $2 0 \%$ )in women under 30 [203]. Data on the impact of taxanes on fertility are conflicting,although a meta-analysis of studies looking at ovarian function recovery (most frequently by menses recovery) concluded that the addition of taxane to an anthracyclinebased regimen adversely affected ovarian function recovery [204].This is consistent with a study of ovarian reserve,as assessed by anti-Mullerian hormone levels,in 50 premenopausal women undergoing adjuvant chemotherapy for breast cancer in which taxane-containing regimens showed increased gonadotoxicity [205]. [Evidence level 2-] All women who are considering chemotherapy for early breast cancer should be counselled about the possible gonadotoxic risk of that chemotherapy in order to allow them to make informed decisions about their treatment. Options to minimise the impact on fertility by selection of a less gonadotoxic regimen are somewhat limited,as a deviation from a standard anthracyclinetaxane regimen would,in general, be associated with a loss of efficacy against the cancer itself.However,as cumulative dose and duration of chemotherapy are both implicated in gonadotoxicity [203],where a six- to eight-cycle regimen is an accepted standard,using six cycles rather than eight may have a lesser impact on fertility [206].Likewise,for low risk HER2 positive breast cancer,l2weeks of paclitaxel and trastuzumab is now an acceptable alternative to standard anthracycline-taxane based regimens [2o7] and appears to result in lower rates of amenorrhoea [208]. [Evidence level 2-] There is limited evidence of the risk of fertility impairment with the use of anti-HER2 therapies.The addition of trastuzumab to a standard anthracycline-taxane based regimen does not appear to increase the rate of treatment-induced amenorrhoea [209,210]. [Evidence level 2-] Endocrine therapy with tamoxifen does not appear to affect ovarian reserve.Several studies have shown no effect of tamoxifen on anti-Müllerian hormone levels [211-2l3]. Many premenopausal women on tamoxifen will not menstruate; the mechanism behind this is incompletely understood but may relate to increased plasma oestrogen levels and consequent impact on the hypothalamic-pituitary-ovarian axis [214].Endocrine therapy is,however, taken for 5-l0 years during which time a woman's fertility would be expected to decline.[Evidence level 2+] # 5.2\| Fertility Preservation After a Diagnosis of Breast Cancer The likelihood of women achieving a first pregnancy after a diagnosis of breast cancer has improved over the last 2oyears but remains approximately $4 0 \%$ lower than those without disease [215]. This is partly explained by chemotherapy-induced gonadotoxicity following treatment with alkylating agents such as cyclophosphamide,and partly because of reduced ovarian reserve in women over 35 years.However it may also be because of the reluctance of women and their clinicians to consider a pregnancy after breast cancer, wrongly believing that pregnancy may adversely affect prognosis.[Evidence level 2-] 5.2.1\| Cryopreservation <table><tr><td>Recommendation At diagnosis, the impact</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>of breast cancer diagnosis and its treatment on future fertility should be discussed between the affected woman, their cancer team and the reproductive medicine service who should take into account maternal age, treatment plan, prognosis of the cancer and expected outcome of subsequent fertility treatment</td><td>4</td><td>GPP</td><td>Input from multiple specialists will provide women with information for informed decision making</td></tr><tr><td>All women who have not completed their family should, at diagnosis, be offered the opportunity to meet with a reproductive medicine specialist Women of reproductive age who are being</td><td>4 2+</td><td>GPP C</td><td>NICE clinical guideline [CG156] recognises the particular circumstances around a diagnosis of cancer and its effect on fertility (nice.org.uk/ guidance/CG156)</td></tr><tr><td>considered for medical treatment for breast cancer that may cause premature ovarian insufficiency (POI) should be offered oocyte or embryo cryopreservation as appropriate</td><td></td><td></td><td>There is substantial evidence outside of oncology that this is the optimal way to maximise future fertility</td></tr></table> Cryopreservation of embryos or OocYTEs is established as the best method for preserving female fertility before gonadotoxic chemotherapy [216]. Controlled ovarian stimulation (COS),which is an essential part ofin vitro fertilisation (IVF),causes supraphysiological levels of estradiol. Concerns have been raised that COSinduced excess estradiol levels may promote proliferation of breast cancer cells in women with a recent diagnosis of breast cancer. Reassuringly,when COS is carried out with co-administration of an aromatase inhibitor,letrozole,peak estradiol levels are reduced compared with conventional COS protocols without affecting oocyte yield [2l7].A meta-analysis of case-control or cohort studies of 1594 women with breast cancer who underwent COS found no detrimental effect on either risk of recurrence (RR 0.58; $9 5 \%$ CI 0.46-73) or mortality (RR 0.54; $9 5 \%$ CI 0.38-0.76) compared with women who did not undergo fertility preservation,even among patients with ER-positive breast cancer. Furthermore,in a nonbreast cancer population,a nationwide register-based cohort study,published in 2Ol7,reported no increased incidence of breast cancer in women who received ovarian stimulation as part of assisted reproduction [218]. [Evidence level 2-] Fertility before gonadotoxic treatment can also be preserved by cryopreservation of ovarian tissue [216]. The process is still being developed,but in general involves laparoscopic removal of an ovary or part of an ovary,cryopreservation until recovery from chemotherapy, then auto-transplantation back into a Woman planning pregnancy [216]. Results are promising,with almost two-thirds of cases having restored ovarian function and around $5 0 \%$ resulting in live births [219].However, the process is still being optimised and is not routinely available on the NHS. [Evidence level 2-] It is vital that women who have not yet completed their family are referred to fertility services at diagnosis by the surgical units,even if the treatment decisions about the need for chemotherapy have not yetbeen made.COS,even with‘fast start'protocols,will take a couple of weeks [2l6] and this early referral will minimise delays to starting systemic therapy.A short delay of this extent in starting chemotherapy is not expected to affect outcomes. [Evidence level 4] Comprehensive guidance for fertility specialists and breast cancer teams working to preserve female fertility before chemotherapy can also be found in NICE Clinical Guideline [CG 156] [220] and the European Society of Human Reproduction and Fertility (ESHRE) guideline [221]. 5.2.2丨 What Is the Role of Gonadotrophin-Releasing Hormone Analogues as Fertility Preservation During Chemotherapy? <table><tr><td>Recommendation Premenopausal women</td><td>Evidence level 1-</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>undergoing (neo)adjuvant chemotherapy for breast cancer and who are interested in fertility preservation should be offered temporary ovarian suppression with a gonadotrophin-releasing hormone (GnRH) agonist during their chemotherapy Fertility preservation with</td><td></td><td>A</td><td>A meta-analysis of randomised trials has shown that GnRH agonists reduce the likelihood of chemotherapy- induced POI. The trials were not however designed to assess pregnancy as</td></tr><tr><td>GnRH agonists should commence, where possible, at least 1 week prior to the first dose of chemotherapy and continue for the</td><td>4</td><td>A GPP</td><td>a primary endpoint The majority of trials investigating the use of GnRH agonists as fertility preservation, commenced dosing at least 1 week before chemotherapy Oocyte or embryo cryopreservation</td></tr><tr><td>duration of treatment Fertility preservation with GnRH agonists should not be offered as an alternative to oocyte or embryo cryopreservation, but should be offered to all regardless of whether or not they are having oocyte/ embryo cryopreservation</td><td></td><td></td><td>remains the most effective option for fertility preservation</td></tr></table> A systematic review and meta-analysis of patient-level data of 873 women from five trials demonstrated that the co-administration of GnRH agonist with (neo)adjuvant chemotherapy was significantly associated with a reduced risk of POI and higher pregnancy rates. The POI rate was $1 4 . 1 \%$ in the GnRH agonist group compared with $3 0 . 9 \%$ in the control group (OR 0.38; $9 5 \%$ CI 0.26-0.57; $p { < } 0 . 0 0 1 $ ,with37 $( 1 0 . 3 \% )$ pregnancies in the treated group compared with 20 $( 5 . 5 \% )$ in the control group (incidence rate ratio 1.83; $9 5 \%$ CI 10.06-3.15; $p { = } 0 . 0 3 0 $ ）[222].The studies were not, however, powered to address pregnancy as a primary endpoint; nor were data captured on the participants' intent to become pregnant after treatment.[Evidence level 2-] Importantly,no differences were seen in either disease-free or overall survival with the use of GnRH agonist in either $\mathrm { E R + }$ or ER- disease.Further reassuring data for the safety of this approach in women with $\mathrm { E R + }$ breast cancer come from a retrospective analysis of the Suppression of Ovarian Function Trial (SOFT)and Tamoxifen and Exemestane Trial(TEXT),in which the concurrent use of GnRH agonist and chemotherapy had no detrimental effect on disease outcomes [223]. [Evidence level 1-] # 5.3\| Contraception After a Diagnosis of Breast Cancer <table><tr><td>Recommendation Women undergoing</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>systemic therapy for breast cancer should be advised to use contraception Women who have</td><td>4 4</td><td>GPP GPP</td><td>All systemic therapy for breast cancer is contraindicated prior to conception and in the first trimester because of the risk of fetal anomalies Hormonal-based</td></tr><tr><td>a history of breast cancer should be advised to use non-hormonal contraception Women who</td><td>4</td><td>GPP</td><td>contraception may increase the risk of recurrence, and non- hormonal approaches should be used if at all possible</td></tr><tr><td>have a history of breast cancer who require emergency contraception can be offered hormonal contraception</td><td></td><td></td><td>A single dose of hormones is very unlikely to have any effect on breast cancer recurrence</td></tr></table> # 5.3.1丨 Hormonal Contraception and the Risk of Breast Cancer Women who currently or have recently used hormonal contraceptives have been shown to be at increased risk of breast cancer (RR 1.20; $9 5 \%$ CI1.14-1.26), rising with each year of use [224]. The absolute risk was one extra case of breast cancer for every 7690 women who used hormonal contraception for lyear. The levonorgestrel intrauterine system is also associated with a higher risk of breast cancer (RR 1.21; $9 5 \%$ CI 1.11-1.33) [224]. [Evidence level $^ { 2 + + ] }$ （204 # 5.3.2\| Contraception After Breast Cancer Approximately $1 3 \%$ of breast cancer in Europe is in premenopausal women (less than 45 years). Contraceptive counselling should form an important part of the care for premenopausal women with breast cancer [225]. The ideal contraception for women with breast cancer is nonhormonal. Safe options include the copper intrauterine device (IUD) [226].The risk of infection associated with chemotherapy is not a contraindication to use of the copper IUD [226]. Other contraceptive options include two simultaneous forms of barrier contraceptive,orif future pregnancy is not desired,sterilisation of the woman or her partner. While small studies do not show an increased risk of recurrence with the levonorgestrel intrauterine system [227], there is insufficient evidence to confirm that this device is safe aftera previous diagnosis of breast cancer,even in women with an ER-cancer,who may be at risk ofa new $\mathrm { E R + }$ cancer.For the rare circumstance where there are no suitable non-hormonal options,input from the women's breast specialist team should be sought prior to use of a progestogen intrauterine device.[Evidence level 4] Emergency hormonal contraception is not contraindicated in women with a history of breast cancer 228]. 5.4\| Preimplantation Genetic Diagnosis for Familial Breast Cancer <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Women who carry</td><td>4</td><td>GPP</td><td> This is in line</td></tr><tr><td>pathogenic genes associated with</td><td></td><td></td><td> with UK Human</td></tr><tr><td>breast cancer</td><td></td><td></td><td>Fertilisation</td></tr><tr><td> should be offered</td><td></td><td></td><td> and Embryology</td></tr><tr><td> preimplantation</td><td></td><td></td><td>Authority guidance</td></tr><tr><td> genetic testing for a</td><td></td><td></td><td>and based on the</td></tr><tr><td> monogenic disorder</td><td></td><td></td><td>woman's preference</td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td>(PGT-M) following</td><td></td><td></td><td></td></tr><tr><td> counselling about</td><td></td><td></td><td></td></tr><tr><td> the IVF process</td><td></td><td></td><td></td></tr><tr><td> and likelihood of a</td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td> successful pregnancy</td><td></td><td></td><td></td></tr><tr><td>outcome</td><td></td><td></td><td></td></tr></table> Women who develop breast cancer during their reproductive years,or who have a family history of breast cancer,are more likely than older women to carry a genetic predisposition to cancer [229]. Pathological gene variants in the autosomal dominant BRCA1 and BRCA2 tumour suppressor genes are the most common and well-known genes accounting for approximately $1 0 \%$ of breast cancer in women younger than 39 years [230].Breast cancer incidences increase rapidly in early adulthood until 30-40years of age for carriers of BRCA1 and until 40-50years for BRCA2 carriers then remain constant [231].By 80years, the cumulative breast cancer risk is $7 2 \%$ 0 $9 5 \%$ CI $6 5 \text{‰}$ $7 9 \%$ )forBRCA1 and $6 9 \%$ 0 $9 5 \%$ CI $6 1 \% - 7 7 \%$ )forBRCA2carriers [231].For this reason, screening tools have been developed to identify women at risk of inheriting a gene variant associated with breast cancer 229]. Other rarer pathogenic variants have also been identified in families with a high incidence of breast cancer [232,233].These include tumour protein 53 (TP53),inherited as the Li-Fraumeni syndrome,PTEN gene as partof Cowden's syndrome and PALB2 genes [232, 234].Improvements in the accuracy and accessibility of gene panel testing now allows a search for these genes in families with a high incidence of breast cancer. Women who carry breast-cancer associated genes can avoid passing them on to their offspring through PGT-M,previously known as preimplantation genetic diagnosis (PGD).PGT-M involves COS,collection of oocytes and IVF.Despite early concerns,women who carry the BRCA gene variants appear to have normal ovarian response to IVF cycles [235].After a period in culture,acell is removed from each viable embryo and tested for the putative gene. Only embryos without the gene variant are selected for subsequent embryo transfer.PGT-M is therefore a selection process which on average will result in $5 0 \%$ of autosomal dominant BRCA embryos being discarded [216]. Furthermore, less than $4 0 \%$ of these IVF cycles results in a healthy live born baby [236].[Evidence level 2-] In the UK,most IVF centres offer PGT-M for women with an inherited risk of breast cancer.The Human Fertilisation and Embryology Authority currently support PGT-M for the BRCA1/2,TP53,PTEN and PALB2 genes [237]. # 6\| What Are the Considerations for Subsequent Pregnancies After a Diagnosis of Breast Cancer? 6.1\| Impact of Pregnancy on Breast Cancer Survival <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Women with a history of early breast cancer who wish to become pregnant should be advised that</td><td>2++</td><td>B</td><td>It is important that women make informed decisions about their choices</td></tr></table> There have been concerns that in women with a history of breast cancer,even after all adjuvant therapies had been completed, any future pregnancy could lead to an increased risk of recurrence.However, this concern has not been borne out by data.A meta-analysis of 14 studies [238] involving l244 cases of women who became pregnant after a diagnosis of breast cancer, compared with 18 145 controls matched for a breast cancer diagnosis and who did not become pregnant, reported that the women who became pregnant had a $4 1 \%$ reduced risk of death compared with those women who did not (RR 0.59; $9 0 \%$ CI 0.50-0.70). The survival advantage may in part be attributable to selection bias, i.e.,a‘healthy mother effect',whereby women well enough to attempt pregnancy are a self-selecting group.The meta-analysis does, nevertheless,provide reassuring data that pregnancy after early breast cancer is a reasonable choice.[Evidence level $^ { 2 + + ] }$ A more recent study aimed to assess the impact of pregnancy on breast cancer survival by ER status.In this multicentre retrospective cohort study,333 women with a pregnancy after a breast cancer diagnosis were matched with 874 non-pregnant controls.After a median follow-up of 7.2years no difference in overall survival was seen in the $\mathrm { E R + }$ $+ \left( \mathrm { H R } 0 . 8 4 , 9 5 \% \mathrm { C I } 0 . 6 0 \mathrm { - } 1 . 1 8 ; \right.$ $p { = } 0 . 3 2 )$ or ER- (HR 0.57, $9 5 \%$ CI $0 . 3 6 - 0 . 9 0 \ p = 0 . 0 1 _ { , }$ ）cohorts [239].The termination of pregnancy rate in this [239],and other studies [240, 24l],was high (at approximately $3 0 \%$ ),which may reflect clinicians'and women's concerns of a detrimental effect of pregnancy on breast cancer survival—concerns which are not borne out by the published data.[Evidence $^ { 2 + ] }$ # 6.2\| Timing of Subsequent Pregnancies After a Diagnosis of Breast Cancer The optimal timing of pregnancy after breast cancer remains uncertain. Two studies have shown a non-significant increased risk of recurrence across 6O pregnancies within 6 months [240] and 12 months [24l] after diagnosis.Data from the metaanalysis of 14 studies investigating pregnancy after breast cancer found that pregnancy within 6-24months after diagnosis or beyond showed no reduction in survival with a pregnancy [238]. Similar results were seen in a more recent cohort study of 7553 women diagnosed between 20o3 and 20l4,in which 196 women with pregnancy 6months or more after diagnosis had a 5-year actuarial survival rate of $9 6 . 7 \%$ $\% \left( 9 5 \% \mathrm { C I } 9 4 . 1 \% - 9 9 . 3 \% \right)$ versus $8 7 . 5 \%$ $9 5 \%$ CI $8 6 . 5 \% - 8 8 . 4 \%$ for women with no pregnancy (age-adjusted hazard ratio 0.22; $9 5 \%$ CI 0.01-0.49; $p { < } 0 . 0 1 $ [242]. Taken as a whole, these studies suggest that timing of a pregnancy after breast cancer does not impact on breast cancer outcome.[Evidence level $^ { 2 + }$ Other considerations pertinent to pregnancy after breast cancer include the woman's age and ovarian reserve, their risk of recurrence and their personal circumstances and wishes.For woman who have been treated with systemic therapy there may be drugrelated safety issues that necessitate delays in pregnancy because of concerns about fetal harm.Women should discontinue tamoxifen 2months prior to conception.This is based on four half-lives of the drug,the standard approach to guide timing of conception after exposure to a toxic drug after which time the drug is considered eliminated [243].Women should not conceive while receiving chemotherapy.Manufacturers also advise a delay of variable intervals of between 6 and 12months after chemotherapy dosing before conception.The data on which this guidance is based are uncertain.For women who have an unplanned pregnancy within a year after completion of chemotherapy, there is no evidence that developmental harm to the embryo will occur.MABs, such as trastuzumab, have slow clearance with sustained post-dosing systemic exposure.The manufacturers recommend women avoid a pregnancy for 7months after the final dose of an anti-HER2 MAB; although as discussed in Section 4.2.3.3,inadvertent short duration exposure in pregnancy is unlikely to be harmful.Women with TNBC treated in the adjuvant setting with pembrolizumab should avoid a pregnancy for at least 4 months after the last treatment dose [244].Prior exposure to the bisphosphonate,zoledronic acid,is not a reason to advise against a subsequent pregnancy, but UKTIS advise that where exposure to bisphosphonates has occurred, either prior to or during pregnancy,monitoring of fetal growth,skeletal development and neonatal calcium levels may be warranted. [Evidence level 4] # 6.3\| Interruption of Endocrine and Other Targeted Therapy <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for the recommendation</td></tr><tr><td>Women planning a pregnancy who are taking adjuvant tamoxifen must discontinue treatment at least 2 months before attempting to conceive</td><td>4</td><td>GPP</td><td>This time is recommended by the manufacturers for adequate washout of tamoxifen and its active metabolites The reduction in risk of</td></tr><tr><td>Any woman receiving endocrine or other targeted therapy and planning a pregnancy should be referred to their oncologist for a discussion regarding their proposed treatment break</td><td>4</td><td>GPP</td><td>breast cancer recurrence from endocrine therapy is individual to the woman, dependent on the primary tumour characteristics. Therefore, their oncologist is best placed to have a discussion regarding the potential loss of treatment efficacy arising from</td></tr></table> Women with an $\mathrm { E R + }$ cancer are recommended adjuvant endocrine therapy for at least 5years,but for up to lOyears in women at higher risk.Five years of adjuvant tamoxifen reduces the risk of death from $\mathrm { E R + }$ breast cancer by $3 0 \%$ [245], with similar gains seen from an additional 5years of therapy [246]. Tamoxifen does not appear to have a direct effect on fertility 247],but during the 5-loyears of therapy a woman's ovarian reserve may fall off substantially owing to natural aging. The POSITIVE (Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer) study is collating outcomes from women who have received adjuvant endocrine therapy for 18-24months and who choose to interrupt that therapy in order to conceive [248]. The first results from this study showed that recurrence rates for women who temporarily interrupted their endocrine therapy to become pregnant were similar to a matched control cohort,with a 3-year incidence of breast cancer events $8 . 9 \%$ in the treatment-interruption group ( $9 5 \%$ Cl $6 . 3 \% \mathrm { - } 1 1 . 6 \% )$ compared with $9 . 2 \%$ in the control cohort [249].Follow-up of the study participants will continue.Women on endocrine therapy who wish to conceive should be given the opportunity to discuss the individual gains from their therapy, using tools such as Predict (breast.predict.cam). Given the established safety of long durations of endocrine therapy, making up any years of therapy missed after a pregnancy attempt is a reasonable approach,although there are no data to suggest this will be of equivalent efficacy to continuous therapy.In addition,an assessment of their fertility and advice on the needs for assisted reproduction can be helpful prior to interrupting endocrine therapy. This planning may enable women wishing to conceive to interrupt their endocrine therapy for as short a time as possible.[Evidence level $^ { 2 + + ] }$ The PARP inhibitor, olaparib,is indicated as an adjuvant treatment for women with a high risk early breast cancer and a germline BRCA1/2 mutation [250].Itis taken orallyfor12 months after completion of chemotherapy and radiotherapy.Abemaciclib,a selective inhibitor of CDKs 4 and 6,is indicated as an adjuvant treatment for women with high risk $\mathrm { E R + }$ HER2 negative early breast cancer and is taken for2years after completion of chemotherapy and radiotherapy [251]. Olaparib needs to be interrupted for 6 months prior to conception [252],and abemaciclib (which is also taken in conjunction with endocrine therapy) for 3 weeks [253].Women considering stopping either drug should have a discussion with their oncologists about the implications of stopping treatment prior to any pregnancy attempt.[Evidence level 4] # 6.4\| Assisted Reproduction After Treatment for Breast Cancer UK and international guidelines recommend fertility preservation at diagnosis prior to starting anti-cancer therapy for all women who have not completed their family. Despite these guidelines,there are little safety data on the use of assisted reproductive technologies (ART) following anti-cancer treatment completion.Four small studies,each with 20-39 women,two with matched-controls [254,255] and two with unmatched controls [256,257] have been published to date.None of the studies showed any detrimental effect on breast cancer recurrences in the women undergoing ART after completion of treatment for breast cancer.[Evidence level 2-] 6.5_\| What Is the Optimal Care in Pregnancy Following Treatment for Breast Cancer? <table><tr><td>Recommendation</td><td>Evidence level</td><td>Strength</td><td>Rationale for recommendation</td></tr><tr><td>Pregnant women who have been treated for breast cancer can be</td><td>1+</td><td>B</td><td>Evidence from mainly retrospective case series</td></tr><tr><td></td><td></td><td></td><td> shows that pregnancy</td></tr><tr><td>reassured that pregnancy will not adversely affect their disease-free survival</td><td></td><td></td><td>following a diagnosis of breast cancer does</td></tr></table> <table><tr><td>Recommendation Pregnant women who</td><td>Evidence level</td><td>Strength</td><td>Rationale for recommendation</td></tr><tr><td>have had chemotherapy for breast cancer should have additional fetal growth scans from 28 weeks (and thereafter according to clinical</td><td>2</td><td>B</td><td>Women who have received chemotherapy have an increased risk of small- for-gestational-age babies</td></tr><tr><td>need) to identify an increased risk of FGR Women who had treatment-related left ventricular dysfunction (LVD) are at risk of heart</td><td>2</td><td>B</td><td>Approximately 30% of women who have chemotherapy-induced cardiotoxicity develop peripartum heart failure</td></tr><tr><td>failure during pregnancy and should be referred for cardiology assessment pre-pregnancy, or as soon as possible during pregnancy Women with no history of treatment-related LVD are</td><td></td><td>GPP</td><td>Women with subclinical heart failure are at risk of becoming symptomatic from 26+0 weeks of</td></tr></table> Breast cancer survivors are less likely to have a subsequent pregnancy compared with the general population (RR 0.40; $9 5 \%$ CI 0.32-0.49) [258]. This may be a consequence of breast cancer being diagnosed relatively late in a woman's reproductive life,gonadotoxic chemotherapy,and prolonged endocrine treatment for those with hormone receptor positive disease. Furthermore,clinicians and their patients may believe that pregnancy adversely affects breast cancer outcomes.This is not the case [242,258].A systematic review and meta-analysis of 1l studies that included 63 968 women with breast cancer, of whom 3387 $( 5 . 3 \% )$ became pregnant, showed no detrimental effect of pregnancy on either disease-free or overall survival [258]. [Evidence level $^ { 2 + + ] }$ Pregnancy outcomes following a diagnosis of breast cancer are generally good.A meta-analysis of nine studies that included almost 5 million women,of whom 3240 became pregnant after a diagnosis of breast cancer, showed a greater risk of small-for-gestational-age (OR 1.16; $9 5 \%$ CI 1.01-1.33), low birthweight (OR 1.50; $9 5 \%$ CI1.31-1.73)and preterm birth (OR 1.45; $9 5 \%$ CI 1.ll-1.88) following a diagnosis of breast cancer [258]. These adverse pregnancy outcomes were more common among women who had received chemotherapy. Following a diagnosis of breast cancer,women were also more likely to have a caesarean birth (OR 1.14; $9 5 \%$ Cl 1.04-1.25), but adverse pregnancy outcomes including risk of miscarriage, fetal anomaly, pre-eclampsia and peripartum haemorrhage were similar to those of women without previous breast cancer [258]. [Evidence level 2-] Women who have had breast cancer treated with anthracyclines (e.g.,epirubicin,doxorubicin) have an increased risk of cardiotoxicity with LVD,which increases further if followed by HER2-directed therapy (e.g., trastuzumab,pertuzumab and trastuzumab-ADCs) [259-26l].However, chemotherapy-induced cardiotoxicity in women younger than 5Oyears of age is rare. This is because of a low incidence of pre-existing hypertension, diabetes,smoking and hyperlipidaemia [259-26l].Anthracyclineinduced cardiotoxicity is also dose-dependent and unlikely to develop in those who receive low dose doxorubicin (less than $2 0 0 \mathrm { m g / }$ $\mathbf { m } ^ { 2 } )$ [259-26l].If it does manifest,almost all cases of cardiotoxicity present within 12 months of treatment [260]. It is these women who are at high risk of developing pregnancy-related heart failure. In one study, $4 / 1 3$ women who developed chemotherapy-induced cardiotoxicity went on to develop pregnancy-related heart failure, whereas all women who did not develop cardiotoxicity following chemotherapy (65/65) remained free of gestational cardiac problems [262].An attenuated gestational increase in cardiac output may also explain the increased risk of FGR and peripartum heart failure following chemotherapy [258,263,264].[Evidence level 3] Women who receive radiotherapy for treatment of breast cancer have a dose-dependent increased risk of ischaemic heart disease that increases over the subsequent 20years [265]. Ischaemic heart disease is rare in pregnant women [266] and despite an aging maternal population, there have been no reports of acute myocardial infarction during pregnancy following left-sided breast radiotherapy. 6.6\| Breastfeeding During and After Treatment for Breast Cancer <table><tr><td>Recommendation Women taking</td><td>Evidence level 3</td><td>Strength D</td><td>Rationale for the recommendation Preclinical studies</td></tr><tr><td>tamoxifen should be advised not to breastfeed</td><td></td><td></td><td>show harmful effects of tamoxifen on urogenital tract development. Clinically significant levels of tamoxifen are present in human breast milk</td></tr><tr><td>Women receiving chemotherapy should be advised not to breastfeed</td><td>2+</td><td>B</td><td>Chemotherapy drugs can be measured in breast milk and could be harmful to the infant Lactation from the</td></tr><tr><td>Women can continue to breastfeed following breast surgery and adjuvant irradiation if they wish to do so</td><td>4</td><td>D</td><td>untreated breast will be unaffected. Milk production and delivery from the treated breast</td></tr><tr><td>Prevention and suppression of lactation can be achieved by administration of oral cabergoline</td><td>1+</td><td>A</td><td>may be attenuated Cabergoline provides rapid, safe inhibition of lactation by decreasing prolactin production</td></tr></table> The literature on caring for women with breast cancer who are pregnant or who are lactating is sparse as these women are frequently excluded from clinical trials,and women are commonly advised to interrupt lactation while on cytotoxic drugs. The importance of breastfeeding in emotional bonding between the woman and infant,and in the infant's cognitive and health development is well-established [267]. # 6.6.1丨 Transfer of Therapeutic Drugs Into Breast Milk A number of breast cancer drugs will pass into breast milk and therefore be transferred to the newborn baby during breastfeeding.Excretion of drugs into milk will depend ona number of factors such as lipid solubility,molecular size and degree of protein binding.However, the most important factor influencing this transfer is the maternal plasma level [268,269]. Involutionary changes seen within breast glandular tissue during the first week and also at cessation of breastfeeding,result in larger gaps between alveolar breast cells permitting greater transfer of medicines from mother to child during lactation [269,270]. 6.6.1.1丨 Tamoxifen. Tamoxifenisaselectiveoestrogen receptor modulator and is part of the standard of care for treatment of premenopausal women with $\mathrm { E R + }$ breast cancer [271]. Women with PABC will be advised to take tamoxifen for 5-loyears depending on tumour histology and local MDT recommendations. Two studies from the 1970s indicated that tamoxifen may inhibit lactation in the puerperium [272, 273]. Tamoxifen can be found in human breast milk within 1day of starting treatment and levels rise until 3 weeks [274]. Similar results are noted for the active metabolites of tamoxifen.As the plasma steady state is not achieved in the woman for 28 days [275],it is possible that levels in breast milk will continue to rise beyond 3weeks.Preclinical studies have shown harmful effects of tamoxifen administered in the neonatal period on urogenital tract development [276].As clinically significant levels of tamoxifen and its active metabolites are present in human milk [274], it is not advisable for women with PrBC to breastfeed while taking tamoxifen.[Evidence level 3] 6.6.1.2丨 Chemotherapeutic Agents. Traditionally, women on cytotoxic drugs have been counselled not to breastfeed because of concerns that these agents could be injurious to the infant and manufacturers in general recommend breastfeeding should cease for the duration of therapy.In many instances there are little data on which to offer evidence-based advice，but small studies have demonstrated that many of the commonly-used chemotherapeutic drugs are excreted into breast milk.Regarding commonly-used drugs,no information of breast milk drug levels are available for either epirubicin or docetaxel.Twice-daily monitoring of milk samples post-chemotherapy for B cell lymphoma found cyclophosphamide levels fell to low levels 1 week after dosing,but toxic metabolites were still present at 2ldays post dosing [277].A similar study with carboplatin found the drug still measurable in breast milk 3l6 hours post dosing[278],and while,in theory, it might be possible to breastfeed intermittently during chemotherapy, in practice the duration of abstinence for chemotherapy drugs is unknown. The US National Institutes of Health Drugs and Lactation Database (LactMed) [279] is an evidence-based resource that provides up-to-date information to guide clinicians about prescribing medicines,including chemotherapy,for women who are lactating. Empirically, chemotherapy is unlikely to have an effect on milk production and if lactation is maintained during treatment by use of breast pumps,breastfeeding could commence several weeks after treatment completion [28o].[Evidence level 2+] 6.6.1.3丨 Monoclonal Antibodies. MABs,such as trastuzumab and pertuzumab,are large protein molecules and it is likely only small amounts will transfer into breast milk,with partial destruction in the infant's gastrointestinal tract.While drug exposure froma woman receivingMAB therapy to a breastfeeding infant may well be minimal, there are no data on which to base useful advice [28l]. The manufacturers advise breastfeeding should discontinue during therapy and for 7months after the last dose.[Evidence level 4] 6.6.1.4丨 Diagnostic Imaging by PET-CT. The International Atomic Energy Agency advise that small amounts of $^ { 1 8 } \mathrm { F }$ -fluorodeoxyglucose is excreted in breast milk [67]. Therefore,if the scan is needed urgently,as in women with PrBC, then it is advisable to collect milk before the scan in order to provide a feed after the scan.Breast milk should be collected and discarded for 2 hours after the scan following which normal breastfeeding may resume [70]. [Evidence level 4] # 6.6.2\| Lactation Following Breast Conserving Surgery and Irradiation There is very little literature examining the effect of breast conserving surgery itself on the ability of women to breastfeed following birth.Almost all publications assess the combined effect of breast conserving surgery and adjuvant radiotherapy. Intuitively, it would be clear to most clinicians and women that surgery which excises or disrupts the subareolar lactiferous ducts/sinuses nipple will potentially impair or negate the ability of the woman to breastfeed from that breast.There are some case reports indicating that circumareolar surgery can prevent breastfeeding [282].Further clues can be obtained from examination of reduction mammoplasty techniques-those which maintain the subareolar paranchyma result in the highest rates of successful postsurgical breastfeeding [283].Therefore, breast conserving surgery to remove cancers near or at the nipple is more likely to impair breastfeeding from that breast,whereas excision of tumours more distant from the nipple areolar complex is less likely to cause an effect. The probability of a previously irradiated breast being able to produce milk depends to a large degree on the delivered radiation dose [284]. Breast conserving surgery followed by adjuvant breast irradiation may induce anatomical distortion,which can limit nipple extension and inhibit latching of the infant to initiate lactation [282].Additionally, breast irradiation invokes histopathological changes within the breast glandular tissue that can disrupt the production and flow of milk from breast alveolar cells to the nipple [284]. Studies examining small numbers of women showed that following radiotherapy,around $8 0 \%$ experienced diminished breast enlargement in the irradiated breast during pregnancy, with reduced postnatal milk production seen in approximately half of the women [285-287].Normal lactation was seen in the untreated breast in almost all cases [286]; and women should be reassured that adequate nutrition for their baby can be provided by feeding from one breast alone. [Evidence level 4] Breastfeeding after breast cancer treatment was evaluated as a secondary endpoint of the POSITIVE trial, which investigated the impact of interrupting adjuvant endocrine therapy in order to attempt a pregnancy [248,249]. Of 317 patients who gave birth,196 $( 6 2 \% )$ women breastfed from the contralateral breast in all but two patients; only 38 $( 1 2 \% )$ breastfed from both breasts. The median duration of breastfeeding was 4.4months [288]. [Evidence level $^ { 2 + + ] }$ # 6.6.3丨 Inhibition of Lactation Cabergoline is a synthetic dopamine D2 agonist,acting on the anterior pituitary gland to decrease synthesis and release of prolactin and hence inhibit lactation.A dose of $1 \mathrm { m g }$ of cabergoline given orally on the first day postpartum inhibits lactation within 1day [289].Where breastfeeding has already commenced,milk production can be stopped by oral administration of 250 micrograms cabergoline 12-hourly for 2days [289,290].Adverse effects include dizziness,headaches and nausea, which occur mainly in the first 3days after intake,but the treatment is generally welltolerated by the majority of women [289].[Evidence level 1+] # 7\|Recommendations for Future Research · Data on the management on breast cancer in pregnancy and subsequent paediatric outcomes are sparse.To facilitate future research,a national database of all women with a diagnosis of breast cancer in pregnancy, to include details of their management and outcomes,should be established as a priority.This database can feed into aligned international projects.The database should clearly discriminate between women with breast cancers diagnosed during pregnancy (PrBC)and women diagnosed with breast cancer in the 5years post pregnancy (PPBC). ·A prospective audit of radiotherapy decision making in women with PrBC (including those with metastatic disease). This will feed into a research project examining safe and effective radiotherapy administration in these women. · The role of proton-beam therapy in women with breast cancer is not established, but may have dosimetric advantages for women who could benefit from radiotherapy during pregnancy. This topic may require a multinational study to achieve a conclusion. · In young women with a previous history of breast cancer, the optimal ART to achieve a pregnancy has not been established.Research into this field could produce valuable results for women wishing to commence a family. <table><tr><td>The time to first breast clinic review for pregnant women following presentation to medical care with a breast lump compared with age-matched non-pregnant women</td><td>Pregnant women with breast symptoms should be seen within the same treatment target times as non-pregnant women</td><td>NHS England Faster diagnostic pathways: implementing a timed breast cancer diagnostic pathway: guidance for local health and social care systems</td><td>100%</td></tr><tr><td>The incidence of haematoma and of lactational fistulae following core biopsy in pregnant and lactating women</td><td>The incidence of these complications in pregnant women is unknown,and because of this there is misconception that core biopsies in pregnant/lactating women lead to complications</td><td>Pregnant women undergoing this diagnostic intervention should have the following outcomes recorded in the medical notes: ·no complication ·post biopsy haematoma · post biopsy lactational fistula</td><td>100%</td></tr><tr><td>Operative choices of pregnant women versus age-matched non-pregnant women corrected for tumour size and preoperative axillary status</td><td>· The surgical choices of pregnant women are poorly recorded · Women may be undergoing mastectomy unnecessarily</td><td>Women undergoing breast cancer surgery while pregnant should have their breast surgery and the gestational age at this breast surgery recorded</td><td>100% Ratesofmervingmy and can then be compared with non-pregnant counterparts using</td></tr><tr><td>Wound complications following mastectomy and pidelocalexcisioinwomenwithPABCandPBCarepooryecoded</td><td>Wound complication rates in women with PABC</td><td>Pregnant women undergoing breast surgery shouldMaplicatidiedby Audi[91 ndJczyk tal[2 rded</td><td>100% Wound complicaion pregnantdwith nons</td></tr><tr><td>Incidence of perioperative deep vein thrombosis following breast surgery in pregnant women</td><td>Women with PABC and PPBC should receive thromboprophylaxis in accordance with RCOG Green-top Guideline No.37a [80]</td><td>Percentage of women with PABC and PPBC who are diagnosed with thromboembolic disease perioperatively</td><td>Incidence rate of <0.5%</td></tr><tr><td>Dosing of chemotherapy</td><td>Women are being underdosed and thus undertreated</td><td>Dosing of chemotherapy should be based on the woman's actual weight, not pre-pregnancy weight. The woman should be reweighed and doses recalculated at each cycle of treatment</td><td>100%</td></tr></table> ·Examination of psychological outcome measures in women with PrBC and PPBC (compared with age-matched controls) could provide information important in the holistic management of this group of women. ·Any database should ideally link maternal exposure to cancer to paediatric data to gain information on long term outcomes following in utero exposure to cancer. # 8丨Auditable Topics Audit of current practice,benchmarked against the above guidance,can provide a valuable lever for change and improvement. Possible topics that could be considered for audit are shown in Table 1. # 9\|Useful Links RCOG patient information Pregnancy and breast cancer Mummy's Star Breast Cancer Now Cancer Research UK Macmillan Cancer Support # References 1.“Cancer Research UK Breast Cancer Survival Statistics,”https:// www.cancerresearchuk.org/health-professional/cancer-statistics/stati stics-by-cancer-type/breast-cancer/survival. 2.L.P.Middleton,M.Amin,K.Gwyn,R.Theriault,andA.Sahin,“Breast Carcinoma in Pregnant Women:Assessment of Clinicopathologic and Immunohistochemical Features,"Cancer 98 (2oo3):1055-1060. 3.Office for National Statistics,“Births in England and Wales:2020,” https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeat hsandmarriages/livebirths/bulletins/birthsummarytablesengland andwales/2020. 4.“MBRRACE-UK:Mothers and Babies: Reducing Risk Through Audits and Confidential Enquiries Across the UK,” Saving Lives, Improving Mothers'Care-Lessons Learned to Inform Maternity Care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2017-19 (2021). 5.American College of Obstetricians and Gynecologists,“Refusal of Medically Recommended Treatment During Pregnancy,”https://www. acog.org/clinical/clinical-guidance/committee-opinion/articles/2016/ 06/refusal-of-medically-recommended-treatment-during-pregnancy. 6.A.L.V. 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Suelmann,C.van Dooijeweert,E.van der Wall, S.Linn, and P.J. van Diest,“Pregnancy-Associated Breast Cancer: Nationwide Dutch Study Confirms a Discriminatory Aggressive Histopathologic Profile,"Breast Cancer Research and Treatment186(2021): 699-704. 18.S.Y. Bae,S.J. Kim,J.S.Lee,et al.,“Clinical Subtypes and Prognosis of Pregnancy-Associated Breast Cancer: Results From the Korean Breast Cancer Society Registry Database,”Breast Cancer Research and Treatment 172 (2018): 113-121. 19.A.L.V. Johansson,T.M.L.Andersson, C.C.Hsieh,et al.,“Tumor Characteristics and Prognosis in Women With Pregnancy-Associated Breast Cancer,”International Journal of Cancer 142(2ol8):1343-1354. 20.C.C.O'Sullivan,S. 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Partridge,S.M.Niman,M.Ruggeri, etal.,“Interrupting Endocrine Therapy to Atempt Pregnancy After Breast Cancer,” New England Journal of Medicine 388 (2023): 1645-1656. 250.A.N.J. Tutt, J. E. Garber, B. Kaufman, et al., “Adjuvant Olaparib for Patients With BRCA1- Or BRCA2 -Mutated Breast Cancer,” New England Journal ofMedicine 384 (2021): 2394-2405. 251.S.R.D. Johnston，N. Harbeck,R.Hegg，et al.,“Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of $\mathrm { H R } +$ HER2-,Node-Positive,High-Risk,Early Breast Cancer (monarchE)," Journal of Clinical Oncology 38 (2020): 3987-3998. 252.Electronic Medicines Compendium，“Olaparib Summary of Product Characteristics,” December 19, 2024, https://www.medicines. org.uk/emc/product/9204/smpc. 253.Electronic Medicines Compendium,“Abemaciclib Summary of Product Characteristics,” October 01, 2024, https://www.medicines. org.uk/emc/product/9532/smpc. 254.M. Condoreli, M. de Vos,S.Lie Fong,et al.,“Impact of ARTs on Oncological Outcomes in Young Breast Cancer Survivors,”Human Reproduction 36 (2021): 381-389. 255.E.Rosenberg，A．Fredriksson，Z.Einbeigi，C.Bergh,and A. Strandell,“No Increased Risk of Relapse of Breast Cancer for Women Who Give Birth After Assisted Conception,” Human Reproduction Open 2019,no.4(2019): hoz039. 256.M. Condorelli, M. Bruzzone,M. Ceppi, et al.,“Safety of Assisted Reproductive Techniques in Young Women Harboring Germline Pathogenic Variants in BRCA1/2 With a Pregnancy After Prior History of Breast Cancer,”ESMO Open 6 (2021):100300. 257. O.Goldrat,N.Kroman,F.A.Peccatori,etal.,“PregnancyFollowing Breast Cancer Using Assisted Reproduction and Its Efect on LongTerm Outcome,”European Journal of Cancer 51(2015): 1490-1496. 258.M.Lambertini,E.Blondeaux,M.Bruzzone,et al.,“Pregnancy AfterBreast Cancer:ASystematic Reviewand Meta-Analysis,"Journal of Clinical Oncology 39 (2021): 3293-3305. 259.L.S. Mehta,K.E.Watson，A.Barac,et al.，“Cardiovascular Disease and Breast Cancer:Where These Entities Intersect:A Scientific Statement From the American Heart Association,”Circulation 137 (2018): e30-e66. 260.D.Cardinale,A. Colombo,G. Bacchiani, et al.,“Early Detection of Anthracycline Cardiotoxicity and Improvement With Heart Failure Therapy,"Circulation 131(2015): 1981-1988. 261.J.Celutkiene,R.Pudil，T. López-Fernandez,J. Grapsa，P. Nihoyannopoulos，and J.Bergler-Klein，“Role of Cardiovascular Imaging in Cancer Patients Receiving Cardiotoxic Therapies: A Position Statement on Behalf of the Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and theCardio-Oncology Council of the European Society of Cardiology (ESC),"European Journal of Heart Failure 22 (2020):1504-1524. 262.S.Liu,N.Aghel,L. Belford,et al.,“Cardiac Outcomes in Pregnant Women With Treated Cancer,” Journal of the American Colege of Cardiol0gy 72 (2018): 2087-2089. 263.V.L.Meah,J.R.Cockcroft,K.Backx,R.Shave,and E.J. Stohr, “Cardiac Output and Related Haemodynamics During Pregnancy: A Series of Meta-Analyses,"Heart 102 (20l6): 518-526. 264.M. R. Hines, D.A. Mulrooney, M. M. Hudson, et al.,“PregnancyAssociated Cardiomyopathyin Survivors of Childhood Cancer,”Journal of Cancer Survivorship 10 (2016): 113-121. 265.S.C.Darby,M.Ewertz,P.McGale,etal.,“Risk of Ischemic Heart Disease in Women After Radiotherapy for Breast Cancer,”New England Journal ofMedicine 368 (2013): 987-998. 266.C.A.Balgobin,X.Zhang,F.V.Lima,et al.,“Risk Factors and Timing of Acute Myocardial Infarction Associated With Pregnancy: Insights From the National Inpatient Sample,” Journal of the American Heart Association 9 (2020): e016623. 267. C.Gertosio,C.Meazza,S.Pagani,and M. Bozzola,“Breastfeeding and Its Gamut of Benefits,”Minerva Pediatrica 68 (20l6): 201-212. 268.E.J.Begg,SB.Dfull,L.P.HackettaK.Fetttuin Drugs in Human Milk: Time to Unify the Approach,"Journal of Human Lactation 18 (2002):323-332. 269.P.O.Anderson and J.B.Sauberan,“Modeling Drug Passage Into Human Milk," Clinical Pharmacology and Therapeutics 1oo (20l6): 4-52. 270.W.A.Bowes,“The Effect of Medications on the LACTAT1NG Mother and Her Infant,”Clinical Obstetrics and Gynecology 23 (1980): 1073-1080. 271.Early Breast Cancer Trialists' Collaborative Group (EBCTCG), “Effects of Chemotherapy and Hormonal Therapy for Early Breast Cancer on Recurrence and 15-Year Survival: An Overview of the Randomised Trials,"Lancet 365 (2005):1687-1717. 272.M.M. Shaaban,“Suppression of Lactation by an Antiestrogen, Tamoxifen,”European Journal of Obstetrics& Gynecologyand Reproductive Biology 4 (1975): 167-169. 273.A. Masala, G. Delitala, G.Lo Dico, I. Stoppelli, S.Alagna, and L. Devilla,“Inhibition of Lactation and Inhibition of Prolactin Release After Mechanical Breast Stimulation in Puerperal Women Given Tamoxifen or Placebo,” British Journal of Obstetrics and Gynaecology 85 (1978): 134-137. 274.F.A.Peccatori, G.Codacci-Pisanelli,G.Mellgren, et al.,“First-InHuman Pharmacokinetics of Tamoxifen and Its Metabolites in the Milk of aLactating Mother: A Case Study,”ESMO Open 5 (2020): e000859. 275.T.Helland,N.Henne,E.Bifulco,et al.,“Serum Concentrations of Active Tamoxifen Metabolites Predict Long-Term Survivalin Adjuvantly Treated Breast Cancer Patients,”Breast Cancer Research19 (20l7):125. 276.S.Karlsson,“Histopathology and Histomorphometry of the Urogenital Tract in 15-Month Old Male and Female Rats Treated Neonatally With SERMs and Estrogens,”Experimental and Toxicologic Pathology 58 (2006): 1-12. 277.G．Codacci-Pisanelli，R．J.Honeywell，N.Asselin，et al., “Breastfeeding During R-CHOP Chemotherapy: Please Abstain!,” European Journal of Cancer 119 (2019):107-111. 278.S.J. Grifin,M.Milla,T.E.Baker,T.Liu,H.Wang,and T.W.Hale, “Transfer of Carboplatin and Paclitaxel Into Breast Milk,” Journal of Human Lactation 28 (2012): 457-459. 279.“Drugs and Lactation Database (LactMed) [Internet],”Bethesda (MD): National Institute of Child Health and Human Development (2006), https://www.ncbi.nlm.nih.gov/books/NBK501922/. 280.B.Pistilli, G. Bellettini,E.Giovannetti, et al.,，“Chemotherapy, Targeted Agents,Antiemetics and Growth-Factors in Human Milk: How Should We Counsel Cancer Patients About Breastfeeding?," Cancer Treatment Reviews 39 (2013): 207-211. 281.“Drugs and Lactation Database (LactMed),". Bethesda (MD): National Institute of Child Health and Human Development, Trastuzumab. [Updated 2023 Mar 18] (2006), https://www.ncbi.nlm. nih.gov/books/NBK500579/. 282.S.Higgins and B.G.Haffty，“Pregnancy and Lactation After Breast-Conserving Therapy for Early Stage Breast Cancer,” Cancer 73 (1994): 2175-2180. 283.R.Y.Kraut,E.Brown,C.Korownyk,et al.,“The Impact of Breast Reduction Surgery on Breastfeeding: Systematic Review of Observational Studies,”PLoS One 12 (20l7): e0186591. 284.S.C.Leal, S.R.Stuart,and H.d.A.Carvalho,“Breast Irradiation and Lactation:A Review,”Expert Review of Anticancer Therapy 13 (2013): 159-164. 285.H.A.Azim,G. Bellettini, S.J. Liptrott, et al.,“Breastfeeding in Breast Cancer Survivors: Pattern,Behaviour and Effect on Breast Cancer Outcome,”Breast 19 (2010): 527-531. 286.M.S.Moran,J.M.Colasanto,B.G.Haffty,L.D.Wilson,M.W. Lund,and S.A.Higgins,“Effects of Breast-Conserving Therapy on Lactation After Pregnancy," Cancer Journal 1l(2oo5):399-403. 287.A.H. Tralins,“Lactation After Conservative Breast Surgery Combined With Radiation Therapy,”American Journal of Clinical Oncology 18(1995):40-43. 288.H.A.Azim,S.Niman,A.H.Partridge,et al.,“18140-Breastfeeding in Women With Hormone Receptor-Positive Breast Cancer Who Conceived After Temporary Interruption of Endocrine Therapy:Results From the POSITIVE Trial,"Annals of Oncology 35,no.suppl_2 (2024): S1076. 289.Y.Yang，I.Boucoiran，K.J.Tulloch，and V.Poliquin，“Is Cabergoline Safe and Effective for Postpartum Lactation Inhibition? ASystematic Review,”International Journal of Women's Health 12 (2020): 159-170. 290.National Institute for Health and Care Excellence British National Formulary,“Cabergoline,”https://bnf.nice.org.uk/drugs/cabergoline. 291.NHS Digital,“National Mastectomy and Breast Reconstruction Audit,Annual Report -20o9," October 1,2009,https://associationofbr eastsurgery.org.uk/media/1083/nmbra-annual-report-2009.pdf. 292.M. M. Jonczyk,J. Jean,R.Graham,and A.Chatterjee,“Trending Towards Safer Breast Cancer Surgeries?Examining Acute Complication Rates FromA13-Year NSQIPAnalysis,"Cancers(Basel) 1l,no.2(2019): 253,https://doi.org/10.3390/cancers11020253. This guideline was produced on behalf of the Royal College of Obstetricians and Gynaecologists by: DrA Armstrong,Manchester; Mr A Gandhi MBChB, MD,FRCS,Manchester； Ms S Frank,Manchester; Professor D Williams FRCOG,London and Dr S Nimalasena,London. Acknowledgements The guideline was reviewed and ratified by the Executive Committee of the Association of Breast Surgery. The following individuals and organisations submited comments at peer review: Dr.A Banerjee FRCP,London; Mr.M Benjamin, Kemptown; British Association of Perinatal Medicine;Dr.M El-Zibdeh FRCOG,Amman,Jordan;H Flint MRPharmS,Liverpool; Dr.C Ovadia，MRCOG,London；K Sampat，MRCOG, Dartford; and Dr.LI Stirrat,MRCOG,Edinburgh. Committee lead reviewers were:Dr.A Campbell FRCOG, Edinburgh;1 Miss L Knight MRCOG, Devon;1 Dr. SJ Pierce MRCOG,Leeds;² Mr.A McKelvey MRCOG,Norwich;Dr. A El-Ghobashy MRCOG, Wolverhampton;4 Dr. M Annappa, FRCOG,Lincolnshire; Dr.N Potdar, Leicester.6 lfrom June 2024; ²until June 2023; 3until May 2024; 4until February 2020; 5until June 2024; until May 2024. The Co-Chairs of the Guidelines Committee were: Dr.A Campbell FRCOG,Edinburgh;1 Miss L Knight MRCOG, Devon;1 Dr.N Potdar FRCOG,Leicester;² Mr.A McKelvey MRCOG,Norwich;² Dr.MA Ledingham MRCOG, Glasgow;3 and Dr. B Magowan FRCOG, Melrose.4 lfrom June 2024; ²until May 2024; until December 2021; 4until June 2021. The final version is the responsibility of the Guidelines Committee of the RCOG. The guideline will be considered for update 3years after publication,with an intermediate assessment of the need to update 2 years after publication. # DISCLAIMER The Royal College of Obstetricians and Gynaecologists produces guidelines as an educational aid to good clinical practice.They present recognised methods and techniques of clinical practice,based on published evidence,for consideration by obstetricians and gynaecologists and other relevant health professionals. The ultimate judgement regarding a particular clinical procedure or treatment plan must be made by the doctor or other attendant in the light of clinical data presented by the patient and the diagnostic and treatment options available. This means that RCOG Guidelines are unlike protocols or guidelines issued by employers,as they are not intended to be prescriptive directions defining a single course of management. Departure from the local prescriptive protocols or guidelines should be fully documented in the patient's case notes at the time the relevant decision is taken. # Appendix A Explanation of Grades and Evidence Levels Classification of evidence levels <table><tr><td>1++</td><td>High-quality meta-analyses,systematic reviews of randomised controlled trials or randomised controlled trials with a very low risk of bias</td></tr><tr><td>1+</td><td>Well-conducted meta-analyses,systematic reviews of randomised controlled trials or randomised controlled trials with a low risk ofbias</td></tr><tr><td>1-</td><td>Meta-analyses,systematic reviews of randomised controlled trials or randomised controlled trials with a high risk of bias</td></tr><tr><td>2++</td><td>High-quality systematic reviews of case- control or cohort studies or high-quality case-control or cohort studies with a very low risk of confounding, bias or chance and a high probability that the relationship is causal</td></tr><tr><td>2+</td><td>Well-conducted case-control or cohort studies with a low risk of confounding,bias or chance andamoderate probability that the relationship is causal</td></tr><tr><td>21</td><td>Case-control or cohort studies with a high risk of confounding,bias or chance and a significant risk that the relationship is not causal</td></tr><tr><td>3</td><td>Non-analytical studies, e.g.case reports, case series</td></tr><tr><td>4</td><td>Expert opinion</td></tr></table> # Grades of Recommendation # A At least one meta-analysis,systematic review orRCT rated as $1 + +$ ,and directly applicable to the target population; or a systematic review of RCTs or a body of evidence consisting principally of studies rated as $1 +$ ,directly applicable to the target population and demonstrating overall consistency of results # B A body of evidence including studies rated as $^ { 2 + + }$ directly applicable to the target population,and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as $1 + +$ or $1 +$ # D A body of evidence including studies rated as $^ { 2 + }$ directly applicable to the target population,and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as $^ { 2 + + }$ # D Evidence level 3 or 4; or Extrapolated evidence from studies rated as $^ { 2 + }$ # Good Practice Points Recommended best practice based on the clinical experience of the guideline development groupa	None	None	None
80c0815f298f492fb83891055da39376	2025+SOGC临床实践指南	原发性痛经（No.345）	# Guideline No. 345: Primary Dysmenorrhea (En français : Ligne directrice No. 345 : Dysménorrhée primaire) The English document is the original version. In the event of any discrepancy between the English and French content, the English version prevails. This clinical practice guideline was prepared by the authors, reviewed by the SOGC Clinical Practice Gynaecology Committee (2025), and approved by the SOGC Guideline Management and Oversight Committee (2025). This clinical practice guideline supersedes No. 345, published in July 2017. # Author Margaret Burnett, MD, Winnipeg, MB Acknowledgements: The author would like to thank the members of the SOGC’s Clinical Practice Gynaecology Committee (2023) for their contributions: Olga Bougie, Innie Chen, Anisha Dubey, Devon Evans, Joann James, Marie Jones, Sari Kives, Ally Murji, Jessica Papillon-Smith, Leslie Po, Elizabeth Randle, David Rittenberg, Jackie Thurston, Paul Yong as well as Kaylee Brooks. SOGC Clinical Gynaecology Committee (2025): Baharak Amir, Roland Antaki, Philippa Brain, Olga Bougie, Aisling Clancy, Devon Evans, Chelsea Elwood, Andréanne Jodoin, Sari Kives, Kiel Luhning, Bryden Magee, Marie-Hélène Mayrand, Sarah McQuillan, Tarek Motan, Ally Murji, Gregg Nelson (chair), Jessica Papillon-Smith, Frank Potestio, David Rittenberg, Jane Schulz, Rachel Spitzer, Susan Thorne, Angela Vinturache, Paul Yong. SOGC Guideline Management Oversight Committee (2025): Melanie Basso, Jocelynn Cook, Diane Francoeur, Bing Guthrie, Kristin Harris, Sarah Healey, Venu Jain, Brent Jim, Andrew Kotaska, Amy Metcalfe, N. Lynne McLeod, Ally Murji, Jessica Papillon-Smith, Vanessa Poliquin, Frank Potestio (Co-chair), Anita Smith, R. Douglas Wilson (Co-chair) Subject Categories: Paediatric and Adolescent Gynaecology, Gynaecology Disclosures: No relationships or activities that could involve a conflict of interest were declared by the author. Keywords: dysmenorrhea; pelvic pain; endometriosis Corresponding Author: Margaret Burnett, MBurnett@exchange.hsc.mb.ca # KEY MESSAGES 1. Health care providers should ask about menstrual pain and be prepared to assist their patients with effective treatment options that are readily available. Symptomatic treatment should be offered to all people reporting menstrual pain. 2. Pelvic examination and diagnostic imaging are not indicated, unless a careful history suggests a secondary cause or a reasonable trial of empiric therapy is not successful. 3. The mainstays of treatment are regular dosing with nonsteroidal anti-inflammatory drugs and/or continuous use of hormonal contraceptives. 4. Local heat, exercise, high-frequency transcutaneous nerve stimulation, acupoint therapy, and ginger are potentially helpful complementary therapies. 5. Unless adequately treated and followed, dysmenorrhea may progress to a chronic pain syndrome with devastating longterm implications for the individual, family, and health care system. # ABSTRACT Objective: This guideline reviews the investigation and treatment of primary dysmenorrhea. Target Population: Individuals experiencing menstrual pain for which no underlying cause has been identified. Benefits, Harms, and Costs: Primary dysmenorrhea is common and frequently undertreated, despite effective therapy being widely available at a minimal cost. Treatment of primary dysmenorrhea has the potential to improve quality of life and decrease time away from school or work. Evidence: Published clinical trials, randomized controlled trials, observational studies, population studies, and systematic review articles indexed in PubMed and the Cochrane database were identified using search the terms “dysmenorrhea” and “menstrual pain.” This search builds on the previous review (January 2005 to March 2016), including new literature between March 2016 and December 2024. Validation Methods: The author rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional [weak] recommendations). Intended Audience: Primary care providers, pediatricians, and obstetrician/gynaecologists. Social Media Abstract: Although menstrual pain is commonly experienced by women and adolescents, it is often undertreated or unfairly dismissed. If left untreated, persistent menstrual pain may develop into a chronic pain syndrome. Treatment includes nonsteroidal anti-inflammatory drugs and hormonal contraceptives and can be provided without the need for pelvic examinations; treatment should not be delayed pending a definitive diagnosis. Effective treatments are available and do not require a pelvic examination or invasive procedures. # SUMMARY STATEMENTS: 1. Dysmenorrhea is highly prevalent and commonly undertreated (low). 2. Risk factors associated with primary dysmenorrhea include age, smoking, alcohol use, diet, level of physical activity, family history, parity and psychosocial factors (high). 3. Primary dysmenorrhea is crampy, suprapubic pain that begins around menstruation, peaks with maximum blood flow, and lasts 2 to 3 days; common symptoms include nausea, vomiting, diarrhea, headache, dizziness, and fatigue (high). 4. MRI is valuable in diagnosing deep endometriosis and adenomyosis but is less effective in detecting superficial endometriosis, which is commonly found during laparoscopy; laparoscopy remains the gold standard for diagnosing endometriosis, particularly when superficial peritoneal lesions are suspected (good practice point). 5. Non-steroidal anti-inflammatory drugs are more effective than placebo but have more gastrointestinal side effects. All currently available non-steroidal anti-inflammatory drugs are of comparable efficacy and safety (high). 6. Most women experience symptom relief with medical therapy, particularly with amenorrhea-inducing treatments (strong). 7. Endometrial ablation is likely to reduce the symptoms of primary dysmenorrhea when it occurs in the presence of heavy menstrual bleeding (high). # RECOMMENDATIONS: 1. A thorough menstrual, pain, and gynaecologic history should be obtained, including symptom onset, severity, and response to prior treatments. (good practice point). 2. Health care providers should consider a pelvic examination in patients who are not responding to conventional therapy and when organic pathology is suspected (good practice point). 3. Health care providers may initiate therapy without first performing a pelvic examination (good practice point). 4. Ultrasound is indicated when symptoms persist despite appropriate therapy or a clinical abnormality is detected on physical examination (good practice point). 5. Magnetic Resonance Imaging (MRI) may be considered when transvaginal ultrasound is inconclusive, or when deep infiltrating endometriosis or adenomyosis is strongly suspected based on clinical presentation (good practice point). 6. Advanced transvaginal ultrasound by an experienced sonographer is preferred over MRI for evaluating deep infiltrative endometriosis (conditional, low). 7. Given significant wait times for MRI in many jurisdictions, laparoscopy should be considered if transvaginal ultrasound is normal but clinical suspicion for endometriosis remains high (conditional, low). 8. Health care providers should offer non-steroidal anti-inflammatory drugs or acetaminophen, administered with regular dosing regimens, as a as first-line treatment for most women unless contraindicated (strong, high). 9. Continuous or extended use combined hormonal contraceptives are recommended for the treatment of dysmenorrhea (strong, high). 10. Both primary and secondary dysmenorrhea are likely to respond to the same hormonal suppression therapy. Therefore, the practitioner should institute symptomatic treatment even though a precise diagnosis has not been made (good practice point). 11. Regular exercise should be recommended to improve the symptoms of dysmenorrhea (conditional, low). 12. High-frequency transcutaneous electrical nerve stimulation (TENS), local heat therapy (heated pads/patches), acupoint stimulation and ginger supplementation may be considered as complementary treatments for dysmenorrhea, especially for women who cannot or choose not to use conventional therapy, though evidence varies in strength and certainty (conditional, low). 13. Surgical intervention should only be considered when dysmenorrhea persists despite optimized medical therapy or when secondary causes are strongly suspected (strong, moderate). 14. A thorough clinical evaluation, including pelvic examination, rectovaginal assessment, and abdominal wall muscle evaluation, should be performed before considering surgical options (strong, moderate). # INTRODUCTION D ysmenorrhea is the most common gynaecologicalsymptom reported by women, and the worldwide prevalence ranges from $45 \%$ to $9 5 \%$ in females of reproductive age, with $2 \%$ to $2 9 \%$ experiencing severe pain.1,2 Primary dysmenorrhea is defined as pain occurring with menses in the absence of pelvic pathology, while secondary dysmenorrhea is menstrual pain associated with underlying pelvic pathology, such as endometriosis.3 Primary dysmenorrhea usually begins in adolescence after the establishment of ovulatory cycles, which are believed to be associated with painful uterine contractions triggered by progesterone withdrawal at the beginning of menses.4 These contractions result in uterine ischemia, causing pain, which can be modulated and augmented by prostaglandins produced in the endometrium. Uterine contractions may last many minutes and sometimes produce uterine pressures greater than $6 0 \ \mathrm { m m H g }$ Multiple other factors may play a role in the perception and the severity of the pain.5 Abnormal neural sensitization may contribute to the higher prevalence of chronic pain occurring over and above dysmenorrhea itself.6,7 Population surveys suggest that dysmenorrhea is widespread in diverse populations, although prevalence varies considerably by geographical location.6,8e 1 2 Many young women with dysmenorrhea report moderate or severe symptoms,13 and symptoms are frequently associated with time away from school, work, and other activities.3,11,13 Despite the frequency and severity of dysmenorrhea, most women do not seek medical treatment for this condition.14,15 This guideline outlines an approach to the treatment of menstrual pain for which no underlying cause has yet been identified. This guideline does not address the investigation and treatment of conditions associated with secondary dysmenorrhea or the broader topic of chronic pelvic pain. Guidance regarding the diagnosis and treatment of endometriosis is available in SOGC Guideline No. 449: Diagnosis and Impact of Endometriosis e A # ABBREVIATIONS <table><tr><td>CHC</td><td>Combined hormonal contraceptive</td></tr><tr><td>COC</td><td>Combined oral contraceptive</td></tr><tr><td>LNG-IUS</td><td>Levonorgestrel intrauterine system</td></tr><tr><td>LUNA</td><td>Laparoscopic uterosacral nerve ablation</td></tr><tr><td>NSAID</td><td>Non-steroidal anti-inflammatory drug</td></tr><tr><td>PSN</td><td>Pre-sacral neurectomy</td></tr><tr><td>TENS</td><td>Transcutaneous electrical nerve stimulation</td></tr></table> Canadian Guideline16 and in the European Society of Human Reproduction and Embryology’s 2022 Guideline.17 Strategies for the investigation and treatment of non-menstrual chronic pain are addressed in detail in SOGC Guideline No.445: Management of Chronic Pelvic Pain.5 # Summary Statement 1 # Risk Factors There are a wide range of risk factors associated with primary dysmenorrhea including age, smoking, alcohol use, diet, and physical activity level, family history, parity, and psychosocial factors.14,18e20 The prevalence of primary dysmenorrhea tends to decrease with age. Menstrual pain is more pronounced among adolescents compared to older women, 14,21 and parous women tend to demonstrate a lower prevalence of dysmenorrhea than nulliparous women. 19,21e23 Smoking is associated with an increased risk of developing dysmenorrhea; and even those who are former smokers have an increased risk of dysmenorrhea .18,24 This risk may increase based on the number of cigarettes per day and the number of year spent smoking. 23 Smoking is known to aggravate menstrual pain,14,21,23,25,26 and a prospective study found that dysmenorrhea is even associated with exposure to environmental tobacco smoke.27 A family history of menstrual pain is also associated with an increased risk of primary dysmenorrhea, especially when a first degree relative has or has had dysmenorrhea.12,13 Theories for this risk include a mix of genetic susceptibility and learned behaviours or lifestyle factors.13 Additionally, psychosocial factors play a role in the symptoms of primary dysmenorrhea. There is some evidence that frequent life changes, fewer social supports, and stressful close relationships are associated with dysmenorrhea. Moreover, people with dysmenorrhea are at an increased risk of mood and anxiety disorders28 and a higher likelihood of engagement in risk behaviours like smoking and illicit drug use.29 Primary dysmenorrhea is also associated with pain hypersensitivity30 and is a risk factor for the development of chronic, nonmenstrual pain.31 Data suggest that pregnancy influences dysmenorrhea; parous women had significantly less dysmenorrhea than women who had never been pregnant.21 Both length of gestation and mode of delivery appear to have an impact on primary dysmenorrhea, with the most significant improvement after the first delivery.32 # DIAGNOSIS # Diagnosis of primary dysmenorrhea Primary dysmenorrhea is characterized by crampy, suprapubic pain that begins between a few hours before or after the onset of the menstrual bleeding. Symptoms peak with maximum blood flow and may persist for 2 to 3 days. Symptoms are reproducible from one menstrual period to the next. The pain is characteristically colicky and located in the midline of the lower abdomen but may also be described as dull and may extend to both lower quadrants, the lumbar area, or the thighs. Associated symptoms include diarrhea, nausea and vomiting, fatigue, lightheadedness, headache, dizziness, and, rarely, syncope and fever. These symptoms have been attributed to prostaglandin release.12 Adolescents may experience menstrual pain with their first period without any demonstrable underlying cause, especially when the bleeding is heavy and accompanied by clots. 33 However, the onset of severe dysmenorrhea with menarche should alert the physician to the possibility of an obstructing malformation of the genital tract, as primary dysmenorrhea is classically associated with ovulatory cycles. # Summary Statement 3 # Differential diagnosis The differential diagnosis of dysmenorrhea is summarized in Box 1. Endometriosis is the most frequent cause of secondary dysmenorrhea. In adolescent girls, endometriosis is found in approximately $70 \%$ of those undergoing laparoscopy for investigation of chronic pelvic pain not responding to non-steroidal anti-inflammatory drugs (NSAIDs) and oral contraceptives. (Ref #34, Janssen, 2013) Non-gynaecological causes of chronic pelvic pain, including pelvic adhesions, inflammatory bowel diseases, irritable bowel syndrome, interstitial cystitis, and psychiatric disorders, may be more symptomatic during menses. 30 Box 1. Differential diagnosis of dysmenorrhea <table><tr><td>1. Primary dysmenorrhea 2. Secondary dysmenorrhea: ·Endometriosis ·Adenomyosis ·Uterine myomas ·Cervical stenosis · Obstructive lesions of the genital tract 3. Other causes of menstrual pain may include the following: · Pelvic inflammatory disease</td></tr></table> # Clinical approach # Many women consider menstrual pain inevitable, even when it is severe or incapacitating and may not seek medical assistance.14,33 Known treatment strategies for dysmenorrhea are also underused by affected women.14 When a health care provider identifies menstrual pain during history taking, an attempt should be made to differentiate between primary and secondary dysmenorrhea. Menstrual history should include age at menarche, length and regularity of cycles, amount of bleeding, and length of time elapsed between menarche and the onset of dysmenorrhea. Dysmenorrhea occurring with menarche may indicate a Müllerian anomaly. The pain should be clearly defined in terms of type, location, radiation, associated symptoms, and the chronology of the onset of pain in relation to menstrual bleeding. The severity and duration of symptoms, its progression over time, and the degree of the patient’s disability should be established. Significant gastrointestinal or urinary symptoms or the presence of pelvic pain not related to the menstrual cycle may suggest non-gynaecological causes of pelvic pain. In obtaining a thorough history, it is important to inquire about sexual activity, dyspareunia, and contraception. Adolescents may use dysmenorrhea as a means to broach the subject of contraception. Past obstetric and gynaecological history, in particular sexually transmitted infections, pelvic infections, infertility, sexual violence, surgery, and other medical and psychiatric conditions (i.e., depression, anxiety, or other mental disorders34) should be documented in the medical record (Box 2). # Box 2. Dysmenorrhea history checklist - Menstrual history - Relationship between menarche and onset of dysmenorrhea - Timing of pain in relation to menses and amount of menstrual flow Characterization, severity, chronology, and resulting disability Sexual history, including inquiry about sexual abuse Inquiry about chronic pain syndromes and medical conditions - Presence of symptoms of depression, anxiety, and other psychiatric disorders - Previous treatment including dosage, duration of use, side effects, and response Additionally, the patient should be asked to list any therapies and medications tried in the past, as many patients do not use medication at the recommended dosages. In a group of high school girls aged 14 to 21years using overthe-counter medications for menstrual discomfort, only $31 \%$ took the recommended daily dosage. Of those using a prescription drug, $1 3 \%$ reported using less than the prescribed dose. In the same study, participants waited a median of 30 minutes after the onset of pain before taking their medication, and only $1 6 \%$ of them took it prophylactically.35 # Recommendation 1 # Physical examination A pelvic examination is recommended in women presenting for the first time with dysmenorrhea because the likelihood of secondary causes is much higher in this population.36 An abdominal examination should be performed to rule out palpable pathology. In a woman who has never been sexually active and presents with a typical history of primary dysmenorrhea, a pelvic examination is not indicated. Some practitioners recommend inspecting the external genitalia of all patients to exclude an abnormality of the hymen (e.g., imperforate hymen).37 On the other hand, when history is suggestive of a structural problem or congenital malformation of the genital tract and the patient’s pain has not responded to the conventional therapy for primary dysmenorrhea, a pelvic examination should be considered. # Recommendations 2 and 3 # Investigations Laboratory testing and ultrasound are not generally helpful or indicated in the initial evaluation and diagnosis of primary dysmenorrhea. However, follow-up visits are critically important to monitor the effects of treatment and to further inform investigations for secondary causes. When history and physical examination suggest pelvic disease, further investigation should be undertaken to determine the causes of secondary dysmenorrhea using transvaginal ultrasound, magnetic resonance imaging, and, possibly, laparoscopy.38 For women who experience dysmenorrhea that does not respond to therapy (e.g., continuous dosing of combined oral contraceptives), or in women who have a clinical abnormality on physical examination, ultrasound may identify causes of secondary dysmenorrhea. Transvaginal ultrasonography is the preferred method for the initial evaluation of pelvic organs. Dysmenorrhea associated with adnexal pathology or uterine abnormalities (e.g. leiomyoma, adenomyosis, pelvic mass, Müllerian anomalies) can be diagnosed with ultrasound.38 Although endometriosis is a common cause of secondary dysmenorrhea, routine pelvic ultrasound is frequently unremarkable unless there is anatomic distortion or an endometrioma.39 While ultrasound may not detect subtle signs of organic disease, a targeted endovaginal ultrasound scan performed by an experienced sonographer may help delineate deep endometriosis.16 Pelvic MRI is a helpful diagnostic tool for fibroids, adenomyosis, endometriomas, and uterine anomalies; however, it is expensive and not generally recommended as an initial step in evaluating dysmenorrhea unless clinical presentation suggests one of these secondary causes.38 Targeted endovaginal ultrasound for endometriosis is preferred over MRI when symptoms or signs are suggestive of deep infiltrating endometriosis;16 MRI should be reserved for the investigation of recalcitrant cases of dysmenorrhea that do not respond to 3 to 6 months of adequate therapy if targeted endovaginal ultrasound is not readily available.16,40,41 Endometriosis may be associated with an elevated CA125 level, and a negative test has sometimes been used as a surrogate marker for primary dysmenorrhea.42 However, because of its low sensitivity and specificity, CA125 is not generally recommended as a method of diagnosis. When surgery is considered, it should combine diagnosis and treatment based on the patient’s symptoms and goals.16 Laparoscopy may be helpful to establish a diagnosis of superficial endometriosis, pelvic inflammatory disease or pelvic adhesions. It should be considered when these pathologies are strongly suspected, when imaging is inconclusive and when a reasonable trial of medical therapy has failed.1 In adolescents who have been compliant but are not responding to therapy, investigation should not be unduly postponed because the prognosis for pain control in endometriosis may be improved with an early diagnosis. Further considerations for diagnosing endometriosis can be found in the SOGC guideline No. 449: Diagnosis and Impact of Endometriosis e A Canadian Guideline.16 Ideally, laparoscopy should be performed by a specialist trained in advanced laparoscopy surgery, although wait lists may be very long. MRI, targeted endovaginal ultrasound and/or diagnostic laparoscopy (depending on availability) may be important in order to inform or expedite referral. Please refer to the SOGC guidelines on Endometriosis16 and Chronic Pelvic $\operatorname { P a i n } ^ { 5 }$ for a complete discussion of investigation and treatment of secondary dysmeorrhea. # Summary Statement 4 and Recommendations 4, 5, 6 and 7 # MEDICAL TREATMENT # Non-hormonal medical therapy # Acetaminophen Acetaminophen is an analgesic that acts as a weak cyclooxygenase inhibitor in the presence of high peroxide concentrations present in inflammatory tissues. It acts centrally and produces analgesia by raising the pain threshold. Acetaminophen has good gastrointestinal tolerance and no inhibition of hemostasis. A randomized trial published in 2007 showed that acetaminophen and acetaminophen with caffeine were superior to placebo in the treatment of primary dysmenorrhea.43 Acetaminophen and pamabrom in combination are marketed for the temporary relief of dysmenorrhea. Pamabrom is a mild, short-acting diuretic that may help to relieve water retention. # Non-steroidal anti-inflammatory drugs Nonsteroidal anti-inflammatory drugs (NSAIDs) should be recommended for the treatment of dysmenorrhea.5 Uterine prostaglandin overproduction is believed to be a contributing factor to dysmenorrhea. NSAIDs are analgesics that inhibit cyclooxygenase enzymes, thereby inhibiting the peripheral production of prostaglandins. In a Cochrane review, NSAIDs were found to be consistently more effective than placebo, although adverse effects were significantly more common. When NSAIDs were compared with each other, there was little evidence of superiority with regard to efficacy or safety. Women taking NSAIDs were less likely to report restrictions of their daily activities and absenteeism from work or school compared to women taking a placebo.44 If effective treatment is initiated with the onset of bleeding and/or associated symptoms, NSAIDs are usually not required for more than 2 or 3 days. Recommended dosing includes starting with an initial loading dose followed by regular, scheduled dosing up to the recommended daily maximum. # Summary Statement 5 and Recommendation 8 # Hormonal Treatment # Combined hormonal contraceptives Dysmenorrhea responds favourably to the inhibition of ovulation. Combined hormonal contraceptives (CHCs) suppress ovulation and endometrial tissue growth, thereby decreasing menstrual blood volume and prostaglandin secretion with subsequent decreases in intrauterine pressure and uterine cramping. Observational studies consistently demonstrate a lower prevalence of dysmenorrhea among individuals who use CHCs.14,45,46 A 2023 Cochrane review reported a greater reduction in pain among women with dysmenorrhea using CHCs compared to placebo.47 However, the authors highlighted the fact that there may be potential adverse effects with CHC use, including unscheduled uterine bleeding, headaches, and nausea. Extended cycle or continuous CHC use may have several advantages over cyclical CHC use, including a decreased prevalence of dysmenorrhe a.48e50 A randomized trial by Dmitrovic et al. compared continuous versus cyclical oral contraceptive regimens and used dysmenorrhea as the primary treatment outcome. In this well-designed study, the combined oral contraceptive (COC) was shown to be significantly more effective when used continuously.51 A Cochrane review concluded that continuous and extended use CHC regimens may be superior to cyclical regimens for pain relief in dysmenorrhea.52 It is important to note that many clinical trials did not differentiate between primary and secondary dysmenorrhea; however, hormonal contraceptives appear to be effective for both. In a secondary analysis of 2 randomized trials, the COC was shown to be beneficial even in women who were subsequently found to have an underlying organic cause for their pain.53 In general, hormonal treatments for primary dysmenorrhea tend to be effective for conditions that produce secondary dysmenorrhea. Therefore, it is reasonable to maximize medical treatment in all women complaining of dysmenorrhea without awaiting the results of further investigations, even if organic pathology is suspected.6 (Figure 1) # Progestin regimens Depot medroxyprogesterone acetate works primarily by suppressing ovulation and inducing endometrial atrophy, and women using depot medroxyprogesterone acetate for contraception tend to report reduced rates of dysmenorrhea.54 ![](images/854857fdefedb35fa1a747e50b974d9b0491ecd55a783dd882b56ae9d5746145.jpg) Figure 1. Primary dysmenorrhea treatment algorithm. NSAID: non-steroidal anti-inflammatory drug (); CHC: combined hormonal contraceptive. The progesterone-only pill may decrease menstrual flow, and some users may develop amenorrhea. Continuous oral progestin is useful as an alternative to CHCs with comparable pain relief and fewer side effects.55 Dienogest is a progestin that is significantly more efficient than placebo and non-inferior to leuprolide acetate in treating dysmenorrhea resulting from endometriosis. It induces a $3 9 \%$ amenorrhea rate at 6 months and presents a generally well-tolerated side effect profile. A number of patients initially presenting with primary dysmenorrhea may have endometriosis lesions. Dienogest and other hormonal options, are likely to address conditions such as endometriosis and adenomyosis that cause secondary dysmenorrhea.56 Dysmenorrhea associated with endometriosis and adenomyosis has been shown to improve in patients who use a $5 2 \mathrm { - m g }$ levonorgestrel-releasing intrauterine system (LNG-IUS).57 In general, women with either primary or secondary dysmenorrhea are likely to report a reduction in menstrual pain with LNG-IUS $5 \dot { 2 } \mathrm { \ m g } . \dot { 5 8 } , 5 9$ In a Cochrane review of LNG-IUS used for heavy menstrual bleeding, dysmenorrhea was significantly decreased in women randomly assigned to LNG-IUS $5 2 ~ \mathrm { m g } ^ { \mathrm { 6 \ell } }$ # Summary Statement 6 and Recommendations 9 and # COMPLEMENTARY AND ALTERNATIVE THERAPY Exercise, local heat, behavioural interventions, and dietary/herbal supplements are commonly used as complementary and alternative therapies by women to relieve dysmenorrhea.61 # Exercise Exercise in the form of either low-intensity activities (e.g., stretching, core strengthening, yoga) and high-intensity activities (e.g., Zumba, aerobic training) may improve menstrual pain intensity among those with dysmenorrhea.11,62,63 In a 2019 Cochrane Review of 10 randomized trials studying exercise and primary dysmenorrhea, the authors concluded that exercise, performed for about $4 5 -$ 60 minutes, 3 times per week or more, may provide a clinically significant reduction in menstrual pain intensity. Assuming that exercise is unlikely to result in harm and may benefit an individuals’ overall health, it is reasonable to recommend a program of regular exercise to women experiencing painful periods. It may also be important to consider the woman’s personal preference for exercise type to improve consistency and maintenance of a regular exercise program, as most types of exercise regimens show similar reductions in menstrual pain intensity within an 8- week period.63 # Recommendation 11 # Transcutaneous electrical nerve stimulation Transcutaneous electrical nerve stimulation (TENS) involves the use of electrodes to stimulate the skin at various frequencies and intensities to diminish pain perception; high- or low-frequency protocols for TENS may be used. A 2024 Cochrane review of 20 randomized controlled trials supports the use of either high- or low-frequency TENS to reduce menstrual pain intensity in comparison to a placebo or no treatment. There was no clinically significant difference in menstrual pain intensity between high and low frequency TENS nor was there enough evidence to show that high- or low-frequency TENS reduced menstrual pain more than other pain relief methods (e.g., acupressure, acetaminophen).64 TENS may still be a useful alternative for women who are unable or choose not to use NSAIDs. Adverse outcomes associated with high-frequency TENS may include muscle tightness, headaches, nausea, and redness or burning of the skin. Combinations of TENS and heat therapy may be effective for primary dysmenorrhea. A randomized, single-blind trial demonstrated that highfrequency TENS in combination with heat therapy reduced menstrual pain intensity.65 # Acupuncture and acupressure Acupoint stimulation (including acupressure and acupuncture) has been actively studied as a treatment for primary dysmenorrhea, both alone and in combination with other therapies. A 2016 Cochrane review analyzing 42 randomized controlled trials (RCTs) with 4,640 women found that most studies had a moderate to high risk of bias. The only low-bias RCT found no significant difference in pain relief between acupuncture and placebo, leading to inconsistent and unreliable evidence for acupuncture’s effectiveness.66 A systematic review of 25 RCTs found that acupoint stimulation offered short-term pain relief, but the trials lacked strong methodological quality. (#68, Chung) Additionally, a randomized trial comparing acupuncture and combined oral contraceptives (COCs) found that COCs provided superior symptom relief, though with more side effects.67 Overall, current evidence suggests that acupoint stimulation should be considered an adjunct or alternative therapy, rather than a primary treatment, for dysmenorrhea. # Behavioural interventions Behavioural interventions used in the treatment of dysmenorrhea include biofeedback, desensitization, Lamaze exercises, hypnotherapy, and relaxation training.68 A Cochrane review based on 5 randomized trials comparing behavioural therapies (relaxation exercises, biofeedback, pain management, and coping skills) with placebo or other treatments reported that the behavioural therapies showed some merit. However, the authors concluded that the results should be viewed with caution because of inconsistency in the reporting of data, small trial sizes, poor methodological quality, and age of the trials (i.e., trials were conducted from 1975 to 1994).69 It would be premature to endorse the use of behavioural therapies as a treatment of choice for primary dysmenorrhea except as an addition to pharmacological therapy. # Topical heat A limited number of studies show that pain intensity is reduced with topical heat - comparable to the reduction found with ibuprofen - and that relief is faster when applied in conjunction with ibuprofen. 70,71 In one RCT, a topical heat wrap provided better analgesia than acetaminophen. A combination of local heat and exercise has also demonstrated a reduction in pain symptoms among adolescents with dysmenorrhea.72 Heated pads, hot water bottles, etc. are easily accessible and inexpensive and can be recommended to all patients for pain relief in primary dysmenorrhea. # Dietary supplements Many medicinal herbs and vitamins have been studied for the treatment of primary dysmenorrhea. However, a Cochrane review of 27 RCTs (3,101 women) found that the quality of data was low due to small sample sizes, poor reporting of methodology, and inconsistency between studies.73 The review found low quality evidence for the efficacy of ginger, fenugreek, fish oil, fish oil plus vitamin B1, valerian, vitamin B1 alone, Zataria, and zinc sulphate, though more research is needed. Oral ginger at dosages of $7 5 0 { - } 2 0 0 0 ~ \mathrm { m g }$ po daily during the first 3 to 4 days of menses has been found to be superior to placebo and comparable to NSAIDs for primary dysmenorrhea treatmen t.74,75e79 Side effects are poorly reported but appear minor (e.g., indigestion and headache).80 While the quality of evidence is low, it may be useful in women wishing complementary treatment; patients should be advised of the low certainty of the evidence for its use and the lack of information on adverse effects. # Recommendation 12 # SURGICAL MANAGEMENT While most women will see their pain improve with medical treatment, especially if amenorrhea is achieved, some will have persisting pain. In these cases, the cause of the pain might not be primary dysmenorrhea and a thorough exploration of other possible etiologies must be performed to optimize therapy. Detailed physical examination, including evaluation of the rectovaginal septum, levator ani, and abdominal wall muscles, should be performed to guide surgical exploration and therapy. Investigations such as pelvic ultrasound and MRI, cystoscopy, and/or colonoscopy may help avoid unnecessary laparoscopy, keeping in mind the utility of each investigation (i.e., MRI does not reliably detect endometriosis). The timing of laparoscopic investigation and treatment of dysmenorrhea is challenging. Physicians should keep the number of surgeries to a minimum, because repeated procedures carry a risk of surgical complications and may increase the risk of other chronic pain syndromes, such as neuropathic pain and adhesions. The woman’s desire for pregnancy must also be considered. Patients should be encouraged to pursue medical treatment until pregnancy is desired or a precise diagnosis becomes essential. # Laparoscopy Ideally, if laparoscopy is performed, the surgeon should be ready to proceed simultaneously to treatment if endometriosis is discovered. Prior to surgery, the desire to preserve fertility must be clearly defined. All options and associated risks must be discussed; a plan should be clearly established that defines procedures to be performed if anomalies are found. Informed consent should be obtained for any procedures that will be considered during the surgery, including their associated risks of complications. # Conservative surgical procedures when future pregnancy is desired Two methods of pelvic denervation have been described in the treatment of intractable primary dysmenorrhea: laparoscopic uterosacral nerve ablation (LUNA) and pre-sacral neurectomy (PSN). These procedures should be performed by a surgeon with specific expertise. Some studies show improvement in pain over time and improvement in quality of life. Johnson et al. reported that women with dysmenorrhea without endometriosisebut not those with endometriosis - improved significantly more with LUNA compared to control patients.81 A 2005 Cochrane review82 concluded that there is randomized trial evidence that LUNA improves pain in primary dysmenorrhea, although this benefit may decrease with time. However, among women with chronic pelvic pain, LUNA did not improve pain, dysmenorrhea, dyspareunia, or quality of life compared with laparoscopy without pelvic denervation.83 PSN may also have a place in conservative surgical treatment of primary dysmenorrhea,84 and success rates of this procedure range from $60 \%$ to $7 5 \%$ ;15 but the literature mainly addresses women with endometriosis. Juang et al. compared the effect of using LUNA alone to using LUNA plus PSN and found no added benefit from the addition of PSN in the treatment of primary dysmenorrhea.85 The incidence of side effects, such as constipation, was higher in the PSN arm. Long-term studies (greater than 12 months post procedure) are lacking. Interest in further research in the use of nerveinterruption modalities appears to have waned in the past 15 years, given that no clear benefit of LUNA has been demonstrated in an large meta-analysis exploring the treatment of chronic pelvic pain.83 Currently, these procedures are seldom performed, as the surgical risks are thought to outweigh potential benefits. At this time, the available evidence does not support the use of nerve-interruption surgery in the treatment of primary dysmenorrhea, except in selected cases where concerted medical therapy has failed and fertility is desired. # Surgical options when future pregnancy is not desired For primary dysmenorrhea not responsive to conservative therapy, without evidence of deep infiltrating endometriosis, surgical options include hysterectomy or endometrial ablation.17 Total or subtotal hysterectomy is associated with a high degree of patient satisfaction.86 It addresses primary dysmenorrhea better than it addresses non-cyclic pelvic pain, which may have myofascial, neuropathic, bladder, or gastrointestinal components. Women should be counselled about the possible complications of hysterectomy for benign conditions including the risk of persistent pain, new myofascial or neuropathic pain, and loss of fertility. 87,88 Endometrial ablation is effective for primary dysmenorrhea when associated with heavy menstrual bleeding and provides a less invasive surgical option for women with primary dysmenorrhea who do not desire future pregnancy, 89,90 It has a lower complication rate than hysterectomy; however it needs to be combined with long-term contraception if conception is a possibility. # Summary Statements 6, 7 and Recommendations 13 and 14 NSAIDs and hormonal contraceptives are recommended as first line therapy. Complementary therapy with local heat, regular exercise, and dietary supplements may also be of benefit. Investigation beyond a focused history and abdominal examination may be reserved for those patients who do not respond to $3 { - } 6$ months of concerted therapy. Abnormal physical findings and symptoms resistant to initial therapy should prompt investigation for causes of secondary amenorrhea: initially pelvic ultrasound, with targeted pelvic ultrasound, MRI and/or diagnostic laparoscopy as indicated. Surgical management of dysmenorrhea is reserved for those women for whom medical management has not been effective. Endometrial ablation may be useful for women with heavy menstrual bleeding. Hysterectomy is highly effective and is indicated in recalcitrant cases when future pregnancy is not desired and secondary dysmenorrhea has been ruled out. # SUPPLEMENTARY MATERIAL Supplementary material related to this article can be found at https://doi.org/10.1016/j.jogc.2025.102840. # REFERENCES 1. Bernardi M, Lazzeri L, Perelli F, et al. Dysmenorrhea and related disorders. F1000Res 2017;6:1645. Available at: https://www.ncbi.nlm.nih.gov/ pubmed/28944048. 2. Mendiratta VLG. 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eba84d9e920746b490807d9b69bce454	2025+SOGC临床实践指南	宫内早期妊娠丢失的管理（No.460）	# SOGC CLINICAL PRACTICE GUIDELINE No. 460, June 2025 # Guideline No. 460: Diagnosis and Management of Intrauterine Early Pregnancy Loss (En français : Directive no 459 : Diagnostic et prise en charge de la perte de grossesse précoce intra-utérine) he English document is the original version; translation may introduce small differences in the French version. This clinical practice guideline was prepared by the authors, reviewed by the SOGC’s Clinical Practice Gynaecology Committee and Sexual and Reproductive Health Committees (2025), and approved by the SOGC Guideline Management and Oversight Committee (2025). # Authors Helen Pymar, MD, MPH, Winnipeg, Manitoba Ashley Waddington, MD, MPA, Kingston, Ontario Sarah Prager, MD, MAS, Seattle, Washington, USA Jade Shorter, MD, MSHP, Palo Alto, California, USA Jackie Thomas, MD, MSc, Toronto, Ontario SOGC Clinical Gynaecology Committee (2025): Baharak Amir, Roland Antaki, Philippa Brain, Olga Bougie, Aisling Clancy, Devon Evans, Chelsea Elwood, Andréanne Jodoin, Sari Kives, Kiel Luhning, Bryden Magee, Marie-Hélène Mayrand, Sarah McQuillan, Tarek Motan, Ally Murji, Gregg Nelson (chair), Jessica Papillon-Smith, Frank Potestio, David Rittenberg, Jane Schulz, Rachel Spitzer, Susan Thorne, Angela Vinturache, Paul Yong. Acknowledgements: The authors would like to acknowledge and thank special contributors Melina Castonguay MW Rimouski, Quebec, and Dustin Costescu MD Hamilton, Ontario. SOGC Sexual and Reproductive Health Committee (2025): Kaitlyn Carson, Heather Cockwell, Dustin Costescu (Co-chair), Céline Desjardins, Christine Duclos, Debra Evaniuk, Michele Farrugia, William Fisher, Paige Grenier, Paige Isabey, Michelle Jacobson, Maria Kielly, Kelsey Mills, Sarah Smith, Nicole Todd (Co-chair), Julie Thorne. SOGC Guideline Management Oversight Committee (2025): Melanie Basso, Jocelynn Cook, Diane Francoeur, Bing Guthrie, Kristin Harris, Sarah Healey, Venu Jain, Brent Jim, Andrew Kotaska, Amy Metcalfe, N. Lynne McLeod, Ally Murji, Jessica This document reflects emerging clinical and scientific advances as of the publication date and is subject to change. The information is not meant to dictate an exclusive course of treatment or procedure. Institutions are free to amend the recommendations. The SOGC suggests, however, that they adequately document any such amendments. Informed consent: Patients have the right and responsibility to make informed decisions about their care, in partnership with their health care provider. To facilitate informed choice, patients should be provided with information and support that is evidence-based, culturally appropriate, and personalized. The values, beliefs, and individual needs of each patient in the context of their personal circumstances should be considered and the final decision about care and treatment options chosen by the patient should be respected. Language and inclusivity: While the SOGC as a rule uses gendered language, in respect for our mission to advance women’s health, there are contexts in which it is important to use gender neutral language, and to be fully inclusive. This guideline speaks to the needs of people are often marginalized or “unseen”. For this reason, except where citing the words of others, the SOGC has chosen to use gender neutral language in this guideline. The SOGC recognizes and respects the rights of all people for whom the information in this document may apply, including but not limited to transgender, non-binary, and intersex people. The SOGC encourages health care providers to engage in respectful conversation with their patients about their gender identity and preferred gender pronouns and to apply these guidelines in a way that is sensitive to each person’s needs. Weeks Gestation Notation: The authors follow the World Health Organization’s notation on gestational age: the first day of the last menstrual period is day 0 (of week 0); therefore, days 0 to 6 correspond to completed week 0, days 7 to 13 correspond to completed week 1, etc. Papillon-Smith, Vanessa Poliquin, Frank Potestio (Co-chair), Anita Smith, R. Douglas Wilson (Co-chair). Disclosures: Statements were received from all authors. Dr Sarah Prager reports authoring six UpToDate topics related to early pregnancy loss and receives honoraria for creating and maintaining these topics. She also received funding from the Washington State Department of Health to teach early pregnancy loss management to health systems. Dr Pymar received an honoraria for consulting from Linepharma. No other relationships or activities that could involve a conflict of interest were declared. All authors have indicated that they meet the journal’s requirements for authorship. Subject Categories: abortion; miscarriage; diagnostic imaging; reproductive endocrinology, and infertility Keywords $:$ abortion; spontaneous abortion; miscarriage; early pregnancy loss; incomplete miscarriage Corresponding Author: Helen Pymar, hpymar@hsc.mb.ca # KEY MESSAGES 1. Intrauterine early pregnancy loss is common, occurring in approximately $1 5 \%$ of pregnancies, and can lead to significant psychological distress, including post-traumatic stress disorder (PTSD). 2. A patient-centred approach to diagnosis and management of early pregnancy loss takes into account the desiredness of pregnancy, social circumstances, access to care and patient preferences. 3. Ultrasound is the preferred first-line method for assessing bleeding during pregnancy, as it minimizes the risk of harm to a desired pregnancy. Canadian health care providers should provide compassionate, expedited care for people experiencing bleeding in the first trimester. 4. Early Pregnancy Assessment Clinics can provide patientcentred care for early pregnancy complications and should be established, supported, promoted and appropriately resourced across Canada utilizing standard practice models. # DEFINITIONS Early Pregnancy Loss: Intrauterine pregnancy gestational sac has reached a stage where it has been diagnosed as non-viable based on ultrasound criteria, is in the cervix, or has passed through the cervix. Early Pregnancy Loss (gestational sac present): Intrauterine gestational sac present and not protruding from cervix on speculum examination or ultrasound. Threatened: Bleeding or cramping; cervix closed, no tissue visualized in the vagina; ultrasound may show viable pregnancy with fetal cardiac activity Complete: Early pregnancy loss has passed, bleeding and cramping has subsided, and no intervention was required on follow-up (best diagnosed 6-8 weeks after passage) Incomplete: Gestational sac has passed but symptomatic (bleeding, pain and/or infection) endometrial thickening # ABSTRACT Objective: To provide an evidence-based approach to guide the diagnosis and management of intrauterine early pregnancy loss. Target Population: This population includes patients experiencing pregnancy loss/miscarriage and incomplete pregnancy loss in the context of a normally sited intrauterine pregnancy. It does not include patients with a pregnancy of unknown location, ectopic pregnancy or recurrent pregnancy loss (2 or more pregnancy losses). Benefits, Harms, and Costs: Incorrect diagnosis of a pregnancy loss increases the risk of harming a live, normally sited pregnancy. Prolonged waiting for confirmation of a diagnosis can increase anxiety and delay treatment. Patient-centred care discussions can help patients understand their pregnancy loss risk and make decisions about their management and follow-up, including time off for bereavement and mental health support. Evidence: The following search terms were entered into PubMed from January 2021 to December 2024: early pregnancy loss, incomplete, spontaneous abortion, diagnosis, and management. The International Society of Ultrasound in Obstetrics and Gynecology (2021 and 2022), and Association of Early Pregnancy Units presentations and references were also used. Validation Methods: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations). Intended Audience: Health care providers who provide care to pregnant patients experiencing intrauterine early pregnancy loss. Tweetable Abstract: Early pregnancy loss is a common experience that can be traumatic. Patient-centred care in an Early Pregnancy Assessment Clinic can help patients make informed decisions. # SUMMARY STATEMENTS: 1. Early pregnancy bleeding and loss are common reasons for health care visits (high). 2. Most early pregnancy loss results from aneuploidy and is not preventable or treatable (high). 3. Early pregnancy loss has significant psychosocial consequences for patients and their families that can include depression, anxiety and Post-Traumatic Stress Disorder (PTSD) (high). 4. The establishment of multidisciplinary Early Pregnancy Assessment clinics across the country is recommended; they improve patient experience by expediting evaluation of early pregnancy bleeding and providing physical and emotional care specific to EPL, reducing visits to the emergency department and surgical wait times (high). 5. Care for early pregnancy should be prioritized to provide patientcentred, evidence based care, reduce complications and manage the mental health needs of patients and their families (high). 6. Social circumstances, access to care, and patient preference influence management decisions. When diagnostic uncertainty is present, desiredness of the pregnancy can influence patient decision-making (high). 7. Canada lacks race-based data about early pregnancy outcomes, although data from other countries show inequities; this should be a consideration when providing care and a focus of research in the future (high). 8. When early pregnancy loss is diagnosed, medically stable patients can review all available management options (expectant, medical, procedural (surgical)) with support to make the decision best for them (high). 9. Successful medical management may avoid the need for a surgical procedure and the associated surgical and anesthetic risks; mifepristone and misoprostol should be free for patients who choose medical management (moderate). 10. Current evidence indicates that the amount of fetal blood in the maternal circulation does not reach a level to induce alloimmunization under 12 weeks of pregnancy and guidelines suggest consideration of RhIg administration between 10-12 weeks on an individual basis, in the context of shared decision-making about the potential benefits and risks (moderate). 11. Providing antibiotics prior to procedural (surgical) management of early intrauterine pregnancy loss with uterine aspiration and avoiding sharp curettage may reduce the risks of infection and intrauterine adhesions (moderate). # RECOMMENDATIONS: 1. Ultrasound criteria should be used to diagnose intrauterine early pregnancy loss. (strong, high) 2. Clinicians should avoid using hCG values alone to diagnose normal intrauterine pregnancy as there is overlap between nonviable intrauterine pregnancy, viable intrauterine pregnancy, and ectopic pregnancy. (strong, high) 3. Clinicians should screen patients diagnosed with pregnancy loss for depression and offer treatment or referral to a mental health care provider when they have symptoms of depression. (strong, moderate) 4. Patients with no prior history of early pregnancy loss should be counselled that no known treatment can change the outcome of a threatened early pregnancy loss. (strong, high) 5. Patient health history (anemia, bleeding disorders, etc.), and proximity to a health care facility that can manage urgent and emergent complications should be considered when counselling patients on management options. (strong, high) 6. For stable patients with EPL without signs of infection, all available management options (expectant, medical, procedural) should be discussed. (strong, high) 7. Patients who choose expectant or medical management of early pregnancy loss should be counselled about the potential need for urgent intervention and provided with instructions on when and where to present for medical assessment if excessive bleeding, pain or signs and symptoms of infection occur. (strong, high) 8. Clinicians should use mifepristone and misoprostol or multidose misoprostol alone for medical management of early pregnancy loss (gestational sac present). (strong, high) 9. Expectant management has high success rates for incomplete Early Pregnancy Loss (thickened endometrium with no gestational sac present) and should be a first choice when the patient does not have heavy bleeding, significant pain, or infection. (strong, moderate) 10. Clinicians should use a misoprostol-only regimen when patients request medical management of incomplete Early Pregnancy Loss (thickened endometrium with no gestational sac present). (strong, high) 11. A definite intrauterine early pregnancy loss managed expectantly or medically that results in heavy bleeding which resolves can be followed clinically. Ultrasound $+ / -$ hCG levels can be reserved for clinical concerns: ongoing heavy bleeding, suspected infection, spotting $> 3$ weeks or amenorrhea $> 8$ weeks. (strong, moderate) 12. Routine RhIg prophylaxis for early pregnancy loss at less than 12 weeks is not recommended (moderate). RhIg administration can be considered on an individual basis between 10-12 weeks in the context of a shared decision-making discussion about the potential benefits and risks. (conditional, moderate) 13. For surgical management, suction curettage is recommended. Sharp curettage should be minimized to reduce the risk of intrauterine adhesions (strong, moderate); antibiotic prophylaxis should be considered to reduce the risk of infection. (strong, moderate) 14. For a clinically complete Early Pregnancy Loss (heavy bleeding that has resolved), expectant management has a high success rate even if retained products are identified on ultrasound with no gestational sac present. (strong, moderate) 15. Pregnant patients who have experienced a prior early pregnancy loss should be offered a reassurance ultrasound at 7 weeks GA to confirm pregnancy location and viability. (strong, low) 16. Clinicians should create local health quality improvement initiatives to improve wait times for requested procedural management and reduce repeat visits to the emergency department. (strong, moderate) # INTRODUCTION t is estimated that around $1 5 \%$ of pregnancies end in I EPL with rates varying based on age and the number of prior EPL.1,2 Many people who experience early pregnancy loss will present with vaginal bleeding during early pregnancy. Data from an Ontario hospital suggest that emergency department rates for the initial and reassessment of early pregnancy hemorrhage are $1 . 2 \%$ and $0 . 3 \%$ , respectively of all emergency department visits over a 10 year period. These patients often wait long hours in emergency departments/urgent care and are sent home without a diagnosis or treatment plan due to a lack of ultrasound availability.3 Patients often receive minimal or no emotional support once sent home.4 Patients living in rural Canadian communities generally have less access to resources (e.g.. ultrasound or access to Obstetrician Gynaecologists) and may require transportation far from their local support networks to receive a diagnosis and treatment.5,6 Patients experiencing early pregnancy loss often avoid sharing this information with friends and family, increasing isolation and self-blame. While there are some modifiable causes of early pregnancy loss, most often there is nothing the patient could have done to impact the outcome, and misinformation is harmful.2 There is an association between pregnancy loss and anxiety, depression, and post-traumatic stress disorder. 2,7e10 Although the current definition of recurrent pregnancy loss includes three or more consecutive unexplained first trimester EPLs, the Royal College of Obstetricians and # ABBREVIATIONS <table><tr><td>CRL</td><td>crown rump length</td></tr><tr><td>EPAC</td><td>Early Pregnancy Assessment Clinic</td></tr><tr><td>EPL</td><td>early pregnancy loss</td></tr><tr><td>GA</td><td>gestational age</td></tr><tr><td>hCG</td><td>human chorionic gonadotropin</td></tr><tr><td>IUP</td><td>intrauterine pregnancy</td></tr><tr><td>MSD</td><td>mean sac diameter</td></tr><tr><td>MUA</td><td>manual uterine aspiration</td></tr><tr><td>POCUS</td><td>point of care ultrasound</td></tr><tr><td>PTSD</td><td>post-traumatic stress disorder</td></tr><tr><td>PUL</td><td>pregnancy of unknown location</td></tr><tr><td>Rh</td><td>Rhesus</td></tr><tr><td>RhIG</td><td>Rhesus immunoglobulin</td></tr><tr><td>STI</td><td>sexually transmitted infection</td></tr></table> Gynaecologists (RCOG) now encourages clinicians “to use their clinical discretion to recommend extensive evaluation after two first trimester EPLs if there is a suspicion that the EPLs are of pathological and not of sporadic nature.1 Canada can look to the United Kingdom (UK) as an example of how to improve care for patients experiencing early pregnancy loss.12 There are over 200 Early Pregnancy Assessment Clinics/Units throughout the UK that provide an alternative to the emergency department and allow for semi-urgent standardized outpatient assessments of nonurgent early pregnancy bleeding and complications.12 Canada has established Early Pregnancy Assessment Clinics in a few areas; however, more work is needed to expand and standardize care across our country. In a 2017 survey of Ontario emergency departments providing at least $3 0 ~ 0 0 0$ visits per year, $54 \%$ did not have access to an Early Pregnancy Assessment Clinic.3 Care for early pregnancy should be prioritized to provide patient-centred, evidence based care, reduce complications and manage the mental health needs of patients and their families. There are regional differences in our diverse country, and a “one size fits all” approach may not be realistic. This guideline addresses care for patients experiencing early pregnancy loss (EPL); it does not address the diagnosis and management of pregnancy of unknown location (PUL), ectopic pregnancy, or recurrent pregnancy loss. # Summary Statements 1, 2, 3,4 and 5 # DIAGNOSIS OF EARLY PREGNANCY LOSS Ultrasound is key to establishing pregnancy location and viability.13 15 Findings of an intrauterine gestational $\mathsf { s a c } >$ $2 5 ~ \mathrm { m m }$ without an embryonic pole or an embryo with a crown rump length of $7 ~ \mathrm { m m }$ without a heartbeat on endovaginal scan are diagnostic of EPL (Box 1).17 Findings with measurements below these thresholds usually establishes intrauterine location but not viability, and follow-up ultrasound is indicated. However, some patients who are uncertain about continuing the pregnancy or unable to attend follow-up # Box 1. Initial Endovaginal Ultrasound Scan Criteria for Early Pregnancy Loss16 <table><tr><td>· No visible embryo and a mean gestational sac diameter of ≥25mm · Embryo with no cardiac activity and a crown-rump length of ≥7mm</td></tr></table> appointments may wish to intervene with medical or surgical management despite diagnostic uncertainty. It is appropriate to offer these patients an intervention prior to obtaining a diagnosis of pregnancy loss with $100 \%$ certainty. Endovaginal ultrasound can provide $100 \%$ certainty of pregnancy loss when performed by appropriately trained clinicians (Figure 1 and Box 1).16,18 When initial ultrasound scan criteria for EPL is not met, and an intrauterine pregnancy is highly likely, Figure 1 reviews optimal timing for a repeat ultrasound scan to make a diagnosis of viable pregnancy or pregnancy loss. Prior to the development of a yolk sac or embryo (definite IUP) there is at least a $9 7 \%$ certainty that any intrauterine sac-like structure on ultrasound will represent an IUP, especially if the sac is eccentric (i.e. intradecidual sac sign) or has 2 concentric echogenic rings (i.e. double decidual sac sign).19,20 In contrast, intrauterine fluid, associated with about $1 7 \%$ of ectopic pregnancies, is more commonly described as “pointy edged” $( 7 8 \% )$ , with echoes or debris $( 7 4 \% )$ , and within the uterine cavity.21 When only intrauterine fluid, a very small gestational sac (e.g., under $4 \mathrm { m m }$ ) or probable incomplete or complete early pregnancy loss is suspected with no prior ultrasound showing a gestational sac with yolk sac or embryo perform a quantitative hCG at diagnosis and repeat in 48 hours to estimate risk of ectopic pregnancy and guide follow-up (Figure 1). Some non-viable gestational sacs do not develop a yolk sac. The absence of a yolk sac on endovaginal ultrasound inside a gestational sac with a mean sac diameter (i.e. the sum of measurements in 3 orthogonal planes divided by 3) of $8 \mathrm { \ m m }$ , $1 2 ~ \mathrm { m m }$ , $1 6 ~ \mathrm { m m }$ , and $2 0 \ \mathrm { m m }$ predicts a $73 \%$ , $8 3 \%$ , $90 \%$ , and $9 6 \%$ final diagnosis of early pregnancy loss, respectively.18 Similarly, the absence of cardiac activity in an endovaginal scan of an embryo with a crown rump length (CRL) of 3, 4, 5, and $6 \mathrm { \ m m }$ predicts a pregnancy loss rate of $94 \%$ , $9 6 \%$ , $9 7 \%$ , and $9 8 \%$ , respectively.18 Slow heart activity (e.g. under 90 beats per minute prior to 6.3 weeks or under 110 beats per minute at 6.3 to 7 weeks) has been associated with a $60 \%$ risk of pregnancy loss. While knowledge of the probability of EPL has not been shown to reduce patients’ anxiety, it can provide psychological preparation. Using risk predictors for pregnancy loss can assist patients who do not require $100 \%$ certainty of pregnancy loss to make individual management decisions. ![](images/f5297efc51e6606deee6b6a324bd0023efb6073128ac352d7874fa6e029e5609.jpg) Figure 1. Timeline of endovaginal ultrasound follow-up to determine pregnancy outcome when initial criteria for pregnancy loss not met. Bleeding and/or pelvic pain in early pregnancy has been shown to slightly increase the composite risk of antenatal complications in a prospective study of 826 patients $2 6 \%$ v s $1 7 \%$ with no pain or bleeding).22 The presence of a large first trimester subchorionic hemorrhage, especially when diagnosed before 7 weeks on ultrasound has been associated with an increased risk of pregnancy loss in some studies but results are conflicting.23,24 Subchorionic hematoma has also been associated with increased risk of preterm labour suggesting a need for increased vigilance during prenatal care. (adjusted odds ratio 1.94. $9 5 \%$ CI 1.07 to 3.52).23,25 Once a pregnancy is confirmed as intrauterine with cardiac activity, a repeat ultrasound should be considered if vaginal bleeding worsens or persists beyond 14 days. To avoid multiple emergency department visits, patients with higher levels of anxiety may benefit from more frequent assessment of viability with early referral to a health care provider that can perform point of care ultrasound and/or doptone where appropriate. Decreasing serum hCG may help clarify the ultrasound diagnosis when uncertainty exists because hCG most commonly rises under 8 weeks of pregnancy. The hCG trajectory can aid in decision-making in situations when imaging is suspicious for, but not diagnostic of EPL and the patient does not wish to wait for, or may have difficulty accessing follow up ultrasound. In a prospective study of 107 patients with a symptomatic intrauterine pregnancy of uncertain viability (gestational sac but no embryo with cardiac activity; not meeting pregnancy loss criteria) an hCG ratio (hCG 48 hours after ultrasound divided by hCG at time of ultrasound) of less than 1.11 had a $100 \%$ specificity and positive predictive value to predict EPL in $24 \%$ of their study group.26 Human chorionic gonadotropin (hCG) levels range broadly and do not accurately differentiate between asymptomatic normal and abnormally developing pregnancies in patients under 45 days gestation.27 In normally developing pregnancies, the quantitative hCG levels plateau around 8-10 weeks, then drop, leading to potential harm of a wanted pregnancy when hCG trends are used without ultrasound to diagnose pregnancy loss.27 Ultrasound is necessary for diagnostic certainty. # Summary Statement 6 and Recommendations 1 an # PSYCHOSOCIAL AND COMMUNICATION CONSIDERATIONS # Rates of Early Pregnancy Loss and Racial Disparities Research exploring disparities within EPL populations is limited but suggests that race may influence one’s risk of EPL. One report found that Black patients were $57 \%$ more likely to have experienced EPL compared to White patients;28 this difference persisted after adjustments for age and alcohol consumption. Similarly, a study in 2021 reported that Black race was associated with a higher risk of EPL when compared with White race.2 The contributing factors to these disparities remain largely unexplored. There are few studies examining EPL rates in First Nations populations. Indigenous individuals may be at higher risk of EPL. In a prospective study of First Nations patients with pregestational type 2 diabetes, the baseline EPL rate was high at $2 7 . 7 \%$ likely due to multiple factors. The authors identified opportunities for management for the prevention of future EPLs including preconception and pregnancy support for smoking cessation, glycemic control, and weight management.29 Systemic factors (e.g. poverty, loss of cultural practices, and geographic segregation) may play a role in disparities in EPL rates among these populations. Data exploring the association between EPL rates and various racial and ethnic groups in Canada is very limited and further research is needed to elucidate this. # Summary Statement 7 # Early Pregnancy Loss and Mental Health Implications EPL is associated with poor psychological outcomes that can persist for months after the loss. 7,30 Patients who experience EPL have higher rates of depression, anxiety, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD).31e33 A study looking at the diagnosis of major depressive disorder after pregnancy loss found that $1 0 . 9 \%$ of patients met the criteria for depression, which was 2.5 times higher than for non-pregnant patients. In a prospective multicentre cohort study, PTSD $( 2 9 \% )$ , anxiety $( 2 4 \% )$ and depression $( 1 1 \% )$ were present in individuals who had recently experienced pregnancy loss, and these mental health states persisted 9 months later at rates of $1 8 \%$ , $1 7 \%$ and $6 \%$ respectively. 34 In a planned secondary analysis of a randomized controlled trial comparing medication regimens for the management of EPL, Shorter et al. found that $24 \%$ of people were at risk for major depression 30 days after EPL. Black participants experienced depression more than twice as often as non-Black participants (adjusted odds ratio: 2.48, $9 5 \%$ CI 1.28-4.81) when controlled for baseline depression, adverse childhood events score, and parity.10 Grief after EPL may be similar to that following the loss of any loved one. Guilt with underlying self-blame was found to be the strongest aspect of grief and required the longest time to resolve. Evidence suggests increased risk for depression and PTSD after EPL and the psychosocial support offered should be similar in these situations.15,30 Clinicians should consider the need for time off for grieving patients experiencing EPL, and should offer psychosocial support resources for patients, ideally in the patient’s first language. Adverse mental health outcomes are common in EPL and are present in up to $30 \%$ of people one month after experiencing EPL.34 This indicates a need for mental health screening and appropriate mental health resources for patients undergoing care for EPL. Individuals displaying depressive symptoms, symptoms of grief or psychological distress, and/or anyone with a positive depression screen should be offered treatment for depression and be referred for mental health care services.35 # Recommendation 3 # Language and Communication The use of language is important in EPL care. Patients most commonly prefer to describe pregnancy loss as a miscarriage, followed by the term Early Pregnancy Loss. Patients reported that the terms early pregnancy failure and spontaneous abortion are less favored and not well understood.36 Early Pregnancy Loss is often misunderstood by both patients and health care providers, and there is a lack of awareness of how frequently EPL occurs and what causes it.2 Patients who experience EPL often report feelings of guilt or shame2 and these beliefs can lead patients to a false sense of responsibility for their pregnancy loss.37 Patients should be reassured that they are not to blame for the loss as most are related to chromosomal abnormalities occurring at conception.2 # Recommendation 4 # Early Pregnancy Assessment Clinics (EPACs) and Health Disparities Visits to the emergency department for vaginal bleeding in early pregnancy are common, with approximately 900,000 visits a year in the US $2 . 7 \%$ of all visits). Underserved communities experience higher rates of early pregnancy loss28 and present to the ED more commonly for early pregnancy complications including vaginal bleeding in early pregnancy. 38,39 EPACs serve as an alternative to the emergency department, providing expedited evaluation of early pregnancy complications. An alternative to the emergency department, EPACs are ambulatory care units that provide streamlined and comprehensive early pregnancy care including sonography, diagnosis and treatment of early pregnancy complications, and emotional resources for EPL. EPACs offer high value and cost-effective early pregnancy care, however regional resource restrictions may limit some EPAC services. By improving access, EPACs can help underserved and historically marginalized patient populations find appropriate counseling, management, and multidisciplinary resources. EPACs are an important component in providing patient-centered care and promoting health equity.1 # Summary Statement 7 # MANAGEMENT AND FOLLOW-UP OF EARLY PREGNANCY LOSS Recommended management of EPL depends on the clinical situation. Surgical aspiration is indicated for patients with heavy bleeding, signs of infection, significant anemia or a bleeding disorder. For clinically stable patients, expectant, medical, and surgical management are all options. In a recent Cochrane analysis, patients who underwent suction aspiration plus cervical preparation with agents such as misoprostol had the highest probability of successful EPL management within 7 days, followed by suction aspiration alone.40,41 Patient health history (anemia, bleeding disorders) social circumstances (distance from home, other family needs, work) and access to emergency care should be considered when creating a management and follow-up plan. Suitable patients should consider the time they are willing to wait for resolution of the EPL, the possible need for unscheduled surgery, and their tolerance of pain and bleeding. When determining an appropriate management strategy, gestational age by ultrasound and last menstrual period should be considered. While all options can be considered for patients in the first trimester, the increasing amount of pain, bleeding, and potential distress at seeing identifiable fetal parts in the products of conception should be contemplated and discussed with patients choosing expectant or medical management in the late first trimester. # Summary Statement 8 and Recommendations 5 # Expectant Management of Early Pregnancy Loss Patients who choose expectant management should be counselled about the potential need for urgent intervention (e.g. surgery, pain management, blood transfusion) and provided with verbal and written instructions on when and where to present for medical assessment if excessive bleeding, pain, or signs and symptoms of infection emerge. A trial of 182 patients with loss under 14 weeks from last menstrual period where patients were randomized to 7 days expectant management followed by medical management if no passage of gestational sac or medical management documented higher percentages of urgent procedural management $20 \%$ vs $4 . 5 \%$ ), and unplanned visits to the emergency department $( 3 4 \%$ vs $1 7 \%$ ), respectively.42 The majority of participants had ultrasound diagnosis of early embryonic demise at 8 weeks size or greater. Expectant management success rates are estimated to be around $64 \%$ within 7 days for patients with an EPL where a gestational sac is visualized on ultrasound.40 In a randomized trial of expectant versus misoprostol management of EPL, complete EPL without procedural evacuation was achieved within 31 days in $8 5 \%$ (76/89) of the women in the $8 0 0 ~ \mathrm { m c g }$ vaginal misoprostol group and $6 5 \%$ (54/83) of those managed expectantly.43 Expectant management is highly effective for asymptomatic patients with retained products of conception (POC) found on routine follow-up ultrasound. Accordingly, routine follow-up ultrasound is not required after a clinically complete EPL when a there was a prior definite IUP; ultrasound can be reserved for patients with ongoing bleeding or cramping (clinically incomplete EPL). # Recommendation 7 # Medical Management of Early Pregnancy Loss Stable patients with a first trimester pregnancy loss and last menstrual period within 13 weeks 6 days who do not have contraindications to mifepristone or misoprostol or any need for more intensive surveillance (i.e. signs or symptoms of infection, significant anemia, bleeding diatheses, etc.) can be offered medical management. Outcomes with regards to infection (slightly favours medical management) and hemorrhage (slightly favours aspiration)41,44,45 are similar between treatments. Successful medical management may avoid the need for a surgical procedure and the associated surgical and anesthetic risks. Patients should be counselled there is an approximate $10 \%$ chance of requiring an unplanned/ emergency surgical procedure,41 and that they may require suction aspiration for prolonged or heavy bleeding, infection or severe pain. Some patients express a preference for medical management as it feels more “natural” and private than a surgical procedure. The mainstay of medical management for non-viable pregnancy is misoprostol, a synthetic prostaglandin E1 analogue which induces contraction of the myometrium and dilation of the cervix, leading to the expulsion of uterine contents. Various dosing regimens and routes of administration have been studied46e50 with $8 0 0 ~ \mathrm { m c g }$ of vaginal or buccal misoprostol the favoured dose and routes.41 In recent years, research into the addition of mifepristone in the setting of medical management for early pregnancy loss has demonstrated a benefit.51,52 Mifepristone, an antiprogestin, promotes the release of endogenous prostaglandins and helps to make the myometrium more responsive to the effects of misoprostol. # Misoprostol for Early Pregnancy Loss Misoprostol is a synthetic prostaglandin E1 analogue which softens the cervix and causes uterine contractions and expulsion of uterine contents. Side effects of misoprostol are dose-related and include nausea, vomiting, diarrhea, fever, and shivering. Individual patients likely have varying sensitivities, and rare cases of severe hyperthermia have been observed.53 Various oral and transmucosal dosing regimens and routes of administration have been studied.54,55 While oral, vaginal, buccal and sublingual routes have all been shown to be effective for treating EPL;46e50 vaginal or less commonly buccal misoprostol are used likely due to increased gastrointestinal side effects with oral and sublingual misoprostol. 41,56 ( see Table 1) Misoprostol alone will result in the complete expulsion of products of conception in around $8 3 \%$ of cases,40 and potentially higher if enough doses are given,48 but repeat doses can cause more side effects. The variation in the dosing, route of administration and follow up protocol accounts for the variation seen in published studies. There are consistent findings that a multi-dose regimen (2 or more doses of misoprostol) is more efficacious than a single dose,45,48 and a longer follow up period results in higher success rates for both expectant and medical management of first trimester pregnancy loss.45,58 Multidose misoprostol only regimens include $6 0 0 ~ \mathrm { m c g }$ misoprostol every 3 hours for up to 3 doses vaginally or sublingually.48 The WHO 2022 abortion care guideline did not provide a recommendation for the number of doses and timing of repeat misoprostol for pregnancy loss beyond the single $8 0 0 ~ \mathrm { \ m c g }$ dosing, suggesting more research is needed. See Table 1 for recommended treatment options. If bleeding and cramping continue after completion of either regimen, reassessment for possible suction aspiration is warranted. # Mifepristone Plus Misoprostol Regimens In recent years, research into the addition of mifepristone in the setting of medical management for early pregnancy loss has demonstrated a benefit.51,52 Mifepristone is an antiprogestin that releases the trophoblast, promotes endogenous prostaglandin production, softens the cervix, and enhances myometrial responsiveness to misoprostol. Two recent studies comparing $2 0 0 ~ \mathrm { { m g } }$ of mifepristone plus $8 0 0 ~ \mathrm { m c g }$ misoprostol to a single dose of $8 0 0 ~ \mathrm { m c g }$ misoprostol found that treatment success was higher in the group that received pretreatment with mifepristone.52,58 Over $90 \%$ of patients in the Schreiber study had a gestational age of 9 weeks or less.52 The Chu study had similar numbers of patients enrolled under and over 70 days’ gestational age (10 weeks) with a maximum of 13 weeks 6 days from last menstrual period. Caution should be exercised in extrapolating this data for patients with a gestational sac size of 10 weeks or more since the participants had a median (IQR) gestational age of 70 (62-82) days from last menstrual period and there was limited data on associated gestational sac size.58 At initial follow up 2-3 days after study enrollment, Schreiber et al found that the mifepristone-misoprostol group had an $8 3 . 8 \%$ treatment success rate (defined as expulsion of gestational sac on ultrasound), compared to the $6 7 . 1 \%$ in the $8 0 0 \mathrm { m c g }$ misoprostol alone group. Ultimately, the need for uterine aspiration by 30 days was $8 . 8 \%$ in the mifepristonemisoprostol group vs. $2 3 . 5 \%$ in the misoprostol-only group. Chu et al found the 7 day treatment failure rate to be $1 7 \%$ and $24 \%$ in the mifepristone-misoprostol group and the misoprostol alone group, respectively.58 It should be noted that around $2 \%$ of the over 1000 patients in these combined medical management studies required blood transfusion. Using an additional dose of misoprostol routinely has been considered. A prospective cohort study routinely providing a routine second dose of vaginal misoprostol 24 hours after the first dose with mifepristone pre-treatment diagnosed complete expulsion of gestational sac in $9 3 \%$ by day 14.57 # Summary of Medical Management Considerations Current evidence suggests that a multi dose misoprostol regimen is superior to a single dose misoprostol regimen, and that the addition of mifepristone to a single dose of misoprostol is superior to a single dose misoprostol regimen for early pregnancy loss when a gestational sac is present. Other important considerations when selecting a medical management regimen include side effects, patient satisfaction with their treatment and accessibility. Mifepristone is only available in Canada as Mifegymiso $^ \mathrm { \textregistered }$ , which includes one tablet of mifepristone $( 2 0 0 ~ \mathrm { m g } )$ and 4 tablets of misoprostol (200 mcg each). This is not enough misoprostol for a multidose regimen, so additional tablets need to be provided. The cost is approximately $\$ 340$ CAD, approximately ten times greater than in the UK, emphasizing the need to advocate for removing cost barriers for Canadian patients Table 1. Recommendations for Medical Management of Early Pregnancy Loss and Incomplete Early Pregnancy Loss <table><tr><td>Timing</td><td>Recommended Regimen</td></tr><tr><td colspan="2">EPL (gestational sac present)-use with caution over 10 weeks gestational sac size given limited data in this size cohort</td></tr><tr><td rowspan="2"><14 Weeks:</td><td>Mifepristone 200 mg orall followed in1-2 days by misoprostol800 mcg administered byany route (vaginal, buccal, sublingual).</td></tr><tr><td>Misoprostolmay be repeatedin 3-24 hours.57 Some evidence that administering misoprostol as soon as 10 hours after mifepristone is equivalently effective.a</td></tr><tr><td>9-14 Weeks:</td><td>Consider at least one aditional dose of misoprostol 40800mcg (vaginal,buccal,sublingual)ata 3-24 hour intervals until expulsion.b</td></tr><tr><td colspan="2"> Alternative Options for EPL</td></tr><tr><td><9 Weeks: 9-14 Weeks:</td><td>Misoprostol 80o mcg administered by any route (vaginal, buccal, sublingual). Suggest giving multiple doses of misoprostol 800 mcg at 3-hour intervals until expulsion.b</td></tr><tr><td></td><td>Misoprostol800 mcgadministered byanyroute (vaginal,buccal,sublingual) Give at least one additional dose of misoprostol 40o-800 mcg at a 3-hour interval. Suggest additional doses of misoprostol 40o-800 mcg at 3-hour intervals until expulsion.b</td></tr><tr><td colspan="2">Incomplete EPL (no gestational sac present)</td></tr><tr><td><14Weeks:</td><td>Misoprostol 600-80 mcg by any route (vaginal, oral or sublingual)bc</td></tr><tr><td>13-17weeks</td><td>Misoprostol 400 mcg by sublingual/buccal routes every 3-hoursb</td></tr></table> a Flynn AN, Roe AH, Koelper N, McAllister A, Sammel MD, Schreiber CA. Timing and efficacy of mifepristone pretreatment for medical management of early pregnancy loss. Contraception. 2021;103(6):404-7. b Based on expert opinion and medical abortion studies for unplanned pregnancies and modified from FIGO Mifepristone and Misoprostol and Misoprostol only Dosin Charts 2023 https://www.figo.org/sites/default/files/2023-12/FIGO-MifeMiso-Chart-11-2023-FINAL.pdf https://www.figo.org/sites/default/files/2023-12/FIGO-Miso-Chart 11-2023%20FINAL.pdf c Modified from the NICE guidelines Ectopic pregnancy and Miscarriage: Diagnosis and Initial Management updated on August 2023 The cost effectiveness of mifepristone plus misoprostol versus misoprostol alone has not been evaluated in a Canadian setting, but is an important consideration for both treatment and future research. Countries in which the addition of mifepristone has been studied typically have a lower medication cost for mifepristone compared to Canada, and so cost-benefit analyses from those countries do not translate to a Canadian context.59,60 While this cost is not typically borne by the patient themselves if they have medical coverage through their provincial or territorial health plan, it is borne by the health care system. In contrast, the wholesale cost of 2 doses of $8 0 0 \ \mathrm { m c g }$ of misoprostol is between $\$ 5.00 – \$ 10.00$ CAD. This cost difference currently represents a significant burden to the Canadian health care system. Research investigating the true benefit of mifepristone plus misoprostol vs. multiple doses of misoprostol, including side effects, success rates, time to treatment completion, ultrasound loss size using mean sac diameter, and patient satisfaction would provide necessary additional information to determine the true cost benefits of a combination regimen. In summary, mifepristone plus misoprostol or multiple doses of misoprostol are currently the most effective, evidence-based regimens for EPL management when a gestational sac is present, though a directly comparative study between mifepristone plus misoprostol versus a multiple dose regimen of misoprostol only has not occurred. Lack of access to mifepristone for any reason, including cost burdens, should not prevent medical management with misoprostol-only regimens; medical management with misoprostol alone is a reasonably effective alternative. A misoprostol-only regimen should be used for medical management of incomplete EPL with no gestational sac present. See Table 1 for suggested dosing regimens. # Summary Statement 9 and Recommendations 8, 9 and 10 # Follow-Up After Medical and Expectant Management When the clinician is very certain of an intrauterine pregnancy loss, routine follow-up for non-procedural management can include either home urine pregnancy test, serum hCG, follow-up ultrasound, or review of clinical symptoms depending on patient preference and the available resources. Patients experiencing spontaneous or medically managed EPL should be informed that they will typically experience bleeding heavier than a normal menstrual period that will abate, followed by tapered lighter bleeding lasting 1-2 weeks. Provided this occurs, patients can be followed clinically, with ultrasound reserved for clinical signs of incomplete EPL: prolonged bleeding or cramping, more than 8 weeks of amenorrhea, or persistent bulky uterus with an open cervix. Routine ultrasound to rule out retained products of conception is not required. If an ultrasound is performed, the absence of a gestational sac without persistence of heavy bleeding, pain or infection should be sufficient to follow expectantly. Serial hCG measurements are not required in the management or follow-up of a confirmed non-viable intrauterine pregnancy. However, expectations for hCG drop one week after spontaneous EPL would be at least 86 to $94 \%$ when initial hCG is $5 0 0 0 \mathrm { I U / L }$ or less.61 In a study of hCG change after medical management, a one week hCG drop of $87 \%$ or greater was the optimal cut-off point to predict no gestational sac, compared to a median drop of $5 9 \%$ for those with a sac present.62 In situations of suspected retained products, a clinical assessment should be performed, and additional investigations arranged based on its findings. Clinical findings associated with retained products of conception include persistent heavy bleeding beyond 2 weeks, persistent pain or cramping, failure to resume menses for more than 6-8 weeks, and enlarged uterus or open cervix on physical exam. If there is clinical suspicion of retained products of conception and no resumption of menses, consider starting with a home urine pregnancy test at least 6-8 weeks from diagnosis or treatment. # Recommendation 11 # Surgical (Procedural) Management of Early Pregnancy Loss Surgical management of EPL is recommended when there is heavy bleeding (when patients are soaking through 2 or more pads per hour for 2 consecutive hours), infection, significant maternal anemia, or severe pain despite oral pain medication. Some patients may prefer definitive management, especially if they live far from emergency care should surgery be required during medical or expectant management. However, clinicians can consider indicated use of ultrasound during procedural management in the setting of very early and late first trimester procedures, concern for retained products of conception, and challenging uterine anatomy to reduce the risk of incomplete EPL. Surgical evacuation of the uterus should be by manual or electric vacuum suction; the use of sharp curettage should be minimized or avoided to reduce pain and potentially the risk of intrauterine adhesions.63 # When is Rh Immunoglobulin (RhIG) Testing and Treatment Necessary for Early Pregnancy Loss? There is a growing body of evidence and guidelines that recommend limiting testing and treatment of RhIG in the first 12 weeks for any indication. Current evidence demonstrates that the amount of fetal blood in the maternal circulation does not reach a level to induce alloimmunization in the first 12 weeks of pregnancy.64e66 The earliest gestational age at which an Rh negative patient has experienced confirmed sensitization without receiving RhIG is 16 weeks.67 A majority of international organizations, including the World Health Organization,68 the Society of Family Planning,64 the National Institute for Health and Care Excellence,69 and the National Abortion Federation70 all now support limiting or eliminating Rh testing and RhIG treatment in the first trimester for any reason. Rh testing and RhIG are not recommended for pregnancy loss at less than 12 weeks. If gestational age is uncertain and may exceed 12 weeks, hIG should be given to unsensitized Rh negative women. RhIg administration may be considered between 10-12 weeks on an individual basis, in the context of shared decision-making about the potential benefits and risks. For further information please refer to the SOGC Position Statement on Rh and Alloimmunization. # Summary Statement 10 and Recommendation 12 # Are prophylactic antibiotics indicated in management of early pregnancy loss? Antibiotic prophylaxis prior to procedural (surgical) management Administration of prophylactic antibiotics in procedural abortion reduces the risk of infection by more than $40 \%$ . Recommendations for antibiotic selection and dosing are provided in the current SOGC guideline on induced abortion. 72 Until recently, no studies specifically evaluated the need for prophylactic antibiotics in surgical management of EPL. In 2019, Lissauer, et al.73 published a multi-centre, multicountry (Malawi, Pakistan, Tanzania, Uganda), doubleblinded, randomized study evaluating whether antibiotics would reduce the risk of infection after surgical management of pregnancy loss in the first trimester. The findings show no overall difference in infection rates in those randomized to receive antibiotics compared to placebo. However, the majority of this surgical management in this study was performed with sharp curettage. In a sub-group of patients who received manual uterine aspiration (MUA), a lower rate of infection was found with antibiotic prophylaxis. There are no data specifically evaluating the risk of infection after sharp curettage versus aspiration with a cannula, however there are some data that sharp curettage is associated with more overall pain. Given that pain is one of the factors leading to a diagnosis of post-procedural infection, higher overall rates of pain may mask any difference that might exist in actual infection rates in those subjects who were managed with sharp curettage. However, in those patients managed with MUA, a benefit of antibiotics could be appreciated given the overall lower post-procedural pain. We have indirect evidence that sharp curettage leads to more scarring/infection, but no direct comparative data. Rates of uterine scarring were much more common when rates of septic abortion were higher, which also predated common use of suction aspiration for surgical management. While this evidence is not conclusive, it does suggest a likely lower risk of uterine scarring with avoidance of sharp curettage and use of prophylactic antibiotics to limit infection.40 The American College of Obstetrics and Gynecologists also recommends that, despite the lack of data, antibiotic prophylaxis also should be considered for patients with early pregnancy loss.74 # Antibiotics for medical management of early pregnancy loss The SOGC guideline for induced medical abortion does not recommend antibiotic prophylaxis.75 In a retrospective cohort study from Planned Parenthood Federation of America the baseline risk of serious infection in patients obtaining induced medical abortions was approximately $1 /$ 1000 after vaginal administration of misoprostol and no antibiotics. Switching to buccal misoprostol and adding a 7-day course of doxycycline (100mg po bid) reduced the risk to approximately $1 / 1 0 { , } 0 0 0$ . Given the rare incidence of serious infection after medication abortion, antibiotics are also not felt to be indicated for medical management of EPL. Individuals presenting with EPL are not at increased risk of sexually transmitted infections (STIs) compared with the general population; screening should be done according to standard recommendations. In summary, we recommend the use of prophylactic antibiotics with procedural management of early pregnancy loss and against the use of prophylactic antibiotics with medical management.40,73 # Summary Statement 11 and Recommendation 13 # MANAGEMENT OF RETAINED PRODUCTS OF CONCEPTION/INCOMPLETE EARLY PREGNANCY LOSS (WITH NO GESTATIONAL SAC) Incomplete EPL lacks a consistent definition. In the Chu study of medical management of EPL, average duration of bleeding was 16 days (SD 12.6) after medical management of EPL. Practically, hemodynamically stable patients presenting with significant ongoing bleeding and cramping more than 6 weeks after heavy bleeding and passage of tissue could be assessed for incomplete EPL with earlier assessment reserved for those with significant pain, drop in hemoglobin or hemodynamic instability. Ultrasound frequently overcalls retained products of conception when a gestational sac has passed and there is a thickened endometrial lining. Several studies have used routine ultrasound to assess for retained products after medical EPL management in patients who have minimal or no symptoms. In these patients, it is common to find retained products of conception (thickened endometrium); however a vast majority pass spontaneously with time. Some studies of retained products used a measurement of the endometrial lining over $1 0 \mathrm { m m }$ without considering patient bleeding, pain or evidence of infection, and considered success based on further ultrasound findings and/or lack of need for surgery within 3 months.76,77 This practice can lead to unnecessary repeat visits, medication side effects, and surgeries. When a gestational sac is passed after EPL, endometrial thickness should not be used to determine need for treatment alone. In a prospective study of 80 patients successfully treated with misoprostol for EPL (gestational sac passed), median endovaginal endometrial thickness decreased over time (day $3 \mathrm { ~ - ~ } 3 6 \%$ over $1 5 ~ \mathrm { m m }$ ; day $8 \text{‰}$ over $1 5 ~ \mathrm { m m }$ ; and day $1 5 \mathrm { ~ - ~ } 1 1 \%$ over $1 5 ~ \mathrm { m m }$ ) and was not predictive of the need for surgery.78 When sac expulsion was documented at the first visit $1 1 \%$ (4/35) of women with an endometrial thickness of $1 5 \ \mathrm { m m }$ or less received future surgical management for symptoms as compared to 0 of 20 women with a thickness exceeding 15 mm. Future studies should determine if there are any ultrasonographic features or symptoms which are best addressed with active management and include endpoints such as need for surgery, blood products, admission to hospital, and number of visits to emergency departments and clinics. The presence of significant blood flow within retained products of conception is associated with an increased risk of heavy bleeding with expectant management; however, even with high flow, over $50 \%$ avoided surgery.79,80 Expectant (watch and wait) is the first-line management recommendation for incomplete EPL which can be tolerated by the patient (no excessive bleeding or infection) due to a high (over $90 \%$ ) rate of success.40 When medical management is requested as an alternative to surgical management for incomplete EPL with no gestational sac present, clinicians should use misoprostol only regimens (See Table 1). As always, patient preference for management modality at any time should be considered and implemented. Hysteroscopic or ultrasound guided resection can be considered in select cases such as repeat surgical procedures related to potential scarring or difficult to access intrauterine locations, but there is currently no evidence to support its routine use.81 A randomized trial of 563 patients comparing vacuum aspiration and hysteroscopic resection of incomplete spontaneous abortion did not show a difference between groups in subsequent pregnancies which progressed to at least 22 weeks’ during 2- year follow-up.82 Clinicians should refer to the SOGC pregnancy of unknown location guidelines to follow hCG when a patient has not been identified as having an intrauterine pregnancy prior to an ultrasound diagnosis of “retained products” or “incomplete EPL” to decrease the risk for ruptured ectopic pregnancy.83 because it is the best time to identify a viable intrauterine pregnancy, reducing the need for repeat tests when initial investigations are performed too early.84 An early ultrasound at 7 weeks provides opportunity for patient reassurance, identification of modifiable risk factors for pregnancy loss, and a review of outpatient options should they experience future bleeding. If a patient has experienced one or more EPLs, the NICE guidelines recommend offering vaginal micronized progesterone $4 0 0 \mathrm { m g }$ twice daily when started within 4 days of the onset of bleeding in patients with a confirmed intrauterine pregnancy under 12 weeks and continued to 16 weeks 0 days gestation.69,85 This recommendation was based upon a subgroup analysis and the overall study was not powered to answer this specific question.86 A prospective cohort study of patients wanting to conceive showed that those who had a repeat pregnancy within 3 months of their EPL had a slightly lower rate of repeat pregnancy loss than those who took longer to conceive.87 Clinicians should consider reversible risk factors for EPL such as poorly controlled diabetes, malnutrition, smoking, and patient mental health when recommending the timing of their next pregnancy.1 # Recommendation 15 # HEALTH QUALITY IMPROVEMENT AND PATIENT SAFETY IN INTRAUTERINE EARLY PREGNANCY LOSS Health quality improvement initiatives are recommended to improve wait times for surgical management and reduce repeat visits to emergency departments. Guidance on creating and assessing the impact of quality improvement activities for EPL can be accessed from the Health Quality Ontario document on Early Pregnancy and Loss which can be adapted to any province or jurisdiction. remote management of early pregnancy complications could address these recommendations. Virtual visits have created more options for assessment and follow-up of early pregnancy complications, however in some jurisdictions virtual care billing restrictions make care less accessible.88 Improved access to point of care and local diagnostic ultrasound, wider rural provision of medical management, and manual uterine aspiration in emergency department and outpatient settings could improve the efficiency of care and patient experience and improve outcomes. # BEST CARE MODIFIED PRACTICES IN LOW RESOURCE SETTINGS While many patients with vaginal bleeding in pregnancy present to the emergency department for care, it is typically not a medical emergency. If patients call with this concern, are not experiencing severe pain, bleeding, or fever, and do not have risk factors for ectopic pregnancy, they can be reassured it is safe to stay at home and come to clinic for a scheduled evaluation. There is nothing that can be done to prevent a first pregnancy loss in-progress, and counseling patients about this ahead of symptoms can also be useful. When patients present for care, the proper location for management needs to be assessed. Clinicians should advise patients under 6 weeks of pregnancy who experience vaginal bleeding in pregnancy without pelvic pain, or risk factors for ectopic pregnancy to receive expectant management (i.e. no ultrasound); they should to return if bleeding continues or pain develops, and to repeat a urine pregnancy test after 7 to 10 days and return if positive for an ultrasound.69 We recommend a patient-centred approach that presents all options and employs shared decision-making to arrive at the best management plan. Point-of-care ultrasound (POCUS) with transabdominal ultrasound can be used in the emergency departments to diagnose intrauterine pregnancy. If there is uncertainty or a strong suspicion for ectopic pregnancy, endovaginal ultrasound with an ultrasonographer/radiologist is advised.89 POCUS-trained health care providers can be used in smaller centers to reduce the need for patient transport. For early pregnancy assessment, endovaginal ultrasound is often superior to transabdominal ultrasound; however, some patients are reluctant to accept the more invasive exam. They should be counselled that the information obtained by endovaginal ultrasound is recommended to establish pregnancy viability and location in a timely fashion when transabdominal ultrasound is not sufficient for diagnosis (consider $1 5 \mathrm { m m }$ crown rump length with no cardiac activity for diagnosis early pregnancy loss).16 For those who decline endovaginal ultrasound where pregnancy location remains uncertain, close follow-up and ectopic precautions are indicated.83 If an intrauterine pregnancy of uncertain viability has been identified, consider a 2 week interval before repeat ultrasound to allow a definitive assessment of viability.69 In rural settings, improved access to quantitative hCG testing, point-of-care ultrasound, and health care providers who perform MVA has the potential to improve early pregnancy care and should considered for future study and implementation, results from quantitative hCG testing can often take time in remote communities. Access to pointof-care hCG and hemoglobin testing, point-of-care ultrasound and health care providers who perform MUA has the potential to improve early pregnancy care and should considered for future study and implementation.40,90 Patients with EPL who desire expectant or medical management can be treated in any location where medications are available, including an emergency department.90e92 Telemedicine counseling and local access to medication should be considered where possible. Patients desiring or requiring procedural management can be treated in an outpatient setting (including an emergency department), as long as they are hemodynamically stable and do not require deep sedation.93e95 Patients should be counseled on the options of surgical aspiration in the operating room or by MVA in the ER or other outpatient setting. In general, there is a longer wait for operating room time; however, deep sedation or general anesthesia are possible. In the absence of an anesthetist, pain management may vary from oral medications and a paracervical block to conscious sedation, and counseling about expectations for pain and the potential for a longer wait time for care should reflect this.96 For patients preferring deeper sedation/more pain management for any reason, surgery in the operating room is preferred. Patients who have significant medical co-morbidities, severe anxiety, or opioid use disorder might be better served by having surgery in an operating room, and this should be evaluated individually for each patient. # CONCLUSION EPL is common and often overlooked as a treatment priority. There are substantial mental health concerns for people suffering from one or more pregnancy loss. Significant resources should be directed to EPL to address and improve access to care, quality of care, and patient experience. Disparities in care exist for marginalized populations including Black, Indigenous, and other People of Colour. EPACs are a bridge between emergency and office care. They improve access to care, efficiency of care, and patient experience, and they can help address current barriers to and disparities in care. Rural communities would benefit from better access to local point-of-care ultrasound, laboratory testing, and treatment options. Throughout EPL diagnosis and treatment, patientcentered care is important to improving patient satisfaction with diagnosis and treatment45 improving outcomes, including those associated with mental health. # SUPPLEMENTARY MATERIAL Supplementary material related to this article can be found at https://doi.org/10.1016/j.jogc.2025.102914. # REFERENCES 1. Kolte AM, Westergaard D, Lidegaard O, et al. Chance of live birth: A nationwide, registry-based cohort study. Hum Reprod 2021;36:1065e73. Available at, https://www.ncbi.nlm.nih.gov/pubmed/33394013. https:// academic.oup.com/humrep/article-abstract/36/4/1065/6062281? redirectedFrom $1 =$ fulltext. 2. 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Management of first trimester pregnancy loss can be safely moved into the office. Rev Obstet Gynecol 2011;4:5e14. Available at, https://www.ncbi.nlm.nih.gov/pubmed/2162 9493. 94. Dalton VK, Harris L, Weisman CS, et al. Patient preferences, satisfaction, and resource use in office evacuation of early pregnancy failure. Obstet Gynecol 2006;108:103e10. Available at, https://www.ncbi.nlm.nih.gov/ pubmed/16816063. 95. Prine LW, MacNaughton H. Office management of early pregnancy loss. Am Fam Physician 2011;84:75e82. Available at, https://www.ncbi.nlm. nih.gov/pubmed/21766758. 96. Whittaker L, Pymar H, Liu XQ. Manual uterine aspiration in the emergency department as a first-line therapy for early pregnancy loss: A single-centre retrospective study. J Obstet Gynaecol Can 2022;44:644e9. Available at, https://www.ncbi.nlm.nih.gov/pubmed/35248776. https://www.jogc. com/article/S1701-2163(22)00070-6/fulltext.	None	None	None
80a7cd7364e34168aa7b9b50a37a23d3	2025+USPSTF建议声明	妊娠期梅毒感染筛查	# Screening for Syphilis Infection During Pregnancy US Preventive Services Task Force Reaffirmation Recommendation Statement US Preventive Services Task Force IMPORTANCE Untreated syphilis infection during pregnancy can be passed to the fetus, causing congenital syphilis. Congenital syphilis is associated with premature birth, low birth weight, stillbirth, neonatal death, and significant abnormalities in the infant such as deformed bones, anemia, enlarged liver and spleen, jaundice, brain and nerve problems (eg, permanent vision or hearing loss), and meningitis. In 2023, there were 3882 cases of congenital syphilis in the US, including 279 congenital syphilis–related stillbirths and neonatal/infant deaths, the highest number reported in more than 30 years. OBJECTIVE The US Preventive Services Task Force (USPSTF) commissioned a reaffirmation evidence update focused on the benefits and harms of screening for syphilis infection in pregnancy. POPULATION Adolescents and adults who are pregnant. EVIDENCE ASSESSMENT The USPSTF concludes with high certainty that screening for syphilis infection in pregnancy has a substantial net benefit. RECOMMENDATION The USPSTF recommends early, universal screening for syphilis infection during pregnancy; if an individual is not screened early in pregnancy, the USPSTF recommends screening at the first available opportunity. (A recommendation) # Editorial Related article and JAMA Patient Page Supplemental content CME at jamacmelookup.com Group Information: The US Preventive Services Task Force (USPSTF) members are listed at the end of this article. Corresponding Author: Michael Silverstein, MD, MPH, Brown University, Hassenfeld Child Health Innovation Institute, 121 South Main St, Providence, RI 02903 (chair@uspstf.net). # Summary of Recommendation <table><tr><td>Population</td><td>Recommendation</td><td>Grade</td></tr><tr><td>Asymptomatic pregnant women</td><td>The USPSTF recommends early,universal screening for syphilis infectionduring pregnancy; if an individual is notscreened early in pregnancy, the USPSTF recommends screening at the first available opportunity.</td><td>A</td></tr></table> See the Summary of Recommendation figure. # Pathway to Benefit To achieve the benefit of screening, it is important that screening occur as early in pregnancy as possible and that everyone with abnormal syphilis test results receive timely, evidence-based evaluation and treatment. # Mission Statement The US Preventive Services Task Force (USPSTF) works to improve the health of people nationwide by making evidence-based recommendations on effective ways to prevent disease and prolong life. # Importance Syphilis is an infection that is primarily sexually transmitted. Untreated syphilis infection during pregnancy can be passed to the fetus, causing congenital syphilis. Congenital syphilis is associated with premature birth, low birth weight, stillbirth, neonatal death, and significant abnormalities in the infant such as deformed bones, anemia, enlarged liver and spleen, jaundice, brain and nerve problems (eg, permanent vision or hearing loss), and meningitis.1 In 2023, there were 3882 cases of congenital syphilis in the US, including 279 congenital syphilis–related stillbirths and neonatal/infant deaths,2 the highest number reported in more than 30 years. Rates of new syphilis cases have continued to rise over the past 3 decades, especially in women. Although men account for the majority of syphilis cases, the change in incidence among women was 2 to 4 times higher than that among men between 2017 and 2021.3 Consequently, cases of congenital syphilis have also increased. Congenital syphilis increased more than 10-fold over a recent decade, from 334 cases in 2012 to 3882 cases in 2023.2,4 It is estimated that almost $90 \%$ of new congenital syphilis cases could have been prevented with timely testing and treatment.4 Certain racial and ethnic groups in the US are disproportionately affected by syphilis. Based on 2023 sexually transmitted infection surveillance data from the Centers for Disease Control and Prevention (CDC), congenital syphilis rates were 9.3 cases per 100 000 live births in Asian women, 222.0 cases per 100 000 live births in Black women, 125.0 cases per 100 000 live births in Hispanic or Latina women, 680.8 cases per 100 000 live births in Native American/Alaska Native women, 295.6 live births per 100 000 live births in Native Hawaiian/Pacific Islander women, 82.2 cases per 100 000 live births in multiracial women, and 57.3 cases per 100 000 live births in White women.5 Reviews of medical, public health, and social science literature have reported that social context and disparities in social factors such as poverty, neighborhood opportunities, incarceration rates, segregation, and ratio of men to women may influence sexual behavior and sexual networks, likely contributing to the observed racial disparities in sexually transmitted infection rates.6-8 # USPSTF Assessment of Magnitude of Net Benefit In 2018, the US Preventive Services Task Force (USPSTF) reviewed the evidence for screening for syphilis infection in asymptomatic pregnant women and issued an A recommendation.9 The USPSTF has decided to use a reaffirmation deliberation process to update this recommendation. The USPSTF uses the reaffirmation process for well-established, evidence-based standards of practice in current primary care practice for which only a very high level of evidence would justify a change in the grade of the recommendation.10 Table 1. Summary of USPSTF Rationale <table><tr><td>Rationale</td><td>Assessment</td></tr><tr><td>Detection</td><td>The USPSTF found adequate evidence that testsare available that can accurately detect syphilis infection during pregnancy.</td></tr><tr><td>Benefits of early detection and intervention and treatment</td><td>The USPSTF found convincing evidence that early universal screening for syphilis infection during pregnancy reduces the incidence of congenital syphilisand the adverse outcomes of pregnancy associated with maternal infection.</td></tr><tr><td>Harms of early detection and intervention and treatment</td><td>Screening for syphilis infection during pregnancy may result in potential harms, including false-positive or discordant results that require additional clinical evaluationandanxietyassociated with the initial screening and clarification of questionable results. Harms of intervention includeadverse effects suchasanallergy totreatment medications or the Jarisch-Herxheimer reaction from treatmentwithantibiotic medications. However, the USPSTF concluded that these harms are no greater than small.</td></tr><tr><td>USPSTF assessment</td><td>Using a reafirmation process,the USPSTF concludes with high certainty that the net benefit of screening for syphilis infection during pregnancy issubstantial.</td></tr></table> Abbreviation: USPSTF, US Preventive Services Task Force. In its deliberation of the evidence, the USPSTF considers whether the new evidence is of sufficient strength and quality to change its previous conclusions about the evidence. Using a reaffirmation process, the USPSTF concludes with high certainty that screening for syphilis infection in pregnancy has a substantial net benefit. See Table 1 for more information on the USPSTF recommendation rationale and assessment and the eFigure in the Supplement for information on the recommendation grade. See the Figure for a summary of the recommendation for clinicians. For more details on the methods the USPSTF uses to determine the net benefit, see the USPSTF Procedure Manual.10 # Practice Considerations # Patient Population Under Consideration This recommendation applies to all adolescents and adults who are pregnant, whether or not risk factors for syphilis are present. # Screening Tests Screening for syphilis involves a blood test that detects antibodies that may reflect infection with Treponema pallidum, the organism that causes syphilis. Treponemal tests, such as the T pallidum particle agglutination (TP-PA) test, detect an antibody response to antigens specific to T pallidum.11 Nontreponemal tests, such as the Venereal Disease Research Laboratory or rapid plasma reagin test, detect antibodies that may reflect tissue damage from T pallidum infection or tissue damage from other conditions that can cause the release of lipoidal antigens. Because of high false-positive rates associated with nontreponemal tests alone, especially in pregnancy, a 2-step process is used to improve diagnostic accuracy. A traditional screening algorithm is a 2-step process that begins with a nontreponemal test (eg, Venereal Disease Research Laboratory or rapid plasma reagin) followed by a confirmatory treponemal test (eg, TP-PA) for persons with positive nontreponemal test results. A reverse sequence algorithm uses an automated treponemal test (eg, enzyme-linked or chemiluminescence immunoassay) for the initial screening, followed by a nontreponemal test for reactive samples. Discordant results in the reverse sequence are resolved with a second confirmatory treponemal test (TP-PA preferred). The automated processes used in reverse sequence may be appropriate for high-volume laboratories.1,11 Figure. Clinician Summary: Screening for Syphilis Infection During Pregnancy <table><tr><td>What does the UsPSTF recommend?</td><td>For pregnantwomen: Provideearlyuniversalscreeningforsyphilisinfectionuringpregnancy;ifsomeone isnotscreenedearlyinpregnancy screenat the first available opportunity. GradeA</td></tr><tr><td>To whom does this recommendation apply?</td><td>This recommendationappliestoalladolescentsandadultswhoarepregnant,whetherornotriskfactors forsyphilisare present.</td></tr><tr><td>What's new?</td><td>This recommendation is consistent with the 2018 USPSTF recommendation.</td></tr><tr><td>How to implement this recommendation?</td><td>·Perform screening asearlyin pregnancyaspossible,whenapregnant patientfirst presents tocare.Ifearlyscreening was not done,screening should occur at the first opportunity,even if that is at presentation for delivery. ·Screening should include both a treponemal and nontreponemal test.</td></tr><tr><td>What additional information should clinicians know?</td><td>The Centers for Disease Controland Prevention(CDC), Women's Preventive Services Initiative (WPSl),American Academy of Pediatrics (AAP),and American CollegeofObstetriciansand Gynecologists (ACOG)recommend initialscreeing forsyphilis infectioninallpregnantwomenattheirfirst prenatalvisit,evenif previously tested.ACOG recommends universalrescreening duringthethirdtrimesterandatbirthandtheCDC,WPSlandAAPrecommendrescreeningat28weeksofgestationandagain at delivery in women at high risk for acquiring syphilis.</td></tr><tr><td>Why is this recommendation and topic important?</td><td>·Untreated syphilis infection during pregnancy can be passed to the fetus,causing congenital syphilis. ·Congenitalsyphilisisssociatedwithprematurebirth,lowbirthweight,stilbirthneonataldeath,andsigificantabnoralities intheinfantsuchasdeformedbones,anemia,enlargedliverandspleen,jaundice,brainandnerve problems (eg,permanent vision or hearing loss),and meningitis. ·In2023,there were 3882casesof congenitalsyphilis in the US,including 279 congenitalsyphilis-relatedstllbirthsand</td></tr><tr><td></td><td>neonatal/infant deaths,the highest number reported in more than 3O years. ·Certainracialandethnic groups in the USaredisproportionatelyaffectedbysyphilis.In2O23,congenitalsyphilis rates were: 09.3 cases per 10o ooo live births in Asian women 222.0 cases per 10o ooo live births in Black women o 125.0 cases per 1Oo ooo live births in Hispanic/Latina women o 680.8 cases per 1Oo ooo live births in Native American/Alaska Native women</td></tr><tr><td>What are other</td><td>0295.6 live births per 1Oo ooo live births in Native Hawaian/Pacific Islander women 082.2 cases per 10o ooo live births in multiracial women 57.3 cases per 10o ooo live births in White women</td></tr><tr><td>relevant USPSTF recommendations? What are additional</td><td>The USPSTF has issued arecommendationon screening forsyphilis in nonpregnant adolescents andadults,available at https://www.uspreventiveservicestaskforce.org/uspstf/ A list of state prenatal syphilis screening laws and regulations</td></tr><tr><td>tools and resources?</td><td>(https://www.cdc.gov/syphilis/hcp/prenatal-screening-laws/index.html) and county-level data on syphilis infection rates (https://www.cdc.gov/sti-statistics/county-level-syphilis-data/)are available from the CDC. The CDC also provides multilingual materials for patients on syphilis prenatal screening (https://www.cdc.gov/sti/php/communication-resources/syphilis-prenatal-screening-protect-your-baby.html).</td></tr><tr><td>Where to read the full recommendation statement?</td><td>Visit the USPSTF website (https://www.uspreventiveservicestaskforce.org/uspstf/)or the JAMA website (https://jamanetwork.com/collections/44068/united-states-preventive-services-task-force)toread thefullrecommendation</td></tr></table> The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision-making to the specific patient or situation. Point-of-care tests for antibodies to T pallidum are available that can be performed in a clinical setting or at home using fingerstick blood samples that do not require laboratory processing.12 It is unclear how results from these tests alone, without additional confirmatory testing, should guide treatment decisions. # Screening Timing and Intervals All pregnant women should be tested for syphilis when they first present to care. Screening for syphilis should occur as early in pregnancy as possible. If early testing is not done, testing should occur at the first opportunity, which could be as late as at admission for delivery. A recent analysis of national data from 2022 found that $5 \%$ of congenital syphilis cases (197/3761 cases) occurred in late pregnancy after having had a negative syphilis screening result earlier in pregnancy.4 Similar to the disparities seen in the burden of syphilis, $4 0 . 6 \%$ of these cases occurred in Black women, $2 8 . 4 \%$ occurred in Hispanic or Latina women, and $1 9 . 8 \%$ occurred in White women.4 Some retrospective studies estimate that $2 5 \%$ to $50 \%$ of congenital syphilis cases could be prevented by repeat screening in the third trimester of pregnancy.13-15 The CDC,16 Women’s Preventive Services Initiative (WPSI),17 American Academy of Pediatrics (AAP),18 and American College of Obstetricians and Gynecologists (ACOG)19 recommend repeat screening in the early third trimester (approximately 28 weeks of gestation) and again at delivery; however, these organizations differ in whether they recommend repeat screening for all pregnant women19 or just for those at high risk for syphilis infection. Women at high risk for syphilis infection include those who live in high-prevalence areas; have a history of HIV, incarceration, or multiple sexual partners; engage in sex in combination with drug use or commercial sex work; or are experiencing homelessness.16,18 Clinicians should be aware of the prevalence of syphilis infection in the communities they serve and state mandates for syphilis screening.Most statesmandate screening for syphilis inall pregnantwomen at the first prenatal visit, and some mandate repeat screening early in the third trimester and at delivery.20 # Treatment The CDC recommends parenteral penicillin G as the only treatment with documented efficacy during pregnancy. Treatment protocols are specific to the stage of syphilis infection, with later-stage infection requiring longer duration of treatment. When syphilis is diagnosed during the second half of pregnancy, management should include a sonographic fetal evaluation for signs of congenital syphilis. Pregnant women with a penicillin allergy should be desensitized and then treated with penicillin. Approximately $10 \%$ of patients report a penicillin allergy, although the number of patients who are truly allergic may be much smaller.16,21,22 Clinicians are encouraged to refer to the CDC’s “Sexually Transmitted Infection Treatment Guidelines” for the most up-to-date treatment guidance.16 # Additional Tools and Resources A list of state prenatal syphilis screening laws and regulations (https:// www.cdc.gov/syphilis/hcp/prenatal-screening-laws/index.html)and county-level data on syphilis infection rates (https://www.cdc.gov/ sti-statistics/county-level-syphilis-data/) are available from the CDC. The CDC also provides multilingual materials for patients on syphilis prenatal screening (https://www.cdc.gov/sti/php/communicationresources/syphilis-prenatal-screening-protect-your-baby.html). # Other Related USPSTF Recommendations The USPSTF has issued recommendations on screening for syphilis in adults and adolescents who are not pregnant,23 as well as screening for other sexually transmitted infections, including chlamydia and gonorrhea,24 hepatitis B virus,25,26 genital herpes,27 and HIV.28 The USPSTF has also issued a recommendation on counseling to prevent sexually transmitted infections.29 Current versions of these and other related USPSTF recommendations are available at https:// www.uspreventiveservicestaskforce.org/uspstf/. # Reaffirmation of Previous USPSTF Recommendation This recommendation is a reaffirmation of the USPSTF 2018 reaffirmation recommendation statement. In 2018, the USPSTF reviewed the evidence for screening for syphilis infection during pregnancy and found that the benefits of screening substantially outweighed the harms.9 The USPSTF found no new substantial evidence that could change its recommendation and, therefore, reaffirms its recommendation to screen for syphilis infection during pregnancy. # Supporting Evidence # Scope of Review To reaffirm its recommendation, the USPSTF commissioned a reaffirmation evidence update. The aim of the evidence update that supports the reaffirmation process is to identify “new and substantial evidence sufficient enough to justify a change in the grade of the recommendation.”10 The reaffirmation update focused on key questions on the benefits and harms of screening for syphilis infection in adolescents and adults who are pregnant. # Benefits of Early Detection and Treatment The USPSTF found no new evidence that was inconsistent with the previously established benefits of screening for syphilis infection during pregnancy. No new studies were identified that evaluated the effectiveness of screening to decrease congenital syphilis rates or improve maternal health outcomes.1,30 Evidence from previous reviews31 demonstrates fewer adverse pregnancy outcomes among pregnant women screened and treated for syphilis infection compared with those not treated. Treatment appears to be more beneficial when provided earlier rather than later in pregnancy.31 A 2014 systematic review of 54 observational studies found that the incidence of congenital syphilis, preterm birth, low birth weight, stillbirth, and neonatal death was dramatically reduced in pregnant women treated for syphilis during pregnancy compared with those who had untreated syphilis.32 The reduction in stillbirth and fetal loss was much smaller when treatment did not occur until the third trimester. The USPSTF previously reviewed evidence on the effects of implementing a free syphilis screening and treatment program for all pregnant women living in Shenzhen, China, from 2002 to 2012 $( \mathsf { n } = 2 4 4 1$ 237).33 During follow-up, screening uptake increased from $8 9 . 8 \%$ to $9 7 . 2 \%$ , and the congenital syphilis case rate decreased from 109.3 to 9.4 cases per 100 000 live births. During the same time, the incidence ofadverse pregnancy outcomes decreased from $4 2 . 7 \%$ to $1 9 . 2 \%$ , and the incidence of stillbirth or fetal loss decreased from $1 9 . 0 \%$ to $3 . 3 \%$ . # Harms of Screening and Treatment Potential harms of screening for and treatment of syphilis infection include false-positive or discordant results from screening that require clinical evaluation, unnecessary anxiety to the patient, and harms of antibiotic medication use for treatment. The current reaffirmation review identified 5 studies (51 118 participants) that evaluated the harms of screening and 2 studies (130 participants) that evaluated the harms of treatment.1,30 The 5 studies34-38 that evaluated the harms of screening were all conducted in the US (1 study was conducted in the US and Argentina38) and reported on falsepositive rates of a single screening test. All 5 of these studies included participants from a variety of racial and ethnic backgrounds; however, only 2 studies34,38 reported this information for their full study cohort. Black participants ranged from $18 \%$ t o $67 \%$ , White participants ranged from $5 \%$ to $20 \%$ , and “Other” participants ranged from $0 . 2 \%$ to $1 3 \%$ . One of the studies additionally reported including $3 \%$ Asian participants and $7 5 \%$ Hispanic participants.34 Two studies, conducted in Canada and Brazil, reported on the harms of treatment, which included rates of JarischHerxhemier reactions (an acute, febrile reaction that often includes body aches, tachycardia, hypotension, and rash and can occur within the first 24 hours of antibiotic treatment of a spirochete infection16,39) and immediate hypersensitivity reactions to penicillin.40,41 For treatment harms, 1 small study ${ \mathfrak { n } } = 3 9$ ) reported that $5 . 1 \%$ of patients receiving penicillin therapy experienced JarischHerxheimer reactions.40 A second small study $( \mathsf { n } = 9 \mathbb { 1 } )$ ) evaluated an algorithm to help guide penicillin desensitization among pregnant patients with syphilis who had a clinical history of immediate hypersensitivity reaction to penicillin.41 Among patients considered at high risk for an immediate hypersensitivity reaction, $2 7 . 3 \%$ experienced it after oral desensitization and $2 . 5 \%$ experienced it after intravenous desensitization; $2 . 5 \%$ of patients considered at low risk for an immediate hypersensitivity reaction experienced it after penicillin provocation.Overall, theUSPSTF found thisevidence consistentwith the previously known harms of syphilis screening and treatment during pregnancy. # Response to Public Comments A draft version of this recommendation statement was posted for public comment on the USPSTF website from November 19 to December 23, 2024. A few comments were received asking that the USPSTF align with recommendations from other organizations and recommend repeat screening later in pregnancy. The USPSTF acknowledges that the recent rise of congenital syphilis cases is concerning and is dedicated to finding evidence-based strategies to prevent congenital syphilis. Due to limited available evidence, the USPSTF was not able to assess the effectiveness of screening more than once during pregnancy and is not making a recommendation for or against repeat screening. The USPSTF is calling for more research on the effectiveness of repeat screening during pregnancy and highlights this in the Research Needs and Gaps section. The USPSTF also describes other organizations’ approaches to repeat screening in the Practice Considerations section and Recommendations of Others section. Some comments also sought clarity on the specific time point when screening should be performed. Although a specific time point for screening could not be identified through the evidence, the USPSTF found that generally, reductions in congenital syphilis rates were greater when treatment was completed earlier in pregnancy rather than later. However, benefits were still seen when screening and treatment occurred later in pregnancy. Thus, the USPSTF recommends that screening occur as early in pregnancy as possible, even when this may be late in pregnancy or at delivery. This has been clarified in the recommendation. Last, a few comments sought clarification on who should be screened for syphilis during pregnancy. The USPSTF recommends universal syphilis screening in all adolescents and adults who are pregnant, whether or not risk factors for syphilis are present. Clarifying language has been added to the Practice Considerations section. Table 2. Research Needs and Gaps for Screening for Syphilis Infection During Pregnancy <table><tr><td>To fulfillits mission to improve health by making evidence-based recommendations for preventive services,the USPSTF routinely highlights the most critical evidence gaps for making actionable preventive services recommendations.The USPSTF often needsadditional evidence to create the</td></tr><tr><td>needed toaddress these evidence gaps,see the Research Gaps Taxonomy table on the USPSTF website (https://www.uspreventiveservicestaskforce.org/ home/getfilebytoken/nfP93-Hva3bvxkvkBStTgm). Screening for Syphilis Infection During Pregnancy</td></tr><tr><td>Studies evaluating the benefitsand harms of repeat screening later in</td></tr><tr><td>pregnancy. Studies evaluating the benefits and harms of screening strategies during</td></tr><tr><td>pregnancy that include rapid point-of-care tests. Studies evaluating interventions to reduce congenital syphilis rates in</td></tr><tr><td>populations experiencing high burdens of disease. Research evaluating disparities in congenital syphilis incidence and syphilis screening rates during pregnancy across populations.</td></tr></table> Abbreviations: USPSTF, US Preventive Services Task Force. # Research Needs and Gaps See Table 2 for research needs and gaps related to screening for syphilis infection during pregnancy. # Recommendations of Others This recommendation statement is consistent with those of other professional and public health organizations. The CDC,16 WSPI,17 AAP,18 and $\mathsf { A C O G } ^ { 1 9 }$ recommend initial screening for syphilis infection in all pregnant women at their first prenatal visit, even if previously tested. ACOG19 recommends universal rescreening during the third trimester and at birth and the CDC,16 WPSI,17 and $\mathsf { A A P } ^ { 1 8 }$ recommend rescreening at 28 weeks of gestation and again at delivery in women at high risk for acquiring syphilis. $\mathsf { A A P } ^ { 1 8 }$ and ACOG19 alsorecommendrepeatscreeningafterexposuretoaninfectedpartner. The American Academy of Family Physicians supports the 2018 USPSTF recommendation on screening for syphilis infection in pregnant women.42 San Antonio (Jaén, Tsevat); Tulane University, New Orleans, Louisiana (Krousel-Wood); University of California, San Francisco (Lee); George Washington University, Washington, DC (Nicholson); Case Western Reserve University, Cleveland, Ohio (Rao); University of Arizona, Tucson (Ruiz); University of Missouri, Columbia (Stevermer); University of Wisconsin, Milwaukee (Underwood); Indiana University, Bloomington (Wiehe). Author Contributions: Dr Silverstein had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The USPSTF members contributed equally to the recommendation statement. Conflict of Interest Disclosures: Authors followed the policy regarding conflicts of interest described at https://uspreventiveservicestaskforce.org/ uspstf/about-uspstf/conflict-interest-disclosures. All members of the USPSTF receive travel reimbursement and an honorarium for participating in USPSTF meetings. Dr Lee reported receiving grants from the National Institute on Aging (K24AG066998, R01AG079982) outside the submitted work. No other disclosures were reported. Funding/Support: The USPSTF is an independent, voluntary body. The US Congress mandates that the Agency for Healthcare Research and Quality (AHRQ) support the operations of the USPSTF. Role of the Funder/Sponsor: AHRQ staff assisted in the following: development and review of the research plan, commission of the systematic evidence review from an Evidence-based Practice Center, coordination of expert review and public comment of the draft evidence report and draft recommendation statement, and the writing and preparation of the final recommendation statement and its submission for publication. AHRQ staff had no role in the approval of the final recommendation statement or the decision to submit for publication. Disclaimer: Recommendations made by the USPSTF are independent of the US government. They should not be construed as an official position of AHRQ or the US Department of Health and Human Services. Additional Contributions: We thank Tina Fan, MD, MPH (AHRQ), who contributed to the writing of the manuscript, and Lisa Nicolella, MA (AHRQ), who assisted with coordination and editing. Additional Information: Published by JAMA®— Journal of the American Medical Association under arrangement with the Agency for Healthcare Research and Quality (AHRQ). ©2025 AMA and United States Government, as represented by the Secretary of the Department of Health and Human Services (HHS), by assignment from the members of the United States Preventive Services Task Force (USPSTF). All rights reserved. # REFERENCES 1. Asher GN, Viswanathan M, Takyi A, Middleton JC, Baker C, Kahwati LC. Screening for Syphilis Infection in Pregnancy: A Limited Systematic Evidence Review Update for the US Preventive Services Task Force. Evidence Synthesis No. 243. Agency for Healthcare Research and Quality; 2025. AHRQ publication 24-05317-EF-1. 2. Centers for Disease Control and Prevention. National overview of STIs in 2023. Published November 12, 2024. Accessed March 17, 2025. https://www.cdc.gov/sti-statistics/annual/ summary.html 3. Centers for Disease Control and Prevention. 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c12c2b3441c94a038370a1a4f5573a17	2025+昆士兰临床指南	早期妊娠丢失（V8）	# Queensland Clinical Guidelines Translating evidence into best clinical practice ![](images/d463537c4976d74e1b5e4d0411fce28c0bad701ce2aaf49b1dd13a884366f8c3.jpg) 文件标题:出版日期:文件编号: 文件补充:修正案:修正日期:替换文档: 作者: 早期妊娠流产 2022 年 10 月 MN22.29-V8-R27 该文件补充详细介绍了开发过程和实施活动，与本指南不可分割，应结合阅读文档补充中提供了完整版本历史 2025 年 8 月 MN22.29-V7-R27 昆士兰临床指南昆士兰州公共和私人孕产妇和新生儿服务的卫生专业人员 2027 年 10 月昆士兰临床指南指导委员会全州孕产妇和新生儿临床网络(昆士兰) 电子邮件:Guidelines@health.qld.go v.au 网址:www.health.qld.gov.au/qcg 观众: 审核日期: 认可者: 联系方式: ![](images/1361eebae9cd4dee4305bad7bc302e22ecf368cdc8678642fd8c89121175f64d.jpg) # 致谢卫生部尊敬昆士兰州陆地、水域和海洋的传统所有者和文化托管人。我们向长老们致敬过去和现在，同时认识到当前和未来领导人在塑造更好的卫生系统方面的作用。本指南旨在作为指南，仅供参考。该信息是根据准备时的最佳信息和证据，采用多学科方法准备的。不能保证信息在各个方面都是完全完整、当前或准确的。该指南不能替代临床判断、知识和专业知识或医疗建议。考虑到个人情况，与指南的差异可能是适当的。本指南并未解决标准实践的所有要素，并接受个别临床医生负责:  在当地可用资源、专业知识和实践范围的背景下提供护理支持消费者权利和知情决策，包括拒绝干预或持续管理的权利在文化适当且能够进行舒适和保密讨论的环境中向消费者建议他们的选择。这包括在必要时使用口译服务确保在提供护理之前获得知情同意满足所有立法要求和专业标准在提供护理时应用标准预防措施，并在必要时采取额外预防措施根据强制性和当地要求记录所有护理昆士兰健康在法律允许的最大限度上，不对因任何原因而发生的所有费用、损失、损害和费用承担一切责任和责任(包括不受限制的，过失责任)，包括本文件内或全文所引用的材料以任何方式不准确、不合情节、不完整或不可用。推荐引用:昆士兰临床指南。早期妊娠流产。指南编号 MN22.29-V8-R27 昆士兰州健康。2025.可从:http://www.health.qld.gov.au/qcg 获取。本作品根据知识共享署名-非商业-无衍生品 V4.0 国际许可证获得许可。本质上，您可以自由地以当前形式复制和传播该作品，以非商业目的，只要您归因于昆士兰临床指南、昆士兰健康并遵守许可证条款。您不得以任何方式改变或调整作品。要查看此许可证的副本，请访问 https://creativecommons.org/licenses/by-nc-nd/4.0/deed.en ![](images/ff0ec697f2a3fe2781f9bc2be795b30ea6af20bcf8c90448d233eec949c86957.jpg) 流程图:疑似早期妊娠流产的评估流程图:F22.29-2-V5-R27 # 流程图:疑似早期妊娠流产的位置和生存能力评估 ![](images/8e4e23ff91b28e757824e6550177774cd6b5bca52931cd060599cd887e770675.jpg) 在建议管理和需要专家转诊时，使用临床判断并考虑妇女的个人情况 # 不可行的诊断标准(TVS) $\bullet$ 全相合同胞供者 $\ge 2 5 ~ \mathsf { m m }$ 且无胎儿  CRL≥7mm的胎儿可见，但观察 $\mathtt { \ge } 3 0$ 秒后未显示胎心运动  扫描显示妊娠囊但没有卵黄囊后 $\geq 2$ 周内没有有心跳的胚胎  扫描显示妊娠囊和卵黄囊后 11 天以上没有有心跳的胚胎  USS 后 7 天或更长时间没有有心跳的胚胎，胎儿极小于 7 毫米，没有心脏活动 # TVS 间隔  根据预期正常孕囊生长率 $1 \mathsf { m m }$ 天估计重复 TVS 间隔 # 工作过的一个例子  如果全相合同胞供者 $= 1 2 ~ \mathsf { m m }$ ，则在 13 天或更长时间内重复 TVS(13 天内 $1 2 \mathsf { m m }$ 全相合同胞供者+ 13 mm 增长等于预期全相合同胞供者 25 mm) $\pmb { \beta }$ -hCG:人绒毛膜促性腺激素(所有β-hCG测量值均以国际单位/L(IU/L))CRL:冠臀长，IUP:宫内妊娠，全相合同胞供者:平均囊直径，PUL:未知部位妊娠，TVS:经阴道扫描，USS:超声扫描，>:大于，<:小于，≥:大于或等于，≤:小于或等于流程图:F22.29-4-V3-R27 # 流程图:宫外孕 # 临床表现(可能包括也可能不包括)  月经不来  不规则阴道流血(点滴出血)  腹部/肩尖疼痛  颈椎运动压痛  心动过速和低血压  可触及的附件肿块(女性 $50 \%$ )  $\beta .$ -hCG 阳性 USS 上不存在 IUP # 讨论与女性偏好和临床适应症相关的护理选择 #  血流动力学稳定  没有破裂的证据  血清 $\beta$ -hCG 较低且下降(就诊时 $\mathsf { < } 1 5 0 0 \mathsf { I U } / \mathrm { L } $ USS 上骨盆内液体极少/没有输卵管肿块 $< 3$ cm疼痛免费妇女接受随访的需要并可以获得医疗服务 # 如果:。请注意:  后续行动尚不确定 # 持续管理  EPAS 或等效$\beta$ -hCG 每 48 小时一次，持续 8天如果出现缓解，则每周进行 $\beta$ -hCG 治疗，直至阴性如果有临床指征，则进行 USS在超声波分辨率之前避免受孕 # 适应症  血流动力学稳定 没有破裂的证据 无活动性出血迹象 正常 FBC，ELFT # 禁忌症  对甲氨蝶呤过敏  地理隔离后续行动不确定存在医疗状况(根据个人情况审查)  母乳喂养 # 如果:。请注意:  基线 $\beta \mathrm { - } \mathsf { h C G } > 5 0 0 0$ IU/L TVS 上的异位 $> 3$ cm 胎儿心脏运动存在 输血不是一个选择 # 甲氨蝶呤  如果 $\mathsf { \beta { - } h C G } \leq 3 0 0 0 \ \mathsf { \| U / l }$ ，则 IM 如果 $\beta \mathrm { - } \mathsf { h C G } > 3 0 0 0 \ \mathsf { l L }$ /L，则 IVI # 持续管理  EPAS 或等效  根据甲氨蝶呤方案进行连续 $\beta$ -hCG然后根据临床指示在一周内进行 USSo 如果 FH 存在，请参阅 MFM 由于潜在的致畸性，避免受孕 4个月 # 外科手术 # 适应症血流动力学不稳定破裂的迹象任何 $\beta$ -hCG 水平持续过度出血  异位妊娠  医疗或期待治疗的禁忌症 # 程序  腹腔镜检查的首选方法 如果:。剖腹手术o 血流动力学不稳定$\circ$ 腹腔镜检查太难了 # 后续  术后 14 天进行 GP 如果输卵管切开，每周进行 $\beta .$ -hCG 检测，直至阴性如果输卵管切除术，术后 3 周尿$\beta$ -hCG如果有临床指征，则进行 USS最佳受孕间隔未知(常见于 0-3 个月) # 如果是医疗或期待:  性交或盆腔检查在急性期存在破裂的风险 如果有指示，请考虑替代治疗(例如， $\beta .$ -hCG 不下降、应女性要求、输卵管破裂或持续疼痛/出血) # 提供有关:  选择的管理选项  预期出血/症状  月经恢复  避孕  后续安排 # 一般护理注意事项  回顾 POC 的组织病理学  如果有指示，建议使用 RhD-Ig 根据需要进行镇痛  向其他护理提供者(例如全科医生)传达信息  下次怀孕时早期 USS(5-6 周) # 考虑妇女的心理需求并提供支持 $\pmb { \beta }$ -hCG:人绒毛膜促性腺激素，ELFT:电解质和肝功能检查，EPAS:早孕评估服务，FBC:全血细胞计数，GP:全科医生，GTD:妊娠滋养细胞疾病，IMI:肌肉注射，IU/L:国际单位每升，IUP:宫内妊娠，IVI:静脉注射，MFM:母胎药，POC:受孕产物，PUL:不明部位妊娠，PV:经阴道，QTC:昆士兰滋养细胞中心，RhD-Ig:RhD免疫球蛋白，TVS:经阴道扫描，USS:超声扫描，>:大于 ![](images/c1316db26663cd79d6b9077e47d45ab00f38849584b870a10bf40665226209d1.jpg) 流程图:稳定的宫内非存活妊娠 $\pmb { \beta }$ -hCG:人绒毛膜促性腺激素(所有β-hCG测量值均为国际单位/L(IU/L))，EPAS:早孕评估服务，FBC:全血细胞计数，GP:全科医生，GTD:妊娠滋养细胞疾病，IUD:宫内节育器，IUP:宫内妊娠，POC:受孕产物，PUL:不明部位妊娠，PV:经阴道，QTC:昆士兰滋养细胞中心，RhD-Ig:RhD免疫球蛋白，TVS:经阴道扫描，USS:超声扫描，>:大于 # 目录 1 简介....... ................................................................................................................................. ..... 9 1.1 临床标准... ............................................................................................................................................ ..... 9 1.2 紧急演示...... .............................................................................................................................. ....... 9 1.3 血流动力学不稳定... ............................................................................................................................... ..... 10 2 EPL 护理原则..... ......................................................................................................................................... 11 2.1 心理支持..... .................................................................................................................. ..... 12 2.2 心理发病率... ..... 13 3 评估...... .............. ...... 14 3.1 确定妊娠的存活率和位置.. ....................... 3.2 非存活宫内妊娠的诊断..... ................ ...... 16 3.3 未知部位的怀孕............. ....................... 17 3.3.1 PUL 分类后结果的频率.. .............. ...... 17 3.4 其他妊娠结局..... ...................... 18 4 宫外孕.... ...... 19 4.1 宫外孕的危险因素... ...... 19 4.2 宫外孕的期待管理.. .... 20 4.3 异位妊娠的医疗管理.. ..... 21 4.3.1 对接受甲氨蝶呤治疗的女性的建议.. ..... 22 4.4 异位妊娠的手术治疗.... ..... 22 5 宫内妊娠不可存活..... .... 23 5.1 风险因素...... .............. ...... 23 5.2 非存活宫内妊娠的期待治疗. ................... .......... .... 24 5.3 妊娠早期非存活宫内妊娠的医疗管理.. ..... 25 5.4 妊娠早期不可行 IUP 的手术治疗.... .... 26 6 中期妊娠流产....... ..... 27 7 妊娠滋养细胞疾病(GTD).. .....28 7.1 GTD 的管理.... ......28 7.2 后续...... ..... 29 8 反复早期妊娠流产.. .... 30 9 对胎儿组织/残骸进行敏感管理.. ....31 参考....... ..... 32 附录 A:早期妊娠评估服务... .... 35 附录 B:超声解剖、地标和文件... .... 36 附录 C:异位妊娠的甲氨蝶呤治疗方案.. ....37 致谢..... .... 38 # 表格列表 # 表 1.临床标准.. ................................................................................................................................................... 9 表 2.在急诊科进行演示.....表3。血流动力学不稳定.... .................................................................................................................................................... 9.................................................................................................................................................. 10表 4.EPL 的一般护理原则.. ................................................................................................................................ ... 11表 5.早期流产的背景和经历.. 表 6.心理发病率..................... 表 7.确认怀孕并进行评估...................................................................................................................................................... 14表 8.确定妊娠的存活率和位置.. ................................................................................................................................... ...... 15表 9.诊断不可行 IUP.. ................................................................................................................................................. 16表 10.未知部位的怀孕... 表 11.PUL 后结果的频率.. ................................................................................................................................... .....17表 12.其他妊娠结局..... 表 13.宫外孕............................................................................................................................................................................19表 14.与异位妊娠相关的危险因素........................................................................................................................................19表 15.宫外孕的期待管理..... ................................................................................................................................. ......20表 16.异位妊娠的医疗管理.. .......................................................................................................................................21表 17.女性甲氨蝶呤后注意事项............................................................................................................................................22表18.异位妊娠的手术治疗.....................................................................................................................................................22表 19.与非存活宫内妊娠丢失相关的危险因素....................................................................................................................23表稳定的不可行的期待管理表21.稳定的不可行 IUP 的医疗管理指征....................................................................................................................... ..... 25表22.稳定的不可行 IUP 的手术治疗.................................................................................................................................... 26表 23.中期妊娠丧失................................................................................................................................................................27表 24.GTD 的分类.................................................................................................................................................................. 28表 25.妊娠滋养细胞疾病... ......................................................................................................................................... ....28表 26.GTD 后随访... ......................................................................................................................................... .. 29表27.反复早期妊娠流产.. ............................................................................................................................................ ...30表28.对胎儿遗骸进行敏感管理. ................................................................................................................................ .....31 缩写 <table><tr><td>β-hCG</td><td>β人绒毛膜促性腺激素</td></tr><tr><td>BMI</td><td>体重指数</td></tr><tr><td>CRL</td><td>冠臀长</td></tr><tr><td>ELFT</td><td>电解质、肝功能检查</td></tr><tr><td>EPAS</td><td>早期妊娠评估服务</td></tr><tr><td>欧洲电力公司</td><td>早期妊娠流产</td></tr><tr><td>红细胞</td><td>全血细胞计数</td></tr><tr><td>FMH</td><td>胎儿母体出血</td></tr><tr><td>总经理</td><td>全科医生</td></tr><tr><td>GTD</td><td>妊娠滋养细胞疾病</td></tr><tr><td>他妈的</td><td>葡萄胎</td></tr><tr><td>IUP</td><td>宫内妊娠</td></tr><tr><td>LNMP</td><td>末次正常月经</td></tr><tr><td>全相合同胞供者</td><td>平均囊直径</td></tr><tr><td>极客</td><td>受孕产物</td></tr><tr><td>放电</td><td>未知部位的怀孕</td></tr><tr><td>PV</td><td>经阴道</td></tr><tr><td>QTC</td><td>昆士兰滋养层中心</td></tr><tr><td>Rh D</td><td>Rh D血型</td></tr><tr><td>RhD-Ig</td><td>RhD免疫球蛋白</td></tr><tr><td>塔斯</td><td>经腹部超声检查</td></tr><tr><td>TVS 美国宇航局</td><td>经阴道超声检查</td></tr><tr><td></td><td>超声波扫描</td></tr></table> 定义 <table><tr><td>胚胎妊娠</td><td>孕囊发育，但胚胎不形成。</td></tr><tr><td>完全流产</td><td>受孕产物(POC)完全排出。进一步不需要通过药物或手术干预来管理流产。</td></tr><tr><td>早期妊娠评估服务</td><td>能够评估和管理早期妊娠流产的医院服务。在昆士兰州，同等的服务可能有不同的名称或结构。</td></tr><tr><td>早期妊娠流产</td><td>出于本文件的目的，早期妊娠流产是指妊娠前 20个完整周内流产。</td></tr><tr><td>宫外孕</td><td>妊娠位于子宫以外，通常位于输卵管，但也可能位于宫角、子宫颈、剖腹产疤痕、卵巢或其他部位。</td></tr><tr><td>期待管理</td><td>无具体干预;等待 POC 的自发通过。</td></tr><tr><td>妊娠滋养细胞疾病</td><td>以胎儿绒毛膜组织或滋养层自主过度生长为特征的一组疾病。包括葡萄胎妊娠(完全或部分)。</td></tr><tr><td>异位妊娠</td><td>宫内妊娠加宫外孕的多胎妊娠(例如输卵管妊娠、宫颈妊娠、卵巢妊娠、腹部妊娠)。</td></tr><tr><td>不完全流产</td><td>POC 排出不完全。</td></tr><tr><td>难免流产</td><td>流产或产品被驱逐即将发生或正在发生。</td></tr><tr><td>医疗管理</td><td>使用药物帮助排出POC。</td></tr><tr><td>流产</td><td>妊娠满20周之前或出生体重低于400克时发生妊娠流产。</td></tr><tr><td>错过了流产</td><td>超声检查证实非活产，无出血。</td></tr><tr><td>未知部位的怀孕</td><td>妊娠试验呈阳性，但超声波无法观察到妊娠情况。</td></tr><tr><td>反复流产</td><td>连续三次或三次以上流产。对于非连续妊娠损失，没有具体的术语。</td></tr><tr><td>威胁流产</td><td>20周前除点滴出血外的所有阴道出血均已完成妊娠，超声检查显示妊娠进展</td></tr><tr><td>女士/女性</td><td>QCG 认识到个人具有不同的性别认同。在QCG文件中，虽然使用了"女人"和"女人"两个术语，但这些该指南涵盖了怀孕或分娩且不认同女性的人。1,2</td></tr></table> # 1 简介据估计，大约 $1 5 \%$ 的已知妊娠会发生早期妊娠流产 (EPL)。它会对身体和心理产生负面后果。身体并发症包括感染、出血、栓塞、子宫和相关结构损伤以及麻醉并发症。悲伤、抑郁和焦虑等心理并发症很常见。33 为了防止先兆流产进展，几乎无能为力。然而，高质量的护理可以提高对护理的满意度，最大限度地减少负面结果，并支持妇女及其家人度过情绪化和压力很大的时期。4 # 1.1 临床标准表 1.临床标准 <table><tr><td>方面</td><td>考虑</td></tr><tr><td></td><td>·有关被视为"常规"或"标准"的护理，请参阅昆士兰临床指南标准护理5</td></tr><tr><td>标准护理</td><td>·例如，包括:隐私、同意、决策以及有关治疗方案风险和益处的讨论，敏感沟通、药物管理、员工教育和支持以及文化上适当的护理、文件</td></tr></table> # 1.2 紧急演示表 2.在急诊科进行演示 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>背景</td><td>·因先兆或实际早期妊娠流产而到急诊室 (ED)就诊很常见6 ·由于急诊室的结构主要是为了解决紧急和创伤护理(即分诊基于医疗紧急情况)，但EPL期间和之后随访时心理社会护理的重要性却未被充分认识7.8</td></tr><tr><td>EPAS</td><td>. 专门的门诊早孕评估服务 (EPAS)可以减少急诊室的住院时间，减少住院治疗，改善服务提供和妇女的护理体验8-10</td></tr><tr><td rowspan="4">护理提供</td><td>。请参阅术语定义和附录A:早期妊娠评估服务 ·个性化护理并承认妇女的损失经历 ·让专家和专门的多学科医疗保健专业人员(包括社会工作者)参与护理计划7</td></tr><tr><td>·尽量减少等待时间，特别是在候诊室等公共区域11</td></tr><tr><td>提供并促进支持人员的存在</td></tr><tr><td>建立并沟通出院后转诊和随访的明确途径(例如向全科医生(GP) 提供与专门研究妊娠流产的当地社区资源的联系和转介将心理护理纳入服务提供模式8</td></tr></table> # 1.3 血流动力学不稳定被认为怀孕、血流动力学不稳定、阴道出血和/或疼痛(腹部、膈肌或肩尖疼痛)的女性需要紧急干预。推测宫外孕破裂或不完全流产伴宫颈休克或大出血。表3。血流动力学不稳定 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>背景</td><td>·2010-2019年间，澳大利亚97例直接孕产妇死亡中有4例是由于宫外</td></tr><tr><td>复苏13</td><td>·按照标准医疗紧急程序进行复苏建立静脉 (IV)通路(例如两个×16 号IV插管) 进行紧急窥器检查，并从子宫颈和/或阴道取出POC 。可以止血并恢复血压将留置导管插入膀胱排空在复苏的同时进行紧急妇科检查考虑护理点USS 评估腹腔积血如果医疗不安全，请勿延迟治疗以实现正式USS 如果确诊或无法排除宫外孕，则继续在前往手术室途中进行复苏紧急全血细胞计数(FBC)，并分组并持有</td></tr><tr><td>控制出血</td><td>如果阴道流血持续存在且已排除异位，请考虑药物治疗请参阅昆士兰州临床指南:原发性产后出血 (PPH)的一线和二线药物治疗方案以及注意事项，包括:14 。马来酸麦角新碱 250 微克静脉注射或肌肉注射 (IM) ）每直肠800-1000微克米索前列醇。严重出血大量输血方案</td></tr><tr><td>手术干预</td><td>血流动力学不稳定是以下临床指征: 。不完全EPL的子宫手术清除13 。腹腔镜检查和/或剖腹手术以切除异位妊娠 O 在妊娠中期，考虑进行子宫切开术或剖腹手术指示</td></tr></table> # 2 EPL 护理原则无论怀孕地点或管理选择如何，经历 EPL 的女性都需要采取以下护理措施。与其他护理建议结合考虑。表 4.EPL 的一般护理原则 <table><tr><td>方面</td><td>考虑 ·收集患有早孕并发症的女性的血型和抗体筛查15</td></tr><tr><td>Rh D免疫球蛋白</td><td>·如果RhD 阴性且没有预先形成的抗D抗体，建议使用一定剂量的Rh D 免疫球蛋白以防止RhD 同种免疫15 如果需要RhD 免疫球蛋白。在流产后72小时内尽快给药。妊娠流产后最多10天内可服用，但疗效可能较低 ○如果妊娠12周或更短，推荐剂量为250国际单位(IU) 。如果妊娠超过12周，推荐剂量为625IU</td></tr><tr><td>组织病理学</td><td>送 POC进行组织病理学以确认怀孕，并排除异位妊娠或未怀疑的妊娠滋养细胞疾病 (GTD) 。经阴道超声(TVS)检测GTD 并不可靠 ·根据个人情况与可能在家流产的女性讨论组织病理学的影响/要求。这可能实际上很困难，有些人可能会觉得很痛苦。如果选择POC 收集，请提供标记的样本容器、病理请求表和送病理的说明</td></tr><tr><td>静脉血栓栓塞 (VTE)</td><td>·如果未收集POC，请确保还有其他后续选择 ·保持对产前和/或产后VTE风险的认识。请参阅昆士兰州临床指南:妊娠期和产褥期静脉血栓栓塞 (VTE)预防16</td></tr><tr><td>恢复正常月经周期</td><td>·恢复正常月经周期表明 EPL并发症已解决并完成治疗17 ·持续、不规则出血需要随访—考虑:17 。β人绒毛膜促性腺激素(β-hCG)以排除GTD 。保留产品感染 ·关于最佳后续方案的证据或共识有限</td></tr><tr><td>持续和后续护理</td><td>·建立当地程序和协议: 0用于后续护理安排。确保根据需要审查组织病理学结果并采取行动 ·将本指南中的随访建议视为临床适当且适用于个别女性 ·如果是GTD，请向昆士兰州滋养层中心(QTC)注册。请参阅第7节妊娠滋养细胞疾病</td></tr><tr><td>EPL后的建议</td><td>提供有关EPL的信息(书面和口头) 。何时寻求紧急援助: ■如果出现扑热息痛无法缓解的剧烈疼痛 ·肩尖或膈肌疼痛 ■60 分钟内浸泡不止一个垫子 ■晕倒了 ■温度升高。后续调查和预约的时间和性质，包括相关护理人员的联系方式 ○恢复性活动 ○受孕间隔的建议(如果有) 。未来的怀孕计划和避孕 0月经恢复/预期出血。获得心理支持请参阅昆士兰临床指南患者信息: ○宫外孕18 。疼痛怀孕初期出血18 流产后18</td></tr></table> # 2.1 心理支持早孕流产是许多女性常见的经历，但它同时也是一种强烈的个人、私密、亲密和个人经历。对于长远的健康和福祉来说，女性的心理需求不被忽视，以及任何悲伤、抑郁和焦虑的症状都能得到卫生专业人员的认可和认可。19 表 5.早期流产的背景和经历 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>EPL面临的独特挑战</td><td>·损失往往是突然和意外的，限制了预期悲伤和实际准备的机会 ·可能在很大程度上没有被社会承认，导致孤立感20.21 ·社会可以淡化EPL的影响，淡化女性哀悼失去母亲的必要性 ·通常没有正式或公开的纪念、葬礼或仪式来纪念损失通常没有已知的原因，导致自责或失败感 ·女性对怀孕的理解各不相同，进而影响她们解释 EPL的方式，作受从缓解到经历并对损失做出不同的以反应-23 。假设作为女性"保护者和支持者"的角色可能会导致忽视伴侣的心理需求23 ·情感护理是女性对所接受护理质量的看法的核心7</td></tr><tr><td>沟通</td><td>·使用反映女性使用的语言的敏感和同理心的沟通和倾听(例如，如果女性使用/喜欢这种语言，请使用"婴儿"而不是"胎儿") ·无论损失发生得多早，都要承认并承认损失7 让经验丰富的从业者参与艰难的讨论提供有关以下问题的实际支持(包括书面资源): 。他们的婴儿的遗体可能是什么样子(在适当的情况下) 。婴儿遗体管理的选择[请参阅第9节胎儿组织/遗体的敏感管理] 0如果需要，在超声扫描(USS)期间观察心跳消失。USS的结果是写下和/或照片作为纪念心理教育可以增加知识和理解，促进控制和应对，减少恐惧和焦虑，并有</td></tr><tr><td>心理教育</td><td>助于预防长期并发症。咨询女性EPL后可能出现悲伤、抑郁和焦虑症状24 O 提供有关患病率和 EPL病因的信息，这可能有助于减轻负罪感、羞耻感和个人失败感24 在适当的时候，让女性相信损失不是由于她们做了或没有做的任何事情造成的</td></tr><tr><td>记忆的创造</td><td>·父母可能希望也可能不希望创造怀孕/婴儿的记忆 ·与父母讨论根据胎龄、环境和文化喜好创建记忆的选择25 。请参阅昆士兰州死产护理临床指南26</td></tr><tr><td>后续支持</td><td>，请咨询、同伴或社区团体或组织寻求后续支持，认识并纳入：。女性的独特情况和个人历史。需要创建适合个人的转诊途径女人</td></tr></table> # 2.2 心理发病率表 6.心理发病率 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>心理发病率</td><td>·自杀是昆士兰州和澳大利亚直接和间接孕产妇死亡的重要原因12,19 ·在 EPL后的第一个月，研究一致表明 EPL与经历以下情况的女性比例之间存在关联：27 ○焦虑(18-32%), ○中度抑郁(8-20%) 0创伤后应激障碍 (PTSD)(25-30%) 病态悲伤(以绝望、深深的感情为特征) 可能会出现无价值和绝望，以及难以恢复正常的日常生活互动和活动)</td></tr><tr><td>心理发病的危险因素</td><td>·长期发病的危险因素尚不清楚3.27.28 可能包括： 0精神疾病史27,28 ○以前怀孕失败28 没有支持伙伴27 。没有活着的孩子27 。达到怀孕的时间间隔较长(超过一年)28</td></tr><tr><td>预防和支持</td><td>关于有效的心理和支持干预措施的证据有限29 积极主动地评估EPL后的心理健康状况评估每个女性对EPL的反应并个性化护理考虑长期发病的危险因素，以帮助识别有围产期心理健康问题风险的女性提供有关社区和同行支持组织的信息考虑是否需要进行正式的围产期心理健康筛查和转诊促进通过医疗保险向目前怀孕或已怀孕的人提供的非指导性妊娠支持咨询服务</td></tr></table> # 3 评估评估和诊断是通过体检、病史和临床检查相结合来做出的。表 7.确认怀孕并进行评估 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>血流动力学不稳定</td><td>·血流动力学稳定性的初步评估至关重要 ·请参阅第1.3节血流动力学不稳定</td></tr><tr><td>历史</td><td>·月经史和末次正常月经(LNMP) ·妊娠试验阳性日期，既往怀孕和结局，特别是流产其他重要的妇科历史如果辅助受孕，请确定受孕方法）相关的超声扫描(USS)和定量 β-hCG ·怀孕初期的症状</td></tr><tr><td>临床体征和症状</td><td>阴道出血(审查时间、范围和严重程度) ·疼痛(下腹部绞痛或腰酸) 姿势性晕厥，呕吐 ·肩尖/膈肌疼痛 ·震惊的迹象 ·POC 通过</td></tr><tr><td>确认怀孕</td><td>·对疑似 EPL的育龄妇女进行紧急血清定量β-hCG(妊娠试验)，无论LNM P、避孕、绝育史或报告的性不活动情况如何。如果预计血清检测报告会延迟，请根据临床指示使用尿液 β-hCG ·血清 β-hCG 阴性基本上排除宫外孕(除外在慢性异位的异常情况下，β-hCG 在过去一直呈阳性) ·基线观察(温度、心率、呼吸频率、血压)</td></tr><tr><td>体检</td><td>·腹部检查 ○压痛(僵硬和守护) ○扩张 ·阴道失血(检查垫子上的失血) ·阴道检查(根据临床指示进行个体化): 。窥器检查: ·出血来源和量 ■宫颈口有 POC 的证据(如果存在，请去除并提交组织学检查) 。双合诊检查: ·颈椎运动压痛 ■颈内口状态 ■评估附件肿块(宫外孕或其他肿块)</td></tr><tr><td></td><td>·子宫相对于月经日期的大小 ·如果有临床指征，请尽快紧急进行USS ·在USS 报告上记录是否进行TVS 或经腹部 (TAS)，以帮助解释</td></tr><tr><td>超声波扫描其他调查</td><td>·请参阅附录B:超声解剖、地标和文件 ·红细胞、血型、抗体筛查 ·根据临床指示筛查性传播感染(例如高危人群的女性)</td></tr></table> # 3.1 确定妊娠的存活率和位置表 8.确定妊娠的存活率和位置 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>β-hCG正常</td><td>·血清β-hCG首先在受孕后9天出现阳性 oβ-hCG 大于5IU/L即可确认怀孕31 ·对于妊娠 3-7 周的潜在可行宫内妊娠 (IUP) 。β-hCG 的平均倍增时间为1.4-2.1天32 。85%的β-hCG 连续每48小时至少上升66%33 。15%的β-hCG 连续每48小时上升53-66%33 。48小时内记录的最慢上升率为53%32</td></tr><tr><td>超声波扫描</td><td>由经验丰富的超声检查师进行的TVS是妊娠早期的黄金标准。如果TVS不可用，请认识到TAS可能不太准确当平均囊直径（全相合同胞供者)大于或等于3mm时，TVS 上通常可见IUP31 ·如果存在子宫肌瘤、弥漫性子宫腺肌病、早期多胎妊娠，USS 的可靠性可能较低</td></tr><tr><td>系列β-hCG</td><td>·在稳定的情况下建议连续使用β-hCG34 ，初始水平后48 小时(最长72小时)重复 β-hCG ·单个β-hCG值: 。不区分可存活妊娠和不可存活妊娠35 。不能用来排除IUP</td></tr><tr><td>歧视区</td><td>. 区分区是血清β-hCG水平，如果存在IUP，则在TVS或TAS上应可见妊娠囊32 。单个 β-hCG 值不被认为具有歧视性 ·对于定义TVS区分区的β-hCG 水平尚未达成共识36 。国际指南(TVS)中为1000 IU/L至3500 IU/L 。如果仅使用TAS，β-hCG水平会高得多</td></tr><tr><td>孕酮正常</td><td>·正常血清孕酮水平会随着怀孕而增加 ·妊娠6至8周之间的下降(第7周最低点)对应于黄体-胎盘移位37 。水平可能受到母亲年龄、体重指数 (BMI)和胎次的影响37 ·可能是妊娠活力的标志，但无法预测未知位置妊娠(PUL)的位置38 昆士兰州病理学协会没有正式的妊娠早期孕酮水平参考范围 ·在某些情况下可能是一个有用的辅助手段</td></tr><tr><td>混合种族评估变量</td><td>·与连续TVS结合使用定量系列血清β-hCG水平通常是区分早期不可存活妊娠和妊娠小于6-7周的宫外孕的唯一方法 ·如果β-hCG水平和TVS不同时进行，请谨慎解释结果，混合种族预测模型中的变量单独表现优于任何变量35.39-41 ·所有管理方案旨在预测和对女性进行风险分层，而不是用作诊断工具39 ·测试性能受到所使用的人群、可用资源和评估单位内PUL率的影响</td></tr></table> # 3.2 非存活宫内妊娠的诊断表 9.诊断不可行 IUP <table><tr><td>方面</td><td>考虑</td></tr><tr><td>背景</td><td>·不可行IUP的诊断需要: 。经验丰富的临床医生。优质TVS设备和经验丰富的操作员34 排除可行妊娠的标准必须足够严格，以避免干预措施无意中损害可行妊娠31</td></tr><tr><td>发现可疑但不能诊断42</td><td>·全相合同胞供者16-24mm，未见胚胎冠臀长度 (CRL)小于7毫米，无心跳 USS 后7-12天，没有有心跳的胚胎，显示妊娠囊，但没有卵黄囊 USS 显示妊娠囊和卵黄囊后7-10天，没有有心跳的胚胎 ·LNMP后6周或更长时间胚胎缺失空羊膜(羊膜位于卵黄囊附近，未见胚胎) 卵黄囊增大(大于7毫米) 与胚胎大小相关的孕囊较小(全相合同胞供者与CRL之间的差异小于5m m)</td></tr><tr><td>TVS诊断标准34</td><td>·全相合同胞供者大于或等于25mm，且不存在胎儿 ·CRL大于或等于7mm 的胎儿可见，但观察至少30 秒后未显示胎心运动 ·USS 显示妊娠囊但没有卵黄囊后2周或更长时间，没有有心跳的胚胎 ·USS 显示妊娠囊和卵黄囊后11天或更长时间，没有有心跳的胚胎 USS 后7天或更长时间没有有心跳的胚胎，胎儿极小于7毫米，没有心脏活动</td></tr><tr><td>重复TVS间隔</td><td>. 当看不到胎儿极时，直到全相合同胞供者为(或未能达到)25 mm 才能做出诊断，因此初始和后续USS之间的间隔取决于初始表现时的全相合同胞供者 ·根据预期正常孕囊生长率1mm/天估计TVS 间隔。示例:如果全相合同胞供者=12mm，则在13天或更长时间内重复 TVS(13 天内12mm 全相合同胞供者+13 mm 增长=预期全相合同胞供者=25 mm) ·避免重复无定论的TVS</td></tr></table> # 3.3 未知部位的怀孕 PUL 是一种分类，而不是最终诊断。在分类 PUL 后，宫外孕的最终诊断使女性面临临床并发症和伤害的最大风险。因此，预测或排除是最重要的结果。3939 表 10.未知部位的怀孕 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>持续保持警惕</td><td>·β-hCG、β-hCG 比率或黄体酮的单一截止水平不能单独在临床上进行解释35 专家审查和密切随访至解决至关重要连续进行 β-hCG(间隔 48-72 小时) 根据临床指示进行TVS 血清黄体酮可能是有用的辅助手段使用数学风险预测模型(例如 M6P，2步分类策略)对PUL进行分类已被证明是一种有用的决策支持工具39，41，43</td></tr><tr><td>系列β-hCG</td><td>根据临床情况进行个体化护理如果连续β-hCG升高超过66% ○IUP的可能性更大。不能排除宫外孕如果连续 β-hCG 下降 50% 或更多 ○更有可能发生不可行的妊娠(IUP 或宫外孕) 如果连续β-hCG上升低于66%或下降低于50%</td></tr><tr><td>黄体酮</td><td>○如果重复TVS没有IUP，则怀疑宫外孕如果初始测量值小于或等于2nmol/L ○可能会出现无法存活的妊娠(IUP或PUL失败) ○不能排除宫外孕</td></tr></table> # 3.3.1 PUL 分类后结果的频率在临床稳定的女性中，通过 TVS 和 PUL 初始分类后对各种截止水平进行评估报告的结果。35 表 11.PUL 后结果的频率 <table><tr><td>切断35</td><td>N</td><td>异位/PP</td><td>不可行的IUP/FPUL</td><td>可行的P</td></tr><tr><td colspan="5">初始β-hCG</td></tr><tr><td>> 1000 IU/L</td><td>832</td><td>10.5(7.5至 13.6)</td><td>70.6(67.6至 73.8)</td><td>18.9(15.9至 22.1)</td></tr><tr><td>> 2000 IU/L</td><td>513</td><td>8.4(5.1至12.0)</td><td>77.8(74.5至 81.4)</td><td>13.8(10.5至 17.5)</td></tr><tr><td>> 2500 IU/L</td><td>428</td><td>7.9（4.4至 11.6)</td><td>80.6(77.1至 84.2)</td><td>11.4(7.9至 15.1)</td></tr><tr><td>> 3000 IU/L</td><td>358</td><td>7.5(3.9至 11.5)</td><td>81.6(77.9至 85.5)</td><td>10.9(7.3至 14.9)</td></tr><tr><td colspan="5">初始黄体酮</td></tr><tr><td>≤ 2 nmol/L</td><td>327</td><td>1.8(0.6至 3.1)</td><td>98.2(96.9至99.4)</td><td>0(0.0至1.2)</td></tr><tr><td>≤10 nmol/L</td><td>1112</td><td>7.8(6.4至9.4)</td><td>92.0(90.6至 93.6)</td><td>0.18(<0.01至1.8)</td></tr><tr><td>β-hCG 比率</td><td></td><td></td><td></td><td></td></tr><tr><td><0.87</td><td>883</td><td>6.2(4.8至 7.8)</td><td>93.8(92.3至 95.3)</td><td>0(0.0至1.5)</td></tr><tr><td><1.5</td><td>1205</td><td>16.9(14.9至 19.1)</td><td>81.7(79.7至84.0)</td><td>1.3(<0.01至 3.5)</td></tr></table> 存活 IUP:在初次随访时看到具有可见心脏活动的胚胎，并且在妊娠 11-14 周进行约会扫描时仍然存在。不可行 IUP，即在 TVS 上看到的 IUP 在进行约会扫描 FPUL 时流产:βhCG 水平自然降低并消退，而 TVS 上没有显示怀孕。异位:TVS 上可见宫外肿块。PPUL 中，当 βhCG 水平超过三个时，TVS 不会揭示妊娠位置间隔超过 48 小时的记录保持静止，每次差异为 $1 5 \%$ 或更少。35 # 3.4 其他妊娠结局表 12.其他妊娠结局 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>完全流产</td><td>·IUP只有在识别卵黄囊后才能最终确认44 ·如果之前没有IUP 的报告或证据，则无法根据"空子宫"的TVS 结果做出完全流产的诊断完全流产的诊断需要随访血清定量β-hCG 直至阴性，并在临床指征的情况下进行TVS以排除</td></tr><tr><td>剖腹产(CS)疤痕妊娠</td><td>未确诊的宫外孕 ·随着CS率的上升和先进成像方式的增加，发病率不断增加45 。既往患有一次或多次CS 的女性，发病率估计为每 531名女性中有1人46 ·为最佳管理提供信息的证据有限45.47 。期待治疗可以导致活产，但也会导致严重的发病率(例如子宫破裂、胎盘植入、出血)45,48 0需要多学科方法48</td></tr><tr><td>威胁流产</td><td>·随访GP可能是合适的 ·黄体酮可以改善既往流产一次或多次和早孕出血的女性的活产结局(ARR: 5.72%;95% Cl1.65至 9.8) ·对于既往没有活产结果的女性来说，活产结果没有改善流产和早期妊娠出血(ARR0.43%;95%CI-3.17至4.02%)</td></tr></table> ARR:绝对风险降低 # 4 宫外孕表 13.宫外孕 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>背景</td><td>·发生在1-2%的妊娠中49 ·92-95%发生在输卵管47 。非输卵管异位妊娠的趋势增加(即间质(角)、剖腹产疤痕、宫颈、异位、卵巢和腹部)，尤其是剖腹产疤痕妊娠47 ·未能及时诊断和管理宫外孕可能会危及生命47 。80%的孕早期孕产妇死亡是其原因47</td></tr><tr><td>临床表现13.49</td><td>·月经不来不规则阴道流血(点滴出血)—一但并非所有情况都是如此 50%的女性出现腹痛、压痛和可触及的附件肿块 ·颈椎运动压痛 TVS上不存在IUP，且血清 β-hCG 呈阳性 ·如果:。怀疑异位破裂 ○肩尖或膈肌疼痛(异位破裂的10-20%) 。严重腹腔内出血引起的心动过速/低血压</td></tr><tr><td>治疗选择</td><td>比较预期、医疗和手术选择的质量证据有限50-52 。不同方案之间复发性异位的发生率相当53 。一项研究报告称，期待治疗、药物治疗和手术治疗的成功率分别为7 0% (49/70)、82.6% (38/46)和 100% (86/86)53 ·选择取决于临床情况和女性的喜好 ·β-hCG下降或稳定并不能排除药物或期待治疗后破裂的风险</td></tr><tr><td>非输卵管异位4 7</td><td>·优化管理尚未建立）根据个人情况(例如地点、妊娠和治疗的紧迫性)，手术或药物可能是合适的。期待管理对于大多数女性来说并不是一个合适的选择 ·个性化管理并根据需要寻求专家建议</td></tr></table> # 4.1 宫外孕的危险因素一半被诊断患有宫外孕的女性没有已知的危险因素54 表 14.与异位妊娠相关的危险因素 <table><tr><td>风险因素55</td><td>(调整后)或</td><td>95% CI</td></tr><tr><td>灭菌</td><td>9.3</td><td>4.9至18.0</td></tr><tr><td>既往宫外孕(如果>1，则风险增加)</td><td>8.3</td><td>6.0至11.5</td></tr><tr><td>既往接受过输卵管手术</td><td>4.0</td><td>2.6至6.1</td></tr><tr><td>有记录的输卵管病理学</td><td>3.7</td><td>1.2至 4.8</td></tr><tr><td>既往生殖器感染确诊</td><td>3.4</td><td>2.4至5.0</td></tr><tr><td>以前流产过</td><td>3.0</td><td>>2</td></tr><tr><td>宫内节育器使用时间超过2年</td><td>2.9</td><td>1.4至2.3</td></tr><tr><td>40 岁或以上(与 25-29 岁相比)</td><td>2.9</td><td>1.4至 6.1</td></tr><tr><td>不孕症(风险随着年龄的增长而增加)</td><td>2.1-2.7</td><td>一</td></tr><tr><td>当前吸烟者(风险随着每天的量而增加)</td><td> 1.7-3.9</td><td></td></tr><tr><td>吸烟(过去或曾经)</td><td>1.5</td><td>1.1至2.2</td></tr></table> \调整后:既往盆腔感染、吸烟、招募地区、教育水平和年龄^ 仅与怀孕对照相比 # 4.2 宫外孕的期待管理期待管理是特定女性的一种选择。明确的选择标准尚未明确。51 表 15.宫外孕的期待管理 <table><tr><td>(视角</td><td>考虑</td></tr><tr><td>背景</td><td>·成像技术的进步使得宫外孕能够更早、更准确地诊断出来51.56 ·据报道，在选定的女性(妊娠早期，β-hCG 值低于1000 IU/L且不断下降) 中，高达70%的女性无需治疗即可自行缓解53.57 ·如果既往没有异位病史，则更有可能成功解决50</td></tr><tr><td>建议的标准51.58</td><td>血流动力学稳定 β-hCG 较低且下降(初次就诊时低于1500 IU/L) 。物理分辨率与初始和最大 βhCG 呈正相关56 输卵管肿块小于3厘米没有疼痛 USS上骨盆内血液的证据极少没有地理隔离 . 如果后续行动不确定，不建议使用 ·通过EPAS跟进</td></tr><tr><td>持续管理</td><td>β-hCG: 。每 48 小时一次，持续8天(以确认水平下降) 。如果出现令人满意的解决方案，请开始每周设置水平，直至为负值 ·USS 不常规推荐—考虑是否: ○β-hCG 不持续下降 ○临床指示 ·提供手术或医疗管理: 。应女方的要求。如果疼痛或出血持续或增加。如果β-hCG不持续下降。如果发生输卵管破裂并伴有腹腔积血</td></tr><tr><td>女性的建议</td><td>建议：。尽管β-hCG 降低，但仍有可能发生输卵管破裂 0盆腔检查和性交在缓解急性期存在破裂的风险。在超声波分辨肿块之前避免未来怀孕，请注意，超声波分辨肿块比β-hC G 生化分辨需要更长的时间56 ·建议在下次怀孕(妊娠 5-6 周)早期进行USS，因为未来宫外孕的风险会增加 ·请参阅表14。与异位妊娠相关的危险因素</td></tr></table> # 4.3 异位妊娠的医疗管理甲氨蝶呤是医疗管理的首选药物，尽管治疗方案各不相同。如果不存在当地方案，请参阅附录 C:异位妊娠的甲氨蝶呤方案。59,60 表 16.异位妊娠的医疗管理 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>背景</td><td>·甲氨蝶呤是一种叶酸拮抗剂，通过干扰DNA合成来阻止快速分裂细</td></tr><tr><td>适应症</td><td>·未破裂的异位妊娠;血流动力学稳定，无活动性出血迹象54,59.62 ·异常部位(例如宫颈异位、间质、剖腹产疤痕)45 ·初始血清 β-hCG 较低 ○β-hCG 低于5000 IU/L即可达到最佳效果，但也可用于未破裂异位中的任何β-hCG 水平60 ·FBC、电解质和肝功能检查(ELFT)均在正常范围内</td></tr><tr><td>禁忌症54</td><td>·血流动力学不稳定 ·对甲氨蝶呤过敏、TVS上腹腔积血的证据肾脏疾病/功能不全(甲氨蝶呤通过肾脏系统清除) FBC 和/或 ELFT异常急性肝病、再生障碍性贫血、血小板减少症免疫功能低下活动性肺部疾病活动性消化性溃疡病共存的可行 IUP(异位妊娠) 母乳喂养无法参加长期随访(35-109天)</td></tr><tr><td>注意事项54</td><td>地理隔离基线血清 β-hCG 大于 5000 IU/L TVS 上异位妊娠直径大于3-4cm ·TVS上存在胎心运动当妇女不能接受输血时如果BMI大于或等于40 kg/m，且肌内注射剂量上限为2m体表面积(BSA)，</td></tr><tr><td>持续管理</td><td>则更可能需要额外剂量才能实现完全缓解2263 ·跟进EPAS ·β-hCG 按照甲氨蝶呤方案。请参阅附录C:异位妊娠的甲氨蝶呤治疗方案一周内及之后根据临床指示重复USS(例如 β-hCG 不持续下降、输卵管以外的异位部位) 。如果USS上出现胎心，请紧急转诊至母胎药房进行随访—可能需要直接注射氯化钾</td></tr></table> # 4.3.1 对接受甲氨蝶呤治疗的女性的建议表 17.女性甲氨蝶呤后注意事项 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>副作用</td><td>·常见的副作用包括:恶心、疲倦、排便习惯改变和口腔溃疡，通常在几天内无需治疗即可消退61 。常规使用止吐药</td></tr><tr><td>细胞毒性预防措施</td><td>·治疗完成后，甲氨蝶呤可在体内(呕吐物、尿液、粪便)停留长达七天。提供有关治疗后细胞毒性预防的信息(例如，使用后关闭马桶盖，使用全冲洗，如果处理或洗涤被体液污染的亚麻布/衣服，请使用手套) ·请参阅昆士兰州临床指南患者信息甲氨蝶呤治疗异位妊娠</td></tr><tr><td>建议在治疗期间避免64</td><td>·过度或长时间暴露在阳光下，并穿戴防护服并使用防晒霜(以限制皮肤炎症) ·治疗期间含有叶酸/叶酸的食物和维生素可能会降低治疗效果性交是解决急性期破裂的风险注射后饮酒七天可能会增加副作用治疗期间和治疗后一周内服用抗炎药物(例如布洛芬和阿司匹林)，因为这会增加副作用的风险</td></tr><tr><td>构思/避孕61</td><td>·由于甲氨蝶呤可能具有致畸性，建议在服用甲氨蝶呤后将下一次怀孕推迟三个月 ·建议避孕和避免怀孕，直到完成医疗随访 ·建议在下次怀孕(妊娠 5-6 周)早期进行USS，因为未来宫外孕的风险会增加</td></tr><tr><td>返回医院</td><td>·建议使用甲氨蝶呤会导致骨髓抑制并增加感染风险(尽管不常见) 。如果身体不适、发烧38℃或更高，请就医 ·如果临床症状有以下症状，建议立即到医院就医(这可能提示异位破裂) ○腹部或肩尖疼痛、头晕或晕厥，。阴道大量流血</td></tr></table> # 4.4 异位妊娠的手术治疗表18.异位妊娠的手术治疗 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>适应症54</td><td>·女人的喜好 ·血流动力学不稳定）持续过度出血期待或医疗管理有禁忌或失败</td></tr><tr><td>方法</td><td>腹腔镜检查是稳定女性的首选方法52.54 ·失血性休克时可能需要剖腹探查术54 ·术后2周左右进行GP 随访</td></tr><tr><td>后续</td><td>。通常不需要USS—考虑β-hCG 不下降或有其他临床适应症 ·如果输卵管切开，每周进行 β-hCG 检测，直至阴性。如果β-hCG不下降，请考虑药物治疗或输卵管切除术如果输卵管切除术。异常情况下可能会出现腹腔植入，尤其是异位腹膜破裂后。如果未确诊异位妊娠，很少会出现持续的宫内妊娠</td></tr><tr><td>女性的建议</td><td>。手术后三周尿β-hCG ·下次受孕的最佳间隔尚不清楚—临床实践从下次月经到3个月不等，建议在下次怀孕(妊娠 5-6 周)早期进行USS，因为未来宫外孕的风险会增加</td></tr></table> # 5 宫内妊娠不可存活对于不可行 IUP，预期、医疗和手术治疗之间没有显着差异。手术治疗是最及时的解决办法(在大多数研究中定义为子宫完全排空且不需要计划外手术)。女性的个人偏好和价值观以及临床情况决定了管理的选择。65 # 5.1 风险因素表 19.与非存活宫内妊娠丢失相关的危险因素 <table><tr><td>危险因素组</td><td>与流产的关系</td></tr><tr><td>母亲年龄3</td><td>·流产风险最低的是20-29岁之间 0不到20年(15.9%) 0 20-29 岁(12%) 0 35-39岁(18%) 40-44 岁(37%) 45岁或以上 (65%)</td></tr><tr><td>以前流产过3</td><td>流产的风险随着之前流产的次数而增加 ○0之前(11%) 。1之前的 (20%) 。2次之前 (28.3%)</td></tr><tr><td>体重指数(BMI)3</td><td>03次或以上之前(42%) ·BMI在18.5-24.9kg/m之间流产风险最低2 ·解剖因素(例如子宫纵隔)</td></tr><tr><td>母亲的情况3</td><td>内分泌疾病(例如甲状腺疾病) ·免疫因素(例如系统性红斑狼疮) 感染。细菌(例如细菌性阴道病、布鲁氏菌病、沙眼衣原体、梅毒) 。病毒(例如疱疹病毒、巨细胞病毒、艾滋病毒、风疹、登革热) ○原虫感染(例如疟疾和弓形虫病) 严重的急性疾病血栓形成倾向(例如V因子莱顿) 不受控制的慢性疾病(例如糖尿病、高血压)</td></tr><tr><td>胎儿</td><td>·染色体异常。在流产中，常染色体三体性是最常见的异常，其次是×单体性和三倍体性 ·先天性异常66</td></tr><tr><td>生活方式</td><td>·吸烟。流产的风险随着数量的增加而增加 ·饮酒。妊娠早期摄入量高时流产的风险会增加 ·环境污染(例如空气污染、农药)</td></tr></table> # 5.2 非存活宫内妊娠的期待治疗表 20.稳定的不可行 IUP 的期待管理 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>适应症</td><td>·女人的喜好 ·最适合不完全流产的治疗67,68 ·β-hCG 和黄体酮值越低，成功的可能性就越高8</td></tr><tr><td>禁忌症</td><td>怀疑GTD 血流动力学不稳定宫内节育器(需要取出) 女性出血风险增加(例如妊娠早期晚期)或出血风险增加(例如无法输血或凝血病) 感染的证据</td></tr><tr><td>风险/收益</td><td>比药物或手术治疗效果较差(定义为需要进一步治疗)67,69.70 与手术治疗相比，出血天数更多，出血量也更大药物治疗和期待治疗后的生育能力相似69 完全流产的时间范围是不可预测的医疗管理和期待管理之间没有差异:71 ○短期和长期的情绪困扰对管理方案的满意度 GP 或 EPAS 在7-10 天内进行随访</td></tr><tr><td>持续管理</td><td>·通过病史和检查进行初步评估。对GTD 和/或异位保持警惕第8天重复β-hCG 考虑USS: 0如果有临床指征(有症状) 。评估是否保留POC 。如果β-hCG水平在7天内没有下降超过90%72 讨论持续期待治疗或手术或医疗管理的选择: ○应女方的要求。如果USS上发现持续大量出血、疼痛或持续性宫内孕囊。如果发现其他临床问题(例如大出血、疼痛) 如果怀疑感染，建议早期进行手术治疗并覆盖抗生素 ·如果出现以下情况，建议在3-6 周进行尿妊娠测试:17 。无POC 组织病理学 04-6 周内未能恢复正常月经</td></tr><tr><td>女性的建议</td><td>。持续异常出血建议使用电话和24小时紧急入院或在地理/社会隔离的情况下使用访问计划 ·预计出血时间长达两周(个别病例更长) 可以稍后选择建议的手术或医疗治疗 ·请参阅QCG患者信息流产</td></tr></table> # 5.3 妊娠早期非存活宫内妊娠的医疗管理表21.稳定的不可行 IUP 的医疗管理指征 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>适应症</td><td>. 女人的喜好 ·稽留或不完全流产 1 怀疑GTD</td></tr><tr><td>禁忌症</td><td>血流动力学不稳定出血风险增加(例如妊娠早期晚期)或出血影响(例如凝血障碍、无法输血）感染的证据宫内节育器(需要取出) 医疗禁忌症(例如高血压、前列腺素过敏)</td></tr><tr><td>风险/收益</td><td>妊娠早期流产手术排空的有效替代方案70 如果稽留流产，医疗管理比期待管理更有效8 如果不完全流产，药物治疗和期待治疗之间的有效性没有显着差异7 3 与刮宫术相比，米索前列醇药物治疗后出血更严重、持续时间更长73</td></tr><tr><td>米非司酮和米索前列醇</td><td>如果稽留流产，米非司酮和米索前列醇联合方案可能比单独使用米索前列醇更有效(更不需要手术干预)74.75 ·对于13 周前的不完全流产，有多种治疗方案的报道，但最佳方案尚</td></tr><tr><td>米索前列醇</td><td>不确定65,73 ）如果没有当地方案，建议的方案是：。第1天:米索前列醇400-800 微克PV，口服或舌下含服。第2天或第3天:重复米索前列醇400-800 微克PV，口服或舌下含服 ■如果POC 病史良好，可以省略第二剂</td></tr><tr><td>行政</td><td>疗可以作为门诊或和手术提供17 β-hCG 第1天(首次使用米索前列醇的一天)和第8天(确认水平下降) 第2天和第8天随访EPAS</td></tr><tr><td>持续管理</td><td>）成功初步评估是通过病史和检查。对GTD 和/或异位保持警惕17 考虑USS: ○如果有临床指征(有症状) 。评估是否保留POC 。如果β-hCG水平在7天内没有下降超过90%72 除非：。女人要求这样做。还有其他临床问题(例如持续大出血、疼痛) ·如果出现以下情况，建议在3-6周进行尿妊娠测试:17 。无POC组织学。4-6周内未能恢复正常月经</td></tr><tr><td>女性的建议</td><td>。持续异常出血告知女性： 0出血量可能比月经量多。痉挛可能伴有出血。如果治疗后24小时内尚未开始出血，请联系医疗保健提供者以确定正在进行的护理。潜在的副作用包括疼痛、腹泻和呕吐</td></tr></table> \有关完整药物信息，请参阅澳大利亚药典 # 5.4 妊娠早期不可行 IUP 的手术治疗表22.稳定的不可行 IUP 的手术治疗 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>适应症</td><td>·女人的喜好 ·医疗或期待管理不成功 ·如果: 。血流动力学不稳定。持续阴道大量流血。保留组织感染的证据。怀疑GTD 吸引刮宫术是推荐的方法76</td></tr><tr><td>注意事项</td><td>·如果:。请注意: ○出血风险增加(例如疑似动静脉畸形或凝血障碍) 。既往子宫穿孔</td></tr><tr><td>风险/收益</td><td>·作为主要方法，手术治疗可以带来更直接的结果，并且随访时间更少67 ·与手术和麻醉相关的标准风险 ·尽管证据有限，但临床经验支持在手术后排空之前使用宫颈成熟剂77</td></tr><tr><td>宫颈启动</td><td>·如果没有当地方案，推荐剂量为：78 。手术前3-4小时使用米索前列醇400 微克 PV 。手术前2-3小时口服、舌下、颊甲状腺素400 微克。使用水作为润滑剂吸引刮除术通常在全身麻醉下进行</td></tr><tr><td>护理提供</td><td>·根据指示提供镇痛没有足够的证据支持手术前常规抗生素预防79 ○根据个体临床指征(例如子宫内膜炎)进行考虑如果有临床指征，在抽吸刮除时考虑USS</td></tr><tr><td>后续</td><td>如果出现持续的临床问题，建议进行全科医生随访 β-hCG 不常规指示 USS 不常规推荐 ·检查组织学结果如果RhD阴性血型，请参阅第2节EPL护理原则有关其他调查，请参阅第9节复发性早期妊娠流产</td></tr><tr><td>重复刮宫</td><td>·如果需要重复刮宫(需要经验丰富的操作员): 。考虑初次宫腔镜检查或USS 引导刮宫术，以促进子宫排空并最大限度地降低阿谢曼综合征的风险。服用抗生素</td></tr></table> \有关完整药物信息，请参阅澳大利亚药典 # 6 中期妊娠流产妊娠中期流产占已知妊娠的 $1 - 2 \%$ 。因果关系很难建立，并且可能存在多种促成病理。关于最佳管理的证据有限。如果有母亲妥协的证据(例如败血症、巨大胎盘早剥、严重或迅速恶化的先兆子痫)，则加速分娩。80 81 73 表 23.中期妊娠丧失 <table><tr><td>方面</td><td>考虑</td><td></td></tr><tr><td>潜在的病因</td><td>·胎儿。染色体异常先天性异常82 ·母亲。子宫畸形83 。胎膜早破80 。既往妊娠中期流产80</td><td>。母亲患有内科疾病(例如心脏病、自身免疫性疾病、血栓形成倾向)80</td></tr><tr><td>演示</td><td>。绒毛膜羊膜炎80</td><td>胎盘并发症(例如早剥)80 ：能数现为高死(IUFD)</td></tr><tr><td>评估</td><td>·进行阴道低位和肛周拭子</td><td>·请参阅昆士兰州临床指南:孕产妇调查的死产护理方案26</td></tr><tr><td>护理设置</td><td>中提供护理 ·适合所有妊娠</td><td>·在可行的情况下，在远离怀孕无并发症或健康婴儿的妇女的环境 ·提供与女性选择一致的充分镇痛</td></tr><tr><td>医疗管理</td><td>低于催产素84 。也可以单独使用米索前列醇催产素</td><td>·如果之前做过子宫手术，米索前列醇破裂的风险较低，并发症发生率 ·如果子宫颈闭合且胎膜完整，米非司酮和米索前列醇是引产的一线药物。如果没有当地方案，请参阅昆士兰州临床指南:终止妊娠79 ·如果胎膜破裂和/或子宫颈扩张，请考虑米索前列醇或静脉注射</td></tr><tr><td>第三分期</td><td>·建议积极管理 ·如果不在:内完成: 。30 分钟—排空膀胱并考虑输注催产素。60分钟—考虑手动取胎盘）预测和准备产后出血(PPH) ·保留脐带、胎膜和胎盘用于组织病理学</td><td></td></tr><tr><td>手术治疗</td><td>一般适用于妊娠满14周85 似GTD的情况</td><td>。可能适用于妊娠早期婴儿死亡且手术被认为是安全的16 周以上）可能适用于持续过度出血、血流动力学不稳定、保留 POC 证据、疑</td></tr><tr><td>哺乳抑制</td><td>顾问)</td><td>、建议采取保守和舒适措施(例如最小程度的乳房刺激、冷敷和镇痛)6 ）如果考虑使用药物，请咨询相关健康专业人员(例如药剂师、哺乳</td></tr><tr><td>后续</td><td>）安排产科医生的后续预约 ·考虑产后USS来评估子宫畸形）告知全科医生并提供临床总结检、病理）26</td><td>请参阅昆士兰州临床指南:死产护理以进行后续孕产妇和胎儿检查(例如尸</td></tr></table> \有关完整药物信息，请参阅澳大利亚药典 # 7 妊娠滋养细胞疾病(GTD) 表 24.GTD 的分类 <table><tr><td>分类</td><td>包括87</td></tr><tr><td>非肿瘤性病变</td><td>·胎盘部位反应夸大 ·良性胎盘部位结节</td></tr><tr><td>葡萄胎妊娠</td><td>·部分葡萄胎(HM) 完全性葡萄胎(HM)</td></tr><tr><td>妊娠滋养细胞肿瘤 (GTN)</td><td>·持续性GTD(侵袭性葡萄胎) ·妊娠绒毛膜癌胎盘部位滋养细胞肿瘤(PSTT) ·非典型胎盘部位结节(APSN) ·上皮样滋养细胞肿瘤(ETT)</td></tr></table> # 7.1 GTD 的管理表 25.妊娠滋养细胞疾病 <table><tr><td>方面</td><td>考虑因素</td></tr><tr><td>昆士兰滋养层中心 (QTC)</td><td>·在滋养层中心接受GTD 治疗的死亡率为2.1%，而初次治疗失败后转诊的女性死亡率为8%88 ·将女性转介至4029 昆士兰州皇家布里斯班妇女医院的QTC ·联系QTC: 。在所有GTD 或可能的GTD 诊断的情况下。对于任何临床问题。电子邮件:QTC@health.qld.gov.au http://www.health.qld.gov.au/rbwh/services/gtd-unit.asp</td></tr><tr><td>临床表现</td><td>最常见:阴道异常出血89 ·妊娠早期偶然发现盆腔超声检查不太常见(由于USS 诊断较早):过度剧吐、甲状腺功能亢进、早发先兆子痫、子宫过度增大89 与欧洲和北美(每 1000 次怀孕不到1次)相比，在亚洲更常见(高达每 1000 次怀孕2例)90</td></tr><tr><td>诊断</td><td>·如果β-hCG异常高，请考虑GTD作为鉴别诊断 ·完全HM比部分HM更有可能通过其特征性USS 特征来识别90 。正常USS 并不排除HM的诊断）定量β-hCG(T)—肿瘤标志物 ·通过 POC 的组织学检查和辅助测试(p57 染色、DNA 指数、QF-PCR 研究)做出最终诊断</td></tr><tr><td>干预措施</td><td>·建议吸刮术并考虑:90 。米索前列醇用于术前宫颈启动。USS指导可以协助性能 ·如果保留 POC 的可能性，QTC 可能会建议重复子宫清除(有或没有宫腔镜检查/USS 指导) 。小心避免阿谢曼综合症如果不希望未来生育，子宫切除术可能是另一种选择，但通常保留给某些持续性GTD病例91 ·通常不建议通过药物引起已知葡萄胎妊娠的撤离90.92 ）如果RhD 阴性，建议使用RhD免疫球蛋白90 ·提供有关后续重要性和影响的咨询</td></tr></table> # 7.2 后续疏散后每周监测 $\beta .$ -hCG (T) 至关重要。表 26.GTD 后随访 <table><tr><td>方面</td><td>考虑因素部分HM</td></tr><tr><td>后续</td><td>·每周血清β-hCG(T)水平直至连续三周阴性90 ·建议每周第三次阴性检测后尝试怀孕 ·QTC每年随访五年完整的HM ·每周血清 β-hCG(T)检测，直至连续三周阴性90 ·然后在第三次阴性结果后每月一次，持续6个月90 建议在6个月的阴性检测后尝试怀孕 QTC每年随访五年</td></tr><tr><td>未来的生育能力</td><td>建议进行有效的避孕以避免怀孕，直到β-hCG随访完成89 随访期间的激素避孕不会增加GTN的风险或严重程度，也不会推迟 hCG 正常化90 ·β-hCG 水平正常化后插入宫内节育器是可以接受的92 ·未来任何怀孕后6周进行β-hCG水平测定 ·GTD复发的风险约为每100次未来怀孕中就有1次92</td></tr><tr><td>磨牙后GTN</td><td>·完全性葡萄胎和部分性葡萄胎葡萄胎后GTN的总体发生率约为20%93 发病风险包括:诊断时β-hCG大于100，000 IU/L、子宫过大、卵泡膜黄体蛋白囊肿和年龄超过40岁90 ，考虑手术后撤离后存在持续性疾病，其中有:90 0 3 周内 β-hCG(+/-10%)连续4个值达到峰值(即第1、7、14、21天) ○2 周内 β-hCG 水平升高(10% 或以上)3个值(即第1、7、14) 。绒毛膜癌的组织学诊断或转移的临床和/或放射学证据</td></tr></table> # 8 反复早期妊娠流产复发性早期流产被定义为两次或两次以上流产，或三次或三次以上流产。由于之前的妊娠流产是否需要连续，定义变得更加复杂。在确定 EPL 复发后是否需要进一步调查时，请考虑每位女性的个人情况3,94 表27.反复早期妊娠流产 <table><tr><td>方面</td><td>考虑</td></tr><tr><td>护理提供</td><td>·连续三次流产后建议进行妇科专家会诊。连续两次流产后，考虑女性的年龄与活产机会的关系 ·如果怀疑有潜在的医疗状况，请根据指示咨询专科医生根据伴侣的全面病史和临床情况，对复发性EPL进行个体化调查调查常常令人失望，因为有关病因、评估和未来管理的问题尚未得到解答</td></tr><tr><td>风险因素3</td><td>每次流产后，随后流产的风险都会增加与非存活宫内妊娠的危险因素类似请参阅第5.1节风险因素</td></tr><tr><td>生活方式95</td><td>·建议：。停止吸烟、饮酒和非法物质的使用。将咖啡因摄入量限制在每天三杯或更少杯。使BMI正常化</td></tr><tr><td>标准调查95</td><td>常规血液(例如 FBC、ELFT、空腹血糖水平(BGL)) ·获得性血栓形成倾向。不建议进行先天性血栓形成倾向测试促甲状腺激素(TSH) 0FT3/4 和抗体(如果TSH 异常) POC的核型分析专门进行盆腔超声扫描以排除结构异常</td></tr><tr><td>需要考虑的可能调查95</td><td>父母的核型分析 ·低/高阴道拭子 ·衣原体抗核抗体(抗心磷脂和抗磷脂抗体</td></tr><tr><td>潜在的治疗方法</td><td>精液分析异常情况 ·对于不明原因反复流产的女性，补充孕激素治疗可能会降低随后怀孕的流产率96 。请参阅第3.4节其他妊娠结局支持低剂量阿司匹林、依诺肝素或静脉注射免疫球蛋白可提高活产率 (与安慰剂相比)97 。在抗磷脂综合征 (APS)的情况下推荐阿司匹林和普通肝素，并咨询产科医生95</td></tr></table> # 9 对胎儿组织/残骸进行敏感管理父母在 EPL 后做出的决定可能会对悲伤过程产生重大影响。即使法律没有要求举行葬礼、埋葬或火葬的条件，父母可能仍然希望这种选择，或者在数月甚至数年后返回询问婴儿遗体的处理方式。98 表28.对胎儿遗骸进行敏感管理 <table><tr><td>考虑</td><td>推荐 ·如果满足以下任何条件，则必须在昆士兰州出生的婴儿登记出生;宝宝是:</td></tr><tr><td>出生登记</td><td>0活产(婴儿分娩完成后心脏跳动的婴儿)99 ○妊娠20 周或以上 o400克或更多如果出生登记是强制性的(即满足上述条件之一或以上)，死亡证明和埋葬或火葬也是强制性的，并且需要收集围产期数据如果出生登记不是强制性的(即上述条件均不满足)，则不需要死亡证明、埋葬或火葬以及围产期数据收集告知家长，“早孕流产识别证明"可以免费从出生、死亡、婚姻登记处获得离婚</td></tr><tr><td>管理选项</td><td>·昆士兰卫生设施可以释放不需要给父母埋葬或火化已故胎儿，前提是：。该设施已满足，不存在传播可通知条件的风险。已告知家长可以依法管理胎儿组织/遗体的方式）管理选项包括：。医院安排火葬 O 转给殡葬总监进行私人安排。如果当地议会没有禁止要求，则私埋财产</td></tr><tr><td>协助责任</td><td>制定当地选项和方案，以促进胎儿遗骸的敏感管理，包括(但不限于): 0确定当地议会关于私有财产埋葬的要求(如果有) 。将胎儿遗骸释放给父母，随后返回医院火葬。如果社区对胎儿遗骸的运输和/或管理提出查询，请提供文件 ·在健康记录中记录胎儿组织管理的安排</td></tr><tr><td>信息提供</td><td>·清楚、敏感地告知父母可用的选择 ·留出时间进行决策，并尽可能提供书面信息 ·如果父母选择将胎儿遗骸带回家，请提供有关最佳保存温度和时间表(例如间歇冷藏)以及预期外观和感觉的信息 ·建议胎儿组织火葬通常不会产生任何散落的灰烬100 ·尊重可能不想参与的父母的意愿 ·请参阅第2.1节心理支持</td></tr></table> # 参考 https://www.midwives.org.au. 2. 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Guidance on the disposal of pregnancy remains following pregnancy loss or termination [Internet]. 2015 [cited 2016 October 10]. Available from: https://www.hta.gov.uk. Appendix A: Early pregnancy assessment service <table><tr><td>方面</td><td>考虑</td></tr><tr><td>专门 EPAS的好处</td><td>·简化护理，提高护理效率和更高的质量 ·减少入院人数并缩短需要入院的住院时间 ·女性对她们感知的护理质量更高的满意度* 可以由 .</td></tr><tr><td>服务提供</td><td>。产科医生和妇科医生 oGP产科医生。社区/农村环境中的GP 。具有相关技能的执业护士拥有专门的EPAS 网络，可根据需要进行咨询和转诊预约系统</td></tr><tr><td>服务要求</td><td>离散的候诊区和适当的咨询室 USS 设备(包括经阴道探针)或USS 评估的访问方便进入实验室设施: 。RhD抗体检测 o选择性血清β-hCG o 理想情况下是孕酮估计周一至周五每天都有空缺。如果可能的话，周末和下班后提供</td></tr><tr><td>治理</td><td>建立临床实践的治理和问责制确定明确的通信线路根据临床服务能力框架确定临床纳入/排除标准建立临床管理的书面途径为预约预订提供指导(即仅转诊或自我转诊)</td></tr><tr><td>文件</td><td>在服务内部和外部建立护理途径的转诊和转移面者信息</td></tr></table> \*Tsartsara E, Johnson MP. Women’s experience of care at a specialised miscarriage unit: an interpretative phenomenological study. Clinical Effectiveness in Nursing 2002;6:55-65 # Appendix B: Sonographic anatomy, landmarks and documentation Sonographic landmarks: TVS is recommended for the accurate assessment of early pregnancy <table><tr><td>方面</td><td>发现 ·怀孕期间最早的超声检查发现</td></tr><tr><td>孕囊</td><td>使用平均囊直径(全相合同胞供者)来确定孕龄，以便清晰测量冠臀长度(C RL) LNMP后4周和3天通常可见(带TVS) 真正的妊娠囊特异性地放置在子宫内膜腔内，并被TVS上的"回声环"包围。腔内液体(以前称为"假妊娠囊")位于子宫内膜腔的中线，取代子宫内膜腔的前表面和后表面妊娠试验呈阳性，TVS上没有子宫内或子宫外妊娠迹象，妊娠被确定为PUL</td></tr><tr><td>约尔克囊</td><td>卵黄囊通常是妊娠囊内可见的第一个结构，通常在妊娠5.5周或全相合同胞供者为8-10mm时可见卵黄囊的存在是将囊区分为妊娠囊的明确证据在双胎妊娠的情况下，卵黄囊的数量通常表明羊膜囊的数量(即两个卵黄囊表明是双羊膜囊双胎妊娠，MCMA 双胞胎只有一个卵黄囊)</td></tr><tr><td>胚胎和心脏活动</td><td>妊娠 5-6 周时通常可以看到胎儿极(胚盘) 6周零天时的CRL为4毫米在胚胎时期(6-10 周)，CRL每天增加约1毫米心血管疾病活性通常在妊娠6至6.5周时检测到妊娠6周之前，心率会缓慢(即每分钟100至115次，6周后迅速增加</td></tr><tr><td>黄体</td><td>外观差异很大，从固体形式到囊性形式，大小可达3厘米妊娠囊(无卵黄囊、胚胎或心跳)=5周</td></tr><tr><td>早期妊娠早期约会</td><td>孕囊和卵黄囊(无胚胎，无心跳)=5.5周孕囊和卵黄囊(活胚胎，CRL小于5 毫米(太小而无法测量)=6 周当提供CRL时，使用澳大利亚超声医学学会的测量结果来确定怀孕日期</td></tr></table> Sourced primarily from Australasian Society of Ultrasound Medicine guidelines. Available from http://www.asum.com.au # Standard ultrasound documentation <table><tr><td>方面</td><td>需要的信息</td></tr><tr><td>方法</td><td>·指定是否使用TVS 或TAS 以帮助解释</td></tr><tr><td>患者病史</td><td>·LNMP，如果LNMP已知且估计交货日期当前怀孕期间进行的任何USS以及结果是否进行β-hCG(尿液或血清)以及何时进行</td></tr><tr><td>宫内</td><td>宫内囊的存在以及是否可视化，是单个还是多个平均囊直径(毫米)和估计妊娠期存在卵黄囊胎儿极的存在和长度存在胎儿心脏运动和/或每分钟心跳次数 (bpm) 任何围产期出血的存在和大小妊娠周数和天数以及该USS 的预计分娩日期保留 POC 的存在和大小</td></tr><tr><td>宫外</td><td>如果多胎妊娠，卵黄囊和绒毛膜的数量以及分裂膜的厚度可能异位宫内植入(角形、壁内、宫颈、疤痕、异位) ·卵巢- 一左和右 ·Adnexa—左和右 ·是否存在游离液体和体积(最小、中等、广泛)(如果有的话)</td></tr></table> # Appendix C: Methotrexate regimens for ectopic pregnancy Follow local protocols for the safe administration/disposal of cytotoxic medications and equipment. Refer to an Australian pharmacopeia for complete drug information. <table><tr><td colspan="2">allantpnanmacopelaTorcompletedruginionmmation.</td></tr><tr><td colspan="2">肌内注射(IM)甲氨蝶呤</td></tr><tr><td>适应症</td><td>·未破裂的输卵管异位妊娠符合以下所有条件：。β-hCG 低于 3000 IU/L(也可静脉注射) 。胎囊小于3.5厘米。无胎儿心脏活动</td></tr><tr><td>剂量计算</td><td>·剂量按每平方米体表面积(BSA)计算。BSA=[身高 (cm)×体重(kg)除以3600]的平方根 ·关于甲氨蝶呤剂量上限尚未达成共识，但通常上限为2m BSA(相当于甲氨蝶呤 100 mg IM 注射)2 。如果加量，病态肥胖的女性可能需要额外的剂量。如果BSA大于2m，请寻求专家建议2</td></tr><tr><td>开始前</td><td>·每次服用甲氨蝶呤前进行FBC、ELFT、β-hCG ·甲氨蝶呤前30 分钟止吐(例如昂丹司琼8mgIV/PO或格拉司琼3 mg IV)</td></tr><tr><td>给药后</td><td>·服用甲氨蝶呤后监测女性30分钟是否有过敏反应(罕见)，考虑使用抗组胺药或类固醇乳膏 ·给予昂丹司琼4 mg BD PRN，持续2天</td></tr><tr><td>第1天(治疗日)</td><td>·β-hCG ·甲氨蝶呤 50 mg/m BSA IM 注射(圆形至最近5 mg)² ·由有化疗能力的临床医生肌内注射到臀部或大腿外侧</td></tr><tr><td>第4天第7天</td><td>· β-hCG ·β-hCG ·如果第7天的 β-hCG 减少量小于第4天的 β-hCG 的15%(或者如果第4天没</td></tr><tr><td>· β-hCG 第14天</td><td>有）水平，然后低于第1天β-hCG 的25%)给予第二剂甲氨蝶呤50 mg/m BSA IM注射2</td></tr><tr><td>β-hCG 静脉注射 (IVI)甲氨蝶呤</td><td>·如果第14天β-hCG 降低低于第7天 β-hCG 的15%，则给予第三剂甲氨蝶呤 50 mg/m BSAIM注射2 ·每周监测β-hCG，直至低于5IU/L</td></tr><tr><td colspan="2">·任何稳定的宫外孕(包括不寻常的部位)由医疗官员自行决定，特别是如果有以下任何情况：</td></tr><tr><td>指示</td><td>。β-hCG 大于 3000 IU/L 。胎囊大于3.5厘米。存在心脏活动 ·β-hCG、FBC、ELFT</td></tr><tr><td>开始前</td><td>·确保充足的水分 ·提前 24 小时(或尽可能尽快)确保尿液pH值大于7.0 。每6小时给予两袋柠檬酸钠，并持续至最终剂量的亚叶酸。测试(治疗期间和出院前的每次尿液排泄) ·甲氨蝶呤前30分钟止吐(例如昂丹司琼8mg IV/PO或格拉司琼3mg IV)</td></tr><tr><td>作为住院病人的承诺</td><td>·负荷剂量甲氨蝶呤100 mg IV stat，持续 5-10 分钟 ·然后在12 小时内将甲氨蝶呤 200mg 静脉输注于 500 mL0.9% 氯化钠中 ·给予昂丹司琼4mg BDPRN，持续2天在以下每个时间口服15mg 亚叶酸(亚叶酸)(时间至关重要):</td></tr><tr><td>负荷后剂量亚叶酸(住院或门诊）</td><td>。负荷后30小时服用甲氨蝶呤。负荷甲氨蝶呤剂量后42小时。负荷甲氨蝶呤剂量后54小时。负荷甲氨蝶呤剂量后66小时</td></tr><tr><td>β-hCG</td><td>出院后第二天通过后续电话确认时间 ·每周监测β-hCG，直至低于5IU/L</td></tr></table> NB: In some circumstances, alternative treatment may involve USS guided direct injection of methotrexate into ectopic pregnancy (plus or minus feticide). Seek expert advice. # Acknowledgements Queensland Clinical Guidelines gratefully acknowledge the contribution of Queensland clinicians and other stakeholders who participated throughout the guideline development process particularly: # Working Party Clinical Lead Dr David Baartz, Senior Staff Specialist Obstetrics and Gynaecology, Royal Brisbane and Women’s Hospital Ms Julia Brownlie, Nurse Practitioner, Department of Emergency Medicine, Royal Brisbane and Women’s Hospital Dr Scott Petersen, Maternal Fetal Medicine Specialist, Mater Mothers’ Hospital Brisbane # QCG Program Officer Ms Jacinta Lee, Manager Queensland Clinical Guidelines # Working Party Members Ms Noor Al-Adhami, Advanced Pharmacist, Royal Brisbane and Women's Hospital Dr Amy Arnold, Staff Specialist, Obstetrics and Gynaecology, Royal Brisbane and Women's Hospital Dr Bob Baade, Staff Specialist, Obstetrics and Gynaecology, Cairns Hospital Dr Lindsay Cochrane, Director, Obstetrics and Gynaecology, Caboolture Hospital Ms Tracey Davies, Registered Midwife, Clinical Coach, Sunshine Coast University Hospital Dr Natasha Frost, Staff Specialist, Obstetrics and Gynaecology, Townsville Hospital Dr Lauren Kearney, Conjoint Professor of Midwifery, Royal Brisbane and Women's Hospital Ms Melanie McKenizie, Consumer Representative, Harrison's Little Wings Ms Shona Morrison, Clinical Nurse Consultant, Queensland Trophoblast Centre, Royal Brisbane and Women's Hospital Ms Ashleigh Rousseaux, Consumer Representative, Red Nose Dr Renuka Sekar, Staff Specialist, Centre for Advanced Prenatal Care, Royal Brisbane and Women's Hospital # Queensland Clinical Guidelines Team Professor Rebecca Kimble, Director Ms Jacinta Lee, Manager Ms Stephanie Sutherns, Clinical Nurse Consultant Ms Cara Cox, Clinical Nurse Consultant Ms Emily Holmes, Clinical Nurse Consultant Ms Janene Rattray, Clinical Nurse Consultant Steering Committee # Funding This clinical guideline was funded by Healthcare Improvement Unit, Queensland Health	None	None	None
0cd7573e3bee481aa4e138afce80e870	NCCN临床实践指南	外阴癌	# NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) # Vulvar Cancer Version 4.2024 — May 1, 2024 # NCCN Guidelines Version 4.2024 Vulvar Cancer \Nadeem R. Abu-Rustum, MD っ/Chair Memorial Sloan Kettering Cancer Center Susana M. Campos, MD, MPH, MS †/ Vice Chair Dana-Farber/Brigham and Women’s Cancer Center \Catheryn M. Yashar, MD $\ S I$ Immediate Past Vice Chair UC San Diego Moores Cancer Center Rebecca Arend, MD っ O'Neal Comprehensive Cancer Center at UAB Emma Barber, MD $\pmb { \Omega }$ Robert H. Lurie Comprehensive Cancer Center of Northwestern University Kristin Bradley, MD $\ S$ University of Wisconsin Carbone Cancer Center Rebecca Brooks, MD っ UC Davis Comprehensive Cancer Center Junzo Chino, MD $\ S$ Duke Cancer Institute Hye Sook Chon, MD っ Moffitt Cancer Center Marta Ann Crispens, MD っ Vanderbilt-Ingram Cancer Center Shari Damast, MD $\ S$ Yale Cancer Center/ Smilow Cancer Hospital Christine M. Fisher, MD, MPH $\ S$ University of Colorado Cancer Center Peter Frederick, MD っ Roswell Park Comprehensive Cancer Center NCCN Sara Espinosa, PhD Nicole McMillian, MS David K. Gaffney, MD, PhD § Huntsman Cancer Institute at the University of Utah Stephanie Gaillard, MD, PhD † The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Robert Giuntoli II, MD っ Abramson Cancer Center at the University of Pennsylvania Scott Glaser, MD $\ S$ City of Hope National Medical Center Jordan Holmes, MD, MPH $\ S$ Indiana University Melvin and Bren Simon Comprehensive Cancer Center Brooke E. Howitt, $\mathsf { M D } \neq$ Stanford Cancer Institute Lisa Landrum, MD, PhD っ Indiana University Melvin and Bren Simon Comprehensive Cancer Center Jayanthi Lea, MD っ UT Southwestern Simmons Comprehensive Cancer Center Nita Lee, MD, MPH っ The UChicago Medicine Comprehensive Cancer Center Gina Mantia-Smaldone, MD っ Fox Chase Cancer Center Andrea Mariani, MD っ Mayo Clinic Comprehensive Cancer Center David Mutch, MD っ Siteman Cancer Center at Barnes Jewish Hospital and Washington University School of Medicine # Christa Nagel, MD っ The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute Larissa Nekhlyudov, MD, MPH Þ Dana-Farber/Brigham and Women’s Cancer Center Karina Nieto, MD $\ S$ Case Comprehensive Cancer Center/ University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute Mirna Podoll, MD ≠ Vanderbilt-Ingram Cancer Center Kerry Rodabaugh, MD っ Fred & Pamela Buffett Cancer Center Ritu Salani, MD, MBA っ UCLA Jonsson Comprehensive Cancer Center John Schorge, MD っ St. Jude Children's Research Hospital/ The University of Tennessee Health Science Center Jean Siedel, DO, MS っ University of Michigan Rogel Cancer Center Rachel Sisodia, MD っ Mass General Cancer Center Pamela Soliman, MD, MPH っ The University of Texas MD Anderson Cancer Center Stefanie Ueda, MD っ UCSF Helen Diller Family Comprehensive Cancer Center Renata Urban, MD っ Fred Hutchinson Cancer Center Emily Wyse ¥ Patient Advocate Vaishnavi Sambandam, PhD NCCN Guidelines Panel Disclosures っ Gynecologic oncology Þ Internal medicine † Medical oncology ≠ Pathology ¥ Patient advocacy § Radiotherapy/Radiation oncology \*Discussion Section Writing Committee # NCCN Guidelines Version 4.2024 Vulvar Cancer NCCN Vulvar Cancer Panel Members Summary of the Guidelines Updates # Squamous Cell Carcinoma or Adenocarcinoma Workup (VULVA-1) Early Stage: Stage I and select Stage II (VULVA-2) Adjuvant Therapy Based on Primary Tumor Risk Factors (VULVA-3) Adjuvant Therapy Based on Nodal Status (VULVA-4) Locally Advanced (VULVA-5) Additional Treatment (VULVA-6) Metastatic Disease Beyond Pelvis: Stage IVB (VULVA-7) Surveillance (VULVA-8) Therapy for Recurrence Clinically Limited to the Vulva (VULVA-9) Therapy for Conirmed Nodal or Distant Recurrence (VULVA-10) Principles of Pathology (VULVA-A) Principles of Imaging (VULVA-B) Principles of Surgery (VULVA-C) Principles of Radiation Therapy (VULVA-D) Systemic Therapy (VULVA-E) Principles of Gynecologic Survivorship (VULVA-F) # Vulvar and Vulvovaginal Melanoma Clinical Presentation; Workup; Primary Treatment; Adjuvant Treatment (VM-1) Follow-up/Surveillance; Treatment for Recurrence (VM-2) Principles of Radiation Therapy (VM-A) Clinical Trials: NCCN believes that the best management for any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Find an NCCN Member Institution: https://www.nccn.org/home/memberinstitutions. # Staging (ST-1) Abbreviations (ABBR-1) NCCN Categories of Evidence and Consensus: All recommendations are category 2A unless otherwise indicated. See NCCN Categories of Evidence and Consensus. # NCCN Categories of Preference: All recommendations are considered appropriate. See NCCN Categories of Preference. The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® $\begin{array} { r } { ( \mathsf { N C C N } ^ { \circledast } ) } \end{array}$ ) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. $\textcircled { \textcircled { \textcircled { \textcircled { \textcircled { ‰} } } } }$ . # Updates in Version 4.2024 of the NCCN Guidelines for Vulvar Cancer from Version 3.2024 include: Vulvar Cancer VULVA-E 1 of 2 Systemic Therapy • Advanced or Recurrent/Metastatic Disease Second-line or Subsequent Therapy; Useful in Certain Circumstances (Biomarker directed therapy); The following revisions made: $\diamondsuit$ The listing for pembrolizumab was revised by biomarker type. $\diamondsuit$ HER2-positive tumors (IHC $^ { 3 + }$ or $^ { 2 + }$ ): Fam-trastuzumab deruxtecan-nxki was added as an option. # VULVA-E 2 of 2 • New reference added: Meric-Bernstam F, Makker V, Oaknin A, et al. E冪cacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol 2024;42:47-58. # Updates in Version 3.2024 of the NCCN Guidelines for Vulvar Cancer from Version 2.2024 include: # Vulvar Cancer VULVA-C 3 of 6 Principles of Surgery: Surgical Staging • The following correction was made to VULVA-C 3 of 6 on March 12, 2024: Last bullet revised as follows: The management of bulky inguinofemoral LNs in the setting of an unresectable or stage III-IVA primary vulvar lesion is unclear. It is reasonable to consider either: 1) primary cytoreductive surgery of the bulky LNs followed by platinum-based chemosensitizing chemotherapy and radiation to the bilateral groins and primary vulvar tumor; or 2) platinum-based chemosensitizing chemotherapy and radiation to the bilateral groins and primary vulvar tumor alone. # Updates in Version 3.2024 of the NCCN Guidelines for Vulvar Cancer from Version 2.2024 include: Vulvar Cancer General • The "Clinical Stage" throughout the algorithms have been revised to relect the addition of the updated International Federation of Gynecology and Obstetrics (2021) staging for carcinoma of the vulva. (VULVA-1, VULVA-2, VULVA-5, VULVA-7, VULVA-B, VULVA-C 3 of 6) • Footnotes removed: Smaller T2 tumors: $\mathtt { \le 4 \mathtt { c m } }$ . Larger T2 tumors: ${ > } 4$ cm and/or involvement of the urethra, vagina, or anus. # MS-1 • The Discussion has been updated to relect the changes in the algorithm. # Updates in Version 2.2024 of the NCCN Guidelines for Vulvar Cancer from Version 1.2024 include: Vulvar Cancer VULVA-E 1 of 2 Systemic Therapy • Chemoradiation Preferred Regimens: "Carboplatin if patient is cisplatin intolerant" was added as an option. Other Recommended Regimens; 2nd bullet revised: "If cisplatin or carboplatin is are unavailable:..." • Second-line or Subsequent Therapy; Other Recommended Regimens: Cemiplimab added as an option. • Footnote b revised: These agents may be considered when cisplatin and carboplatin is are unavailable. # VULVA-E 2 of 2 Migden MR, Rischin D, Schmults CD, et al. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. N Engl J Med. 2018 Jul 26;379(4):341-351. Tewari KS, Monk BJ, Vergote I, et al. Survival with Cemiplimab in Recurrent Cervical Cancer. N Engl J Med 2022;386:544-555. # Updates in Version 1.2024 of the NCCN Guidelines for Vulvar Cancer from Version 1.2023 include: General • Terminologies modiied to advance the goals of equity, inclusion, and representation. Vulvar Cancer VULVA-1 • Workup: Last bullet revised: "For elderly patients with vulvar cancer who are older with vulvar cancer..." # VULVA-4 • Footnote m revised: "If ipsilateral groin is positive, the contralateral groin should be evaluated. surgically and/or treated with EBRT. In select cases of a single, small-volume, unilateral, positive inguinal node with a well-lateralized small primary tumor diameter ≤2 cm and depth of invasion ${ \le } 5 \mathsf { m m }$ and with a clinically negative contralateral groin examination, a contralateral inguinofemoral lymphadenectomy or radiation may be omitted. # VULVA-5 • Clinical Stage; Bullet revised: Radiologic imaging workup if not previously done • 2nd Column; Bottom pathway revised: "Radiographically positive suspicious nodes... # VULVA-6 • Resect pathway revised: Positive margins for invasive disease. • After "Best supportive care" a link to the NCCN Guidelines for Palliative Care was added. # VULVA-10 • Site of Recurrence revised: Clinical Conirmed nodal or distant recurrence • Isolated inguinofemoral/pelvic LN recurrence pathway extensively revised. VULVA-A Pathology VULVA-A 1 of 4 • This page was extensively revised including the separation of the recommendations for HPV-associated and HPV-independent disease # VULVA-A 2 of 4 • Pathologic Assessment for Squamous Cell Carcinoma; 5th bullet revised: Consider tumor mutational burden (TMB) testing through a validated and/ or FDA-approved assay as determined by an FDA-approved assay, or a validated test performed in a Clinical Laboratory Improvement Amendments (CLIA)-certiied laboratory. • This page was extensively revised including the update of Figure 1 (Depth of Invasion) # VULVA-A 4 of 4 • Reference 3 updated to: Höhn AK, Brambs CE, Hiller GGR, May D, Schmoeckel E, Horn LC. 2020 WHO Classiication of Female Genital Tumors. Geburtshilfe Frauenheilkd 2021;81:1145-1153. # Updates in Version 1.2024 of the NCCN Guidelines for Vulvar Cancer from Version 1.2023 include: # VULVA-B Imaging • Initial Workup; 1st bullet revised: "Consider chest imaging with plain radiography (chest x-ray)..." • Follow-up/Surveillance; 2nd Bullet revised: Consider FDG-PET/CT at 3–6 months to assess treatment response if primary treatment was with after deinitive primary treatment intent. • Footnote a revised: MRI is performed with and without contrast and CT are is performed with contrast throughout the guidelines unless contraindicated. Contrast is not required for screening chest CT. # VULVA-C Surgery VULVA-C 2 of 6 • 1st bullet revised: Vulvar cancer is staged using the American Joint Committee on Cancer (AJCC) and the International Federation of Gynecology and Obstetrics (FIGO) staging systems (Table ST-1). # VULVA-C 3 of 6 • 3rd Bullet revised: "In the setting of positive LN disease after unilateral inguinofemoral lymphadenectomy, contralateral inguinofemoral lymphadenectomy or radiation of the contralateral groin is recommended. Any nodes..." # VULVA-C 4 of 6 • New bullets added: For lateralized and near midline tumors with unilateral SLN metastasis, unilateral groin treatment by either inguinofemoral lymphadenectomy or RT is acceptable. For midline tumors with unilateral SLN metastasis, unilateral groin treatment can be performed if the contralateral groin has negative sentinel node or negative inguinofemoral lymphadenectomy. • Bullet removed: If ipsilateral SLN is positive, the contralateral groin should be evaluated surgically and/or treated with EBRT. # VULVA-C 5 of 6 • Principles of Surgery: SLNB Management is a new section added to the Guidelines that also includes Table 1: Management of Sentinel Lymph Node(s) Mapping # VULVA-C 6 of 6 • References updated to relect changes in the algorithm. Updates in Version 1.2024 of the NCCN Guidelines for Vulvar Cancer from Version 1.2023 include: VULVA-D Principles of Radiation Therapy VULVA-D 2 of 5 • Treatment Information – 3D Conformal/Anterior-Posterior/Posterior-Anterior (AP/PA) Fields Target Volumes $\diamondsuit$ 3rd arrow sub-bullet revised: "In both the locally advanced and postoperative settings, especially when there is ≥1 ≥2 LN clinically suspicious or pathologically positive, the bilateral inguinal and pelvic lymphatic regions are typically included in the radiotherapy clinical target volume (CTV). Selective coverage of the primary may be appropriate. While classic indications for treating the primary site include close/positive margin, LVSI, and >5-mm depth of invasion, groin involvement may also be considered a relative indication to include the primary site. While it may be tempting to add a midline block in the postoperative setting to avoid radiation toxicity to sensitive central structures, use of a midline block in stage III–IV vulvar cancer has been associated with a high rate of central recurrence; thus, such practice Other indications for treating the primary site include close/ positive margin, LVSI, and ${ > } 5$ -mm depth of invasion. Additionally, groin involvement may be considered a relative indication to include the primary site. Use of a midline block (to avoid toxicity to sensitive central structures) in stage III–IV vulvar cancer has been associated with a high rate of central recurrence and is usually discouraged. • Treatment Information – 3D Conformal/Anterior-Posterior/Posterior-Anterior (AP/PA) Fields Target Volumes; New bullets added: $\diamondsuit$ If there are clinically or radiographically suspicious LNs (1 or more), then bilateral pelvic and groin radiotherapy is recommended. RT may be administered adjuvantly (after dissection) or deinitively (unresectable). roin is clinically node negative, but pathologically node positive (by sentinel node procedure or dissection), then the number of positive size of LN metastasis, features of the primary lesion, and extent of surgery may impact recommendations for adjuvant RT. a single positive SLN and no completion inguinofemoral lymphadenectomy done, then adjuvant RT or chemoradiation is recommende of size of LN metastasis. – If there are 2 or more pathologic positive nodes or extracapsular extension (ECE) is present, then adjuvant RT or chemoradiation is recommended. – In the setting of a single pathologic LN without ECE and a completion IFLD, there are scenarios where adjuvant RT or chemoradiation may be favored such as larger primary tumor size, larger LN size, inadequate LN dissection, lymph node ratio ${ > } 2 0 \%$ , presence of LVSI, or radiographically suspicious indings. We favor evaluation of these patients by a radiation oncologist and consideration of postoperative PET imaging to help with decision making. – There is some data that suggests the contralateral groin could be observed in patients with documented ipsilateral drainage, a lateralized lesion, and small primary tumor. # VULVA-D 5 of 5 New reference added: Cao Y, Viswanathan A. When is it safe to omit contralateral groin management in unilateral sentinel node-positive early stage vulvar cancer? Gynecol Oncol 2022;167:1-2. # NCCN Guidelines Version 4.2024 Vulvar Cancer # Updates in Version 1.2024 of the NCCN Guidelines for Vulvar Cancer from Version 1.2023 include: VULVA-E Systemic Therapy • Chemoradiation; Other Recommended Regimens updated: New bullet and corresponding regimens added: $\diamondsuit$ If cisplatin is unavailable: ザ Capecitabine/mitomycin ザ Gemcitabine ザ Paclitaxel • Advanced or Recurrent/Metastatic Disease Second-line or Subsequent Therapy $\diamondsuit$ Useful in Certain Circumstances – Section revised to separate out regimens by mutation type ene fusion-positive tumors: Single agent Larotrectinib and Entrectinib changed from category 2B to category 2A. new: Cisplatin, carboplatin, and paclitaxel may cause drug reactions (See NCCN Guidelines for Ovarian Cancer--Management of Drug V-D]). • Footnote b is new: These agents may be considered when cisplatin is unavailable. • Footnote f revised:"... tumors, as determined by a validated and/or FDA-approved test an FDA-approved assay, or a validated test performed in a CLIAcertiied laboratory, that have progressed following prior treatment and who have no satisfactory alternative treatment options. • Footnote g revised: "... as determined by a validated and/or FDA-approved test an FDA-approved assay or a validated test performed in a CLIA-certiied laboratory. • References have been updated to relect the new regimens added to the algorithm. VULVA-F Principles Of Gynecologic Survivorship • Physical E冩ects; New bullet added: Prior pelvic RT may contribute to bone loss and increase the risk of pelvic fractures. Consider bone density testing and prophylactic use of bisphosphonates, particularly in patients with osteoporosis. • Clinical approach; 4th Bullet revised: For premenopausal patients, hormone replacement therapy should be considered. For treatment-related menopause, hormone therapy should be considered. Vulvar and Vulvovaginal Melanoma General • Algorithm title changed to: Vulvar and Vulvovaginal Melanoma # VM-1 • Conirmed cutaneous vulvar melanoma; Resectable; Stage II; Adjuvant Treatment $\diamondsuit$ New pathway added for "If negative SLNB" ◊ Revised: If positive SLNB, consider completion lymph node dissection (CLND) – After "If positive SLNB, recommendation revised: "Systemic therapyStage III; Adjuvant Treatment; Recommendation revised: "Systemic ther $\pm$ Rpy changed to "Systemic therapy and/or RT or Observation" RT" changed to "Systemic therapy and/or RT or Observation".Contin $\pm$ # Updates in Version 1.2024 of the NCCN Guidelines for Vulvar Cancer from Version 1.2023 include: Vulvar and Vulvovaginal Melanoma--continued VM-1A • Footnote c revised: Vulvovaginal melanoma should be staged the same as cutaneous melanoma. Clinical staging for cutaneous vulvar melanoma and vulvovaginal melanoma should be done using the AJCC staging system (TNM staging system). See Staging (ST-1) in the NCCN Guidelines for Melanoma: Cutaneous VM-2 • Follow-up/Surveillance; 1st Bullet revised: Recommend groin nodal ultrasound for stage ≥ IB VM-A Principles of Radiation Therapy VM-A 1 of 3 • Adjuvant Therapy; 2nd Bullet; 3rd arrow sub-bullet revised: "27–30 Gy in 5 fractions over 2 weeks..." # VM-A 2 of 3 Adjuvant Regional Disease; 3rd Bullet; 1st arrow sub-bullet revised: 50–66 60–66 Gy in 25–33 fractions over 5–7 weeks ST-1 Staging • Tables 1 and 2: The combined AJCC Tumor-Node-Metastases (TNM) and International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging Systems for Carcinoma of the Vulva Table was removed and replaced with updated staging from the International Federation of Gynecology and Obstetrics (FIGO) New (2021) FIGO staging for carcinoma of the vulva. Reprinted from: Olawaiye AB, Cotler J, Cuello MA, et al. FIGO staging for carcinoma of the vulva: 2021 revision. Int J Gynecol Obstet 2021;155:43-47. https://obgyn.onlinelibrary.wiley.com/doi/epdf/10.1002/ijgo.13880 # NCCN Guidelines Version 4.2024 Vulvar Cancer ![](images/951d68299c3a5e9165d583070ffd256e83925bdc824a21e8efec232fbefe2609.jpg) a Principles of Pathology (VULVA-A). If vulvovaginal melanoma is suspected, see Principles of Biopsy and Pathology (ME-B) in the NCCN Guidelines for Melanoma: Cutaneous. b Principles of Imaging (VULVA-B). If vulvovaginal melanoma is suspected, See Principles of Imaging (ME-D) in the NCCN Guidelines for Melanoma: Cutaneous. c Consider HIV testing, especially in younger patients suspected of having squamous cell carcinoma (SCC) of the vulva or other HPV-related disease. Patients with vulvar cancer and HIV should be referred to an HIV specialist and should be treated for vulvar cancer as per these guidelines. Modifications to cancer treatment shou not be made solely on the basis of HIV status. d Histologic high-grade squamous intraepithelial lesion (HSIL; formerly defined as carcinoma in situ [CIS] and incorporates vulvar intraepithelial neoplasia 2 and 3 [VIN2/3]) can be treated with wide local excision. # NCCN Guidelines Version 4.2024 Vulvar Cancer # # ![](images/3f18c078bfb15aa1f8d87a38981b28977b45c919c5d2220535dedbb235e7af11.jpg) e Principles of Surgery (VULVA-C). f If partial superficial vulvectomy pathology reveals tumor in aggregate of ${ \ge } 1$ mm invasion, then additional surgery may be warranted. g Inguinofemoral lymphadenectomy is required on side(s) where sentinel nodes are not detected. h Principles of Surgery: Tumor Margin Status (VULVA-C 1 of 6). # PRIMARY TUMOR RISK FACTORS # ADJUVANT THERAPY TO THE PRIMARY SITE ![](images/0399670aabb4982dee906b0909fe241f318edd9bcb0cc051fb13e134632b174f.jpg) # NCCN Guidelines Version 4.2024 Vulvar Cancer ![](images/bf7999d1cc3840cf65ff0d73ea1ba9894493e06d0581b81454be6e8cbfd13bd4.jpg) l If ipsilateral groin is positive, the contralateral groin should be evaluated. In select cases of a single, small-volume, unilateral, positive inguinal node with a well-lateralized small primary tumor and depth of invasion ${ \ttle 5 } \mathsf { m m }$ and with a clinically negative contralateral groin examination, a contralateral inguinofemoral lymphadenectomy or radiation may be omitted. (Gonzalez Bosquet J, et al. Gynecol Oncol 2007;105:742-746.) m Principles of Surgery: Inguinofemoral Sentinel Lymph Node Biopsy (VULVA-C 4 of 6). n The size of $_ { 2 \mathsf { m m } }$ is used to inform treatment selection/management and the 5-mm cutoff is used for staging. See Principles of Pathology (VULVA-A). o Systemic Therapy (VULVA-E). # NCCN Guidelines Version 4.2024 Vulvar Cancer # CLINICAL STAGE # PRIMARY TREATMENT ![](images/e0f9b74b120e573dc130306a0ea49d3c6f81c51e0789fb301794741eaeab5e84.jpg) # EVALUATION OF RESPONSE TO EBRT $^ +$ CONCURRENT CHEMOTHERAPY ADDITIONAL TREATMENT ![](images/fca1958f67ac8599b0ed4abad49ab0257bdc9c848b2c243a99d7459b1a643db4.jpg) Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. PRIMARY TREATMENT ![](images/c9fd54288d1989c22b15c93133940c28315a8f07b1e2ad524b1f8c7771abde93.jpg) # NCCN Guidelines Version 4.2024 Vulvar Cancer # SURVEILLANCE WORKUP ![](images/39daedba00d22225200ce92c7d8669231d96c4d4e92c6396b953b351e2710041.jpg) • Interval H&P every 3–6 months for 2 years, every 6–12 months for 3–5 years, then annually based on patient's risk of disease recurrence • Cervical/vaginal cytology screeningu,v as indicated for the detection of lower genital tract neoplasia (may include HPV testing) • Imaging as indicated based on symptoms or examination indings suspicious for recurrencep • Laboratory assessment (CBC, blood urea nitrogen [BUN], creatinine) as indicated based on symptoms or examination indings suspicious for recurrence • Patient education regarding symptoms of potential recurrence and vulvar dystrophy, periodic self-examinations, lifestyle, obesity, exercise, sexual health (including vaginal dilator use and lubricants/moisturizers), smoking cessation, nutrition counseling, and potential long-term and late e冩ects of treatmentw (Also See NCCN Guidelines for Survivorship and NCCN Guidelines for Smoking Cessation) # NCCN Guidelines Version 4.2024 Vulvar Cancer ![](images/b41b1a32b52fc5a3cd40fe69bf3e74b8d0067e2621191e91c73db930ad01718e.jpg) ![](images/ee3da29b35add3b5e7c5de43a42edcf01fcf14498d05e288fc131bb31f9a690e.jpg) THERAPY FOR RECURRENCE # PRINCIPLES OF PATHOLOGY1-4 # Procedure: Vulvectomy # General Principle • Histologic grading of squamous cell carcinoma (SCC) is not well-deined and can be subjective. Two pathways of vulvar intraepithelial neoplasia (VIN) and SCC have been identiied in the vulva: HPV-associated and HPV-independent. • A meta-analysis showed that HPV-associated SCC had a better prognosis than HPV-independent SCC. # HPV-associated • HPV-associated SCC frequently occurs in younger patients, is frequently multifocal, is associated with classic VIN, and can be seen in association with additional sites of lower genital tract squamous neoplasia. • Immunohistochemistry (IHC) shows strong, di冩use, block-like positive nuclear and cytoplasmic staining with p16 and wild-type p53 (heterogeneous staining pattern). # HPV-independent PV-independent VIN and SCC are identiied in the setting of chronic vulvar inlammatory disorders such as lichen sclerosus. • HPV-independent SCC is split into two main groups: those associated with TP53 mutations and those with wild-type TP53 status. The p53 abnormal, HPV-independent SCC usually occurs in older patients, is unifocal, and is associated with di冩erentiated VIN (dVIN). $\diamondsuit$ IHC usually shows aberrant p53 staining (widespread, strong nuclear expression or complete absence/null expression) and patchy (negative) p16 staining. $\diamondsuit$ The p53 abnormal SCCs have the worst clinical outcomes of the three molecular categories (HPV positive, HPV-negative/p53 mutant, and HPV-negative $\mathsf { p } 5 3$ wild type).5 • Assessing the presence and depth of invasion in vulvar SCC can be challenging. • Depth of invasion (measured in millimeters) has previously been from the epithelial-stromal junction of the adjacent, most supericial dermal papilla to the deepest point of invasion6 (Figure $\pmb { 1 , }$ method B). Alternative ways to measure the depth of invasion have recently been proposed7 (Figure 1, method A). # PRINCIPLES OF PATHOLOGY1-4 # Pathologic Assessment for Squamous Cell Carcinoma Procedure type (total or partial vulvectomy) Depth of surgical procedure (supericial or skinning, simple, or radical) Tumor site Tumor size; include greatest dimension and additional two dimensions Number of tumor foci Histologic type Histologic grade Depth of invasion (in mm). Pathologists should describe their methodology for measuring depth of invasion Surgical resection margin status Lymphovascular space invasion (LVSI) • Other tissue/organ involvement (eg, vagina, urethra, anus, bladder mucosa, rectal mucosa, pelvic bone) • LNs (when resected)a SLNs should undergo ultrastaging for detection of low-volume metastasisb Number of LNs withc: $\diamondsuit$ Metastasis $\ r _ { 5 } \ r _ { \mathsf { m m } }$ or greater $\diamondsuit$ Metastasis 5 mm or less $\diamondsuit$ Isolated tumor cells $( \leq 0 . 2 \ \mathsf { m m } )$ • Consider mismatch repair (MMR)/microsatellite instability (MSI), programmed death ligand 1 (PD-L1), and/or NTRK gene fusion testing for patients with recurrent, progressive, or metastatic disease • Consider tumor mutational burden (TMB) testing as determined by an FDA-approved assay, or a validated test performed in a Clinical Laboratory Improvement Amendments (CLIA)-certiied laboratory8 • Recommend ancillary testing to determine HPV status either by p16 IHC or RNA in situ hybridization or DNA sequencing Recommend p53 IHC to determine p53 status9 a In situations where SLN metastases are , the size of greatest metastasis should be reported. (VULVA-4). b Ultrastaging commonly entails thin serial sectioning of the gross SLN and review of multiple hematoxylin and eosin (H&E)-stained sections with or without cytokeratin IHC for all blocks of SLNs. There is no standard protocol for LN ultrastaging. c Report on the number of LNs with metastases of the following sizes: $< 2 ~ \mathsf { m m }$ ; $2 { - } 5 ~ \mathsf { m m }$ ; and $> 5 \mathsf { m m }$ . The $_ { 2 - \mathsf { m m } }$ threshold is used to inform treatment selection and 5-mm threshold is used to inform staging. PRINCIPLES OF PATHOLOGY Figure 1: Depth of Invasion (Pathologists should describe their methodology for measuring depth of invasion. ![](images/bc0d37fc32c51b2a17be444681afeb58de66064a61435a4c224a93d201a5b1bf.jpg) Diagram showing the new International Federation of Gynecology and Obstetrics (FIGO) (A) and previous (B) methods of measuring depth of invasion for vulvar squamous cell carcinoma. In the new FIGO method (A), the depth of invasion is measured from the basement membrane of the deepest adjacent dysplastic/noninvasive rete ridge to the deepest point of invasion. The previous method (B) used the distance from the adjacent most supericial dermal papilla to the deepest point of invasion. # PRINCIPLES OF PATHOLOGY REFERENCES 1 Movahedi-Lankarani S, Krishnamurti U, Bell D, et al. Protocol for the Examination of Specimens from Patients with Primary Carcinoma of the Vulva. College of American Pathologists 2018. 2 Del Pino M, Rodriguez-Carunchio L, Ordi J. Pathways of vulvar intraepithelial neoplasia and squamous cell carcinoma. Histopathology 2013;62:161-175. 3 Höhn AK, Brambs CE, Hiller GGR, May D, Schmoeckel E, Horn LC. 2020 WHO Classification of Female Genital Tumors. Geburtshilfe Frauenheilkd 2021;81:1145- 1153. 4 Zhang J, Zhang Y, Zhang Z. Prevalence of human papillomavirus and its prognostic value in vulvar cancer: A systematic review and meta-analysis. PLoS One 2018:13:e0204162. 5 Kortekaas KE, Bastiaanet E, van Doorn HC, et al. Vulvar cancer subclassification by HPV and p53 status results in three clinically distinct subtypes. Gynecol Oncol 2020;159:649-656. 6 Pecorelli S. Revised FIGO staging of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2009;105:103-104. 7 van den Einden LC, Massuger LF, Jonkman JK, et al. An alternative way to measure the depth of invasion of vulvar squamous cell carcinoma in relation to prognosi Mod Pathol 2015;28:295-302. 8 Merino DM, McShane LM, Fabrizio D, et al. Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project. J Immunother Cancer 2020;8:e000147. 9 Tessier-Cloutier B, Kortekaas KE, Thompson E, et al. Major p53 immunohistochemical patterns in in situ and invasive squamous cell carcinomas of the vulva and correlation with TP53 mutation status. Mod Pathol 2020;33:1595-1605. # PRINCIPLES OF IMAGINGa,1-5 # Initial Workup • Consider chest imaging (chest x-ray). If an abnormality is seen, then chest CT without contrast may be performed. • Consider pelvic MRI to aid in surgical and/or radiation treatment planning.b Consider neck/chest/abdomen/pelvis/groin luorodeoxyglucose (FDG)-PET/CT or chest/abdomen/pelvis CT for clinical Stage II or higher tumors or if metastasis is suspected.b • Other initial imaging should be based on symptomatology and clinical concern for metastatic disease.b • FDG-PET/CT may be considered in patients with positive sentinel nodes to evaluate for undissected nodal disease in the groin or pelvis th needs additional treatment. # Follow-up/Surveillance • CT chest/abdomen/pelvis or neck/chest/abdomen/pelvis/groin FDG-PET/CT if recurrence/metastasis is suspected. • Consider FDG-PET/CT at 3–6 months to assess treatment response after deinitive primary treatment. • Other imaging should be based on symptomatology and clinical concern for recurrent/metastatic disease.c Imaging for Suspected or Documented Recurrence • Consider neck/chest/abdomen/pelvis/groin FDG-PET/CT if not previously performed during surveillance. • Consider pelvic MRI to aid in further treatment planning. # Footnotes a MRI is performed with and without contrast and CT is performed with contrast unless contraindicated. Contrast is not required for screening chest CT. b Indications may include abnormal physical exam findings; bulky vulvar tumor $\geq 4$ cm or close to critical structures); vaginal, urethral, or anal involvement; delay presentation or treatment; and pelvic, abdominal, or pulmonary symptoms. c Indications may include abnormal physical exam findings such as palpable new mass or adenopathy, or new pelvic, abdominal, or pulmonary symptoms. # References 1 Salani R, Khanna N, Frimer M, et al. An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations. Gynecol Oncol 2017;146:3-10. 2 Kataoka MY, Sala E, Baldwin P, et al. The accuracy of magnetic resonance imaging in staging of vulvar cancer: a retrospective multi-centre study. Gynecol Oncol 2010;117:82-87. 3 Robertson NL, Hricak H, Sonoda Y, et al. The impact of FDG-PET/CT in the management of patients with vulvar and vaginal cancer. Gynecol Oncol 2016;140:420-424. 4 Elit L, Reade CJ. Recommendations for follow-up care for gynecologic cancer survivors. Obstet Gynecol 2015;126:1207-1214. 5 Viswanathan C, Kirschner K, Truong M, et al. Multimodality imaging of vulvar cancer: staging, therapeutic response, and complications. AJR AM J Roentgenol 2013; 200:1387-1400. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. # PRINCIPLES OF SURGERY: TUMOR MARGIN STATUS • Studies suggest a high overall incidence of local recurrence (or new primary lesions) in vulvar carcinoma.1 Tumor margin of resection has been postulated as a signiicant prognostic factor for recurrence in SCC of the vulva; however, presence of dVIN and lichen sclerosus may also play a signiicant role in recurrence or development of new primary carcinomas.2,3,4,5 • E冩orts should be made to obtain adequate gross surgical margins (at least 1 cm) at primary surgery. Recent studies have questioned the traditional $( 8 - \mathsf { m m } )$ pathologic free margin and suggested that a smaller margin may be acceptable, particularly to preserve sensitive areas on the vulva and maintain sexual function.6,7,8 • The deinition of a pathologic close margin has also varied from $1 { - } 8 ~ \mathsf { m m }$ for formalin-ixed tissue.9,10 In the setting of a close margin for invasive cancer at primary resection, observation with regular close follow-up is reasonable. Re-excision should be considered in cases with positive margin for cancer.9,11 Adjuvant local radiation therapy (RT) is another alternative.12 The risk-beneit ratio and morbidity of these approaches must be considered and individualized in each patient. The survival advantage of re-excision and adjuvant vulvar radiation remains to be determined.10 • Positive margins that involve the urethra, anus, or vagina may not be resectable without incurring signiicant potential morbidity and adverse impact on patient quality of life. • Other factors including nodal status should be considered in the decision whether to perform subsequent surgery. Re-excision of close or positive vulvar tumor margins may not be beneicial in patients with metastases to the inguinal nodes that require treatment with EBRT ± chemotherapy after surgery. # PRINCIPLES OF SURGERY: SURGICAL STAGING • Vulvar cancer is staged using the FIGO staging system (Table ST-1).13 • Staging involves complete surgical resection of the primary vulvar tumor(s) with at least 1-cm clinical gross margins and either a unilateral or bilateral inguinofemoral lymphadenectomy or an SLNB in select patients. Inguinofemoral lymphadenectomy removes the LNs along the inguinal ligament, within the proximal femoral triangle, and deep to the cribriform fascia. • LN status is the most important determinant of survival.14 • Historically, en bloc resection of the vulvar tumor and complete bilateral inguinofemoral lymphadenectomy (resection of supericial inguinal and deep femoral nodes) were performed, but this approach was associated with signiicant morbidity.15 • The current standard involves resection of the vulvar tumor and LNs through separate incisions.15 • The choice of vulvar tumor resection technique depends on the size and extent of the primary lesion and may include partial or total vulvectomy, and the depth of resection may be supericial/skinning, simple, or radical.16 • The depth of the resection for radical vulvectomy is to the urogenital diaphragm, or median perineal fascia or periosteum of pubic bone.17 • There are no prospective trials comparing the resection techniques above. Retrospective data suggest there is no di冩erence in recurrence outcome between radical partial vulvectomy compared with radical total vulvectomy. • For a unifocal primary vulvar tumor that is $\pmb { < 4 }$ cm diameter, located 2 cm or more from the vulvar midline and in the setting of clinically negative inguinofemoral LNs, a unilateral inguinofemoral lymphadenectomy or SLNB is appropriate (Principles of Surgery: Inguinofemoral Sentinel Lymph Node Biopsy VULVA-C 4 of 6).18 • For a primary vulvar tumor located within 2 cm from or crossing the vulvar midline, a bilateral inguinofemoral lymphadenectomy18 or SLNB is recommended. • Inguinofemoral lymphadenectomy or SLNB can be omitted in patients with stage IA primary disease with clinically negative groins due to a $< 1 \%$ risk of lymphatic metastases.18 # PRINCIPLES OF SURGERY: SURGICAL STAGING • For patients with stage IB–II disease, inguinofemoral lymphadenectomy is recommended due to a risk of $58 \%$ of lymphatic metastases.18 • A negative unilateral inguinofemoral lymphadenectomy is associated with a $< 3 \%$ risk of contralateral metastases.19 • Any nodes that are grossly enlarged or suspicious for metastases during the unilateral inguinofemoral lymphadenectomy should be evaluated by frozen section pathology intraoperatively in order to tailor the extent and bilaterality of the lymphadenectomy. • Those with locally advanced disease may beneit from neoadjuvant radiation with concurrent platinum-based radiosensitizing chemotherapy. If a complete response is not achieved, surgical resection of the residual disease is recommended in patients with resectable disease who are appropriate surgical candidates.18 • The management of bulky inguinofemoral LNs in the setting of an unresectable or stage III-IVA primary vulvar lesion is unclear. It is reasonable to consider either: 1) primary cytoreductive surgery of the bulky LNs followed by platinum-based chemotherapy and radiation to the bilateral groins and primary vulvar tumor; or 2) platinum-based chemotherapy and radiation to the bilateral groins and primary vulvar tumor alone.20 • Unilateral or bilateral inguinofemoral lymphadenectomy is associated with a high rate of postoperative morbidity; $20 \% - 4 0 \%$ of patients are at risk of wound complications and $30 \% - 7 0 \%$ of patients are at risk for lymphedema.21,22 • Increasing evidence suggests that the use of SLNB of the inguinofemoral LN basin is an alternative standard-of-care approach to lymphadenectomy in select patients with SCC of the vulva.23,24 • SLNB results in decreased postoperative morbidity without compromising detection of LN metastases.23,25 • Prospective, cooperative group trials have evaluated the SLN technique and demonstrate feasibility, safety, validity, and a low risk of groin recurrences with this surgical approach in vulvar cancer.23,24 • Candidates for SLNB include patients with negative clinical groin examination and/or imaging, and a primary unifocal vulvar tumor size of <4 cm.24,26,27 • If SLNB is considered, it should be performed by an experienced high-volume SLN surgeon, as high-volume surgeons exhibit improved SLN detection rates.24,26 • Increased sensitivity of SLN detection is observed when both radiocolloid and blue dye are used.23,24,25 The radiocolloid most commonly injected into the vulvar tumors is technetium-99m sulfur colloid. It is most commonly injected 2–4 hours prior to the vulvectomy and lymphadenectomy procedure. A preoperative lymphoscintigraphy may be performed to aid in anatomically locating the sentinel node. The blue dye most commonly used is Isosulfan Blue $1 \%$ . Approximately 4 cc of dye is injected peritumorally using a four-point injection technique at 2, 5, 7, and 10 o’clock. The blue dye is injected in 4 quadrants intradermally around the leading edges of the tumor. • It is recommended that the SLN procedure is performed prior to the excision of the vulvar tumor, so as not to disrupt the lymphatic network between the primary vulvar tumor and the inguinofemoral LN basin. Additionally, the injected blue dye will only transiently localize (ie, for 30–60 minutes) in the irst group of nodes that correspond to the primary vulvar tumors. Indocyanine green (ICG) with technetium has also been used for SLN mapping in vulvar cancer with encouraging results. • Use of a gamma probe to detect the injected radiocolloid within the inguinofemoral region is recommended prior to making the groin incision in order to tailor the location and size of the incision. • A side-speciic complete inguinofemoral lymphadenectomy is recommended if an ipsilateral SLN is not detected. • Completion inguinofemoral lymphadenectomy is the preferred approach in the presence of metastases $> 2 ~ \mathsf { m m }$ in diameter in the SLNs.28 • For lateralized and near midline tumors with unilateral SLN metastasis, unilateral groin treatment by either inguinofemoral lymphadenectomy or RT is acceptable. • For midline tumors with unilateral SLN metastasis, unilateral groin treatment can be performed if the contralateral groin has negative sentinel node or negative inguinofemoral lymphadenectomy.29,30 • Selective frozen section of sentinel node may guide the intraoperative decision regarding need for completion unilateral or bilateral inguinofemoral lymphadenectomy. PRINCIPLES OF SURGERY: SLNB MANAGEMENT Table 1: Management of Sentinel Lymph Node(s) Mapping <table><tr><td>Lesion location</td><td>Sentinel lymph node mapping</td><td>Management</td></tr><tr><td rowspan="4">Midline</td><td>None</td><td>Bilateral inguinofemoral lymphadenectomy Sentinel lymph node biopsy (SLNB)</td></tr><tr><td>Unilateral</td><td>on mapped side + inguinofemoral lymphadenectomy on non-mapped side</td></tr><tr><td>Bilateral</td><td>Bilateral SLNB</td></tr><tr><td>None</td><td>Bilateral inguinofemoral lymphadenectomy</td></tr><tr><td rowspan="4">Lateral ambiguous/Near midline</td><td>Ipsilateral</td><td>Ipsilateral SLNBb</td></tr><tr><td>Bilateral</td><td>Bilateral SLNB</td></tr><tr><td>Contralateral</td><td>Ipsilateral inguinofemoral lymphadenectomy</td></tr><tr><td>None</td><td>+ contralateral SLNB Ipsilateral inguinofemoral lymphadenectomy</td></tr><tr><td rowspan="4">Laterala</td><td>Ipsilateral</td><td>Ipsilateral SLNB</td></tr><tr><td>Bilateral</td><td>Bilateral SLNB</td></tr><tr><td>Contralateral</td><td>Ipsilateral inguinofemoral lymphadenectomy</td></tr><tr><td></td><td>+ contralateral SLNB</td></tr></table> # Lesion locations: • Midline: Crossing or involving the midline • Lateral ambiguous/Near midline: Located within 2 cm of the midline, but not crossing or involving the midline • Lateral: Greater than 2 cm from the midline a True lateral lesions are rare as 2 cm often extends lateral to the genitocrural fold. b Given limited data regarding management of lesions that do not involve the midline but are not true lateral lesions (lateral ambiguous/near midline), it is reasonable to consider only ipsilateral lymph node evaluation in patients who have preoperative lymphoscintigraphy that demonstrates ipsilateral drainage only. A contralateral lymph node evaluation should be performed in patients who do not undergo preoperative lymphoscintigraphy, and in patients where preoperative lymphoscintigram demonstrates contralateral drainage.30 # NCCN Guidelines Version 4.2024 Vulvar Cancer # PRINCIPLES OF SURGERY REFERENCES 1 Rouzier R, Haddad B, Plantier F, et al. Local relapse in patients treated for squamous cell vulvar carcinoma: incidence and prognostic value. Obstet Gynecol 2002;100:1159-1167. 2 Te Grootenhuis NC, Pouwer AW, de Bock GH, et al. Margin status revisited in vulvar squamous cell carcinoma. Gynecol Oncol 2019;154:266-275. 3 Pleunis N, Leermakers MEJ, van der Wurff AA, et al. Surgical margins in squamous cell carcinoma, different for the vulva? Eur J Surg Oncol 2018;44:1555-1561. 4 Heaps JM, Fu YS, Montz FJ, et al. Surgical pathologic variables predictive of local recurrence in squamous cell carcinoma of the vulva. Gynecol Oncol 1990;38:309-314. 5 De Hullu JA, Hollema H, Lolkema S, et al. Vulvar carcinoma. The price of less radical surgery. Cancer 2002;95:2331-2338. 6 Woelber L, Griebel L, Eulenburg C, et al. Role of tumour-free margin distance for loco-regional control in vulvar cancer--a subset analysis of the Arbeitsgemeinschaft Gynakologische Onkologie CaRE1 multicenter study. Eur J Cancer 2016;69:180-188. 7 Woelber L, Choschzick M, Eulenburg C, et al. Prognostic value of pathological resection margin distance in squamous cell cancer of the vulva. Ann Surg Oncol 2011;18:3811-3818. 8 Groenen SMA, Timmers PJ, Burger CW. Recurrence rate in vulvar carcinoma in relation to pathological margin distance. Int J Gynecol Cancer 2010;20:869- 873. 9 Ioffe YJ, Erickson BK, Foster KE, et al. Low yield of residual vulvar carcinoma and dysplasia upon reexcision for close or positive margins. Gynecol Oncol 2013;129:528-532. 10 Bedell SM, Hedberg C, Grifin A, et al. Role of adjuvant radiation or re-excision for early stage vulvar squamous cell carcinoma with positive or close surgical margins. Gynecol Oncol 2019;154:276-279. 11 Arvas M, Kahramanoglu I, Bese T, et al. The role of pathological margin distance and prognostic factors after primary surgery in squamous cell carcinoma of the vulva. Int J Gynecol Cancer 2018;28:623-631. 12 Faul CM, Mirmow D, Huang Q, et al. Adjuvant radiation for vulvar carcinoma: improved local control. Ing J Radiat Oncol Biol Phys 1997;38:381-389. 13 Olawaiye AB, Cotler J, Cuello MA, et al. FIGO staging for carcinoma of the vulva: 2021 revision. Int J Gynecol Obstet 2021;155:43-47. 14 Burger MP, Hollema H, Emanuels AG, et al. The importance of the groin node status to survival of T1 and T2 vulvar carcinoma patients. Gynecol Oncol 1995;57:327-334. 15 DiSaia PJ, Creasman WT, Rich WM. An alternate approach to early cancer of the vulva. Am J Obstet Gynecol 1979;133:825-832. 16 Micheletti L, Haefner H, Zalewski K, et al. The International Society for the study of vulvovaginal disease surgical oncological procedure definitions committee "surgical terminology for vulvar treatment". J Low Genit Tract Dis 2020;24:62-68. 17 De Hullu JA, Hollema H, Lolkema S, et al. Vulvar carcinoma. The price of less radical surgery. Cancer 2002;95:2331-2338. 18 Stehman FB, Look KY. Carcinoma of the vulva. Obstet Gynecol 2006;107:719-733. 19 Gonzalez-Bosquet J, Magrina JF, Magtibay PM, et al. Patterns of inguinal groin node metastases in squamous cell carcinoma of the vulva. Gynecol Oncol 2007;105:742-746. 20 Moore DH, Ali S, Koh WJ, et al. A phase II trial of radiation therapy and weekly cisplatin chemotherapy for the treatment of locally-advanced squamous cell carcinoma of the vulva: a gynecologic oncology group study. Gynecol Oncol 2012;124:529-533. 21 DiSaia PJ, Creasman WT, Rich WM. An alternate approach to early cancer of the vulva. Am J Obstet Gynecol 1979;133:825-832. 22 Carlson JW, Kauderer J, Hutson A, et al. GOG 244, the lymphedema and gynecologic cancer (LEG) study: Incidence and risk factors in newly diagnosed patients. Gynecol Oncol 2020;156:467-474. 23 Van der Zee AG, Oonk MH, De Hullu JA, et al. Sentinel lymph node dissection is safe in the treatment of early-stage vulvar carcinoma. J Clin Oncol 2008;26:884-889. 24 Levenback CF, Ali S, Coleman RL, et al. Lymphatic mapping and sentinel lymph node biopsy in women with squamous cell carcinoma of the vulva: a gynecologic oncology group study. J Clin Oncol 2012;30:3786-3791. 25 Oonk MH, van Hemel BM, Hollema H, et al. Size of sentinel-node metastasis and chances of non sentinel-node involvement and survival in early stage vulvar cancer: results from GROINSS-V, a multicentre observational study. Lancet Oncol 2010;11:646-652. 26 Covens A, Vella ET, Kennedy EB, et al. Sentinel lymph node biopsy in vulvar cancer: Systematic review, meta-analysis and guideline recommendations. Gynecol Oncol 2015;137:351-361. 27 Te Grootenhuis NC, van der Zee AG, van Doorn HC, et al. Sentinel nodes in vulvar cancer: Long-term follow-up of the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) I. Gynecol Oncol 2016;140:8-14. 28 Oonk MHM, Slomovitz B, Baldwin PJW, et al. Radiotherapy versus inguinofemoral lymphadenectomy as treatment for vulvar cancer patients with micrometastases in the sentinel node: Results of GROINSS-V II. J Clin Oncol 2021;39:3623-3632. 29 Van der Kolk WL, Van der Zee AGJ, Slomovitz BM, et al. Unilateral inguinofemoral lymphadenectomy in patients with early-stage vulvar squamous cell carcinoma and a unilateral metastatic sentinel lymph node is safe. Gynecol Oncol 2022;167:3-10. 30 Coleman RL, Ali S, Levenback CF, et al. Is bilateral lymphadenectomy for midline squamous carcinoma of the vulva always necessary? An analysis from Gynecologic Oncology Group (GOG) 173. Gynecol Oncol 2013;128:155-159. # PRINCIPLES OF RADIATION THERAPY # General Principles • RT is often used in the treatment of patients with vulvar cancer as adjuvant therapy following initial surgery, as part of primary therapy in locally advanced disease, or for secondary therapy/palliation in recurrent/metastatic disease. • Radiation technique and doses are important to maximize tumor control while limiting adjacent normal tissue toxicity. • Tumor-directed RT refers to RT directed at sites of known or suspected tumor involvement. In general, tumor-directed EBRT is directed to the vulva and/or inguinofemoral, external, and internal iliac nodal regions. Brachytherapy can sometimes be used as a boost to anatomicall amenable primary tumors. Careful attention should be taken to ensure adequate tumor coverage by combining clinical examination, imagin indings, and appropriate nodal volumes at risk to deine the target volume. For example, invasion into the anus above the pectinate line would necessitate coverage of the perirectal nodes.1,2 • Ensure coverage of gross tumor burden with margin. In highly selected cases where only a supericial vulvar target is to be treated, an enface electron beam may be used. • Utilization of imaging studies are an important part of the treatment planning process. The use of CT-based treatment planning and conformal blocking is considered the standard of care for EBRT. • Historically, a widely disparate range of approaches has been described. In an attempt to better standardize RT use and techniques, a recen international survey, with consequent recommendations, has been reported.3 • Acute e冩ects during RT (eg, diarrhea, bladder irritation, fatigue, mucocutaneous reaction) are expected to some degree in most patients, an can be further accentuated by concurrent chemotherapy. These toxicities should be aggressively managed (eg, local skin care, symptomati medications), and treatment breaks should be avoided or minimized. Many patients may develop an overgrowth of Candida albicans; treatment with oral and local antifungal agents will markedly reduce skin reaction. If a bacterial infection develops, prompt recognition and appropriate treatment is essential. These acute e冩ects generally resolve several weeks after completion of radiation. operative adjuvant treatment should be initiated as soon as adequate healing is achieved, preferably within 6–8 weeks. # NCCN Guidelines Version 4.2024 Vulvar Cancer PRINCIPLES OF RADIATION THERAPY Treatment Information – 3D Conformal/Anterior-Posterior/Posterior-Anterior (AP/PA) Fields • Target Volumes The target is best deined by both physical examination and CT-based treatment planning; contouring of the target structures is recommended. When an AP/PA technique is primarily used, often wide AP and narrower PA ields are used with electrons supplementing the dose to the inguinal region if the depth of the inguinal nodes allows for electron coverage. More conformal techniques such as three- or four-ield approaches may allow for greater sparing of bowel and/or bladder, depending on tumor extent and patient anatomy. CT or MRI planning, with possible image fusion technology, should be used to assure adequate dosing and coverage with contouring of the primary, and the inguinofemoral and iliac nodes. Radio-opaque markers should be placed on key landmarks at the time of simulation to assist in deinition of the primary target volume. The superior ield border should be no lower than the bottom of the sacroiliac joints or higher than the L4/L5 junction unless pelvic nodes are involved. If pelvic nodes are involved, the upper border can be raised to at least 2 cm above the most cephalad-positive node. The superior border should extend as a horizontal line to cover the inguinofemoral nodes at the level of the anterior-inferior iliac spine. The lateral border will be a vertical line drawn from the anterior-inferior iliac spine. To adequately cover the inguinal nodes, the inferior-lateral inguinal nodal border should be parallel to the inguinal crease and inferior enough to encompass the inguinofemoral nodal bed to the intertrochanteric line of the femur or 1.5–2 cm distal to the saphenofemoral junction. The inferior vulvar border will be lower and should be at least 2 cm below the most distal part of the vulva. Care should be taken to spare the femoral heads and necks. In both the locally advanced and postoperative settings, especially when there is ≥2 LN pathologically positive, the bilateral inguinal and pelvic lymphatic regions are typically included in the radiotherapy clinical target volume (CTV). Other indications for treating the primary site include close/positive margin, LVSI, and $> 5 - \mathsf { m m }$ depth of invasion. Additionally, groin involvement may be considered a relative indication to include the primary site. Use of a midline block (to avoid toxicity to sensitive central structures) in stage III–IV vulvar cancer has been associated with a high rate of central recurrence and is usually discouraged. Conversely, there may be clinical situations in which it is desirable to cover the primary site only and avoid the nodes. If there are clinically or radiographically suspicious LNs (1 or more), then bilateral pelvic and groin radiotherapy is recommended. RT may be administered adjuvantly (after dissection) or deinitively (unresectable). If the groin is clinically node negative, but pathologically node positive (by sentinel node procedure or dissection), then the number of positive nodes, size of LN metastasis, features of the primary lesion, and extent of surgery may impact recommendations for adjuvant RT.4 $\diamondsuit$ If there is a single positive SLN and no completion inguinofemoral lymphadenectomy done, then adjuvant RT or chemoradiation is recommended regardless of size of LN metastasis. re are 2 or more pathologic positive nodes or extracapsular extension (ECE) is present, then adjuvant RT or chemoradiation is mmended. $\diamondsuit$ In the setting of a single pathologic LN without ECE and a completion IFLD, there are scenarios where adjuvant RT or chemoradiation may be favored such as larger primary tumor size, larger LN size, inadequate LN dissection, lymph node ratio $> 2 0 \%$ , presence of LVSI, or radiographically suspicious indings. We favor evaluation of these patients by a radiation oncologist and consideration of postoperative PET imaging to help with decision making. $\diamondsuit$ There is some data that suggests the contralateral groin could be observed in patients with documented ipsilateral drainage, a lateralized lesion, and small primary tumor. # PRINCIPLES OF RADIATION THERAPY # Treatment Information – Intensity-Modulated Radiation Therapy (IMRT)5 • The vulvar and nodal targets should be contoured on the planning CT. Any gross vulvar disease should be contoured as a gross tumor volume (GTV) and include any visible and/or palpable extension. The vulvar CTV target is deined as the GTV or tumor bed plus the adjacent skin, mucosa, and subcutaneous tissue of the vulva excluding bony tissue. A wire placed clinically to deine the vulvar skin borders and the GTV during CT simulation is essential. In addition, a marker on the anus, urethra, clitoris, and the wiring of any scars will aid in planning. • To ensure adequate distal margin on the vulvar target volume, a “false structure” or bolus should be placed over the vulva for treatment planning purposes. Doses to the target areas should be conirmed using thermoluminescent dosimeter (TLD) at irst treatment. • Symmetrical geometric expansions on the vessels should NOT be used for the inguinofemoral nodes. The inguinofemoral nodal CTV will extend laterally from the inguinofemoral vessels to the medial border of the sartorius and rectus femoris muscles, posteriorly to the anterior vastus medialis muscle, and medially to the pectineus muscle or 2.5–3 cm medially from the vessels. Anteriorly, the volume should extend to the anterior border of the sartorius muscle (the most anterior muscle on the lateral inguinofemoral border). The caudal extent of the inguinofemoral nodal basin is the top of the lesser trochanter of the femur.2 • The pelvic nodal CTV is the vasculature of the bilateral external iliac, obturator, and internal iliac nodal regions with a minimum of 7 mm of symmetrical expansion excluding bone and muscle. • The groin CTV volume will not extend outside the skin and should be trimmed by $\mathfrak { s m m }$ in the absence of skin involvement (with skin involvement, the CTV should extend to the skin with bolus material applied during treatment). Planning target volume (PTV) expansion is then $\mathbf { 7 - } 1 0 \mathrm { ~ m m }$ . • Image-guided IMRT is an essential component of treatment (to account for vulva edema or marked tumor regression). • Planning should be taken with care to respect normal tissue tolerances such as rectum, bladder, small bowel, and femoral head and neck.6 # General Treatment Information • Bolus should be used to ensure adequate dosing to supericial target volume both at the primary site and when LNs are just below the skin surface. • TLD, optically stimulated luminescence dosimeter (OSLD), or electronic dosimetry to skin may be used for dose veriication. # PRINCIPLES OF RADIATION THERAPY # Dosing Prescription Regimen • The target tissues should be treated once daily, 5 days per week. Breaks from treatment should be minimized. Adequate dosing is crucial and can be accomplished with either 3D conformal approaches or IMRT as long as care is given to assure adequate dosing and coverage of tissues at risk for tumor involvement.1,7 • Doses range from 45–50.4 Gy in 25–28 fractions (1.8 Gy fractions) for adjuvant therapy to 59.4–64.8 Gy in 33–36 total fractions (1.8 Gy fractions) for unresectable disease. In select cases, bulky/persistent primary disease or large nodes that are unresectable may be boosted to 70 Gy. • Suggested dosing to areas of risk: Gross primary vulva disease $\mathbf { \delta 6 0 - 7 0 }$ Gy Primary surgical bed (postoperative, negative margins) $= 4 5 - 5 0$ Gy Primary surgical bed (postoperative close or positive margins) $= 5 4 - 6 0$ Gy Clinically and/or radiographically uninvolved inguinofemoral L $N \mathsf { s } = 4 5 \mathrm { - } 5 0$ Gy Inguinofemoral LNs (positive, no ECE or gross residual disease) $1 = 5 0 - 5 5$ Gy Inguinofemoral LNs $( \mathsf E \mathsf C \mathsf E ) = 5 4 - 6 4$ Gy LNs (gross residual or unresectable disease) $\mathbf { \delta 6 0 - 7 0 }$ Gy # PRINCIPLES OF RADIATION THERAPY REFERENCES Beriwal S, Shukla G, Shinde A, et al. Preoperative intensity modulated radiation therapy and chemotherapy for locally advanced vulvar carcinoma: analysis of pattern of relapse. Int J Radiat Oncol Biol Phys 2013;85:1269-1274. Kim CH, Olson AC, Kim H, Beriwal S. Contouring inguinal and femoral nodes; how much margin is needed around the vessels? Pract Radiat Oncol 2012;2:274-278. Gaffney DK, King B, Viswanathan AN, et al. Consensus recommendations for radiation therapy contouring and treatment of vulvar carcinoma. Int J Radiat Oncol Biol Phys 2016;95:1191-1200. Cao Y, Viswanathan A. When is it safe to omit contralateral groin management in unilateral sentinel node-positive early stage vulvar cancer? Gynecol Oncol 2022;167:1-2. Rishi A, Rollins M, Ahmed KA, et al. High-dose intensity-modulated chemoradiotherapy in vulvar squamous cell carcinoma: Outcome and toxicity. Gynecol Oncol 2020;156:349-356. Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2013;86:27-33. Moore DH, Ali S, Koh WJ, et al. A phase II trial of radiation therapy and weekly cisplatin chemotherapy for the treatment of locally-advanced squamous cell carcinoma of the vulva: a gynecologic oncology group study. Gynecol Oncol 2012;124:529-533. SYSTEMIC THERAPYa,1 <table><tr><td>Chemoradiation</td><td colspan="2">Advanced or Recurrent/Metastatic Disease</td></tr><tr><td>Preferred Regimens</td><td>First-line Therapyc Preferred Regimens</td><td>Second-line or Subsequent Therapy Other Recommended Regimens</td></tr><tr><td>· Cisplatin · Carboplatin if patient is cisplatin intolerant</td><td>· Cisplatin/paclitaxel/bevacizumabd · Cisplatin/paclitaxel · Carboplatin/paclitaxel</td><td>· Paclitaxel · Erlotinib (category 2B)8 ·Cemiplimabe,6,7</td></tr><tr><td>Other Recommended Regimens · Cisplatin/fluorouracil · If cisplatin or carboplatin are</td><td>· Carboplatin/paclitaxel/bevacizumab (category 2B)d Other Recommended Regimens</td><td>· Cisplatin/gemcitabine (category 2B) Useful in Certain Circumstances (Biomarker directed therapy) ·TMB-high (TMB-H)</td></tr><tr><td>Capecitabine/mitomycin² Gemcitabine3 Paclitaxel4,5 unavailable:b</td><td>·Cisplatin ·Carboplatin</td><td>Pembrolizumabe,f,9 · PD-L1-positive Pembrolizumabe,g ·MSI-high (MSI-H)/MMR deficient (dMMR) tumors10 · HER2-positive tumors (IHC 3+ or 2+) Fam-trastuzumab deruxtecan-nxki11 · HPV-related tumors Nivolumabe,12 Pembrolizumabe,10</td></tr></table> # Footnotes a Cisplatin, carboplatin, and paclitaxel may cause drug reactions (See NCCN Guidelines for Ovarian Cancer--Management of Drug Reactions [OV-D]). b These agents may be considered when cisplatin and carboplatin are unavailable. c If not used previously, first-line agents can be used as second-line or subsequent therapy as clinically appropriate. d An FDA-approved biosimilar is an appropriate substitute for bevacizumab. e NCCN Guidelines for Management of Immunotherapy-Related Toxicities. f For the treatment of patients with unresectable or metastatic tumor mutational burden-high (TMB-H) $[ \ge 1 0$ mutations/megabase (mut/Mb)] tumors, as determined by an FDA-approved assay, or a validated test performed in a CLIA-certified laboratory, that have progressed following prior treatment and who have no satisfactory alternative treatment options. g Recommended for disease progression on or after chemotherapy in patients whose tumors express PD-L1 (combined positive score $[ \mathsf { C P S } ] \geq 1$ ) as determined by an FDA-approved assay or a validated test performed in a CLIA-certified laboratory. # SYSTEMIC THERAPY REFERENCES # NCCN Guidelines Version 4.2024 Vulvar Cancer # PRINCIPLES OF GYNECOLOGIC SURVIVORSHIP # Physical E冩ects Gynecologic cancer treatment typically involves surgery, chemotherapy, hormone therapy, RT, and/or immunotherapy. These treatments cause acute, short-term, and long-term toxicities. Surgical approaches may be extensive and pose risks such as adhesion formation, which may cause pain and may contribute to small bowel obstruction, urinary or gastrointestinal complications (eg, incontinence, diarrhea), pelvic loor dysfunction (manifested by a variety of urinary, bowel, and/or sexual e冩ects), and lymphedema. Chemotherapy agents vary, although commonly used regimens may pose a signiicant risk of neurotoxicity, cardiac toxicity, development of hematologic cancers, and cognitive dysfunction. Long-term estrogen deprivation may cause symptoms such as hot lashes, vaginal dryness, and bone loss. RT may cause long-term complications (eg, ibrosis, vulvovaginal atrophy) and may predispose patients to secondary cancers of the subcutaneous tissue, and/or underlying organs that are proximal to the radiation ield. Prior pelvic RT may contribute to bone loss and increase the risk of pelvic fractures. Consider bone density testing and prophylactic use of bisphosphonates, particularly in patients with osteoporosis. Immunotherapy use is emerging, and to date, long-term e冩ects of these treatments are unknown. # Psychosocial E冩ects • Psychosocial e冩ects after cancer may be psychological (eg, depression, anxiety, fear of recurrence, altered body image), inancial (eg, return to work, insurance concerns), and/or interpersonal (eg, relationships, sexuality, intimacy) in nature. # Clinical Approach • All gynecologic cancer survivors should receive regular general medical care that focuses on managing chronic disease, monitoring cardiovascular risk factors, providing recommended vaccinations, and encouraging adoption of a healthy lifestyle. • In order to assess the late and long-term e冩ects of gynecologic cancers, clinicians should comprehensively document the patient’s history, conduct a thorough physical examination, and provide any necessary imaging and/or laboratory testing. All patients, whether sexually active or not, should be asked about genitourinary symptoms, including vulvovaginal dryness. Referral to appropriate specialty providers (eg, physical therapy, pelvic loor therapy, sexual therapy, psychotherapy) is recommended. As most treatments for gynecologic cancers will cause sexual dysfunction, early menopause, and infertility, special attention to the resultant medical and psychosocial implications is needed. • Post-radiation use of vaginal dilators and moisturizers is recommended. • For treatment-related menopause, hormone therapy should be considered. • Communication and coordination with all clinicians involved in the care of survivors, including primary care clinicians, is critical. Providing cancer survivors with a summary of their treatment and recommendations for follow-up is recommended. # Additional Guidance • NCCN Guidelines for Distress Management • NCCN Guidelines for Smoking Cessation • NCCN Guidelines for Survivorship # NCCN Guidelines Version 4.2024 Vulvar and Vulvovaginal Melanoma ![](images/fac0e01c3bd61a4e126ed6544573595391cc3890c3004678609e6d22a19951a1.jpg) # FOOTNOTES FOR VM-1 a Clinical presentation: Cutaneous vulvar melanoma is defined as lesions that occur on the vulva vestibule outside Hart's line; mucosal vulvovaginal melanoma is defined as lesions that occur on the vulva vestibule inside Hart's line. b See Principles of Imaging (ME-D) in the NCCN Guidelines for Melanoma: Cutaneous. c Vulvovaginal melanoma should be staged the same as cutaneous melanoma. Clinical staging for cutaneous vulvar melanoma and vulvovaginal melanoma should be done using the AJCC staging system (TNM staging system). See Staging (ST-1) in the NCCN Guidelines for Melanoma: Cutaneous d See Principles of Biopsy and Pathology (ME-B) in the NCCN Guidelines for Melanoma: Cutaneous. e See Principles of Surgical Margins for Wide Excision of Primary Melanoma (ME-E) in the NCCN Guidelines for Melanoma: Cutaneous. Based on limited data, topical imiquimod may be helpful in selected cases of vulvar melanoma in situ (MIS) when histologic clearance is not possible surgically. f See Principles of Sentinel Lymph Node Biopsy (SLNB) in the NCCN Guidelines for Melanoma: Cutaneous. g See Systemic Therapy for Metastatic or Unresectable Disease (ME-I) in the NCCN Guidelines for Melanoma: Cutaneous. h Principles of Vulvovaginal Melanoma Radiation (VM-A). i Principles of Surgery (VULVA-C). j For invasive melanoma, recommend at least 1-cm margins, if feasible, with cautionary measures to avoid disfigurement. # NCCN Guidelines Version 4.2024 Vulvar and Vulvovaginal Melanoma # TREATMENT FORRECURRENCE ![](images/41013d7febf9f930719c1479e82d9c3433a7a03f8fa0d04159f5fa700a2ae90c.jpg) k Nodal ultrasound assessment for melanoma requires specific radiologic expertise. Criteria concerning for early melanoma nodal involvement include the following: hypoechoic island(s) in the cortex, asymmetrical focal cortical thickening, and peripheral vascularity, particularly when there is detectable perfusion to the area of cortical thickening. Core biopsy or FNA of suspicious LNs should be directed to the atypical area(s) within the cortex identified on ultrasound. • van Akkooi ACJ, Voit CA, Verhoef C, Eggermont AMM. Potential cost-e冩ectiveness of US-guided FNAC in melanoma patients as a primary procedure and in follow-up Ann Surg Oncol 2010;17:660-662. • Voit CA, van Akkooi ACJ, Schafer-Hesterberg G, et al. Rotterdam Criteria for sentinel node (SN) tumor burden and the accuracy of ultrasound (US)-guided ine-needl aspiration cytology (FNAC): Can US-guided FNAC replace SN staging in patients with melanoma? J Clin Oncol 2009;27:4994-5000. • Voit CA, Ophuis CMCO, Ulrich J, et al. Ultrasound of the sentinel node in melanoma patients: echo-free island is a discriminatory morphologic feature for node positivity. Melanoma Res 2016;26;267-271. • Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med 2017;376:2211-2222. • Bartlett EK, Lee AY, Spanheimer PM, et al. Nodal and systemic recurrence following observation of a positive sentinel lymph node in melanoma. Br J Surg 2020;107:1480-1488. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. PRINCIPLES OF RADIATION THERAPY Consider RT in medically inoperable patients or symptomatic gross metastatic disease unresponsive to other therapies. It can be considered for adjuvant therapy in situations where recurrent disease may cause excessive morbidity. Advanced techniques such as IMRT, image-guided RT (IGRT), and interstitial high dose-rate (HDR) brachytherapy should be used to maximize dose to the target and minimize dose to the normal tissues.1,2 # Gross Disease • Unresectable treated with RT alone • PTV high risk: primary tumor plus involved regional nodes • PTV low to intermediate risk: suspected to have subclinical disease • Dosing Regimens: More hypofractionated regimens may be chosen for smaller volume radiation. If primary and nodal volumes are targeted, then the more protracted courses will give less long term toxicity. Optimal doses are not well-established, but potential regimens include: EBRT alone: $\diamondsuit$ 66 (2.2 Gy/fx)–70 Gy (2 Gy/fx) in 30–35 fractions over 6–7 weeks for PTV high risk with low to intermediate risk 44–50 Gy (2 Gy/ fx) to 54–63 Gy (1.6–1.8 Gy/fx) ◊ 35 Gy in 5 fractions over 1 week for ields $< 3 c m ^ { 3 }$ EBRT plus brachytherapy boost: $\diamondsuit$ 44–50 Gy (2 Gy/fx) to PTV high and low to intermediate risk followed by brachytherapy to PTV high risk $\diamondsuit$ Potential brachytherapy boost regimens: 4 Gy x 8 fxs; 6 Gy $\textsf { \textsf { X 5 } }$ fxs; 7 Gy x 4 fxs; 8.5 Gy x 3 fxs $\diamondsuit$ Goal: Combined equivalent dose in 2 Gy/fx (EQD2) $> 8 5 - 9 0 \odot y ^ { \mathbf { a } , \mathbf { b } }$ Brachytherapy alone – for primary disease only: $\diamondsuit$ Potential brachytherapy regimens: 5 Gy $\pmb { \times }$ 10 fxs; 6 Gy x 8 fxs; 7 Gy x 7 fxs; 8 Gy $\textsf { \textsf { X 5 } }$ fxs # Adjuvant Therapy • May be considered for recurrent disease or close or positive margins where re-resection may be too morbid with interval from surgery to RT is $\pmb { < 6 }$ weeks unless adjuvant systemic therapy is given irst. • Dosing Regimens: More hypofractionated regimens may be chosen for smaller volume radiation. If primary and nodal volumes are targeted, then the more protracted courses will give less long-term toxicity. Optimal doses are not wellestablished, but potential regimens includec: 60–66 Gy (2 Gy/fx) in 30–33 fractions over 6–7 weeks3 48 Gy in 20 fractions over 4 weeks4 27–30 Gy in 5 fractions over 2 weeks (twice per week or every other day) – for primary disease only5 a Malignant melanoma is a heterogeneous disease with $\alpha / \beta$ ratios ranging from low (similar to late responding tissues) to high (similar to acutely responding tissues).1 Therefore, when calculating EqD2, it is unclear which $\alpha / \beta$ ratio to use. The above dose combinations give an EQD2 ${ \tt > } 8 5 { \ - } 9 0 $ Gy for ${ \tt G } / { \beta }$ ratios ranging from $< 1 . 0 { - } 1 0 . 0 $ . Furthermore, they are used commonly for other gynecologic malignancies and are known to be safe for surrounding normal structures. Of note, smaller fraction sizes may be preferred as higher doses per fraction have been known to increase toxicity.2 b Clinicians must balance the risks of normal tissue toxicity with tumor control but suggested dose constraints are provided. Studies indicate that $2 0 \% { - } 3 0 \%$ of cases may not meet every constraint. c Hypofractionated regimens may increase long-term complications. # NCCN Guidelines Version 4.2024 Vulvar and Vulvovaginal Melanoma # PRINCIPLES OF RADIATION THERAPY # Adjuvant Regional Disease • Should be considered for patients with high risk of regional recurrence, although increase in survival is not well-documented and must be weighed against potential toxicities such as lymphedema of the vulva or lower extremities. The impact of these potential toxicities should be considered in the context of adjuvant systemic options. • Risk factors for recurrence include gross residual disease, ECE, clinically (macroscopic) involved node(s), ≥3 inguinofemoral nodes and/or a single node ≥4 cm, inguinofemoral nodes, or matted nodes. • Dosing Regimens: More hypofractionated regimens may be chosen for smaller volume radiation. If primary and nodal volumes are targeted, then the more protracted courses will give less long-term toxicity. Optimal doses are not well-established, but potential regimens includec,6: 60–66 Gy in 25–33 fractions over 5–7 weeks7,8 48 Gy in 20 fractions over 4 weeks9 # Deinitive or Palliative Therapy for Regional Metastases • Unresectable or residual nodal, satellite, or in-transit disease • Dosing Regimens: More hypofractionated regimens may be chosen for smaller volume radiation. If primary and nodal volumes are targeted, then the more protracted courses will give less long-term toxicity. Optimal doses are not well-established, but potential regimens include: 48–50 Gy in 20 fractions over 4 weeks10 30 Gy in 10 fractions over 2 weeks11 30–36 Gy (6 Gy/fx) for small ields5 • Distant Metastatic Disease: Refer to Principles of Radiation Therapy (ME-H 3 of 7 and 4 of 7) in the NCCN Guidelines for Melanoma: Cutaneous. • Managing Systemic Therapy During Radiation: Refer to Principles of Radiation Therapy (ME-H 5 of 7) in the NCCN Guidelines for Melanoma: Cutaneous. # NCCN Guidelines Version 4.2024 Vulvar and Vulvovaginal Melanoma PRINCIPLES OF RADIATION THERAPY REFERENCES # Staging-Vulvar Cancer # Table 1. International Federation of Gynecology and Obstetrics (FIGO) New (2021) FIGO staging for carcinoma of the vulva FIGO Description Stage Tumor conined to the vulva and/or perineum. IA Tumor size $\leq 2$ cm and stromal invasion $\leq 1 \ \mathsf { m m } ^ { \mathsf { a } }$ IB Tumor size $^ { > 2 }$ cm or stromal invasion $> 1 \mathsf { m m } ^ { \mathsf { a } }$ II Tumor of any size with extension to lower one-third of the urethra, lower one-third of the vagina, lower one-third of the anus with negative nodes III Tumor of any size with extension to upper part of adjacent perineal structures, or with any number of nonixed, nonulcerated lymph node IIIA Tumor of any size with disease extension to upper two-thirds of the urethra, upper two-thirds of the vagina, bladder mucosa, rectal mucosa, or regional lymph node metastases ${ \le } 5 \mathsf { m m }$ IIIB Regionalb lymph node metastases $> 5 \mathsf { m m }$ IIIC Regionalb lymph node metastases with extracapsular spread IV Tumor of any size ixed to bone, or ixed, ulcerated lymph node metastases, or distant metastases IVA Disease ixed to pelvic bone, or ixed or ulcerated regionalb lymph node metastases IVB Distant metastases # ABBREVIATIONS <table><tr><td>AP</td><td>anterior-posterior (or anteroposterior)</td><td>H&P</td><td>history and physical</td></tr><tr><td></td><td></td><td>HDR HPV</td><td>high dose rate human papillomavirus</td></tr><tr><td>BUN</td><td>blood urea nitrogen</td><td>HSIL</td><td> high-grade squamous</td></tr><tr><td>CIS</td><td>carcinoma in situ</td><td></td><td>intraepithelial lesion</td></tr><tr><td>CBC</td><td>complete blood count</td><td></td><td></td></tr><tr><td>CLIA</td><td>Clinical Laboratory</td><td>ICG</td><td>indocyanine green</td></tr><tr><td></td><td>Improvement Amendments</td><td>IGRT</td><td> image-guided radiation therapy</td></tr><tr><td>CPS CTV</td><td>combined positive score</td><td>IHC</td><td>immunohistochemistry</td></tr><tr><td></td><td>clinical target volume</td><td>IMRT</td><td>intensity-modulated radiation therapy</td></tr><tr><td>dMMR dVIN</td><td>deficient mismatch repair</td><td></td><td></td></tr><tr><td></td><td>differentiated vulvar intraepithelial neoplasia</td><td>LFT</td><td>liver function test</td></tr><tr><td></td><td></td><td>LN</td><td>lymph node</td></tr><tr><td>EBRT</td><td>external beam radiation</td><td>LVSI</td><td>lymphovascular space invasion</td></tr><tr><td></td><td>therapy</td><td>MIS</td><td>melanoma in situ</td></tr><tr><td>ECE</td><td>extracapsular extension</td><td></td><td></td></tr><tr><td></td><td></td><td>MMR</td><td>mismatch repair</td></tr><tr><td>EUA</td><td>examination under anesthesia</td><td>MSI</td><td>microsatellite instability</td></tr><tr><td>EqD2</td><td>equivalent dose at 2 Gy</td><td>MSI-H</td><td> microsatellite instability-high</td></tr><tr><td>(or EQD2)</td><td></td><td>OSLD</td><td>optically stimulated</td></tr><tr><td>FDG</td><td>fluorodeoxyglucose</td><td></td><td>luminescence dosimeter</td></tr><tr><td>FNA</td><td>fine-needle aspiration</td><td></td><td></td></tr><tr><td></td><td></td><td>PA</td><td> posterior-anterior (or</td></tr><tr><td>GTV</td><td> gross tumor volume</td><td></td><td>posteroanterior)</td></tr><tr><td></td><td></td><td>pCR</td><td> pathologic complete response</td></tr></table> <table><tr><td colspan="2"></td><td>PD-L1</td><td> programmed death ligand 1</td></tr><tr><td>H&P</td><td>history and physical</td><td>PTV</td><td>planning target volume</td></tr><tr><td>HDR HPV</td><td>high dose rate</td><td></td><td></td></tr><tr><td>HSIL</td><td>human papillomavirus high-grade squamous</td><td>SCC</td><td> squamous cell carcinoma</td></tr><tr><td rowspan="2"></td><td>intraepithelial lesion</td><td>SLN</td><td>sentinel lymph node</td></tr><tr><td></td><td> SLNB</td><td>sentinel lymph node biopsy</td></tr><tr><td>ICG</td><td>indocyanine green</td><td></td><td></td></tr><tr><td>IGRT</td><td> image-guided radiation therapy</td><td>TLD</td><td>thermoluminescent dosimeter</td></tr><tr><td>IHC</td><td>immunohistochemistry</td><td>TMB-H</td><td> tumor mutational burden-high</td></tr><tr><td>IMRT</td><td>intensity-modulated radiation therapy</td><td></td><td></td></tr><tr><td></td><td></td><td>VIN</td><td>vulvar intraepithelial neoplasia</td></tr><tr><td>LFT</td><td>liver function test</td><td></td><td></td></tr><tr><td>LN</td><td>lymph node</td><td></td><td></td></tr><tr><td>LVSI</td><td>lymphovascular space invasion</td><td></td><td></td></tr><tr><td>MIS</td><td>melanoma in situ</td><td></td><td></td></tr><tr><td>MMR</td><td>mismatch repair</td><td></td><td></td></tr><tr><td>MSI</td><td>microsatellite instability</td><td></td><td></td></tr><tr><td>MSI-H</td><td>microsatellite instability-high</td><td></td><td></td></tr><tr><td rowspan="2">OSLD</td><td></td><td></td><td></td></tr><tr><td>optically stimulated luminescence dosimeter</td><td></td><td></td></tr><tr><td rowspan="2">PA</td><td></td><td></td><td></td></tr><tr><td> posterior-anterior (or</td><td></td><td></td></tr><tr><td></td><td>posteroanterior)</td><td></td><td></td></tr><tr><td>pCR</td><td> pathologic complete response</td><td></td><td></td></tr></table> # NCCN Guidelines Version 4.2024 Vulvar Cancer <table><tr><td colspan="2">NCCN Categories of Evidence and Consensus</td></tr><tr><td>Category 1</td><td>Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.</td></tr><tr><td>Category 2A</td><td> Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.</td></tr><tr><td>Category 2B</td><td> Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.</td></tr><tr><td>Category 3</td><td> Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.</td></tr></table> All recommendations are category 2A unless otherwise indicated. <table><tr><td colspan="2">NCCN Categories of Preference</td></tr><tr><td>Preferred intervention</td><td>Intryetisttreasuprorficacysafetyndevidene; andprpra</td></tr><tr><td>.Other recommended intervention</td><td>Other interventions that may be somewhat less effcacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.</td></tr><tr><td>Usefulinceran</td><td>Other interventions that may be used for selected patient populations (defined with recommendation).</td></tr></table> All recommendations are considered appropriate. # NCCN Guidelines Version 4.2024 Vulvar Cancer ![](images/f80f67fbae3c5268eab5147449d58b6a2ce68b8d7d84e84364792bfe3b408c78.jpg) # NCCN Guidelines Version 4.2024 Vulvar Cancer # Overview In 2023, an estimated 6470 individuals will be diagnosed with vulvar cancer, and 1670 deaths are expected from the disease.1 Vulvar cancer accounts for $5 \%$ to $8 \%$ of gynecologic malignancies and median age of diagnosis is 68 years. Based on data from the SEER database, 5-year survival rates range from $8 5 . 6 \%$ for localized disease (stages I/II), to $4 7 . 5 \%$ for regional or locally advanced disease (stages III/IVA), and finally to $2 3 . 3 \%$ for patients with stage IVB (which includes patients with pelvic nodal disease).2 Studies of the SEER database and the National Cancer Database (NCDB) have shown that treatment approaches/modalities vary considerably with sociodemographic factors such as race/ethnicity, age, and non-private insurance, particularly for individuals with advanced disease.3,4 Ninety percent of vulvar cancers are of squamous cell carcinoma (SCC) histology.5 Risk factors for the development of vulvar neoplasia include increasing age, infection with human papillomavirus (HPV), cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages.6 Rarer histologies exist and include melanoma, extramammary Paget’s disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma.7 The International Society for the Study of Vulvovaginal Disease (ISVVD) has revised the terminology used to characterize vulvar lesions over the years. In 2004, vulvar intraepithelial neoplasia (VIN) terminology was refined to include two types of lesions, usual-type VIN and differentiated VIN (dVIN).8 Usual-type VIN was linked to persistent infection with carcinogenic strains of HPV, while dVIN was commonly associated with vulvar dermatologic conditions such as lichen sclerosus. In 2015, the ISVVD updated the description to three classes of vulvar lesions: 1) lowgrade squamous intraepithelial lesion (LSIL) due to flat condyloma or HPV effect; 2) high-grade squamous intraepithelial lesions (HSIL, formerly considered usual-type VIN); and 3) dVIN.9 The 2020 WHO Classification of Female Genital Tumors, VIN is now classified as HPV-associated or HPV-independent. HPV-associated VIN corresponds to low- and highgrade squamous intraepithelial lesion (SIL) similar to other anatomic sites in the anogenital tract.10 HPV-independent VIN is associated with a faster rate of progression to invasive SCC. It is the less common form of VIN and is often associated with lichen sclerosus. The histologic grade of SCC is not well-defined and can be subjective. HPV-associated SCC has a better prognosis than HPV-independent SCC. HPV-associated SCC frequently occurs in younger patients, is multifocal, is associated with classic VIN, and can be seen in conjunction with additional sites of lower genital tract squamous neoplasia. Immunohistochemistry (IHC) shows strong, diffuse, block-like positive nuclear and cytoplasmic staining with p16 and wild-type p53 (heterogeneous staining pattern). HPV-independent SCC is split into two main groups: those associated with TP53 mutations and those with wildtype TP53 status.11 The p53 abnormal, HPV-independent SCC usually occurs in older patients, is unifocal, and is associated with dVIN by histological evaluation. IHC usually shows aberrant p53 staining and negative or weak p16 staining. The p53 abnormal SCCs have the worst clinical outcomes of the three molecular categories (HPV positive, HPVnegative/p53 mutant, and HPV-negative p53 wild type). Assessing the presence and depth of invasion in vulvar SCC can be challenging. Estimates of the percentage of vulvar cancers attributable to HPV infection range from conservative estimates of $30 \%$ to up to $69 \%$ , with a metaanalysis reporting an HPV prevalence of $3 9 . 7 \%$ .12-15 A recent metaanalysis showed the prevalence of HPV in vulvar cancer and VIN to be $3 9 . 1 \%$ and $7 6 . 1 \%$ , respectively. Of the HPV-positive disease, $7 8 . 1 \%$ were HPV-16, followed by HPV-33 in vulvar cancer. A similar trend was # NCCN Guidelines Version 4.2024 Vulvar Cancer observed in VIN. The prevalence of p16-positive vulvar cancer was $3 4 . 1 \%$ while it was $6 5 . 7 \%$ in VIN.16 However, HPV infection is detected in $80 \%$ to $90 \%$ of patients with SIL. Historically, VIN has been diagnosed in younger patients (median age 45–50 years) while vulvar cancers have been diagnosed in older patients (median age 65–70 years).17,18 Because a large majority of HPV-related vulvar cancers are associated with HPV-16 and HPV-18 strains, vaccination with currently available HPV vaccines may reduce the burden of HPV-related vulvar cancers in the future.12,17 By definition, the NCCN Guidelines cannot incorporate all possible clinical variations and are not intended to replace good clinical judgment or individualization of treatments. “Many exceptions to the rule” were discussed among the members of the panel during the process of developing these guidelines. Recommendations in the NCCN Guidelines are category 2A unless otherwise noted. # Guidelines Update Methodology The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org. # Literature Search Criteria Prior to the update of this version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Vulvar Cancer an electronic search of the PubMed database was performed to obtain key literature in vulvar cancer published since the previous Guidelines update, using the following search terms: vulvar cancer or carcinoma of the vulva. The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature. The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies. The data from key PubMed articles as well as articles from additional sources deemed as relevant to these guidelines as discussed by the panel during the Guidelines update have been included in this version of the Discussion section. Recommendations for which high-level evidence is lacking are based on the panel’s review of lower-level evidence and expert opinion. # Sensitive/Inclusive Language Usage NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation. NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist, antimisogynist, anti-ageist, anti-ableist, and anti-weight-biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non-gendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses. # NCCN Guidelines Version 4.2024 Vulvar Cancer # Diagnosis and Workup These guidelines utilize the FIGO (International Federation of Gynecology and Obstetrics) staging system for carcinoma of the vulva which was updated in ${ 2 0 2 1 ^ { 1 9 } }$ from the 2009 system. 20-23 The updated FIGO system has included a revised definition for depth of invasion, lymph node (LN) metastases definition, and allows the incorporation of findings from crosssectional imaging. The presentation of vulvar cancer can be widely varied. The majority of vulvar cancers are located in the labia majora. Other possible sites include the labia minora, clitoris, mons pubis, or perineum. In patients with HPVnegative tumors, vulvar cancer often presents as a single mass or ulcer on the labia majora or minora. In HPV-positive tumors, multifocal lesions and concurrent cervical neoplasia are more common.17,18,24 Although many symptoms; vulvar bleeding or discharge may also occur. A majority of patients present with early-stage localized disease.2 Diagnosis is made through biopsy of all suspicious areas followed by pathologic review. The College of American Pathologists (CAP) protocol for vulvar carcinoma is a useful guide (https://documents.cap.org/protocols/Vulva_4.2.0.2.REL_CAPCP.pdf). This CAP protocol was revised in 2021. Workup includes history and physical examination, complete blood count (CBC), and liver and renal function tests. In addition to vulva examination, evaluation of the vagina and cervix (including cytologic smears) should be emphasized due to the multifocal nature of squamous cell intraepithelial neoplasia. CT, PET/CT, and MRI may be used to delineate the extent of tumor and/or for treatment planning.25-28 Examination-under-anesthesia (EUA) cystoscopy or proctoscopy should be considered as indicated. Appropriate patients should receive smoking cessation counseling, cervical HPV testing, and cytology testing. Consider HIV testing, especially in younger patients. Those with vulvar cancer and HIV should be referred to an HIV specialist; modifications to the recommended cancer treatments in these Guidelines should not be modified solely on the basis of HIV status. For patients with vulvar cancer who are $\mathtt { \ge 6 5 }$ years, also see the NCCN Guidelines for Older Adult Oncology at www.NCCN.org. # Prognostic Factors Historically, en bloc vulvectomy with wide margins was combined with complete inguinofemoral (IF) lymphadenectomy to treat vulvar SCC. While effective in promoting survival, this approach was associated with serious short- and long-term morbidity (eg, wound complications, lymphedema, decreased sexual function, adverse impacts on body image). The emergence of data on important prognostic factors in vulvar cancer informed the evolution of surgical staging and primary treatment.24 Based on a retrospective review of 586 patients enrolled in Gynecologic Oncology Group (GOG) trials through 1984, independent predictors of survival included the presence and number of involved LNs and primary tumor size.29 LN metastasis is considered the most important prognostic factor and determinant of treatment in vulvar cancer,30,31 and extracapsular extension has been linked to poorer prognosis.32-35 Factors that may be predictive of recurrence and/or survival include depth of invasion, pathologic margin distance, tumor thickness, and presence of lymphovascular space invasion (LVSI).17,29,36-41 However, these findings are primarily derived from retrospective analyses. A systematic review of the collective data on prognostic factors for local recurrence in vulvar cancer concluded that the weight of each individual prognostic variable remained equivocal when compared to one another.42 Prognostic data have guided the shift towards more conservative primary tumor resection and regional LN management for early-stage disease.43 The preferred surgical approach evolved towards vulvar-sparing # NCCN Guidelines Version 4.2024 Vulvar Cancer techniques with separate incisions for lymphadenectomy in patients who were clinically node negative.24,44 Current surgical approaches involve tailored primary tumor resection and LN evaluation based on individual patient characteristics.45,46 Data suggest that survival is not negatively impacted by less radical surgical approaches for early-stage cancers.46 # Surgical Staging Previously, the AJCC and the 2009 FIGO systems staged vulvar cancer according to extent of primary tumor (T), LN status (N), and distant metastasis (M). Clinical staging alone provides inadequate evaluation of LN involvement. Because LN metastasis is a key prognostic factor in vulvar cancer survival,30,46 these systems used a hybrid surgical and clinical/pathologic approach for more accurate evaluation of nodal status. Complete staging using the existing system requires primary tumor resection and full IF lymphadenectomy. However, common practice has increasingly included the use of sentinel LN (SLN) biopsy in lieu of complete lymphadenectomy, as well as diagnostic imaging to determine extent of disease.47,48 In the new 2021 staging system, the revisions have been made to allow imaging to be used to assign stage. For stage 1 disease, the new method for measurement of depth of invasion has been added, which is now measured from the basement membrane of the deepest, adjacent, dysplastic, tumor-free rete ridge (or nearest dysplastic rete peg) to the deepest point of invasion. Stage IIIA now also includes the upper two-thirds of the urethra, upper two-thirds of the vagina, and bladde mucosa or rectal mucosa, which were previously part of stage IVA. Stage IIIA includes any number of LNs less than or equal to 5 mm and no longer includes LN metastasis in a single node greater than $5 \mathsf { m m }$ ; this is now considered stage IIIB. Stage IVA includes disease fixed to pelvic bone or fixed or ulcerated regional LN metastases, and stage IVB includes any distant metastases.19 # Pathologic Evaluation Surgicopathologic factors may be used to guide the extent of surgical staging and treatment decisions. Findings from pathologic assessment of the surgical specimen should be carefully documented, including procedure type (ie, partial or total vulvectomy) and depth of procedure (ie, superficial or skinning, simple, or radical). Important elements of primary tumor evaluation include tumor site; size (in multiple dimensions); number of tumor foci; histologic type and grade; depth of stromal invasion; surgical margin status; and the presence of LVSI. When resected, the number of LNs with isolated tumor cells, micrometastases, and macrometastases should be recorded. If SLN mapping is performed, SLNs should undergo ultrastaging for detection of low-volume metastasis. Other important factors include tumor involvement of tissues/organs such as the vagina, urethra, anus, bladder mucosa, rectal mucosa, and pelvic bone. Mismatch repair (MMR), microsatellite instability (MSI), programmed death ligand 1 (PD-L1), neurotrophic tyrosine receptor kinase (NTRK) gene fusion, and tumor mutational burden (TMB) testing may also be considered for treatment planning purposes in patients with recurrent, progressive, or metastatic disease. Additional testing to determine HPV status is recommended. Various methods can be used to detect HPV including detection of overexpressed p16 via IHC, and HPV-specific polymerase chain reaction (PCR) and in situ hybridization (ISH) techniques (for viral mRNA and DNA detection). The NCCN Guidelines recommend p53 IHC to determine p53 status. Evaluation of p53 IHC in vulvar SCC may be challenging and has unique features compared to p53 staining patterns encountered in ovarian and endometrial cancers.49 # Primary Tumor Resection Depending on the size and extent of the primary tumor, simple partial/total vulvectomy or radical partial/total vulvectomy may be required. No prospective data are available to compare outcomes between these resection techniques; however, retrospective data suggest no difference in # NCCN Guidelines Version 4.2024 Vulvar Cancer recurrence and/or survival.50-52 Both surgical approaches involve resection of approximately a 1- to 2-cm radial margin of grossly normal tissue and to the deep fascia or a minimum of a 1-cm deep margin. Vulvar cancer is associated with significant risk of local recurrence, and data demonstrate tumor margin status to be a significant prognostic factor.36,39,53 A review identified 4-year recurrence-free rates of $8 2 \%$ , $6 3 \%$ , and $3 7 \%$ for patients with negative, close, and positive margins, respectively $\langle P = . 0 0 5 \rangle$ . The highest risk of recurrence was associated with margins less than or equal to $5 \mathsf { m m }$ .54 The goal of primary tumor resection is complete removal with negative pathologic margins. The definition of a negative margin continues to evolve, and more data confirm the importance of a negative margin but put less emphasis on the actual distance (in mm) of the margin. In the setting of close or positive tumor margins, re-resection to obtain negative margins or adjuvant local radiation therapy (RT) are options.36,55 In a study, tumor-free margins of at least $_ { 2 \mathsf { m m } }$ were associated with lower local recurrence risk.40 The risk-benefit ratio and morbidity of each approach must be weighed and individualized for each patient. Evidence supports improved recurrence rates and survival with re-resection or adjuvant external beam RT (EBRT) to the primary site.56 However, for close or positive margins involving the urethra, anus, or vagina, re-resection may incur significant morbidity and negatively impact patient quality of life. Re-resection may also be inappropriate for patients with close or positive margins who have inguinal node involvement requiring adjuvant treatment with EBRT ± concurrent chemotherapy. # Lymph Node Evaluation Because LN status is the most important determinant of survival in vulvar cancer, careful evaluation and determination of nodal status is paramount. LN resection is performed through a separate incision from the primary tumor and may entail ipsilateral or bilateral IF lymphadenectomy, or SLN biopsy in select cases. IF lymphadenectomy involves removal of superficial inguinal and deep femoral LN. Further emphasizing the importance of adequate IF lymph node (IFLN) evaluation and treatment at initial presentation, it has been widely reported that subsequent groin relapses are rarely amenable to successful secondary treatment. Lymphadenectomy in patients with clinically negative groin nodes is informed by the size and location of the primary tumor. Because the risk of LN metastasis is less than $1 \%$ in patients with stage IA primary disease,45 lymphadenectomy or SLN evaluation can be omitted in patients with stage IA primary disease with clinically negative groins. However, IF lymphadenectomy is recommended for patients with stage IB/II disease because the risk of nodal metastasis is estimated at greater than $8 \%$ for stage IB and even higher for stage II tumors.45 For primary vulvar tumors less than 4 cm in diameter, located at least 2 cm from the vulvar midline, with clinically negative IFLNs, ipsilateral IF lymphadenectomy or SLN biopsy are appropriate.57,58 However, bilateral LN evaluation (IF lymphadenectomy or SLN biopsy, if indicated) is recommended for patients with primary tumors that are within 2 cm of, or crossing, the vulvar midline.58 Lymphadenectomy for stage III/IV disease is individualized, and integrated with combined modality approaches. # SLN Biopsy Reported rates of postoperative morbidity with unilateral or bilateral IF lymphadenectomy are high. An estimated $20 \%$ to $40 \%$ of patients have wound complications and $30 \%$ to $70 \%$ of patients experience lymphedema.59-61 Studies have begun to investigate whether complete IF lymphadenectomy could be safely avoided in patients who are determined to have a negative SLN. Several prospective multicenter trials have evaluated the feasibility, safety, validity, and risk of groin recurrences with SLN biopsy in early vulvar cancer. # NCCN Guidelines Version 4.2024 Vulvar Cancer The safety and accuracy of SLN assessment was examined in a multicenter observational study (GROINSS-V I) of 403 females with primary vulvar tumors less than 4 cm. IF lymphadenectomy was omitted if SLN(s) were negative on ultrastaging. With a median follow-up period of 35 months (24-month minimum), groin recurrences were detected among 6 of 259 patients $( 2 . 3 \% )$ with a unifocal primary tumor and negative SLN. The 3-year survival rate was $9 7 \%$ , leading to the conclusion that a negative SLN in this patient population provided sufficient management of the groin(s). Short- and long-term morbidity was reduced if the SLN only was removed compared with SLN removal followed by full groin lymphadenectomy.62 In GOG 173, 452 females (with vulva-confined primary tumors $2 { - } 6 \mathsf { c m }$ , at least 1-mm invasion, and clinically node negative) underwent SLN mapping and biopsy followed by IF lymphadenectomy. SLNs were identified in 418 females, and 132 females were node positive (including 11 false-negative nodes). SLN biopsy had a sensitivity of $9 1 . 7 \%$ , negative predictive value of $9 6 . 3 \%$ , and false-negative predictive value of $3 . 7 \%$ overall ( $2 \%$ for primary tumors ${ < } 4$ cm).63 A subgroup analysis of the AGO-CaaRE-1 study compared outcomes of patients with tumors less than 4 cm who underwent radical groin lymphadenectomy or sentinel node lymphadenectomy with negative findings for LN/SLN metastasis $( \mathsf { n } = 5 5 6 )$ . The radical groin lymphadenectomy cohort had larger tumor diameter (20 mm vs. $1 3 \mathsf { m m }$ ; $P$ $\textless . 0 0 1 $ ) and greater depth of invasion (4.0 mm vs. 3.0 mm; $P = . 0 0 2 )$ , but isolated groin recurrence rates did not differ between the groups. Multivariate analysis controlling for tumor characteristics such as diameter, depth of invasion, grade, and LVSI revealed no statistical differences in progression-free survival (PFS) and overall survival (OS) between the radical and sentinel node lymphadenectomy cohorts.64 A systematic review and meta-analysis of the cumulative data on SLN biopsy revealed a per-groin detection rate of $87 \%$ when using dual tracers, and a false-negative rate of $6 . 4 \%$ . When comparing IF lymphadenectomy, superficial IF lymphadenectomy, and SLN biopsy, recurrences rates were $1 . 4 \% , 6 . 6 \%$ , and $3 . 4 \%$ in patients deemed node-negative by the surgical groin approach used, respectively.65 The GROINSS-V I observational study also evaluated patients with positive SLNs. Within the 135 of 403 patients who had positive SLNs $( 3 3 \% )$ , investigators examined the relationship between size of SLN metastasis and risk of non-sentinel node disease among 115 patients who underwent IF lymphadenectomy following detection of positive sentinel nodes. Risk of non-SLN involvement increased steadily with the size of SLN metastasis, beginning at $4 . 2 \%$ with detection of isolated tumor cells and increasing to $6 2 . 5 \%$ with SLN metastases greater than $1 0 \mathsf { m m }$ , suggesting no disease threshold below which further treatment of an SLNpositive groin could be safely omitted. Disease-specific survival (DSS) was worse among those with SLN metastases greater than $_ { 2 \mathsf { m m } }$ versus less than or equal to $_ { 2 \mathsf { m m } }$ $( 6 9 . 5 \%$ vs. $9 4 . 4 \%$ , $P = . 0 0 1$ ).66 Patients undergoing SLN biopsy reported less treatment-related morbidity compared with those undergoing IF lymphadenectomy.67 Long-term follow-up of the GROINSS-V I cohort compared outcomes of SLN-positive patients who underwent completion IF lymphadenectomy with those of SLN-negative patients (no IF lymphadenectomy). At a median follow-up of 105 months, the data revealed a 5- and 10-year local vulvar recurrence rate of $2 4 . 6 \%$ and $3 6 . 4 \%$ for SLN-negative patients, and $3 3 . 2 \%$ and $4 6 . 4 \%$ for SLN-positive patients $\left( P = . 0 3 \right)$ . The isolated groin recurrence rate was $2 . 5 \%$ for SLN-negative patients and $8 . 0 \%$ for SLNpositive patients at 5 years, despite more radical treatment in the latter group. DSS at 10 years was $91 \%$ in the SLN-negative group and $65 \%$ in # NCCN Guidelines Version 4.2024 Vulvar Cancer the SLN-positive group $( P < . 0 0 0 1 )$ , again attesting to the prognostic significance of groin nodal involvement.68 The GROINSS-V II/GOG 270 observational study (NCT01500512) compared the safety of IF radiotherapy with that of IF lymphadenectomy among patients with SLN metastases.69 The trial further evaluated the treatment-related morbidity (short and long term) with radiotherapy in these patients. Among 322 patients with metastatic SLN, 160 had micrometastases $( \leq 2 \mathsf { m m } )$ and 162 patients had macrometastases $^ { ( > 2 }$ mm). Among 160 patients with SLN micrometastases, 126 received IF radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of $1 . 6 \%$ . In 162 patients with SLN macrometastases, the isolated groin recurrence rate at 2 years was $22 \%$ in those who underwent radiotherapy, and $6 . 9 \%$ in those who underwent IFL $( P \neq . 0 \neq 1 )$ . Treatment-related morbidity after radiotherapy was less frequent compared with IF lymphadenectomy. The ongoing GROINSS-V III/NRG-GY024 phase 2 study is investigating the feasibility and safety of replacing IF lymphadenectomy with chemoradiation in patients with early-stage vulvar cancer with a macrometastasis and/or extracapsular extension in the sentinel node.70 # Panel Recommendations In the current version of the Guidelines, the section on principles of surgery has been updated to include management of mapping based on tumor location in reference to midline structures of the vulva. For appropriate individuals, the panel considers SLN mapping and biopsy of the IFLN basin to be a reasonable alternative approach to decrease postoperative morbidity while maintaining a low rate of groin recurrences.62,63,66 Candidates for SLN biopsy should have clinically/radiologically negative groin nodes, unifocal primary tumor less than 4 cm, and no history of previous vulvar surgery.65,66 Mapping and biopsy should be performed by a high-volume SLN surgeon using dual tracers (ie, radiocolloid and dye) to ensure the best detection rates.63,65 The panel recommends complete IF lymphadenectomy if no ipsilateral SLN is detected. If the ipsilateral SLN is positive, completion lymphadenectomy or treatment of the affected groin is warranted. The contralateral groin should be evaluated surgically and/or treated with EBRT. In select cases of a single, small-volume, unilateral, positive inguinal node with a well-lateralized small primary tumor and depth of invasion less than or equal to $5 \mathsf { m m }$ and with a clinically negative contralateral groin examination, a contralateral groin lymphadenectomy or radiation may be omitted.71 # Primary Treatment For the purposes of primary treatment, these guidelines provide recommendations by clinical stage, separating patients into those with early-stage (stage I; select stage II tumors), locally advanced (unresectable without removing proximal urethra/bladder/anus), and distant metastatic disease beyond the pelvis. # Early-Stage Disease After careful clinical evaluation and staging, the standard primary treatment of early-stage vulvar cancer is conservative, individualized tumor excision with IFLN evaluation.44,51,72-75 Clinicians should strive for primary tumor resection with oncologically appropriate margins of 1 to 2 cm if feasible.36,39,53,55 See Primary Tumor Resection and Lymph Node Evaluation in this discussion. Although there are no prospective data comparing radical local incision to radical vulvectomy, existing data from retrospective analyses do not demonstrate a difference in recurrence or survival outcomes.51,52 Surgical dissection and RT have been evaluated for treatment of the groin in early-stage disease. Limited data suggest that primary groin radiation # NCCN Guidelines Version 4.2024 Vulvar Cancer results in less morbidity than surgical dissection.76 However, surgical treatment of the groin (followed by tailored adjuvant RT if LN-positive) has been associated with lower groin recurrence rates and remains the preferred approach.77 Primary radiation may have some benefit for those unable to undergo surgery.78,79 # Panel Recommendations For stage I tumors with less than or equal to 1 mm depth of invasion, the panel recommends simple partial vulvectomy; IFLN evaluation is not required due to the low risk of LN metastasis in these patients.45,73,80-83 Patients should be observed following resection. If surgical pathology reveals greater than 1-mm invasion, additional surgery may be indicated. In treatment for patients with stage IB $( > 1 - \mathsf { m m }$ invasion) or select stage II tumors, primary treatment is dictated by tumor location. Patients with lateralized lesions located greater than or equal to 2 cm from the vulvar midline should undergo radical partial vulvectomy accompanied by ipsilateral IFLN evaluation.57,58,80 IF node evaluation can be performed through SLN biopsy or ipsilateral IF lymphadenectomy; the latter should be performed if no SLN(s) is/are detected. Adjuvant therapy is informed by primary tumor risk factors and nodal surgical pathology. Patients with anterior or posterior central vulvar lesions should undergo radical partial vulvectomy accompanied by bilateral IF node evaluation consisting of SLN biopsy or bilateral IF lymphadenectomy.51,58,80 IF lymphadenectomy is required on side(s) for which sentinel nodes are not detected. Adjuvant therapy is informed by primary tumor risk factors and nodal surgical pathology. For lateralized and near midline tumors with unilateral SLN metastasis, unilateral groin treatment by either IF lymphadenectomy or RT is acceptable. For midline tumors with unilateral SLN metastasis, unilateral groin treatment can be performed if the contralateral groin has negative sentinel node or negative IF lymphadenectomy.58,84 # Locally Advanced Disease Historically, locally advanced vulvar cancers were treated primarily with radical surgeries such as en bloc radical vulvectomy with bilateral IF lymphadenectomy or pelvic exenteration. These surgeries resulted in some cures, but also led to significant postoperative complications, loss of function, and reduced quality of life.24,85-87 Additionally, complete resection of locally advanced disease may be complicated by tumor fixed to vital organs or vessels, rendering the disease unresectable.88 A shift to multimodality treatment was explored to improve organ preservation and reduce surgical treatment morbidity.89 Preoperative RT was shown in some earlier studies to result in tumor debulking and reduce the extent of surgery required for locally advanced disease.88,90-93 Subsequently, borrowing on experience from advanced cervical and anal cancers, chemotherapy typically has been added as a “radiosensitizer” when radiation is delivered in patients with advanced disease. # Chemoradiation Research directly comparing treatment approaches for locally advanced vulvar cancers is limited. Data from small patient cohorts have shown a generally high response rate to chemoradiation among most patients with stage III/IVA disease, as well as the feasibility of resection for residual disease following chemoradiation. Following chemoradiation, at least partial tumor responses were noted among a wide majority of the patients in these cohorts,94-98 with several studies revealing complete tumor responses among more than 60% of the cohort.99-103 Primary chemoradiation may confer a survival benefit over primary RT in vulvar cancer. OS after primary chemoradiation was superior to OS following primary RT in a series of 54 patients with locally advanced disease.104 A similar survival benefit was reported in a study using NCDB data from patients who were not candidates for surgery, comparing cohorts who received primary chemoradiation $( \mathsf { n } = 9 9 9 )$ ) or primary RT $( { \mathsf n } =$ # NCCN Guidelines Version 4.2024 Vulvar Cancer 353). The chemoradiation cohort was younger with more advanced disease based on FIGO staging. Chemoradiation was associated with significantly higher 5-year OS than primary RT $4 9 . 9 \%$ vs. $2 7 . 4 \%$ , $P$ ${ < } 0 . 0 0 1 $ ) and multivariate analysis revealed a reduced hazard of death (hazard ratio [HR], 0.76; $9 5 \%$ CI, 0.63–0.91; $P = . 0 0 3 )$ .105 In the GOG 101 study, preoperative chemoradiation was examined in 73 patients with stage III/IV disease.96 The study investigated whether chemoradiation allowed for less radical surgery in patients with T3 tumors and avoidance of pelvic exenteration in patients with T4 tumors. Only $3 \%$ of patients (2/71) had residual unresectable disease following chemoradiation, and preservation of urinary and/or gastrointestinal (GI) continence was possible in $96 \%$ of patients (68/71). Two prospective studies from the GOG more closely examined the benefits of surgery after chemoradiation for patients with locally advanced disease. GOG 101 examined 46 patients with vulvar SCC and N2/N3 nodal involvement.106 Subsequent surgery was performed on 38 patients with resectable disease after chemoradiation with cisplatin/5-fluorouracil (5-FU). Local control of nodal disease was achieved in 36 of 37 patients and for the primary tumor in 29 of 38 patients. The GOG 205 study examined the feasibility of surgery after chemoradiation with cisplatin in 58 patients with T3/T4 tumors that were initially unresectable by radical vulvectomy.107 Complete clinical response was noted in $64 \%$ of patients (37 of 58), with pathologic complete response (pCR) in $78 \%$ (29 of 34) of patients undergoing surgical biopsy. Of the total population, approximately $50 \%$ achieved pCR after chemoradiation therapy. The high pCR rates have led many to believe that surgery can be avoided in patients with locally advanced tumors who achieve clinical complete responses. A phase II, multicenter, prospective trial evaluated treatment feasibility, percentage of locoregional control, survival, and toxicity after locoregional radiotherapy combined with sensitizing chemotherapy with capecitabine in 52 patients with T2/T3 tumors.108 Of the total patients, $58 \%$ had no evidence of disease at a median of 35 months. PFS was $58 \%$ , $51 \%$ , and $45 \%$ , and OS was $76 \%$ , $66 \%$ , and $52 \%$ at 1, 2, and 5 years, respectively. Most acute toxicity greater than or equal to grade 3 reported were related to skin/mucosa $( 5 4 \% )$ and pain $( 3 7 \% )$ . Late toxicity greater than or equal to grade 3 was reported for skin/mucosa $( 1 0 \% )$ , fibrosis $( 4 \% )$ , GI incontinence $( 4 \% )$ and stress fracture or osteoradionecrosis $( 4 \% )$ . An analysis of NCDB data (2004–2012) compared outcomes of 2046 females with locally advanced vulvar cancer who received primary radiation (RT or chemoradiation), or preoperative radiation (RT or chemoradiation) followed by surgery. Patients who underwent surgery after RT/chemoradiation had longer OS than patients who underwent primary RT/chemoradiation without subsequent resection $( 5 7 . 1 \%$ vs. $4 1 . 7 \%$ at 3 years, respectively; $P { \bf \Phi } < . 0 0 1 \mathrm { \cdot }$ ). However, multivariate analysis revealed a radiation dose-dependent effect, and survival was not significantly worse if the dose exceeded 55 Gy. With sufficient RT dose and concurrent chemotherapy, the primary RT cohort had comparable survival to the group who underwent lower-dose preoperative RT/chemoradiation followed by surgery.109 A 2011 Cochrane database review of the existing randomized controlled trial data on 141 females with locally advanced vulvar SCC revealed no difference in OS when comparing primary surgery to primary or neoadjuvant chemoradiation.110 However, the data did not allow for broad conclusions to be drawn regarding treatment-related quality of life and adverse events. An earlier Cochrane database review of five nonrandomized trials suggested that patients with unresectable primary disease and those requiring exenteration may benefit from neoadjuvant chemoradiation if disease was rendered resectable or requiring less radical surgery.111 # NCCN Guidelines Version 4.2024 Vulvar Cancer The combination regimen used for radiosensitization was most commonly cisplatin/fluorouracil,96,97,99,101,102 but also included fluorouracil/mitomycin $\mathsf { C } ^ { 2 9 5 , 9 8 , 1 0 3 }$ or single-agent therapy.100,107 The selection of radiosensitizing chemotherapy is often based on extrapolation of findings from cervical, anal, or head and neck cancer. # Panel Recommendations Patients with locally advanced tumors (unresectable without removing proximal urethra/bladder/anus) should undergo radiologic imaging to examine potential nodal involvement. The panel recommends that all patients with locally advanced disease receive EBRT with concurrent chemotherapy. IF lymphadenectomy may be used to assess nodal metastasis and inform RT treatment planning. If IF lymphadenectomy is not performed, or if positive IFLNs are found during the procedure, EBRT coverage should include the primary tumor, groin, and pelvic nodes. If no positive nodes are detected following IF lymphadenectomy, EBRT with concurrent chemotherapy should be provided with RT coverage of the primary tumor, with or without selective coverage of IFLNs. Patients with radiographically suspicious nodes (including those with pelvis-confined metastases) should be evaluated for IF lymphadenectomy. If IF lymphadenectomy is not performed, fine-needle aspiration (FNA) of enlarged LNs can be considered. Patients should receive EBRT and concurrent chemotherapy; EBRT coverage should include the primary tumor, IF nodes, and pelvic nodes. Selective IFLN RT coverage can be considered if lymphadenectomy reveals no positive LNs. Agents recommended by the panel for chemoradiation include cisplatin (preferred) and carboplatin if the patient is intolerant to cisplatin. The panel also lists cisplatin/fluorouracil under “other recommended regimens.”112 In addition, if cisplatin or carboplatin are unavailable, the panel has included capecitabine/mitomycin, gemcitabine, and paclitaxel as options that may be considered under the “other recommended regimens” category. These radiosensitizers were added based on a few early-phase studies extrapolated from cervical cancer that have shown their efficacy and tolerability when administered concomitantly with radiation.113-116 # Metastasis Beyond the Pelvis The NCCN Panel recommends primary treatment options for extra-pelvic metastatic disease including EBRT for control of locoregional disease and symptom palliation, and/or systemic therapy. Best supportive care is also an alternative in this setting. Data on systemic treatments for vulvar cancer with distant metastasis are extremely limited.117-119 Treatment regimens are often extrapolated from agents that are active against advanced cervical cancer. See the section on Systemic Therapy for Recurrent/Metastatic Disease in this discussion for information about specific regimens. # Adjuvant Therapy Due to the rarity of vulvar cancer, especially advanced disease, prospective randomized trials on adjuvant therapy are extremely limited. Much of the common adjuvant treatment approaches have been drawn from studies describing heterogenous, often-individualized treatment approaches, or extrapolated from effective adjuvant therapies for cervical and anal cancers. # Adjuvant RT and Chemoradiation Although it is commonly accepted that LN involvement is a critical prognostic factor in vulvar cancer, the optimal patient selection criteria and adjuvant therapy regimens to address nodal disease continue to be determined.120 As previously emphasized, it is crucial to prevent metachronous groin relapses, as these often prove refractory to secondary management and are often ultimately fatal. # NCCN Guidelines Version 4.2024 Vulvar Cancer Early randomized trial data on adjuvant RT were published from GOG 37, which enrolled 114 patients with IF node-positive vulvar cancer after radical vulvectomy and bilateral IF lymphadenectomy.121,122 Patients were randomized to receive pelvic lymphadenectomy or adjuvant RT to the groin/pelvis. Two- and 6-year survival were superior in the adjuvant RT group, but the most significant survival benefits were observed among patients with greater than or equal to 2 positive IF nodes or those with fixed ulcerative IF nodes. Long-term follow-up (median $= 7 4$ months) revealed higher rates of disease-related death for the group receiving pelvic node resection compared with pelvic/groin RT ( $5 1 \%$ vs. $2 9 \%$ ; HR, 0.49; $P = . 0 1 5$ ).122 A study using SEER-Medicare–linked data examined outcomes for 444 older patients (aged $\mathtt { \ge 6 6 }$ years; median age 78) with node-positive vulvar cancer who underwent adjuvant RT. Compared to surgery alone, better disease outcomes were associated with adjuvant RT when the following metrics were met: completion of at least 20 fractions, treatment duration of less than 8 weeks, and less than 1 week of intra-treatment break. However, only half of the cohort that received RT met these treatment benchmarks.123 There are conflicting data on the benefit of adjuvant RT in patients with a single positive LN. Some studies in patients with a single positive LN have reported no benefit of adjuvant RT in this setting. 124,125 However, examination of SEER data from 208 patients with stage III, single nodepositive vulvar SCC revealed significant improvements in 5-year DSS with the addition of adjuvant RT compared with those receiving no RT.126 The survival benefit was more pronounced among patients who underwent less extensive lymphadenectomy (≤12 nodes excised). In a case series of 157 patients, disease-free survival (DFS) at 2 years was $8 8 \%$ in node-negative patients, but $60 \%$ , $43 \%$ , and $2 9 \%$ in patients with 1, 2, and greater than 2 positive nodes. The number of involved nodes negatively impacted prognosis in patients receiving no adjuvant RT, but among patients receiving adjuvant RT to the groin/pelvis, the number of metastatic nodes did not harm prognosis.127 The large, multicenter, retrospective AGO-CaRE-1 study reported significant survival benefits in node-positive patients receiving adjuvant RT or chemoradiation (3-year PFS of $3 9 . 6 \%$ vs. $2 5 . 9 \%$ , $P = . 0 0 4$ ; 3-year OS of $5 7 . 7 \%$ vs. $5 1 . 4 \% . { \sf P } =$ .17).125 RT coverage most commonly included the groin and pelvis $\pm$ coverage of the vulva, with a smaller subset receiving coverage to the groin ± vulvar coverage. Again, the benefits of adjuvant RT were most clear for patients with greater than or equal to 2 positive LNs. An examination of data from the NCDB supported the addition of chemotherapy to RT in the adjuvant setting. Among 1797 patients with node-positive vulvar cancer, $2 6 . 3 \%$ received adjuvant chemotherapy in addition to RT after primary surgery. Adjuvant chemotherapy increased survival time and reduced mortality risk (44 months vs. 29.7 months; HR, 0.62; $9 5 \%$ CI, 0.48–0.79; $\pmb { P } < . 0 0 \hat { \imath }$ ).128 Based on SEER data, outcomes of adjuvant RT were examined in 519 patients aged $\mathtt { \ge 6 6 }$ years who received primary surgery for node-positive vulvar cancer. Adjuvant RT was associated with improved OS over surgery alone in this cohort of older females (HR, 0.71; $9 5 \%$ CI, 0.57–0.88; $P = . 0 0 2 \mathrm { \Omega }$ ) along with a trend towards improved cause-specific survival (CSS) (HR, 0.79; $9 5 \%$ CI, 0.59– 1.05; $P =$ .11).129 Parameters for delivery of RT were important among this cohort; 3-year OS and CSS were significantly improved in patients who received greater than or equal to 20 fractions (3-year OS: $34 \%$ vs. $26 \%$ , $P$ = .008; 3-year CSS: $48 \%$ vs. $3 7 \%$ , $ { \boldsymbol { P } } = . 0 3 )$ . Research has also examined the role of adjuvant RT to the primary tumor site. Studies have indicated that isolated primary site recurrences may be addressed effectively by subsequent surgery, or that late recurrences may actually represent secondary tumors. The benefit of adjuvant RT to the # NCCN Guidelines Version 4.2024 Vulvar Cancer vulva in patients with close/positive surgical margins has also been investigated.130 Among patients with close/positive surgical margins at the primary site, 5-year OS was significantly improved by the addition of adjuvant RT to the primary site $( 6 7 . 6 \%$ vs. $2 9 \%$ ; HR, 0.36; ${ \cal P } = . 0 3 8 )$ . Patients receiving adjuvant RT for close/positive margins had a similar $5 -$ year OS to those with negative margins. A retrospective study examined the association of RT dose with vulvar recurrence, revealing lower risk of recurrence in patients receiving doses of greater than or equal to 56 Gy compared with those receiving less than or equal to 50.4 Gy.54 # Panel Recommendations For patients with early-stage disease (stage I) and a depth of invasion less than or equal to $1 \mathsf { m m }$ , observation is appropriate following primary surgery if negative margins are present, and the patient does not have any primary risk factors. Risk factors that may require adjuvant EBRT to the primary site are close tumor margins, LVSI, tumor size, depth of invasion, and pattern of invasion (spray or diffuse). Those with positive margins should undergo re-excision, or if unresectable without removing proximal urethra/bladder/anus, adjuvant EBRT. After re-excision, the panel recommends that patients with negative margins undergo observation or risk-factor-dependent EBRT; those with continued positive margins after re-excision should all undergo EBRT.130 For patients with stage IB $( > 1 \mathsf { m m }$ invasion) and stage II disease, surgical evaluation of the groin is indicated in addition to primary site surgery. Nodal status is an important determinant of adjuvant therapy recommendations. For patients with a negative SLN or negative IFLNs, observation can be considered.62,131-134 Adjuvant therapy is warranted if the SLN or IFLNs contain metastases. Adjuvant therapy for patients with SLN involvement includes: 1) RT $\pm$ concurrent chemotherapy; or 2) completion IF lymphadenectomy followed by EBRT $\pm$ concurrent chemotherapy. Adjuvant therapy for patients who have positive IFLNs detected during IF lymphadenectomy includes EBRT (category 1) $\pm$ concurrent chemotherapy. Chemoradiation is strongly recommended for patients with two or more positive IFLNS or a single IFLN with greater than 2-mm metastasis.121,125 For patients with locally advanced disease, adjuvant therapy decisions should be made based on clinical evaluation of treatment response after EBRT with concurrent chemotherapy (potentially preceded by IF lymphadenectomy). These guidelines provide adjuvant therapy recommendations based on whether patients are clinically negative or positive for residual tumor at the primary site and in the groin. Patients with no clinical evidence of residual tumor after EBRT with concurrent chemotherapy should undergo surveillance. Biopsy of the tumor bed can also be considered to confirm pCR. Patients with residual tumor should be considered for resection. In the case of positive margins on resection, providers should consider additional surgery, additional EBRT, and/or systemic therapy, or best supportive care. For unresectable residual disease, providers should consider additional EBRT and/or systemic therapy, or best supportive care. # Surveillance Most recurrences of vulvar cancer occur within the first 1 to 2 years, although recurrences beyond 5 years have been observed in a significant subset of patients.135,136 Accordingly, long-term follow-up is indicated. Definitive data on an optimal surveillance strategy are lacking.137 However, the panel concurs with the Society of Gynecologic Oncology (SGO) recommendations for post-treatment surveillance.138 The recommended surveillance is based on the patient’s risk for recurrence and personal preferences. History and physical examination are recommended every 3 to 6 months for 2 years, every 6 to 12 months for another 3 to 5 years, and then annually (see Surveillance in the NCCN Guidelines for Vulvar Cancer). Patients with high-risk disease can be # NCCN Guidelines Version 4.2024 Vulvar Cancer assessed more frequently (eg, every 3 months for the first 2 years) than patients with low-risk disease (eg, every 6 months). Annual cervical/vaginal cytology tests, which may include HPV testing, can be considered as indicated for detection of lower genital tract dysplasia, although its value in detecting recurrent cancers is limited and the likelihood of detecting asymptomatic recurrence is low. In addition, the accuracy of these tests may be affected in patients who have received pelvic radiation as radiotherapy can induce changes in cellular morphology that may result in cytological misdiagnosis. Imaging (ie, chest/abdomen/pelvis CT, neck/chest/abdomen/pelvis/groin FDG-PET/CT, pelvic MRI) and laboratory testing (ie, CBC, blood urea nitrogen [BUN], creatinine) are recommended as indicated by suspicious examination findings or symptoms of recurrence. Patient education regarding symptoms suggestive of recurrence or vulvar dystrophy is recommended, as well as periodic self-examination. Patients should also be counseled on healthy lifestyle, obesity, nutrition, exercise, and sexual health (including vaginal dilator use and lubricants/moisturizers). For information on these and other issues related to survivorship (ie, pain/neuropathy, fear of recurrence, depression), see the Gynecologic Survivorship section at the end of this document and the NCCN Guidelines for Survivorship (available at www.NCCN.org). Smoking cessation and abstinence should be encouraged; see the NCCN Guidelines for Smoking Cessation (available at www.NCCN.org). If persistent or recurrent disease is suspected, patients should be evaluated using additional imaging studies and biopsy to confirm local and/or distant recurrence as outlined in the next section. # Treatment for Recurrent Disease A multicenter case series evaluated the rate and patterns of recurrence among 502 patients, 187 $( 3 7 \% )$ of who developed a recurrent vulvar SCC. Just over half of recurrences were vulvar $( 5 3 . 4 \% )$ , followed by inguinal $( 1 8 . 7 \% )$ , multi-site $( 1 4 . 2 \% )$ , distant $( 7 . 9 \% )$ , and pelvic $( 5 . 7 \% )$ . Survival rates at 5 years were $60 \%$ for vulvar recurrence, $2 7 \%$ for inguinal/pelvic, $1 5 \%$ for distant sites, and $14 \%$ for multiple sites.31 While localized vulvar recurrences can be successfully addressed with subsequent surgery, some studies have suggested higher risk of cancer-related death. Given the rarity of primary vulvar cancer, data for treating recurrences are even scarcer and no clear standard of care exists.139 Treatment approach and patient outcomes depend on the site and extent of recurrent disease.139,140 Isolated local recurrences can often be treated successfully with radical local excision,31,136,141 and RT ± chemotherapy provided some degree of DFS in several studies.92,93 A retrospective review evaluated patients with locoregional recurrences treated via chemoradiation, neoadjuvant chemotherapy, or RT alone. Five-year DFS and OS were around $20 \%$ ; however, those with single-site recurrence and lesions less than or equal to 3 cm who received RT dose at or above 64.8 Gy remained disease-free at 5 years.142 Conversely, another series noted decline in survival with the presence of nodal metastases, tumors greater than 3 cm, or high-grade lesions.143 For central/large recurrences, pelvic exenteration has been shown to prolong survival when performed on carefully selected patients.85,86,144 Regardless of treatment approach, prognosis for nodal recurrences was very poor.136,141,143,145,146 # Panel Recommendations If recurrence is suspected, the panel recommends workup for metastatic disease with imaging studies to include chest/abdominal/pelvis CT or neck/chest/abdomen/pelvis/groin FDG-PET/CT. Biopsy can be considered to confirm local and/or distant metastasis. Treatment recommendations for recurrent disease are outlined according to site of recurrence and previous therapies received. # NCCN Guidelines Version 4.2024 Vulvar Cancer # Vulva-Confined Recurrence If recurrence is clinically limited to the vulva with clinically negative nodes, and the patient did not receive prior RT, the panel recommends surgical and RT treatment pathways. Surgical recommendations include partial or total radical vulvectomy $\pm$ unilateral or bilateral IF lymphadenectomy. Pelvic exenteration can be considered for select cases with a central recurrence. Additional therapy is indicated by margin status and nodal status. Observation or EBRT is appropriate for negative margins and nodes. In patients with positive margins but no evidence of nodal involvement, options include re-excision or EBRT ± brachytherapy and/or concurrent chemotherapy (category 2B for chemotherapy). EBRT ± concurrent chemotherapy is recommended for patients with negative surgical margins but surgically positive IFLNs. In patients with both positive margins and surgically positive IFLNs, the panel recommends EBRT ± brachytherapy, concurrent chemotherapy, and/or re-excision as needed/appropriate. Nonsurgical therapy for recurrence includes EBRT ± brachytherapy and/or concurrent chemotherapy. Resection can be considered for patients with gross residual tumor. When feasible, partial or total radical vulvectomy is also indicated for patients with vulva-confined recurrence who were previously irradiated. After treatment for recurrence, patients should undergo surveillance. # Confirmed Nodal or Distant Recurrence For patients with multiple pelvic nodes, distant metastasis, or prior pelvic EBRT, the panel recommends systemic therapy and/or selective EBRT (if feasible) or palliative/best supportive care. If recurrence is limited to IF/pelvic LNs, resection should be considered for clinically enlarged and suspicious nodes. Resection followed by systemic therapy can be considered for select cases of isolated IF/pelvic recurrence that were previously irradiated. If no prior RT was given, then EBRT $\pm$ concurrent chemotherapy is appropriate. All patients should undergo surveillance following treatment for recurrence. # Systemic Therapy for Recurrent/Metastatic Disease No standard systemic therapy regimens exist for treating advanced or recurrent/metastatic disease. Several reports provide anecdotal evidence for various regimens, at times extrapolating from regimens with known activity in advanced cervical and anal cancers and other SCCs. See the review articles by Reade et al and Mahner et al for an overview of systemic therapies that have been utilized to treat vulvar SCC.112,139 Preferred, first-line regimens recommended by the panel for treating advanced, recurrent/metastatic disease include cisplatin/paclitaxel, carboplatin/paclitaxel, and cisplatin/paclitaxel/bevacizumab. Carboplatin/paclitaxel/bevacizumab is included as a category 2B regimen under the preferred, first-line options. Other recommended regimens include single-agents cisplatin and carboplatin. Cisplatin is a commonly employed radiosensitizing agent in locally advanced vulvar cancer, and is recommended for single-agent or combination chemotherapy for treatment of metastatic disease.88,147 Cisplatin/paclitaxel and cisplatin/paclitaxel/bevacizumab are preferred regimens based on extrapolation of randomized phase III trial data in advanced or recurrent/metastatic cervical cancer.148,149 Carboplatin is an alternative platinum agent active in metastatic cervical cancer that can be used as a single agent or in combination. A small series in 6 patients with advanced or recurrent/metastatic vulvar cancer noted limited clinical benefit of the combination regimen;117 however, it has been included in these guidelines based on data from patients with advanced or recurrent/metastatic cervical cancer that suggest noninferiority to cisplatin.150,151 # NCCN Guidelines Version 4.2024 Vulvar Cancer For the second-line or subsequent treatment, the NCCN Panel has listed paclitaxel, erlotinib (category 2B for erlotinib), and cisplatin/gemcitabine (category 2B) as options. Single-agent paclitaxel was modestly active in a phase II trial of 31 females with advanced, recurrent/metastatic vulvar cancer, generating a response rate of $14 \%$ and PFS of 2.6 months.118 Erlotinib was studied in a phase II trial that included a cohort of females with metastatic disease. Short-duration responses were observed, with partial responses and stable disease noted in $2 7 . 5 \%$ and $40 \%$ of enrolled patients, respectively.119 Cisplatin/gemcitabine is also included as a category 2B option extrapolating from cervical cancer data; however, findings from case reports have been mixed.152,153 In the recent Guidelines update, the NCCN Panel also included cemiplimab as a second-line or subsequent therapy option under “other recommended regimens.” The recommendation of cemiplimab has been extrapolated from its efficacy shown in cervical cancer and in advanced cutaneous SCC. In a phase 2 trial with patients with metastatic cutaneous SCC, a response was observed in 28 out of 59 patients.154 Median followup was 7.9 months. The phase 3, randomized, Empower-Cervical-1 clinical trial evaluated the efficacy of cemiplimab or investigator’s choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) in patients with recurrent or metastatic cervical cancer who have progressed on prior therapy. The trial enrolled 608 patients who had previously received one or more lines of systemic therapy for recurrence; they were randomized to either receive cemiplimab or chemotherapy. The median OS and PFS were significantly longer in the cemiplimab arm than in the control arm (12 months vs. 8.5 months; HR, 0.69; $9 5 \%$ CI, 0.56– 0.84; $P < . 0 0 1$ and 2.8 vs. 2.9 months; HR, 0.75; $9 5 \%$ CI, 0.63–0.89; $P <$ .001, respectively). Sixteen percent of the patients in the test arm achieved an OR $9 5 \%$ CI, 12.5–21.1) as compared to $6 . 3 \%$ $9 5 \%$ CI, 3.8– 9.6) in the chemotherapy arm.155 Biomarker-directed systemic therapies are an emerging class of treatments that may be useful in patients with advanced or recurrent/metastatic cancer. Monoclonal antibodies that function as programmed cell death protein 1 (PD-1) inhibitors are one such example of these treatments. PD-1 functions as an immune checkpoint protein that promotes antitumor T-cell activity. Many tumors, including vulvar cancer, are known to overexpress PD-L1, which disrupts PD-1 function. Thus, blocking PD-L1/PD-1 binding restores T-cell–mediated antitumor activity.156-158 An estimated $10 \%$ to $50 \%$ of vulvar cancers express PDL1. 159,160 Pembrolizumab is one such PD-1 inhibitor that may be effective in patients with vulvar cancer. A case study was published of a single patient with recurrent vulvar SCC who was treated with single-agent pembrolizumab, as part of a phase II basket clinical trial to evaluate efficacy and safety,161 and had $30 \%$ reduction in tumor lesions before the treatment was discontinued due to grade 3 mucositis.162 The single-arm phase II KEYNOTE-158 basket trial (NCT02628067) measured response to pembrolizumab monotherapy in patients with advanced solid tumors that progressed after standard-of-care systemic therapy.163 Among 101 patients enrolled in the vulvar SCC cohort, median follow-up was 36 months. The overall response rate (ORR) was $10 . 9 \%$ overall, $9 . 5 \%$ in the PD-L1–positive population, and $2 8 . 6 \%$ among the PD-L1–negative population. Median PFS and OS were 2.1 and 6.2 months, respectively.164 Pembrolizumab is FDA-approved for recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 $( \mathsf { C P S } \ge 1 )$ ). The panel has added pembrolizumab as a recommended second-line, useful in certain circumstances option for PDL1–positive advanced or recurrent/metastatic vulvar cancer. # NCCN Guidelines Version 4.2024 Vulvar Cancer Monoclonal antibodies targeting the PD-1 pathway may also be effective in tumors that have high TMB (TMB-H) or are deficient in MMR (dMMR)/have high levels of MSI (MSI-H). Of the 71 patients in the KEYNOTE-158 trial with advanced vulvar cancer, 12 had TMB-H tumors. The ORR for TMB-H vulvar cancer was approximately $1 7 \%$ , while the ORR for non–TMB-H disease was $3 . 4 \%$ .165 The KEYNOTE-158 study authors also analyzed pembrolizumab response in 233 enrolled patients with non-colorectal MSI-H/dMMR tumors, one of which had vulvar cancer. ORR for the entire cohort was $34 . 3 \%$ . Median PFS was 4.1 months and median OS was 23.5 months.166 Based on these data, the FDA expanded pembrolizumab’s approval for treatment of TMB-H and MSI-H/dMMR tumors that progressed after prior therapy, regardless of tumor type.167,168 Based on these additional data/FDA approvals, the panel also recommends pembrolizumab as a second-line, useful in certain circumstances option for patients with advanced or recurrent/metastatic vulvar cancer whose tumors are MSI-H/dMMR or TMB-H. Nivolumab is another PD-1 inhibitor shown to have some efficacy in certain patients with vulvar cancer. The single-arm phase I/II CheckMate 358 trial (NCT02488759) measured response to nivolumab monotherapy in a small cohort of 5 patients with recurrent or metastatic vaginal or vulvar cancer who were HPV-positive or had an unknown HPV status. The 12- and 18-month OS rates for the combined cohort were $40 \%$ and $20 \%$ , respectively; 6-month PFS was $40 \%$ .169 Based on these data, the panel added nivolumab as a second-line, useful in certain circumstances option for HPV-related advanced or recurrent/metastatic vulvar cancer. NTRK gene fusions lead to constitutively active tropomyosin receptor kinases (TRKs), which in turn promote development and progression of cancer. Approximately $0 . 3 \%$ of solid tumors express NTRK gene fusions, although expression varies widely by cancer type.170 Entrectinib and larotrectinib are broadly active TRK inhibitors that are effective in patients with a variety of advanced or metastatic NTRK fusion-positive solid tumors.170-172 In a primary analysis, the efficacy and safety of larotrectinib was reported in 55 patients enrolled in three clinical studies who had locally advanced or metastatic tumors with NTRK gene fusions and had progressed on standard chemotherapy received previously.171 The three clinical trials included a phase 1 dose-finding study in adults, phase 1/2 dose-finding study in the pediatric population, and a phase 2, single-arm, basket trial. The ORR of larotrectinib in these patients was $7 5 \%$ $9 5 \%$ CI, $6 1 \% - 8 5 \%$ ), with $2 2 \%$ complete response and $53 \%$ partial response with median duration of response and PFS not reached at the time. In a longterm follow-up analysis, out of 153 patients, 121 patients $7 9 \%$ ; $9 5 \%$ CI, 72–85) had objective response with $16 \%$ having a complete response, $6 3 \%$ having a partial response, and $12 \%$ having stable disease. The median duration of response was 35.2 months (22.8–NE) and the median PFS was 28.3 months.173 Similarly, entrectinib showed a durable and clinically meaningful response in 54 patients with advanced/metastatic NTRK gene fusion tumors enrolled in three phase $_ { 1 / 2 }$ clinical trials with $5 7 . 4 \%$ ORR, 10.4-month median duration of response, and 11.2-month median PFS.170 In a long-term efficacy and safety analysis in 121 patients at median follow-up of 25.8 months, $61 \%$ reported complete or partial responses, and median duration of response was 20 months $( 9 5 \%$ CI, 10.1–19.9). Both larotrectinib and entrectinib are FDA-approved for NTRK gene fusion solid tumors for patients who have progressed following treatment or have no satisfactory standard therapy. The NCCN Guidelines for Vulvar Cancer recommend larotrectinib and entrectinib as a secondline or subsequent, useful in certain circumstances option for NTRK gene fusion-positive tumors and recently changed the category of evidence from category 2B to category 2A. # Gynecologic Survivorship Treatment for gynecologic cancer typically involves surgery, chemotherapy, hormone therapy, RT, and/or immunotherapy, which may # NCCN Guidelines Version 4.2024 Vulvar Cancer cause acute, short-term, and long-term toxicities. Surgical approaches may be extensive and cause adhesions to form, which in turn may cause pain and contribute to the development of small bowel obstruction, urinary or gastrointestinal complications (eg, incontinence, diarrhea), pelvic floor dysfunction (manifested by a variety of urinary, bowel, and/or sexual effects), and lymphedema.174,175 Chemotherapy agents vary, though commonly used regimens may pose a significant risk of neurotoxicity, cardiac toxicity, cognitive dysfunction, and the development of hematologic cancers.176 Long-term estrogen deprivation may cause symptoms such as hot flashes, vaginal dryness, and bone loss. RT may cause long-term complications (eg, fibrosis, stenosis, vulvovaginal atrophy)177,178 and may predispose patients to subsequent cancers of the skin, subcutaneous tissue, and/or underlying organs that are proximal to the radiation field.179 Prior pelvic RT may contribute to bone loss and increase the risk of pelvic fractures. Consideration should be given to bon density testing and prophylactic use of bisphosphonates, particularly in patients with osteoporosis. Use of immunotherapy agents in gynecologic cancers is emerging, and to date, long-term effects of these treatments are unknown.180,181 Following completion of treatment, all gynecologic cancer survivors should receive regular general medical care that focuses on managing chronic diseases (eg, depression, diabetes, hypertension), monitoring cardiovascular risk factors, receiving recommended vaccinations, and encouraging adoption of a healthy lifestyle (eg, promoting exercise, smoking cessation).182,183 In order to assess the late and long-term effects of gynecologic cancers, clinicians should comprehensively document the patient’s history, including prior treatment history, and conduct a thorough physical examination and provide any necessary imaging and/or laboratory testing.183 As most treatments for gynecologic cancers will cause sexual dysfunction, early menopause, and infertility, special attention to the resultant medical and psychosocial implications is needed. All patients, whether sexually active or not, should be asked about genitourinary symptoms, including vulvovaginal dryness.184 Post-radiation use of vaginal dilators and moisturizers is recommended.177,185 For treatment-related menopause, hormone therapy should be considered. Psychosocial effects may include psychological (eg, depression, anxiety, fear of recurrence, altered body image), financial (eg, return to work, insurance concerns), and interpersonal (eg, relationships, sexuality, intimacy).183 Patients should be referred to appropriate specialty providers (eg, physical therapy, pelvic floor therapy, sexual therapy, psychotherapy) as needed, based on prior treatment history and assessed risk of developing late effects and/or existing concerns. Communication and coordination with all clinicians involved in the care of survivors, including primary care clinicians, is critical.183,186 Providing survivors with a summary of their treatment and recommendations for follow-up is also recommended. To this end, the SGO has developed templates for gynecologic cancer-specific Survivorship Care Plans to aid survivors and their clinicians in summarizing cancer history, treatments received, possible side effects, and recommended follow-up.187 # NCCN Guidelines Version 4.2024 Vulvar Cancer # References 1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17-48. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36633525. 2. SEER Cancer Statistics Factsheets: Vulvar Cancer. Bethesda, MD: National Cancer Institute; Available at: http://seer.cancer.gov/statfacts/html/vulva.html. Accessed November 8, 2023. 3. Tergas AI, Tseng JH, Bristow RE. 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Available at: https://www.ncbi.nlm.nih.gov/pubmed/29466156. 172. Hong DS, Bauer TM, Lee JJ, et al. Larotrectinib in adult patients study. Ann Oncol 2019;30:325-331. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30624546. with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol 2020;21:531-540. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32105622. 174. Dessources K, Aviki E, Leitao MM, Jr. Lower extremity lymphedema in patients with gynecologic malignancies. Int J Gynecol Cancer 2020;30:252-260. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31915136. 175. Bona AF, Ferreira KR, Carvalho RBM, et al. Incidence, prevalence, and factors associated with lymphedema after treatment for cervical cancer: a systematic review. Int J Gynecol Cancer 2020;30:1697-1704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32863276. 176. Loprinzi CL, Lacchetti C, Bleeker J, et al. Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update. J Clin Oncol 2020;38:3325-3348. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32663120. 177. Stahl JM, Qian JM, Tien CJ, et al. Extended duration of dilator use beyond 1 year may reduce vaginal stenosis after intravaginal high-doserate brachytherapy. Support Care Cancer 2019;27:1425-1433. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30187220. 178. Park HS, Ratner ES, Lucarelli L, et al. Predictors of vaginal stenosis after intravaginal high-dose-rate brachytherapy for endometrial carcinoma. Brachytherapy 2015;14:464-470. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25887343. 179. Dracham CB, Shankar A, Madan R. Radiation induced secondary malignancies: a review article. Radiat Oncol J 2018;36:85-94. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29983028. 180. Borella F, Preti M, Bertero L, et al. Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review. Int J Mol Sci 2020;22. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33375467. 181. Schepisi G, Casadei C, Toma I, et al. Immunotherapy and Its Development for Gynecological (Ovarian, Endometrial and Cervical) Tumors: From Immune Checkpoint Inhibitors to Chimeric Antigen Receptor (CAR)-T Cell Therapy. Cancers (Basel) 2021;13. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33671294. 182. Lin KY, Frawley HC, Denehy L, et al. Exercise interventions for patients with gynaecological cancer: a systematic review and metaanalysis. Physiotherapy 2016;102:309-319. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27553642. 183. Nekhlyudov L, Mollica MA, Jacobsen PB, et al. Developing a Quality of Cancer Survivorship Care Framework: Implications for Clinical Care, Research, and Policy. J Natl Cancer Inst 2019;111:1120-1130. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31095326. 184. Bober SL, Reese JB, Barbera L, et al. How to ask and what to do: a guide for clinical inquiry and intervention regarding female sexual health after cancer. Current Opinion in Supportive and Palliative Care 2016;10. Available at: https://journals.lww.com/cosupportiveandpalliativecare/Fulltext/2016/03000/How_to_ask_and_what_ to_do__a_guide_for_clinical.12.aspx. 185. Damast S, Jeffery DD, Son CH, et al. Literature Review of Vaginal Stenosis and Dilator Use in Radiation Oncology. Pract Radiat Oncol 2019;9:479-491. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31302301. 186. Campbell G, Thomas TH, Hand L, et al. Caring for Survivors of Gynecologic Cancer: Assessment and Management of Long-term and Late Effects. Semin Oncol Nurs 2019;35:192-201. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30867102. 187. SGO/FWC Survivorship Toolkit. Available at: https://www.sgo.org/resources/survivorship-toolkit/. Accessed November 8, 2023.	None	None	None
7f65054d003b4e7bb2a183a93038b68a	NCCN临床实践指南	子宫肿瘤	# NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) # Uterine Neoplasms Version 3.2025 — March 7, 2025 NCCN.org NCCN recognizes the importance of clinical trials and encourages participation when applicable and available. Trials should be designed to maximize inclusiveness and broad representative enrollment. NCCN Guidelines for Patients® available at www.nccn.org/patients # NCCN Guidelines Version 3.2025 Uterine Neoplasms \Nadeem R. Abu-Rustum, MD Ω/Chair Memorial Sloan Kettering Cancer Center \Susana M. Campos, MD, MPH, MS †/ Vice Chair Dana-Farber/Brigham and Women’s Cancer Center Sudha Amarnath, MD $\ S$ Case Comprehensive Cancer Center/ University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute Rebecca Arend, MD Ω O'Neal Comprehensive Cancer Center at UAB Emma Barber, MD Ω Robert H. Lurie Comprehensive Cancer Center of Northwestern University Kristin Bradley, MD $\ S$ University of Wisconsin Carbone Cancer Center Rebecca Brooks, MD Ω UC Davis Comprehensive Cancer Center Junzo Chino, MD $\ S$ Duke Cancer Institute Hye Sook Chon, MD Ω Moffitt Cancer Center Marta Ann Crispens, MD Ω Vanderbilt-Ingram Cancer Center Shari Damast, MD $\ S$ Yale Cancer Center/ Smilow Cancer Hospital Christine M. Fisher, MD, MPH $\ S$ University of Colorado Cancer Center Peter Frederick, MD Ω Roswell Park Comprehensive Cancer Center David K. Gaffney, MD, PhD $\ S$ Huntsman Cancer Institute at the University of Utah Stephanie Gaillard, MD, PhD † Johns Hopkins Kimmel Cancer Center Robert Giuntoli II, MD Ω Abramson Cancer Center at the University of Pennsylvania Scott Glaser, MD $\ S$ City of Hope National Medical Center Brooke E. Howitt, $\ M \mathbf { D } \neq$ Stanford Cancer Institute Lisa Landrum, MD, PhD Ω Indiana University Melvin and Bren Simon Comprehensive Cancer Center Jayanthi Lea, MD Ω UT Southwestern Simmons Comprehensive Cancer Center Nita Lee, MD, MPH Ω The UChicago Medicine Comprehensive Cancer Center Gina Mantia-Smaldone, MD Ω Fox Chase Cancer Center Andrea Mariani, MD Ω Mayo Clinic Comprehensive Cancer Center David Mutch, MD Ω Siteman Cancer Center at Barnes Jewish Hospital and Washington University School of Medicine Christa Nagel, MD Ω The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute Larissa Nekhlyudov, MD, MPH Þ Dana-Farber/Brigham and Women’s Cancer Center # Karina Nieto, MD $\ S$ Case Comprehensive Cancer Center/ University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute Chika Nwachukwu, MD, PhD $\ S$ UC San Diego Moores Cancer Center Mirna Podoll, MD ≠ Vanderbilt-Ingram Cancer Center Kerry Rodabaugh, MD Ω Fred & Pamela Buffett Cancer Center Ritu Salani, MD, MBA Ω UCLA Jonsson Comprehensive Cancer Center John Schorge, MD Ω St. Jude Children's Research Hospital/ The University of Tennessee Health Science Center Scott Schuetze, MD, PhD †/Liaison University of Michigan Rogel Cancer Center Jean Siedel, DO, MS Ω University of Michigan Rogel Cancer Center Rachel Sisodia, MD Ω Mass General Cancer Center Pamela Soliman, MD, MPH Ω The University of Texas MD Anderson Cancer Center Stefanie Ueda, MD Ω UCSF Helen Diller Family Comprehensive Cancer Center Renata Urban, MD Ω Fred Hutchinson Cancer Center Emily Wyse ¥ Patient advocate NCCN Nicole McMillian, MS Vaishnavi Sambandam, PhD Ω Gynecologic oncology Þ Internal medicine † Medical oncology ≠ Pathology ¥ Patient advocacy § Radiotherapy/Radiation oncology \Discussion Section Writing Committee # NCCN Guidelines Version 3.2025 Uterine Neoplasms NCCN Uterine Neoplasms Panel Members Summary of the Guidelines Updates Uterine Neoplasms Uterine Neoplasms (UN-1) # Endometrial Carcinoma Disease Limited to the Uterus (ENDO-1) Suspected or Gross Cervical Involvement (ENDO-2) Suspected Extrauterine Disease (ENDO-3) Adjuvant Treatment for Surgically Staged Disease (ENDO-4), (ENDO-5), (ENDO-6) Incompletely Surgically Staged (ENDO-7) Criteria for Considering Fertility-Sparing Options (ENDO-8) Surveillance (ENDO-9) Locoregional Recurrence (ENDO-10) Serous Carcinoma (ENDO-11) Clear Cell Carcinoma (ENDO-12) Undifferentiated/Dedifferentiated Carcinoma (ENDO-13) Carcinosarcoma (ENDO-14) Principles of Pathology and Molecular Analysis (ENDO-A) Principles of Imaging (ENDO-B) Principles of Evaluation and Surgical Staging (ENDO-C) Systemic Therapy for Endometrial Carcinoma (ENDO-D) # Uterine Sarcoma Diagnosed After Total Hysterectomy or Supracervical Hysterectomy ± Bilateral Salpingo-Oophorectomy (UTSARC-1) Diagnosed by Biopsy or Myomectomy (UTSARC-1) Low-Grade Endometrial Stromal Sarcoma (ESS) or Adenosarcoma Without Sarcomatous Overgrowth (UTSARC-2) Adenosarcoma With Sarcomatous Overgrowth (UTSARC-2) High-Grade ESS, Undifferentiated Uterine Sarcoma, Leio myosarcoma, and Other Sarcomas Such as Perivascular epithelioid cell tumor (PEComa) (UTSARC-3) Surveillance (UTSARC-4) Recurrence (UTSARC-5) Principles of Pathology and Molecular Analysis (UTSARC-A) Principles of Imaging (UTSARC-B) Systemic Therapy for Uterine Sarcoma (UTSARC-C) Uterine Neoplasms Principles of Radiation Therapy (UN-A) Principles of Gynecologic Survivorship (UN-B) Staging (ST-1) Find an NCCN Member Institution: https://www.nccn.org/home/memberinstitutions. NCCN Categories of Evidence and Consensus: All recommendations are category 2A unless otherwise indicated. See NCCN Categories of Evidence and Consensus. # NCCN Categories of Preference: All recommendations are considered appropriate. See NCCN Categories of Preference. # NCCN Guidelines Version 3.2025 Uterine Neoplasms # Updates in Version 3.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 2.2025 include: Uterine Neoplasms ENDO-D 2A of 5 • Footnote j revised: If not used previously, Tthese agents can be used as second-line or subsequent therapy as clinically appropriate. MS-1 • The Discussion has been updated to reflect the changes in the algorithm. # Updates in Version 2.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 1.2025 include: Uterine Neoplasms ENDO-D 1 of 5 • Footnote e revised: For adult patients with primary advanced endometrial carcinoma (post surgery): stage IIIA, IIIB, or IIIC1 with measurable disease post surgery, stage IIIC1 with carcinosarcoma, clear-cell, serous, or mixed histology regardless of the presence of measurable disease, and stage IIIC2 or stage IV regardless of the presence of measurable disease. # ENDO-D 2A of 5 • Footnote s regarding Nivolumab and hyaluronidase-nvhy subcutaneous injection is new: Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and administration instructions compared to IV nivolumab. # ENDO-D 4 of 5 • Reference 13 revised: Leslie K, Filiaci V, Mallen A, et al. Mutated p53 portends improvement in outcomes when bevacizumab is combined with chemotherapy in advanced/recurrent endometrial cancer: An NRG Oncology study. Gynecol Oncol 2021;161:113-121. Aghajanian C, Filiaci V, Dizon DS, et al. A phase II study of frontline paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus, or ixabepilone/carboplatin/bevacizumab in advanced/recurrent endometrial cancer. Gynecol Oncol 2018;150:274-281. # NCCN Guidelines Version 3.2025 Uterine Neoplasms Updates in Version 1.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2024 include: # General • The staging text box noted throughout the algorithm was revised: "All staging in guideline is based on updated 2009 FIGO staging..." # UN-1 • Initial evaluation; 2nd bullet revised: "Complete blood count (CBC) (including platelets), liver function test..." • Footnote c: "... Principles of Pathology for Uterine Sarcoma and Molecular Analysis for Uterine Sarcoma (UTSARC-A)" # Endometrial Carcinoma ENDO-2 • Additional Workup: Cervical biopsy or pelvic pelvis MRI (if not previously done) # ENDO-7 • The page for incompletely surgically staged was extensively revised. # ENDO-7A • Footnote h added: Systemic Therapy for Endometrial Carcinoma (ENDO-D). • Footnote t is new: Consider omitting imaging for stage IA, grade 1–2 endometrium-limited carcinoma. # ENDO-8 • Primary Treatment; New bullet added: Consider dual-progestin therapy [(megestrol or medroxyprogesterone) $^ +$ levonorgestrel IUD] • Endometrial cancer present at 6–12 mo pathway; Recommendation revised: TH/BSO with staging (preferred by 12 months) • Footnote removed: Gunderson CC, et al. Gynecol Oncol 2012;125:477-482 and Hubbs JL, et al. Obstet Gynecol 2013;121:1172-1180. # ENDO-8 • Primary Treatment; New bullet added: Consider dual-progestin therapy [(megestrol or medroxyprogesterone) $^ +$ levonorgestrel IUD] • Endometrial cancer present at 6–12 mo pathway; Recommendation revised: TH/BSO with staging (preferred by 12 months) • Footnote removed: Gunderson CC, et al. Gynecol Oncol 2012;125:477-482 and Hubbs JL, et al. Obstet Gynecol 2013;121:1172-1180. # ENDO-9 2nd bullet revised: CA-125 if initially elevated or serous histology 4th bullet revised: "Patient education regarding symptoms of potential recurrence, lifestyle, obesity, exercise, smoking cessation, sexual health (including vaginal dilator use and lubricants/moisturizers), nutrition counseling, and Clinical evaluation and management of potential long-term and late effects of treatment (Also see Principles of Gynecologic Survivorship (UN-B). • Footnote v revised: Principles of Gynecologic Survivorship (UN-B). Patient education should include symptoms of potential recurrence, lifestyle, obesity, exercise, sexual health (including vaginal dilator use, lubricants/moisturizers, and local estrogen and hormone therapy for menopause), smoking cessation, and nutrition counseling. # NCCN Guidelines Version 3.2025 Uterine Neoplasms Updates in Version 1.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2024 include: ENDO-A Principles of Pathology ENDO-A 1 of 4 ino HER2 immunohistochemistry (IHC) testing (with reflex to HER2 fluorescence in situ hybridization [FISH] for equivocal IHC) is recommended for all serous and carcinosarcoma tumors. Consider HER2 testing for p53 abnormal carcinomas regardless of histology. Estrogen receptor (ER) and progesterone receptor (PR) testing is recommended in the settings of stage III, stage IV, and recurrent disease. ENDO-A 2 of 4 Principles of Molecular Analysis 1st bullet: "...no specific molecular profile (NSMP), and p53 abnormal aberrant." 3rd bullet: "Ancillary studies for POLE mutations (hotspot pathogenic mutations in the exonuclease domain), immunohistochemical (IHC) staining for mismatch repair (MMR) or MSI testing, and p53 IHC are strongly encouraged recommended to complement morphologic assessment regardless of histologic tumor type..." 5th bullet: For tumors that are POLE-mutated, MSI-H, or copy number high $p 5 3$ aberrant, or NMSP, clinical trial enrollment is strongly encouraged. 7th bullet: Universal testing of endometrial carcinomas for MMR proteins is recommended. Evaluation for MMR status is commonly done using IHC. Molecular profiling via NGS panels or MSI PCR assay are acceptable alternatives is an acceptable alternative. $\diamondsuit$ 1st arrow sub-bullet: MSI testing is recommended if IHC results are equivocal. $\diamondsuit$ 3rd arrow sub-bullet: Genetic counseling, molecular analysis, and testing for all other MMR abnormalities is recommended. Genetic counseling for any suspected germline mutation is strongly recommended. $\diamondsuit$ 4th arrow sub-bullet: "...testing are recommended regardless of MMR or MLH1 promoter methylation results [see Lynch Syndrome (LS1) (Hereditary Nonpolyposis Colorectal Cancer Syndrome) in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric]. HER2 IHC testing (with or without reflex to HER2 fluorescence in situ hybridization [FISH] for equivocal IHC) is recommended for all p53 aberrant carcinomas regardless of histology. Estrogen receptor (ER) and progesterone receptor (PR) testing is recommended in the settings of stage III, stage IV, and recurrent disease. ENDO-A 3 of 4 Principles of Molecular Analysis • Term revised in figure: Pole hotspot pathogenic mutation # ENDO-A 4 of 4 • Reference 2 updated: Crothers BA Harik LR, Krishnamurti UG, Turashvilli G Movahedi-Lankarani S, Birdsong GG, et al. Protocol for the examination of specimens from patients with carcinoma and carcinosarcoma of the endometrium. (Version 4.4.0.0) College of American Pathologists 2019 2023. ENDO-B Principles of Imaging • Follow-up/Surveillance; 2nd bullet; New arrow sub-bullet added: Consider pelvic ultrasound surveillance for patients with ovarian preservation. # NCCN Guidelines Version 3.2025 Uterine Neoplasms Updates in Version 1.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2024 include: Endometrial Carcinoma–continued ENDO-C Principles of Evaluation and Surgical Staging ENDO-C 1 of 6 • Principles of Surgical Staging for Endometrial Cancer 4th bullet revised: "... and often comprises either SLN mapping and resection of sentinel nodes or a pelvic nodal dissection with or without para-aortic nodal dissection..." 5th bullet: "SLN mapping is preferred (see pages 2–6 of ENDO-C)" reordered to be the 5th bullet. Previously it was the 7th bullet. # ENDO-C 2 of 6 • Principles of Sentinel Lymph Node(s) Mapping for Endometrial Cancer Staging; Bullets revised New bullet added: Indocyanine green (ICG) is the preferred imaging dye for SLN mapping 12th bullet revised: For cases of failed SLN mapping, reinjection of the cervix may be considered. An additional 1 mL in the non-detected side can be infiltrated in the superficial cervical area. Bullet removed: Indocyanine green (ICG) recently emerged as a useful imaging dye that requires a near-infrared camera for localization, provides a very high SLN detection rate, and is commonly used in many practices at the present time # ENDO-C 5 of 6 • Retroperitoneal evaluation text box revised: Excision of all mapped SLN with ultrastaging ENDO-D Systemic Therapy for Endometrial Carcinoma ENDO-D 1 of 5 • Chemoradiation Therapy Other Recommended Regimens; The following agents changed from category 2A to category 2B $\diamondsuit$ Capecitabine/mitomycin $\diamondsuit$ Gemcitabine $\diamondsuit$ Paclitaxel • Primary or Adjuvant Therapy (Stage I–IV); Preferred Regimens revised The 4th and 5th bullets were combined as follows: Carboplatin/paclitaxel/trastuzumab (for stage III–IV HER2-positive uterine serous carcinoma or carcinosarcoma) Carboplatin/paclitaxel/bevacizumab (stage III–IV with measurable disease) added as an option Carboplatin/paclitaxel moved down the list to be the last regimen Footnote a is new: An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Footnote b: For stage III or IVA with measurable disease post surgery or stage IVB with or without measurable disease. For patients not meeting the eligibility criteria for NRG-GY018, carboplatin/paclitaxel $^ +$ pembrolizumab should be considered for stage III–IV dMMR tumors (Van Gorp T, et al. Ann Oncol. Published online August 23, 2024). Footnote e: For adult patients with primary advanced endometrial carcinoma (post surgery): stage IIIA, IIIB, or IIIC1 with measurable disease, stage IIIC1 with carcinosarcoma, clear-cell, serous, or mixed histology regardless of the presence of measurable disease, and stage IIIC2 or stage IV regardless of the presence of measurable disease. Footnote f is new: For stage III with measurable disease post surgery and stage IV with or without measurable disease. Footnote removed: An FDA-approved biosimilar is an appropriate substitute for trastuzumab. # NCCN Guidelines Version 3.2025 Uterine Neoplasms Updates in Version 1.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2024 include: Endometrial Carcinoma–continued # ENDO-D 2 of 5 • First-Line Therapy for Recurrent Disease; Preferred Regimens The 4th and 5th bullets were combined as follows: Carboplatin/paclitaxel/trastuzumab (for HER2-positive serous carcinoma or carcinosarcoma) Carboplatin/paclitaxel (category 1 for carcinosarcoma) moved down the list to be the last regimen • Second-Line or Subsequent Therapy Other Recommended Regimens; Two agents added as options: ◊ Lenvatinib $\diamondsuit$ Gemcitabine Useful in Certain Circumstances (Biomarker-directed therapy) ◊ NTRK gene fusion-positive tumors: Repotrectinib added as an option # ENDO-D 2A of 5 • The following footnote changes were made: Footnote n revised: NCCN recommends TMB-H testing if not previously done. Pembrolizumab is indicated for patients with unresectable or metastati tumors with TMB-H [≥10 mutations/megabase (mut/Mb)], as determined by an FDA-approved assay, or a validated test performed in a CLIA-certified laboratory, whose disease has progressed following prior treatment and who have no satisfactory alternative treatment options. Footnote s is new: NTRK-positive tumors that are naïve to prior NTRK-targeted therapy or have progressed on prior NTRK therapy. Footnotes removed: $\diamondsuit$ An FDA-approved biosimilar is an appropriate substitute for bevacizumab. $\diamondsuit$ An FDA-approved biosimilar is an appropriate substitute for trastuzumab. # ENDO-D 3 of 5 • Hormonal Therapy for Recurrent or Metastatic Endometrial Carcinoma; Other Recommended Regimens 3rd bullet; Aromatase inhibitors; Added: $\diamondsuit$ Anastrozole $\diamondsuit$ Letrozole $\diamondsuit$ Exemestane • Hormonal Therapy for Uterine-Limited Disease Not Suitable for Primary Surgery or for Those Desiring Uterine Preservation for Fertility; Other Recommended Regimens; Added the following new bullet and sub-bullets Dual progestin agents $\diamondsuit$ Megestrol acetate $^ +$ levonorgestrel IUD $\diamondsuit$ Medroxyprogesterone acetate $^ +$ levonorgestrel IUD # ENDO-D 4 of 5 • References updated to reflect changes in the algorithm # NCCN Guidelines Version 3.2025 Uterine Neoplasms Updates in Version 1.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2024 include: Uterine Sarcoma UTSARC-2 • Low-grade ESS or Adenosarcoma without sarcomatous overgrowth (SO) Additional Therapy for Stage I; Revised: BSO (preferred) # UTSARC-4 1st bullet: H&P exam every 3–4 mo (consider every 6 months for low-grade, early-stage sarcomas) for 2–3 y, then every 6–12 mo 3rd bullet: "Patient education regarding symptoms of potential recurrence, lifestyle, obesity, exercise, nutrition, sexual health (including vaginal dilator use and lubricants/moisturizers), smoking cessation, nutrition counseling, and Clinical evaluation and management of potential long-term and late effects of treatment (also see Principles of Gynecologic Survivorship (UN-B)..." • Footnote m revised: Principles of Gynecologic Survivorship (UN-B). Patient education should include symptoms of potential recurrence, lifestyle, obesity, exercise, sexual health (including vaginal dilator use, lubricants/moisturizers, and local estrogen and hormone therapy for menopause), smoking cessation, and nutrition counseling. UTSARC-A Principles of Pathology and Molecular Analysis UTSARC-A 1 of 8 • Molecular Analysis for Sarcoma 2nd bullet revised: "... is informative for predicting rare pan-tumor targeted therapy opportunities and should include at least NTRK, MSI, RET-fusion, and TMB. Preferred on tissue; if tissue is not available, blood-based assays may be considered...." UTSARC-A 2 of 8 through UTSARC-A 7 of 8 • Table 1 was extensively revised. # UTSARC-A 8 of 8 Chapel DB, Nucci MR, Quade BJ, Parra-Herran C. Epithelioid leiomyosarcoma of the uterus: Modern outcome-based appraisal of diagnostic criteria a large institutional series. Am J Surg Pathol 2022;46:464-475. Chiang S, Vasudevaraja V, Serrano J, et al. TSC2-mutant uterine sarcomas with JAZF1-SUZ12 fusions demonstrate hybrid features of endometrial stromal sarcoma and PEComa and are responsive to mTOR inhibition. Mod Pathol 2022;35:117-127. UTSARC-B 1 of 2 Principles of Imaging • Follow-up/Surveillance; 2nd bullet revised: "Optional abdominal/pelvic abdomen/pelvis MRI and chest CT without contrast every 3–6 months..." # NCCN Guidelines Version 3.2025 Uterine Neoplasms Updates in Version 1.2025 of the NCCN Guidelines for Uterine Neoplasms from Version 3.2024 include: UTSARC-C Systemic Therapy for Uterine Sarcoma UTSARC-C 1 of 3 • First-Line Therapy Preferred Regimens revised: Doxorubicin/dacarbazine (for LMS or ifosfamide ineligible) Useful in Certain Circumstances $\diamondsuit$ Biomarker-directed therapy; NTRK gene fusion-positive tumors: Repotrectinib added as an option ◊ Selpercatinib added for RET-fusion positive tumors • Second-Line or Subsequent Therapy Preferred Regimens revised: Trabectedin (for LMS) Other Recommended Regimens: Regorafenib added as an option. • Footnote c is new: NTRK-positive tumors that are naïve to prior NTRK-targeted therapy or have progressed on prior NTRK therapy. • Footnote d revised: For the treatment of patients with unresectable or metastatic TMB-high (TMB-H) ${ \geq } 1 0$ mut/Mb) tumors, as determined by an FDA approved assay, or a validated test performed in a CLIA-certified laboratory, that have progressed following prior treatment and have no satisfactory alternative treatment options. • Footnote removed: For LMS that has been treated with a prior anthracycline-containing regimen. # UTSARC-C 2 of 3 Anti-Estrogen Hormone Therapy for Low-Grade ESS or Adenosarcoma Without SO or Hormone Receptor-Positive (ER/PR) Uterine Sarcomas Preferred Regimens $\diamondsuit$ 1st bullet; For "Aromatase inhibitors for low-grade ESS or adenosarcoma without SO" the following agents added – Anastrozole Letrozole – Exemestane $\diamondsuit$ New bullet added: Consider gonadotropin-releasing hormone (GnRH) analogs with aromatase inhibitors in patients who are premenopausal and not suitable for surgery (BSO) Other recommended Regimens revised $\diamondsuit$ 1st bullet; For "Aromatase inhibitors (for ER/PR-positive uterine sarcomas)" the following agents added: – Anastrozole – Letrozole $\diamondsuit$ Bullet removed: GnRH analogs (category 2B for low-grade ESS, adenosarcoma without SO, and ER/PR-positive uterine sarcomas) # UTSARC-C 3 of 3 Solomon BJ, Drilon A, Lin JJ, et al. 1372P Repotrectinib in patients (pts) with NTRK fusion-positive $( \mathsf { N T R K } ^ { + } )$ advanced solid tumors, including NSCLC: Update from the phase I/II TRIDENT-1 trial [abstract]. Ann Oncol 2023;34:S787-S788. Subbiah V, Wolf J, Konda B, et al. Tumor-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol 2022;23:1261-1273. Berry V, Basson L, Bogart E, et al. REGOSARC: Regorafenib versus placebo in doxorubicin-refractory soft-tissue sarcoma-A quality-adjusted time without symptoms of progression or toxicity analysis. Cancer 2017;123:2294-2302. # NCCN Guidelines Version 3.2025 Uterine Neoplasms All staging in guideline is based on 2009 FIGO staging. (ST-1, ST-2, ST-3 and ST-4) # INITIAL EVALUATIONa • History and physical (H&P) • Complete blood count (CBC), liver function test [LFT], renal function tests, chemistry profile; and consider CA-125 • Expert pathology review with additional endometrial biopsy as clinically indicatedb,c • Imagingd • Recommend molecular evaluation of tumor and evaluation for inherited cancer risk (ENDO-A and UTSARC-A) • For patients who are older with uterine cancer also see the NCCN Guidelines for Older Adult Oncology • Consider germline and/or multigene panel testing ![](images/afa71f039f3ea51a14fccd709a5d99cbb39fa875e277f3c2bb524d32919919c0.jpg) # NCCN Guidelines Version 3.2025 Endometrial Carcinoma # INITIAL CLINICAL FINDINGS(Endometrioid Histology)a # PRIMARY TREATMENT ![](images/5d149d03e929d994f471dae169dc7ca0fe51ffd37ee0ff735220d4d63ecd08bd.jpg) # NCCN Guidelines Version 3.2025 Endometrial Carcinoma # ADDITIONAL WORKUP # PRIMARY TREATMENT ![](images/9f784fc4f9409bdec9082ede77f79f1011893e2cd81c872ba678724e8b2b2615.jpg) # NCCN Guidelines Version 3.2025 Endometrial Carcinoma ![](images/58975fd5a1cfb76672fb25997448068502d30a0a0a29d117ba0fe9dae36717ab.jpg) # NCCN Guidelines Version 3.2025 Endometrial Carcinoma All staging in guideline is based on 2009 FIGO staging. (ST-1) CLINICAL FINDINGS(EndometrioidHistology)a HISTOLOGIC GRADE/ADJUVANT TREATMENTg,h,m <table><tr><td>FIGO Stage</td><td> Histologic Grade</td><td>Adjuvant Treatment</td></tr><tr><td rowspan="2">IA</td><td>G1, G2</td><td>Observation preferred or Consider vaginal brachytherapy if lymphovascular space invasion (LVSl) and/or age ≥60 yn</td></tr><tr><td>G3</td><td>Vaginal brachytherapy preferred or Consider observation if no myoinvasion or Consider EBRT if either age ≥70 y or LVSl (category 2B)</td></tr><tr><td rowspan="4">IB</td><td>G1</td><td>Vaginal brachytherapy preferred or Consider observation if age <60 y and no LVSl</td></tr><tr><td>G2</td><td>Vaginal brachytherapy preferred or Consider EBRT if ≥60 y and/or LVSI</td></tr><tr><td>G3</td><td>or Consider observation if age <60 y and no LVSl</td></tr><tr><td></td><td>RT (EBRT and/or vaginal brachytherapy)± systemic therapy (category 2B for systemic therapy)</td></tr></table> Surgically staged: Stage Ie # NCCN Guidelines Version 3.2025 Endometrial Carcinoma All staging in guideline is based on 2009 FIGO staging. (ST-1) # HISTOLOGIC GRADE/ADJUVANT TREATMENTg,h,m <table><tr><td rowspan="2">Surgically stagede: Stage Io,p</td><td>FIGO Stage</td><td>Histologic Grade</td><td> Adjuvant Treatment</td></tr><tr><td>=</td><td>G1-G3</td><td>EBRT (preferred) and/or vaginal brachytherapyq ± systemic therapy (category 2B for systemic therapy)</td></tr></table> # Note: All recommendations are category 2A unless otherwise indicated. # NCCN Guidelines Version 3.2025 Endometrial Carcinoma # All staging in guideline is based on 2009 FIGO staging. (ST-1) # ADJUVANT TREATMENTg,h # NCCN Guidelines Version 3.2025 Endometrial Carcinoma # All staging in guideline is based on 2009 FIGO staging. (ST-1) ![](images/83a8bcb666514eb34afce246000d95b904422a46230c319cb1f4f9d5764dc102.jpg) # Note: All recommendations are category 2A unless otherwise indicated. # FOOTNOTES FOR ENDO-7 # NCCN Guidelines Version 3.2025 Endometrial Carcinoma ![](images/81541f32a1b624f3b1a7b1af6fe907399eb5854475d084bf27e491b20c496599.jpg) # NCCN Guidelines Version 3.2025 Endometrial Carcinoma # SURVEILLANCE CLINICAL PRESENTATION ![](images/b71c5b02a17e4974662aeee54337d3d08b9dc8fa7146e02a410da6f8dc21db72.jpg) THERAPY FOR RELAPSE # NCCN Guidelines Version 3.2025 Endometrial Carcinoma THERAPY FOR RELAPSE ![](images/e58b6c0bed6b3d7826ee1b34491fe1cd7d21c6d7940fa1b5e80f398d20661480.jpg) aa Consider brachytherapy for locoregional disease with a vaginal component. bb Post-resection consolidation EBRT can be considered in patients who were not previously irradiated or who are deemed to have additional tolerance for radiation. # NCCN Guidelines Version 3.2025 Endometrial Carcinoma : Serous Carcinoma ![](images/36c442418c8e45ea77e22326dbeb4bbc8b64d3a223eb24784d95f7c9f2c456df.jpg) b Disease is not amenable to resection or patient is not suitable for surgery based on comorbidities. d MIS is the preferred approach when technically feasible. See Principles of Evaluation and Surgical Staging (ENDO-C). e The degree of surgical staging to assess disease status depends on intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO-C). g Principles of Radiation Therapy for Uterine Neoplasms (UN-A). h Systemic Therapy for Endometrial Carcinoma (ENDO-D). i Principles of Imaging (ENDO-B). cc HER2 testing is recommended for advanced or metastatic disease. # NCCN Guidelines Version 3.2025 Endometrial Carcinoma :Clear Cell Carcinoma ![](images/3e6b6eed516b1eb6031a07e0e6a598bbb5c73025c8452854c9d7bdb84fd573d4.jpg) # All staging in guideline is based on 2009 FIGO staging. (ST-1) b Disease is not amenable to resection or patient is not suitable for surgery based on comorbidities. d MIS is the preferred approach when technically feasible. See Principles of Evaluation and Surgical Staging (ENDO-C). # Note: All recommendations are category 2A unless otherwise indicated. ![](images/accf3503dd5135ce20a9e41df8c5cfaae48088cf00261ccfa5e36e9d739b4e79.jpg) # NCCN Guidelines Version 3.2025 Endometrial Carcinoma : Carcinosarcoma ![](images/454646f32e942239c9097cebc5e42bff01ffa7bf72c82ac6790e6cc51a6c3e1e.jpg) d MIS is the preferred approach when technically feasible. See Principles of Evaluation and Surgical Staging (ENDO-C). e The degree of surgical staging to assess disease status depends on intraoperative findings. Multidisciplinary expertise is recommended. See Principles of Evaluation and Surgical Staging (ENDO-C). g Principles of Radiation Therapy for Uterine Neoplasms (UN-A). h Systemic Therapy for Endometrial Carcinoma (ENDO-D). i Principles of Imaging (ENDO-B). cc HER2 testing is recommended for advanced or metastatic disease. dd Also known as malignant mixed mesodermal tumor or malignant mixed Müllerian tumor. ee Initiation of chemotherapy within 3–6 weeks postoperatively should be considered. Vaginal brachytherapy can be interdigitated with chemotherapy starting 6 weeks postoperatively. ff Consider EBRT if both high-grade epithelial components and sarcoma are dominant $( > 5 0 \%$ of sarcoma component in uterine tumor) (Matsuo K, et al. Surg Oncol 2018;27:433-440). # NCCN Guidelines Version 3.2025 Endometrial Carcinoma PRINCIPLES OF PATHOLOGYa,1,2,3 # Procedure: • TH/BSO: Total hysterectomy $^ { + }$ bilateral salpingo-oophorectomy • RH: Radical hysterectomy Pathologic Assessment for Carcinoma (including carcinoma, carcinosarcoma, and neuroendocrine carcinoma): • Uterus Hysterectomy type Specimen integrity (intact, opened, morcellated, other) Tumor site (endometrium, lower uterine segment, polyp) Tumor size Histologic type Histologic grade (if applicable) Myometrial invasion (depth of invasion in mm/myometrial thickness in mm) Cervical stromal involvementb LVSIc • Other tissue/organ involvement (fallopian tubes, ovaries, vagina, parametrium, peritoneum, omentum, other) • Peritoneal/ascitic fluid cytologyd • Lymph nodes (when resected) Sentinel lymph nodes (SLNs) should undergo ultrastaging for detection of low-volume metastasis.e Isolated tumor cells are staged $\mathsf { N O } ( \mathsf { i + } )$ and should not upstage patients, but should be considered in the discu Level of nodal involvement (ie, pelvic, common iliac, para-aortic) Number of lymph nodes with isolated tumor cells, micrometastasis, and macrometastasis Thorough gross evaluation of the SLN tissue specimen is recommended to ensure that lymph node tissue is either by the surgeon (depending on experience/comfort level with gross evaluation) or by seeking an intraop aluation of endometrial carcinoma to determine histologic type—especially in high-grade cancers—is challenging and issues exist regarding diagnostic reproducibility. 4,5 # a Principles of Evaluation and Surgical Staging (ENDO-C). b Additional information including depth of invasion in mm/cervical wall thickness in mm may be requested by radiation oncologists to aid in the decision for EBRT. c Pathologists may be asked to quantify LVSI. The current definition of substantial LVSI is ≥4 (LVSI-involved vessels in at least one hematoxylin and eosin [H&E] slide) for defining clinically relevant LVSI in endometrial cancer (Peters EEM, et al. Int J Gynecol Path 2022;41:220-226). d Although cytology by itself does not affect FIGO staging, cytology results should still be obtained because positive cytology is an adverse risk factor. e Ultrastaging commonly entails thin serial sectioning of the gross SLN and review of multiple H&E-stained sections with or without cytokeratin immunohistochemistry (IHC) for all blocks of SLN. There is no standard protocol for lymph node ultrastaging. # NCCN Guidelines Version 3.2025 Endometrial Carcinoma # PRINCIPLES OF MOLECULAR ANALYSIS • Molecular analysis of endometrial carcinoma has identified four clinically significant molecular subgroups associated with differing clinical prognoses: POLE mutations, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), no specific molecular profile (NSMP), and p53 aberrant.6,7 Retrospective analyses indicate that these four molecular subgroups may respond to therapy differently and therefore may require escalation or de-escalation of therapy compared to previous guidelines. Prospective randomized trials are ongoing to determine the role of a molecular profile–guided treatment strategy in the management of high-intermediate-risk and high-risk endometrial carcinomas. • Ancillary studies for POLE mutations (pathogenic mutations in the exonuclease domain), immunohistochemical (IHC) staining for mismatch repair (MMR) or MSI testing, and p53 IHC are recommended to complement morphologic assessment regardless of histologic tumor type.8 See Figure 1: Pathology and Genomics in Endometrial Carcinoma (ENDO-A 3 of 4). Comprehensive molecular profiling is strongly encouraged via an FDA-approved assay, or a validated test performed in a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory, in the initial evaluation of uterine neoplasms. tumors that are POLE-mutated, MSI-H, p53 aberrant, or NSMP, clinical trial enrollment is strongly encouraged. olecular testing may be performed on the initial biopsy or D&C material or the final hysterectomy specimen. valuation for MMR status is commonly done using IHC. Molecular profiling via NGS panels or MSI PCR assay are acceptable alternatives. MSI testing is recommended if IHC results are equivocal. MLH1 loss should be further evaluated for promoter methylation to assess for an epigenetic mechanism. Genetic counseling for any suspected germline mutation is strongly recommended. For those who have a strong family history of endometrial and/or colorectal cancer, genetic counseling and testing are recommended regardless of MMR or MLH1 promoter methylation results [see Lynch Syndrome (LS-1) in the NCCN Guidelines for Genetic/Familial HighRisk Assessment: Colorectal, Endometrial, and Gastric]. HER2 IHC testing (with or without reflex to HER2 fluorescence in situ hybridization [FISH] for equivocal IHC) is recommended for all p53 aberrant carcinomas regardless of histology.9-12 Estrogen receptor (ER) and progesterone receptor (PR) testing is recommended in the settings of stage III, stage IV, and recurrent diseas Consider NTRK gene fusion testing for metastatic or recurrent endometrial carcinoma. • Consider tumor mutational burden (TMB) testing through an FDA-approved assay, or a validated test performed in a CLIA-certified laboratory.13 # NCCN Guidelines Version 3.2025 Endometrial Carcinoma PRINCIPLES OF MOLECULAR ANALYSIS FIGURE 1: PATHOLOGY AND GENOMICS IN ENDOMETRIAL CARCINOMA (The decision to use molecular testing/classification depends on the availability of resources and the multidisciplinary team of each center.)f,g ![](images/de0e4caeb001ff038a2338a4066fce1dd688e1c9f9854ec81c28992d8dd9a4f6.jpg) # NCCN Guidelines Version 3.2025 Endometrial Carcinoma # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS REFERENCES American College of Obstetricians and Gynecologists. ACOG practice bulletin, clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol 2005;106:413-425. Crothers BA Harik LR, Krishnamurti UG, Turashvilli G, et al. Protocol for the examination of specimens from patients with carcinoma and carcinosarcoma of the endometrium. (Version 4.4.0.0) College of American Pathologists 2023. Longacre TA, Broaddus R, Chuang LT, et al. Template for reporting results of biomarker testing of specimens from patients with carcinoma of the endometrium. Arch Pathol Lab Med 2017;141:1508-1512. Hoang LN, Kinloch MA, Leo JM, et al. Interobserver agreement in endometrial carcinoma histotype diagnosis varies depending on The Cancer Genome Atlas (TCGA)- based molecular subgroup. Am J Surg Pathol 2017;41:245-252. Thomas S, Hussein Y, Bandyopadhyay S, et al. Interobserver variability in the diagnosis of uterine high-grade endometrioid carcinoma. Arch Pathol Lab Med 2016;140:836-843. The Cancer Genome Atlas (TCGA) Research Network; Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013;497:67-73. Rios-Doria E, Momeni-Boroujeni A, Friedman CF, et al. Integration of clinical sequencing and immunohistochemistry for the molecular classification of endometrial carcinoma. Gynecol Oncol 2023;174:262-272. Murali R, Delair DF, Bean SM, et al. Evolving roles of histologic evaluation and molecular/genomic profiling in the management of endometrial cancer. J Natl Compr Canc Netw 2018;16:201-209. Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu. J Clin Oncol 2018;36:2044-2051. 0 Moukarzel LA, Ferrando L, Da Cruz Paula A, et al. The genetic landscape of metaplastic breast cancers and uterine carcinosarcomas. Mol Oncol 2021;15:1024-1039. Crane E, Naumann W, Tait D, et al. Molecular variations in uterine carcinosarcomas identify therapeutic opportunities. Int J Gynecol Cancer 2020;30:480-484. 2 Rottmann D, Snir OL, Wu X, et al. HER2 testing of gynecologic carcinosarcomas: tumor stratification for potential targeted therapy. Mod Pathol 2020;33:118-127. 3 Merino DM, McShane LM, Fabrizio D, et al. Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project. J Immunother Cancer 20208;8:e000147. # NCCN Guidelines Version 3.2025 Endometrial Carcinoma PRINCIPLES OF IMAGINGa,1-9 # Initial Workup • Non–Fertility-Sparing Treatment Consider chest imaging (chest $\pmb { \times }$ -ray). If an abnormality is seen, then chest CT without contrast may be performed. Consider pelvis MRI to establish the origin of the tumor (endocervical vs. endometrial) and assess local disease extent. Consider preoperative pelvis ultrasound if uterine size is not clear on exam. For high-grade carcinoma,b consider chest/abdomen/pelvis CT (preferred) to evaluate for metastatic disease. For patients who underwent TH with incidental finding of endometrial cancer or whose cancer was incompletely staged (ENDO-7) with uterine risk factors,c consider chest/abdomen/pelvis CT to evaluate for metastatic disease. Consider neck/chest/abdomen/pelvis/groin fluorodeoxyglucose (FDG)-PET/CT if metastasis is suspected in select patients. Other initial imaging should be based on symptomatology and clinical concern for metastatic disease.d Fertility-Sparing Treatment Pelvis MRI (preferred) to exclude myoinvasion and assess local disease extent; pelvic transvaginal ultrasound if MRI is contraindicated or unavailable. Consider chest imaging (chest $\pmb { \times }$ -ray). If an abnormality is seen, then chest CT without contrast may be performed. Consider neck/chest/abdomen/pelvis/groin FDG-PET/CT if metastasis is suspected in select patients. Other imaging should be based on symptomatology and clinical concern for metastatic disease.e # Follow-up/Surveillance Imaging should be guided by patient symptoms, risk assessment, and clinical concern for recurrent or metastatic disease.e • Fertility-Sparing Treatment Repeat pelvis MRI (preferred) for patients with persistent endometrial carcinoma after 6–9 months of ineffective treatment, especially if considering further fertility-sparing approaches. Other imaging should be based on symptomatology and clinical concern for metastatic disease.e Consider pelvis ultrasound surveillance for patients with ovarian preservation. # Suspected Recurrence or Metastasis • Abdomen/pelvis CT and/or chest CT is recommended based on symptoms or physical exam findings.e • Consider whole body FDG-PET/CT and/or abdomen/pelvis MRI in select patients as clinically indicated. a MRI is performed with and without contrast and CT is performed with contrast unless contraindicated. Contrast is not required for screening chest CT. b High-grade endometrial carcinoma includes: poorly differentiated endometrioid, serous, clear cell, undifferentiated carcinoma, and carcinosarcoma. c Uterine risk factors identified post TH include: high-grade carcinomas (above criteria), myoinvasion $50 \%$ , cervical stromal involvement, LVSI, and tumor $^ { > 2 }$ cm. d Indications may include abnormal physical exam findings; bulky uterine tumor; vaginal or extrauterine involvement; delay in presentation or treatment; and abdominal or pulmonary symptoms. e Indications may include abnormal physical exam findings such as vaginal tumor; palpable mass or adenopathy; and new pelvic, abdominal, or pulmonary symptoms. Refer # NCCN Guidelines Version 3.2025 Endometrial Carcinoma PRINCIPLES OF IMAGING REFERENCES # NCCN Guidelines Version 3.2025 Endometrial Carcinoma # PRINCIPLES OF EVALUATION AND SURGICAL STAGING Principles of Surgical Staging for Endometrial Cancer1-15 • TH/BSO and lymph node assessment is the primary treatment for apparent uterine-confined endometrial carcinoma, unless patients desire (and are candidates for) fertility-sparing options (ENDO-8). 1-3 Select patients with metastatic endometrial carcinoma are also candidates for hysterectomy (Principles of Pathology and Molecular Analysis [ENDO-A]). • Endometrial carcinoma should be removed en bloc to optimize outcomes; intraperitoneal morcellation or tumor fragmentation should be avoided. • TH/BSO and lymph node assessment may be performed by any surgical route (eg, laparoscopic, robotic, vaginal, abdominal), although the standard in those with apparent uterine-confined disease is to perform the procedure via a minimally invasive approach. Randomized trials, a Cochrane Database Systematic Review, and population-based surgical studies support that minimally invasive techniques are preferred in this setting due to a lower rate of surgical site infection, transfusion, venous thromboembolism, decreased hospital stay, and lower cost of care, without compromise in oncologic outcome.4-9 • The lymph node assessment includes evaluation of the nodal basins that drain the uterus, and often comprises either SLN mapping and resection of sentinel nodes or a pelvic nodal dissection with or without para-aortic nodal dissection. This continues to be an important aspect of surgical staging in patients with uterine-confined endometrial carcinoma, as the procedure provides important prognostic information that may alter treatment decisions. • SLN mapping is preferred (see pages 2–6 of ENDO-C).15 • Pelvic lymph nodes from the external iliac, internal iliac, obturator, and common iliac nodes are frequently removed for staging purposes. • Para-aortic nodal evaluation from the inframesenteric and infrarenal regions may also be utilized for staging in patients with high-risk tumors such as deeply invasive lesions, high-grade histology, and tumors of serous carcinoma, clear cell carcinoma, or carcinosarcoma. • Excision of suspicious or enlarged lymph nodes in the pelvic or aortic regions is important to exclude nodal metastasis. • Some patients may not be candidates for lymph node dissection. • Visual evaluation of the peritoneal, diaphragmatic, and serosal surfaces with biopsy of any suspicious lesions is important to exclude extrauterine disease. • While peritoneal cytology does not impact staging, FIGO and AJCC nonetheless recommend that surgeons continue to obtain this during the TH/BSO. • Cytology results should not be taken in isolation to guide adjuvant therapy. • Omental biopsy is commonly performed in those with serous carcinoma, clear cell carcinoma, or carcinosarcoma histologies. • For stage II disease, TH/BSO is the standard procedure. RH should only be performed if needed to obtain negative margins. # NCCN Guidelines Version 3.2025 Endometrial Carcinoma PRINCIPLES OF EVALUATION AND SURGICAL STAGING WHEN SLN MAPPING IS USED • Prospective and retrospective studies demonstrate that compared to systemic lymphadenectomy (LND), SLN mapping with ultrastagingmay increase the detection of lymph node metastasis with low false-negative rates in patients with apparent uterine-confined disease.10-23,26 mapping may also be used in high-risk histologies (ie, serous carcinoma, clear cell carcinoma, carcinosarcoma).24,25 be considered for the surgical staging of apparent uterine-confined malignancy when there is no metastasis demonstrated s or no obvious extrauterine disease at exploration. injection with dye has emerged as a useful and validated technique for identification of lymph nodes that are at high risk for s (ie, SLN in patients with early-stage endometrial cancer10-12). • Superficial $( 1 - 3 ~ \mathsf { m m } )$ and optional deep $( 1 - 2 \cos m )$ cervical injection leads to dye delivery to the main layers of lymphatic channel origins in the cervix and corpus, namely the superficial subserosal, intermediate stromal, and deep submucosal lymphatic sites of origin (see Figure 1 on ENDO-C 4 of 6).26 e uterine cervix provides excellent dye penetration to the uterine vessels and main uterine lymphatic trunks that condense in the parametria and appear in the broad ligament leading to pelvic and occasionally paraaortic sentinel nodes.• The uterine body lymphatic trunks commonly cross over the obliterated umbilical artery with the most common location of pelvic SLN being medial to the external iliac, ventral to the hypogastric, or in the superior part of the obturator region (see Figure 2 on ENDO-C 4 of 6). • A less common location is usually seen when the lymphatic trunks do not cross over the obliterated umbilical and move cephalad following the mesoureter; in these cases, the SLN is usually seen in the common iliac presacral region (see Figure 3 on ENDO-C 4 of 6). • Indocyanine green (ICG) is the preferred imaging dye for SLN mapping.20,26,27 ed colloid most commonly injected into the cervix is technetium-99m (99mTC); colored dyes are available in a variety of forms $1 \%$ , Methylene Blue $1 \%$ , and Patent Blue $2 . 5 \%$ sodium). nodal metastasis to SLN detected only by enhanced pathologic ultrastaging is another potential value to staging with SLN.10,21 The key point to successful SLN mapping is adherence to the SLN algorithm, which requires the performance of a side-specific nodal dissection in cases of failed mapping and removal of any suspicious or grossly enlarged nodes regardless of mapping (see Figure 4 on ENDO-C 5 of 6).10-12,23,25 failed SLN mapping, reinjection of the cervix may be considered. An additional 1 mL in the non-detected side can be infiltrated ficial cervical area. • If there is no mapping on a hemi-pelvis, then a side-specific LND is recommended. However, if expert gynecologic pathology is available, a frozen section to assess myoinvasion can be obtained and LND can be avoided if no myoinvasion or cervical invasion is identified. • SLN identification should always be done prior to hysterectomy, except in cases where a bulky uterus must be removed to allow access to iliac vessels and lymph nodes. # NCCN Guidelines Version 3.2025 Endometrial Carcinoma PRINCIPLES OF EVALUATION AND SURGICAL STAGING WHEN SLN MAPPING IS USED Principles of Sentinel Lymph Node(s) Mapping for Endometrial Cancer Staging (continued)10-26 • SLNs are processed using ultrastaging, which typically includes two components: serial sectioning with review of multiple hematoxylin and eosin (H&E)-stained slides with or without cytokeratin IHC staining. Protocols of serial sectioning and ultrastaging vary among gynecologic pathologists.28 Comparison of two different ultrastaging protocols in endometrial cancer SLN did not reveal significant advantages when serial H&E sectioning and IHC staining were used.29 • Recent data highlight the potential importance of ultrastaging for detection of low-volume metastasis. In general, SLN mapping allows for increased intraoperative surgical precision to identify nodes more likely to harbor metastasis combined with enhanced pathology protocols, which has been shown to increase the detection of nodal metastasis, which may alter stage and adjuvant therapy recommendations. • Lymph nodes with isolated tumor cells should be clearly reported. In endometrial cancer, when isolated tumor cells are detected in the absence of macrometastasis and micrometastasis, the lymph node stage is designated $\mathsf { p N O } ( \mathsf { i } + )$ .30 # NCCN Guidelines Version 3.2025 Endometrial Carcinoma PRINCIPLES OF EVALUATION AND SURGICAL STAGING WHEN SLN MAPPING IS USED Figure 1: Common cervical injection sites for mapping uterine cancera ![](images/75ef3df78b2de3a910ea15372d01198a74377282440520472a5e869ad7807df1.jpg) Figure 2: Most common location of SLNs (blue, arrow) following a cervical injectiona ![](images/5737d9d09c640506edc87a21966ed2ee120b3171fe7a3b05149a11adad6f715a.jpg) Figure 3: Less common location of SLNs (green, arrow) usually seen when lymphatic trunks are not crossing over the umbilical ligament but following the mesoureter cephalad to common iliac and presacral regiona ![](images/ad7eb750e7c6e864ebf74e123bd43486a210324c4bceb28515a659f7a3d339d3.jpg) # NCCN Guidelines Version 3.2025 Endometrial Carcinoma PRINCIPLES OF EVALUATION AND SURGICAL STAGING WHEN SLN MAPPING IS USED Figure 4: The SLN algorithm for surgical staging of endometrial cancerb ![](images/d1e9033ece1547488864d7e47e277a65307890e8ffc3ed14a24987717104ceef.jpg) # NCCN Guidelines Version 3.2025 Endometrial Carcinoma # PRINCIPLES OF EVALUATION AND SURGICAL STAGING REFERENCES 1 American College of Obstetricians and Gynecologists. ACOG practice bulletin, clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol 2005;106:413-425. 2 Bakkum-Gamez JN, Gonzalez-Bosquet J, Laack NN, et al. Current issues in the management of endometrial cancer. Mayo Clin Proc 2008;83:97-112. 3Edge SB, Byrd DR, Compton CC. AJCC Cancer Staging Manual, 7th edition. New York: Springer; 2010. 4 Walker JL, Piedmonte MR, Spirtos NM, et al. Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J Clin Oncol 2009;27:5331-5336. 5 Kornblith AB, Huang HQ, Walker JL, et al. Quality of life of patients with endometrial cancer undergoing laparoscopic international federation of gynecology and obstetrics staging compared with laparotomy: a Gynecologic Oncology Group study. J Clin Oncol 2009;27:5337-5342. 6 Galaal K, Bryant A, Fisher AD, et al. Laparoscopy versus laparotomy for the management of early stage endometrial cancer. Cochrane Database Syst Rev 2012;9:CD006655. 7 Scalici J, Laughlin BB, Finan MA, et al. The trend towards minimally invasive surgery (MIS) for endometrial cancer: an ACS NSQIP evaluation of surgical outcomes. Gynecol Oncol 2015;136:512-515. 8 Fader AN, Weise RM, Sinno AK, et al. Utilization of minimally invasive surgery in endometrial cancer care: a quality and cost disparity. Obstet Gynecol 2016;127:91- 100. 9 Mannschreck D, Matsuno RK, Moriarty JP, et al. Disparities in surgical care among women with endometrial cancer. Obstet Gynecol 2016;128:526-534. 10 Abu-Rustum NR, Khoury-Collado F, Pandit-Taskar N, et al. Sentinel lymph node mapping for grade 1 endometrial cancer: is it the answer to the surgical staging dilemma? Gynecol Oncol 2009;113:163-169. 11 Khoury-Collado F, Glaser GE, Zivanovic O, et al. Improving sentinel lymph node detection rates in endometrial cancer: how many cases are needed? Gynecol Oncol 2009;115:453-455. 12 Khoury-Collado F, Murray MP, Hensley ML, et al. Sentinel lymph node mapping for endometrial cancer improves the detection of metastatic disease to regional lymph nodes. Gynecol Oncol 2011;122:251-254. 13 Frimer M, Khoury-Collado F, Murray MP, et al. Micrometastasis of endometrial cancer to sentinel lymph nodes: is it an artifact of uterine manipulation? Gynecol Oncol 2010;119:496-499. 14 Leitao MM Jr, Khoury-Collado F, Gardner G, et al. Impact of incorporating an algorithm that utilizes sentinel lymph node mapping during minimally invasive procedures on the detection of stage IIIC endometrial cancer. Gynecol Oncol 2013;129:38-41. 15 Holloway RW, Abu-Rustum NR, Backes FJ, et al. Sentinel lymph node mapping and staging in endometrial cancer: A society of gynecologic oncology literature review with consensus recommendations. Gynecol Oncol 2017;146:405-415. 16 Kim CH, Soslow RA, Park KJ, et al. Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrial cancer staging. Int J Gynecol Cancer 2013;23:964-970. 17 Barlin JN, Khoury-Collado F, Kim CH, et al. The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: Beyond removal of blue nodes. Gynecol Oncol 2012;125:531-535. 18 Vidal F, Leguevaque P, Motton S, et al. Evaluation of the sentinel lymph node algorithm with blue dye labeling for early-stage endometrial cancer in a multicentric setting. Int J Gynecol Cancer 2013;23:1327-1243. 19 Abu-Rustum NR. The Increasing credibility of sentinel lymph node mapping in endometrial cancer. Ann Surg Oncol 2013;20:353-354. 20 Sinno AK, Fader AN, Roche KL, et al. A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer. Gynecol Oncol 2014;134:281-286. 21 Holloway RW, Gupta S, Stavitski NM, et al. Sentinel lymph node mapping with staging lymphadenectomy for patients with endometrial cancer increases the detection of metastasis. Gynecol Oncol 2016;141:206-210. 22 Paley P, Veljovich DS, Press JZ, et al. A prospective investigation of fluorescence imaging to detect sentinel lymph nodes at robotic-assisted endometrial cancer staging. Am J Obstet Gynecol 2016;215:117.e1-7. 23 Sinno AK, Peijnenberg E, Fader AN, et al. Reducing overtreatment: a comparison of lymph node assessment strategies for endometrial cancer. Gynecol Oncol 2016; 143:281-286. 24 Schiavone MB, Zivanovic O, Zhou Q, et al. Survival of patients with uterine carcinosarcoma undergoing sentinel lymph node mapping. Ann Surg Oncol 2016;23:196-202. 25 Soliman PT, Westin SN, Dioun S, et al. A prospective validation study of sentinel lymph node mapping for highrisk endometrial cancer. Gynecol Oncol 2017;146:234- 239. 26 Rossi EC, Kowalski LD, Scalici J, et al. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. Lancet Oncol 2017;18:384-392. 27 Frumovitz M, Plante M, Lee PS, et al. Near-infrared fluorescence for detection of sentinel lymph nodes in women with cervical and uterine cancers (FILM): a randomised, phase 3, multicentre, non-inferiority trial. Lancet Oncol 2018;19:1394-403. 28 Cormier B, Rozenholc AT, Gotlieb W, et al. Sentinel lymph node procedure in endometrial cancer: A systematic review and proposal for standardization of future research. Gynecol Oncol 2015;138:478-485. 29 Euscher E, Sui D, Soliman P, et al. Ultrastaging of sentinel lymph nodes in endometrial carcinoma according to use of 2 different methods. Int J Gynecol Pathol 2018;37:242-251. 30 Olawaiye AB, Mutch DG. Lymphnode staging update in the American Joint Committee on Cancer 8th Edition cancer staging manual. Gynecol Oncol 2018;150:7-8. # NCCN Guidelines Version 3.2025 Endometrial Carcinoma SYSTEMIC THERAPY FOR ENDOMETRIAL CARCINOMAa <table><tr><td colspan="2">Primary or Adjuvant Therapy (Stage I-IV)</td></tr><tr><td>Chemoradiation Therapy</td><td>Systemic Therapy</td></tr><tr><td>Preferred Regimen · Cisplatin plus RT followed by carboplatin/paclitaxel1,2</td><td>Preferred Regimens · Carboplatin/paclitaxel/pembrolizumab (for stage Il-IV tumors, except for carcinosarcoma) (category 1)b,c,d,7,8</td></tr><tr><td>Other Recommended Regimens (if cisplatin and carboplatin are unavailable) ·Capecitabine/mitomycin³ (category 2B) ·Gemcitabine4 (category 2B) ·Paclitaxel5,6 (category 2B)</td><td>Carboplatin/paclitaxel/dostarlimab-gxly (for stage l-IV tumors) Carboplatin/paclitaxel/durvalumab (for stage Il-IV dMMR tumors only) (category 1)c,d,e,9 (category 1)c,d,f,10°</td></tr></table> # NCCN Guidelines Version 3.2025 Endometrial Carcinoma SYSTEMIC THERAPY FOR ENDOMETRIAL CARCINOMAa <table><tr><td colspan="2">SYSTEMIC THERAPYFORENDOMETRIAL CARCINOMA?</td></tr><tr><td>RECURRENTDISEASEh,i</td><td></td></tr><tr><td>First-Line Therapy for Recurrent Diseasej Preferred Regimens</td><td>Second-Line or Subsequent Therapyj Other Recommended Regimens ·Cisplatin/doxorubicin20°</td></tr><tr><td>·Carboplatin/paclitaxel/pembrolizumab (except for carcinosarcoma) · Carboplatin/paclitaxel/dostarlimab-gxly (category 1)c,d,k,9 ·Carboplatin/paclitaxel/durvalumab (for dMMR only) (category 1)c,d,k,10 ·Carboplatin/paclitaxel/trastuzumab (for HER2-positive uterine serous carcinoma or carcinosarcoma)d,g,11 ·Carboplatin/paclitaxel (category 1 for carcinosarcoma)l,14 (category 1)c,dk</td><td>· Cisplatin/doxorubicin/paclitaxelp,20 Cisplatin/gemcitabine21 Cisplatin Carboplatin Doxorubicin Liposomal doxorubicin Paclitaxel22</td></tr></table> # Footnotes on ENDO-D 2A of 5 # NCCN Guidelines Version 3.2025 Endometrial Carcinoma # SYSTEMIC THERAPY FOR ENDOMETRIAL CARCINOMA FOOTNOTES FOR ENDO-D 2 OF 5 a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. c NCCN Guidelines for Management of Immunotherapy-Related Toxicities. d Checkpoint inhibitors and/or monoclonal antibodies included in this regimen may be continued as maintenance therapy. Refer to the original study protocol for maintenance therapy dosing schedules. g For patients who have not received prior trastuzumab therapy. h Cisplatin, carboplatin, liposomal doxorubicin, paclitaxel, and docetaxel may cause drug reactions (see NCCN Guidelines for Ovarian Cancer–Management of Drug Reactions [OV-D]). i Chemotherapy regimens can be used for all carcinoma histologies. Carcinosarcomas are now considered and treated as high-grade carcinomas. j If not used previously, these agents can be used as second-line or subsequent therapy as clinically appropriate. k For adult patients with recurrent endometrial carcinoma with or without measurable disease. l Carboplatin/paclitaxel is preferred only for patients who have not received any prior systemic therapy. Can be considered as an option under the "Other Recommended Regimens" list if or when re-use is appropriate in the first-line setting for recurrent disease. m Docetaxel may be considered for patients in whom paclitaxel is contraindicated. n NCCN recommends TMB-H testing if not previously done. Pembrolizumab is indicated for patients with unresectable or metastatic tumors with TMB-H [≥10 mutations/ megabase (mut/Mb)], whose disease has progressed following prior treatment and who have no satisfactory alternative treatment options. o For recurrent endometrial cancer, NCCN recommends MSI-H or dMMR testing if not previously done. p The cisplatin/doxorubicin/paclitaxel regimen is not widely used because of concerns about toxicity. q Albumin-bound paclitaxel is a reasonable substitute for patients with a hypersensitivity to paclitaxel. If a skin test is done, and is positive, then the patient requires desensitization to paclitaxel. Albumin-bound paclitaxel is not a reasonable substitute for paclitaxel if the patient’s skin test is positive. r Bevacizumab may be considered for use in patients whose disease has progressed on prior cytotoxic chemotherapy. s Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and administration instructions compared to IV nivolumab. t NTRK-positive tumors that are naïve to prior NTRK-targeted therapy or have progressed on prior NTRK therapy. # NCCN Guidelines Version 3.2025 Endometrial Carcinoma SYSTEMIC THERAPY FOR ENDOMETRIAL CARCINOMA <table><tr><td colspan="3">Hormonal Therapy for Recurrent or Metastatic Endometrial Carcinomat</td></tr><tr><td>Preferred Regimens · Megestrol acetate/tamoxifen (alternating) ·Everolimus/letrozole</td><td>Other Recommended Regimens · Medroxyprogesterone acetate/tamoxifen (alternating) · Progestational agents Medroxyprogesterone acetate Megestrol acetate ·Aromatase inhibitors Anastrozole Letrozole Exemestane · Tamoxifen</td><td>Useful in Certain Circumstances ·ER-positive tumors Letrozole/ribociclib Letrozole/abemaciclib</td></tr></table> <table><tr><td colspan="2">Hormonal Therapy for Uterine-Limited Disease Not Suitable for Primary Surgery or forThose Desiring Uterine Preservation for Fertility (ENDO-1)t</td></tr><tr><td>Preferred Regimen · Levonorgestrel IUD</td><td>Other Recommended Regimens · Progestational agents Megestrol acetate</td></tr></table> # NCCN Guidelines Version 3.2025 Endometrial Carcinoma # SYSTEMIC THERAPY FOR ENDOMETRIAL CARCINOMA – REFERENCES 1 de Boer SM, Powell ME, Mileshkin L, et al. Toxicity and quality of life after adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol 2016;17:1114-1126. 2 Greven K, Winter K, Underhill K, et al. Final analysis of RTOG 9708: adjuvant postoperative irradiation combined with cisplatin/paclitaxel chemotherapy following surgery for patients with high-risk endometrial cancer. Gynecol Oncol 2006;103:155-159. 3 Lorvidhaya V, Chitapanaarux I, Sangruchi S, et al. Concurrent mitomycin C, 5-fluorouracil, and radiotherapy in the treatment of locally advanced carcinoma of the cervix: a randomized trial. Int J Radiat Oncol Biol Phys 2003;55:1226-1232. 4 Pattaranutaporn P, Thirapakawong C, Chansilpa Y, et al. Phase II study of concurrent gemcitabine and radiotherapy in locally advanced stage IIIB cervical carcinoma. Gynecol Oncol 2001;81:404-407. 5 Candelaria M, Garcia-Arias A, Cetina L, A Dueñas-Gonzalez. Radiosensitizers in cervical cancer. Cisplatin and beyond. Radiat Oncol 2006;1:15. 6 Cerrotta A, Gardan G, Cavina R et al. Concurrent radiotherapy and weekly paclitaxel for locally advanced or recurrent squamous cell carcinoma of the uterine cervix. A pilot study with intensification of dose. Eur J Gynaecol Oncol 2002;23:115-119. 7 Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med 2023;388:2159-2170. 8 Van Gorp T, Cibula D, Lv W, et al. ENGOT-en11/GOG-3053/KEYNOTE-B21: A randomised, double-blind, phase III study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer. Ann Oncol 2024;35:968-980. 9 Powell MA, Bjørge L, Willmott L, et al. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial. Ann Oncol 2024;35:728-738. 10 Westin SN, Moore K, Chon HS, et al. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: The phase III DUO-E trial. J Clin Oncol 2024;42:283-299. 11 Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatinpaclitaxel compared with carboplatin-paclitaxel-trastuzumab in advanced (stage III-IV) or recurrent uterine serous carcinomas that overexpress Her2/ Neu (NCT01367002): Updated overall survival analysis. Clin Cancer Res 2020;26:3928-3935. 12 Rose PG, Ali S, Moslemi-Kebria M, Simpkins F. Paclitaxel, carboplatin, and bevacizumab in advanced and recurrent endometrial carcinoma. Int J Gynecol Cancer 2017;27:452-458. 13 Aghajanian C, Filiaci V, Dizon DS, et al. A phase II study of frontline paclitaxel/ carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus, or ixabepilone/ carboplatin/bevacizumab in advanced/recurrent endometrial cancer. Gynecol Oncol 2018;150:274-281. 14 Miller DS, Filiaci VL, Mannel RS, et al. Carboplatin and paclitaxel for advanced endometrial cancer: Final overall survival and adverse event analysis of a phase III trial (NRG Oncology/GOG0209). J Clin Oncol 2020;38:3841-3850. 15 Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus pembrolizumab in previously treated advanced endometrial cancer: updated efficacy and safety from the randomized phase III Study 309/KEYNOTE-775. J Clin Oncol 2023;41:2904-2910. 16 Marth C, Moore RG, Bidziński M, et al. First-Line Lenvatinib Plus Pembrolizumab Versus Chemotherapy for Advanced Endometrial Cancer: A Randomized, Open-Label, Phase III Trial. Journal of Clinical Oncology 2024;0:JCO-24-01326. 17 Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 2020;21:1353-1365. 18 O'Malley DM, Bariani GM, Cassier PA, et al. Pembrolizumab in patients with microsatellite instability-high advanced endometrial cancer: Results from the KEYNOTE-158 study. J Clin Oncol 2022;40:752-761. 19 Oaknin A, Tinker AV, Gilbert L, et al. Clinical activity and safety of the anti– programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair–deficient endometrial cancer a nonrandomized phase 1 clinical trial. JAMA Oncol 2020;6:1766-1772. # NCCN Guidelines Version 3.2025 Endometrial Carcinoma # SYSTEMIC THERAPY FOR ENDOMETRIAL CARCINOMA – REFERENCES 20 Homesley HD, Filiaci V, Gibbons SK, et al. A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: A Gynecologic Oncology Group study. Gynecol Oncol 2009;112:543-552. 21 Brown J, Smith JA, Ramondetta L, et al. Combination of gemcitabine and cisplatin is highly active in women with endometrial carcinoma: Results of a prospective phase 2 trial. Cancer 2010;116:4973-4979. 22 Picard M, Pur L, Caiado J, et al. Risk stratification and skin testing to guide re-exposure in taxane-induced hypersensitivity reactions. J Allergy Clin Immunol 2016;137:1154-1164. 23 Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol 2011;29:2259-2265.24 Oza AM, Elit L, Tsao MS, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol 2011;29:3278-3285. 25 Vergote I, Powell MA, Teneriello MG, et al. Second-line lenvatinib in patients with recurrent endometrial cancer. Gynecol Oncol 2020;156:575-582. 26 Grisham RN, Adaniel C, Hyman DM, et al. Gemcitabine for advanced endometrial cancer: a retrospective study of the Memorial Sloan-Kettering Cancer Center experience. Int J Gynecol Cancer 2012;22:807-11. 27 Homesley HD, Filiaci V, Markman M, et al. Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group Study. J Clin Oncol 2007;25:526-531. 28 Azad NS, Gray RJ, Overman MJ, et al. Nivolumab is effective in mismatch repair-deficient noncolorectal cancers: Results from Arm Z1D-A Subprotocol of the NCIMATCH (EAY131) study. J Clin Oncol 2020;38:214-222. 29 Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: DESTINYPanTumor02 phase II trial. J Clin Oncol 2024;42:47-58.30 Solomon BJ, Drilon A, Lin JJ, et al. 1372P Repotrectinib in patients (pts) with NTRK fusion-positive $( \mathsf { N T R K } ^ { + } )$ advanced solid tumors, including NSCLC: Update from the phase I/II TRIDENT-1 trial [abstract]. Ann Oncol 2023;34:S787-S788. # NCCN Guidelines Version 3.2025 Uterine Sarcoma # ADDITIONAL EVALUATION # PRIMARY TREATMENT ![](images/b0024646d06c212cc91e16a473e03aaa36abeea7f4b133bbbc7621ee82e5b55a.jpg) aPreoperative imaging and biopsy may help to identify uterine sarcomas, although biopsy sensitivity is less than for endometrial cancer. If there is suspicion of malignant mesenchymal sarcoma, fragmentation/morcellation should be avoided. b Principles of Pathology and Molecular Analysis (UTSARC-A). c Principles of Imaging (UTSARC-B). d For incidental finding of uterine sarcoma after TH/BSO or fragmented specimen: recommend imaging and consider additional surgical resection on an individual basis. e Disease is not amenable to resection, or patient is not suitable for surgery based on comorbidities. f Oophorectomy is individualized for patients of reproductive age. Favor BSO if ER/PR positive. g Morcellation should be avoided. h Systemic Therapy (UTSARC-C). i Principles of Radiation Therapy for Uterine Neoplasms (UN-A). # NCCN Guidelines Version 3.2025 Uterine Sarcoma ![](images/4b55ba9b03c18f82198239c2912dd9312e8962d814720967259ee313438b13da.jpg) # NCCN Guidelines Version 3.2025 Uterine Sarcoma # PATHOLOGIC FINDINGS/ HISTOLOGIC GRADEj # ADDITIONAL THERAPY ![](images/a4193b489a1ad7e6a9f0f8a9a1e15deb3b721ef9d30701275eacad21f14f598a.jpg) # NCCN Guidelines Version 3.2025 Uterine Sarcoma # SURVEILLANCE # RECURRENCE # THERAPY FOR RELAPSE H&P exam every $\ldots + m 0$ (consider every 6 months for low-grade, early-stage sarcomas) for ${ \bf 2 - 3 \Delta y , }$ then every 6–12 mo Imagingc Clinical evaluation and management of potential long-term and late effects of treatmentl (also see Principles of Gynecologic Survivorship (UN-B), NCCN Guidelines for Survivorship, and NCCN Guidelines for Smoking Cessation) ![](images/cb4a7240ff1879a9bf9560e931942a6e0dca6c537a6e46306c2695c7e29b35b5.jpg) # NCCN Guidelines Version 3.2025 Uterine Sarcoma # RECURRENCE THERAPY FOR RELAPSE ![](images/84f15011f4e32fe8d9ef4e2e040dd0763b33f4f2bb60b715305c04dd7c24e0a4.jpg) # NCCN Guidelines Version 3.2025 Uterine Sarcoma # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSISa,1,2 # Procedure: • TH ± BSO: Total hysterectomy ± bilateral salpingo-oophorectomy and en bloc resection of tumor Pathologic Assessment for Sarcoma (including LMS, adenosarcoma, ESS, and UUS): • Expert gynecologic pathology review is highly recommended • Uterus Hysterectomy type Specimen integrity (intact, opened, morcellated, other) Tumor size Myometrial invasion (for adenosarcoma only) Histologic type Histologic grade (for adenosarcoma only) LVSI • Other tissue/organ involvement (fallopian tubes, ovaries, vagina, parametrium, peritoneum, omentum, other) • Peritoneal/ascitic fluid cytology (if collected) • Lymph nodes (when resected) Level of nodal involvementb (ie, pelvic, common iliac, para-aortic) Number of lymph nodes with metastasis # Molecular Analysis for Sarcoma: • Recommend molecular profiling in gynecologic mesenchymal malignancies for accurate classification3 (Table 1 [UTSARC-A 2 of 8]). • Comprehensive genomic profiling in setting of metastatic disease as determined by an FDA-approved assay, or a validated test performed in a CLIA-certified laboratory, is informative for predicting rare pan-tumor targeted therapy opportunities and should include at least NTRK, MSI, RET-fusion, and TMB. Preferred on tissue; if tissue is not available, blood-based assays may be considered. Footnotes a Also see Principles of Evaluation and Surgical Staging (ENDO-C). b Routine node dissection is not required in the absence of clinical suspicion of nodal involvement. # References American College of Obstetricians and Gynecologists. ACOG practice bulletin, clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol 2005;106:413-425. Krishnamurti U and Crothers BA. Protocol for the examination of specimens from patients with primary sarcoma of the uterus. College of American Pathologists 2021. https://documents.cap.org/protocols/Uterus.Sarc_4.2.0.0.REL_CAPCP.pdf3 Parra-Herran C, Howitt BE. Uterine mesenchymal tumors: Update on classification, staging, and molecular features. Surg Pathol Clin 2019;12:363-396. Continued # NCCN Guidelines Version 3.2025 Uterine Sarcoma # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS Table 1 <table><tr><td colspan="6">Uterine Sarcoma</td></tr><tr><td>Tumor</td><td>Hallmarks for Histologic Diagnosis Cellular spindle cell proliferation with</td><td>Relevant Molecular Complex Finding</td><td>Tests Needed to Confirm Diagnosis Immunoexpression of smooth muscle</td><td>Relevant Prognostic Features Prognosis is</td><td>Other</td></tr><tr><td>Conventional (spindle cell) Leiomyosarcoma （LMS)</td><td>interlacing long fascicles with ≥2 of the colwing: ermtetiex r high-power fields (HPFs).</td><td>karyotypes are Lh hallmermkot commonly altered genes include TP53,ATRX,RB1, PTEN，DAXX， MDM2, CDKN2A, CDKN2C, PDGFRB,and BRCA2.</td><td>markers such as desmin,smooth muscle tutin (Saadesonhoe and even lose expression of ≥1 markers. Approximately1/3of LMS express ER/ PR. Abnormal expression of ≥2 immunohistochemical markers TP53, ATRX, RB1,PTEN,DAXX,MDM2,and MTAP may favor LMS in smooth muscle tumors that do not fulfill traditional histologic criteria for LMS. Genomic risk stratification may predict clinical outcomes.</td><td>best predicted Morphology has not been shown to predict clinical behavior.Limited data suggest PR expression may be a positive prognostic marker in low-stage LMS.</td><td></td></tr><tr><td>Epithelioid LMS1</td><td>Epithelioid histology comprising ≥50% of the overall tumor supports classification as an epithelioid smooth muscle tumor. Diagnostic criteria for epithelioid LMS are controversial. By WHO 5th edition,epithelioid LMS is assigned when ≥1 of the following features is present: moderate to severe atypia, tumor cell necrosis,MI.of ≥4/10 HPFs.Recent studies suggest assigning epithelioid LMS when ≥2 features are present.2</td><td>PGR fusions by FISHand/ or targeted RNA sequencing in a small subset with uniform nuclear atypia and rhabdoid features.</td><td>Immunoexpression of desmin, SMA,and/ or caldesmon without MelanA expression is supportive. In some cases of epithelioid LMS,HMB-45maybeexpressed.</td><td>Unknown</td><td>Epithelioid LMS may morphologically and immunohistochemically overlap with malignant PEComa for which there is no gold standard diagnostic test. Detection of pathogenicTSC1/2 mutations or_TFE3 fusion may favor PEComa.</td></tr></table> # NCCN Guidelines Version 3.2025 Uterine Sarcoma # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS Table 1 (continued) <table><tr><td>Tumor</td><td>Hallmarks for Histologic Diagnosis</td><td>Relevant Molecular Finding</td><td>Tests Needed to Confirm Diagnosis</td><td>Relevant Prognostic Features</td></tr><tr><td>Myxoid LMS3,4</td><td>Infiltrative spindle cell proliferation with variable myxoid matrixand tumor necrosis or moderate to severe atypia or MI >1/10 HPFs.</td><td>PLAG1 fusion by FISH and/or targeted RNA sequencing in a subset (~25%). NR4A3 fusions are detected in a subset of myxoid LMS.</td><td>IHC panel of CD10, ER, PR, desmin, SMA, caldesmon, cyclinD1,and ALK is recommended to exclude morphologic mimics.</td><td>Unknown</td></tr><tr><td>Low-Grade Endometrial Stromal Sarcoma (ESS)5-7</td><td>Cytologically bland spindle cell neoplasm resembling proliferativeendometrial stroma with distinctive finger- like myoinvasion and/or LVSl.</td><td>JAZF1::SUZ12 fusion most common (>50%) followed by JAZF1:PHF1,EPC1::PHF1, and MEAF6::PHF1 fusions; MBTD1-CXorf67, BRD8:PHF1,EPC2:PHF1,and EPC1:SUZ12.C</td><td>CD10, ER positivity，PR positivity,and/ or demonstration of a low-grade ESS- associated fusion by FISH and/or targeted RNA sequencing is confirmatory.</td><td>Stage is the most important prognostic factor.</td></tr></table> # NCCN Guidelines Version 3.2025 Uterine Sarcoma # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS Table 1 (continued) <table><tr><td colspan="5"> Uterine Sarcoma</td></tr><tr><td>Tumor High-Grade</td><td>Hallmarks for Histologic Diagnosis YWHAE::NUTM2 fusion-positive tumors</td><td>Relevant Molecular Finding YWHAE:NUTM2 fusion,</td><td>Additional Confirmatory Tests IHC panel of CD10,ER,PR,cyclinD1,</td><td>Relevant Prognostic Features Slightly higher rate of lymph node involvement</td></tr><tr><td>Endometrial Stromal Sarcoma (ESS)5-13</td><td>have a high-grade round cell component with delicate branching vasculature.Generally the MI is≥10/10 HPFs.YWHAE-altered high-grade ESS may be associated with a low-grade fibrous or fibromyxoid spindle_cell component with low MI. ZC3H7B:BCOR fusion-positive tumors have high-grade spindle cells embedded in myxoid matrix. BCOR internal tandem duplication (ITD)- positive tumors share morphologic features of ZC3H7B::BCOR fusion-positive tumors. Tongue-like infiltration and LVSl are present</td><td>ZC3H7B::BCOR fusion, or BCOR ITD.</td><td>±BCOR are recommended. Diffuse strong expression of cyclin D1 is present inall subtypes,and/orBCoRisstrongly and diffusely expressed in the YWHAE- rearranged sarcomas but positive in only ~50% of the BCOR-altered sarcomas. CD10 is negative in the high-grade round cell component of altered subtype,but may be positive in_BCOR-altered mutant subtypes. ER and PR are negative in the high-grade component of YWHAE-altered subtype,and variably positive in BCOR-altered tumors.</td><td>and trend towards worse outcomes when compared to low-grade ESS.</td></tr><tr><td>Undifferentiated Uterine Sarcoma (UUS)13-16</td><td>in all subtypes. Infiltrative sheets of pleomorphic epithelioid and/or spindle cells.</td><td></td><td>This is essentially a diagnosis of exclusion, and thus there are no confirmatory tests.An IHC panel of CD10,cyclin D1, desmin,A, caldesmon,pan-CK, EMA,BRG1, INI1, pan-Trk, ALK,HMB45,MelanA, SOX10, S100, CD34, and STAT6 is recommended to consider other tumor types. Absence of ESS-associated fusions by FISH and/or targeted RNAsequencing is recommended.</td><td>ER and/or PR expression may correlate with improved survival. MI ≥11/mm2 is associated with decreased survival.</td></tr></table> # NCCN Guidelines Version 3.2025 Uterine Sarcoma # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS Table 1 (continued) <table><tr><td>Tumor</td><td>Hallmarks for Histologic Diagnosis</td><td>Relevant Molecular Finding</td><td>Additional Confirmatory Tests</td><td>Relevant Prognostic Features</td></tr><tr><td>Perivascular Epithelioid Cell Tumor (PEComa)17-19</td><td>Mesenchymal neoplasm comprised of perivascular epithelioid and/or spindled cells that coexpress melanocytic and muscle markers.The tumor cells can demonstrate variable cytologic atypia, mitotic activity, and melanin pigment in a background of thin-walled vascular spaces and sclerotic stroma. Proposed algorithms stratify tumors</td><td>Inactivating mutations of TSC1/TSC2,and fusions of TFE3,RAD51B,or HTR4::ST3GAL1 can be seen. In situ hybridization to confirmrearrangement into uncertain malignant potential and malignant as outlined or fusion of TFE3 in TFE3-</td><td>Immunoexpression of cathepsin K, variable expression of melanocytic markers (HMB45 is most sensitive and MelanA is most specific), and ≥1 smooth muscle marker (SMA, desmin, and caldesmon).Keratins and hormone receptors can be variably expressed. Translocation-</td><td>Tumor behavior is best predicted using tumor stratification into uncertain malignant potential and malignant subgroups. Treatment with mTOR inhibitors may be considered.17,21</td></tr><tr><td>Inflammatory Myofibroblastic Tumor (IMT)</td><td>Malignant if ≥3 features (>5 cm, infiltrative growth, high nuclear grade,>1 mitosis/50 mm²,necrosis,and vascular invasion). Spindle cell neoplasm comprised of spindled cells with admixed inflammatory infiltrate (usually lymphoplasmacytic) in a myxoid stroma. Histologic patterns include myxoid hypocellular areas (resembling fasciitis),storiform or fascicular pattern with compact cellular areas with intersecting fascicles,and hyalinized dense collagenous matrix.</td><td>ALK rearrangements by FISH are seen in approximately 75% of patients. Common fusion partners include IGFBP5，THBS1,and TIMP3. RANBP2-ALK and RRBP1::ALK fusions are seen in aggressive IMT with epithelioid morphology. ALK-</td><td>morphologic/immunophenotypic features,and TSC2 mutation identified,consideration for fusion Immunoexpression of ALK (granular cytoplasmic) is sensitive and specific; seen in approximately 95% of patients and can be variable and focal. Immunoexpression of desmin, SMA,and/or caldesmon is common. testing is advised to exclude ESS.20</td><td>Typically benign and confined to the uterus; recurrence and extrauterine spread can occur. Tumors >7 cm with necrosis, lymphovascular invasion,severe cytologic atypia,and high Ml behaveaggressively as do peritoneai iMTs. ALK-rearranged tumor may respond to ALK</td></tr></table> # NCCN Guidelines Version 3.2025 Uterine Sarcoma # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS Table 1 (continued) <table><tr><td colspan="6"> Uterine Sarcoma</td></tr><tr><td>Tumor</td><td>Hallmarks for Histologic Diagnosis</td><td>Relevant Molecular Finding</td><td> Additional Confirmatory Tests</td><td>Relevant Prognostic Features</td><td>Other</td></tr><tr><td>SMARCA4-Deficient Uterine Sarcoma (SDUS)</td><td>SDUS is characterized by sheets of epithelioid/ rhabdoid cells associated with hyalinized matrix. LVSI,highdroisrecoAll cell component or even spindled morphology may be focally present.</td><td>Biallelic SMARCA4 inactivation</td><td>Absent CK expression and BRG1 Ioss (SMARCA4) and/or SMARCA4 mutation detectable by DNA sequencing is helpful to support a diagnosis of SDUS,in the</td><td></td><td>Germline SMARCA4 mutation testing should be considered.</td></tr><tr><td colspan="6">New and Emerging Entities</td></tr><tr><td>NTRK-Rearranged Sarcoma</td><td>Spindle cell neoplasm with fascicular, herringbone, or patternless growth. Entrapped glands may be present,sometimes with polypoid projections simulating adenosarcoma; however, there is typically no periglandular stromal condensation.</td><td>NTRK1/2/3 fusions</td><td>Frequent positivity for CD34 and/ or S100 (generally both but with variable extent). IHC for pan-TRK is typically positive,but this marker is not specific for the gene fusion.</td><td>Typically present with stage I disease;~1/3 recur or metastasize. Targeted therapy against NTRK inhibitors has shown clinical benefit.</td><td>More commonly occurs in the uterine cervix.</td></tr></table> # NCCN Guidelines Version 3.2025 Uterine Sarcoma # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS Table 1 (continued) <table><tr><td>Tumor</td><td>Hallmarks for Histologic Diagnosis</td><td>Relevant Molecular Finding</td><td>Additional Confirmatory Tests</td><td>Relevant Prognostic Features</td></tr><tr><td>Uterine Tumor Resembling Ovarian SexCord Tumor (UTROSCT)22-24</td><td>Bland spindle cell proliferation with extensive sex cord-like differentiation and no endometrial stromal component.</td><td>ESR1 or GREB1 fusions in the majority of tumors.</td><td>Immunohistochemical expression of sex cord markers (inhibin, calretinin,SF1, FOXL2) and/ or detection of GREB1or ESR1 fusions by FISH (NCOA1,NCOA2, NCOA3) and/or targeted RNA</td><td>Tumors have uncertain malignant potential with~25% being malignant. Necrosis and MI ≥2/10 HPFs and/ or presence of GREB1 fusion may increase likelihood of malignant behavior.</td></tr><tr><td>Rhabdomyosarcoma (RMS)25-27</td><td>Embryonal subtype consists of small primitive cells that may forma cambium layer in botryoid tumors; strap cellsand fetal cartilage can be seen.Marked atypia defines the pleomorphic subtype. Alveolar subtype consists of small primitive cells growing in nests or alveoli.</td><td>DICER1 mutations are present in ≥95% of embryonal RMS. PIK3CA and TP53 mutations in pleomorphic tumors.FOXO1 fusion in alveolar tumors.</td><td>sequencing is confirmatory. IHC expression of myogenin and/ orMyoD1 isconfirmatoryof RMS differentiation. Extensive sampling must be performed to exclude carcinosarcoma or adenosarcoma with SO. FISH and/or targeted RNA sequencing for FOXO1 fusion is recommended to confirm alveolar subtype.</td><td>Embryonal subtype has better prognosis than pleomorphic and alveolar subtypes. Age and stage are prognostic factors.</td></tr><tr><td>Mullerian Adenosarcoma (MAS)28-31</td><td>Biphasic tumor with benign often metaplastic epithelium associated with an atypical usually low-grade spindlecell proliferation exhibiting phyllodes growth and periglandular stromal condensation. SO is defined by sarcoma comprising ≥25%of the tumor volume.</td><td>BAP1 loss is seen in a subset. ESR1 fusions are found in a minority of cases and BCORL1 fysions have been reported.d</td><td>Ancillary testing is usually not required.</td><td>High grade, myoinvasion,and SO are poor prognostic factors. High-grade cytologic features may also portend a worse prognosis.</td></tr></table> # NCCN Guidelines Version 3.2025 Uterine Sarcoma # PRINCIPLES OF PATHOLOGY AND MOLECULAR ANALYSIS REFERENCES 1Chiang S, Samore W, Zhang L, et al. PGR gene fusions identify a molecular subset of uterine epithelioid leiomyosarcoma with rhabdoid features. Am J Surg Pathol 2019;43:810-818. 2 Chapel DB, Nucci MR, Quade BJ, Parra-Herran C. Epithelioid leiomyosarcoma of the uterus: Modern outcome-based appraisal of diagnostic criteria in a large institutional series. Am J Surg Pathol 2022;46:464-475. 3 Arias-Stella JA 3rd, Benayed R, Oliva E, et al. Novel PLAG1 gene rearrangement distinguishes a subset of uterine myxoid leiomyosarcoma from other uterine myxoid mesenchymal tumors. Am J Surg Pathol 2019;43:382-388. 4 Yoon JY, Mariño-Enriquez A, Stickle N, et al. Myxoid smooth muscle neoplasia of the uterus: comprehensive analysis by next-generation sequencing and nucleic acid hybridization. Mod Pathol 2019;32:1688-1697. 5 Lee CH, Ali RH, Rouzbahman M, et al. Cyclin D1 as a diagnostic immunomarker for endometrial stromal sarcoma with YWHAE-FAM22 rearrangement. Am J Surg Pathol 2012;36:1562-1570. 6 Lee CH, Mariño-Enriquez A, Ou W, et al. The clinicopathologic features of YWHAE-FAM22 endometrial stromal sarcomas: a histologically highgrade and clinically aggressive tumor. Am J Surg Pathol 2012;36:641-653. 7 Lee CH, Ou WB, Mariño-Enriquez A, et al. 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma. Proc Natl Acad Sci U S A 2012;109:929-934. 8Chiang S, Lee CH, Stewart CJR, et al. BCOR is a robust diagnostic immunohistochemical marker of genetically diverse high-grade endometrial stromal sarcoma, including tumors exhibiting variant morphology. Mod Pathol 2017;30:1251-1261. 9Hoang LN, Aneja A, Conlon N, et al. Novel high grade endometrial stromal sarcoma: a morphologic mimicker of myxoid leiomyosarcoma. Am J Surg Pathol 2017;41:12-24. 10Juckett LT, Lin DI, Madison R, et al. A pan-cancer landscape analysis reveals a subset of endometrial stromal and pediatric tumors defined by internal tandem duplications of BCOR. Oncology 2019;96:101-109. # Note: All recommendations are category 2A unless otherwise indicated. 11 Lewis N, Soslow RA, Delair DF, et al. ZC3H7B-BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity. Mod Pathol 2018;31:674-684. 12 Mariño-Enriquez A, Lauria A, Przybyl J, et al. BCOR internal tandem duplication in high-grade uterine sarcomas. Am J Surg Pathol 2018;42:335-341. 13 Cotzia P, Benayed R, Mullaney K, et al. Undifferentiated uterine sarcomas represent underrecognized high-grade endometrial stromal sarcomas. Am J Surg Pathol 2019;43:662-669. 14 Binzer-Panchal A, Hardell E, Viklund B, et al. Integrated molecular analysis of undifferentiated uterine sarcomas reveals clinically relevant molecular subtypes. Clin Cancer Res 2019;25:2155-2165. 15 Kolin DL, Dong F, Baltay M, et al. SMARCA4- deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus): a clinicopathologic entity distinct from undifferentiated carcinoma. Mod Pathol 2018;31:1442-1456. 16 Kolin DL, Quick CM, Dong F, et al. SMARCA4- deficient uterine sarcoma and undifferentiated endometrial carcinoma are distinct clinicopathologic entities. Am J Surg Pathol 2020;44:263-270. 17 Bennett JA, Braga AC, Pinto A, et al. Uterine PEComas: A morphologic, immunohistochemical, and molecular analysis of 32 tumors. Am J Surg Pathol 2018;42:1370-1383. 18 Folpe AL, Mentzel T, Lehr H-A, et al. Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature. Am J Surg Pathol 2005;29:1558-1575. 19 Schoolmeester JK, Howitt BE, Hirsch MS, et al. Perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: clinicopathologic and immunohistochemical characterization of 16 cases. Am J Surg Pathol 2014;38:176-188. 20 Chiang S, Vasudevaraja V, Serrano J, et al. TSC2- mutant uterine sarcomas with JAZF1-SUZ12 fusions demonstrate hybrid features of endometrial stromal sarcoma and PEComa and are responsive to mTOR inhibition. Mod Pathol 2022;35:117-127. 21WHO Classification of Tumours Editorial Board. Female Genital Tumours. Lyon (France): International Agency for Research on Cancer; 2020. WHO Classification of Tumours, 5th ed.; vol. 4. 22 Dickson BC, Childs TJ, Colgan TJ, et al. Uterine tumor resembling ovarian sex cord tumor: A distinct entity characterized by recurrent NCOA2/3 gene fusions. Am J Surg Pathol 2019;43:178-186. 23 Goebel EA, Hernandez Bonilla S, Dong F, et al. Uterine tumor resembling ovarian sex cord tumor (UTROSCT): A morphologic and molecular study of 26 cases confirms recurrent NCOA1-3 rearrangement. Am J Surg Pathol 2020;44:30-42. 24 Lee CH, Kao YC, Lee WR, et al. Clinicopathologic characterization of GREB1-rearranged uterine sarcomas with variable sex-cord differentiation. Am J Surg Pathol 2019;43:928-942. 25 Leiner J, Le Loarer F. The current landscape of rhabdomyosarcomas: an update. Virchows Arch 2020;476:97-108. 26 Pinto A, Kahn RM, Rosenberg AE, et al. Uterine rhabdomyosarcoma in adults. Hum Pathol 2018;74:122- 128. 27 de Kock L, Yoon JY, Apellaniz-Ruiz M, et al. Significantly greater prevalence of DICER1 alterations in uterine embryonal rhabdomyosarcoma compared to adenosarcoma. Mod Pathol 2020;33:1207-1219. 28 Hodgson A, Amemiya Y, Seth A, et al. High-grade Müllerian adenosarcoma: genomic and clinicopathologic characterization of a distinct neoplasm with prevalent TP53 pathway alterations and aggressive behavior. Am J Surg Pathol 2017;41:1513-1522. 29 Lee JC, Lu TP, Changou CA, et al. Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup. Mod Pathol 2016;29:1070-1082. 30 Howitt BE, Sholl LM, Dal Cin P, et al. Targeted genomic analysis of Müllerian adenosarcoma. J Pathol 2015;235:37-49. 31 Piscuoglio S, Burke KA, Ng CKY, et al. Uterine adenosarcomas are mesenchymal neoplasms. J Pathol 2016;238:381-388. # NCCN Guidelines Version 3.2025 Uterine Sarcoma # PRINCIPLES OF IMAGINGa,1-9 # Initial Workup • Chest/abdomen/pelvis CT • For patients who underwent TH with incidental finding of uterine sarcoma or incompletely resected uterus/adnexa (ie, SCH, myomectomy, possible tumor fragmentation, intraperitoneal morcellation) perform chest/abdomen/pelvis CT or abdomen/pelvis MRI and chest CT without contrast to evaluate for metastatic disease. • Consider pelvis MRI to evaluate local tumor extension or residual abnormality in cases where the uterus or adnexa were not resected or incompletely resected (ie, SCH, myomectomy, possible tumor fragmentation, intraperitoneal morcellation). • Consider neck/chest/abdomen/pelvis/groin FDG-PET/CT to clarify ambiguous findings. • Additional imaging should be based on symptomatology and clinical concern for metastatic disease.b # Follow-up/Surveillance • Chest/abdomen/pelvis CT every 3–6 months for the first 3 years and then every 6–12 months for the next 2 years. Depending on histology grade and initial stage, consider imaging annually or every other year thereafter up to an additional 5 years.c • Optional abdomen/pelvis MRI and chest CT without contrast every 3–6 months for the first 3 years and then every 6–12 months for the next 2 years. Depending on histology, grade, and initial stage, consider imaging annually or every other year thereafter up to an additional 5 years.c • Consider neck/chest/abdomen/pelvis/groin FDG-PET/CT if metastasis is suspected in select patients. • Additional imaging should be based on symptomatology and clinical concern for metastatic disease.d a MRI is performed with and without contrast and CT is performed with contrast unless contraindicated. Contrast is not required for screening chest CT. b Indications may include abnormal physical exam finding, bulky uterine tumor, vaginal or extrauterine involvement, delay in presentation or treatment, and abdominal or pulmonary symptoms. c Follow-up imaging may be as frequent as every 3 months or change based on histology grade and/or stage of tumor. d Indications may include abnormal physical exam findings such as vaginal involvement; palpable mass or adenopathy; and new pelvic, abdominal, or pulmonary symptoms. # NCCN Guidelines Version 3.2025 Uterine Sarcoma # PRINCIPLES OF IMAGING REFERENCES 1 Salani R, Khanna N, Frimer M, et al. An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations. Gynecol Oncol 2017;146:3-10. 2Haldorsen IS, Salvesen HB. What is the best preoperative imaging for endometrial cancer? Curr Oncol Rep 2016;18:25. 3 Elit L, Reade CJ. Recommendations for follow-up care for gynecologic cancer survivors. Obstet Gynecol 2015;126:1207-1214. 4Vargas HA, Akin O, Zheng J, et al. The value of MR imaging when the site of uterine cancer origin is uncertain. Radiology 2011;258:785-792. 5Sohaib SA, Houghton SL, Meroni R, et al. Recurrent endometrial cancer: patterns of recurrent disease and assessment of prognosis. Clin Radiol 2007;62:28-34; discussion 35-36. 6 Hensley ML, Barrette BA, Baumann K, et al. Gynecologic Cancer InterGroup (GCIG) consensus review: uterine and ovarian leiomyosarcomas. Int J Gynecol Cancer 2014;24(9 Suppl 3):S61-S66. 7 Lakhman Y, Katz SS, Goldman DA, et al. Diagnostic performance of computed tomography for preoperative staging of patients with non-endometrioid carcinomas of the uterine corpus. Ann Surg Oncol 2016;23:1271-1278. 8Colombo N, Creutzberg C, Amant F, et al; ESMO-ESGO-ESTRO Endometrial Consensus Conference Working Group. ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment and follow-up. Ann Oncol 2016;27:16-41. 9 Sala E, Rockall AG, Freeman SJ, et al. The added role of MR imaging in treatment stratification of patients with gynecologic malignancies: what the radiologist needs to know. Radiology 2013;266:717-740. # NCCN Guidelines Version 3.2025 Uterine Sarcoma SYSTEMIC THERAPY FOR UTERINE SARCOMAa <table><tr><td colspan="2">(Clinical trials strongly recommended)</td></tr><tr><td colspan="2">Advanced, Recurrent/Metastatic or Inoperable Disease</td></tr><tr><td>First-Line Therapyb</td><td>Second-Line or Subsequent Therapyb</td></tr><tr><td>Preferred Regimens</td><td>Preferred Regimen</td></tr><tr><td>·Doxorubicin</td><td>· Trabectedin (for LMS)</td></tr><tr><td>·Docetaxel/gemcitabine</td><td></td></tr><tr><td>· Doxorubicin/trabectedin (for LMS)1</td><td> Other Recommended Regimens</td></tr><tr><td>·Doxorubicin/ifosfamide</td><td>· Gemcitabine/dacarbazine</td></tr><tr><td>·Doxorubicin/dacarbazine (for LMS or ifosfamide ineligible)</td><td>·Gemcitabine/vinorelbine</td></tr><tr><td></td><td>· Dacarbazine</td></tr><tr><td>Useful in Certain Circumstances</td><td>·Gemcitabine</td></tr><tr><td>· Biomarker-directed therapy</td><td>·Epirubicin</td></tr><tr><td> NTRK gene fusion-positive tumors</td><td>· Ifosfamide</td></tr><tr><td>Larotrectinib</td><td>· Liposomal doxorubicin</td></tr><tr><td>Entrectinib</td><td>· Pazopanib</td></tr><tr><td>Repotrectinibc,2 IMT with ALK translocation</td><td>· Temozolomide</td></tr><tr><td>Crizotinib³</td><td>· Regorafenib8</td></tr><tr><td>Ceritinib4</td><td>· Eribulin (category 2B)</td></tr><tr><td>Brigatinib5,6</td><td>Useful in Certain Circumstances (Biomarker-directed therapy)</td></tr><tr><td>Lorlatinib</td><td>·TMB-H tumorsd</td></tr><tr><td>Alectinib</td><td>Pembrolizumab</td></tr><tr><td>· RET-fusion positive tumors</td><td>·Consider PARP inhibitors for BRCA-altered LMSe,9-11</td></tr><tr><td>Selpercatinib7 · PEComa</td><td>Olaparib12</td></tr><tr><td> Albumin-bound sirolimus</td><td>Rucaparib</td></tr><tr><td></td><td>Niraparib</td></tr><tr><td></td><td>· PEComa</td></tr><tr><td></td><td>Sirolimus</td></tr><tr><td></td><td>Everolimus</td></tr><tr><td></td><td>Temsirolimus</td></tr></table> a NCCN Guidelines for Ovarian Cancer–Management of Drug Reactions (OV-D). b If not used previously, first-line agents can be used as second-line or subsequent therapy as clinically appropriate. c NTRK-positive tumors that are naïve to prior NTRK-targeted therapy or have progressed on prior NTRK therapy. # Note: All recommendations are category 2A unless otherwise indicated. d For the treatment of patients with unresectable or metastatic TMB-H $( \geq 1 0$ mut/Mb) tumors that have progressed following prior treatment and have no satisfactory alternative treatment options. e For oncogenic or likely oncogenic mutations in BRCA2, may refer to definitions at oncokb.org. # NCCN Guidelines Version 3.2025 Uterine Sarcoma SYSTEMIC ENDOCRINE THERAPY FOR UTERINE SARCOMAa (Clinical trials strongly recommended) <table><tr><td colspan="2"> Anti-Estrogen Hormone Therapy for Low-Grade ESS</td></tr><tr><td colspan="2">orAdenosarcoma Without SO or Hormone Receptor-Positive (ER/PR) Uterine Sarcomasf</td></tr><tr><td>Preferred Regimens</td><td>Other Recommended Regimens</td></tr><tr><td>· Aromatase inhibitors for low-grade ESS</td><td>· Aromatase inhibitors9 (for ER/PR-positive uterine sarcomas)</td></tr><tr><td> or adenosarcoma without SOg</td><td>Anastrozole</td></tr><tr><td>Anastrozole</td><td>Letrozole</td></tr><tr><td>Letrozole</td><td>Exemestane</td></tr><tr><td colspan="2">Exemestane · Fulvestrantg · Consider gonadotropin-releasing hormone (GnRH) · Megestrol acetate</td></tr></table> # NCCN Guidelines Version 3.2025 Uterine Sarcoma # SYSTEMIC ENDOCRINE THERAPY FOR UTERINE SARCOMA REFERENCES Pautier P, Italiano A, Piperno-Neumann S, et al. Doxorubicin alone versus doxorubicin with trabectedin followed by trabectedin alone as first-line therapy for metastatic or unresectable leiomyosarcoma (LMS-04): a randomized, multicenter, open-label phase 3 trial. Lancet Oncol 2022;23:1044-1054. Solomon BJ, Drilon A, Lin JJ, et al. 1372P Repotrectinib in patients (pts) with NTRK fusion-positive $( \mathsf { N T R K } { + } )$ advanced solid tumors, including NSCLC: Update from the phase I/II TRIDENT-1 trial [abstract]. Ann Oncol 2023;34:S787-S788. Butrynski JE, D’Adamo DR, Hornick JL, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med 2010;363:1727-1733. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370:1189-1197. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med 2018;379:2027-2039. Gettinger SN, Bazhenova LA, Langer CJ, et al. Activity and safety of brigatinib in ALK-rearranged non-small –cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial. Lancet Oncol 2016;17:1683-1696. Subbiah V, Wolf J, Konda B, et al. Tumor-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol 2022;23:1261-1273. 8 Berry V, Basson L, Bogart E, et al. REGOSARC: Regorafenib versus placebo in doxorubicin-refractory soft-tissue sarcoma-A quality-adjusted time without symptoms of progression or toxicity analysis. Cancer 2017;123:2294-2302. Hensley ML, Chavan SS, Solit DB, et al. Genomic landscape of uterine sarcomas defined through prospective clinical sequencing. Clin Cancer Res 2020;26:3881- 3888. 10 Shammas N, Yang T, Abidi A, et al. Clinical use of PARP inhibitor in recurrent uterine leiomyosarcoma with presence of a somatic BRCA2 mutation. Gynecol Oncol Rep 2022;42:101044. 11 Seligson ND, Kautto EA, Passen EN, et al. BRCA1/2 functional loss defines a targetable subset in leiomyosarcoma. Oncologist 2019;24:973-979. 12 Pan M, Ganjoo K, Karam A. Rapid response of a BRCA2/TP53/PTEN-deleted metastatic uterine leiomyosarcoma to olaparib: A case report. Perm J 2021;25:20.251. # NCCN Guidelines Version 3.2025 Uterine Neoplasms # PRINCIPLES OF RADIATION THERAPY FOR UTERINE NEOPLASMS # General Principles–Uterine Neoplasms • RT is directed at sites of known or suspected tumor involvement and may include EBRT and/or brachytherapy. Imaging is required to assess locoregional extent and to rule out distant metastases before administration of RT. In general, EBRT is directed to the pelvis with or without the para-aortic region. Brachytherapy can be delivered: 1) to an intact uterus, either preoperatively or definitively; or 2) more commonly, to the vagina after hysterectomy. For the purposes of these guidelines, whole abdominal radiotherapy is not considered to be tumor-directed RT. • Chemoradiation can be given concurrently or sequentially. # General Treatment Information • Target Volumes Pelvic radiotherapy should target the gross disease (if present), the lower common iliacs, external iliacs, internal iliacs, obturators, parametria, upper vagina/para-vaginal tissue, and presacral lymph nodes (in patients with cervical involvement). Extended-field radiotherapy should include the pelvic volume and also target the entire common iliac chain and para-aortic lymph node region. The upper border of the extended field depends on the clinical situation but should at least be 1–2 cm above the level of the rena vessels. Pelvic tissues at risk, especially in the post-hysterectomy setting, can be highly variable depending on bowel and bladder filling. In this situation, the internal target volume (ITV), which encompasses the range of organ movement and deformation, is considered the clinical target volume (CTV), and should be fully covered in the treatment volume. # NCCN Guidelines Version 3.2025 Uterine Neoplasms # PRINCIPLES OF RADIATION THERAPY FOR UTERINE NEOPLASMS # General Treatment Information (continued) • Dosing Prescription Regimen – External Beam External-beam doses for microscopic disease should be 45–50 Gy. CT treatment planning should be utilized, and intensity-modulated RT (IMRT) for normal tissue sparing should be considered, with appropriate attention to quality assurance (QA) and tissue interfraction mobility. Treating with IMRT technique is preferred to minimize toxicities in definitive treatment of the pelvis with or without para-aortic treatment. Regular use of image-guided RT (IGRT) with orthogonal imaging and/or routine volumetric imaging (such as cone beam CT) at the time of treatment delivery is essential to ensure appropriate coverage of targets and sparing of normal tissues. ively, if there is gross residual disease and the area(s) can be sufficiently localized, a boost can be added to a total dose of especting normal tissue sensitivity. uvant radiation, doses of 45–50 Gy are typically used. One could consider adding 1–2 high dose-rate (HDR) insertions to a tot –80 Gy low dose-rate (LDR) equivalent, to minimize risk of positive or close margins at hysterectomy. For pelvic-confined recurrent endometrial cancer without a prior history of radiation, fields would mirror adjuvant radiation. For reirradiation, fields should be limited to gross disease and target dose prescribed to maximize control while minimizing risk to normal tissues. # • Dosing Prescription Regimen – Brachytherapy Initiate brachytherapy as soon as the vaginal cuff is healed, preferably 6–8 weeks after surgery but in general initiation of brachytherapy should not exceed 12 weeks. For vaginal brachytherapy, the dose should be prescribed to the vaginal surface or at a depth of 0.5 cm from the vaginal surface; the dose depends on the use of EBRT. The target for vaginal brachytherapy after hysterectomy should be no more than the upper two-thirds of the vagina; in cases of extensive LVSI or positive margins, a longer segment of the vagina may be treated. $\diamondsuit$ For postoperative HDR vaginal brachytherapy alone, regimens include 6 Gy $\textsf { \textsf { X 5 } }$ fractions prescribed to the vaginal surface, or 7 Gy x 3 fractions or 5.5 Gy x 4 fractions prescribed to 5 mm below the vaginal surface. While 7 Gy x 3 fractions prescribed at a depth of $\pmb { 0 . 5 } \mathtt { c m }$ from the vaginal surface is a regimen used by many, the use of smaller fraction sizes may be considered to potentially further limit toxicity in selected patients. DR brachytherapy is used as a boost to EBRT, doses of 4–6 Gy x 2 to 3 fractions prescribed to the vaginal mucosa are commonly For medically inoperable uterine cancer, risk of extrauterine spread determines the combination of EBRT plus brachytherapy or brachytherapy alone. Brachytherapy doses for definitive therapy are individualized based on the clinical situation. When available, imageguided therapy should be used. Based on the best available evidence, an equivalent dose at 2 Gy (EQD2) fractions D90 of ≥48 Gy should be delivered to the uterus, cervix, and upper 1–2 cm of vagina if brachytherapy alone is used, and should be increased to 65 Gy for the combination of EBRT and brachytherapy. If an MRI is used as part of planning, the target dose for the gross tumor volume (GTV) would be an EQD2 of ≥80 Gy. # NCCN Guidelines Version 3.2025 Uterine Neoplasms # PRINCIPLES OF RADIATION THERAPY FOR UTERINE NEOPLASMS # General Treatment Information (continued) • Interstitial Brachytherapy Interstitial brachytherapy is an advanced technique where multiple needles/catheters are inserted in the gross disease/target. Interstitial brachytherapy may be preferred to maximize dose to the target and minimize dose to the organs at risk (OARs) for cases where intracavitary brachytherapy is not possible, or anatomy favors interstitial brachytherapy. Three-dimensional treatment planning allows volumetric delineation of targets and OARs on CT and/or MRI with dose-volume histograms. Dose and fractionation depend on prior RT dose, target volume, and OAR doses. # Stereotactic Radiosurgery (SRS) and Stereotactic Body RT (SBRT) for Metastatic Disease • SRS and SBRT are radiation treatment modalities that utilize advanced three-dimensional anatomic targeting accuracy to deliver precise, ablative, high-dose ionizing radiation. The therapy maximizes the cell-killing effect of ionizing radiation while minimizing radiation-induced injury in adjacent sensitive normal tissues. SRS and SBRT demand precise target localization, reproducibility of patient setup, and a sharp radiation dose gradient. SRS is delivered exclusively to intracranial targets while SBRT describes stereotactic therapy to extracranial targets. SRS and SBRT are delivered in 1 to 5 fractions of therapy with the expectation of durable control at the radiated site. # NCCN Guidelines Version 3.2025 Uterine Neoplasms # PRINCIPLES OF GYNECOLOGIC SURVIVORSHIP # Physical Effects • Gynecologic cancer treatment typically involves surgery, chemotherapy, hormone therapy, RT, and/or immunotherapy. These treatments cause acute, short-term, and long-term toxicities. • Surgical approaches may be extensive and pose risks such as adhesion formation, which may cause pain and may contribute to small bowel obstruction, urinary or gastrointestinal complications (eg, incontinence, diarrhea), pelvic floor dysfunction (manifested by a variety of urinary, bowel, and/or sexual effects), and lymphedema. • Chemotherapy agents vary, though commonly used regimens may pose a significant risk of neurotoxicity, cardiac toxicity, development of hematologic cancers, and cognitive dysfunction. • Long-term estrogen deprivation may cause symptoms such as hot flashes, vaginal dryness, and bone loss. • RT may cause long-term complications (eg, fibrosis, vulvovaginal atrophy) and may predispose patients to secondary cancers of the subcutaneous tissue, and/or underlying organs that are proximal to the radiation field. • Prior pelvic RT may contribute to bone loss and increase the risk of pelvic fractures. Consider bone density testing and prophylactic use of bisphosphonates, particularly in patients with osteoporosis. • Immunotherapy use is emerging, and to date, long-term effects of these treatments are unknown. # Psychosocial Effects • Psychosocial effects after cancer may be psychological (eg, depression, anxiety, fear of recurrence, altered body image), financial (eg, return to work, insurance concerns), and/or interpersonal (eg, relationships, sexuality, intimacy) in nature. # Clinical Approach • All gynecologic cancer survivors should receive regular general medical care that focuses on managing chronic disease, monitoring cardiovascular risk factors, providing recommended vaccinations, and encouraging adoption of a healthy lifestyle. • In order to assess the late and long-term effects of gynecologic cancers, clinicians should comprehensively document the patient’s history, conduct a thorough physical examination, and provide any necessary imaging and/or laboratory testing. All patients, whether sexually active or not, should be asked about genitourinary symptoms, including vulvovaginal dryness. Referral to appropriate specialty providers (eg, physical therapy, pelvic floor therapy, sexual therapy, psychotherapy) is recommended. As most treatments for gynecologic cancers will cause sexual dysfunction, early menopause, and infertility, special attention to the resultant medical and psychosocial implications is needed. • Post-radiation use of vaginal dilators and moisturizers is recommended. • For treatment-related menopause, hormone therapy should be considered. • Communication and coordination with all clinicians involved in the care of survivors, including primary care clinicians, is critical. Providing cancer survivors with a summary of their treatment and recommendations for follow-up is recommended. # Additional Guidance • NCCN Guidelines for Distress Management • NCCN Guidelines for Smoking Cessation NCCN Guidelines for Survivorship # Note: All recommendations are category 2A unless otherwise indicated. # NCCN Guidelines Version 3.2025 Uterine Neoplasms # Staging–Uterine Carcinomas and Carcinosarcoma AJCC Tumor-Node-Metastases (TNM) and International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging Systems for Endometrial Cancer <table><tr><td colspan="2">Definitions for T, N, M</td><td></td></tr><tr><td>T</td><td>FIGOPrimary Tumor Stage</td><td></td></tr><tr><td>TX</td><td></td><td>Primary tumor cannot be assessed</td></tr><tr><td>TO</td><td></td><td>No evidence of primary tumor</td></tr><tr><td>T1</td><td>一</td><td>Tumor confined to the corpus uteri, including endocervical glandular involvement</td></tr><tr><td>T1a</td><td>IA</td><td>Tumor limited to the endometrium or invading less than half the myometrium</td></tr><tr><td>T1b</td><td>IB</td><td>Tumor invading one half or more of the myometrium</td></tr><tr><td>T2</td><td>I</td><td>Tumor invading the stromal connective tissue of the cervix but not extending beyond the uterus. Does NOT include endocervical glandular involvement</td></tr><tr><td>T3</td><td></td><td>Tumor involving serosa, adnexa, vagina, or parametrium</td></tr><tr><td>T3a</td><td>IIA</td><td>Tumor involving the serosa and/or adnexa (direct extension or metastasis)</td></tr><tr><td>T3b</td><td>IIIB</td><td>Vaginal involvement (direct extension or metastasis) or parametrial involvement</td></tr><tr><td>T4</td><td>IVA</td><td>Tumor invading the bladder mucosa and/or bowel mucosa (bullous edema is not sufficient to classify a tumor as T4)</td></tr></table> Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. # NCCN Guidelines Version 3.2025 Uterine Neoplasms N FIGO Regional Lymph Nodes Stage NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N0(i+) Isolated tumor cells in regional lymph node(s) no greater than $0 . 2 \mathsf { m m }$ N1 IIIC1 Regional lymph node metastasis to pelvic lymph nodes N1mi IIIC1 Regional lymph node metastasis (greater than $0 . 2 \mathsf { m m }$ but not greater than $2 . 0 \mathsf { m m }$ in diameter) to pelvic lymph nodes N1a IIIC1 Regional lymph node metastasis (greater than $2 . 0 \mathsf { m m }$ in diameter) to pelvic lymph nodes N2 IIIC2 Regional lymph node metastasis to para-aortic lymph nodes, with or without positive pelvic lymph nodes N2mi IIIC2 Regional lymph node metastasis (greater than $0 . 2 \mathsf { m m }$ but not greater than $2 . 0 \mathsf { m m }$ in diameter) to para-aortic lymph nodes, with or without positive pelvic lymph nodes N2a IIIC2 Regional lymph node metastasis (greater than $2 . 0 \mathsf { m m }$ in diameter) to paraaortic lymph nodes, with or without positive pelvic lymph nodes Table 1 - Continued <table><tr><td></td><td>Stage</td><td></td></tr><tr><td>M0 M1</td><td>IVB</td><td>No distant metastasis</td></tr><tr><td></td><td></td><td>Distant metastasis (includes metastasis to inguinal lymph nodes, intraperitoneal disease, lung, liver, or bone). (It excludes metastasis to pelvic or para-aortic lymph nodes,vagina, uterine serosa, or adnexa).</td></tr><tr><td>G GX</td><td>Histologic Grade</td><td></td></tr><tr><td>G1</td><td>Grade cannot be assessed Well differentiated</td><td></td></tr><tr><td>G2</td><td>Moderately differentiated</td><td></td></tr><tr><td>G3</td><td>Poorly differentiated or undifferentiated</td><td></td></tr><tr><td></td><td></td><td></td></tr></table> Suffix (sn) is added to the N category when metastasis is identified only by sentinel lymph node biopsy. # M FIGO Distant Metastasis Table 2. AJCC Prognostic Stage Groups <table><tr><td>T</td><td>N</td><td>M</td></tr><tr><td>Stage l</td><td>T1 NO</td><td>M0</td></tr><tr><td> Stage IA</td><td>T1a NO</td><td>MO</td></tr><tr><td>Stage IB</td><td>T1b NO</td><td>M0</td></tr><tr><td> Stage Il</td><td>T2 NO</td><td>MO</td></tr><tr><td> Stage Il</td><td>T3 NO</td><td>M0</td></tr><tr><td> Stage IlIA</td><td>T3a NO</td><td>M0</td></tr><tr><td> Stage IlIB</td><td>T3b NO</td><td>M0</td></tr><tr><td> Stage IlIC1</td><td>T1-T3</td><td>N1/N1mi/N1a M0</td></tr><tr><td>Stage IlIC2</td><td>T1-T3 N2/N2mi/N2a</td><td>M0</td></tr><tr><td> Stage IVA</td><td>T4 Any N</td><td>M0</td></tr><tr><td> Stage IVB</td><td>Any T Any N</td><td>M1</td></tr></table> Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. # Staging–Uterine Sarcoma AJCC Tumor-Node-Metastases (TNM) and International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging Systems for Uterine Sarcomas (includes Leiomyosarcoma and Endometrial Stromal Sarcoma) Leiomyosarcoma and Endometrial Stromal Sarcoma <table><tr><td>T</td><td>FIGO Primary Tumor Stage</td><td></td></tr><tr><td>TX</td><td></td><td>Primary tumor cannot be assessed</td></tr><tr><td>TO</td><td></td><td>No evidence of primary tumor</td></tr><tr><td>T1</td><td>1</td><td>Tumor limited to the uterus</td></tr><tr><td>T1a</td><td>IA</td><td>Tumor 5 cm or less in greatest dimension</td></tr><tr><td>T1b</td><td>IB</td><td>Tumor more than 5 cm</td></tr><tr><td>T2</td><td>I</td><td>Tumor extends beyond the uterus,within the pelvis</td></tr><tr><td>T2a</td><td>IIA</td><td>Tumor involves adnexa</td></tr><tr><td>T2b T3</td><td>IIB</td><td>Tumor involves other pelvic tissues Tumor infiltrates abdominal tissues</td></tr><tr><td>T3a</td><td>IIIA</td><td>One site</td></tr><tr><td>T3b</td><td>IIB</td><td>More than one site</td></tr><tr><td>T4</td><td>IVA</td><td>Tumor invades bladder or rectum</td></tr><tr><td>N</td><td>FIGO</td><td>Regional Lymph Nodes</td></tr><tr><td>NX</td><td>Stage</td><td>Regional lymph nodes cannot be assessed</td></tr><tr><td>NO</td><td></td><td>No regional lymph node metastasis</td></tr><tr><td>NO(i+)</td><td></td><td>Isolated tumor cells in regional lymph node(s) no</td></tr><tr><td>N1</td><td>IIIC</td><td>greater than 0.2 mm Regional lymph node metastasis</td></tr></table> <table><tr><td>M</td><td>FIGO Distant Metastasis Stage</td><td></td></tr><tr><td>M0</td><td></td><td>No distant metastasis</td></tr><tr><td>M1</td><td>IVB</td><td>Distant metastasis (excluding adnexa, pelvic, and abdominal tissues)</td></tr><tr><td>G</td><td>Histologic Grade</td><td></td></tr><tr><td>GX</td><td>Grade cannot be assessed</td><td></td></tr><tr><td>G1</td><td>Well differentiated</td><td></td></tr><tr><td>G2</td><td>Moderately differentiated</td><td></td></tr><tr><td>G3</td><td></td><td>Poorly differentiated or undifferentiated</td></tr></table> Table 4. AJCC Prognostic Stage Groups <table><tr><td></td><td>T N M</td></tr><tr><td>Stage I T1</td><td>NO MO</td></tr><tr><td>Stage IA T1a</td><td>NO M0</td></tr><tr><td>Stage IB T1b</td><td>NO M0</td></tr><tr><td>Stage Il T2</td><td>NO M0</td></tr><tr><td>Stage IlA T3a</td><td>NO M0</td></tr><tr><td>Stage IlIB T3b</td><td>NO M0</td></tr><tr><td>Stage IIC T1-3</td><td>N1 MO</td></tr><tr><td>Stage IVA T4</td><td>Any N MO</td></tr><tr><td>Stage IVB Any T</td><td>Any N M1</td></tr></table> # Continued # NCCN Guidelines Version 3.2025 Uterine Neoplasms Staging–Uterine Sarcoma Table 4 AJCC Tumor-Node-Metastases (TNM) and International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging Systems for Uterine Sarcomas (includes Müllerian adenosarcoma) <table><tr><td>T</td><td>FIGO Primary Tumor Stage</td><td></td></tr><tr><td>TX</td><td></td><td>Primary tumor cannot be assessed</td></tr><tr><td>TO</td><td></td><td>No evidence of primary tumor</td></tr><tr><td>T1</td><td>一</td><td>Tumor limited to the uterus</td></tr><tr><td>T1a</td><td>IA</td><td>Tumor limited to the endometrium/endocervix</td></tr><tr><td>T1b</td><td>IB</td><td>Tumor invades less than or equal to half myometrial invasion</td></tr><tr><td>T1c</td><td>IC</td><td>Tumor invades more than half myometrial invasion</td></tr><tr><td>T2</td><td>I</td><td>Tumor extends beyond the uterus, within the pelvis</td></tr><tr><td>T2a</td><td>IIA</td><td>Tumor involves adnexa</td></tr><tr><td>T2b</td><td>IIB</td><td>Tumor involves other pelvic tissues</td></tr><tr><td>T3</td><td>三</td><td>Tumor infiltrates abdominal tissues</td></tr><tr><td>T3a</td><td>IIIA</td><td>One site</td></tr><tr><td>T3b</td><td>B</td><td>More than one site</td></tr><tr><td>T4</td><td>IVA</td><td>Tumor invades bladder or rectum</td></tr><tr><td>N</td><td>FIGO Stage</td><td>Regional Lymph Nodes</td></tr><tr><td>NX</td><td></td><td>Regional lymph nodes cannot be assessed</td></tr><tr><td>NO</td><td></td><td>No regional lymph node metastasis</td></tr><tr><td>N0(i+)</td><td></td><td>Isolated tumor cells in regional lymph node(s) no greater than 0.2 mm</td></tr><tr><td>N1</td><td>IIC</td><td>Regional lymph node metastasis</td></tr></table> \There is a discrepancy between the 2009 FIGO and 2017 AJCC staging documents in the tumor definitions for FIGO stages IB and IC. The NCCN Panel has chosen to use 2009 FIGO language as noted in Corrigendum to “FIGO staging for uterine sarcomas” [International Journal of Gynecology and Obstetrics (2009) 104:179]. Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. <table><tr><td>M</td><td>FIGO Stage</td><td>Distant Metastasis</td></tr><tr><td>M0</td><td></td><td>No distant metastasis</td></tr><tr><td>M1</td><td>IVB</td><td>Distant metastasis (excluding adnexa, pelvic, and abdominal tissues)</td></tr><tr><td>G</td><td>Histologic Grade</td><td></td></tr><tr><td>GX</td><td>Grade cannot be assessed</td><td></td></tr><tr><td>G1</td><td>Well differentiated</td><td></td></tr><tr><td>G2</td><td>Moderately differentiated</td><td></td></tr><tr><td>G3</td><td></td><td>Poorly differentiated or undifferentiated</td></tr></table> Table 4. AJCC Prognostic Stage Groups <table><tr><td></td><td>T N</td><td>M</td></tr><tr><td>Stage I</td><td>T1 NO</td><td>M0</td></tr><tr><td>Stage IA</td><td>T1a NO</td><td>M0</td></tr><tr><td>Stage IB</td><td>T1b NO</td><td>M0</td></tr><tr><td>Stage IC</td><td>T1c NO</td><td>M0</td></tr><tr><td>Stage Il</td><td>T2 NO</td><td>M0</td></tr><tr><td>Stage IA</td><td>T3a NO</td><td>M0</td></tr><tr><td>Stage IlIB</td><td>T3b NO</td><td>M0</td></tr><tr><td>Stage IlIC</td><td>T1-3 N1</td><td>M0</td></tr><tr><td>Stage IVA</td><td>T4 Any N</td><td>M0</td></tr><tr><td>Stage IVB</td><td>Any T Any N</td><td>M1</td></tr></table> # NCCN Guidelines Version 3.2025 Uterine Neoplasms # ABBREVIATIONS <table><tr><td rowspan="2">99mTC technetium-99m</td><td rowspan="2"></td><td colspan="2">ABBREVIATIONS</td><td rowspan="2">OAR</td><td rowspan="2"> organ at risk</td></tr><tr><td>ICG</td><td> indocyanine green</td></tr><tr><td>BSO</td><td>bilateral salpingo-oophorectomy</td><td>IGRT</td><td> image-guided radiation therapy</td><td>PEComa</td><td> perivascular epithelioid ce</td></tr><tr><td></td><td></td><td>IHC IMRT</td><td>immunohistochemistry intensity-modulated radiation</td><td></td><td>tumor</td></tr><tr><td>CBC</td><td> complete blood count</td><td>IMT</td><td>therapy inflammatory myofibroblastic</td><td>pMMR PR</td><td>mismatch repair proficient progesterone receptor</td></tr><tr><td>CLIA</td><td>Clinical Laboratory Improvement Amendments</td><td></td><td>tumor</td><td></td><td></td></tr><tr><td>CTV</td><td> clinical target volume</td><td>IORT ITD</td><td>intraoperative radiation therapy internal tandem duplication</td><td>QA</td><td>quality assurance</td></tr><tr><td rowspan="2">D&C</td><td></td><td>ITV</td><td> internal target volume</td><td>RH</td><td>radical hysterectomy</td></tr><tr><td> dilation and curettage</td><td>IUD</td><td> intrauterine device</td><td></td><td></td></tr><tr><td>dMMR</td><td> mismatch repair deficient</td><td></td><td></td><td>RMS</td><td>rhabdomyosarcoma</td></tr><tr><td rowspan="2">EBRT</td><td></td><td>LDR</td><td>low dose rate</td><td> SBRT</td><td> stereotactic body radiatiol</td></tr><tr><td> external beam radiation therapy</td><td>LFT</td><td>liver function test</td><td></td><td>therapy</td></tr><tr><td>EQD2</td><td> equivalent dose at 2 Gy</td><td>LMS</td><td>leiomyosarcoma</td><td>SCH</td><td> supracervical hysterectom</td></tr><tr><td>ER</td><td> estrogen receptor</td><td>LND</td><td>lymphadenectomy</td><td> SDUS</td><td>SMARCA4-deficient uterin</td></tr><tr><td>ESS</td><td> endometrial stromal sarcoma</td><td>LVSI</td><td>lymphovascular space invasion</td><td></td><td> sarcoma</td></tr><tr><td></td><td></td><td></td><td></td><td>SLN</td><td> sentinel lymph node</td></tr><tr><td>FDG</td><td>fluorodeoxyglucose</td><td>MAS</td><td>Müllerian adenosarcoma</td><td> SMA</td><td> smooth muscle actin</td></tr><tr><td>FIGO</td><td>International Federation of</td><td>MI</td><td> mitotic index</td><td>SO</td><td> sarcomatous overgrowth</td></tr><tr><td>FISH</td><td>Gynecology and Obstetrics fluorescence in situ hybridization</td><td>MIS</td><td> minimally invasive surgery</td><td>SRS</td><td> stereotactic radiosurgery</td></tr><tr><td rowspan="2"></td><td></td><td>MMR</td><td></td><td></td><td></td></tr><tr><td></td><td></td><td>mismatch ite instalt</td><td>TH</td><td> total hysterectomy</td></tr><tr><td>GnRH GTV</td><td>gonadotropin-releasing hormone gross tumor volume</td><td>MSI-H</td><td> microsatellite instability-high</td><td>TMB</td><td> tumor mutational burden</td></tr><tr><td></td><td></td><td>mut/Mb</td><td> mutations/megabase</td><td>TMB-H</td><td>tumor mutational burden-l</td></tr><tr><td>H&E</td><td>hematoxylin and eosin</td><td></td><td></td><td>UUS</td><td>undifferentiated uterine</td></tr><tr><td>H&P</td><td>history and physical</td><td>NGS</td><td> next-generation sequencing</td><td></td><td> sarcoma</td></tr><tr><td>HDR</td><td> high dose rate</td><td>NSMP</td><td> no specific molecular profile</td><td></td><td>UTROSCT uterine tumor resembling</td></tr><tr><td>HPE</td><td>biah-power field</td><td></td><td></td><td></td><td>ovarian sex cord tumor</td></tr></table> # NCCN Guidelines Version 3.2025 Uterine Neoplasms <table><tr><td colspan="2">NCCN Categories of Evidence and Consensus</td></tr><tr><td>Category1</td><td>Based uponhigh-level evidence (≥1randomized phase 3trialsor high-quality，robust meta-analyses),there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.</td></tr><tr><td>Category 2A</td><td>Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.</td></tr><tr><td>Category 2B</td><td>Based upon lower-level evidence,there is NCCN consensus (≥50%, but <85% support of the Panel) that the intervention is appropriate.</td></tr><tr><td>Category 3</td><td>Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.</td></tr></table> All recommendations are category 2A unless otherwise indicated. <table><tr><td colspan="2">NCCN Categories of Preference</td></tr><tr><td>Preferred intervention</td><td>Interventinsthatreaseduperoreffiacysfetyandevidence; and,henaprprat</td></tr><tr><td>Other recommended intervention</td><td>Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.</td></tr><tr><td>Useful in certain</td><td> Other interventions that may be used for selected patient populations (defined with recommendation).</td></tr></table> All recommendations are considered appropriate. # NCCN Guidelines Version 3.2025 Uterine Neoplasms # Discussion Table of Contents This discussion corresponds to the NCCN Guidelines for Uterine Neoplasms. Last updated: March 7, 2025. Overview . 2 Guidelines Update Methodology . 2 Literature Search Criteria.. . 2 Sensitive/Inclusive Language Usage . . 2 Initial Evaluation . . 3 Endometrial Cancer. 3 Molecular Analysis and Genetic Factors . 4 Diagnosis and Workup .. . 5 Imaging ...... .. 5 Disease Staging ... .. 5 Principles of Evaluation and Surgical Staging for Endometrial Carcinoma . . 6 Pathology ....... ... 6 Lymphadenectomy .. . 7 SLN Ultrastaging... . 10 Minimally Invasive Procedures ... ... 10 Primary Treatment.. . 12 Disease Limited to the Uterus . . 12 Suspected or Gross Cervical Involvement . . 13 Suspected Extrauterine Disease . .. 14 Adjuvant Therapy ... . 14 Uterine-Confined Disease . . 14 Advanced Stage/Extrauterine Disease. ..18 High-Risk Endometrial Carcinoma Histologies . ..21 Overview .... ..21 Primary Treatment.. ..21 Treatment of Recurrent or Metastatic Disease . ..22 Locoregional Recurrence. ..22 Distant Metastases ... ..23 Hormonal Therapy .... ..23 Systemic Therapy for Recurrent Disease. ..24 Systemic Therapy Options for High-Risk Endometrial Histologies . ..27 Radiotherapy Principles ... ..28 Post-Treatment Surveillance. ..28 Hormone Therapy for Hypoestrogenism.. ..29 Uterine Sarcomas . ..30 Overview .... ....30 Pathology and Molecular Analysis.. ..30 Staging and Treatment . ...33 Treatment of Recurrent or Metastatic Disease . ..35 Systemic Therapy for Advanced, Metastatic/Recurrent or Inoperable Disease .. ....36 Post-Treatment Surveillance.. ...37 Drug Reactions .. ..37 Gynecologic Survivorship. ..38 References . .39 # NCCN Guidelines Version 3.2025 Uterine Neoplasms # Overview Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the fourth most common malignancy of the female genital tract in the United States with fastest increasing mortality. It is estimated that 69,120 new uterine cancer cases will occur in 2025, with 13,860 deaths resulting from the disease. 1 The incidence of uterine corpus cancer has also continued to increase by about $1 \%$ per year since the mid‐2000s.2 It is also the only cancer with reduced survival over the past four decades. Stromal or mesenchymal sarcomas are uncommon subtypes accounting for approximately $3 \%$ of all uterine cancers.3,4 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Uterine Neoplasms describe malignant epithelial tumors and uterine sarcomas; each of these major categories contains specific histologic groups that require different management (see Initial Clinical Findings in the NCCN Guidelines for Uterine Neoplasms). Risk factors for uterine neoplasms include increased levels of estrogen (caused by obesity, diabetes, and high-fat diet), early age at menarche, nulliparity, late age at menopause, Lynch syndrome, ages between 55 and 64 years, and tamoxifen use.5-8 Thus, the incidence of endometrial cancer is increasing because of increased life expectancy and obesity. The Summary of the Guidelines Updates describes the most recent revisions to the algorithm, which have been incorporated into this revised Discussion text (see the NCCN Guidelines® for Uterine Neoplasms). The NCCN Guidelines cannot incorporate all possible clinical variations and are not intended to replace good clinical judgment or individualization of treatments. “Many exceptions to the rule” were discussed among the Panel members during the update process for these Guidelines. Recommendations in the NCCN Guidelines are category 2A unless otherwise noted. # Guidelines Update Methodology The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org. # Literature Search Criteria Prior to the update of this version of the NCCN Guidelines for Uterine Neoplasms an electronic search of the PubMed database was performed to obtain key literature in uterine neoplasms published since the previous Guidelines update, using the following search terms: endometrial cancer or endometrial carcinoma or uterine sarcoma or endometrial stromal sarcoma or uterine leiomyosarcoma. The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature. The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies. The data from key PubMed articles as well as articles from additional sources deemed relevant to these guidelines as discussed by the Panel during the Guidelines update process have been included in this version of the Discussion section. Recommendations for which high-level evidence is lacking are based on the Panel’s review of lower-level evidence and expert opinion. # Sensitive/Inclusive Language Usage NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation. NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist, antimisogynist, anti-ageist, anti-ableist, and anti-weight-biased; and inclusive # NCCN Guidelines Version 3.2025 Uterine Neoplasms of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non-gendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses. # Initial Evaluation For patients with known or suspected uterine neoplasms, the initial preoperative evaluation/workup for known or suspected malignancy includes a history and physical examination, complete blood count, expert pathology review with additional endometrial biopsy as indicated, imaging, recommendation of genetic evaluation of tumor and for inherited cancer risk, consideration of liver function tests (LFTs)/renal function tests or chemistry profile, and other studies (see Initial Evaluation and Principles of Imaging in the NCCN Guidelines for Uterine Neoplasms).9 Preoperative imaging and biopsy may help to identify uterine sarcomas, although biopsy sensitivity is less than that for endometrial cancer. An expert pathology review will determine whether a patient has a malignant epithelial tumor or a stromal/malignant mesenchymal tumor. Epithelial tumor types include pure endometrioid cancer and carcinomas with high-risk endometrial histology (including uterine serous carcinoma, clear cell carcinoma, carcinosarcoma [also known as malignant mixed Müllerian tumor (MMMT)], and undifferentiated/dedifferentiated carcinoma). Stromal or mesenchymal tumor types (interchangeable terms) include uterine leiomyosarcoma (uLMS), endometrial stromal sarcoma (ESS), undifferentiated uterine sarcoma (UUS, previously called high-grade undifferentiated endometrial sarcoma), adenosarcoma, and perivascular epithelioid cell neoplasm (PEComa). Given the typical age group at risk for uterine neoplasms (ie, $\mathtt { \ge 5 5 }$ years) and the presence of comorbid illnesses, please also see the NCCN Guidelines® for Older Adult Oncology. # Endometrial Cancer Data shows that almost $67 \%$ of patients with adenocarcinoma of the endometrium are diagnosed with disease confined to the uterus at diagnosis. 10 Regional and distant disease comprise approximately $2 1 \%$ and $8 \%$ of cases, respectively. Many physicians believe that adenocarcinoma of the endometrium is a more treatable malignancy because the early symptoms of metrorrhagia or post-menopausal vaginal bleeding often trigger patients to seek care when the disease is at an early and treatable stage. However, data show that the mortality rate for uterine cancer has increased more rapidly than the incidence rate.11 This increased mortality may be related to an increased rate of advanced-stage cancers, high-risk histologies (eg, serous carcinomas), and patients being diagnosed at $\mathtt { \ge 6 5 }$ years of age. Analysis of SEER data suggests that survival is increased in patients who are younger, have early-stage disease, and have lower-grade disease.12 In addition to grade and depth of myometrial invasion, other risk factors associated with poor prognosis include age, lymph node (LN) involvement, tumor size, lymphovascular space invasion (LVSI), and lower uterine segment invasion. 13,14 Depth of myometrial invasion is considered one of the critical criteria for evaluation of surgical-pathologic staging.15,16 To further improve outcomes for patients with this disease, physicians need to identify patients who are at high risk and to tailor treatment appropriately to provide the best long-term survival. The Panel suggests that # NCCN Guidelines Version 3.2025 Uterine Neoplasms gynecologic oncologists be involved in the primary management of all patients with endometrial cancer. # Molecular Analysis and Genetic Factors Most endometrial cancer $( 9 5 \% )$ is caused by sporadic (somatic) mutations. However, genetic mutations cause endometrial cancer in about $5 \%$ of patients, which occurs 10 to 20 years before sporadic cancer.17 Since there is increasing overlap in histopathologic features of these tumors, molecular analysis (eg, identification of characteristic translocations and/or mutations) and subtype classification are useful in selecting appropriate therapies. The Cancer Genome Atlas (TCGA) study performed an integrated genomic, transcriptomic, and proteomic analysis of 373 endometrial carcinomas including low-grade endometrioid, highgrade endometrioid, and serous carcinomas for their molecular classification. The study identified four major clinically significant molecular subtypes with differing clinical prognosis: POLE (DNA polymerase epsilon) mutations, microsatellite instability-high (MSI-H), copy number-low (wildtype $p 5 3 \AA$ ), and copy number-high (abnormal $p 5 3 \AA$ . The POLE comprises tumors with POLE exonuclease domain mutations that includes P286R, V411L, S297F, A456P, and S459F and are collectively referred to as “hotspot POLE mutations”, with P286R and V411L being the most prevalent. Aside from these pathogenic mutations, numerous mutations exist whose significance remain unknown. 18 The copy number-high group is characterized by an elevated incidence of TP53 alterations. These genomic classes are also associated with characteristic phenotypes. The endometrial cancers with POLE mutations are usually high-grade tumors with deep myometrial invasion and LVSI and usually have a good prognosis. 19,20 The $p 5 3$ mutant is the most aggressive subtype and requires a multimodality treatment, especially chemotherapy. The MSI-H tumors have an intermediate prognosis, but could be associated with other genetic cancer predispositions, and sensitivity to chemotherapy has been under investigation. Further studies have attempted to study the association of TCGA subgroups with histologic features such as tumor grade and histologic type.21 The NCCN Guidelines for Uterine Neoplasms include a diagnostic algorithm for integrated genomic-pathologic classification of endometrial carcinomas based on the TCGA study and add that the decision to use molecular testing/classification depends on resource availability and each center’s multidisciplinary team. The Panel encourages comprehensive molecular profiling via a validated and/or FDA-approved assay in the initial evaluation of uterine neoplasms to help facilitate cancer diagnoses. The Panel also encourages ancillary studies of POLE mutations, mismatch repair (MMR)/MSI, and aberrant $p 5 3$ expression to complement the morphologic assessment of histologic tumor type. In addition, the Panel includes consideration for NTRK gene fusion testing for metastatic or recurrent endometrial carcinoma, and for tumor mutational burden (TMB) testing through a validated and/or FDA-approved assay. HER2 immunohistochemistry (IHC) testing (with or without reflex to HER2 fluorescence in situ hybridization [FISH] for equivocal IHC) is recommended for all p53 aberrant carcinomas regardless of histology. 22-25 Estrogen receptor (ER) and progesterone receptor (PR) testing is recommended in the settings of stage III, stage IV, and recurrent disease. Screening of the tumor for defective DNA MMR using IHC and/or MSI is used to identify which patients should undergo mutation testing for Lynch syndrome (see Lynch Syndrome in the NCCN Guidelines® for Colorectal Cancer Screening).17,26-32 Evaluation of MMR deficient (dMMR) status is commonly done using IHC and molecular profiling is an acceptable alternative. Testing may be performed on the initial biopsy, dilation and curettage (D&C) material, or the final hysterectomy specimen. MLH1 loss should be further evaluated for promoter methylation to assess for an epigenetic process rather than a germline mutation.29 Genetic counseling, molecular analysis, and testing are recommended for patients with all # NCCN Guidelines Version 3.2025 Uterine Neoplasms other MMR abnormalities. Patients with a significant family history of endometrial and/or colorectal cancer (even for those without MMR defects, who are MSI-stable, or those without screening) should be referred for genetic counseling and evaluation (See Lynch Syndrome in the NCCN Guidelines $\textsuperscript { \textregistered }$ for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric). Screening for genetic mutations should be considered, especially for patients $\mathtt { < 5 0 }$ years of age.8,17,26,33-36 If these patients have Lynch syndrome, they are at a higher lifetime risk $( \leq 6 0 \% )$ for endometrial cancer; thus, close monitoring and discussion of risk-reducing strategies is recommended.26,37,38, 6,33,39 In addition, their relatives may have Lynch syndrome. For patients and family members with Lynch syndrome but without endometrial cancer, a yearly endometrial biopsy is recommended to assess for cancer.35,40 This strategy also enables select patients to defer surgery (and surgical menopause) and to preserve fertility. Prophylactic hysterectomy/bilateral salpingo-oophorectomy (BSO) is recommended after childbearing is complete.41,42 In addition, interventions to decrease the risk from colorectal cancer are recommended (eg, annual colonoscopy). # Diagnosis and Workup Currently, there is no validated screening test for endometrial carcinoma.43,44 About $90 \%$ of patients with endometrial carcinoma have metrorrhagia, most commonly in the postmenopausal period. The workup was previously described above (see Initial Evaluation). Diagnosis can usually be made by an office endometrial biopsy, with a false-negative rate of about $10 \%$ .45,46 Thus, a negative endometrial biopsy in a symptomatic patient must be followed by a fractional D&C under anesthesia.45,47 Hysteroscopy may be helpful in evaluating the endometrium for lesions, such as a polyp, if the patient has persistent or recurrent bleeding.48 Endometrial biopsy may not be accurate for diagnosing malignancies of the uterine wall such as mesenchymal tumors. The histologic information from the endometrial biopsy (with or without endocervical curettage) is sufficient for planning definitive treatment. # Imaging For detailed imaging recommendations by stage and planned treatment approach, see Principles of Imaging in the NCCN Guidelines for Uterine Neoplasms. Consideration of preoperative chest imaging (chest x-ray) is recommended. Based on the fertility-sparing or non–fertility-sparing treatment criteria, other imaging tests such as CT, MRI, ultrasound (US), and/or fluorodeoxyglucose (FDG)-PET/CT may be used to assess disease extent and to evaluate for metastatic disease as indicated based on clinical symptoms, physical findings, or abnormal laboratory findings.49-55 In patients with extrauterine disease, a serum CA-125 assay may be helpful in monitoring clinical response.56,57 However, serum CA-125 levels can be falsely increased in patients who have peritoneal inflammation/infection or radiation injury, may be normal in patients with isolated vaginal metastases, and may not predict recurrence in the absence of other clinical findings.58-60 # Disease Staging The FIGO (International Federation of Gynecology and Obstetrics) system is most commonly used for staging uterine cancer. The original 1970 criteria for staging endometrial cancer only used information gained from the presurgical evaluation (including physical examination and diagnostic fractional D&C). The 1970 staging system is rarely used today (eg, when the patient is not a surgical candidate). Several studies demonstrated that clinical staging was inaccurate and did not reflect actual disease extent in $1 5 \%$ to $20 \%$ of patients.61-63 This reported under staging and, more importantly, the ability to identify multiple prognostic factors with a full pathologic review made possible with surgical staging motivated a change in the staging classification. # NCCN Guidelines Version 3.2025 Uterine Neoplasms Therefore, in 1988, FIGO modified its staging system to emphasize thorough surgical/pathologic assessment of data, such as histologic grade, myometrial invasion, and the extent and location of extrauterine spread (including retroperitoneal lymph node metastases).64 FIGO updated and refined the surgical/pathologic staging criteria for uterine neoplasms in 2009.65-68 Separate staging systems for malignant epithelial tumors and uterine sarcomas are now available (see Staging section of the algorithm). In 2017, the AJCC Cancer Staging Manual was further updated (which took effect in January 2018).69 The 2009 FIGO staging system streamlined stages I and II of endometrial carcinoma. These revisions were made because the survival rates for some of the previous sub-stages were similar.67 Currently stage IA describes tumors with $\mathtt { < 5 0 \% }$ myometrial invasion, and stage IB describes those with $\ge 5 0 \%$ myometrial invasion. Stage II describes patients with tumors that invade the cervical stroma. Patients with uterine-confined disease and endocervical glandular involvement (mucosal involvement) without cervical stromal invasion are no longer considered stage II.67 Stage IIIC is subdivided into IIIC1 (pelvic nodal involvement alone) and IIIC2 (para-aortic involvement $+ / -$ pelvic node involvement), reflecting the inferior survival in those patients with positive para-aortic nodes.67 To maintain consistency, the NCCN Panel has reinterpreted historical studies using the 1988 FIGO staging system to reconcile those studies with the 2009 staging system. In the 2009 FIGO staging the presence of positive peritoneal cytology no longer increases the disease stage, as its importance as an independent risk factor has been called into question. 68 However, FIGO and AJCC continue to recommend that peritoneal washings be obtained and results be recorded (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma).70 # Principles of Evaluation and Surgical Staging for Endometrial Carcinoma Staging should be done by a team with expertise in imaging, pathologic evaluation, and surgery. The amount of surgical staging that is necessary to determine disease status depends on preoperative and intraoperative assessment by experienced surgeons. Pathologic nodal assessment for apparent uterine-confined endometrial cancer informs both stage and adjuvant therapy. However, if final pathology shows a noninvasive endometrioid histology, nodal assessment can be eliminated. The NCCN sentinel lymph node (SLN) algorithm is recommended if sentinel node mapping is utilized. # Pathology An expert pathologic review determines the specific epithelial histology of the tumor (endometrioid, serous, clear cell, carcinosarcoma, or undifferentiated). Morphologic evaluation of endometrial carcinoma to determine histologic type—especially in high-grade cancers—is challenging and issues exist regarding diagnostic reproducibility. The pathologic assessment of the uterus and the nodes is described in the algorithm. The assessment of the uterus includes the hysterectomy type, specimen integrity, tumor site and size, histologic type and grade if applicable, myometrial invasion (depth of invasion in mm/myometrial thickness in mm), cervical stromal involvement, and LVSI. Pathologists may be asked to quantify LVSI. The current definition of substantial LVSI is $\geq 4$ LVSI-involved vessels in at least one hematoxylin and eosin (H&E) slide (for clinically relevant LVSI in endometrial cancer).71 The pathologic assessment should also include assessment of involvement by other tissues such as the fallopian tubes, ovaries, vagina, parametrium, peritoneum, and omentum. The assessment of peritoneal/ascitic fluid cytology should also be obtained. If nodal resection was performed, the level of nodal involvement (ie, pelvic, common iliac, para-aortic) should be determined. SLNs should undergo ultrastaging for the detection of low # NCCN Guidelines Version 3.2025 Uterine Neoplasms volume metastases (LVMs). Ultrastaging commonly entails thin serial sectioning of the gross SLN and review of multiple H&E-stained sections with or without cytokeratin IHC for all blocks of SLN. There is no standard protocol for lymph node ultrastaging. See Principles of Pathology in the NCCN Guidelines for Endometrial Carcinoma. The Protocol for the Examination of Specimens From Patients With Carcinoma and Carcinosarcoma of the Endometrium from the College of American Pathologists (CAP) is a useful guide. This CAP protocol was revised to reflect the updated pathologic TNM requirements from the AJCC Cancer Staging Manual ( $8 ^ { \mathrm { t h } }$ edition) and 2015 FIGO Cancer Report.69,72 ER and PR testing is recommended in the setting of stage III, IV, or recurrent endometrioid carcinoma. Evaluation of HER2 overexpression should also be considered. Rottmann et al recently showed that $16 \%$ of 80 gynecologic carcinosarcomas (including uterine carcinosarcoma) showed HER2 overexpression and amplification when using the 2013 ASCO/CAP scoring system.22 Similar results were reported by Jenkins et al, Yoshida et al, and others.23,73-76 The Panel recommends HER2 IHC testing (with reflex to HER2 FISH for equivocal IHC) for possible treatment for advanced-stage or recurrent serous endometrial carcinoma or carcinosarcoma. HER2 IHC testing should also be considered in TP53- aberrant endometrial carcinoma regardless of histotyping. As the grade of the tumor increases, the accuracy of intraoperative evaluation of myometrial invasion decreases (ie, assessment by gross examination of fresh tissue).77 In one study, the depth of invasion was accurately determined by gross examinations in $8 7 . 3 \%$ of grade 1 lesions, $6 4 . 9 \%$ of grade 2 lesions, and $30 . 8 \%$ of grade 3 lesions.78 Studies show that in $1 5 \%$ to $20 \%$ of cases, the preoperative grade (as assessed by endometrial biopsy or curettage) is upgraded on final fixed pathologic evaluation of the hysterectomy specimen.79 # Lymphadenectomy Previously, a full standard lymphadenectomy (ie, dissection and assessment of both pelvic and para-aortic nodes) was recommended for all patients; however, to decrease side effects, a more selective and tailored nodal evaluation approach that includes the SLN algorithm is recommended by the NCCN Panel.80 No randomized trial data support routine full lymphadenectomy,81 although some retrospective studies have suggested that it is beneficial.82-84 Two randomized clinical trials from Europe reported that routine lymph node dissection did not improve the outcome of patients with endometrial cancer, but lymphadenectomy did identify those with nodal disease.85,86 However, these findings remain a point of contention.87-89 To avoid over-interpretation of these results, it is important to address the limitations of these randomized studies, including selection of patients, extent of lymph node dissection, and standardization of postoperative therapy.90 One of the trials did not standardize adjuvant treatment after staging surgery with lymphadenectomy; this has been identified as a weakness of the trial and may have contributed to the lack of difference in recurrence and survival in the two groups.84 The other concerns include the lack of central pathology review, subspecialty of surgeons, and adequacy of statistical power. Decisions about whether to perform lymphadenectomy, and, if done, to what extent (eg, pelvic nodes only or both pelvic and para-aortic nodes), can be made based on preoperative and intraoperative findings. Criteria have been suggested as indicative of low risk for nodal metastases: 1) $\textless 5 0 \%$ myometrial invasion; 2) tumor $^ { < 2 }$ cm; and 3) well or moderately differentiated histology.91,92 However, this may be difficult to accurately determine before final pathology results are available. If an expert gynecologic pathology is available, a frozen section to assess myoinvasion can be obtained and lymphadenectomy avoided if no myoinvasion or cervical invasion is identified.93 # NCCN Guidelines Version 3.2025 Uterine Neoplasms Nodal evaluation will identify those patients with nodal metastases. Identification of metastatic disease guides appropriate adjuvant treatment that has been shown to improve survival and decrease locoregional recurrence. The question of whether to add para-aortic lymphadenectomy to pelvic node dissection has been debated. Prior studies have shown conflicting information regarding the risk of para-aortic nodal metastases in patients without disease in the pelvic nodes.63,91,94,95 Para-aortic lymphadenectomy up to the renal vessels may be considered for selective patients, including those with pelvic lymphadenectomy or high-risk histologic features. Many surgeons do not do a full lymphadenectomy in patients with grade 1 early-stage endometrial cancer.80 In summary, lymph node dissection identifies patients requiring adjuvant treatment with radiation therapy (RT) and/or systemic therapy.96 A subset of patients may not benefit from lymphadenectomy; however, it may be difficult to preoperatively identify these patients. The NCCN Panel recommends that nodal evaluation be performed in patients with endometrial carcinoma, including para-aortic lymphadenectomy in patients who are at higher risk (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines® for Uterine Neoplasms).7 SLN mapping is the preferred alternative to full lymphadenectomy in the setting of apparent uterine-confined disease. The SLN surgical algorithm is described below. Lymphadenectomy is not recommended for patients with uterine sarcoma as metastasis to the nodes is unusual. # Sentinel Lymph Node Mapping The section on surgical staging (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines $\textsuperscript { \textregistered }$ for Uterine Neoplasms) includes recommendations about SLN mapping. SLN mapping may be considered for patients without suspicion of metastatic disease by preoperative imaging and no obvious extrauterine disease at exploration.97-101 In SLN mapping, dye is injected into the cervix, which travels to the sentinel nodes. This has emerged as a useful and validated technique for identification of lymph nodes that are at high risk for metastases (ie, SLN in patients with early-stage endometrial cancer).102 Superficial $( 1 { - } 3 ~ \mathsf { m m } )$ and optional deep $( 1 { - } 2 \mathsf { c m } )$ cervical injection leads to dye delivery to the main layers of lymphatic channel origins in the cervix and corpus, namely the superficial subserosal, intermediate stromal, and deep submucosal lymphatic sites of origin.103 Injection into the uterine cervix provides excellent dye penetration to the uterine vessels and main uterine lymphatic trunks that condense in the parametria and appear in the broad ligament leading to pelvic and occasionally paraaortic sentinel nodes. The uterine body lymphatic trunks commonly cross over the obliterated umbilical artery with the most common location of pelvic SLN being medial to the external iliac, ventral to the hypogastric, or in the superior part of the obturator region. A less common location is usually seen when the lymphatic trunks do not cross over the obliterated umbilical and move cephalad following the mesoureter; in these cases, the SLN is usually seen in the common iliac presacral region (see Figures 1–3 in Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma). The radiolabeled colloid most commonly injected into the cervix is technetium-99m $( ^ { 9 9 \mathrm { m } } \mathsf { T c } )$ ; colored dyes are available in a variety of forms (Isosulfan Blue $1 \%$ , Methylene Blue $1 \%$ , and Patent Blue $2 . 5 \%$ sodium). Indocyanine green (ICG) is the preferred imaging dye for SLN mapping.93,103-109 A surgical SLN algorithm is proposed to decrease the false-negative rate in patients with apparent uterine-confined disease (see Figure 4 in Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma).97,110 SLN mapping may be most appropriate for those at low to intermediate risk for metastases and/or for those who may not tolerate a standard lymphadenectomy.101,103,111-116 SLN identification should always be done prior to hysterectomy, except in cases where a # NCCN Guidelines Version 3.2025 Uterine Neoplasms bulky uterus must be removed to allow access to iliac vessels and lymph nodes. For example, suspicious or grossly enlarged nodes should be removed regardless of SLN mapping results. In SLN mapping, the surgeon’s expertise and attention to technical detail are critical. Patients may be able to avoid the morbidity of a standard lymphadenectomy with SLN mapping.115,117 Because SLNs identify the primary lymphatic pathway, this increases the yield of finding metastatic disease during the mapping process. For cases of failed SLN mapping, reinjection of the cervix may be considered. An additional 1 mL in the non-detected side can be infiltrated in the superficial cervical area. However, if SLN mapping fails, a reflex side-specific nodal dissection should be performed and any suspicious or grossly enlarged nodes should be removed regardless of mapping.97,116 A literature review and consensus recommendations for SLN mapping in endometrial cancer were released by the Society of Gynecologic Oncology (SGO).101 Close adherence to the NCCN SLN surgical algorithm was found to result in accurate prediction of pelvic lymph node metastasis with a $\textless 5 \%$ false-negative rate.97 Additionally, results were published from the FIRES trial, which compared SLN mapping to lymphadenectomy for endometrial cancer in the largest multicenter prospective study to date (n $= 3 8 5$ ).103 Mapping of at least one SLN was successful in $86 \%$ of patients; sensitivity was $9 7 . 2 \%$ ( $9 5 \%$ CI, 85.0–100), and negative predictive value was $9 9 . 6 \%$ $9 5 \%$ CI, 97.9–100). A systematic review of 17 studies with $\mathsf { n } > 3 0$ patients revealed detection rates of $60 \%$ to $100 \%$ ; detection rates for studies with larger cohorts $( \mathsf { n } >$ 100) were at least $80 \%$ . Retrospective application of a surgical algorithm generated $9 5 \%$ sensitivity, $9 9 \%$ predictive value, and a $5 \%$ false-negative rate.118 Another systematic review and meta-analysis of 55 studies with n $> 1 0$ patients $( \mathsf { n } = 4 9 1 5 )$ ) generated an overall detection rate of $81 \%$ with a $50 \%$ bilateral pelvic node detection rate and $1 7 \%$ paraaortic detection rate.93 In a retrospective analysis of patients with early-stage endometrial cancer $( \mathsf { n } = 7 8 0 )$ who underwent SLN mapping with lymphadenectomy versus lymphadenectomy alone, SLN mapping led to the detection of more metastasis $( 3 0 . 3 \%$ vs. $1 4 . 7 \%$ , $P < . 0 0 1 _ { \cdot }$ ) and was associated with greater use of adjuvant therapy.119 Long-term follow-up was reported from a prospective multicenter study in 125 patients with early-stage endometrial carcinoma who underwent SLN biopsy. Patients with a positive SLN underwent external beam RT (EBRT) and chemotherapy at a higher rate than those with a negative SLN. In patients with a detected SLN, relapse-free survival (RFS) at 50 months was $8 4 . 7 \%$ , and no difference was detected between patients with and without a positive SLN $( P = . 5 )$ .120 SLN mapping should be done in institutions with expertise in this procedure. If patients have apparent distant metastatic disease (based on imaging and/or surgical exploration), removal of nodes for staging purposes is not necessary because it will not change management.49,55 Historically, SLN mapping was controversial in patients with high-risk histology (eg, serous carcinoma, clear cell carcinoma, carcinosarcoma).80,121 However, SLN mapping in patients with high-risk histologies (ie, grade 3, serous, clear cell, carcinosarcoma) has been reported with promising results as a potential alternative to complete lymphadenectomy.116,122,123 A recent multi-institutional retrospective study concluded that SLN mapping versus SLN mapping with lymphadenectomy in high-risk endometrial cancer did not impact survival outcomes.124 A recent prospective, multicenter cohort study (SENTOR trial) examined the diagnostic accuracy of SLN mapping versus lymphadenectomy for intermediate- and high-grade endometrial cancer in 156 patients. Of 27 patients with nodal metastasis, SLN mapping correctly identified 26 of them $9 6 \%$ sensitivity; $9 5 \%$ CI; $8 1 \% - 1 0 0 \% )$ , thus concluding the acceptable accuracy of SLN mapping in high-grade endometrial cancer. 125 # NCCN Guidelines Version 3.2025 Uterine Neoplasms More studies have suggested the value of using SLN mapping for surgical staging in high-grade endometrial cancer.126 # SLN Ultrastaging In general, SLN mapping allows for increased intraoperative surgical precision to identify nodes more likely to harbor metastasis combined with enhanced pathology protocols, which has been shown to increase the detection of nodal metastasis, which may alter stage and adjuvant therapy recommendations. Studies have suggested that SLN ultrastaging leads to upstaging in 5% to 15% of patients.100,112,114,117,118 Ultrastaging typically includes two components: serial sectioning with review of multiple H&E-stained slides with or without cytokeratin IHC staining.127 Recent data highlight the potential significance and impact of SLN ultrastaging to improve the accuracy of detecting micrometastases.128 In a cohort of 508 patients who underwent SLN mapping, ultrastaging detected 23 additional cases of micrometastasis that would have been missed by conventional H&E staining.129 A multicenter study of 304 patients with presumed low- or intermediate-risk disease showed that SLN biopsy and ultrastaging detected metastatic SLNs in a 3-fold greater number of patients than standard lymphadenectomy.130 The implications and appropriate management of micrometastases and isolated tumor cells (ITCs), jointly referred to as LVM, detected via SLN ultrastaging are not yet clear.101,114,117,131-135 Studies have recently begun to investigate the significance of ITCs discovered during SLN mapping in early-stage endometrial cancer. The AJCC $8 ^ { \mathrm { t h } }$ edition cancer staging manual indicates that the lymph nodes with ITCs should be clearly reported even though they do not affect the overall staging.136 When ITCs are detected in the absence of macrometastasis and micrometastasis, the lymph node stage is designated as $\mathsf { p N O } ( \mathsf { i } + )$ . A retrospective review examined 844 patients with endometrial cancer that underwent SLN mapping.137 The majority of patients with ITCs, micrometastasis, and macrometastasis received adjuvant chemotherapy $( 8 3 \%$ , $81 \%$ , and $89 \%$ , respectively). RFS at 3 years was $90 \%$ for those with negative SLNs, $86 \%$ for ITCs, and $86 \%$ for micrometastasis. Only patients with SLN macrometastasis had significantly lower RFS $( 7 1 \% , P <$ .001). A prospective observational study of 519 patients compared outcomes for patients with SLN macrometastasis, micrometastasis, and ITCs, taking into account adjuvant treatment.138 Patients with SLN ITCs had a significantly better 3-year progression-free survival (PFS) compared with patients with SLN macrometastasis $( 9 5 . 5 \%$ vs. $5 8 . 5 \%$ ), and outcomes were similar between patients with negative SLNs, ITCs, and micrometastasis. Recurrence was detected in only 1 of 31 patients with ITCs (stage IB carcinosarcoma) and adjuvant treatment did not appear to influence outcomes. Based on these early data, it is unclear if patients with SLN ITCs would derive significant benefit from adjuvant treatment.139 Future evaluation of prognosis/outcome may need to prospectively examine the threshold for and impact of adjuvant therapy for patients with scattered ITCs. # Minimally Invasive Procedures Over the past decade, practice has trended towards minimally invasive approaches to total abdominal hysterectomy (TAH)/bilateral salpingo oophorectomy (BSO) and lymph node assessment in patients with earlystage endometrial cancer. 140 Although these procedures may be performed by any surgical route (eg, laparoscopic, robotic, vaginal, abdominal), the standard in those with apparent uterine-confined disease is to perform the procedure via a minimally invasive approach. Randomized trials, a Cochrane Database Systematic Review, and population-based surgical studies support that minimally invasive # NCCN Guidelines Version 3.2025 Uterine Neoplasms techniques are preferred in the appropriate candidate due to a lower rate of surgical site infection, transfusion, venous thromboembolism, decreased hospital stay, and lower cost of care, without compromise in oncologic outcome.140-146 Despite data showing that minimally invasive procedures result in lower perioperative complications and lower cost of care, racial and geographic disparities in access to minimally invasive surgical care have been observed.142,146 A randomized phase III trial evaluated laparoscopy for comprehensive surgical staging; patients $n = 2 6 1 6 )$ with clinical stage I to IIA disease (GOG-LAP2) were assessed.145,147 Patients were randomly allocated 2:1 to laparoscopy or laparotomy. Results from LAP2 indicate that $26 \%$ of patients needed conversion to laparotomy because of poor visibility, metastatic cancer, bleeding, increased age, or increased body mass index (BMI). Detection of advanced cancer was not significantly different between the groups. However, significant differences were noted in removal of pelvic and para-aortic nodes $8 \%$ not removed with laparoscopy vs. $4 \%$ with laparotomy, $P < . 0 0 0 1$ ).148,149 Significantly fewer postoperative adverse events and shorter hospitalization occurred with laparoscopy compared with laparotomy. Recurrence rates were $1 1 . 4 \%$ for laparoscopy versus $1 0 . 2 \%$ for laparotomy. The 5-year overall survival (OS) rate was $84 . 8 \%$ for both arms of LAP2.147 Laparoscopic staging was associated with improved postoperative quality of life across several parameters.144 The LACE trial compared outcomes of patients with stage I endometrial carcinoma $( \mathsf { n } = 7 6 0 )$ who were randomized to undergo total abdominal hysterectomy (TAH) or total laparoscopic hysterectomy (TLH), where half of the patients received concomitant lymphadenectomy.141 At a median follow-up of 4.5 years, disease-free survival (DFS) was $8 1 . 3 \%$ for laparotomy versus $8 1 . 6 \%$ for laparoscopy, with no significant differences observed between groups for recurrence and OS. Another randomized trial $( \mathsf { n } = 2 8 3 )$ comparing laparoscopy versus laparotomy reported shorter hospital stay, less pain, and faster resumption of daily activities with laparoscopy.150 A recent follow-up study of a multicenter randomized trial evaluated outcomes for TLH versus TAH in 279 patients with early-stage, low-risk endometrial cancer who did not undergo concomitant lymphadenectomy and reported comparable disease recurrence and 5- year survival rates. The results were also similar to studies with lymphadenectomy.151 Laparotomy may still be required for certain clinical situations (eg, patients who are older, those with a very large uterus) or certain metastatic presentations.145,152,153 Robotic surgery is a minimally invasive technology that has been increasingly used in the surgical staging of endometrial carcinoma due to its potential advantages over laparotomy, especially for patients who are affected by overweight. 154-158 Prospective cohort and retrospective studies suggest that robotic approaches perform similarly to laparoscopy and result in comparable or improved perioperative outcomes.158-163 Oncologic outcomes appear to be comparable to other surgical approaches, although longer-term outcomes are still being investigated.164-166 In certain patients, robotic surgery may result in less frequent conversion to laparotomy when compared with laparoscopic approaches and also appears to be safe and feasible in patients at higher anesthesiologic risk.158,159,167 Costs for robotic equipment and maintenance remain high.168 154,155,164- 166,169 The SGO, American Association of Gynecologic Laparoscopists (AAGL), and American Congress of Obstetricians and Gynecologists (ACOG) have published guidelines or position statements about robotic surgery.170-172 For reviews on the robotic-assisted surgery for gynecologic malignancies and associated cost issues, see Sinno and Fader and Gala et al.173,174 # NCCN Guidelines Version 3.2025 Uterine Neoplasms # Primary Treatment These NCCN Guidelines divide pure endometrioid cancer into three categories for delineating treatment: 1) disease limited to the uterus; 2) suspected or gross cervical involvement; and 3) suspected extrauterine disease. Most patients with endometrial cancer have stage I disease at presentation, and surgery (with or without adjuvant therapy) is recommended for patients who are medically operable. As a general principle, endometrial carcinoma should be removed en bloc to optimize outcomes; intraperitoneal morcellation should be avoided.175-178 # Disease Limited to the Uterus To stage patients who are medically operable with endometrioid histologies clinically confined to the fundal portion of the uterus, the recommended surgical procedure includes removal of the uterus and bilateral tubes and ovaries with lymph node and abdominal assessment (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines® for Uterine Neoplasms and in this Discussion and Lymphadenectomy and Sentinel Lymph Node Mapping in this Discussion).87 Ovarian preservation may be safe in select premenopausal patients with stage I endometrioid cancer.179-181 Minimally invasive surgery is the preferred approach when technically feasible and is considered a quality measure by the SGO and the American College of Surgeons (www.sgo.org/quality-outcomes-and-research/quality-indicators; https://www.facs.org/quality-programs/cancer-programs/national-cancerdatabase/quality-of-care-measures). During surgery, the intraperitoneal structures should be carefully evaluated, and suspicious areas should be biopsied. While not specifically affecting staging, FIGO and AJCC recommend that peritoneal cytology should be collected, and results should be recorded. Cytology results should not be taken in isolation to guide adjuvant therapy. Enlarged or suspicious lymph nodes should be excised to confirm or rule out metastatic disease. Retroperitoneal node dissection with pathologic evaluation—in the absence of clinically apparent lymphadenopathy—is useful when using the 2009 FIGO staging criteria, but its routine use has been questioned (see Lymphadenectomy in this Discussion). For stage II patients, TH/BSO is the standard procedure. Radical hysterectomy should only be performed if needed to obtain negative margins. Patients with apparent uterine-confined endometrial carcinoma are candidates for sentinel node mapping, which assesses the pelvic nodes bilaterally and may be less morbid than complete lymphadenectomy (see Sentinel Lymph Node Mapping in this Discussion). Adherence to the NCCN SLN algorithm is critical. # Incomplete Surgical Staging For patients with incomplete surgical staging and high-risk intrauterine features, imaging is recommended, especially in patients with higher grade histologies. 182,183 Imaging can be omitted for stage 1A, grade 1–2 endometrium-limited carcinoma. Surgical restaging, including lymph node dissection, can also be done.91 Based on the imaging and/or surgical restaging results, recommended adjuvant treatment options are provided in the algorithm (see Adjuvant Treatment for Incompletely Surgically Staged in the NCCN Guidelines for Endometrial Carcinoma). For stage IB disease, any grade or any myometrial invasive carcinoma with LVSI and negative imaging that has not been surgically restaged, RT (EBRT and/or vaginal brachytherapy with or without systemic therapy) is recommended. The NCCN Panel notes systemic therapy as category 2B in this scenario. # Fertility-Sparing Therapy Although the primary treatment of endometrial cancer is usually hysterectomy, continuous progestin-based therapy may be considered for highly selected patients with grade 1, stage IA (noninvasive) disease who wish to preserve fertility.184-188 Likewise, it may also be selectively used for # NCCN Guidelines Version 3.2025 Uterine Neoplasms young patients with endometrial hyperplasia who desire fertility preservation. The guidelines include an algorithm for fertility-sparing therapy in selected patients with biopsy-proven grade 1 (preferably by D&C), stage IA noninvasive endometrioid adenocarcinoma (see Criteria for Considering Fertility-Sparing Options in the NCCN Guidelines for Endometrial Carcinoma). The Panel recommends consultation with a fertility expert and genetic evaluation of tumor and evaluation for inherited cancer risk. When considering fertility-sparing therapy, all of the criteria must be met as outlined in the algorithm (eg, no metastatic disease) and a negative pregnancy test must be ensured. Patients should also receive counseling that fertility-sparing therapy is not the standard of care for the treatment of endometrial carcinoma. TH/BSO with surgical staging is recommended after childbearing is complete, if therapy is not effective, or if progression occurs. Fertility-sparing therapy is not recommended for patients at high risk (eg, those with high-grade endometrioid adenocarcinomas, uterine serous carcinoma, clear cell carcinoma, carcinosarcoma, and uLMS). Continuous progestin-based therapy may include megestrol acetate, medroxyprogesterone, or an intrauterine device (IUD) containing levonorgestrel.184,185,189 A complete response (CR) occurs in about $50 \%$ of patients.184 The use of progestin-based therapy should be carefully considered in the context of other patient-specific factors, including contraindications such as breast cancer, stroke, myocardial infarction, pulmonary embolism, deep vein thrombosis, and smoking. The use of dual- progestin therapy can also be considered, which includes either megestrol acetate or medroxyprogesterone acetate and IUD containing levonorgestrel. The Panel also recommends counseling for weight management and lifestyle modification (see Healthy Lifestyles and Nutrition and Weight Management in the NCCN Guidelines for Survivorship). In patients receiving progestin-based therapies, the NCCN Panel recommends close monitoring with endometrial sampling (biopsies or D&C) every 3 to 6 months. TH/BSO with staging is recommended: 1) after childbearing is complete; 2) if patients have documented progression on biopsy; or 3) if endometrial cancer is still present after 6 to 12 months of progestin-based therapy.188,190 Total hysterectomy with possible removal of ovaries with staging is the preferred option by 12 months of progestinbased therapy. Although some young patients who had subsequent negative endometrial biopsies after hormonal therapy were able to become pregnant $( 3 5 \% )$ , the ultimate recurrence rate was high $( 3 5 \% )$ .184,187,191-193 In patients with persistent endometrial carcinoma after 6 months of disease progression on hormonal therapy, the Panel recommends pelvic MRI to exclude myoinvasion and nodal/ovarian metastasis before continuing fertility-sparing therapy. In a study of premenopausal patients with stage IA to B endometrial cancer, median 16-year follow-up data suggest that ovarian preservation is safe and not associated with an increased risk of cancer-related mortality.179 Other studies also suggest that ovarian preservation may be safe in select patients.180,181 # Suspected or Gross Cervical Involvement For patients with suspected or gross cervical involvement (endometrioid histologies), cervical biopsy or pelvic MRI should be performed if not done previously (see Additional Workup in the NCCN Guidelines for Endometrial Carcinoma).182,183,194,195 If negative, patients are assumed to have disease that is limited to the uterus and are treated as previously described, although a radical hysterectomy may be performed when necessary to obtain negative margins. It may be difficult to distinguish primary cervical carcinoma from stage II endometrial carcinoma. Thus, for patients suitable for primary surgery, TH or radical hysterectomy is recommended along with BSO, cytology (peritoneal lavage), and # NCCN Guidelines Version 3.2025 Uterine Neoplasms evaluation of lymph nodes if indicated (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma).87 In these patients, radical or modified radical hysterectomy may improve local control and survival when compared with TH.196,197 Alternatively, the patient may undergo EBRT and brachytherapy (category 2B) followed by TH/BSO and surgical staging 4 to 12 weeks post RT. # Suspected Extrauterine Disease If extrauterine disease (endometrioid histologies) is suspected, imaging studies are recommended along with CA-125 testing (see Additional Workup in the NCCN Guidelines for Endometrial Carcinoma). ER testing is recommended in the setting of stage III or IV endometrioid tumors. Patients with no evidence of extrauterine disease are treated using guidelines for disease limited to the uterus. Patients with abdominal- or pelvic-confined disease require surgical intervention using TH/BSO with surgical staging and surgical debulking with the goal to have no measurable residual disease; several studies support debulking.87,198-200 Consider preoperative chemotherapy.201 For distant visceral metastasis (eg, liver involvement), recommended options include systemic therapy with (or without) EBRT with (or without) TH/BSO and with (or without) stereotactic body RT (SBRT). Ablative radiation can be considered for 1 to 5 metastatic lesions if disease is otherwise controlled (category 2B).202 # Patients Not Suited for Primary Surgery For uterine-confined diseases not suitable for primary surgery, EBRT and/or brachytherapy is the preferred treatment approach. Alternatively, progestational agents (such as medroxyprogesterone acetate and megestrol acetate) and levonorgestrel IUD can also be considered for select patients (eg, ER- and PR-positive). Patients receiving hormonal therapy alone should be closely monitored by endometrial biopsy (eg, consider endometrial biopsies every 3–6 months).43,203 For suspected gross cervical involvement in patients who are not suited for primary surgery, EBRT and brachytherapy is an effective treatment that can provide pelvic control and long-term PFS (see Principles of Radiation Therapy in the NCCN Guidelines for Uterine Neoplasms).204-207 If rendered operable, local treatment consisting of surgery should follow 4 to 12 weeks post RT or definitive RT if inoperable. Systemic therapy alone is also a primary treatment option (category 2B) but should be followed by EBRT $^ +$ brachytherapy if the patient remains inoperable and surgical resection if rendered operable. Patients with unresectable extrauterine pelvic disease (ie, vaginal, bladder, bowel/rectal, nodal, or parametrial involvement) are typically treated with EBRT with (or without) brachytherapy with (or without) systemic therapy, followed by re-evaluation of tailored surgery 4 to 12 weeks post RT. 208-211 Systemic therapy alone can also be considered. Based on treatment response, patients should be re-evaluated for surgical resection and/or RT. # Adjuvant Therapy # Uterine-Confined Disease Thorough surgical staging provides important information to assist in selection of adjuvant therapy for endometrial tumors (see Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma). Patients with stage I endometrial cancer who have thorough surgical staging are stratified by adverse risk factors (age, positive LVSI, tumor size, and lower uterine segment or surface glandular involvement).212,213 Recommended adjuvant treatment is outlined in the algorithm (see the NCCN Guidelines for Endometrial Carcinoma). Note that the treatment algorithm was revised in 2010 based on the updated FIGO staging.67 However, by necessity, much of the discussion in this manuscript has been based on data from patients staged using the older # NCCN Guidelines Version 3.2025 Uterine Neoplasms FIGO/AJCC staging system. The implications of stage migration should be considered when evaluating historical data. The basic concept underlying the recommendations in the NCCN Guidelines is the trend toward selection of more aggressive adjuvant therapy for patients as tumor grade and myometrial and/or cervical invasion increase, as risk of systemic metastases increases.214-216 In surgical stage I and II endometrial cancer, other pathologic factors that may influence the decision regarding adjuvant therapy include LVSI, patient age, tumor volume, depth of invasion, and lower uterine segment or cervical glandular involvement. When administering adjuvant RT, it should be initiated as soon as the vaginal cuff has healed, but no later than 12 weeks after surgery. Significant controversy centers on how much adjuvant therapy is necessary in patients with surgical stage I endometrial cancer. The practice of surgical staging has led to a decrease in the use of adjuvant therapy for stage I endometrial carcinoma, which is reflected in the option of observation in the NCCN Guidelines for selected patients with low-risk features (see section on Adjuvant Treatment in the NCCN Guidelines for Endometrial Carcinoma).96,213,214,217-219 The NCCN Panel prefers observation for patients with stage IA, grade 1/2 disease, but strongly suggests treatment with adjuvant vaginal brachytherapy for those $\mathtt { \ge 6 0 }$ years and/or those with LVSI. For patients with stage IA, grade 3 tumors, especially in those who have been surgically staged, vaginal brachytherapy is the preferred option, or observation can be considered if no myometrial invasion is present. If higher risk factors are present, ie, age $\mathtt { \ge } 7 0$ years or LVSI, EBRT can be considered as a category 2B option. For patients with stage IB, grade 1–2 disease, vaginal brachytherapy is preferred although observation can be considered if no adverse risk factors are present. In these patients, the PORTEC-2 trial, without evaluation of pelvic nodes, found pelvic recurrence to be low with vaginal brachytherapy alone.220 EBRT can be considered in grade 2 tumors if additional risk factors are present such as age $\mathtt { \ge 6 0 }$ years and/or if LVSI is present. For stage IB, grade 3 disease with adverse risk factors, systemic therapy is added as a category 2B option (in addition to EBRT and/or vaginal brachytherapy). The recommended postoperative (ie, adjuvant) treatment options for surgical stage II patients (using thorough surgical staging) are shown in the algorithm (see Adjuvant Treatment for stage II in the NCCN Guidelines for Endometrial Carcinoma). The NCCN Panel generally agrees on the role of adjuvant therapy for patients with an invasive cervical component if extrafascial hysterectomy is performed. However, for patients with stage II disease who have had a radical hysterectomy with negative surgical margins and no evidence of extrauterine disease, EBRT (preferred) and/or vaginal brachytherapy with (or without) systemic therapy (category 2B) are options. As with stage I disease, the presence of adverse risk factors (including depth of stromal invasion, grade, LVSI, and adverse fundal risk factors) should be considered when selecting adjuvant therapy for stage II disease.221 # Adjuvant RT Several phase III trials have assessed adjuvant therapy in patients with uterine-confined disease. In summary, the use of adjuvant RT improves pelvic control in patients with selected risk factors (and may improve PFS) but has not been shown to improve OS. However, many of the earlier trials had limitations as the patients were primarily low risk (ie, they had low-risk intrauterine pathologic risk factors). It is recognized that in patients with uterine-confined disease, there is a spectrum of risk based on intrauterine pathologic findings. Adverse intrauterine pathologic risk factors include high-grade tumors, deep myometrial invasion (and consequently more advanced stage), LVSI (especially extensive), and serous or clear cell carcinoma histologies. # NCCN Guidelines Version 3.2025 Uterine Neoplasms Four trials have evaluated the role of adjuvant external-beam pelvic RT in patients with endometrial carcinoma. In two of these trials, the patients were not formally staged (Postoperative Radiation Therapy in Endometrial Carcinoma [PORTEC-1], Aalders).222,223 In the third trial (ASTEC/EN.5), only $50 \%$ of the patients were thoroughly staged as part of a companion surgical protocol.85,224 However, formal surgical staging was mandated for all patients in the GOG 99 trial. 225 Note that these trials used the older staging system (ie, before 2009). The PORTEC-1 and GOG 99 trials suggest that external-beam pelvic RT provides a locoregional control benefit in selected patients with uterine-confined disease.222,226 Radiation was not shown to increase OS.227 It is important to note that the PORTEC-1 trial was powered to evaluate OS, although the GOG 99 trial was not. Similarly the Aalders’ randomized trial found that RT reduced vaginal (ie, locoregional) recurrences but did not reduce distant metastases or improve survival.223 A pooled randomized trial (ASTEC/EN.5) suggested that adjuvant pelvic RT alone did not improve either RFS (ie, PFS) or OS in patients with intermediate-risk or high-risk early-stage endometrial cancer, but there was an improvement in pelvic control.224 However, the ASTEC/EN.5 study is very controversial; $51 \%$ of the patients in the ASTEC observation group received vaginal brachytherapy. Vaginal brachytherapy has been shown to decrease vaginal recurrence, and in PORTEC-2 vaginal brachytherapy was compared in a prospective randomized trial with EBRT in patients at low risk. Vaginal brachytherapy alone was shown to sufficiently control the pelvis and was less toxic than full pelvic RT. As most pelvic recurrences are vaginal, inclusion of vaginal brachytherapy in the “observation” arm of the ASTEC/EN.5 study weakens any conclusions regarding pelvic radiation. 89,228 The Keys’ trial (GOG 99) showed that adjuvant pelvic RT improved locoregional control and relapse-free interval (ie, PFS), without an OS benefit, although the study was not powered to evaluate OS. 225,229,230 In both trials pelvic radiation was found to be of greater benefit in patients $\mathtt { > 6 0 }$ years with higher grade and more deeply invasive disease. To help select the appropriate patient population that may benefit from adjuvant pelvic RT, the GOG 99 and PORTEC trials defined risk factors for patients at high-intermediate risk (HIR) for recurrence, although the definition differed between these trials. 222,225 Risk factors for recurrence identified in both trials included higher age, deep myometrial invasion $( > 5 0 \% )$ , higher grade (grade 2 or 3, serous or clear cell), and LVSI (especially extensive as defined in the PORTEC trials). Based on risk factors identified in GOG 99, HIR disease was defined as patients $\mathtt { < 5 0 }$ years with grade 2 or 3 disease, myometrial invasion $50 \%$ , and LVSI. 225 Patients 50 to 70 years of age were considered HIR if they had 2 of the 3 identified high-risk features. Patients $\mathtt { \ge } 7 0$ years were defined as HIR if they also had one risk feature present. Based on data from PORTEC-1, HIR patients were defined as having 2 of 3 risk factors (ie, age $\mathtt { > 6 0 }$ years, deep myometrial invasion, grade 3 histology).222,229 LVSI was not considered in the original PORTEC trials, but a subsequent retrospective evaluation demonstrated increased recurrence with extensive LVSI, as defined by the protocol. Due to concerns about potential toxicity of external-beam pelvic RT, the role of vaginal brachytherapy alone in uterine-confined disease has been evaluated. PORTEC-2 randomly assigned patients to external-beam pelvic RT versus vaginal brachytherapy alone in uterine-confined disease. PORTEC-2 showed excellent and equivalent vaginal and pelvic control rates with both adjuvant radiation approaches and no difference in OS.220 Given that vaginal brachytherapy is associated with significantly less toxicity than pelvic RT, vaginal brachytherapy alone is a reasonable choice for patients with uterine-confined endometrial cancer as defined in the PORTEC-2 trial. 220,229-237 The use of vaginal brachytherapy and/or whole pelvic RT should be carefully tailored to a patient’s pathologic findings. # NCCN Guidelines Version 3.2025 Uterine Neoplasms Both PORTEC-1 and PORTEC-2 specifically excluded patients with 1998 FIGO stage 1C and grade 3 endometrial carcinoma (2009 FIGO stage IB, grade 3);67 thus, the use of adjuvant brachytherapy alone in this higher risk subset remains more controversial. PORTEC studies did not evaluate lymph nodes and, therefore, in the context of complete surgical staging and the lack of a survival benefit, the need for pelvic irradiation remains controversial in uterine-confined disease. A meta-analysis evaluated results from studies that compared adjuvant postoperative EBRT with or without vaginal brachytherapy and vaginal brachytherapy alone in stage II endometrial cancer. EBRT $^ +$ vaginal brachytherapy significantly reduced locoregional recurrence versus vaginal brachytherapy alone. OS was comparable in both arms.238 The GOG 249 trial examined vaginal cuff brachytherapy and 3 cycles of carboplatin/paclitaxel therapy (3 cycles) versus pelvic EBRT only in patients with high-risk, uterine-confined endometrial carcinoma $( \mathsf { n } = 6 0 1$ ), including serous and clear cell carcinoma. GOG 249 reported significantly increased rates of nodal recurrence (primarily pelvic) in the brachytherapy plus chemotherapy arm compared with the pelvic EBRT arm. No significant between-group differences in vaginal or distant recurrence rates were observed. However, there were more extravaginal pelvic failures in the brachytherapy plus chemotherapy arm. At a median follow-up of 53 months, 3-year RFS was $82 \%$ for both treatment arms; 3-year OS was $8 8 \%$ for the brachytherapy plus chemotherapy cohort and $91 \%$ for the pelvic EBRT cohort. Acute toxicity was more common and severe for patients receiving brachytherapy with chemotherapy. No differences in late-onset toxicities were observed.239 Questions were raised whether 3 cycles of chemotherapy were sufficient to control distant disease. Analysis of pooled data from PORTEC-1 and PORTEC-2 ranked the predictive power of multiple variables on patient outcomes examined in these trials. Patient age, tumor grade, and LVSI were highly predictive for locoregional relapse (LRR), distant relapse (DR), OS, and DFS, and treatment given (EBRT vs. vaginal brachytherapy) was predictive for LRR and DFS.212 The benefit of adjuvant EBRT in the highest risk spectrum of uterine-confined disease remains controversial. Most NCCN Panel Members feel that patients with deeply invasive grade 3 tumors should receive adjuvant treatment. Two large retrospective SEER analyses of patients with endometrial cancer found that adjuvant RT improved OS in those with high-risk disease.240,241 In a meta-analysis of randomized trials, a subset analysis found that adjuvant pelvic RT for stage I disease was associated with a trend towards a survival advantage in the highest-risk spectrum (eg, those with 1988 FIGO stage IC grade 3) but not in patients at lower risk; however, other reviews have shown conflicting results.232,242- 246 The long-term follow-up study (median 20.5 years) of 568 patients with early-stage endometrial carcinoma enrolled in the Aalders trial compared long-term outcomes in patients who received vaginal brachytherapy plus EBRT versus vaginal brachytherapy alone. The findings suggested no statistical difference in OS between the study groups, and in this cohort, patients $\mathtt { < 6 0 }$ years of age who received EBRT had increased incidence of secondary cancers and subsequent higher mortality rates.232 Evaluation of secondary malignancies in the context of increased genetic susceptibility (eg, MSI-H) and radiation is ongoing. # Adjuvant Systemic Therapy Patients with deeply invasive, grade 3, uterine-confined disease (2009 FIGO stage IB, grade 3 [formerly 1988 FIGO stage IC, grade 3]) have a relatively poor prognosis. Despite adjuvant therapy with pelvic RT, a significant number of patients continue to have a significant risk of distant metastases, and an optimal adjuvant therapy is still sought. 225,226 Therefore, some clinicians suggested that adding systemic therapy to adjuvant RT may provide added therapeutic benefit (ie, decrease in distant # NCCN Guidelines Version 3.2025 Uterine Neoplasms metastases).214,247 Studies have evaluated the role of systemic therapy in highest risk uterine-confined disease.247,248 PFS is improved with adjuvant sequential chemotherapy.247 However, the NCCN Panel feels that adjuvant systemic therapy is a category 2B recommendation in this setting because an OS advantage has not been shown.247 The GOG-249 phase 3 trial evaluated the benefit of adjuvant pelvic RT versus vaginal cuff brachytherapy plus 3 cycles of paclitaxel/carboplatin combination in 601 patients with high-intermediate and high-risk early-stage endometrial cancer. The 5-year RFS and OS were similar in both groups and the superiority of any of these treatments was not demonstrated. Acute toxicity was greater in the combination therapy.249 # Advanced Stage/Extrauterine Disease There is a consensus that patients with documented extrauterine disease are at increased risk for recurrence and need adjuvant therapy; however, the optimal form of adjuvant therapy has yet to be determined.250-252 Patients with extrauterine disease confined to the lymph nodes or the adnexa may be treated with pelvic or extended-field RT alone or with chemotherapy (radiation is targeted to sites of nodal disease). 253 However, systemic therapy is regarded as the foundation of adjuvant therapy for patients with extrauterine disease. The NCCN Guidelines include carboplatin/paclitaxel as the preferred systemic therapy option in the primary/adjuvant setting for advanced-stage disease or high-risk histologies.254-256 The NCCN Guidelines recently added the pembrolizumab/carboplatin/paclitaxel and dostarlimab carboplatin/paclitaxel triplet regimens as category 1, preferred, primary therapy options for stage III or IV disease based on the data from phase III NRG-GY018 and RUBY trials, respectively, and the expanded FDA approvals. 257-260 The pembrolizumab/carboplatin/paclitaxel regimen is recommended for stage III or IVA with measurable disease post-surgery or for stage IVB with or without measurable disease. Since the NRG-GY018 trial did not include patients with carcinosarcoma histology, the NCCN Panel does not recommend the pembrolizumab/carboplatin/paclitaxel treatment option for patients with carcinosarcoma disease. The ENGOTen11/GOG-3053/KEYNOTE-B21 trial261 evaluated the addition of pembrolizumab to adjuvant chemotherapy (with/without RT) among patients with newly diagnosed, high-risk endometrial cancer with dMMR and pMMR status. Although Kaplan-Meier estimates of 2-year DFS rates in a total of 1095 randomized patients (pembrolizumab, $\mathtt { n } = 5 4 5$ ; placebo, $\mathsf { n } = 5 5 0 $ ) were $7 5 \%$ and $76 \%$ in the pembrolizumab and placebo groups, respectively, the hazard ratio (HR) for DFS was 0.31 ( $9 5 \%$ CI, 0.14–0.69) in the dMMR population $a _ { \mathsf { n } } = 2 8 1$ ). For patients not meeting the eligibility criteria for NRG-GY018, carboplatin/paclitaxel $^ +$ pembrolizumab should be considered for stage III–IV dMMR tumors. The dostarlimab carboplatin/paclitaxel option is recommended for adult patients with primary advanced endometrial carcinoma: stage IIIA, IIIB, or IIIC1 post-surgery with measurable disease, stage IIIC1 with carcinosarcoma, clear-cell, serous, or mixed histology regardless of the presence of measurable disease; and stage IIIC2 or stage IV disease regardless of the presence of measurable disease. Another phase III trial (RUBY)262 evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit with a statistically significant reduction in the risk of death [HR, 0.69; $9 5 \%$ CI, 0.54–0.89, $P = . 0 0 2 0 ]$ in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile. For stages III and IV disease, carboplatin/paclitaxel/durvalumab regimen is recommended as a preferred regimen for dMMR tumors based on DUO-E trial and FDA approval.263,264 The DUO-E trial is a phase III, global, doubleblind, placebo-controlled trial that randomly assigned advanced or # NCCN Guidelines Version 3.2025 Uterine Neoplasms recurrent endometrial cancer 1:1:1 to carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab $^ +$ olaparib arm). In the intention-totreat population, statistically significant PFS benefit was observed in the durvalumab (HR, 0.71; $9 5 \%$ CI, 0.57–0.89; $P = . 0 0 3 )$ and durvalumab $^ +$ olaparib arms (HR, 0.55; $9 5 \%$ CI, 0.43–0.69; $P < . 0 0 0 1$ ) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab vs. control], 0.42; $9 5 \%$ CI, 0.22–0.80; HR [durvalumab $^ +$ olaparib vs. control], 0.41; $9 5 \%$ CI, 0.21–0.75). In the dMMR subgroup, median PFS was not reached (NR) versus 7.0 months for durvalumab versus control and median PFS was 31.8 versus 7.0 months for durvalumab $^ +$ olaparib versus control. Based on these data and the FDA approval, the NCCN Panel recommends carboplatin/paclitaxel/durvalumab as a category 1, preferred regimen for stage III–IV dMMR tumors only. A randomized phase II study examined the addition of trastuzumab to carboplatin/paclitaxel for patients with advanced or recurrent HER2/neupositive uterine serous carcinoma.265 Among patients with stage III/IV disease undergoing primary treatment $( \mathsf { n } = 4 1$ ), median PFS was 17.7 months versus 9.3 months for the experimental and control arms, respectively $\langle P = . 0 1 3 )$ . PFS for patients with recurrent disease $( \mathsf { n } = 1 7 )$ was 9.2 months versus 6.0 months (HR, 0.44; $90 \%$ CI, 0.23–0.83; $P =$ .015). The addition of trastuzumab appeared to improve PFS without increasing overall toxicity. The safety and tolerability of the trastuzumab combination was further evaluated in 60 patients with advanced/recurrent uterine serous carcinoma with HER2/neu overexpression in a recent phase 2 trial with PFS as the primary endpoint. Trastuzumab appears to be safe and has a manageable toxicity profile when used in combination with chemotherapy. 266 The triplet therapy regimen carboplatin/paclitaxel/trastuzumab is recommended by the NCCN Panel as a preferred option for HER2-positive uterine serous carcinoma or HER2-positive carcinosarcoma as a primary therapy for stage III/IV disease. The GOG performed a phase 2 trial of bevacizumab following 1 or 2 chemotherapy regimens.267 Among 52 eligible patients, 7 patients $( 1 3 . 5 \% )$ experienced clinical responses (1 CR and 6 partial responses [PRs]; median response duration, 6.0 months), and 21 patients $( 4 0 . 4 \% )$ survived progression-free for at least 6 months. Adverse events were consistent with those expected of bevacizumab treatment. The efficacy of bevacizumab addition to paclitaxel and carboplatin and as a maintenance in advanced or recurrent endometrial cancer was further evaluated in another phase 2 trial with a larger cohort of post protocol patients. 268 Collectively, the median PFS of 27 patients with endometrial cancer who received this triplet regimen was 20 months, and median OS was 56 months. Among 29 patients with measurable disease, the response rate was $8 2 . 8 \%$ ( $9 5 \%$ CI, $6 9 . 0 \% - 9 6 . 5 \%$ ; 15 CRs and 9 PRs). This triplet regimen of carboplatin/paclitaxel/bevacizumab is recommended as a preferred regimen for patients with stage III–IV disease with measurable disease. For stages III and IV disease, systemic therapy forms the mainstay of treatment and can be combined with EBRT with (or without) vaginal brachytherapy. The combination of therapies depends on assessment of both locoregional and distant metastatic risk. Combination therapy can be considered for stages IIIB and IIIC disease. Previously, whole abdominal RT was used for carefully selected patients deemed at risk for peritoneal failure, and RT appeared to have provided therapeutic benefit in retrospective studies. However, it is considered too toxic and has largely been abandoned. 269,270 A randomized phase III GOG # NCCN Guidelines Version 3.2025 Uterine Neoplasms (122) trial assessed optimal adjuvant therapy for patients with endometrial cancer who had extrauterine disease. In this trial, patients with stage III and intra-abdominal stage IV disease who had minimal residual disease were randomly assigned to whole abdominopelvic RT versus 7 cycles of combined doxorubicin $( 6 0 ~ \mathsf { m g } / \mathsf { m } ^ { 2 } )$ and cisplatin $( 5 0 \mathrm { m g } / \mathrm { m } ^ { 2 } )$ treatment, with an additional cycle of cisplatin (AP). This GOG trial reported that AP chemotherapy improved PFS and OS when compared with whole abdominopelvic RT; however, acute toxicity (eg, peripheral neuropathy) was greater in the AP chemotherapy arm.209 The GOG 122 study established the role of adjuvant multiagent systemic chemotherapy for curative intent in patients with extrauterine disease. Thus, in the NCCN Guidelines, systemic therapy forms the established framework of adjuvant therapy for patients with stage III or IV disease. The whole abdominal RT as a single modality (as used in GOG 122) is considered inferior to chemotherapy and is too toxic; therefore, it is no longer recommended. For the purposes of these guidelines, whole abdominal RT is not considered to be tumor-directed RT (see Principles of Radiation Therapy in the NCCN Guidelines for Uterine Neoplasms). Recurrences were frequent in both treatment arms of GOG 122, occurring in the pelvis and abdomen. Approximately $52 \%$ of patients with advanced endometrial carcinoma had recurrences, indicating the need for further therapeutic improvement in this high-risk patient population.209 A study found that combined modality adjuvant therapy (using chemotherapy and tumor-directed RT) may provide a therapeutic benefit when compared with single-modality adjuvant therapy. 211,271,272 A follow-up study evaluated the role of chemotherapy “intensification” for this patient population. The GOG 184 trial compared two chemotherapy regimens (cisplatin and doxorubicin with [or without] paclitaxel) with tumordirected radiation (involved-field radiation either to the pelvis or to the pelvis plus para-aortic nodes). Results indicate that the 3-drug regimen did not improve survival when compared with the 2-drug regimen after 3 years of follow-up and that the more intensive chemotherapy resulted in greater toxicity (eg, hematologic toxicity, sensory neuropathy, myalgia).210 In a retrospective review of 116 patients with stage IIIC endometrial cancer, adjuvant RT significantly improved OS in patients with endometriod histology, high-grade tumors, and positive para-aortic lymph nodes. Conversely, patients with low-grade tumors and non-endometrioid histology who received RT had similar OS compared with those who did not.273 In a multicenter retrospective review of 73 patients with stage IIIA endometrial carcinoma, surgery followed by both chemotherapy and RT provided the highest 5-year OS.274 A prospective study of 122 patients with fully resected locally advanced disease suggested a potential benefit of adjuvant chemoradiation followed by chemotherapy, with an estimated 5-year PFS and OS of $73 \%$ and $84 \%$ .275 Adjuvant therapy options were compared in a multicenter retrospective analysis of 265 patients with optimally resected stage IIIC endometrial carcinoma. Compared with patients receiving adjuvant RT or adjuvant RT plus chemotherapy, patients who received adjuvant chemotherapy alone had a 2.2-fold increased risk of recurrence and a 4.0-fold increased risk of death.252 Multimodality therapy is now the basis of randomized trials evaluating therapy. The phase 2, RTOG 9708 trial assessed 46 patients for safety, toxicity, recurrence, and survival when chemotherapy (cisplatin/paclitaxel) was combined with adjuvant radiation in patients with high-risk endometrial cancer. The trial participants included patients with grade 2 or 3 endometrial adenocarcinoma with either $50 \%$ myometrial invasion, cervical stromal invasion, or pelvic-confined extrauterine disease. The OS and DFS favored the combined modality treatment.276 The phase 3, PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and EBRT versus EBRT alone in 686 patients with endometrial cancer (stage I, grade 3 with deep invasion, LVSI, or both; # NCCN Guidelines Version 3.2025 Uterine Neoplasms stage II; stage III; or any patient with stage I to III serous or clear cell endometrial cancer). The 5-year OS was $8 1 . 4 \%$ ( $9 5 \%$ CI, 77.2–85.8) with chemoradiotherapy versus $7 6 . 1 \%$ $9 5 \%$ CI, 71.6–80.9) with RT alone (HR, 0.70; $9 5 \%$ CI, 0.51–0.97; $P = . 0 3 4 \rangle$ ) and 5-year failure-free survival was $7 6 . 5 \%$ $9 5 \%$ CI, 71.5–80.7) versus $6 9 . 1 \%$ (63.8–73.8; HR, 0.70; $9 5 \%$ CI, 0.522–0.94; $P = . 0 1 6 ^ { \prime }$ .277,278 Patients with serous cancers and stage III disease were shown to benefit the most from the addition of systemic therapy. The combination treatment was also shown to be associated with more severe adverse events.279 The GOG-258 phase 3 trial evaluated 707 patients with stage III or IVA, high-risk endometrial cancer who were randomly assigned 1:1 to receive chemoradiotherapy or chemotherapy only.280 This trial supported the benefit of using chemotherapy alone by concluding that the combined therapy was not associated with longer RFS when compared with chemotherapy alone $5 9 \%$ vs. $58 \%$ , respectively). OS results are pending. A follow-up molecular analysis was performed of the PORTEC-3 trial to study the impact of chemoradiotherapy for each molecular subtype using tissue samples from the trial participants. The tumors were classified into $p 5 3$ abnormal, POLE, dMMR, or no specific molecular profile. The 5-year RFS with chemoradiotherapy versus RT alone was $p 5 3$ abnormal, $59 \%$ versus $36 \%$ ; POLE, $100 \%$ versus $9 7 \%$ ; dMMR, $6 8 \%$ versus $76 \%$ ; and $80 \%$ versus $6 8 \%$ for no specific molecular profile, suggesting that systemic therapy was beneficial for those patients whose disease was $p 5 3$ abnormal. 281 Results are awaited for an ongoing PORTEC-4a trial investigating molecular profile-based directed adjuvant treatment in highrisk endometrial cancer.282 # High-Risk Endometrial Carcinoma Histologies # Overview Uterine serous carcinomas, clear cell carcinomas, carcinosarcomas, and undifferentiated/dedifferentiated carcinomas are considered more aggressive histologic variants of malignant epithelial tumors, with a higher incidence of extrauterine disease at presentation.283-290 Carcinosarcomas are aggressive tumors that are staged as high-grade endometrial cancer.291,292 Carcinosarcomas (also known as MMMTs) are metaplastic carcinomas and not uterine sarcomas; therefore, carcinosarcomas are included as part of the high-risk malignant epithelial tumors. 287,290,293,294 Even patients with apparent early-stage disease may have distant metastases. Thus, fertility-sparing therapy is not recommended for these aggressive tumors. If done, SLN mapping should proceed with particular caution. Serous carcinomas, clear cell carcinomas, carcinosarcomas, and undifferentiated/dedifferentiated carcinomas are all considered high-risk histologies and high grade by default, although they are staged using the same FIGO/AJCC staging system as endometrial cancers.69 Patients with uterine serous carcinoma, clear cell carcinoma, carcinosarcoma, or undifferentiated/dedifferentiated carcinomas may present with pelvic masses, abnormal cervical cytology, or ascites in addition to postmenopausal bleeding. Both the NCCN Panel and the SGO recommend that CA-125 and MRI or chest/abdomen/pelvis CT may be useful before surgery to assess if extrauterine disease is present; PET may also be useful.283 # Primary Treatment Suitable for Primary Surgery Multimodality therapy is typically recommended for these histologically aggressive tumors. Primary treatment includes TH/BSO with surgical staging, peritoneal lavage for cytology, omental and peritoneal biopsies, and consideration of maximal tumor debulking for gross disease (see # NCCN Guidelines Version 3.2025 Uterine Neoplasms Principles of Evaluation and Surgical Staging in the NCCN Guidelines for Endometrial Carcinoma).295 Minimally invasive surgery is the preferred approach when technically feasible.296-300 Additional treatment options are highly individualized and are based on the histology and stage of the tumor.301-308 For patients with clear cell or serous carcinomas with no residual uterine disease and negative surgical staging in the hysterectomy specimen, observation is the recommended option. For stage IA disease without myometrial invasion with negative peritoneal washings, options include vaginal brachytherapy with (or without) systemic therapy (category 2B for systemic therapy) or observation. If the washings are positive, both systemic therapy and vaginal brachytherapy are recommended. 309,310 For patients with invasive stage IA, IB, or II, options include systemic therapy with (or without) EBRT with (or without) vaginal brachytherapy; or EBRT with (or without) vaginal brachytherapy. For patients with clear cell or serous carcinoma at a more advanced stage (ie, stage III or IV), or with undifferentiated/dedifferentiated histology, systemic therapy with (or without) EBRT with (or without) vaginal brachytherapy is recommended.285,302,306,311 For the patients with carcinosarcoma histology at stage IA, systemic therapy and vaginal brachytherapy are recommended with an option for EBRT, if it has high-grade epithelial components and is sarcoma dominant $( > 5 0 \%$ of sarcoma component in uterine tumor).312 The Panel notes that the initiation of chemotherapy within 3 to 6 weeks postoperatively should be considered and vaginal brachytherapy can be integrated with chemotherapy. For patients with advanced histologies, whole abdominopelvic RT with (or without) vaginal brachytherapy is no longer recommended as a primary treatment option.209,311,313 302 Multimodality therapy including systemic therapy, EBRT, and vaginal brachytherapy appears to be more effective. Data are conflicting regarding the rate of abdominal recurrence in these patients.311,314-318 Whole abdominal radiotherapy is not considered to be tumor-directed RT (see Principles of Radiation Therapy in the NCCN Guidelines for Uterine Neoplasms). As previously mentioned, tumor-directed RT refers to RT directed at sites of known or suspected tumor involvement and may include EBRT with (or without) vaginal brachytherapy. In general, tumor-directed EBRT is directed to the pelvis with (or without) the para-aortic region. # Not Suitable for Primary Surgery For patients with disease that is not amenable to resection, or is not suitable for surgery due to comorbidities, the primary treatment option is EBRT with (or without) brachytherapy with (or without) systemic therapy and then re-evaluation for surgery. Alternatively, systemic therapy could be given first, and then patients can be re-evaluated for surgery before giving RT based on the tumor response. For patients with carcinosarcoma histology with unresectable tumor that has metastasized, the Panel recommends systemic therapy with (or without) EBRT or best supportive care. # Treatment of Recurrent or Metastatic Disease # Locoregional Recurrence Patients with local or regional recurrences (negative for distant metastases on radiologic imaging) can be evaluated for further treatment (see Clinical Presentation in the NCCN Guidelines for Endometrial Carcinoma). For recurrences confined to the vagina or the pelvis alone, second-line treatment (typically with RT and/or surgery or systemic therapy) can be effective and selection depends on prior therapy. For patients with no prior RT exposure at the recurrence site or previous vaginal brachytherapy, the Panel recommends EBRT with (or without) brachytherapy and systemic therapy, or surgery with (or without) intraoperative RT (IORT) and systemic therapy (category 3 for IORT). # NCCN Guidelines Version 3.2025 Uterine Neoplasms For patients previously treated with EBRT at the recurrence site, recommended therapy for isolated relapse includes surgery with (or without) IORT (category 3 for IORT) plus or minus systemic therapy. Use of RT in the context of recurrence depends on the site of recurrence (inside or outside the prior radiation field), and dose of prior therapy. Reirradiation is used only in the context of limited disease for palliation and lack of other options. In selected patients, radical surgery (ie, pelvic exenteration) has been performed with reported 5-year survival rates approximating 20%.319-322 Isolated vaginal recurrences treated with RT have good local control and 5-year survival rates of $50 \%$ to $70 \%$ .323-325 Prognosis is worse if there is extravaginal extension or pelvic lymph node involvement.324 After RT, it is unusual for patients to have recurrences confined to the pelvis. The management of such patients remains controversial. Additional therapy options for disease confined to vagina or paravaginal soft tissues include EBRT with (or without) brachytherapy with (or without) systemic therapy. EBRT and systemic therapy are also included as options for the additional treatment of pelvic lymph node recurrence, para-aortic lymph node invasion, and upper abdominal or peritoneal microscopic residual recurrences as shown in the algorithm (see Additional Therapy in the NCCN Guidelines for Endometrial Carcinoma). # Distant Metastases For gross upper abdominal residual disease, more aggressive treatment for relapse is recommended, as outlined for disseminated metastases in Therapy for Relapse in the NCCN Guidelines for Endometrial Carcinoma. For resectable isolated metastases, consider surgical resection and/or EBRT, or ablative therapy. Ablative RT can be considered for 1 to 5 metastatic lesions if the primary cancer has been controlled (category 2B).202 Providers can also consider systemic therapy (category 2B). Further recurrences or disease not amenable to local therapy are treated as disseminated metastases. Treatment options for disseminated metastases are systemic therapy with (or without) palliative EBRT. For persistent progression of disseminated metastases, best supportive care is recommended (see the NCCN Guidelines for Palliative Care and http://emedicine.medscape.com/article/270646-overview). # Hormonal Therapy The role of hormonal therapy in recurrent or metastatic cancer has been primarily evaluated in patients with endometrioid histologies only. Hormonal therapy is typically used for lower grade endometrioid histologies, preferably in patients with small tumor volume or an indolent growth pace. Hormonal agents for treating metastatic disease include megestrol acetate with alternating tamoxifen, everolimus/letrozole combination, progestational agents (such as medroxyprogesterone acetate and megestrol acetate), aromatase inhibitors, tamoxifen alone, or fulvestrant.326-331 No particular drug, dose, or schedule has been found to be superior. The main predictors of response in the treatment of metastatic disease are well-differentiated tumors, expression of ER/PR receptors, a long disease-free interval, and the location and extent of extrapelvic (particularly pulmonary) metastases. For asymptomatic or low-grade disseminated metastases, hormonal therapy with progestational agents has shown good responses, particularly in patients with ER/PR-positive disease.332-335 Tamoxifen has a $20 \%$ response rate in disease that does not respond to standard progesterone therapy.336,337 Tamoxifen has also been combined with progestational agents; however, a few patients had grade 4 thromboembolic events with this combination regimen.328,329,338 In some patients, aromatase inhibitors (eg, anastrozole, letrozole) may be substituted for progestational agents or tamoxifen.334,335,339,340 Everolimus combined with letrozole is recommended for recurrent disease of endometrioid histology. In the phase 2 trial, in patients with progressive # NCCN Guidelines Version 3.2025 Uterine Neoplasms or recurrent endometrial cancer who had received up to two prior therapies, the clinical benefit rate and objective response rate among 35 evaluable patients was $40 \%$ and $32 \%$ , respectively.341 In a following phase 2 study, patients (with or without prior chemotherapy) were treated either with the everolimus/letrozole combination or medroxyprogesterone acetate/tamoxifen regimen. Twenty-two percent of patients had disease respond to the everolimus/letrozole therapy, while $2 5 \%$ showed a response with the medroxyprogesterone acetate/tamoxifen regimen.342 Median PFS was 6 months for the everolimus/letrozole arm and 4 months for the hormonal therapy arm. Median OS was 31 months and 17 months for the everolimus/letrozole and medroxyprogesterone acetate/tamoxifen arms, respectively. Higher PFS was observed in both arms for patients who had not received any prior chemotherapy. Other hormonal modalities have not been well-studied, and adjuvant therapy with hormonal agents has not been compared with cytotoxic agents.334,343 If disease progression is observed after hormonal therapy, cytotoxic chemotherapy can be considered. However, clinical trials or best supportive care (see the NCCN Guidelines for Palliative Care) are appropriate for patients with disseminated metastatic recurrence who have a poor response to hormonal therapy and chemotherapy. # Systemic Therapy for Recurrent Disease Based on the current data, multiagent regimens are preferred for advanced disease, if tolerated. The NCCN Guidelines for Endometrial Carcinoma have updated the systemic therapy recommendation by including immunotherapy and chemotherapy-based combination regimens as preferred, first-line options for recurrent disease. The NRG-GY018, randomized, phase III trial evaluated the benefits of pembrolizumab/carboplatin/paclitaxel regimen over the carboplatin/paclitaxel regimen in 816 patients with stage III or IVA endometrial carcinoma with measurable disease, or stage IVB or recurrent disease of any histologic subtype, except for carcinosarcoma. 258 The patients who had received adjuvant therapy at least 12 months before were included. The patients were stratified based on the dMMR or MMRproficient (pMMR) status of the tumors. The PFS was $74 \%$ versus $38 \%$ in the dMMR cohort for the triplet regimen versus the chemotherapy arm, respectively (HR, 0.30; $9 5 \%$ CI, 0.19–0.48; $P < . 0 0 1$ ). In pMMR tumors, the median PFS was 13.1 months in the pembrolizumab arm versus 8.7 months in the chemotherapy arm (HR, 0.54; $9 5 \%$ CI, 0.41–0.71; $P < . 0 0 1 )$ . Another phase III, randomized trial (RUBY) showed benefits of adding dostarlimab to the carboplatin/paclitaxel regimen in 494 patients with stage III or IV or recurrent disease, including all histologies.257 At 24 months, PFS was $3 6 . 1 \%$ versus $1 8 . 1 \%$ (HR, 0.64; $9 5 \%$ CI, 0.51–0.80; $P < . 0 0 1 _ { \cdot }$ ) and OS was $7 1 . 3 \%$ versus $56 \%$ (HR, 0.64; $9 5 \%$ CI, 0.46–0.87) in the dostarlimab-based arm versus the chemotherapy arm, respectively. Significantly more benefits were observed in patients with dMMR/MSI-H tumors with PFS of $6 1 . 4 \%$ versus $1 5 . 7 \%$ (HR, 0.28; $9 5 \%$ CI, 0.16–0.50; P $< . 0 0 1 )$ in the triplet versus the doublet therapy arms, respectively. From second interim analysis of the RUBY trial,262 dostarlimab in combination with carboplatin-paclitaxel also demonstrated a statistically significant and clinically meaningful OS benefit with a statistically significant reduction in the risk of death [HR, 0.69; $9 5 \%$ CI, 0.54–0.89, $P = . 0 0 2 0 ]$ in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile. Based on the results from the NRG-GY018 and RUBY trials, the NCCN Panel has added pembrolizumab/carboplatin/paclitaxel (except for carcinosarcoma histology) and dostarlimab/carboplatin/paclitaxel as category 1, preferred, first-line therapy options for recurrent endometrial carcinoma. Carboplatin/paclitaxel/durvalumab is also recommended as a category 1, preferred regimen for dMMR tumors only based on the DUO-E trial and recent FDA approval.263,264 The carboplatin/paclitaxel/trastuzumab regimen is also recommended for HER2-positive uterine serous carcinoma # NCCN Guidelines Version 3.2025 Uterine Neoplasms or carcinosarcoma as a preferred regimen for first-line therapy for recurrent disease.265 Chemotherapy for endometrial cancer has been extensively studied.344,345 Other multiagent regimens such as carboplatin/paclitaxel, carboplatin/docetaxel, and carboplatin/paclitaxel/bevacizumab are included as first-line therapy options for the recurrent disease setting. Carboplatin and paclitaxel is an increasingly used regimen for advanced/metastatic or recurrent endometrial cancer; the response rate is about $40 \%$ to $62 \%$ , and OS is about 13 to 29 months.346-349 A phase III trial (GOG 209) compared carboplatin and paclitaxel versus cisplatin, doxorubicin, paclitaxel, and filgrastim (granulocyte colony-stimulating factor).346 Trial data show that oncologic outcomes are similar, but the toxicity and tolerability profile favor carboplatin/paclitaxel.350 Thus, the carboplatin/paclitaxel regimen is a preferred, first-line option in the NCCN Guidelines. For patients in whom paclitaxel is contraindicated, docetaxel can be considered in combination with carboplatin.351,352 A phase II trial initially examined the addition of bevacizumab to carboplatin and paclitaxel among 15 patients with advanced or recurrent endometrial carcinoma.353 Although this study was closed early due to the initiation of a national trial, a retrospective analysis was performed to include data from an additional 27 patients who had received carboplatin/paclitaxel/bevacizumab for advanced or recurrent disease.268 Collective median PFS was 20 months with a median OS of 56 months. An overall response rate (ORR) of $8 2 . 8 \%$ was noted, with an $8 7 . 5 \%$ response rate among the subset of 8 patients who received this triplet regimen as second-line therapy after carboplatin/paclitaxel.268 Another phase 2 randomized study showed that the carboplatin/paclitaxel/bevacizumab combination improved OS from 29.7 months to 40 months compared to the doublet regimen.354 Another metaanalysis of three studies also concluded similar results where the triplet combination increased the OS and PFS at ${ > } 1 2$ months with an ORR of 76%.355 Other combination therapies such as cisplatin/doxorubicin, cisplatin/doxorubicin/paclitaxel, ifosfamide/paclitaxel (for carcinosarcoma), and cisplatin/ifosfamide (for carcinosarcoma) have been added as subsequent-therapy options. A phase III randomized trial (GOG 177) compared 2 combination chemotherapy regimens in females with advanced/metastatic or recurrent endometrial carcinoma. The 273 participants were randomly assigned to 1) cisplatin/doxorubicin/paclitaxel; or 2) cisplatin/doxorubicin. The 3-drug regimen was associated with improved survival (15 vs. 12 months, $P < . 0 4 )$ ) but with significantly increased toxicity (ie, peripheral neuropathy); therefore, it is not widely used.356-358 These regimens are recommended as subsequent therapy options in the NCCN Guidelines, because most Panel members feel that carboplatin/paclitaxel is a less toxic and preferred first-line option. The response rates with other multiagent chemotherapies ranged from $31 \%$ to $81 \%$ , but with relatively short durations. The median survival for patients in such trials remains approximately 1 year.344,345 If multiagent chemotherapy regimens are contraindicated, then single-agent therapy options for recurrent disease include cisplatin, carboplatin, doxorubicin, liposomal doxorubicin, paclitaxel, albumin-bound paclitaxel, topotecan, bevacizumab, temsirolimus, cabozantinib, lenvatinib, gemcitabine, and docetaxel (category 2B for docetaxel). 334,359-361335,362 When single agents are used as second-line treatment, responses range from $4 \%$ to $2 7 \%$ ; paclitaxel is the most active in this setting.362 Some oncologists have used liposomal doxorubicin, because it is less toxic than doxorubicin; the response rate of liposomal doxorubicin is $9 . 5 \%$ .363 Docetaxel is recommended for use as a single agent; however, it is a category 2B recommendation because it is less active $7 . 7 \%$ response rate) than other agents.364,365 Bevacizumab was shown to have a $1 3 . 5 \%$ # NCCN Guidelines Version 3.2025 Uterine Neoplasms response rate and OS rate of 10.5 months in a phase II trial for persistent or recurrent endometrial cancer.267 Based on these studies, the NCCN Panel considers bevacizumab as an appropriate single-agent biologic therapy for patients who have progressed on previous cytotoxic chemotherapy.267,366-368 Useful in Certain Circumstances, Biomarker-Directed Therapies In the advanced endometrial cancer cohort $( \mathsf { n } = 2 4 )$ ) of the phase Ib KEYNOTE-028 trial, durable antitumor responses were noted in a small subset of patients with programmed death ligand 1 (PD-L1)–positive tumors (3 PR, 3 stable disease).369 Studies have also indicated that dMMR tumors are sensitive to programmed cell death protein 1 (PD-1) blockade.370-372 Results were published from a study of patients with dMMR tumors of various disease sites. Among patients with dMMR endometrial carcinoma who received pembrolizumab $( \mathsf { n } = 1 5 )$ , the objective response rate was $52 \%$ and the disease control rate was $73 \%$ (3 CR, 5 PR, and 3 stable disease).370 The phase 2 Keynote-158 trial further demonstrated robust antitumor activity of pembrolizumab with encouraging survival outcomes in patients with previously treated MSI-H/dMMR endometrial cancer and manageable adverse events.373 Pembrolizumab is included as a treatment option for patients with recurrent endometrial cancer with MSI-H/dMMR disease that has progressed on or following prior treatment with a platinum-containing regimen in any setting including neoadjuvant or adjuvant therapy. The Panel recommends that recurrent endometrial tumors be tested for MSI-H or dMMR if not done previously. The Panel also recommends TMB-H testing if not previously done and has included the pembrolizumab option for patients with TMB-H tumors $( > 1 0$ mut/Mb), as determined by a validated and/or FDA-approved test, who have progressed following prior treatment and who have no satisfactory alternative treatment options.374 Further studies have indicated that pembrolizumab monotherapy is less active in patients with microsatellite-stable or pMMR disease versus MSIH/dMMR disease. Only $16 \%$ to $31 \%$ of endometrial cancers are MSIH/dMMR.369,375,376 The Keynote-146 phase $_ { 1 / 2 }$ trial showed that the combination of pembrolizumab/lenvatinib had a promising antitumor response in patients with advanced endometrial cancer regardless of their tumor MSI status.377 The Keynote-775 phase 3 trial randomly assigned 827 patients with pMMR (MSI-stable), previously treated advanced endometrial cancer to receive pembrolizumab/lenvatinib combination or chemotherapy (doxorubicin or paclitaxel).378 The median PFS for the pembrolizumab/lenvatinib arm was 7.2 months versus 3.8 months for the chemotherapy arm (HR, 0.56; $9 5 \%$ CI, 0.47–0.66; $P < . 0 0 1$ ). The median OS was also longer for the pembrolizumab/lenvatinib arm than for the chemotherapy arm (18.3 vs. 11.4 months; HR, 0.62; $9 5 \%$ CI, 0.51–0.75; $P$ $< . 0 0 1 $ ). On the basis of Keynote-775 data, FDA approved pembrolizumab in combination with lenvatinib for patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. Based on these data, the NCCN Guidelines for Endometrial Carcinoma include lenvatinib/pembrolizumab as a category 1 option for pMMR tumors for patients who have received prior platinum-based therapy in any setting, including neoadjuvant and adjuvant therapy. ENGOT-En9/LEAP-001 is another phase 3, randomized (1:1), open-label, active-controlled trial that evaluated the efficacy and safety of first-line pembrolizumab (PEM) plus lenvatinib (LEN) versus paclitaxel plus carboplatin (TC) in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease. $\langle \mathsf { N } = 8 4 2 \rangle$ .379 The prespecified statistical criteria were not met for PFS and OS. In the pMMR subgroup $( \mathsf { n } = 6 4 2 )$ , median PFS was 9.6 months $( 9 5 \%$ CI, 8.2–11.9) in the LEN $^ +$ PEM arm $( \mathsf { n } = 3 2 0 )$ versus 10.2 months $9 5 \%$ CI, # NCCN Guidelines Version 3.2025 Uterine Neoplasms 8.4–10.5) in the TC arm $( \mathsf { n } = 3 2 2 )$ with an HR of 0.99 $9 5 \%$ CI, 0.82–1.21). The median OS was 30.9 months $9 5 \%$ CI, 25.4–37.7) versus 29.4 months $9 5 \%$ CI, 26.2–35.4), respectively, with an HR of 1.02 ( $9 5 \%$ CI, 0.83–1.26; nominal $P = . 2 4 6 )$ ). A subgroup analysis for PFS in the pMMR population of patients who had previously received neoadjuvant or adjuvant therapy showed a trend favoring LEN $^ +$ PEM compared to TC (HR, 0.60; $9 5 \%$ CI, 0.37–0.97). Data from ENGOT-En9/LEAP-001, along with the results from Study 309/KEYNOTE-775, support the recommendation for $\mathsf { L E N + P E M }$ as a firstline therapy for recurrent endometrial cancer, and useful in certain circumstances as a biomarker-directed therapy for pMMR tumors after prior platinum-based therapy in any setting, including the neoadjuvant and adjuvant settings. Other anti-PD-1 inhibitors, such as dostarlimab and nivolumab, have also shown antitumor activity against MSI-H tumors. Dostarlimab demonstrated durable antitumor activity in dMMR/MSI-H endometrial cancer (ORR $4 3 . 5 \% )$ with a manageable safety profile in the GARNET trial,380 an ongoing, single-arm, open-label, phase I trial of IV dostarlimab in advanced solid tumors. The NCCN Panel recommends dostarlimab for the treatment of patients with recurrent dMMR/MSI-H endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen in any setting including neoadjuvant or adjuvant therapy. Nivolumab monotherapy has also demonstrated promising activity in endometrial carcinoma with dMMR tumors.381 Following FDA approval382 of nivolumab and hyaluronidase for subcutaneous injection across approved adult, solid tumor as monotherapy, monotherapy maintenance following completion of nivolumab, the NCCN Panel added that nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and administration instructions compared to IV nivolumab. The PD-L1 inhibitor, avelumab, has shown an ORR of $2 6 . 7 \%$ in advanced endometrial cancer with dMMR tumor as monotherapy. Nivolumab and avelumab are included as biomarker-directed subsequent therapy options for recurrent dMMR/MSI-H endometrial tumors. The NCCN Panel also recommends larotrectinib or entrectinib for NTRK gene fusion-positive endometrial tumors as a category 2A subsequent therapy option. Repotrectinib is also recommended for NTRK gene fusion-positive tumors that are naïve to prior NTRK-targeted therapy or have progressed on prior NTRK therapy. 383,384 # Systemic Therapy Options for High-Risk Endometrial Histologies The NCCN Panel notes that the systemic therapy options recommended in the NCCN Guidelines can be used for all carcinoma histologies. Among these, carboplatin/paclitaxel is included as category 1, preferred option for patients with carcinosarcoma histology. A randomized phase II study examined the addition of trastuzumab to carboplatin/paclitaxel for patients with advanced or recurrent HER2/neu-positive uterine serous carcinoma.25 Among patients with stage III/IV disease undergoing primary treatment (n $= 4 1$ ), median PFS was 17.9 months versus 9.3 months for the experimental and control arms, respectively $( P = . 0 1 3 )$ . PFS for patients with recurrent disease $( \mathsf { n } = 1 7 )$ was 9.2 months versus 6.0 months $( P =$ .003). The addition of trastuzumab appeared to improve PFS without increasing overall toxicity. The safety and tolerability of the trastuzumab combination was further evaluated in 61 patients in a recent phase 2 trial with PFS as the primary endpoint.266 The triplet therapy regimen carboplatin/paclitaxel/trastuzumab is recommended by the NCCN Panel as a preferred option for HER2-positive uterine serous carcinoma or HER2-positive carcinosarcoma as: 1) primary therapy for stage III/IV disease; or 2) a first-line option for recurrent disease. This triplet regimen is recommended for patients who have not received any prior trastuzumab therapy. In subsequent therapy, the NCCN Panel has included ifosfamide, ifosfamide/paclitaxel, and ifosfamide/cisplatin as options for # NCCN Guidelines Version 3.2025 Uterine Neoplasms carcinosarcoma treatment only. For treating carcinosarcoma, ifosfamide was historically considered the most active single agent.385-387 A phase III trial for advanced carcinosarcoma showed that the combination of ifosfamide and paclitaxel increased survival and was less toxic than the previously used cisplatin/ifosfamide regimen.385,388 OS was 13.5 months with ifosfamide/paclitaxel versus 8.4 months with ifosfamide alone.313,385 # Radiotherapy Principles RT has been a widely used modality in the treatment of patients with endometrial cancer; it clearly improves locoregional control. Tumor-directed RT refers to RT directed at sites of known or suspected tumor involvement and may include EBRT and/or vaginal brachytherapy.215 Imaging is required to assess locoregional extent and to rule out distant metastases before administration of RT. In general, EBRT is directed to the pelvis with or without the para-aortic region. Brachytherapy can be delivered: 1) to an intact uterus, either preoperatively or definitely; or 2) more commonly, to the vagina after hysterectomy. For the purposes of these guidelines, whole abdominal radiotherapy is not considered to be tumor-directed RT. The Panel notes that chemoradiation can be given concurrently or sequentially. RT is described in detail in the algorithm, including target areas and doses for pelvic RT and brachytherapy (see Principles of Radiation Therapy in the NCCN Guidelines for Uterine Neoplasms). Although adjuvant RT is typically not associated with high rates of severe morbidity,389 studies have focused on subtle effects on quality of life (eg, diarrhea, bowel symptoms) that deserve further investigation.233,235,390 In the PORTEC-2 trial, vaginal brachytherapy was associated with better quality of life when compared with EBRT without a significant detriment to outcome.233 Therefore, many patients who were previously treated with adjuvant EBRT are now appropriately treated with vaginal brachytherapy; this recommendation is reflected in the NCCN Guidelines. Patients treated with RT are prone to vaginal stenosis, which can impair sexual function. Individuals assigned female at birth can use vaginal dilators to prevent or treat vaginal stenosis. Dilator use can start 2 to 4 weeks after RT is completed and can be used indefinitely (https://www.mskcc.org/cancer-care/patient-education/vaginalhealth). # Post-Treatment Surveillance The recommended post-treatment surveillance protocol for endometrial cancer is shown in the algorithm (see Surveillance in the NCCN Guidelines for Endometrial Carcinoma).49,55 These recommendations recognize that the value of intensive surveillance has not been demonstrated in this disease; therefore, ancillary testing is not recommended.391,392 Patients with clinical stage I and stage II endometrial cancer have a recurrence rate of approximately $1 5 \% ; 3 9 2 - 3 9 5 ~ 5 0 \%$ to $70 \%$ of these patients are symptomatic. For most patients, disease recurs within 3 years of initial treatment. Because most recurrences are symptomatic, all patients should receive verbal and written information regarding the symptoms of potential recurrence. 392 Patients with bleeding (vaginal, bladder, or rectal), decreased appetite, weight loss, pain (in the pelvis, abdomen, hip, or back), cough, shortness of breath, and swelling (in the abdomen or legs) should seek prompt evaluation and not delay until the next scheduled appointment. History and physical exam is recommended every 3 to 6 months for the first 2 to 3 years, and then every 6 to 12 months thereafter for up to the fifth year, then annually. For non–fertility-sparing treatment, imaging should be guided by patient symptoms, risk assessment, and clinical concern for recurrent or metastatic disease. The indications of metastatic disease may include abnormal physical exam finding, bulky uterine tumor, vaginal or extrauterine involvement, delay in presentation or treatment, and abdominal or pulmonary symptoms. For fertility-sparing treatment, the # NCCN Guidelines Version 3.2025 Uterine Neoplasms Panel recommends repeat pelvic MRI (preferred) for patients with persistent endometrial carcinoma after 6 to 9 months of disease progression on medical therapy, especially if considering further fertilitysparing approaches. Pelvic US surveillance can be considered for patients with ovarian preservation. Abdomen/pelvis MRI and/or chest CT is recommended based on symptoms or physical exam findings. Whole body FDG-PET/CT and/or abdomen/pelvis MRI can be considered in select patients as clinically indicated. Physical exam also includes CA-125 if initially elevated or serous histology is also recommended for surveillance. In the absence of recurrence, post-treatment surveillance provides psychosocial reassurance and improves quality of life for patients and their families. Health maintenance has been incorporated into the follow-up schedule (eg, blood pressure determination, breast examination, mammography as clinically indicated, stool guaiac test, immunizations). Patients should receive counseling and education regarding lifestyle, obesity, exercise, smoking cessation, sexual health, nutrition, and potential late or long-term effects of treatment (see the NCCN Guidelines for Survivorship, NCCN Guidelines for Smoking Cessation, and https://www.cancer.org/cancer/survivorship.html ).390,396-398 Other health problems that often coexist in patients with endometrial cancer can also be evaluated during follow-up. Given the lack of prospective studies regarding the optimal frequency of post-treatment follow-up, the NCCN Panel believes that the algorithm represents a reasonable surveillance scheme. The use of vaginal cytology is no longer recommended for patients who are asymptomatic consistent with the SGO guidelines.391,392,395,399 Patients with stage I endometrial cancer have a low risk of asymptomatic vaginal recurrence $( 2 . 6 \% )$ , especially after adjuvant brachytherapy, and vaginal cytology is not independently useful for detecting recurrences in this group of patients.391,400 A multi-institutional review examined the utility of various surveillance methods in 254 patients with high-grade disease, revealing that symptoms led to the detection of the most recurrences $( 5 6 \% )$ , followed by physical exam $( 1 8 \% )$ , surveillance CT $( 1 5 \% )$ , CA-125 $( 1 0 \% )$ , and vaginal cytology $( 1 \% )$ .401 # Hormone Therapy for Hypoestrogenism After BSO, hypoestrogenism is associated with hot flashes, mood lability, vaginal dryness, pelvic soft tissue atrophy, osteoporosis, and an increased risk of cardiovascular disease. In patients who are postmenopausal, estrogen therapy was believed to reduce or reverse some of these signs and symptoms. However, patients who have had BSO for endometrial adenocarcinoma have usually been denied estrogen therapy for fear of inducing a higher relapse rate, because this cancer has historically been considered an estrogen-linked malignancy.402,403 As such, estrogen therapy for such patients remains controversial. However, it has never been proven that relapse rates are higher in patients with endometrial cancer who receive estrogen therapy after hysterectomy. Several retrospective trials of estrogen therapy after treatment of early-stage endometrial cancer have shown no increase in tumor recurrence or cancer-related deaths.404-406 In females with stage I to II endometrial cancer who had hysterectomy, a randomized trial of estrogen therapy versus placebo did not find an increased rate of recurrence or new malignancy; the median follow-up was 35.7 months.407 However, estrogen trials in postmenopausal females without a history of malignancy have demonstrated a significantly increased risk for breast cancer.408 Initially, the Women’s Health Initiative (WHI) Estrogen-Alone Trial in females who had hysterectomy $( \mathsf { n } = 1 0 , 7 3 9 )$ ) reported that the risk of breast cancer and cardiovascular disease (eg, stroke) were increased and that estrogen therapy was of concern; thus, the trial was stopped.409 # NCCN Guidelines Version 3.2025 Uterine Neoplasms However, recent long-term follow-up data from this trial suggest that the risk from estrogen-alone replacement therapy (without progesterone) may not be as high in younger patients $_ { < 6 0 }$ years) who have had hysterectomy.410 The NCCN Panel agrees that estrogen therapy is a reasonable option for patients who are at low risk for tumor recurrence, but initiating such therapy should be individualized and discussed in detail with the patient.411,412 If adjuvant treatment is carried out, there should be a 6- to 12-month waiting period before initiation of hormone therapy, and participation in clinical trials is strongly encouraged. Selective estrogen-receptor modulators (SERMs) may prove to be attractive options for hormone therapy.413,414 Long-term comparisons between conjugated estrogens and SERMs for hormone therapy are needed. Non-hormonal therapy may be considered in patients who are deemed poor candidates for hormone therapy (eg, people who smoke, those with a history of breast cancer, those with a history of multiple strokes).415,416 # Uterine Sarcomas # Overview Uterine sarcomas are uncommon malignant mesenchymal tumors, accounting for approximately $3 \%$ of all uterine cancers, and include high or low-grade ESS, UUS, uLMS, and others such as PEComas (see Initial Clinical Findings in the NCCN Guidelines for Uterine Sarcoma).417 According to a 2012 systematic review of data from 1970 to 2011, uLMS was the most common subtype $( 6 3 \% )$ , followed by ESS $( 2 1 \% )$ and less common subtypes such as UUS.418 Even rarer subtypes of malignant mesenchymal tumors that can occur in the uterus include adenosarcoma, rhabdomyosarcoma (RMS), and PEComa.419 Carcinosarcomas were previously categorized and included in the sarcoma treatment algorithms until the mid-2000s, but are now considered and treated as high-grade epithelial tumors (carcinomas).287 Screening for Lynch syndrome is not usually done for patients with malignant mesenchymal tumors. # Pathology and Molecular Analysis Expert gynecologic pathology review is recommended for the assessment and histologic differentiation of uterine sarcomas including uLMS, UUS, ESS, and adenosarcoma. 87 The pathologic assessment of the uterus should include hysterectomy type, specimen integrity (intact, opened, morcellated, or other), tumor size, myometrial invasion (for adenosarcoma only), histologic type, grade (for adenosarcoma only), and LVSI. The assessment should also include other tissues/organ involvement (fallopian tubes, ovaries, vagina, parametrium, omentum, or other). Peritoneal/ascitic fluid cytology should also be done. If the lymph nodes are resected, the level of nodal involvement and the number of lymph nodes with metastasis should be determined. Routine node dissection is not required in the absence of clinical suspicion of nodal involvement. Recent advances have expanded our understanding of the molecular features of these tumors, leading to the identification of genetic signatures that characterize some of the uterine sarcoma subtypes. Historically, mesenchymal tumors were primarily diagnosed using histopathologic criteria, and the results of molecular studies were not used in routine pathologic evaluation. However, given the overlap in histopathologic features of these tumors, molecular analysis (eg, identification of characteristic translocations) can help classify difficult cases and provide future therapeutic targets. The Panel notes that comprehensive genomic profiling in the setting of metastatic disease with a validated and/or FDAapproved assay is informative for predicting rare pan-tumor–targeted therapy opportunities. The Panel recommends testing of at least NTRK, MSI, and TMB proteins. The testing is preferred on tissue; if tissue is not available, then blood-based assays can be considered. Since the molecular profiling is informative in many mesenchymal malignancies for # NCCN Guidelines Version 3.2025 Uterine Neoplasms accurate classification, 420 the NCCN Guidelines for Uterine Neoplasms include a table containing information on histologic and molecular findings, specific biomarkers, relevant confirmatory molecular tests, prognostic features, and other clinically useful information to help clinicians differentiate between and classify uterine sarcoma subtypes. This information is intended to complement histopathologic testing to improve differential diagnosis of relatively rare uterine sarcoma subtypes and provide safer, more effective care for patients with the disease. The Panel notes that this information is not exhaustive and intends to update these recommendations as more data become available. Low-Grade and High-Grade Endometrial Stromal Sarcoma (ESS) ESSs are the second most common mesenchymal tumors of the uterus. ESSs are composed of cells resembling the endometrial stroma in the proliferative phase.419,421 Low-grade ESSs have distinct fingerlike patterns of myometrial invasion, and LVSI is usually present. ESS displays a heterogenous mix of morphologic and genetic features. A significant proportion of these tumors (ie, up to half) harbor JAZF1, PHF1, or EPC1 gene fusions and present as earlier-stage tumors.422-425 The Panel notes that diagnosis of low-grade ESS can be confirmed by identifying any low-grade ESS-associated gene fusion by using FISH and/or targeted RNA sequencing, though the lack of rearrangement or fusion does not exclude the diagnosis. It is worth noting that in rare instances, low-grade ESS can transform into high-grade ESS (either at the time of primary diagnosis or recurrence), which will require histopathologic and molecular (eg, JAZF1 or PHF1 translocation) confirmation. There are a few sarcomas reported as low-grade ESS harboring novel fusions and a subset behave more aggressively than typical low-grade ESS. A higher-grade and more aggressively behaving ESS variant with a unique genetic rearrangement YWHAE::FAM22A/B, also known as YWHAE::NUTM2A/B, has been identified.426,427 This subtype is known as high-grade ESS. Another subtype of high-grade ESS harboring BCOR is either in the form of a ZC3H7B::BCOR fusion or an internal tandem duplication. Both ZC3H7B::BCOR fusion-positive and BCOR internal tandem duplication high-grade ESS have spindle and/or round cells embedded in myxoid matrix, and demonstrate strong and diffuse positivity for cyclin D1 and variable positivity for CD10, ER, and PR.428 IHC testing for CD10, cyclin D1, and BCOR and, in some cases, molecular analysis of BCOR alterations, may help differentiate between BCOR-altered high-grade ESS and myxoid ULMS due to overlapping morphologic features. It is currently unclear whether specific types of high-grade ESS (ie, YWHAE-altered or BCOR-altered) differ in prognosis and/or response to chemotherapy. These findings provided support for subdividing ESS into distinct low- and high-grade entities based on histopathology, clinical behavior, and patient outcomes. The updated 2014 edition of the WHO Classification of Tumors of Female Reproductive Organs recognizes low-grade ESS and highgrade ESS as distinct histopathologic entities.429 The 5th edition on Female Genital Tumors in 2020 also recognizes BCOR-altered sarcomas as a distinct subtype of high-grade ESS.430 # Undifferentiated Uterine Sarcoma (UUS) UUSs are a group of high-grade/aggressive sarcomas characterized by infiltrative sheets of epithelioid and/or spindle cells that may be uniform or pleomorphic. As a class, it is a heterogenous group of high-grade mesenchymal neoplasms of the uterus that does not meet the diagnostic threshold for other characterized uterine mesenchymal neoplasms. As such, UUS is usually reserved as a diagnosis of exclusion, after other defined uterine mesenchymal neoplasms have been excluded using a multiprong approach that often requires a combination of extensive IHC panel and next-generation sequencing (NGS) molecular analysis. For # NCCN Guidelines Version 3.2025 Uterine Neoplasms example, high-grade ESS is often misdiagnosed as UUS due to a shared lack of smooth muscle differentiation.431 The Panel notes that molecular testing for BCOR alterations, which can occur in high-grade ESS as noted above, is useful to exclude a high-grade ESS diagnosis before rendering a diagnosis of UUS. A subset of UUSs called SMARCA4-deficient uterine sarcomas (SDUSs) have distinctive morphology (eg, phyllodiform architecture) along with biallelic inactivation of SMARCA4 that results in loss of SMARCA4::BRG1 expression. These tumors occur in younger patients and may be associated with very aggressive clinical behavior.432 The Panel recommends analysis of SMARCA4::BRG1 by IHC and/or SMARCA4 by DNA sequencing to confirm a diagnosis of SDUS with otherwise appropriate morphologic and immunophenotypic features. However, loss of SMARCA4::BRG1 alone does not constitute a diagnosis of SDUS, and other aggressive malignancies such as undifferentiated endometrial carcinoma may show loss of expression of this protein. # Uterine Leiomyosarcoma (uLMS) uLMS are usually of the spindle cell (conventional) type, but less common variants with myxoid or epithelioid morphology also exist. Although morphology differs between subtypes, all express varying degrees of the smooth muscle markers, including desmin, smooth muscle actin (SMA), and caldesmon. The Panel recommends an IHC panel including desmin and SMA to support a uLMS diagnosis, particularly if myxoid or epithelioid uLMS is suspected. Abnormal expression of at least two immunohistochemical markers TP53, ATRX, RB1, PTEN, DAXX, MDM2, and MTAP suggests LMS in smooth muscle tumor of uncertain malignant potential or atypical smooth muscle tumors that do not fulfill histologic criteria for LMS. Genomic risk stratification may predict clinical outcomes. Myxoid uLMSs may appear histologically similar to BCOR-altered High Grade ESSs or inflammatory myofibroblastic tumor (IMT). The Panel recommends cyclin D1 and/or BCOR IHC to help exclude an HGESS diagnosis, as the latter is often overexpressed in HGESS. A subset $( 2 5 \% )$ of myxoid ULMSs also harbor PLAG1 fusions. Therefore, a myxoid ULMS diagnosis may be supported by positive desmin and SMA IHC along with PLAG1 rearrangement by FISH assay or RNA sequencing. NR4A3 fusions are detected in a subset of myxoid LMS. One differential diagnosis that must be considered for epithelioid uLMS is PEComa, given the observed similarities in morphology and IHC for smooth muscle markers. IHC testing for HMB45 and melanA may be performed if a diagnosis of PEComa is being considered, with HMB45 being fairly sensitive and melanA being specific for PEComa compared with uLMS. However, it is recognized that uterine mesenchymal tumors with myomelanocytic differentiation can still be challenging to classify solely by IHC. A study examining this specific group of diagnostically challenging tumors supported the use of genomic profiling to aid in their classification.433 Uterine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT) UTROSCTs are very rare tumors with sex cord-like differentiation, but without a stromal component as observed in ESSs. Most of these tumors harbor either ESR1 or GREB1 fusions.434,435 The Panel recommends an IHC panel that includes sex cord markers (eg, inhibin, calretinin, SF1, FOXL2); UTROSCTs are often positive for a broad range of biomarkers. In some cases, FISH or RNA sequencing for ESR1 or GREB1 fusions may be helpful to confirm the diagnosis. Approximately $2 5 \%$ of these tumors are malignant; the Panel notes that the presence of necrosis, high mitotic index, and GREB1 fusions may be associated with malignant behavior. # Rhabdomyosarcoma Uterine RMSs are an aggressive, heterogeneous group of tumors that are extremely rare in adult patients. Subtypes include alveolar, embryonal, and pleiomorphic; all express myogenic biomarkers (eg, myogenin and MyoD1).436 Therefore, the Panel notes that diffuse expression of myogenic # NCCN Guidelines Version 3.2025 Uterine Neoplasms biomarkers by IHC can help confirm a uterine RMS diagnosis. Prognosis differs between subtypes, with embryonal RMS having the best prognosis of the 3 subtypes. Molecular alterations also differ between subtypes. $F O X O 1$ fusions are found in alveolar RMS, whereas PIK3CA and TP53 mutations are found in pleomorphic RMS. DICER1 mutations are present in up to $9 5 \%$ of embryonal RMS. The embryonal subtype also is known to harbor FGFR4/RAS/AKT pathway mutations.437 The Panel notes that extensive sampling should be performed to exclude epithelial components and diagnoses of carcinosarcoma and adenosarcoma with heterologous rhabdomyosarcomatous differentiation. The Panel recommends FISH and/or RNA sequencing for FOXO1 to help confirm cases of suspected uterine alveolar RMS. # Mullerian Adenosarcoma Risk factors for worse outcome in Müllerian adenosarcoma generally include myometrial invasion or sarcomatous overgrowth.438 The presence of a high-grade stromal component has been proposed as an important pathologic predictor of outcome. Hallmarks for histologic diagnosis include biphasic tumor with benign often metaplastic epithelium associated with an atypical usually low-grade spindle cell proliferation exhibiting phyllodes growth and periglandular stromal condensation. Sarcomatous overgrowth (SO) is defined by sarcoma comprising $\geq 2 5 \%$ of the tumor volume. In a genome-wide copy number analysis of Mullerian adenosarcoma,439 16 tumors (8 with SO and 8 without SO) were subjected to a molecular inversion probe array analysis. Frequent gains of chromosomal 12q were noted (CDK4, MDM2, CPM, YEATS4, DDIT3, GLI1, HMGA2, and STAT6) without association with SO status. The most frequent losses involved chromosomes 13q, 9p, 16q, and 17q and were almost limited to cases with SO. BAP1 loss is seen in a subset of patients. ESR1 fusions are found in a minority of cases and BCORL1 fusions have been reported. Other genomic alterations are also observed in different subsets: 8q13 amplification and copy number gains of MYBL1; NCOA2/3 fusions; rare FGFR2, KMT2C, DICER1, ATRX, and TP53 mutations; and MDM2/CDK4 and TERT amplifications.439,440 # Staging and Treatment When evaluating suspected uterine sarcomas, biopsy may be helpful but is less sensitive than for endometrial cancers. The diagnosis of ESS and uLMS is often made after hysterectomy. The previous FIGO/AJCC staging systems for endometrial cancer were not appropriate for staging ESS and uLMS; patients were often upstaged when using the older AJCC staging system.441 A new staging system for ESS and uLMS from FIGO/AJCC took effect in 2009 accounting for the differences between uterine sarcomas and endometrial cancers.69,442 Confirmation of the type of mesenchymal malignancy by expert pathology review is critical. In addition, initial evaluation should include imaging of the chest/abdomen/pelvis by CT or combination MRI/CT. It is important to determine if the sarcoma is confined to the uterus or if extrauterine disease is present. Pelvic MRI can be used to evaluate local tumor extension or residual abnormality in cases where the uterus or adnexa were not resected or incompletely resected (ie, supracervical hysterectomy, myomectomy, possible tumor fragmentation, intraperitoneal morcellation). Neck/chest/abdomen/pelvis/groin FDG-PET/CT may be used to clarify ambiguous findings. If medically operable, then hysterectomy with (or without) BSO and en bloc resection of tumor is the initial treatment of choice for uterine sarcomas (see Primary Treatment in the NCCN Guidelines for Uterine Sarcoma).443 The Panel recommends ER/PR testing for LMS, ESS, and adenosarcoma to guide decisions regarding management of ovaries, particularly in young patients who are premenopausal. In general, BSO is favored for low-grade ESS or tumors expressing ER/PR, although management of the ovaries may be individualized in patients of reproductive age.444 A systemic review # NCCN Guidelines Version 3.2025 Uterine Neoplasms and meta-analysis of 786 patients reported $4 6 . 8 \%$ of tumor recurrence rate in ovarian preservation group versus $2 4 . 2 \%$ recurrence in the BSO group.445 In another multicenter retrospective study, the PFS for patients who underwent BSO versus ovarian preservation as 38 versus 11 months $( P = . 0 7 1 )$ .446 Uterine sarcoma should be removed en bloc to optimize outcomes; intraperitoneal morcellation is contraindicated.175,178 For incidental diagnoses of uterine sarcoma after hysterectomy, or in the case of a fragmented specimen, imaging is recommended and re-exploration for surgical resection can be considered. The ovaries may be preserved in selected patients with early-stage uLMS who wish to retain hormonal function.447 Additional surgical resection should be individualized based on clinical scenarios and intraoperative findings. Lymphadenectomy is controversial.3,419,447-450 High-grade uterine sarcomas tend to show hematogenous metastases to the lungs; lymph node metastases are uncommon. For medically inoperable sarcomas, options include systemic therapy and/or palliative EBRT with (or without) brachytherapy. Low-Grade Endometrial Stromal Sarcoma Recommended adjuvant therapy options for stage I ESS include BSO or observation (if menopausal or prior BSO). BSO with (or without) antiestrogen hormone therapy is recommended for stages II to IV ESS. Adjuvant EBRT may be added for stage II, III, or IVA (category 2B). Palliative EBRT may be added for patients with stage IVB disease.419,451,452 Anti-estrogen hormone therapy is also recommended for ESSs that have recurred or are unresectable (see Therapy for Relapse in the NCCN Guidelines for Uterine Sarcoma).453 Given the histologic similarities between low-grade ESS and uterine adenosarcoma, the Panel recommends similar adjuvant therapy options for adenosarcoma as provided for low-grade ESS. For patients with uterine adenosarcoma with SO in advanced stages, the Panel recommends BSO with a consideration of systemic therapy and EBRT. EBRT is palliative for stage IVB disease. Case series of patients with ESS suggest long disease-free intervals in the absence of specific therapy and raise questions about the use of adjuvant RT.454 Adjuvant radiotherapy in ESS has been demonstrated to reduce local recurrence rates but again with limited effect on survival.455,456 Because of concerns about radiation exposure, frequent routine surveillance imaging is no longer recommended for patients who are young and asymptomatic after primary therapy for ESS.457 Although anti-estrogen hormone therapy is recommended for low-grade ESS, studies have not yet determined the optimal therapeutic approach for high-grade ESS. However, due to the more aggressive nature of these tumors (eg, those with YWHAE::FAM22 rearrangements), the NCCN Panel has recommended that high-grade ESS be treated according to the algorithms in place for uLMS and UUS. Typical hormone therapy for low-grade ESS or adenosarcoma without SO or ER/PR-positive uterine sarcoma includes aromatase inhibitors458 (preferred for low-grade ESS or adenosarcoma without SO), fulvestrant, megestrol acetate (category 2B for ER/PR-positive uterine sarcoma), or medroxyprogesterone acetate (category 2B for ER/PR-positive uterine sarcoma). Gonadotropin-releasing hormone [GnRH] analogs with aromatase inhibitors are also considered as a preferred regimen in premenopausal patients who are not suitable for surgery (BSO). 419,447,453 For ER/PR-positive uterine sarcomas, the anti-estrogen hormone therapy should preferably be considered for patients with small tumor volume or an indolent growth pace. # NCCN Guidelines Version 3.2025 Uterine Neoplasms High-Grade Endometrial Stromal Sarcoma, Leiomyosarcoma, Undifferentiated Uterine Sarcoma, and PEComa The role of adjuvant radiotherapy in nonmetastatic disease is controversial. Most available data are retrospective except for a phase III randomized trial.459 Most retrospective studies of adjuvant RT suggest an improvement in local pelvic control but no appreciable or consistent improvement in OS, given the propensity of metastatic extrapelvic disease as a site of first or eventual recurrence.460-463 In many series, the patients treated with adjuvant radiation presumably had higher-risk factors (eg, larger tumors, deeper myometrial invasion), thus biasing the data against radiotherapy. However, a phase III randomized trial in stage I and II uterine sarcomas reported that postoperative pelvic radiotherapy did not improve OS for uLMS when compared with observation.459 Therefore, routine postoperative RT is not recommended for stage I patients with uLMS and UUS.451 If used in more advanced stages, adjuvant RT needs to be individualized and based on careful analysis of surgical pathologic findings. The role of adjuvant systemic therapy is also poorly defined; however, adjuvant systemic therapy has been used because of the high risk of systemic relapse. Given the uncertainties regarding any adjuvant treatment for stage I high-grade ESS, uLMS, USS, and other sarcomas (such as PEComa) after complete resection, observation is the only option. A systemic review and meta-analysis concluded that adjuvant chemotherapy in early-stage uLMS was not beneficial in reducing locoregional and distant recurrences over observation.464 Because of the increased risk profile in patients with completely resected stage II and III tumors, the Panel believes that it is appropriate to consider adjuvant systemic therapy and/or EBRT. Observation can be considered for patients with completely resected tumors with negative margins. (see Additional Therapy in the NCCN Guidelines for Uterine Sarcoma).465 In patients with stage IV incompletely resected or metastatic disease, systemic therapy and/or EBRT is generally recommended. For stage IVB disease, systemic therapy with an option of palliative EBRT is recommended. # Treatment of Recurrent or Metastatic Disease The recurrence rate is high in uLMS $( 5 0 \% - 7 0 \% )$ .3 The guidelines provide recommendations based on tumor resectability and patients’ prior RT exposure (see Therapy for Relapse in the NCCN Guidelines for Uterine Sarcoma). Treatment recommendations are made according to the site and nature of the recurrence. Local recurrences are classified as recurrence in the vagina/pelvis with imaging that is negative for distant metastatic disease. Surgical and RT treatment pathways are provided. The surgical pathway for treating local recurrence in patients without prior RT exposure includes the option of IORT (category 3 for IORT). Preoperative EBRT with (or without) systemic therapy are also options to consider. For residual disease following surgery in patients without preoperative RT, EBRT with (or without) brachytherapy with (or without) systemic therapy can be considered. Primary RT offers an alternative pathway for treating localized recurrence in patients without prior exposure. EBRT should be given along with the option of brachytherapy and systemic therapy. For both the surgical and RT treatment pathways, further adjuvant systemic therapy should be considered after initial treatment. Patients with local recurrence who have had prior RT exposure can be treated with 1) surgery with the option of IORT with (or without) systemic therapy (category 3 for IORT); 2) systemic therapy; or 3) selected reirradiation with EBRT and/or brachytherapy. A retrospective analysis of patients with ESS suggested that cytoreductive resection improved OS in patients with recurrent lesions.466 # NCCN Guidelines Version 3.2025 Uterine Neoplasms Systemic therapy with (or without) palliative EBRT or best supportive care is recommended for metastatic disease.467 For patients with isolated metastases that is resectable, surgical resection or other ablative therapy (eg, radiofrequency ablation, SBRT) may be appropriate. Patients with uLMS who experience longer time to recurrence may have improved survival outcomes following metastasectomy.468 Pre-or post-operative EBRT and/or systemic therapy can be considered. Observation may be an option in select, completely resected cases with no evidence of disease on postoperative imaging. Systemic therapy and/or local therapy (tumordirected EBRT or local ablative therapy) are reasonable options for patients with unresectable isolated metastases (see Therapy for Relapse in the NCCN Guidelines for Uterine Sarcoma).469-472 For recurrent lowgrade ESS, the first choice of systemic therapy is anti-estrogen hormone therapy. # Systemic Therapy for Advanced, Metastatic/Recurrent or Inoperable Disease If systemic therapy is used for treating high-grade uterine sarcoma, preferred first-line therapy options include single-agent doxorubicin, gemcitabine/docetaxel, 473-478 doxorubicin/trabectedin for LMS,479 doxorubicin/ifosfamide, and doxorubicin/dacarbazine for LMS or ifosfamide-ineligible patients (see Systemic Therapy in the NCCN Guidelines for Uterine Sarcoma).419,421,467 Doxorubicin is an active single agent for uLMS and is less toxic than combination regimens.419,467 The LMS-04 phase 3 randomized trial with 150 patients (67 with uLMS and 83 with soft tissue LMS) tested the benefits of doxorubicin/trabectedin versus doxorubicin alone as first-line therapy. Median PFS for the combination arm was longer than for the doxorubicin arm (12.2 months vs. 6.2 months, respectively; HR, 0.41; $9 5 \%$ CI, 0.29–0.58; $P < . 0 0 0 1$ ). Based on these findings, the Panel recommends doxorubicin/trabectedin for patients with LMS. For second-line or subsequent therapy, trabectedin is included as a preferred option for unresectable or metastatic uLMS. Data indicate that trabectedin may be useful in patients who have exhausted standard chemotherapy.480-483 The phase III data revealed a 2.7-month PFS benefit versus dacarbazine in metastatic liposarcoma or leiomyosarcoma that progressed after anthracycline-based therapy.484 Follow-up subgroup analysis of patients with uLMS $( \mathsf { n } = 2 3 2 )$ ) revealed PFS of 4.0 months for trabectedin versus 1.5 months for dacarbazine (HR, 0.57; $9 5 \%$ CI, 0.41– 0.81; $P = . 0 0 1 2$ ).485 However, OS did not differ significantly between the treatment arms (13.4 months for trabectedin vs. 12.9 months for dacarbazine; HR, 0.89; $9 5 \%$ CI, 0.65–1.24; ${ \cal P } = . 5 1$ ). Other recommended regimens include gemcitabine/dacarbazine, gemcitabine/vinorelbine, dacarbazine, gemcitabine, epirubicin, ifosfamide, liposomal doxorubicin, pazopanib, temozolomide, regorafenib, and eribulin (category 2B).387,470,473,474,486-503 Eribulin is included based on results from a phase III trial comparing the survival benefit of eribulin and dacarbazine in 452 patients with advanced leiomyosarcoma or adipocytic sarcoma.504 Median OS was 13.5 and 11.5 months for eribulin and dacarbazine, respectively (HR, 0.77; $9 5 \%$ CI, 0.62–0.95; $P = . 0 1 7 \mathrm { \rangle }$ ). Eribulin was designated as category 2B upon Panel review of the mature trial data. For first-line biomarker-directed therapies, the Panel recently added crizotinib, ceritinib, brigatinib, lorlatinib, and alectinib for anaplastic lymphoma kinase (ALK) fusion-positive IMTs for uterine sarcomas based on the literature evidence derived from non-small cell lung cancer.505-508 The Panel also recommends larotrectinib or entrectinib for NTRK gene fusion-positive tumors. Repotrectinib is also recommended for NTRK gene fusion-positive tumors that are naïve to prior NTRK-targeted therapy or have progressed on prior NTRK therapy. 383,384 Selpercatinib is recommended for RET-fusion positive tumors. 509 Selpercatinib showed # NCCN Guidelines Version 3.2025 Uterine Neoplasms clinically meaningful activity in the RET fusion-positive tumour-agnostic population, with a safety profile consistent with that observed in other indications. For PEComa, albumin-bound sirolimus is recommended as a first-line therapy option and sirolimus, everolimus, and temsirolimus are recommended as second-line or subsequent therapy options. Pembrolizumab has been added for the treatment of patients with unresectable or metastatic TMB-H tumors that have progressed following prior treatment and have no satisfactory alternative treatment options. Olaparib, rucaparib, and niraparib are included as second-line/subsequent therapy options for BRCA2-altered uLMS.510 # Post-Treatment Surveillance The recommended post-treatment surveillance protocol for uterine sarcoma is depicted in the algorithm (see Surveillance in the NCCN Guidelines for Uterine Sarcoma). History and physical exam is recommended every 3 to 4 months (consider every 6 months for lowgrade early-stage sarcomas) for the first 2 to 3 years, and then every 6 to 12 months thereafter. Imaging surveillance should include chest/abdomen/pelvis CT every 3 to 6 months for the first 3 years and then every 6 to 12 months for the next 2 years. Depending on histology, grade, and initial stage, annual to biannual imaging can be considered for an additional 5 years. Follow-up imaging may be as frequent as every 3 months or change based on histology grade and/or stage of tumor. Abdomen/pelvis MRI and chest CT without contrast is optional. Neck/chest/abdomen/pelvis/groin FDG-PET/CT can be considered if metastasis is suspected in select patients. Additional imaging should be based on symptomatology and clinical concern for metastatic disease. Patients should receive education regarding the symptoms of recurrent disease. Patients with bleeding (vaginal, bladder, or rectal), decreased appetite, weight loss, pain (in the pelvis, abdomen, hip, or back), cough, shortness of breath, and swelling (in the abdomen or legs) should seek prompt evaluation and not delay until the next scheduled appointment. Imaging may be helpful in the detection of recurrence. Patients should be educated regarding healthy lifestyle choices, obesity, exercise, smoking cessation, nutrition, and potential long-term and late effects of treatment. See Principles of Gynecologic Survivorship within the NCCN Guidelines for Uterine Neoplasms (also see the NCCN Guidelines for Survivorship, NCCN Guidelines for Smoking Cessation, and https://www.cancer.org/cancer/survivorship.html).396-398 The Panel also recommends patient education regarding sexual health, vaginal dilator use, and vaginal lubricants or moisturizers. # Drug Reactions Virtually all drugs have the potential to cause adverse hypersensitivity reactions, either during or after the infusion.511 In gynecologic oncology treatment, drugs that more commonly cause adverse reactions include carboplatin, cisplatin, docetaxel, liposomal doxorubicin, and paclitaxel. Most of these drug reactions are mild infusion reactions (ie, skin reactions, cardiovascular reactions, respiratory or throat tightness), but more severe allergic reactions (ie, life-threatening anaphylaxis) can occur.512-514 In addition, patients can have mild allergic reactions or severe infusion reactions. Infusion reactions are more common with paclitaxel.515 Allergic reactions (ie, true drug allergies) are more common with platinum agents (ie, carboplatin, cisplatin).515,516 Management of drug reactions is discussed in the NCCN Guidelines for Ovarian Cancer. 515 It is important to note that patients who have had severe life-threatening reactions should not receive the implicated agent again unless under the care of an allergist or expert in managing drug reactions. If a mild allergic reaction has previously occurred and it is appropriate to administer the drug again, a desensitization regimen should be used even if the symptoms have resolved; various desensitization regimens have been published and should be followed.517-519 Patients # NCCN Guidelines Version 3.2025 Uterine Neoplasms must be desensitized with each infusion if they previously had a reaction. Almost all patients can be desensitized (about $90 \%$ ).511 To maximize safety, it is prudent to desensitize patients in the intensive care unit.511 # Gynecologic Survivorship Treatment for gynecologic cancer typically involves surgery, chemotherapy, hormone therapy, RT, and/or immunotherapy, which may cause acute, short-term, and long-term toxicities. Surgical approaches may be extensive and cause adhesions to form, which in turn may cause pain and contribute to the development of small bowel obstruction, urinary or gastrointestinal complications (eg, incontinence, diarrhea), pelvic floor dysfunction (manifested by a variety of urinary, bowel, and/or sexual effects), and lymphedema. Chemotherapy agents vary, though commonly used regimens may pose a significant risk of neurotoxicity, cardiac toxicity, cognitive dysfunction, and the development of hematologic cancers. Longterm estrogen deprivation may cause symptoms such as hot flashes, vaginal dryness, and bone loss. RT may cause long-term complications (eg, fibrosis, stenosis, vulvovaginal atrophy) and may predispose patients to subsequent cancers of the skin, subcutaneous tissue, and/or underlying organs that are proximal to the radiation field. Use of immunotherapy agents in gynecologic cancers is emerging, and to date, long-term effects of these treatments are unknown. Following completion of treatment, all gynecologic cancer survivors should receive regular general medical care that focuses on managing chronic diseases (eg, depression, diabetes, hypertension), monitoring cardiovascular risk factors, receiving recommended vaccinations, and encouraging adoption of a healthy lifestyle (eg, promoting exercise, smoking cessation). In order to assess the late and long-term effects of gynecologic cancers, clinicians should comprehensively document the patient’s history, including prior treatment history, and conduct a thorough physical examination followed by necessary imaging and/or laboratory testing. As most treatments for gynecologic cancers will cause sexual dysfunction, early menopause, and infertility, special attention to the resultant medical and psychosocial implications is needed. All patients, whether sexually active or not, should be asked about genitourinary symptoms, including vulvovaginal dryness. Post-radiation use of vaginal dilators and moisturizers is recommended. Psychosocial effects may include psychological (eg, depression, anxiety, fear of recurrence, altered body image), financial (eg, return to work, insurance concerns), and interpersonal (eg, relationships, sexuality, intimacy). 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102f531d38484730aa0613df603834af	中华医学会	2018SOGC多囊卵巢综合征诱导排卵实践指南(No. 362)解读	# 2018 SOGC多囊卵巢综合征诱导排卵实践指南（No. 362）解读张巧利贾婵维周丽颖刘艳君余兰徐潇雨王树玉首都医科大学附属北京妇产医院生殖医学中心 100026通信作者：王树玉，Email：yushu572000@126.com，电话：+86-10-85960837 【摘要】多囊卵巢综合征（PCOS）是临床常见的妇科内分泌紊乱性疾病，是引起育龄期女性无排卵性不孕的主要原因。年加拿大妇产科医师协会（）针对患者制定了诱导排卵的临床实践指南，推荐生活方式干预，雌激素受体拮抗剂枸橼酸氯米芬（）和选择性芳香化酶抑制剂来曲唑（LE）为一线治疗，促性腺激素（Gn）为二线治疗，体外受精为三线治疗。胰岛素抵抗者可服用胰岛素增敏剂二甲双胍；或抵抗者，如果存在腹腔镜手术的其他指征可行腹腔镜卵巢打孔术。指南提出在临床实践过程中应遵循个体化和渐进性原则对PCOS患者进行规范诱导排卵。【关键词】多囊卵巢综合征；诱导排卵；胰岛素抵抗；生活方式干预；受精，体外基金项目：北京市属医院科研培育计划项目（PX2019053）；首都医科大学附属北京妇产医院中青年学科骨干培养专项（fcyy201606） # Interpretation to SOGC clinical practice guideline: No. 362-Ovulation Induction in Polycystic Ovary Syndrome Zhang Qiaoli, Jia Chanwei, Zhou Liying, Liu Yanjun, Yu Lan, Xu Xiaoyu, Wang Shuyu Department of Human Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China Corresponding author: Wang Shuyu, Email: yushu572000@126.com, Tel: +86-10-85960837 【Abstract】 Polycystic ovary syndrome (PCOS), a common clinical endocrine disorder, is the main cause of anovulatory infertility in women of childbearing age. The clinical practice guideline for ovulation induction in PCOS patients has been supported by the Society of Obstetricians and Gynaecologists of Canada (SOGC) in 2018. First line management of infertility once a diagnosis of PCOS is made should include weight loss and lifestyle modifications. Subsequently, first line medical therapy for ovulation induction should include selective estrogen receptor modulator—clomiphene citrate (CC) and aromatase inhibitor—letrozole (LE). The gonadotropins (Gn) should be considered as the second-line medical therapy, and in vitro fertilization treatment should be the third-line medical therapy. Insulin resistant patients can take the insulin sensitizer—metformin. When there are other indications for laparoscopy, laparoscopic ovarian drilling (LOD) may be considered in cases of CC or LE resistant PCOS. The clinical preventive action, that individual and progressive principles should be followed to normalize ovulation induction in PCOS patients. 【Key words】 Polycystic ovary syndrome; Ovulation induction; Insulin resistance; Lifestyle modifications; Fertilization in vitro Fund program: Beijing Municipal Administration of Hospitals Incubating Program (PX2019053); Beijing Obstetrics and Gynecology Hospital, Capital Medical University (fcyy201606) 多囊卵巢综合征（polycystic ovary syndrome，PCOS）是育龄期女性最常见的生殖内分泌疾病，患病率为 $5 \% \sim 1 0 \%$ ［1］，中国育龄期女性PCOS患病率约为 $5 . 6 1 \% ^ { [ 2 ] }$ 。不孕是PCOS常见的并发症，大约有 $7 5 \%$ 的患者伴有无排卵性不孕［3］。关于PCOS患者诱导排卵（ovulation induction）的非药物和药物治疗，加拿大妇产科医师协会（the Society ofObstetricians and Gynaecologists of Canada，SOGC）妇科临床实践委员会检索了2000—2016年Medline发表的文献，综述了多种PCOS诱导排卵方法，形成版的患者诱导排卵实践指南（362）［4］，对临床具有很大的指导意义。本文对该指南形成的治疗推荐进行详细解读，证据等级参见表1。 # 一、生活方式干预指南推荐：不孕患者超重可通过锻炼和生活方式调整减轻体质量至体质量指数（bodymass index，BMI） ${ < 3 5 \mathrm { ~ k g } / \mathrm { m } ^ { 2 } }$ 或体质量减轻 $5 \% \sim 1 0 \%$ ，对恢复排卵有效，可作为一线治疗，然而，目前证据有限，尚缺乏高质量研究（Ⅱ-3A）。病理性肥胖（ $\mathrm { \Delta B M I { \gtrsim } } 4 0 ~ \mathrm { k g / m } ^ { 2 } ,$ ）的患者应转诊至专科咨询专家建议，了解安全减重方法和妊娠风险（Ⅲ-A）。 PCOS 患者约 $50 \%$ 存在肥胖，多表现为腹型肥胖。肥胖的患者较体型瘦者更容易发生排卵障碍，且更容易出现严重的内分泌紊乱和代谢异常［5］，加重对不孕的影响。大多数肥胖的患者伴有不同程度的胰岛素抵抗（insulin resistance，）和代偿性的高胰岛素血症，促进垂体释放黄体生成素（luteinizing hormone，LH），直接刺激卵巢卵泡膜细胞 $1 7 \alpha$ -羟化酶，导致卵泡局部雄激素合成增多，发生卵泡闭锁和排卵障碍。此外，高水平胰岛素还可降低性激素结合球蛋白（sex hormone-binding globulin，SHBG）在肝脏的合成，使血清游离睾酮（free testosterone，FT）升高，对下丘脑-垂体-卵巢轴产生负反馈抑制，影响卵泡发育。近年多项指南推荐将生活方式干预作为PCOS的一线治疗措施，主要是通过饮食控制、运动和行为干预等多种途径［6］。PCOS中国诊疗指南（2018版）［7］提出应坚持低热量饮食、调整主要的营养成分、必要时进行替代饮食等；适量规律的耗能体格锻炼（ $3 0 \mathrm { m i n / d }$ ，每周至少次）及减少久坐，是减重最有效的方法；同时还应改变不良的饮食习惯、减少精神应激、戒烟、减少酒和咖啡摄入。如果患者还有严重的心理问题需要干预，应及时到精神心理科咨询疏导。生活方式干预减重失败且 $\mathrm { B M I } { \geqslant } 4 0 \mathrm { ~ k g } / \mathrm { m } ^ { 2 }$ 或 $\mathrm { B M I } { \geqslant } 3 5 \mathrm { ~ k g } / \mathrm { m } ^ { 2 }$ 伴随有高风险肥胖相关病症的患者，如高血压或糖尿病，可咨询相关专家，考虑手术减重［8］。成功的生活方式干预可改善PCOS患者的代谢异常，包括、高雄激素血症［9］、脂代谢异常，改善多毛、痤疮；改善月经紊乱、恢复卵巢功能，改善排卵障碍［10］；改善子宫内膜激素受体的表达，提高子宫内膜容受性［11］；还可辅助不孕治疗，改善妊娠结局［12］。生活方式干预可使 $30 \%$ 的PCOS不孕患者恢复排卵并自然妊娠，且改善妊娠结局［13］。研究显示，针对合并超重或肥胖的患者，体质量减轻 $5 \% \sim 1 0 \%$ 后可明显改善症状，降低血液中胰岛素水平，SHBG及胰岛素样生长因子（insulin-like growth factor，）结合蛋白含量增加，循环雄激素水平下降［14］。体质量下降 $5 \%$ 时可使 $7 5 \%$ 患者恢复规律的月经周期和排卵，且对后续的诱导排卵甚至辅助生殖助孕也有帮助［15］。研究表明，运动结合控制饮食治疗6 周可以增加卵巢对枸橼酸氯米芬（clomiphene，）的反应和改善超重及肥胖患者的排卵率［16］。但关于生活方式对于PCOS不孕改善的临床数据有限，目前有一项研究证实了生活方式干预可提高超重PCOS患者的生育能力［17］。世界卫生组织（WHO）依据BMI界值对肥胖程度分类为，BMI在 $2 5 . 0 { \sim } 2 9 . 9 \mathrm { k g } / \mathrm { m } ^ { 2 }$ 为超重， ${ \geqslant } 3 0 \mathrm { ~ k g } / \mathrm { m } ^ { 2 }$ 为肥胖。由于人种的差异，中国肥胖问题工作组提出对中国成人判断标准： $2 4 . 0 { \sim } 2 7 . 9 \ \mathrm { k g / m } ^ { 2 }$ 为超重， ${ \geqslant } 2 8 \mathrm { \ k g } / \mathrm { m } ^ { 2 }$ 为肥胖［18］。我国PCOS患者可参考这一标准，如能将BMI控制在正常范围最佳，但大部分患者存在减重不科学、减重困难等问题，如将体质量减轻 $5 \% \sim 1 0 \%$ 时应可明显改善临床症状。表1 加拿大预防保健工作组对于循证医学证据和推荐等级的说明[4] <table><tr><td>证据评估质量“</td><td>推荐分类</td></tr><tr><td>I：证据来源于至少1项高质量RCT</td><td>A：具有良好的临床干预推荐证据</td></tr><tr><td>Ⅱ-1:证据来源于较高质量的对照实验,但未随机分组</td><td>B：具有一般的临床干预推荐证据</td></tr><tr><td>Ⅱ-2:证据来源于较高质量的队列试验(前瞻性或回顾性)或病例对照研究，最好来源于大于1个中心或研究团体</td><td>C：现有证据存在争议,不足以为临床决策提供支持或反对的推荐;其他因素可影响临床决策</td></tr><tr><td>Ⅱ-3：证据来源于不同时间和地点,有或无干预</td><td>D：具有一般的证据反对临床干预</td></tr><tr><td>Ⅲ：权威机构的意见，依据临床经验,描述性研究，或专家委员会报告</td><td>E：具有良好的证据反对临床干预</td></tr><tr><td></td><td>I:证据(数量或质量)不足以提供推荐,其他因素会影响临床决策</td></tr></table> 注：示随机对照试验；a 示根据加拿大预防保健工作组证据评估标准进行修改；b示根据加拿大预防保健工作组推荐分类标准进行修改 # 二、CC诱导排卵指南推荐：对于患者使用诱导排卵有效，是一线治疗方案，应告知患者双胎妊娠或多胎妊娠的风险增加（Ⅰ-A）。年指南重申了的使用剂量和时限，可从自然月经或撤退性出血的第日开始口服 CC $5 0 ~ \mathrm { m g / d }$ ，连续服用 5 d，如果多个卵泡发育，可降至 $2 5 ~ \mathrm { m g / d }$ ，如果诱导排卵无效，可增加至$5 0 ~ \mathrm { m g / d ^ { [ 4 ] } }$ 。生产厂家建议不超过 $\mathrm { 1 0 0 ~ m g / d }$ ，然而许多有临床经验的医生考虑到使用其他方法如$\mathrm { G n }$ 的风险和花费时，选用C $\mathrm { ~ C ~ } 1 5 0 ~ \mathrm { m g / d }$ ，甚至高达$2 5 0 ~ \mathrm { m g / d }$ ，连用 $5 ~ \mathrm { d } ^ { [ 1 9 ] }$ ，而我国最大剂量至 $1 5 0 \mathrm { \ m g / d _ { c } }$ 。进行诱导排卵时，如卵泡期长或黄体期短提示剂量可能过低，可适当增加CC剂量。 CC诱导排卵时排卵率可达 $7 5 \% { \sim } 8 0 \%$ ，每一排卵周期有 $22 \%$ 的PCOS妇女妊娠，6个周期的累积妊娠率为 $60 \% \sim 7 0 \%$ ，双胎发生率为 $7 \% \sim 9 \%$ ，三胎发生率为 $0 . 3 \% ^ { [ 2 0 ] }$ 。资料报道妊娠的PCOS患者中大约$50 \%$ 应用 $\mathrm { C C } 5 0 \ \mathrm { m g } / \mathrm { d } , 2 0 \% { \sim } 2 5 \%$ 应用 C $\mathrm { ~ \ ; ~ 1 0 0 ~ m g / d ~ }$ ，$10 \%$ 应用CC $1 5 0 \mathrm { m g / d } ^ { [ 2 1 ] }$ 。使用C $\mathrm { ~ C ~ } 1 5 0 ~ \mathrm { m g } / \mathrm { d } ~ 3$ 个周期无排卵，为CC抵抗，PCOS患者的发生率为 $1 5 \%$ \~$4 0 \% ^ { [ 2 2 ] }$ ，应积极寻找原因，考虑是否存在肥胖、等。年指南指出如果个排卵周期未妊娠应考虑使用其他诱导排卵方法，年我国《促排卵药物使用规范》明确提出诱导排卵妊娠多发生于治疗最初个月，治疗超过个月不推荐再用 $\mathrm { C C } ^ { [ 2 3 ] }$ 。 # 三、来曲唑（letrozole，LE）诱导排卵推荐：近期研究证明PCOS患者使用芳香化酶抑制剂诱导排卵安全有效，尤其是肥胖患者。在加拿大，LE用于诱导排卵被认为是超适应证用药，在不可获得的情况下，患者知情同意后可使用（Ⅰ-B）。 LE为第三代芳香化酶抑制剂，2001年LE首次被正式用于诱导排卵，目前在我国也被广泛应用。2018年SOGC指南更多关注使用LE的子代安全性，报道曾采用大鼠实验进行胚胎毒性、胎盘毒性和致畸性研究［4］。尽管目前 LE 被认为是诱导排卵的一线药物，但在加拿大，LE仍被告知是超适应证用药，我国也面临着同样的情况，因此用药前需向患者讲明情况，知情同意后应用。有回顾性研究比较使用与非诱导排卵的妊娠结局，显示组心脏和骨骼畸形发生率高［24］。另一项回顾性研究比较和CC诱导排卵出生的新生儿，未发现LE组先天性畸形和染色体异常发生率增加（ $2 . 4 \%$ 比 $4 . 8 \%$ ）［25］。对于有CC抵抗的PCOS患者可选择LE进行诱导排卵［26］。与CC相比，LE不会减少ER数量，不会对子宫内膜产生抑制作用。而且LE半衰期短，没有外周抗雌激素作用，因此多诱导单个卵泡发育，可防止多胎妊娠发生。从自然月经或撤退性出血的第2\~5日开始服用， $2 . 5 ~ \mathrm { m g / d }$ ，共5 d；如无排卵则每周期增加 $2 . 5 ~ \mathrm { m g }$ ，直至 $7 . 5 ~ \mathrm { m g / d }$ 。妇女使用的排卵率为 $6 1 \% { \sim } 8 1 \%$ ，妊娠率为 $10 \% { \sim } 4 0 \%$ ，多胎妊娠发生率低［27］。一项多中心随机双盲对照试验选取名妇女为研究对象，显示的排卵率和活产率较高［28］，对于 $\mathrm { B M I } { > } 3 0 . 3 \ \mathrm { k g / m } ^ { 2 }$ 的妇女明显缩短实现活产的时间［4］。系统综述提示，在无排卵的PCOS妇女中，LE较CC具有更高的妊娠率，使用LE $5 ~ \mathrm { m g }$ 和$7 . 5 ~ \mathrm { m g }$ 临床妊娠率无区别；同样证实LE较CC具有更高的活产率［29］。有资料提出：根据循证医学证据，2018年推出的三项国际指南［美国生殖医学会（ASRM）/欧洲人类生殖与胚胎学学会（ESHRE）/美国妇产科医师学会（ACOG）/SOGC］均建议LE可作为患者一线诱导排卵药物［13］。 # 四、二甲双胍在诱导排卵中的作用指南推荐：二甲双胍联合与单用比较，可增加患者的排卵率和妊娠率，但未提高活产率（ - ）。二甲双胍联合可用于年龄较大（ ${ > } 2 8$ 岁）和腹型肥胖（腰臀比 ${ > } 0 . 8 5$ ）的 CC 抵抗PCOS患者（Ⅰ-A）。是发病的关键环节， $50 \% { \sim } 7 0 \%$ 的PCOS患者存在 $\mathrm { I R } ^ { [ 3 0 ] }$ ，即使是体质量正常的患者也存在一定程度的IR，IR可加重高雄激素血症和排卵障碍。应用胰岛素增敏剂可改善，使血中胰岛素水平下降，从而使雄激素水平下降，有利于恢复规律的月经周期和排卵。二甲双胍是PCOS患者应用最为广泛的胰岛素增敏剂，有降低高血糖的作用，但不降低正常血糖。二甲双胍可降低高胰岛素血症介导的卵巢雄激素过剩［31］，纠正多毛和痤疮，恢复排卵性月经。二甲双胍还可改善血管炎症、脂质代谢等动脉粥样硬化危险因素，并对子宫内膜功能有改善作用［32］。二甲双胍常用于 PCOS 伴 IR 的患者，或 CC 抵抗的 PCOS 患者 $\mathrm { G n }$ 诱导排卵前的预治疗。二甲双胍开始服用剂量为 $2 5 0 { \sim } 5 0 0 ~ \mathrm { m g / d }$ ，逐渐增加剂量至$5 0 0 { \sim } 7 5 0 ~ \mathrm { m g }$ ，tid，随餐服用3\~6个月。有研究证实，PCOS患者服用二甲双胍后 $8 3 \% { \sim } 9 5 \%$ 可恢复排卵性月经， $6 4 \%$ 体质量下降， $52 \%$ 血清雄激素下降，尤其FT下降，SHBG升高，LH下降，这些改变都有利于改善IR，从而防止远期并发症的发生［33］。2017年的 Cochrane综述显示，二甲双胍较安慰剂于活产有益；而且二甲双胍联合CC较单用CC有更好的排卵率和妊娠率。二甲双胍较安慰剂有更好的活产效果；对肥胖的PCOS妇女在临床妊娠和排卵改善方面，CC优于二甲双胍；单用二甲双胍或二甲双胍联合均未见流产率增加，两组的活产率差异无统计学意义［34］。研究提出年龄较大（ ${ > } 2 8$ 岁）且腹型肥胖（腰臀比 ${ > } 0 . 8 5$ ）的患者，加用二甲双胍可能受益［35］。 # 五、 $\mathrm { G n }$ 诱导排卵指南推荐：PCOS无排卵的不孕患者， $\mathrm { G n }$ 是二线治疗。Gn诱导排卵时应进行超声和实验室监测。常因多卵泡发育、多胎妊娠和卵巢过度刺激风险促排卵周期取消率高（Ⅱ-2A）。用于口服诱导排卵药物无排卵或虽有排卵但未妊娠的PCOS患者。应用 $\mathrm { G n }$ 每周期的妊娠率为 $2 0 \% { \sim } 2 5 \% ^ { [ 3 6 ] }$ ，常见并发症是卵巢过度刺激综合征（ovarian hyperstimulation syndrome，OHSS），其发生与超生理水平的卵泡刺激素（follicle-stimulatinghormone，FSH）有关；另一并发症是多胎妊娠，有报道使用 $\mathrm { G n }$ 诱导排卵时多胎妊娠风险高达 $20 \%$ ，而口服药物诱导排卵仅为 $5 \%$ 。 $\mathrm { G n }$ 诱导排卵方案多样，医师需根据患者具体情况来选择最合适的诱导排卵方案，并尽量避免并发症的发生。Gn可辅助CC、LE治疗，为避免多卵泡发育，也可考虑低剂量递增方案或者常规剂量递减方案。应用低剂量递增方案时，如 $\mathrm { G n }$ 剂量增加至 $2 2 5 ~ \mathrm { I U / d }$ 仍不理想，则终止用药［37］。 2018 年指南指出使用 $\mathrm { G n }$ 诱导排卵时应由经过培训的医生进行，而且需要超声和激素监测。当卵泡直径达到 $1 8 ~ \mathrm { m m }$ ，子宫内膜厚度至 $0 . 8 ~ \mathrm { c m }$ 时注射人绒毛膜促性腺激素（human chorionic gonadotropin，），促进排卵，一般注射后$2 4 { \sim } 3 6 \mathrm { h }$ 发生排卵。对PCOS患者使用 $\mathrm { G n }$ 诱导排卵的目标是单卵泡生长发育，单胎妊娠，尽可能减少OHSS和多胎妊娠的发生。如果PCOS患者有大量的卵泡生长，必要时停止治疗，将多胎妊娠和OHSS的发生风险降至最小。如直径 $\geqslant 1 6 \ \mathrm { m m }$ 的卵泡数 $\geqslant 3$ 个或直径≥$1 4 ~ \mathrm { m m }$ 卵泡数 ${ \geqslant } 4$ 个时建议取消周期，禁止注射hCG，严格避孕，以免发生OHSS和多胎妊娠［38］，必要时可转体外受精-胚胎移植（in vitro fertilization-embryo transfer，IVF-ET）治疗。六、卵巢打孔术指南推荐：对于 CC 和/或 LE 抵抗的 PCOS 患者，如果存在腹腔镜手术的其他指征，可考虑行腹腔镜下卵巢打孔术（Ⅰ-A）。应明确手术的相关风险和降低卵巢储备功能的风险（Ⅲ-A）。对CC和/或LE抵抗的患者，如果存在腹腔镜手术的其他指征，可选择腹腔镜下卵巢打孔术（laparoscopic ovarian drilling，LOD），推测可能是通过破坏卵巢生成雄激素的组织发挥作用，局部雄激素水平下降，一部分卵巢组织内卵泡发育成熟并排卵。LOD术如果破坏卵巢组织过多，卵巢储备功能下降，但一般不会导致卵巢早衰的发生，常规剂量操作对卵巢功能安全［39］。研究报道可降低患者的睾酮水平，降低比值，提高排卵率和妊娠率［40］。对于抵抗的患者，与药物治疗的排卵率、妊娠率相似，然而药物治疗的多胎妊娠和OHSS等并发症发生率较高［41］。最新分析报道，对于CC抵抗的PCOS患者，LOD治疗后的活产率与LE治疗差异［42］。有研究认为LOD诱导排卵效果在术后1年会自动消失 $45 \%$ ，因此建议患者及时试孕，如治疗效果不佳，无自然受孕机会，可尽早选择辅助生殖技术助孕［20］。 LOD仅能使部分患者获益，应进行术前评估，避免不必要的手术治疗。基于目前的证据，LOD术后不良生殖结局的预测指标包括：重度肥胖（$3 5 \mathrm { k g / m } ^ { 2 }$ ）、低基础LH水平、雄激素增多症（游离雄激素指数 $\geqslant 1 5$ ，术前雄烯二酮 ${ < } 4 . 1 \ \mathrm { m m o l / L }$ ）、抗苗勒管激素（anti-Müllerian hormone，AMH） ${ \geqslant } 7 . 7 ~ \mu \mathrm { g } / \mathrm { L } ,$ 、不孕年限 ${ > } 3 . 5$ 年、年龄 ${ > } 3 5$ 岁［43］。可参考以上指标对患者进行风险收益评估，选择适宜的个体化治疗方案。七、IVF 指南推荐：PCOS患者 $\mathrm { G n }$ 诱导排卵失败或有其他IVF指征时可选择体外受精（Ⅱ-2A）。 $72 \%$ 的PCOS不孕患者经过生活方式干预、CC或诱导排卵、或诱导排卵以及治疗后会获得累积活产［44］，如治疗失败或存在其他IVF指征（如：高龄、输卵管病变、男性精液异常等）时，推荐应用三线治疗方案IVF-ET助孕。PCOS患者的高胰岛素血症和高雄激素血症会导致颗粒细胞过早黄素化，生长因子旁分泌功能紊乱，损害卵泡内环境，阻碍卵子胞质和核的成熟［45］。所以，对PCOS患者进行 IVF 治疗前应先纠正 IR 和高雄激素血症。PCOS患者IVF助孕时每周期妊娠率为 $40 \% { \sim } 5 0 \%$ ，妊娠率与年龄相关［46］。由于PCOS患者卵巢窦卵泡数较多，且对 $\mathrm { G n }$ 反应阈值较窄，控制性超促排卵时药物用量难以把握，低剂量时卵泡发育停滞，而无优势卵泡，加大剂量则卵泡容易募集过多，往往导致大量卵泡发育，雌二醇水平偏高，OHSS风险增加或周期取消率增加。故需要选择合适的个体化控制性超促排卵方案，目前拮抗剂方案和温和刺激方案尝试较多。对于PCOS患者建议全部胚胎冷冻择期移植，可以有效避免新鲜胚胎移植妊娠后内源性hCG加重或诱发晚发型，是一种安全有效的助孕策略，可以提高PCOS不孕患者的妊娠率，同时降低发生率。一项大样本多中心研究显示妇女冻融胚胎移植较新鲜胚胎移植有更高的活产率，降低OHSS的发生，但可能增加子痫前期的潜在风险［47］。对PCOS不孕患者遵循由易到难的原则进行个体化逐级干预可使大部分女性妊娠。生活方式干预是肥胖不孕患者的基础一线治疗，如需要可进行或诱导排卵的一线治疗；如无效可考虑Gn促排卵二线治疗或LOD；对于以上治疗无效的患者，或合并适应证时，可以采取三线治疗，提高患者的妊娠率。胰岛素增敏剂二甲双胍可改善IR，可作为条件状态下用药。2018SOGC指南对每种诱导排卵方法都进行了循证分级用以指导临床实践。总之，PCOS不孕的治疗原则是尽可能采用简单的方法实现妊娠，遵循由简单到复杂，循序渐进助孕。利益冲突所有作者均声明不存在利益冲突 # 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a63c0228509349df800b303a0499da64	中华医学会	2019年ERAS协会更新的_妇科肿瘤围手术期管理指南_解读	·指南解读· # 2019年ERAS协会更新的“妇科肿瘤围手术期管理指南”解读王祎祎汪沙段华首都医科大学附属北京妇产医院妇科微创中心100006通信作者：段华，Email：duanhuasci@163.com 【摘要】加速康复外科（ERAS）的实质是降低医疗应激反应，促进机体生理功能快速恢复；其临床实现需要基于循证医学证据的判定标准及实施规范。自年丹麦哥本哈根大学教授首次提出理念、年欧洲正式成立协会以来，已发布了针对不同学科、不同手术的管理指南。年月，协会对“妇科肿瘤围手术期管理指南”进行了更新，基于年首版指南及循证医学证据，提出了最新的共识意见。本文通过对国际更新指南进行解读，以期对妇科肿瘤的围手术期临床管理进行优化、补充，对我国妇科肿瘤围手术期的优化管理提供新的思路和参考，为在我国妇科肿瘤手术领域中得以规范、有序地开展提供参考和指导。 DOI:10.3760/cma.j.issn.0529‐567x.2019.11.014 加速康复外科（enhanced recovery after surgery，ERAS）是指基于多学科协作及循证医学证据，对一系列围手术期处理措施予以优化，以实现减少手术应激反应、减轻术后疼痛、降低围手术期并发症发生风险、促进患者术后加速康复、改善患者生命质量的目标；另一方面，实施可缩短住院时间、降低医疗费用，给医患双方带来成本效益［1］。自1997年丹麦哥本哈根大学Kehlet教授首次提出ERAS理念［2］、年欧洲正式成立协会以来，已发布了针对不同学科、不同手术的管理指南。年月，协会对“妇科肿瘤围手术期管理指南”进行了更新［3］，基于年首版指南及循证医学证据，提出了最新的共识意见。见表1，2。本文对2019版指南的主要内容进行解读，以期对妇科肿瘤的围手术期临床管理进行优化、补充，为在我国妇科肿瘤手术领域中得以规范、有序地开展提供参考和指导。 # 一、术前评估与准备 1. 术前病史采集、宣教、沟通：术前与患者充分沟通，就麻醉及手术方式征询患者意见，并参考患者意愿制定术后医疗护理计划。术前宣教可使患者对手术应激有相对充分的心理准备，利于缓解术后紧张、焦虑情绪，也有助于减轻术后疼痛、恶心等不适感，使身心加快恢复。尽管术前沟通应采取口头及书面双重形式，但在妇科肿瘤手术的随机对照研究中发现，书面形式的知情同意告知对医患双方更有利；沟通时应强调充分告知病情，并给予安慰、鼓励，以此妇科恶性肿瘤患者的术后焦虑情绪可有长达6个月的缓解［4］。总结和推荐：术前宣教、征询及与患者充分沟通对加速患者术后康复有显著益处。本指南推荐：术前对妇科肿瘤手术患者常规进行详细的病史采集、病情宣教及意向征询（强烈推荐、中等级别证据）。 2. 术前预康复：“肿瘤预康复”是在诊断肿瘤后、开始治疗前采取的持续的医疗护理过程，旨在对患者术后的身心应激性损伤进行基础预估、筛查危险因素，并进行有效的预处理，以减少近期、远期疾病性损伤的发生［5］。尽管目前关于“预康复”的涵义尚无共识，但多元模式的预康复训练方法逐渐获得认可，主要包括：（1）有氧运动和阻力运动；（2）针对性的功能锻炼；（）饮食干预；（）心理干预。预康复对患者的预后有一定的积极作用，来自结直肠手术的荟萃分析显示，术前营养干预的患者平均住院时间缩短 $2 ~ \mathrm { d } ^ { [ 6 ] }$ ；而采取有氧运动或阻力运动的患者，其术后腹腔并发症风险显著降低（ $O R = 0 . 5 9 ,$ ）［7］。另有前瞻性研究证实，与单独实施ERAS相比，“三元模式”（营养、运动、心理干预）的预康复训练有利于促进结直肠手术患者术后运动能力的恢复［8］。然而，ERAS管理模式中加入预康复对改善妇科肿瘤手术患者的预后是否有效，目前尚缺乏直接的证据。总结和推荐：结直肠手术的相关研究显示，预康复对某些患者的术后恢复有益，但其推广到妇科肿瘤手术患者中的有效性仍需更多深入研究的证实（推荐等级：弱，低级别证据）。 3. 术前机械性肠道准备：传统上认为，术前常规口服泻药、灌肠等机械性肠道准备可降低肠道内粪便负荷，进而降低吻合口瘘及术后感染的发生风险。然而，术前肠道准备不当可能造成患者脱水、电解质紊乱，并增加患者焦虑、紧张情绪而影响术后恢复。妇科微创手术中应用肠道准备的随机对照试验证实，肠道准备的实施与改善手术视野、降低手术操作难度并无相关性；尽管目前尚缺乏肠道准备在妇科开腹手术中应用的研究数据，但从4项结直肠手术的荟萃分析结果推导，机械性肠道准备与总死亡率、手术部位感染（surgical site infection，SSI）发生率、吻合口瘘发生率及再次手术干预率等均无明显关联［9‐10］；此外，对卵巢上皮性癌（卵巢癌）肿瘤细胞减灭术（伴结直肠切除）的患者实施无肠道准备的ERAS干预，其SSI发生率仅为 $2 . 4 \% ^ { [ 1 1 ] }$ 。表1 2019年ERAS协会对“妇科肿瘤围手术期管理指南”更新的内容注：ERAS表示加速康复外科 <table><tr><td>ERAS项目</td><td>2019版指南与2016版指南的对比</td></tr><tr><td>术前病史采集、宣教、沟通</td><td>推荐等级相同但证据质量更高(从低级别升到中等级别)</td></tr><tr><td>术前预康复</td><td>2019版指南更新了内容</td></tr><tr><td>术前肠道准备</td><td>推荐等级及证据质量未变,但参考文献更新</td></tr><tr><td>术前禁食及碳水化合物补充治疗</td><td>更新建议及总结的内容，增加新参考文献</td></tr><tr><td>预防静脉血栓栓塞(VTE)</td><td>更新建议及总结的内容，增加化疗期间VTE预防的内容</td></tr><tr><td rowspan="2">降低手术部位感染(SSI)发生率</td><td>2019版指南更新了内容(包括预防性抗生素的应用，皮肤准备，低体温的预防，</td></tr><tr><td>避免应用引流,控制围手术期高血糖)</td></tr><tr><td>标准麻醉方法</td><td>更新建议及总结的内容</td></tr><tr><td>微创手术</td><td>推荐等级相同但证据质量更高(从低级别升到高级别)</td></tr><tr><td>围手术期液体管理</td><td>2019版指南更新了内容，增加目标导向性液体治疗(GDFT)新内容</td></tr><tr><td>术后阿片类药物镇痛</td><td>2019版指南重新修订,包括数种镇痛方法的推荐等级及证据质量进行更新</td></tr><tr><td>围手术期营养</td><td>2019版指南更新了内容,增加免疫营养新内容</td></tr><tr><td>术后肠梗阻的预防</td><td>推荐等级及证据质量均更新(2019版为强烈推荐、高级别证据)</td></tr><tr><td>患者自我报告结局指标(PRO) 盆腔脏器廓清术和腹腔热灌注化疗(HIPEC)</td><td>2019版指南更新了内容，增加功能康复新内容</td></tr><tr><td></td><td>2019版指南更新了内容，将此两类患者纳入ERAS管理人群,但循证医学证据有限，推荐等级及证据质量均较低</td></tr><tr><td rowspan="2">出院途径</td><td>2019版指南更新了内容,强调以患者感受为中心,结合病情及术后恢复的客观指标，</td></tr><tr><td>制定个体化的出院标准(推荐等级弱、高级别证据)</td></tr></table> 表2 2019版“妇科肿瘤围手术期管理指南”维持2016版指南的内容 <table><tr><td>ERAS项目</td><td>推荐建议</td></tr><tr><td>术前优化措施</td><td>(1)术前4周戒烟(强烈推荐、高级别证据）禁酒(强烈推荐、中等级别证据);(2)术前积极纠正贫血 (强烈推荐、高级别证据)</td></tr><tr><td>术前镇静药物的应用</td><td>避免术前常规应用镇静药物缓解焦虑(强烈推荐、低级别证据)</td></tr><tr><td>术后预防恶心呕吐</td><td>实施妇科手术的患者术后应接受>2种止吐药物预防恶心及呕吐(强烈推荐、中等级别证据)</td></tr><tr><td>术后尿液引流</td><td>术后应短期尿液引流，最好<24h(强烈推荐、低级别证据)</td></tr><tr><td>术后早期活动</td><td>鼓励患者术后早期(24h内)活动(强烈推荐、低级别证据)</td></tr></table> 注：ERAS表示加速康复外科总结和推荐：妇科微创手术及开腹手术前不应常规行机械性肠道准备；若评估有肠管损伤的可能或病变累及肠管，可酌情考虑肠道准备（强烈推荐、中等级别证据）。 4. 术前禁食及碳水化合物补充治疗：手术应激会明显加重术后的代谢反应，可通过麻醉诱导前避免禁食并补充口服碳水化合物得到缓解。相关的随机对照研究已证实，口服碳水化合物可降低术后胰岛素抵抗，并对心功能产生保护效应。此外，腹部手术的荟萃分析显示，术前补充能量制剂反而能促进肠道功能的恢复，且不增加术后感染的发生风险［12］。在术前2 h给予清流质饮食的经腹子宫肌瘤切除术患者中，术后恶心、呕吐的发生率明显下降，且住院时间缩短、就诊满意度较术前禁食者显著提高［13］。但目前就肥胖、糖尿病、胃肠功能紊乱患者能否从术前进食碳水化合物中获益，以及实施的安全性问题，尚需更多的循证医学证据。总结和推荐：对于无胃排空延迟者，应避免术前彻夜禁食，鼓励术前摄轻食、术前 $^ { 2 \mathrm { ~ h ~ } }$ 口服碳水化合物饮料（强烈推荐、高级别证据）。对于合并胃肠功能障碍者，术前夜或术前8 h应禁食。口服碳水化合物对于非糖尿病患者可改善胰岛素抵抗、加速术后康复（强烈推荐、中等级别证据）。 5. 评估静脉血栓栓塞风险及预防性抗凝治疗：妇科肿瘤患者是罹患静脉血栓栓塞（VTE）的高危人群，其在子宫颈癌、子宫内膜癌及卵巢癌中的发生率分别达 $3 \% \sim 4 \%$ 、$4 \% { \sim } 9 \% , 1 7 \% { \sim } 3 8 \%$ ，新辅助化疗期间也有高达 $12 \%$ 的发生风险［14］。除恶性肿瘤外，年老、体质指数高、长期应用皮质类固醇激素、制动和血液高凝状态等均证实为发生的独立风险因素。因此，对实施妇科肿瘤手术的高危患者要重视预防性抗凝治疗，预估手术时间超过 $3 0 \mathrm { m i n }$ 者应给予机械性及药物双重预防。术前预防性抗凝治疗的有效性已获循证医学的证实。大型回顾性队列研究显示，术前应用低分子肝素者深静脉血栓形成及肺栓塞的风险显著降低，且并未增加术中出血及血小板减少的发生［15］。此外，气压装置或弹力袜等机械性预防抗凝的措施，均可减少VTE的发生，联合肝素等药物抗凝时效果更优。 VTE风险贯穿围手术期始终，因此，符合高危美国胸科医师协会（）标准的妇科肿瘤患者，美国国家综合癌症网络（NCCN）指南建议药物抗凝治疗延长至术后 $2 8 \textup d$ 。总结和推荐：术前应给予高危人群机械性和药物双重预防性抗凝治疗；术后应继续预防；对于符合高危标准的患者（包括晚期卵巢癌患者），应延长低分子肝素抗凝治疗至术后28 d（强烈推荐、高级别证据）。 6. 预防 SSI：SSI 是指术后 $3 0 \textup d$ 内手术切口或器官周围发生的感染。在妇科肿瘤手术中发生率达 $20 \% { \sim } 3 0 \%$ ，可造成围手术期患病率、死亡率上升，医疗支出负担加重［16］。目前，预防的系列措施主要包括：抗生素的预防应用、皮肤准备、预防低体温、避免引流、控制高血糖。总结和推荐：（）抗生素的预防应用：第代头孢菌素作为子宫切除术的抗生素预防首选；对于盆腔恶性肿瘤或累及肠管的手术建议补充抗厌氧菌药物预防感染；应根据患者自身的免疫状态、手术时间、出血量等合理调整用药方案（强烈推荐、高级别证据）。（）皮肤准备：级证据表明，与聚维酮碘相比，使用氯己定‐乙醇制剂者SSI发生率降低 $4 0 \% ^ { \left[ 1 7 \right] }$ 。推荐术前使用氯己定成分的抗菌肥皂淋浴，术日备皮并于手术室进行氯己定‐乙醇皮肤消毒（强烈推荐、高级别证据）。（）预防低体温：术中低温与及心血管意外的风险增加相关。美国疾病控制及预防中心认可围手术期维持正常体温作为ⅠA类推荐［18］。建议术前即给予保温毯、暖风机等预保暖处理，术中及术后也应密切监测体温变化，采取主动保温措施。推荐低体温的预防纳入所有的ERAS指南中（强烈推荐、高级别证据）。（4）避免引流：目前的证据显示，放置腹腔或皮下引流管可增加SSI风险，并可能使腹腔内出血延误诊断［19］；放置鼻胃管并未显著降低术后腹部切口裂开、肠瘘等的风险，且增加患者的异物感。因此，本指南推荐应避免妇科肿瘤开腹手术常规放置腹腔、皮下引流管及鼻胃管（强烈推荐、高级别证据）。（5）控制高血糖：围手术期接受严格血糖控制管理的妇科肿瘤手术患者，其术后SSI发生率降低 $3 5 \% \sim 5 5 \% ^ { [ 2 0 ] }$ 。推荐所有患者术前均行血糖水平检测，糖尿病及非糖尿病患者的围手术期血糖水平均应维持在 $1 1 . 1 \mathrm { m m o l } / \mathrm { L }$ （即 $2 0 0 \mathrm { m g / d l }$ ）以下（强烈推荐、高级别证据）。 # 二、术中麻醉及手术方式 1. 麻醉方案：麻醉的主要目的包括：术中诱导催眠、镇痛、优化循环功能、维持正常的血氧水平，术后实现神经认知功能快速恢复、恶心呕吐等麻醉副反应控制在最低水平等。可采用吸入麻醉、全身静脉麻醉或联合局部阻滞麻醉。异丙酚作为诱导全身麻醉的标准药物，具有起效快、恢复快、止吐效果好的优势；全静脉给药右美托咪定被证实可促进术后肺泡复张；氯胺酮及利多卡因则可显著缓解术后疼痛，并可改善术后肠道功能的恢复［21］。应避免应用高剂量及长效阿片类镇痛药物，可考虑应用瑞芬太尼等短效阿片类药物以术后较快苏醒。使用周围神经刺激器监测神经肌肉阻滞效果，确保手术结束时及时解除阻滞效应，以降低肌无力的发生风险。使用双频指数对麻醉深度进行标记、监测，一方面避免麻醉过浅、术中知晓，另一方面实现快速复苏、减少麻醉后遗效应的发生。此外，采用保护性肺通气策略可有效降低开腹手术者肺部并发症的发生率［22］。总结和推荐：建议使用短效麻醉剂；客观监测神经肌肉阻滞水平并确保术后完全逆转；采用保护性肺通气策略，潮气量$6 { \sim } 8 ~ \mathrm { m l / k g }$ ，呼气末正压为 $6 { \sim } 8 \ \mathrm { c m H } _ { 2 } \mathrm { O }$ （1 $_ { \mathrm { c m H _ { 2 } O = 0 . 0 9 8 \ k P a } , }$ ）。（强烈推荐、高级别证据） 2. 手术方式：ERAS管理的关键是减少手术带来的应激性损伤及异常的免疫炎症反应。应基于人性化、规范化、标准化、个体化的治疗原则，全面评估患者情况后选择恰当的术式。与传统开腹术式相比，经阴道、腹腔镜、机器人辅助的腹腔镜等微创手术路径联合 ERAS，可通过减少术中出血、缓解术后疼痛、促进肠道功能恢复、缩短住院时间等增加患者围手术期的获益。总结和推荐：微创手术作为的重要原则，在符合指征的妇科肿瘤手术患者中建议适当优先应用（强烈推荐、高级别证据）。 # 三、术后管理与预防围手术期液体管理及目标导向性液体治疗：维持正常的循环血容量对预防围手术期并发症及加速术后恢复至关重要。目前尚无针对不同妇科手术的专业补液指南。目标导向性液体治疗（goal‐directed fluid therapy，GDFT）是结合患者自身的血液动力学因素采取静脉输注为主的方式给予适当量的液体补充，以改善组织灌注和氧合效应［23］。多中心研究证实，与传统限制性补液相比，术后采取模式的自由补液可显著降低急性肾损伤及SSI的发生风险［24］；然而，补液量过度也会有潜在风险、延缓患者恢复，造成妇科开腹手术患者住院时间延长 $12 \% \sim 1 4 \%$ 。总结和推荐：GDFT能降低妇科肿瘤开腹手术患者术后并发症的发生风险、加速术后恢复、缩短住院时间。建议在高危手术风险人群中应用GDFT（强烈推荐、高级别证据）。术后营养补充及免疫营养：术后维持机体正常的营养状态益处颇多，包括改善胃肠道功能、促进创面愈合、减少腹水生成、防止感染等并发症的发生，进而利于患者加速康复。基于妇科肿瘤术后营养补充的研究显示，增加补充精氨酸的高蛋白饮食可改善血管舒张和组织氧合，利于机体免疫功能的恢复、抵御感染；与单纯高热量饮食相比，早期饮食中增加蛋白质补充者住院时间明显缩短。术后蛋白质补充的标准量目前尚未统一，急症营养补充指南中推荐术后日均蛋白质摄入量达每公斤体重 $\mathbf { g } ^ { [ 2 5 ] }$ 。总结和推荐：推荐妇科恶性肿瘤患者术后 $2 4 \mathrm { h }$ 内开始饮食过渡（强烈推荐、高级别证据）；建议予高蛋白饮食（强烈推荐、中等级别证据）。 3. 预防术后肠梗阻：肠麻痹及肠梗阻是影响患者术后恢复的关键因素。妇科恶性肿瘤患者术后并发肠梗阻者达$30 \%$ ，而在伴有肠切除的卵巢癌肿瘤细胞减灭术中甚至高达 $4 0 \% ^ { [ 2 6 ] }$ 。阿片类镇痛药物、疾病的复杂程度、手术范围、术中输血等均是影响术后肠道功能恢复的重要因素。术后早进食、合理补液、早期下床活动、减少阿片类药物的应用等ERAS干预措施，已被证实可降低术后肠梗阻的发生风险2.5倍。也有报道术后饮用咖啡可使妇科恶性肿瘤患者术后肠梗阻的发生率由 $30 \%$ 降至 $10 \%$ ；尚无证据证实咀嚼口香糖对促进肠道功能恢复有显著作用；卵巢癌等腹部手术的随机对照研究表明，阿维莫泮（阿片类药物的拮抗剂）可明显改善胃肠动力、促进肠蠕动，预防术后肠麻痹及肠梗阻的发生［27‐28］。总结和推荐：减少使用阿片类镇痛药物、术后早进食、早活动、维持体液平衡、饮用咖啡等措施经济、可行，预防肠梗阻安全、有效，建议在妇科肿瘤手术患者术后推广应用（强烈推荐、高级别证据）。 4. 术后多模式镇痛：术后疼痛可使患者活动受限，增加静脉血栓、肠梗阻等并发症的发生率、延长住院时间，甚至发展为长期慢性疼痛，影响患者的生命质量。常用的阿片类镇痛药物易引发术后恶心、疲乏、眩晕及增加成瘾风险，因此，ERAS强调减少单一阿片类药物的使用，代之以非甾体类抗炎药、加巴喷丁、塞来昔布等非阿片类药物联合应用，发挥多模式镇痛效应，同时最大限度降低药物的副反应［29］。口服用药为主，不推荐静脉滴注作为常规。丁丙诺啡作为阿片类受体拮抗剂，可明显削弱镇痛效果，且该药的半衰期较长，因此术前3\~7d应注意停药。总结和推荐：避免应用单一阿片类药物，推荐联合对乙酰氨基酚等非甾体类抗炎药行多模式镇痛（强烈推荐、高级别证据）；术前有丁丙诺啡药物应用史的患者应向专业的麻醉医师咨询镇痛方案（强烈建议、中等级别证据）。 # 四、结语 ERAS的实质是降低医疗应激反应，促进机体生理功能快速恢复［30］。其临床实现需要基于循证医学证据的判定标准及实施规范。在妇科领域，国际ERAS协会及国内学术组织相继发布了相关的指南，旨在促进ERAS临床路径于妇科手术中的规范化、流程化、标准化、个体化实施。本文通过对国际更新指南进行解读，以期对我国妇科肿瘤围手术期的优化管理提供新的思路和参考；另一方面，针对我国妇科手术中尚处于起步阶段的ERAS发展现状，亟需打破学科壁垒，加强多学科通力合作，改变传统单一的诊疗模式，在实施ERAS的过程中进行科学的临床验证，并依托大数据环境下的医学评估不断做出调整、优化，达到加速患者康复、甚至改善患者肿瘤学结局的最终目标。利益冲突所有作者均声明不存在利益冲突 # 参考文献 [1] Ljungqvist O, Scott M, Fearon KC. 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Abdominal incision injection of liposomal bupivacaine and opioid use after laparotomy for gynecologic malignancies[J]. Obstet Gynecol, 2016, 128(5):1009‐1017. DOI: 10.1097/AOG.000000 0000001719. [28] de Leede EM, van Leersum NJ, Kroon HM, et al. Multicentre randomized clinical trial of the effect of chewing gum after abdominal surgery[J]. Br J Surg, 2018, 105(7): 820‐828. DOI: 10.1002/bjs.10828. [29] Schwartz AR, Lim S, Broadwater G, et al. Reduction in opioid use and postoperative pain scores after elective laparotomy with implementation of enhanced recovery after surgery protocol on a gynecologic oncology service[J]. Int J GynecolCancer, 2019,29(5):935‐943. DOI: 10.1136/ijgc‐2018‐000131.[30] 陶凝, 陈昌贤, 李力. 快速康复外科理念在妇科肿瘤手术中的应用 [J]. 中华妇产科杂志 , 2015, 50(8): 632‐636. DOI:10.3760/cma.j.issn.0529‐567x.2015.08.017. （收稿日期：2019‐06‐27）（本文编辑：沈平虎） # 2019年11期继续教育题目（单项选择题）： 1.根据《2019年ERAS妇科肿瘤围手术期管理指南》的建议，预防妇科肿瘤患者围手术期低体温的措施包括？（）暖风机保持温暖环境； B.加热毯、加热床垫； C.密切监测体温变化；静脉输注或体腔冲洗液体加温； E. 以上都是 2.根据《2019年ERAS妇科肿瘤围手术期管理指南》的建议，以下哪项不作为预防手术部位感染（SSI）发生率的措施？（）盆腔恶性肿瘤或累及肠管的手术前预防性应用抗生素； B. 皮肤消毒；预防术中低体温；常规放置皮下、腹盆腔引流管； E.围手术期控制高血糖 3. 以下哪项不是《2019年ERAS妇科肿瘤围手术期管理指南》对妇科肿瘤麻醉管理的建议？（） A.高剂量应用长效类阿片类药物；应用双频指数对麻醉深度进行标记、监测； C. 客观监测神经肌肉阻滞水平并确保术后可完全逆转； D.采用保护性肺通气策略； E.尽可能应用瑞芬太尼等短效阿片类药物 4.妇科恶性肿瘤患者术后并发肠梗阻者达 $30 \%$ ，以下哪项可降低术后肠梗阻的发生风险？（） A.避免应用阿片类镇痛药物； B. 术后早进食； C. 维持体液平衡； D.早期下床活动； E.以上都是 5. $\langle \langle 2 0 1 9 $ 年ERAS妇科肿瘤围手术期管理指南》中强调对妇科肿瘤患者围手术期进行静脉血栓栓塞（VTE）风险评估及预防性抗凝治疗，以下哪项不是的独立风险因素？（） A. 年老； B. 体质指数低值； C. 长期制动；长期应用皮质类固醇激素； E.血液高凝状态（继续教育的答题方式及获得学分的方法见插页。答案见下期）（2019 年10 期继续教育题目的答案：1.A 2.C 3.C 4.B 5.E）	None	None	None
42c726be0f3f431ab3db1f7502182c2f	中华医学会	2021国际妇科内镜学会宫腔镜子宫肌瘤切除术指南解读	·指南解读· # 2021国际妇科内镜学会宫腔镜子宫肌瘤切除术指南解读任常1 冯力民2 段华3 朱兰1 1 中国医学科学院北京协和医学院北京协和医院妇产科国家妇产疾病临床医学研究中心疑难重症及罕见病国家重点实验室，北京 100730；2 首都医科大学附属北京天坛医院妇产科，北京 100070；3 首都医科大学附属北京妇产医院妇科微创中心，北京 100006通信作者：朱兰，Email：zhu_julie@vip.sina.com 【摘要】子宫肌瘤发病率高，黏膜下子宫肌瘤常造成明显的症状，影响患者的生命质量。宫腔镜子宫肌瘤切除术是黏膜下子宫肌瘤的一线微创手术治疗方式。2021 年 12 月，国际妇科内镜学会（ISGE）制订了“宫腔镜子宫肌瘤切除术指南”，为临床实施宫腔镜子宫肌瘤切除术提出了具体的推荐建议。本文对此指南中的推荐建议进行解读，便于中国妇产科同道借鉴参考。基金项目：国家重点研发计划（）国际妇科内镜学会（International Society forGynecologic Endoscopy，ISGE）的宫腔镜子宫肌瘤切除术（hysteroscopic myomectomy）工作组总结了与宫腔镜子宫肌瘤切除术相关的重要临床问题，见表1；并据此在PubMed及数据库中进行了文献检索，收集并分析了年1月至2021年6月期间发表的相关英文文献，包括论著、综述以及欧洲妇科内镜学会（European Society forGynaecological Endoscopy，ESGE）和美国妇科腹腔镜医师协会（American Association of Gynecologic Laparoscopists，AAGL）发表过的相关指南，于2021年12月发布了“2021ISGE宫腔镜子宫肌瘤切除术指南”［1］（以下简称：ISGE指南），是目前针对宫腔镜子宫肌瘤切除术的最新国际性指南。ISGE 指南依据推荐意见分级的评估、制订和评价（grading of recommendations assessment，development andevaluation，GRADE）系统对可用信息进行了证据分级，并提出了推荐建议。【解读】 ISGE指南凝练出临床医师在宫腔镜子宫肌瘤切除术实践中最关注以及最需要注意的 9 个问题，并围绕这些问题提出了推荐意见。对于此类手术的规范化开展提供了借鉴。 # 一、术前评估出现异常子宫出血（AUB）时临床上需怀疑黏膜下子宫肌瘤的存在，可通过影像学检查进行诊断，如：超声、生理盐水灌注子宫超声造影（saline infusion sonohysterography，表1 宫腔镜子宫肌瘤切除术的相关临床问题 <table><tr><td>序号</td><td>问题</td></tr><tr><td>问题1</td><td>宫腔镜子宫肌瘤切除术前应如何对患者进行评估?</td></tr><tr><td>问题2</td><td>黏膜下子宫肌瘤与手术结局相关的最佳分类系统是什么？</td></tr><tr><td>问题3</td><td>手术前药物预处理的指征?</td></tr><tr><td></td><td>问题40型黏膜下子宫肌瘤最佳的切除技巧和最适合的切除器械是什么？</td></tr><tr><td></td><td>问题5I型和Ⅱ型黏膜下子宫肌瘤最佳的切除技巧和最适合的切除器械是什么？</td></tr><tr><td></td><td>问题6减少宫腔镜子宫肌瘤切除术中子宫穿孔并发症的措施?</td></tr><tr><td></td><td>问题7减少宫腔镜子宫肌瘤切除术中和术后出血的措施?</td></tr><tr><td></td><td></td></tr><tr><td></td><td>问题8液体超负荷的极限值和减少膨宫液相关并发症的措施?</td></tr><tr><td></td><td>问题9哪些措施可以减少子宫颈损伤、感染和粘连?</td></tr></table> SIS）、磁共振成像（magnetic resonance imaging，MRI）、诊断性宫腔镜检查［2‑4］。需要采集和分析患者的病史并查体，排除妊娠和妇科恶性疾病（子宫颈癌和子宫内膜癌）［5］，充分评估子宫情况以确定所有的子宫病变，明确黏膜下子宫肌瘤的数量、位置、大小、深度以及肌瘤与浆膜之间的最小距离，对子宫肌瘤与其他子宫疾病进行鉴别诊断（如子宫腺肌瘤）。超声检查具有实用性、可靠性和成本效益比高等优势，是评估子宫肌层情况首选的影像学检查手段。以宫腔镜检查为“金标准”评价经阴道超声检查诊断宫内病变的准确性，其诊断子宫肌瘤的敏感度为 $4 6 . 7 \%$ ，特异度为 $9 5 . 0 \%$ ，准确率为 $8 7 . 9 \%$ ，Kappa指数为 $0 . 4 6 ^ { [ 6 ] }$ 。高质量的证据支持在诊断黏膜下子宫肌瘤方面与宫腔镜检查同样有效，而SIS和宫腔镜检查均优于经阴道超声检查［7‑8］。 MRI检查诊断子宫肌瘤的敏感度为 $9 4 . 1 \%$ ，特异度为$6 8 . 7 \%$ ，阳性预测值为 $9 5 . 7 \%$ ，阴性预测值为 $6 1 . 1 \% ^ { [ 9 ] }$ 。MRI在提供黏膜下子宫肌瘤的准确信息方面被认为优于其他检查［9‑12］，但常规使用时成本效益比低。对于体质指数（BMI）高、肌瘤数量多、子宫增大明显、同时存在子宫肌瘤和其他子宫或盆腔内病变的患者，可以行MRI检查。MRI检查在诊断子宫腺肌病（包括子宫腺肌瘤）方面具有与超声检查同等的特异性，但敏感性更高［2，13］。当超声检查提示非典型病变时，增强MRI检查对于子宫肌层恶性病变的术前评估有帮助［14］。门诊宫腔镜检查可以直观地观察子宫腔，判断子宫内膜性状，判断是否存在黏膜下子宫肌瘤和其他宫腔内的病变。与此同时，宫腔镜还可以对子宫内膜和看到的病变进行活检。宫腔镜、和检查对于判断宫腔内病变同样有效，且均优于经阴道超声检查［11］。为了正确判断肌瘤的深度，门诊宫腔镜检查应联合经阴道超声检查［ 4］。推荐1：术前评估应包括详细的病史、查体（1A）；推荐2：所有患者均需经超声检查评估（1A）；推荐：宫腔镜子宫肌瘤切除术前最好采用或经阴道超声 $^ +$ 宫腔镜检查进行评估（1A）；MRI检查适用于超声检查受限的情况，如：患者高、多发肌瘤、子宫增大明显、同时存在子宫肌瘤和其他子宫或盆腔病变以及子宫肿瘤性质不明（1A）；推荐：术前需要向患者说明其他的替代治疗方案、宫腔镜子宫肌瘤切除术的潜在风险、可能需要二次手术以及肌瘤复发的问题，充分知情同意（1A）。［解读］黏膜下子宫肌瘤常表现为AUB，术前需要全面评估患者的病史和查体情况，并对子宫肌层病变情况进行全面评估以取得最佳的手术效果并减少并发症的发生风险。术前子宫评估的内容包括：了解子宫所有的病变情况，确认肌瘤的数量以及黏膜下肌瘤的位置、深度和大小。辅助检查首选超声检查，推荐采用SIS或经阴道超声结合宫腔镜检查进行评估。MRI检查适用于肥胖、多发肌瘤、子宫增大明显、怀疑有子宫腺肌病或肉瘤的患者，但不应作为常规检查方法。术前需要充分知情同意。 # 二、黏膜下子宫肌瘤的分类 Lasmar 提出了“STEPW”分类系统，对黏膜下子宫肌瘤的 5 个特点进行评分［15］，包括：大小（size）、宫腔部位（topography）、基底宽度占宫壁范围（extension of the base）、肌瘤位于肌层的占比（penetration into the myometrium）、侧壁位置（lateral wall position），见表 2。包括我国浙江省人民医院在内的个国家的个宫腔镜中心的前瞻性多中心研究发现，STEPW分类系统对于预测宫腔镜子宫肌瘤切除术的复杂性、手术时间、不完全切除、液体出入量和并发症发生情况的效果好于ESGE提出的分类系统［16‑17］。由于宫腔镜子宫肌瘤切除术可能需要多次手术才能完全完成，STEPW分类系统能够比仅靠子宫肌瘤大小和深度更好地预测多次手术的风险［18‑20］。推荐5：推荐用黏膜下子宫肌瘤STEPW分类系统来预测手术复杂性、手术时间、手术不完全切除和并发症发生情况（1B）。［解读］为取得最佳疗效、减少并发症发生，ISGE指南推荐在宫腔镜子宫肌瘤切除术前采用黏膜下子宫肌瘤STEPW 分类系统进行评分。ISGE 认为，与 ESGE 和FIGO只简单地把黏膜下肌瘤分为0型（完全在宫腔内）、Ⅰ型（肌瘤在肌层的部分 ${ \bf < 5 0 \% }$ 、肌瘤表面与子宫肌壁角度 $\mathbf { \nabla } { < } 9 \mathbf { 0 } ^ { \circ }$ ）和Ⅱ型黏膜下子宫肌瘤（肌瘤在肌层的部分 $3 5 0 \%$ 、肌瘤表面与子宫肌壁角度 $\mathbf { \nabla } \geqslant \mathbf { 9 0 } ^ { \circ }$ ）相比，STEPW分类系统通过计算黏膜下肌瘤的大小、肌瘤位于肌层的自身占比、基底宽度占宫壁的范围、肌瘤在宫腔的部位和位于侧壁位置共5个维度的评分，将患者分为3组并推荐相应的手术方式，可以更好地预测手术复杂性、手术时间、不完全切除的可能性、液体吸收量和并发症发生情况。但国内有学者尝试采用STEPW 分类系统进行术前评估后发现，STEPW 分类系统与传统的ESGE分类法在手术时间、灌流量和完整切除率方面并无显著差异［21］。因此，在国内广泛普及STEPW分类系统之前还需要进一步的大样本量随机对照研究验证其效果。 # 三、术前预处理促性腺激素释放激素（gonadotropin‑releasing hormone，表2 STEPW分类系统 <table><tr><td>评分(分)</td><td>大小(cm)</td><td>宫腔部位</td><td>基底宽度占宫壁范围</td><td>肌瘤位于肌层的占比</td><td>侧壁位置"</td></tr><tr><td>0</td><td><2</td><td>下1/3</td><td><1/3</td><td>0</td><td>+1</td></tr><tr><td>1</td><td>2~5</td><td>中1/3</td><td>1/3~2/3</td><td>≤50%</td><td></td></tr><tr><td>2</td><td>>5</td><td>上1/3</td><td>>2/3</td><td>>50%</td><td></td></tr><tr><td>评分(分）</td><td colspan="5">治疗选择</td></tr><tr><td>0~4</td><td>I</td><td colspan="4">低复杂性宫腔镜子宫肌瘤切除术</td></tr><tr><td>5~6</td><td>Ⅱ</td><td colspan="4">高复杂性宫腔镜子宫肌瘤切除术,两步法切除肌瘤,应用促性腺激素释放激素类似物</td></tr><tr><td>7~9</td><td>Ⅲ</td><td colspan="4">需要考虑宫腔镜子宫肌瘤切除术以外的方案</td></tr></table> 注：a 若肌瘤位于侧壁，则额外加1分（无论其他4项的评分）；b 为上述5项评分之和 GnRH）类似物（analogues）已被用于术前缩小子宫肌瘤、减少血流［22‑23］。最新的系统评价研究了术前应用类似物后黏膜下子宫肌瘤完全切除、手术时间、液体吸收和并发症（如：大量出血、子宫穿孔和肠损伤）情况，发现应用GnRH类似物对于以上情况并无改善［22］。推荐6：并无证据表明术前应用GnRH类似物可以提高黏膜下子宫肌瘤完全切除率、缩短手术时间、减少液体吸收、避免并发症发生，所以，GnRH类似物不作为常规推荐（）。［解读］ ISGE 指南基于证据不推荐术前常规应用GnRH类似物治疗。但ISGE指南未讨论贫血的患者术前应用GnRH类似物的情况。在临床实践中，对于部分月经量多已造成中度及以上贫血，单纯依靠补铁治疗很难纠正的患者，可以酌情使用GnRH类似物纠正贫血、增加手术耐受性。 # 四、手术方法宫腔镜手术可以使用以下器械：电外科器械（电切环、气化电极或激光）和冷器械（剪刀、钳子或冷刀环）。微型器械可以通过标准宫腔镜（ $1 2 { \sim } 1 5 \ \mathrm { F r }$ ）的操作通道 $( 5 \ \mathrm { F r } )$ ）对小肌瘤进行切除。型子宫肌瘤：根据所使用的器械不同，可应用不同技术进行宫腔镜下0型子宫肌瘤的切除［4，24］。传统宫腔镜通过电切环对病变进行反复切割以切除肌瘤。虽然电切技术通常被认为是0型子宫肌瘤切除术的“金标准”，但文献中并无确凿的证据证明其优于其他技术［25］。采用宫内分碎术（intrauterine morcellation，IUM）与电切镜电切术的比较性研究数量有限，通常仅用于子宫肌瘤和子宫内膜息肉的切除；IUM在手术时间和学习曲线方面被证明更优［26］。系统评价分析了IUM处理黏膜下子宫肌瘤的可行性后发现，其治疗型和型肌瘤的预后良好［27］，但证据非常有限。一旦黏膜下子宫肌瘤完全暴露在宫腔内，可以使用切除。 2. Ⅰ型和Ⅱ型子宫肌瘤：（1）电切术与IUM的选择：2017 年的系统评价述分析了 8 项研究，但未能提供关于IUM 用于Ⅰ型和Ⅱ型子宫肌瘤的结论性信息［27］。目前，也无研究比较这两种技术的安全性。有鉴于此，在出现新的高质量证据前，推荐使用电切技术。（）冷环与热环电切术：Mazzon 首次提出和描述了冷环电切技术，避免了热量扩散到健康的子宫内膜和肌层的风险，因此认为比热环电切技术侵入性更小［28］。然而，在假包膜平面切除肌瘤时，即使对于型黏膜下子宫肌瘤使用热环电切时，其副损伤也较少出现。尚无高质量研究准确估计由冷切技术完成的子宫肌瘤切除术患者的血管渗透率。（3）单极与双极电切术：仅有1项小样本量随机对照试验比较了使用单极或双极进行肌瘤电切术治疗子宫肌瘤伴月经过多的不孕症妇女的效果，两组术后月经症状均显著改善，妊娠相关的结局也是相似的［29］。（4）其他技术：水按摩和双合诊按摩可促使肌壁间肌瘤挤压入宫腔，以减少不完整切除的风险［30］，但可靠性尚需未来随机对照试验证实。术中可以考虑超声监视，帮助一次性切除子宫肌瘤并可避免子宫穿孔等并发症［31‑32］。推荐7：对于0型子宫肌瘤，除了电切镜电切术外，IUM也是推荐的方法；相比电切术，的手术时间和学习曲线均更短（1C）；推荐：对于、型子宫肌瘤，因为可行性和可重复性高，推荐分次电切，而非IUM（1C）；推荐9：对于Ⅰ、Ⅱ型子宫肌瘤选择冷刀环还是电切环尚无定论（2C）；推荐10：对于Ⅰ、Ⅱ型子宫肌瘤单极与双极电切对于缓解月经症状和改善生育结局是相当的（）。［解读］对于0型黏膜下子宫肌瘤，其治疗目标是彻底切除，分次电切或者IUM的方法均可以考虑，后者具有手术时间和学习曲线更短的优势，但电切术仍是“金标准”术式。电切环应置于肌瘤后方，在回拉时通电切除，以减少对正常肌层的热损伤以及子宫穿孔的风险，保证手术安全。对于Ⅰ、Ⅱ型黏膜下子宫肌瘤建议分次切除，配合水按摩、双合诊按摩促进肌瘤突向宫腔并行超声监视，以完整切除并减少并发症。冷刀环是否优于电切环尚无定论，采用单极或者双极电切的治疗效果和妊娠结局是相似的。但ISGE指南并未讨论宫腔镜下切开肌瘤假包膜后分离肌瘤与周围肌层后切除的相关问题，目前国内外部分医院已尝试采用这种方法施行手术并取得了成功，在有合适的工具的情况下实现较大肌瘤的一次性切除；在今后的国内指南及专家共识制定时可以纳入这部分研究进行分析，确定其适用范围，进一步规范宫腔镜黏膜下子宫肌瘤切除的手术操作。五、宫腔镜子宫肌瘤切除术的主要并发症和预防措施子宫颈损伤和子宫穿孔：穿孔可发生在子宫颈扩张、放置宫腔镜或肌瘤切除时，肌瘤距离浆膜非常近是一个重要的危险因素。如果是激活的电器械造成的穿孔，周围器官损伤的风险较高。有时即使未穿孔，术后数天内也可能发现周围器官的迟发性热损伤［33］。对于大部分钝性穿孔，观察 $^ +$ 抗生素保守治疗可行。但对于电损伤，应行腹腔镜或开腹探查术以充分评估并处理周围器官可能的损伤［33］。不同研究报道的术前阴道应用或者口服米索前列醇软化子宫颈便于扩张和置入宫腔镜的结果尚不一致［34‑36］。尽管使用米索前列醇软化子宫颈有一定的前景，但最终结论还需要进一步的研究证实［34‑35］。推荐11：不推荐术前常规阴道应用米索前列醇减少子宫颈损伤和穿孔（2B）。 2. 膨宫液相关并发症：在宫腔镜手术过程中，可能发生短时吸收大量膨宫液，而导致严重的并发症。出现的症状和并发症的严重程度取决于吸收量以及患者合并症的情况（如：合并心血管或肾脏疾病）。液体超负荷可导致心力衰竭、肺水肿、低钠血症（非等渗膨宫液）、脑水肿伴癫痫发作、昏迷和呼吸骤停。持续和准确地监测膨宫液全身吸收量，即所谓的“液体差值（即灌流介质入量和出量的差值）”，对于预防并发症的发生至关重要［37］。液体超负荷由于补充性渗透压失衡，可引起进一步的低渗、低钠血症（非等渗膨宫液）和低钾血症，需要包括麻醉医师和重症监护医师在内的多学科诊疗［38］。研究发现，应用生理盐水行双极电切时液体负荷超过$1 0 0 0 \mathrm { m l }$ 会增加气栓的风险［39］。然而，这并非是因为液体量的问题，降低双极电切的功率能减少热量，在同样的液体吸收进入循环的情况下更少出现气栓。同时，电切电凝会产生一氧化碳等废物，随着液体进入循环形成碳氧血红蛋白［40‑41］，其水平与心电图段改变及血管内渗透压具有高度相关性，可导致心肌缺血，因此，麻醉医师应参与并发症的处理。一旦发现心电图改变时应立即停止手术。推荐：育龄期患者应用生理盐水双极电切时液体差值不超过 $1 0 0 0 \mathrm { m l }$ ，发生严重并发症的风险较低；生理盐水差值达到 $1 0 0 0 { \sim } 2 5 0 0 \mathrm { m l }$ 时需要严密监测，注意栓塞的征象；液体差值超过 $2 5 0 0 \mathrm { m l }$ 需要立即停止手术（1C）；推荐13：对于老年或有心肾疾病或其他合并症的患者，液体差值超过 $7 5 0 ~ \mathrm { m l }$ 就需要引起警惕（）。3. 感染：宫腔镜手术的感染风险很低，是否需要常规给予预防性抗生素尚无定论，未来需要高质量的研究证实［42］。4. 粘连：宫腔内放置自交联透明质酸钠凝胶可减少粘连［43‑44］。宫腔镜二次探查简单易行，可诊断和分离膜状粘连，尤其适用于不孕症妇女［45］。推荐 14：宫腔镜子宫肌瘤切除术后推荐常规应用自交联透明质酸钠凝胶，尤其是多发肌瘤切除的患者（1B）。［解读］宫腔镜通过子宫颈内口进入宫腔时最容易出现子宫包括子宫颈的损伤。产科和计划生育科常使用米索前列醇软化子宫颈，国内也有较多应用于非孕患者宫腔镜手术前软化子宫颈的文献报道，但ISGE指南认为其效果尚无定论，不推荐作为常规术前用药。国内发表的《宫腔镜手术子宫颈预处理临床实践指南》推荐宫腔镜术前至少4 h阴道后穹隆放置米索前列醇 $2 0 0 { \sim } 4 0 0 ~ \mu \mathbf { g } ^ { [ 4 6 ] }$ ，但其中国药品说明书上无子宫颈软化的适应证，因此超适应证应用时需要谨慎，严格选择患者并充分知情同意。目前，国内应用较为广泛的方法包括术前 $3 { \sim } 1 5 \ \mathrm { m i n }$ 静脉给予非罂粟碱类平滑肌解痉药间苯三酚，其具有价格低廉、副反应轻微、扩张效果好的优势；为避免药物副反应，还可以采用术前放置一次性子宫颈扩张棒，缓慢扩张子宫颈的方法。宫腔镜手术最常见的并发症是液体超负荷，需要高度重视，对于不同年龄和身体状况的患者，需要引起警惕的液体差值不同，育龄期患者应将 $\mathbf { 1 0 0 0 m }$ 作为安全限度，超过$\bf { 2 5 0 0 m l }$ 需要立即终止手术；而对于老年或有合并症的患者液体差值达到 $7 5 0 ~ \mathrm { m l }$ 就需要高度警惕。术中要重视患者体征的监测。严格消毒和无菌操作的情况下宫腔镜子宫肌瘤切除术的感染风险很低，不一定需要预防性使用抗生素。术后放置自交联透明质酸钠凝胶可减少宫腔粘连的发生，宫腔镜二次探查手术可以发现并分离新的宫腔粘连；但这两种处理均会增加患者的费用，涉及医疗保险问题，在我国是否适用还需要斟酌。利益冲突所有作者声明无利益冲突 # 参考文献 [1] Loddo A, Djokovic D, Drizi A, et al. 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DOI: 10.3760/cma.j.cn112141‑20200828‑ 00677. # 《中华妇产科杂志》第十二届编辑委员会名单顾名誉总编辑：曹泽毅总编辑：郎景和副总编辑：魏丽惠沈铿孔北华张为远狄文陈子江杨冬梓杨慧霞张震宇朱兰编辑委员：（以下按姓氏汉语拼音字母顺序排列）陈春林陈敦金\* 陈倩程利南崔恒崔满华崔竹梅\* 丁岩段华段涛范玲丰有吉古航郭丽娜黄荷凤李广太梁德杨\* 郝敏黄薇\* 贺晶\* 胡小良胡娅莉华克勤黄向华孔为民冷金花李斌\* 李佩玲李小平李笑天\李旭梁志清林建华林金芳林兆强凌斌刘彩霞\ 刘继红刘俊涛\* 刘兴会刘朝晖\卢彦平鲁永鲜马丁马玉燕漆洪波乔杰沈丹华盛修贵宋磊宋岩峰陶光实\ 童晓文万小平汪希鹏王波\* 王和王建六王少为王谢桐王益夫王泽华温宏武吴令英吴瑞芳吴尚纯吴小华向阳谢幸徐丛剑薛凤霞颜婉嫦杨孜姚元庆郁琦余艳红张国楠张建平张淑兰张廷彰\* 张晓薇赵一鸣郑博仁\周灿权周先荣周应芳 Felix Wong(澳大利亚)Jinsong Liu(美国) Wenxin Zheng(美国) \注：为新任编委	None	None	None
67aa6353ae954109af67d0bd85cf009e	中华医学会	2023年ERAS在妇科肿瘤患者中的应用指南更新解读	·指南与共识· # 2023 年 ERAS 在妇科肿瘤患者中的应用指南更新解读马飞飞1 冯宪凌2 杨长永1 白杨2 史子月1 1 河南大学护理与健康学院，开封 475000；2 河南省人民医院妇科，郑州 450000 通信作者：冯宪凌，Email：fengxianling@163.com 【摘要】加速康复外科（ERAS）是一种标准化的围手术期护理计划，目的是通过一系列具有循证医学证据的处理措施优化围手术期的管理。近年来针对妇科肿瘤 ERAS 相关的指南相继更新，在 2016、2019年，国际ERAS协会发布了ERAS在妇科肿瘤患者中的应用指南。随着循证证据以及研究的深入，在2023年对该指南进行了更新。本文就2023年ERAS在妇科肿瘤患者中的应用指南更新要点进行解读，以期更好实现围手术期的管理。【关键词】加速康复外科；围手术期；妇科肿瘤；指南；解读基金项目：河南省医学科技攻关计划项目（LHGJ20200035）DOI：10.3760/cma.j.cn115682-20240122-00426 Interpretation of the 2023 updated guidelines for the use of ERAS in gynecologic oncology patients Ma Feifei1 ， Feng Xianling2 ， Yang Changyong1 ， Bai Yang2 ， Shi Ziyue1 1 School of Nursing and Health， Henan University， Kaifeng 475000， China；2 Department of Gynecology， Henan Provincial People's Hospital， Zhengzhou 450000， China Corresponding author： Feng Xianling， Email： fengxianling@163.com 【Abstract】 Enhanced Recovery After Surgery （ERAS） is a standardized perioperative care plan aimed at optimizing perioperative management through a series of evidence-based interventions. In recent years， guidelines related to ERAS in gynecologic oncology have been successively updated. The International ERAS Society published guidelines on the application of ERAS in gynecologic oncology in 2016 and 2019. With the advancement of evidence-based research， these guidelines were further updated in 2023. This paper interprets the key points of the 2023 updated guidelines for the use of ERAS in gynecologic oncology patients， aiming to enhance perioperative management. 【Key words】 Enhanced recovery after surgery； Perioperative； Gynecologic neoplasms； Guideline；Interpretation Fund program： Medical Science and Technology Research Project of Henan Province （LHGJ20200035）DOI：10.3760/cma.j.cn115682-20240122-00426 妇科恶性肿瘤是危害女性生理和心理健康的主要危险因素，随着人们生活压力以及不良生活方式的增加，妇科恶性肿瘤的发病率逐年升高且呈年轻化的趋势。在我国，卵巢癌、宫颈癌、子宫内膜癌是发病率最高的妇科恶性肿瘤［1］。研究表明，处于围手术期的妇科恶性肿瘤患者会出现睡眠质量不佳、口干、腹部疼痛、排尿困难等不良临床症状，不仅影响了患者术后的早期康复，而且患者的生存质量也受到了严重的影响［2］。加速康复外科（enhancedrecovery after surgery， ERAS）是由丹麦哥哈根大学的 Kehlet［3］教授提出，通过多学科的协作最大限度地减轻患者围手术期的不良反应、减少术后并发症和住院时间及住院费用，最大化促进患者的康复。在我国当下的阶段中，虽然部分医疗中心已在妇科实施ERAS，但整体开展ERAS现状并不清晰，临床推广仍存在一些问题和阻碍。ERAS是通过基于更新的高质量的循证医学证据对围手术期进行优化处理，在2023年，国际ERAS协会更新了ERAS在妇科肿瘤患者中的应用指南［4］，旨在促进ERAS在妇科肿瘤领域更好地实施。 # 一、指南概述与2019年版指南［5］相比，2023年版更新指南侧重于关注解决医务人员视角定义的ERAS的实施挑战，通过更新的最佳证据，对ERAS在实施过程中遇到的问题进行了整合与更新。主要涉及进行手术的妇科患者的护理。2023年版指南聚焦于妇科恶性肿瘤围手术期加速康复过程中常见的临床问题，如围手术期禁食禁饮的时间、术前用药、青霉素过敏反应的处理、术中镇痛最佳方法、尿管拔除时机、静脉血栓预防、术后阿片类药物的应用、出院准备计划以及 ERAS 实施的障碍。2023 年版《ERAS 在妇科肿瘤患者中的应用指南》（以下简称《指南》）于 2023 年 4 月 21 在 Gynecologic Oncology 发表，现就指南推荐意见进行解读（见表 1、2），以促进指南更好地实施推广，进一步规范妇科恶性肿瘤患者围手术期加速康复的管理。 # 二、指南推荐意见解读根据临床医生利益相关者团体确定的差距，对9 个实施挑战的条目主题进行了优先审查。使用 Embase和PubMed对出版物进行数据库检索（2018—2023年）。通过荟萃分析、随机对照试验和大型前瞻性队列研究选择了一个主题的研究。然后由国际小组根据建议、评估、发展和评估分级（GRADE）系统对这些研究进行审查和分级。 1.围手术期禁食禁饮时间：围手术期患者的营养是加速患者康复的重要措施之一。然而，由于妇科肿瘤患者手术类型差异较大，在相关指南中没有明确关于围手术期经口进食的时间。且目前关于传统的禁食时间对妇科肿瘤手术的益处或危害的数据有限，现有证据多数是从腹部手术或结直肠手术的研究中推断出来的。既往妇科肿瘤手术推荐意见为对于无胃排空延迟、血糖正常的患者，术前 $6 \mathrm { ~ h ~ }$ 禁食固体食物， $^ { 2 \mathrm { ~ h ~ } }$ 禁食清流质饮食。而2023版指南中根据麻醉学学会的指导方针，鼓励患者在术前 $^ { 2 \mathrm { ~ h ~ } }$ 饮用清流质饮食。在最新的临床随机试验中，与严格禁食相比，在术前 $^ { 2 \mathrm { ~ h ~ } }$ 进食复合性碳水化合物溶液的患者术后住院时间缩短了 $0 . 4 \mathrm { ~ d ~ }$ ，且术后并发症发病率低于单独饮水的患者［6-7］。原因为复合性碳水化合物溶液可有助于缓解患者术前口渴和患者由于对手术的恐惧与焦虑而带来的负性情绪，同时降低了围手术期胰岛素抵抗，减少术后恶心、呕吐等不良并发症的发生［8-9］。总结与推荐：无胃排空延迟的患者，在麻醉前$^ { 2 \mathrm { ~ h ~ } }$ 进食复合性碳水化合物在内的清流质饮食，可有效降低患者围手术期胰岛素抵抗，且可提高患者的满意度和舒适度，促进了患者的康复（证据级别：高；表1 2023年 ERAS 协会对《ERAS 在妇科肿瘤患者中的应用指南》更新内容 <table><tr><td>条目</td><td>2023版与2019版指南的对比</td></tr><tr><td>术前用药</td><td>2023年版指南修订了内容,增加了术前可常规使用的镇静药物</td></tr><tr><td>青霉素过敏反应的处理</td><td>2023年版指南更新了内容</td></tr><tr><td>术中镇痛最佳方法</td><td>2023年版指南修订了内容,推荐使用局部麻醉和腹横肌平面阻滞技术</td></tr><tr><td>尿管拔除时机</td><td>推荐等级相同但证据级别更高(从低级别升到中等级别)</td></tr><tr><td>术后阿片类药物的应用</td><td>2023年版指南修订了内容,增加了出院后患者采用分级阿片类药物镇痛的方法(证据级别：中等;推荐水平：强)</td></tr><tr><td>ERAS实施的障碍</td><td>2023年版指南更新了内容</td></tr></table> 注：ERAS 为加速康复外科。表2 2023年版《ERAS 在妇科肿瘤患者中的应用指南》维持 2019 版指南的内容 <table><tr><td>条目</td><td>推荐建议</td></tr><tr><td>静脉血栓预防</td><td>围手术期禁食禁饮的时间麻醉前2h可进食包括复合性碳水化合物在内的清流质饮食(证据级别：高;推荐级别：强) 静脉血栓栓塞风险增加的患者应接受术前开始的物理预防和药物预防双重预防(证据级别：高；推荐水平：强)。</td></tr><tr><td></td><td>对于高危标准或因妇科癌症患者接受大手术的患者，应接受为期28d的静脉血栓栓塞预防(证据级别：中等;</td></tr><tr><td>出院准备计划社及遵循ERAS围手术期原则(证据级别：中等；推荐水平：强)</td><td>推荐水平:强)。微创手术患者的长期药物预防静脉血栓证据有限(证据级别：中等;推荐水平：强) 建议妇科肿瘤微创手术应考虑多学科出院计划项目,出院计划的实施需要多学科协作、教育、患者和案例选择以</td></tr></table> 推荐级别：强）。 2.术前用药：术前出现负性情绪是围手术期患者常有的现象，负性情绪可能会导致患者围手术期止痛需求的增加，且有研究表明，女性肿瘤患者出现负性情绪的比例高于男性［10］。考虑围手术期患者的个人情况，在术前用药时需充分了解患者使用的缓解负性情绪的药物，方可保障患者的用药安全。在一项回顾性队列研究表明，短期口服镇静剂（如苯二氮䓬类药物）可解决术前焦虑，但可能会引起患者认知障碍，会增加术后不良事件的发生［11］。在术前对患者应选择合适的镇静剂或抗焦虑药物。研究表明，术前预防性的静脉注射对乙酰氨基酚可有效减轻患者术后恶心、呕吐，同时也降低患者术后疼痛评分［12］。而术前应用加巴喷丁类药物可减少术后 $2 4 \mathrm { h }$ 的累积吗啡用量，降低术后疼痛评分及恶心、呕吐、皮肤瘙痒等不良反应［13］。总结与推荐：在多模式镇痛策略保留的情况下，术前推荐使用非甾体抗炎药（证据级别：高；推荐水平：强）、对乙酰氨基酚（证据级别：低；推荐水平：强）和加巴喷丁类药物（证据级别：高；推荐水平：强）。但老年患者应谨慎使用加巴喷丁类药物。 3.青霉素过敏的处理：预防性使用抗生素是减少术后手术部位感染的重要措施之一，青霉素类抗生素是一类具有重要临床价值且应用广泛的抗菌药物，但青霉素类药物过敏是医疗记录中最常见的药物过敏，其患病率为 $6 \% \sim 1 5 \%$ ，但其中 $8 5 \% \sim 9 0 \%$ 青霉素皮试阴性并且可以耐受［14］。而青霉素速发型过敏反应发生率约为 $0 . 0 1 \% \sim 0 . 0 4 \%$ ，死亡率约为$0 . 0 0 2 \%$ ，在美国每年约 $5 0 0 \sim 1 ~ 0 0 0$ 人由于青霉素过敏而死亡［15］。正确地判断青霉素过敏反应和询问详细的过敏史对青霉素过敏评估至关重要，但仅凭过敏史无法预测青霉素过敏皮试的阳性结果，必要时可行药物激发试验。对青霉素严重过敏者需要及时停止使用相关药物，并根据医生的建议进行治疗和管理，以避免出现更为严重的过敏反应。总结与推荐：对于青霉素过敏的预防，在使用青霉素时，通常建议进行皮试，以预测可能的过敏反应。对于青霉素过敏的患者，建议使用替代抗生素进行预防治疗，如头孢唑林或厄他培南（如适用）（证据级别：高；推荐水平：强）。 4.术中镇痛的最佳方法：术中疼痛管理已成为围手术期麻醉管理的重要组成部分，近年来，神经阻滞和局部麻醉镇痛在减轻患者疼痛的同时也避免了其他镇痛方式引起的血流动力学波动及运动阻滞，因此逐渐被医生和患者接受。局部麻醉可降低术后 $^ { 2 4 \mathrm { ~ h ~ } }$ 内吗啡需求量，通过抑制手术中的交感神经/肾上腺素和炎症反应，为患者带来许多益处，如癌症复发和持续的术后疼痛的降低［16］，也可用于改善和减少阿片药物的消耗，提高麻醉效果。腹横肌平面阻滞是在超声引导下将麻醉药物注射到腹横肌筋膜面，使前侧腹壁神经被阻滞，进而起到镇痛的效果［17］，也可减轻患者术后疼痛和改善胃肠功能恢复，进而促进患者术后康复。总结与推荐：避免使用高剂量和长效阿片类镇痛药物，考虑术后并发症和麻醉后出现的不良反应的可能性，推荐使用局部麻醉剂和腹横肌平面阻滞技术（证据级别：中等；推荐水平：强）。在手术中，使用局部麻醉剂和腹横肌平面阻滞技术的具体方法和剂量可能因为手术类型、患者的身体状况和麻醉医生的经验而有所不同，但局部麻醉剂和腹横肌平面阻滞技术是外科手术中为患者减轻疼痛和提高手术效果的重要手段。 5.尿管拔除时机：留置尿管的主要目的是促进卧床患者的尿液引流，监测尿量，以便进行容量管理。妇科肿瘤手术时间较长，对手术质量的要求也极为严格，为了避免患者尿潴留的发生，在临床中术前会常规留置尿管以观察患者尿液以保证手术质量。但在临床中会发现患者留置尿管时间越长，尿道出现疼痛、泌尿系统感染的风险越高，严重影响了患者的术后康复。研究表明，留置尿管 $1 \sim 5 \mathrm { d } , >$ $5 \sim 7 ~ \mathrm { d } , > 7 ~ \mathrm { d }$ 时，尿管相关性尿路感染发生率分别为 $1 8 . 7 5 \% , 3 . 0 4 \% , 5 0 . 9 8 \%$ 。因此，缩短留置导尿的时间，减少尿管不必要的插入可有效减少尿管相关性感染。在最新的证据中，留置导尿管的使用天数与尿潴留、感染和压力性损伤更高风险直接相关。总结与推荐：术后患者立即拔除尿管可有效降低泌尿系统感染的发生率，缩短手术后首次排尿的时间，因此，根据患者的情况在术后尽早拔除尿管 $( 2 4 \mathrm { h }$ 内）。对于微创手术的患者，术后当天即可拔除尿管，同时，应详细评估患者术后的残余尿量，确保患者不会发生尿潴留（证据级别：中等；推荐水平：强）。 6.静脉血栓栓塞的预防：静脉血栓栓塞是导致妇科肿瘤患者死亡的第二大病症，是术后常见的并发症，也是妇科肿瘤术后患者30 d内死亡最常见和最主要的因素［19-20］。在最新的研究中，未采取预防措施的围手术期患者静脉血栓发生率高达 $1 0 \% \sim 4 0 \% ^ { [ 2 1 - 2 }$ 22］，而对围手术期患者进行正确评估、早期预防可使静脉血栓发生率降低 $5 0 \% \sim 6 0 \% ^ { [ 2 3 ] }$ 。因此，美国肿瘤学会（ASCO）和国家综合癌症网络（NCCN）的临床实践指南建议，所有接受大手术的癌症患者均应接受血栓栓塞预防［24-25］。在临床中有多种方法可以降低血栓栓塞的风险，包括物理预防（弹力袜、间歇充气加压泵）和药物预防（普通肝素、低分子肝素、磺达肝癸钠）。总结与推荐：术前高风险的静脉血栓患者推荐使用药物联合物理预防（证据级别：中等；推荐水平：强），在进行药物预防时应观察药物的不良反应；低血栓高出血风险的患者建议使用机械预防。所有接受妇科癌症开腹手术的患者应接受为期28 d的静脉血栓延长预防（证据级别：中等；推荐水平：强）。对于高风险的患者，如年龄较大、神经功能缺损、有静脉血栓栓塞病史的患者在术前可采用机械和药物双重预防。妇科微创手术的患者进行长期药物预防静脉血栓是否有效，尚缺乏高质量的证据研究证实（证据级别：中等；推荐水平：强）。。 7.阿片类药物的应用：妇科肿瘤围手术期充分镇痛是 ERAS 理念的关键部分。妇科肿瘤手术多为经腹开口手术，在腹部会留有切口，术后疼痛剧烈。切口的疼痛不利于患者早期下床活动，同时会降低患者的舒适感和满意度。阿片类镇痛药物是术后疼痛管理的常见的药物，在缓解疼痛和治疗方面有显著的效果，然而阿片类药物会带来一系列的不良反应如呼吸抑制、恶心、头疼以及成瘾性等，因此，在术后疼痛管理中，阿片类药物的使用是多模式镇痛的一部分，多模式镇痛方案以改善患者疼痛控制效果，减少阿片类药物的使用，可使用去阿片类药物（包括非甾体类抗炎药、加巴喷丁等）。同时，密切观察患者用药后的不良反应。对出院后的患者，指南建议采用分级使用阿片类药物的方法，如对于轻度疼痛，可能会建议患者采用非处方的镇痛药物；对于中度疼痛，医生可能会开具处方给患者一些较强效的镇痛药物；对于重度疼痛，可能需要更强效的镇痛药物，通常需要医生的处方和监督。目前仅有少数患者需要使用自控式镇痛泵，因此自控式镇痛泵作为需要反复静脉注射阿片类药物治疗的最后手段。总结与推荐：最大限度地减少使用阿片类药物，可使用去阿片类药物（包括非甾体类抗炎药、加巴喷丁等多模式镇痛）（证据级别：中等；推荐水平：强），可减少患者对阿片类药物的依赖。术后出院的患者可根据患者的个人疼痛状况采用分级镇痛方法（证据级别：中等；推荐水平：强）。自控式镇痛泵作为需要重复注射阿片类药物治疗患者疼痛最后的手段（证据级别：中等；推荐水平：强）。 8.出院准备计划：出院计划是帮助患者从某一护理阶段衔接到下一护理阶段，是以患者需求为导向。通过多学科、多机构提供个性化的信息，保证医疗服务的连续性及患者安全的目的［26］。基于妇科肿瘤患者ERAS方案的更新与修改，最近的证据表明微创手术患者可在完成手术当天即可出院。从医疗角度上，出院计划可控制患者住院时间、提高医院床位周转率、降低再入院率，从而节省了医疗成本；从患者及家属角度上，出院计划可有效提高患者的自我效能、生活质量及就医满意度，减少了计划外住院的风险；从社会角度上，出院计划的发展与成熟有助于学科团队的建设和培养服务专业人才，改善医疗保健服务质量［27］。目前患者出院计划的成功指标包括住院时间、计划外门诊和急诊就诊、再入院和患者满意度。具体的出院准备计划需要根据患者的具体情况和不同学科的医生的建议来制定。总结与推荐：出院准备计划是患者出院过程中的核心组成部分，可实现患者、医院、社会的共赢，出院准备计划的实施需要多学科的协作，对医护人员的教育与培训以及根据患者的具体情况和手术情况来选择合适的患者和案例进行多学科出院准备计划项目，在手术前后以及出院后的康复过程中，遵循ERAS围手术期原则（证据级别：中等；推荐水平：强），如术前宣教、术后早期下床活动、饮食调理和心理支持等，通过以上计划为患者提供更全面、个性化的康复方案。 9. ERAS实施的障碍：妇科肿瘤患者人群的特殊性且涉及生殖系统，患者存在疾病和预后的不确定感和负面情绪问题更为突出。同时，妇科肿瘤的治疗多以盆腔、腹部手术治疗为主，紧邻肠道和膀胱，存在复杂性和危险性，尽管指南规范，但受传统观念的影响，在临床治疗中实践与指南有较大差异［28］。ERAS 的实施需要多学科团队的共同协调，涉及术前咨询到出院后康复的各个环节，而 ERAS 理念和标准化实施方案具有独特优势，最新证据表明，多数患者对 ERAS 表示认可，并认为可从中获益，但目前加速康复尚未在全球范围内应用，尤其是在中低收入国家［29］。基于我国当下的医疗环境和医患关系现状，部分医生和患者对于传统的手术方式和术后恢复模式有着固有的认知，对于新的加速康复外科理念仍存在抵触情绪。且 ERAS 理念需要医疗机构具备一定的技术设备和专业人员支持，而一些医疗机构可能在这方面存在不足。考虑不同患者的身体状况和疾病特点，ERAS理念需要更加个体化的治疗方案，这也对医生的临床经验和技术水平提出了更高的要求。且部分医保政策对于新的治疗方式可能存在一定的限制，而加速康复外科理念可能需要更多的医疗资源投入，这也可能成为障碍因素之一。因此，在推广ERAS理念在妇科肿瘤临床应用中，需要综合考虑以上因素，促进医疗机构、医生和患者对于新理念的认知和接受，同时也需要政府和医保部门的支持和配合。总结与推荐：ERAS的实施需要多学科的合作，但由于多数医务人员受传统观念的影响对ERAS理念不熟悉或认知局限，未形成路径化的流程和标准方案。因此，ERAS 的实施需要对医院进行变革管理原则和对患者进行多层次的健康教育，在一定程度上可克服加速康复实施的障碍（证据级别：中等；推荐水平：强）。 # 三、总结综上所述，ERAS 是一种康复理念而不是具体方案，ERAS 是以患者为中心，最佳循证医学证据为基础，最大化降低患者在围手术期的各种不良反应为目的。目前全球范围内，妇科手术ERAS的执行一直面临着一定的挑战，许多国家已经发布了妇科手术的ERAS指南或共识，但真正将ERAS策略执行到位仍是临床工作的难题。为了更好地将ERAS理念应用到妇科手术中，医务人员需要进一步理解ERAS实施要点，并掌握ERAS策略执行过程中的关键问题和注意事项。另一方面，ERAS是一种安全有效的围手术期管理理念，在未来，ERAS的实践需要继续加强多学科协作，进一步优化围手术期管理方案。本指南分别从围手术期禁食禁饮时间、术前用药、青霉素过敏的处理、术中镇痛的最佳方法、尿管拔除时机、静脉血栓栓塞预防、阿片类药物的应用、出院准备计划以及 ERAS 实施的障碍等给出了建议及详细的解释，为妇科肿瘤患者围手术期的规范化管理提供了直接的循证证据，以实现妇科肿瘤患者快速的康复。利益冲突所有作者声明无利益冲突作者贡献声明马飞飞、史子月：指南翻译；马飞飞、冯宪凌、白杨：原文解读；马飞飞、白杨：论文撰写；冯宪凌、杨长永：论文指导参考文献［1］中国抗癌协会妇科肿瘤专业委员会.妇科恶性肿瘤多学科诊疗中国专家共识（2022 年版）［J］. 中国癌症杂志，2022，32（8）：747-756. 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b03795f454d04e3796a938a40fbc48ff	中华医学会	MR引导聚焦超声治疗子宫肌瘤中国专家共识	·规范与共识· # MR引导聚焦超声治疗子宫肌瘤中国专家共识中国医学装备协会磁共振应用专业委员会微创治疗学组通信作者:金征宇，中国医学科学院北京协和医学院北京协和医院放射科 100730， Email：jin_zhengyu@163.com 【摘要】子宫肌瘤是育龄期女性最常见的妇科良性肿瘤，引导下聚焦超声（）是一种无创治疗子宫肌瘤的新手段，以为引导，精准地将超声波聚焦于肌瘤瘤体组织，产生 $6 5 { \sim } 8 5 \ \mathrm { ^ { \circ } C }$ 的高温，使肿瘤细胞蛋白质失活、细胞凋亡并凝固坏死，在精准消融肌瘤组织的同时避免损伤治疗区域以外的正常组织。为了进一步提高我国子宫肌瘤的治疗水平，减少和避免并发症的发生，为患者提供更加安全、有效、规范的治疗，由中国医学装备协会磁共振应用专业委员会微创治疗学组组织相关专家在总结国内外临床应用经验的基础上，制定了《MR引导聚焦超声治疗子宫肌瘤的中国专家共识》。【关键词】子宫肌瘤；磁共振成像；聚焦超声 # China consensus on MR guided focused ultrasound for uterine fibroids Minimally Invasive Therapeutics Group of MRI Application Committee of China Medical Equipment Association Corresponding author: Jin Zhengyu, Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China, Email: jin_zhengyu@163.com 子宫肌瘤是育龄期女性最常见的妇科良性肿瘤，至少 $2 5 \% { \sim } 4 0 \%$ 女性患有子宫肌瘤，约 $2 5 \%$ 患者会出现较明显的影响生活的症状［1‐3］。子宫肌瘤的治疗方法多样，包括药物、子宫动脉栓塞术（uterineartery embolization，UAE）、子宫肌瘤剔除手术和子宫全切术等。随着生活质量的提高，越来越多的患者特别是有生育要求的女性希望能在保留子宫的前提下选择无创而有效的治疗方法。MR引导下聚焦超声（MR‐guided focused ultrasound，MRgFUS）是一种无创治疗子宫肌瘤的新手段，以 MRI为引导，精准地将超声波聚焦于肌瘤瘤体组织，产生 $6 5 \sim$ $8 5 ~ \mathrm { { ^ \circ C } }$ 的高温，使肿瘤细胞蛋白质失活、细胞凋亡并凝固坏死，在精准消融肌瘤组织的同时避免损伤治疗区域以外的正常组织。年以来，大量研究对MRgFUS用于子宫肌瘤治疗的安全性及有效性进行了论证［4‐20］，2004年美国 FDA 批准 MRgFUS 用于子宫肌瘤的治疗。 2013年中国 FDA 批准了MRgFUS在症状性子宫肌瘤中的应用。目前，国内越来越多的医疗机构陆续引进了MRgFUS的治疗设备并开展了子宫肌瘤的无创治疗［4‐7］。为了进一步提高我国子宫肌瘤的 MRgFUS治疗水平，减少和避免并发症的发生，为患者提供更加安全、有效、规范的治疗，由中国医学装备协会磁共振应用专业委员会微创治疗学组组织相关专家，在总结国内外临床应用经验的基础上，制定了《MR 引导聚焦超声治疗子宫肌瘤的中国专家共识》。一、MRgFUS治疗子宫肌瘤患者的适应证和禁忌证 # （一）适应证经临床诊断明确的子宫肌瘤患者，满足如下条件者：（1）术前MRI显示子宫肌瘤 $\mathrm { T } _ { 2 } \mathrm { W I }$ 信号较低，接近肌肉信号；（）术前显示子宫肌瘤位于肌壁间，或为无蒂的浆膜下或黏膜下肌瘤，即国际妇产科联盟（International Federation of Gynecologyand Obstetrics，FIGO）分型 2\~6型；（3）术前 MRI 显示单发子宫肌瘤最长径 $\leqslant 1 0 \ \mathrm { c m }$ 或多发子宫肌瘤最长径之和 $\leqslant 1 0 \ \mathrm { c m }$ ；（）术前显示子宫肌瘤与腹壁间无肠管阻挡或通过处理可消除肠管阻挡的影响，具有安全治疗路径；（5）术前MRI显示腹部皮下脂肪厚度 ${ \leqslant } 4 \ \mathrm { c m }$ ；（6）术前MRI显示腹壁皮肤到治疗肌瘤靶区最远距离 $\leqslant 1 4 ~ \mathrm { c m }$ ；（）患者一般情况好，能够耐受并保持 $^ { 2 \mathrm { ~ h ~ } }$ 或更长时间俯卧体位。 # （二）绝对禁忌证绝对禁忌证包括：（）临床诊断不明确；（）扫描禁忌证；（）子宫肌瘤在短期内迅速增大或影像学提示有恶变倾向，或恶性潜能未定；（4）治疗区域皮肤有急性感染；（5）未被控制的急性盆腔炎症；（）一般状况差，有严重的心、肝、肾等重要脏器功能障碍；（）有严重的出凝血功能障碍；（）下腹部治疗区域有较大面积皮肤瘢痕；（9）无法使用镇静、镇痛等相关药物；（10）绝经后增大的子宫肌瘤。 # （三）相对禁忌证相对禁忌证包括：（）术前显示子宫肌瘤信号较高，或者高低混杂信号，增强扫描显示肌瘤血供丰富；（2）术前MRI显示为带蒂的浆膜下或黏膜下肌瘤，即分型为和型；（）有生育要求，术前MRI显示子宫肌瘤位于子宫角及输卵管区域；（4）术前MRI显示单个子宫肌瘤最长径 ${ > } 1 0 ~ \mathrm { c m }$ 或者多发子宫肌瘤最长径之和 $\mathrm { \| { > } 1 0 ~ c m }$ 。 # 二、术前盆腔MRI扫描规范 # （一）重要性 MRgFUS并不适合所有子宫肌瘤患者，因此筛选合适的患者非常重要。MRI以其多方位、多序列（包括功能和解剖序列）的成像优势在术前筛选患者中担任重要角色，MRI术前可显示子宫肌瘤以及与周围组织的关系，从而对 MRgFUS 治疗的可行性、安全性和有效性做出预判。明确子宫肌瘤的诊断：肌瘤恶变、恶性潜能未定的子宫肌瘤，或其他类似肌瘤表现的肿瘤，或确诊为子宫内膜癌或卵巢肿瘤合并子宫肌瘤的患者，应根据临床评估积极进行手术治疗，不适合MRgFUS无创治疗。明确子宫肌瘤的位置：根据位置，子宫肌瘤分为肌壁间、黏膜下、浆膜下肌瘤。在对黏膜下肌瘤进行MRgFUS治疗中，应注意对子宫内膜的保护，建议划定治疗区域的边缘为 $5 \mathrm { m m }$ ，避免灼伤内膜导致持续阴道排液。浆膜下肌瘤通过狭小的蒂与子宫相连者，MRgFUS 治疗可能会使蒂坏死、中断导致肌瘤脱落在腹腔内，有引起感染的风险，建议谨慎选择。明确子宫肌瘤的大小：治疗系统在制定治疗计划时会根据消融肌瘤的体积计算出靶点的数目。对于单发最长径 $< 2 . 5 ~ \mathrm { c m }$ 的肌瘤，不建议立即行MRgFUS治疗，可随访观察。对于体积巨大的肌瘤建议两种可选择方案：（）分两个阶段治疗，每个阶段消融不同的肌瘤部分；（2）考虑在MRgFUS治疗前先用促性腺激素释放激素类似物（gonadotropin releasing hormone analogue，GnRHa）预治疗，待肌瘤体积缩小后再择期进行 MRgFUS治疗。 4.明确肌瘤数量：6个或以上肌瘤或弥漫型肌瘤不适合MRgFUS治疗，但可通过对导致症状肌瘤的综合性分析，进行选择性治疗 5. 明确肌瘤血供和信号：根据肌瘤 $\mathrm { T } _ { 2 } \mathrm { W I }$ 信号特征，判断肌瘤变性的程度。 $\mathrm { T } _ { 2 } \mathrm { W I }$ 的信号强度是决定该肌瘤是否适合行MRgFUS的重要参考因素。$\mathrm { T } _ { 2 } \mathrm { W I }$ 信号均质指肌瘤内不均匀高信号部分 $\leqslant$ 肌瘤体积的 $2 5 \%$ ， ${ > } 2 5 \%$ 为不均质。肌瘤变性可能会对能量聚焦产生不利影响，降低疗效。 $\mathrm { T } _ { 2 } \mathrm { W I }$ 高信号往往表示肌瘤的血供丰富，可通过增强扫描确认肌瘤 $\mathrm { T } _ { 2 } \mathrm { W I }$ 高信号与血供丰富程度之间的关系。血供丰富的肌瘤因血流能够把热量带离治疗区域导致瘤体无法达到消融温度，因此不建议此类肌瘤患者选择MRgFUS治疗［8］。 6. 明确肌瘤与周围组织的关系：（1）肌瘤与皮肤的距离：ExAblate系统能够在与皮肤垂直距离最远 $1 4 ~ \mathrm { c m }$ 以内产生聚焦束，超出治疗范围的肌瘤可通过使用更薄的声学耦合胶垫缩短肌瘤与发生器间的距离，或通过直肠注胶将子宫和肌瘤推向前方以缩短距离。或术前口服泻药排空肠管后再次评估。（2）肌瘤与骨、神经丛的距离：骨组织比软组织更易吸收超声波能量，靠近加热骨表面的神经会因高温刺激产生疼痛甚至坏死。肌瘤前方耻骨可在治疗计划中进行设定加以规避，靠近腰骶丛或其他骨表面的肌瘤需慎重考虑是否适合MRgFUS治疗。操作者可通过调整聚焦超声束的路径或调整超声束能量来规避骨的加热，或直肠内注胶将肌瘤向前推离骨组织。（3）肌瘤与肠管关系：肠道气体可反射超声波能量影响治疗，可调整能量束的入射角度规避肠管，也可使用推移肠管的方法，如膀胱内注入生理盐水或肠内注胶。 # （二）MRI扫描规范有宫内金属节育环者应先去除，避免金属伪影影响诊断。检查前排空膀胱，扫描体位为俯卧位，足先进，扫描范围以子宫为中心。常规扫描序列包括： $( 1 ) \mathrm { T } _ { 2 } \mathrm { W I }$ ，常规行轴位、矢状位、冠状位扫描，层厚 $4 \mathrm { m m }$ ，层间距 $1 ~ \mathrm { m m }$ ，可增加扫描矢状位脂肪抑制 $\mathrm { T } _ { 2 } \mathrm { W I }$ 序列，以更清晰地显示病变。 $( 2 ) \mathrm { T } _ { 1 } \mathrm { W I }$ ，轴位扫描，当肌瘤合并亚急性期出血显示为高信号，且可显示病变与周围正常组织结构的关系。（3）提倡注射钆对比剂后行轴位、矢状位容积增强扫描，层厚 $3 . 0 { \sim } 4 . 0 ~ \mathrm { m m }$ ，层间距 $0 . 5 { \sim } 1 . 0 \ \mathrm { m m }$ ；利用该序列进行多时相动态增强扫描，明确病变血供情况，获得增强曲线，也可通过减影技术更清楚显示病变特征。（4）如条件允许可进行盆腔灌注加权成像，较常规序列可更好地显示肿瘤边界，并可对MRgFUS治疗后疗效进行评价。（）如条件允许可进行轴位扩散加权成像扫描，可提高病变的检出率及明确病变界限，以及评价MRgFUS治疗后瘤体是否坏死。（6）如条件允许可进行磁敏感加权成像，提供肿瘤内静脉血管及病变出血的信息。 # 三、术前综合评估筛选合适的子宫肌瘤患者是MRgFUS治疗获得成功的关键。术前评估主要因素包括子宫肌瘤的信号、血供、位置、大小及数目，同时需结合患者年龄、治疗路径及临床症状。研究表明子宫肌瘤MRI图像 $\mathrm { T } _ { 2 } \mathrm { W I }$ 信号强度和患者年龄是影响疗效的主要因素，肌瘤 $\mathrm { T } _ { 2 } \mathrm { W I }$ 信号低和年龄较大的患者其治疗的成功率更高。因此，术前的盆腔MRI扫描结果，以及患者的年龄、症状、未来妊娠计划等都需要充分考虑。充分了解影响MRgFUS治疗安全性和有效性的各种因素，能够给子宫肌瘤患者制定个性化的治疗方案。 # （一）子宫肌瘤的组织特征 $1 . \mathrm { T } _ { 2 } \mathrm { W I }$ 信号特征： $\mathrm { T } _ { 2 } \mathrm { W I }$ 信号强度是决定肌瘤是否适合行 MRgFUS 治疗最重要的 MRI 指标。根据$\mathrm { T } _ { 2 } \mathrm { W I }$ 不同信号强度，子宫肌瘤可分为3种类型。Ⅰ型：子宫肌瘤的 $\mathrm { T } _ { 2 } \mathrm { W I }$ 信号低于骨骼肌信号（图 1）；Ⅱ型：子宫肌瘤的 $\mathrm { T } _ { 2 } \mathrm { W I }$ 信号低于子宫平滑肌信号但高于骨骼肌信号（图2）；Ⅲ型：子宫肌瘤的 $\mathrm { T } _ { 2 } \mathrm { W I }$ 信号强度高于子宫平滑肌信号（图）。不同 $\mathrm { T } _ { 2 } \mathrm { W I }$ 信号强度的子宫肌瘤有着不同的生物学特性，不同的生物学特性决定了其对 MRgFUS治疗反应不同。研究表明Ⅰ型子宫肌瘤MRgFUS治疗后的无灌注区体积比（non‐perfusion volumeratio，NPVR）高于其他类型的肌瘤［8］。Zhao 等［9］研究发现 $\mathrm { T } _ { 2 } \mathrm { W I }$ 高信号肌瘤含有更多的新生血管，含水量更加丰富而含纤维组织成分更少，而 $\mathrm { T } _ { 2 } \mathrm { W I }$ 低信号或等信号肌瘤则含有较少的新生血管和更多的胶原纤维组织。Mikami等［10］报道相对于子宫肌层高信号或不均匀高信号的肌瘤，其MRgFUS治疗失败率较高，而相对于子宫肌层低信号的肌瘤治疗成功率较高。因此在接受MRgFUS治疗的患者中，为确保治疗效果，通常不推荐选择Ⅲ型肌瘤患者，但若在充分告知治疗效果的前提下，患者有强烈的治疗意愿，可作为临床治疗备选方案。灌注加权成像：根据生物传热方程可以知道，肌瘤中的血液灌注情况是影响聚焦超声治疗过程中升温的主要因素，从而影响MRgFUS治疗效果，因此准确评估肌瘤组织的灌注信息，对预测治疗反应非常重要。 $\mathrm { T } _ { 2 } \mathrm { W I }$ 的信号强度只能反映组织中含水量多少，不能反映组织的灌注信息。$\mathrm { T } _ { 1 } \mathrm { W I }$ 灌注成像是评估肌瘤血液灌注的有效方法，能间接预测肌瘤对MRgFUS的治疗反应，尤其是在$\mathrm { T } _ { 2 } \mathrm { W I }$ 高信号的肌瘤评估中至关重要。如子宫肌瘤$\mathrm { T } _ { 2 } \mathrm { W I }$ 呈高信号，但呈现延迟强化，或者强化程度低于子宫肌层，此类患者MRgFUS治疗效果较好［11］。$\mathrm { K i m }$ 等［12‐13］研究表明子宫肌瘤的容量转移（transferconstant, $\mathrm { K } ^ { \mathrm { t r a n s } }$ ）越大，治疗效果越差。因此灌注成像作为 $\mathrm { T } _ { 2 } \mathrm { W I }$ 的重要补充，在筛查合适的肌瘤患者中起着重要作用。肌瘤的位置：根据子宫肌瘤生长位置不同，FIGO分型分为9型（图4）。但在MRgFUS筛查过程中，无需按照FIGO分型进行筛选，推荐根据子宫肌瘤的类型和所在的位置大致分为：肌壁间肌瘤，对应型；黏膜下肌瘤，对应型；浆膜下肌瘤，对应FIGO 7型。肌壁间肌瘤是MRgFUS治疗的适宜人群［14］。浆膜下带蒂肌瘤一直被认为是子宫动脉栓塞和聚焦超声治疗的禁忌证，因其存在治疗后蒂坏死进而导致子宫肌瘤脱落入盆腔的风险。但Park等［15］研究表明针对带蒂浆膜下肌瘤，MRgFUS是一种安全有效的治疗方式，其治疗了例孤立性带蒂浆膜下肌瘤患者，治疗过程将主要消融区域集中在肌瘤组织内，而对蒂进行保护，不仅能很好地消融肌瘤组织，而且能避免蒂坏死从而避免肌瘤组织脱落入盆腔。针对黏膜下肌瘤进行MRgFUS治疗存在损伤子宫内膜基底层的可能，进而影响患者的生育功能，因此对于希望保留生育功能的育龄期女性应特别慎重选择。但 $\mathrm { K i m }$ 等［13］最新的研究表明，即便在MRgFUS治疗过程中轻微损伤子宫内膜，也能在一定时间内自我修复，并不影响后续受孕。但对于黏膜下肌瘤是否选择MRgFUS治疗尚缺乏大规模的多中心随机对照临床研究，因此不推荐期望保留生育功能的患者接受MRgFUS治疗。 ![](images/20aebcd8a1a85baeefdc12fadfa5ecb3e06e23d30768fce685c801b044b76ab7.jpg) 图 1\~3 根据 $\mathrm { T } _ { 2 } \mathrm { W I }$ 不同信号强度，子宫肌瘤分为3种类型。图1为Ⅰ型，子宫肌瘤 $( \triangle ) \mathrm { T } _ { 2 } \mathrm { W I }$ 信号低于骨骼肌（??）。图2为Ⅱ型，子宫肌瘤 $( \triangle )$ 的 $\mathrm { T } _ { 2 } \mathrm { W I }$ 信号低于子宫平滑肌信号（红）但高于骨骼肌信号（白）。图为型，子宫肌瘤 $( \triangle )$ 的 $\mathrm { T } _ { 2 } \mathrm { W I }$ 信号强度高于子宫平滑肌信号（??）图4 子宫肌瘤国际妇产科联盟（FIGO）分型示意图。子宫肌瘤按照FIGO分型分为9型。0：0型，有蒂黏膜下肌瘤；1：型，无蒂黏膜下肌瘤，向肌层扩展 $\leqslant 5 0 \%$ ；：型，无蒂黏膜下肌瘤，向肌层扩展 $5 5 0 \%$ ；：型，肌壁间肌瘤，位置靠近宫腔，瘤体外缘距子宫浆膜层 ${ \geqslant } 5 \ \mathrm { m m } ; 4 { : } 4$ 型，肌壁间肌瘤，位置靠近子宫浆膜层，瘤体外缘距子宫浆膜层 $< 5 \ \mathrm { m m } ; 5 : 5$ 型，肌瘤贯穿全部子宫肌层；6：6型，肌瘤突向浆膜；：型，肌瘤完全位于浆膜下（有蒂）；：型，其他特殊类型或部位的肌瘤（子宫颈、宫角、阔韧带肌瘤） 4.肌瘤的数目和大小：长时间的俯卧位治疗，将会明显增加深静脉血栓的发生概率，因此基于证据分析的多中心研究在 2015年提出推荐 MRgFUS治疗的子宫肌瘤最长径 $\leqslant 1 0 \mathrm { ~ c m } ^ { [ 1 4 ] }$ ，但是随着治疗方式的改进，目前并未在肌瘤大小方面有特别限制，或给予GnRHa药物治疗2\~3周期后，再次评价子宫肌瘤最大径，决定是否可行MRgFUS治疗。目前一般不推荐肌瘤数目 ${ > } 5$ 个的患者行MRgFUS治疗。 # （二）技术限制 1.瘢痕组织：因瘢痕组织含有较少的血管及神经末梢和较多的纤维组织，瘢痕组织更易使热量蓄积，从而导致皮肤灼伤，因此针对治疗区域存在瘢痕组织的患者应该谨慎选择MRgFUS治疗，对于横形瘢痕组织可以尽量避开，对于纵行瘢痕组织无法避开的前提下有学者推荐使用瘢痕贴，认为可以有效避免皮肤灼伤［16］。 2.皮下脂肪厚度：皮下脂肪厚度的增加会明显增加能量在该区域蓄积，并阻挡聚焦超声的能量送达病灶部位，从而导致皮下脂肪坏死和病灶消融不彻底，因此对于皮下脂肪厚的患者，选择MRgFUS治疗应该持慎重态度。通常体重指数（body massindex，BMI） ${ > } 2 9 . 9 \mathrm { k g } / \mathrm { m } ^ { 2 }$ （诊断肥胖）不建议行MRgFUS治疗。 3.皮肤与子宫肌瘤间的距离：不同设备的有效消融距离不同，因此在选择患者时必须考虑该肌瘤在有效消融范围内，从而保证治疗效果。 4.骶尾骨与肌瘤间的距离：通常消融子宫后壁肌瘤需要考虑该因素，若子宫后壁肌瘤距离骶尾骨过近，在消融肌瘤过程中后方的残留能量有可能损伤骶尾部神经，一般建议子宫后壁肌瘤距离骶尾骨 ${ > } 4 \ \mathrm { c m }$ 为宜［17］。 5.治疗路径中肠道的保护：治疗路径中存在肠道是MRgFUS治疗的禁忌证，因肠道内气体或肠内容物对聚焦超声存在全反射的特性，从而极易导致肠道损伤，因此如何确保治疗路径中不存在肠道组织非常关键。Park等［18］推荐使用膀胱‐直肠‐膀胱的方法推挤肠道，使治疗路径中不存在肠道组织。对于前位子宫推荐使用膀胱充盈法推挤位于子宫前方的肠道，或治疗前一日口服泻药，排出肠道内容物及积气，但无论使用何种方法，如何确保治疗路径中无肠道组织，是治疗成败的关键［19］。四、治疗流程及操作规范 # （一）患者术前准备完善治疗前常规检查，包括血常规、尿常规、大便常规、凝血功能、胸片、心电图、血CA‐125、子宫附件超声、盆腔MRI平扫及增强检查和宫颈细胞学及白带常规检查。 2.向患者详细告知MRgFUS治疗方法的优势与不足，预期疗效、潜在的并发症及副作用，了解患者的诉求。 3.确认患者盆部无金属植入物或已去除。 4.由患者本人和（或）授权人签属MRgFUS治疗知情同意书。 5.填写子宫肌瘤症状、健康相关生活质量问卷调查表。 6.术前备皮，剃除会阴部毛发。建议术前 $^ { 8 \mathrm { ~ h ~ } }$ 流质饮食及清肠准备（口服泻药）。 8. 术前 $3 0 ~ \mathrm { m i n }$ 留置并开放导尿管、建立静脉通路。 9.有下腹部瘢痕患者根据情况放置瘢痕贴。麻醉科医师评估麻醉情况（根据各医院情况选择是否需要麻醉科医师介入治疗过程）。 11.如子宫体积较大，预计手术时间较长，可行双下肢静脉血管超声检查，排除静脉血栓。 # （二）治疗流程 1.术前校准：术前需完成常规治疗设备质量检测（daily quality assure，DQA），对超声脉冲聚焦精度进行校准。 2.术前准备：放置治疗胶垫，根据患者体型、子宫位置选择胶垫的类型，注入去气泡水覆盖治疗胶垫。扫描：患者取膝胸卧位，经肛门插管注入适量超声耦合胶（ $1 5 0 { \sim } 3 0 0 \mathrm { m l }$ ）；定位后患者俯卧于治疗胶垫上，如配合1.5或 $3 . 0 \mathrm { T }$ MRI使用需放置表面线圈，然后固定；扫描获得三维定位图像，据此调整患者体位至满意。 4. 制定治疗计划：MRI 扫描获得盆腔 $\mathrm { T } _ { 2 } \mathrm { W I }$ 轴位、矢状位和冠状位图像，据此制定治疗计划，计划包括在矢状位 $\mathrm { T } _ { 2 } \mathrm { W I }$ 上勾画出皮肤线、耻骨、子宫前上方肠管、骶椎孔等解剖结构的边界，标注子宫的轮廓，勾勒出治疗区域（region of treatment，ROT），建议ROT边界线位于肌瘤边缘内侧 $3 { \sim } 5 ~ \mathrm { m m }$ 。校正：选择一点进行聚焦治疗以判断超声脉冲聚焦的精度和温控情况，如有偏差可进行校正。 6.治疗：进入治疗阶段，系统会根据计划计算出需治疗肿瘤的体积和治疗体素（spot）的数目，此时一般可根据系统设定的参数逐个进行治疗。每个体素治疗时MRI持续扫描，会有实时图像及温度曲线呈现，实时显示热消融的效果。每个治疗体素的治疗时间约为25 s，患者治疗时长与治疗体素的数目、治疗过程中患者配合程度、是否需要重复制定计划有关。 7.术中处理：根据患者术中疼痛情况，相应调整镇静、镇痛药物、治疗间隔时间，并进行心理疏导。治疗间隔中，可鼓励患者少量进食高能量食物（如巧克力）或饮料以补充体力，让患者获得更好的治疗体验。为预防长时间治疗导致的低血糖，术中可静脉输入葡糖糖盐溶液。 8.术后评估：术后常规行脂肪抑制 $\mathrm { T } _ { 2 } \mathrm { W I }$ ，判断是否有腹壁软组织、肠系膜、盆腔内肠管壁和骨质水肿情况；然后静脉注射对比剂进行增强扫描，测量肌瘤的NPVR。 9.术后护理：去除导尿管及静脉留置针；观察患者一般情况及治疗区域皮肤有无红肿压痛；患者静卧休息半小时；与患者交流进行心理疏导，告知术后注意事项。 # （三）操作规范术者资质：术者应该经过系统的影像诊断学临床训练并具备相应的资质。 2.临床治疗团队：建议包含妇科医师、影像科医师或者相同资质医师，设备操作技师或相同资质技师，以及护士；麻醉科医师可根据医院及手术情况配置。 3.技术培训：术者、MR设备操作技师及护士需接受相关技术培训，术者在经过规范化培训并完成若干病例的治疗后，方可独立操作。 4.病历记录：患者应该具备完整的病历资料及影像学资料，整个就医过程完全可回溯。 # （四）手术记录手术记录应包括：子宫肌瘤的大小、数目和位置；消融肌瘤体积、治疗体素数量、消融的最小及最大能量、治疗时长；消融后NPVR数据；术中给予药物；术中补液量、尿量；患者生命体征；术中患者出现的不良反应、停止治疗的次数；消融后的注意事项等。建议手术记录附治疗图像。 # 五、并发症的预防及处理 1.恶心、呕吐：多数情况可能是镇静、镇痛药物的不良反应，偶有因消融后疼痛引起的内脏反应，一般不需处理可数小时内自行缓解；如症状明显可对症处理，如注射胃复安等止吐药物。预防：治疗前做好充分的准备工作，避免镇痛、镇静剂过量使用，术中及术后根据患者的反应酌情增减药物。 2.疼痛：多表现为下腹部疼痛、排尿疼痛，约$10 \%$ 患者在治疗后 $^ { 8 \mathrm { ~ h ~ } }$ 内可出现消融部位疼痛，大部分患者可耐受， $^ { 8 \mathrm { ~ h ~ } }$ 内可自行缓解，无需用药，个别患者需对症治疗，如口服止痛药物。 3.月经周期变化：治疗后可出现月经周期的短暂性改变，一般会自行恢复不需特别处理；如持续出现，需对症处理及排除其他妇科疾病。皮肤或皮下软组织灼伤：一般程度较轻，予以冷敷处理后短期内可以恢复；未缓解者可进行相关临床对应处理。阴道排液：部分患者术后会出现阴道排液，呈粉红色或洗肉水样，多在周内自行消失。预防：治疗中尽量不要损伤子宫内膜，划定ROT范围时建议距离子宫内膜 $5 \mathrm { m m }$ 。对于有生育要求的患者应尽量避免大面积的子宫内膜热损伤，尤其是近子宫底部的内膜。如阴道排液持续增多，伴异味，应行妇科检查，排除炎症及其他妇科疾病。 6.骨质水肿、神经损伤：极少数患者治疗后会出现臀部和（或）下肢放射状疼痛或体位相关疼痛，短期内不能恢复的需到神经科就诊处理，一般经积极治疗后可恢复。预防：术前告知患者，若术中如出现臀部和（或）下肢放射状疼痛应及时按下“停止”键中断消融治疗；术前经肛门插管注入适量超声耦合胶；术中精确勾画骶骨保护线；当患者出现骶尾部疼痛时，可尝试调整治疗参数，包括降低消融能量和改变超声束的聚焦方向等，如患者疼痛无改善，则中止相关靶点治疗；适当控制治疗时间，以尽量避免因能量累积而发生腰骶椎骨质水肿和神经损伤。 7.大便习惯改变：部分患者术后会出现便秘或腹泻的情况，一般不需处理短期可恢复；如症状持续，可对症处理。 8.感染：少数患者因消融范围大或靠近内膜，可能出现逆行感染，伴有发热、腹痛等症状及相应实验室检查结果的变化，应及时给予抗感染治疗。预防：嘱患者术后注意个人卫生，1个月内禁止同房。 9.严重并发症：肠穿孔、子宫破裂等严重并发症罕见发生，国内未见相关报道。术者经过系统培训，严格掌握适应证，遵照操作规范，可避免严重不良事件的发生。六、术后随访及治疗效果的评价术后即刻行MRI增强扫描，计算靶肌瘤NPVR以评估消融效果［19‐25］；术后3个月、6个月、1年及以后每间隔1年进行随访观察，随访内容包括影像学评估和临床疗效评价。如治疗前有超声检查结果，在以上评估间期，即治疗后个月、个月、个月间，可行经阴道超声检查，监测肌瘤体积。 # （一）影像学评估 1. 完全消融：消融后即刻 MRI 增强扫描NPVR ${ \% } 8 0 \%$ 。 2. 大部分消融：消融后即刻 MRI 增强扫描$6 0 \% { \leqslant } \mathrm { N P V R } { < } 8 0 \%$ 。 3. 部分消融：消融后即刻 MRI 增强扫描$\mathrm { N P V R } { < } 6 0 \%$ 。 # （二）临床疗效评估评价指标包括：子宫肌瘤体积缩小率、症状严重度评分（symptoms severity score，SSS）和子宫肌瘤症状‐生活质量问卷（uterine fibroid symptomsquality of life questionnaire，UFS‐QOL）评分［26‐29］。 1.疗效非常显著：符合下列条件之一，消融后3个月子宫肌瘤体积缩小率 $5 5 0 \%$ ；SSS评分下降>治疗前分值的 $50 \%$ ；UFS‐QOL 评分升高 $>$ 治疗前分值的 $50 \%$ 。疗效显著：符合下列条件之一，消融后个月子宫肌瘤体积缩小率 $20 \% { \sim } 4 9 \%$ ；SSS评分下降治疗前分值的 $30 \% { \sim } 4 9 \%$ ；UFS‐QOL评分升高治疗前分值的 $30 \% { \sim } 4 9 \%$ 。治疗有效：符合下列条件之一，消融后个月子宫肌瘤体积缩小率 $10 \% { \sim } 1 9 \%$ ；SSS评分下降治疗前分值的 $10 \% { \sim } 2 9 \%$ ；UFS‐QOL评分升高治疗前分值的 $10 \% { \sim } 2 9 \%$ 。 4.治疗无效：符合下列条件之一，消融后3个月子宫肌瘤体积缩小率 ${ < } 1 0 \%$ ；SSS评分下降 $<$ 治疗前分值的 $10 \%$ ；UFS‐QOL 评分升高 $<$ 治疗前分值的$10 \%$ 。七、MRgFUS治疗子宫腺肌症的展望子宫腺肌症是因子宫内膜的间质和腺体进入子宫肌层形成的一种疾病，是子宫内膜异位症的一种类型，好发于 30\~50岁的育龄期女性，总体患病率为 $8 \% { \sim } 6 2 \%$ ，近年来有明显上升趋势，已成为一种严重影响女性身心健康的常见疾病。子宫腺肌症的确切发病机制尚不清楚，保守治疗的方法多样但疗效不确切、易复发，子宫切除术仍是根治方法。子宫腺肌症在发病机制、症状与子宫肌瘤有部分相似性，使用MRgFUS进行子宫腺肌症治疗具有可行性。目前，国内外开展了一些MRgFUS治疗子宫腺肌症的临床研究，初步结果疗效比较满意。特别是对于局限性子宫腺肌症患者，其临床症状改善较明显。Fukunishi 等［30］采用 MRgFUS 治疗 20例子宫腺肌症患者并随访6个月，子宫体积缩小 $1 2 . 7 \%$ ，临床症状得到缓解。Ferrari 等［31］报道 18例 MRgFUS 治疗子宫腺肌症随访1年结果，SSS评分从28.4分降低到10.1分， $83 \%$ 患者的结合带厚度于治疗1年后<$1 2 \mathrm { m m }$ 。Polina 等［32］对接受 MRgFUS 治疗的 2例子宫腺肌症患者进行3\~6个月的随访，结果显示临床症状得到了有效缓解，其中 BMI 为 $2 4 . 2 \mathrm { k g } / \mathrm { m } ^ { 2 }$ 的43岁患者SSS评分由50分减少至24分，疼痛评分由最高10分降至0分。以上研究表明，MRgFUS治疗子宫腺肌症是安全、有效的，但远期疗效尚需大样本、多中心研究。临床中发现，预行 MRgFUS 治疗的部分子宫腺肌症患者，治疗前可给予2\~3个周期的GnRHa治疗，术后继续巩固治疗2\~3个周期，以达到满意的治疗效果。术后1年，如子宫腔大小适合，还可放置曼月乐环，继续巩固治疗效果。但目前，MRgFUS治疗子宫腺肌症的临床应用在术前病例筛选、治疗方案设定、术后用药和随访、如何巩固长期疗效、预防并发症等方面未达成共识、形成规范，尚需要做更多的探讨和研究。作为子宫肌瘤的新的治疗技术，无创是其最显著的优势。MRgFUS 治疗子宫肌瘤的安全性和有效性已经得到临床证实。合理筛选患者、规范治疗和评估流程能减少和避免并发症的发生，为患者提供更加安全、有效的治疗，以实现患者最大受益。执笔者：张俊海（复旦大学附属华山医院放射科）、石海峰（北京协和医院放射科）、周慷（北京协和医院放射科）、苏佰燕（北京协和医院放射科）策划顾问：金征宇（北京协和医院放射科）、陈敏（北京医院放射科）、马林（解放军总医院第一医学中心放射科）、陆建平（海军军医大学附属长海医院影像医学科）、周晓东（空军军医大学西京医院超声科）、彭卫军（复旦大学附属肿瘤医院放射诊断科）策划负责人：薛华丹（北京协和医院放射科）、王梅云（河南省人民医院放射科）、王悍（上海市第一人民医院放射科）、叶晓华（北京医院放射科）、娄昕（解放军总医院第一医学中心放射科）、姚振威（复旦大学附属华山医院放射科）、顾雅佳（复旦大学附属肿瘤医院放射诊断科）参与共识制定专家（按姓氏拼音为序）：陈世林（海南省肿瘤医院放射科）、范文生（解放军总医院第一医学中心妇产科），谷涛（北京医院放射科）、何健风（解放军总医院第一医学中心放射科）、李叶（北京医院妇产科）、李振玉（河南省新乡市中心医院放射科）、罗文（空军军医大学西京医院超声科）、唐纳（上海市第一人民医院放射科）、王娟（广东省佛山市中医院放射科）、王升平（复旦大学附属肿瘤医院放射诊断科）、王英伟（哈尔滨市第一医院介入科）、阳青松（海军军医大学附属长海医院影像医学科）、叶锦棠（北京美中宜和医院磁共振室），袁庆海（吉林大学第二医院放射科）、张盛箭（复旦大学附属肿瘤医院放射诊断科）、张羽（北京协和医院妇产科）、赵文俐（南方科技大学医院放射科）、周守国（广东省佛山市中医院放射科）利益冲突所有作者均声明不存在利益冲突志谢图4由海军军医大学附属长海医院影像医学科阳青松绘制 # 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4c5e716e91854399ae3571ce402a06a9	中华医学会	ⅡB期宫颈癌诊治中国专家共识（2024）	·指南/共识· # ⅡB期宫颈癌诊治中国专家共识（2024）尧良清向阳王育林仲秋王平胡克中国医师协会妇产科医师分会妇科肿瘤学组中国医药教育学会妇科肿瘤专业委员会通信作者：尧良清，广州医科大学附属妇女儿童医疗中心妇瘤科，广州 510180，Email：yaoliangqing@163.com；向阳，北京协和医院妇瘤中心，北京 100730，Email：xiangy@pumch.cn；王育，同济大学附属妇产科医院妇瘤科，上海 200040，Email：renjiwangyu@126.com；林仲秋，中山大学孙逸仙纪念医院妇瘤科，广州 510120，Email：lin‑zhongqiu@163.com；王平，四川大学华西第二医院妇科，成都 610044，Email：wangping886@126.com；胡克，北京协和医院放疗科，北京100730，Email：huke8000@163.com 【摘要】 ⅡB期宫颈癌在所有宫颈癌患者中占一定比例。由于妇科检查的主观性及影像学检查对宫旁组织受侵诊断的局限性，其诊断可能与临床分期存在分期升级或降级现象，因此选择同步放化疗还是手术治疗也成为临床上最大的困惑和争议。目前，关于ⅡB期宫颈癌的诊断和治疗在各国临床指南中尚存争议，对于不同患者的推荐治疗模式尚无统一共识。提高期宫颈癌的精准诊断和个体化治疗是改善患者生存的关键。为此，编委会组织专家制订本共识，以期为期宫颈癌诊断及治疗决策提供参考和借鉴。【关键词】　子宫颈癌； ⅡB期；　诊断；　治疗；　同步放化疗；　根治性全子宫切除术 # The Chinese expert consensus of the diagnosis and treatment of FIGO stage Ⅱ B cervical cancer (2024 version) Yao Liangqing, Xiangyang, Wang Yu, Lin Zhongqiu, Wang Ping, Hu Ke, The Gynecological Oncology Group of Chinese Obstetricians and Gynecologists Association, The Gynecological Oncology Committee of Chinese Medicine Education Association Corresponding authors: Yao Liangqing, Department of Gynecologic Oncology, Guangzhou Women and Children′s Medical Center, Guangzhou 510180, China, Email: yaoliangqing@163. com; Xiang Yang, Gynecological Oncology Center, Peking Union Medical College Hospital, Beijing 100730, China, Email: xiangy@pumch.cn; Lin Zhongqiu,Department of Gynecologic Oncology,Sun Yat-sen Memorial Hospital , Sun Yat-sen University, Guangzhou 510120,China, Email:lin-zhongqiu@163.com; Wang Yu, Department of Gynecologic Oncology, Tongji University Affiliated Obstetrics and Gynecology Hospital, Shanghai 200040, China, Email: renjiwangyu@126. com; Wang Ping, Department of Gynecology, West China Second Hospital of Sichuan University, Chengdu 610044, China, Email: wangping886@126.com; Hu Ke, Department of Rdiotherapy, Peking Union Medical College Hospital, Beijing 100730, China, Email: huke8000@163.com 【Abstract】 Stage ⅡB cervical cancer accounts for a certain proportion of all cervical cancer patients. Due to the subjectivity of gynecological examination and the limitation of imaging examination in the diagnosis of parametrial tissue invasion, the diagnosis of stage Ⅱ B cervical cancer may be inconsistent with the true clinical stage, which is often upgraded or downgraded. Therefore, the choice of concurrent chemoradiotherapy or surgery has become the biggest confusion and controversy in clinical practice. At present, the diagnosis and treatment of stage Ⅱ B cervical cancer are still controversial in the clinical guidelines of various countries, and there is no consensus on the recommended treatment mode for different patients. To improve the accurate diagnosis and individualized treatment of stage ⅡB cervical cancer is the key to improve the survival of patients. Therefore, the Editorial Board organized experts to formulate this expert consensus, in order to provide reference for diagnosis and treatment decision-making of stage ⅡB cervical cancer. 【Key words】 Cervical cancer; Stage Ⅱ B; Diagnosis; Treatment; Concurrentchemoradiotherapy; Radical hysterectomy 本共识仅适用于占宫颈癌病理类型 $90 \%$ 以上的宫颈鳞癌、腺癌及腺鳞癌，其他特殊病理类型如小细胞癌、透明细胞癌、肉瘤等发病率低，目前国际国内尚未达成共识。本共识借鉴了国际上公认的宫颈癌诊疗指南，如美国国家综合癌症网络（National Comprehensive Cancer Network,NCCN)指南、国际妇产科联盟（International Federation ofGynecology and Obstetrics，FIGO）指南等，并结合我国以往指南进行修订。在临床实践中，宫颈癌注重规范化综合治疗理念，同时也注重个体化治疗，需结合医院的设备、技术条件以及患者的病情选择治疗方法。对于病情复杂的宫颈癌患者、本共识未涵盖的患者，建议参加临床试验。本共识证据等级和推荐等级及其代表意义详见表1、2。表1 本共识证据等级及其代表意义 <table><tr><td colspan="2">证据等级代表意义</td></tr><tr><td>1a级</td><td>同质性较好的随机对照试验的系统综述或同质性良好的队列研究系统综述</td></tr><tr><td>1b级</td><td>95%CI较窄的单项随机对照试验；单项起点一致的队列研究，随访率>80%</td></tr><tr><td>1c级</td><td>传统治疗全部无效；系列病例报告全部死亡或全部生存</td></tr><tr><td>2a级</td><td>同质性较好的队列研究的系统综述；回顾性队列或对照组为空白对照(未治疗)的或随机对照试验的系统综述</td></tr><tr><td>2b级</td><td>单项队列研究及质量较差的随机对照试验;单项回顾性队列或对照组为空白对照(未治疗)的或随机对照试验结局研究</td></tr><tr><td>3a级</td><td>同质性较好的病例对照研究的系统综述</td></tr><tr><td>3b级</td><td>单项病例对照研究</td></tr><tr><td>4级 5级</td><td>系列病例分析或质量差的病例对照研究系列病例报告或质量差的队列研究，随访率<80% 无分析评价的专家意见或在病理生理基础上的意见</td></tr></table> 表2 本共识推荐等级及其代表意义 <table><tr><td>推荐等级</td><td>代表意义</td></tr><tr><td>I类</td><td>基于高级别临床研究证据,专家意见高度一致</td></tr><tr><td>Ⅱa类</td><td>基于低级别临床研究证据，专家意见高度一致;基于</td></tr><tr><td>Ⅱb类</td><td>高级别临床研究证据，专家意见基本一致</td></tr><tr><td></td><td>基于低级别临床研究证据,专家意见基本一致</td></tr><tr><td>Ⅲ类</td><td>不论基于何种级别临床证据，专家意见明显分歧</td></tr></table> # 一、介绍 # （一）期宫颈癌的总体概述宫颈癌是全球最常见的妇科恶性肿瘤，据估计，全球每年新诊断病例 ${ > } 6 0$ 万例，2020年报告死亡人数为万例［1］。本专家共识的宫颈癌分期基于 2018 年 FIGO 分期系统［2‑3］。根据美国 NCCN 报道，与早期宫颈癌（ⅠA‑ⅠB2期）患者相比，晚期宫颈癌（ⅠB3‑ⅣB期）患者的复发率更高，生存结果更差［4］。期宫颈癌分为期和期，其中期定义为肿瘤侵犯宫旁但未延伸至盆腔侧壁。文献报道期宫颈癌患者的年生存率约为$7 3 . 7 \% ^ { [ 5 ] }$ 。 # （二）ⅡB期宫颈癌治疗国际指南对于ⅡB 期宫颈癌患者的治疗，美国、中国和韩国目前建议采用同步放化疗。美国NCCN指南指出只有大部分患者采用同步放化疗；此外仍有部分国家在选择性采用根治性手术。一些欧洲指南中提到新辅助化疗辅以根治性全子宫切除术也可以作为一种治疗选择［6］。而日本学界推荐对ⅡB期宫颈癌患者进行根治性全子宫切除或同步放化疗，大约 $40 \%$ 的医疗机构采用根治性全子宫切除［3，7‑8］（表 3）。造成不同国家治疗差异的原因有 3 个：一是可能因对根治性全子宫切除术不同的认知［9‑11］；二是一些临床医生倾向于采用新辅助化疗以避免潜在的长期放疗相关并发症［12］；三是放疗常常导致相关并发症增加（常见于一些体重过轻患者）。有证据表明体重过轻患者（体重指数 $< 1 8 . 5 \mathrm { k g / m } ^ { 2 } .$ ）与正常体重或肥胖患者相比，接受同步放化疗治疗的总生存（，）率较差，发生放射性肠炎、肠瘘、肠梗阻以及淋巴水肿的并发症率更高。然而由于女性的平均体重指数因国家或地区而异［13］，因此同步放化疗的不良反应也可能因国家或地区而异。 # （三）ⅡB期宫颈癌的术前诊断难点 ⅡB期宫颈癌的诊断难点主要在于宫旁浸润的界定。有研究表明ⅡB期宫颈癌的最终手术分期和临床FIGO分期之间的一致率仅为 $2 0 . 5 \% ^ { [ 1 4 ] }$ 。表3 不同国家对于期宫颈癌的治疗推荐 <table><tr><td>地区</td><td>组织</td><td>推荐治疗</td></tr><tr><td></td><td></td><td>美国美国国家综合癌症网络铂类同步放化疗+近距离治疗欧洲欧洲肿瘤内科学会铂类同步放化疗;新辅助化疗+根</td></tr><tr><td></td><td></td><td>治性全子宫切除;新辅助化疗+ 放疗</td></tr><tr><td></td><td></td><td>中国中国国家卫生健康委顺铂同步放化疗+近距离治疗</td></tr><tr><td></td><td></td><td>日本日本妇科肿瘤学会鳞癌:根治性全子宫切除(+辅助治疗);同步放化疗。腺癌：根治性</td></tr><tr><td></td><td>韩国韩国妇科肿瘤学组</td><td>全子宫切除(+辅助治疗) 顺铂同步放化疗</td></tr></table> 有无宫旁浸润是期宫颈癌患者治疗前需评估的重要方面之一，被认为是ⅡB期宫颈癌诊断和后续治疗选择的决定性因素。妇科检查：期宫颈癌有宫旁浸润但未累及盆壁，因此妇科检查的重点在于触诊，包括肿瘤的质地、浸润范围及其与周围的关系等。三合诊检查可了解阴道旁、宫颈旁及子宫旁有无浸润、肿瘤与盆壁关系、子宫骶骨韧带、子宫直肠陷凹、直肠本身及周围情况等。然而，妇科检查判断宫旁浸润的准确率较低，依赖于检查者丰富的临床经验，且早期宫旁浸润不易发现，不建议作为宫旁浸润的主要判断依据。影像学检查：其在期子宫颈癌诊断中的价值主要是对肿瘤转移、侵犯范围和程度的了解（包括评价肿瘤局部侵犯的范围、淋巴结转移及远处器官转移等），以指导临床决策并用于疗效评价。用于子宫颈癌的影像检查方法包括腹盆腔超声、盆腔、腹盆腔、核医学影像检查、胸部射线摄影及胸部 CT 检查。（1）腹盆腔超声：主要用于宫颈局部病变的观察，同时可以观察盆腔及腹膜后区淋巴结转移情况，以及腹盆腔其他脏器的转移情况，此外还可发现浅表淋巴结的转移情况。由于分辨率的限制，目前对于宫颈局部病变以及全身转移情况的评估主要还是依靠和检查。但据既往研究报道，经直肠超声检查（transrectal ultrasound， TRUS）是评估宫旁侵犯的有用工具［15］。有研究报道显示，TRUS检测宫旁侵犯的阳性预测值为 $9 8 . 9 \%$ ，阴性预测值为 $8 3 . 3 \% ^ { [ 1 6 ] }$ 。这项检查可能有助于识别临床怀疑但未经病理证实的期病例，但该技术在很大程度上取决于操作人员的技能和专业知识，因此在基层医院和技术落后地区可能不易开展。基于此，本共识建议有经验的医疗中心为初诊或第1次转诊的患者完善TRUS检查（2a证据等级）。（）盆腔：它无辐射，多序列、多参数成像，具有优异的软组织分辨力，是子宫颈癌最佳影像学检查方法。它有助于病变的检出和大小、位置的判断，能明确病变侵犯范围，为治疗前分期提供重要依据。其可显示病变侵犯宫颈基质的深度，判断病变是否局限于宫颈、侵犯宫旁或是否侵犯盆壁［17］。它能够显示阴道内病变的范围，但有时对病变突入阴道腔内贴邻阴道壁与直接侵犯阴道壁难以鉴别。它还能够提示膀胱、直肠壁的侵犯，但需结合镜检；还能够同时检出盆腔、腹膜后区及腹股沟区的淋巴结转移。对于非手术治疗的患者，它可用于放疗靶区勾画、治疗中疗效监测、治疗末疗效评估及治疗后随诊。据研究报道宫旁受累的术前临床诊断准确率约为 $50 \%$ ［3，16］。这意味着大约 $50 \%$ 临床诊断的ⅡB期宫颈癌病例属于过度诊断病例，而盆腔被认为可有效提高特定病例的诊断准确性。有研究表明对评估宫旁受累的阳性预测值为$80 \% \sim 9 0 \%$ ，MRI 排除宫旁侵犯的阴性预测值为94%［18‑19］。有研究表明接受根治性全子宫切除和淋巴结清扫治疗的患者的性功能障碍比接受放疗患者要少［20‑21］。如果想要准确选择适合根治性全子宫切除的患者、避免放疗带来的长期不良反应（卵巢功能下降、性功能障碍等），则准确的诊断至关重要［22］。研究表示临床ⅡB期宫颈癌（肿瘤直径<$4 \mathrm { { c m } }$ ）患者非常适合进行MRI或TRUS术前评估，使用此法 $5 5 0 \%$ 患者能够避免放疗［23‑24］（ $2 \mathbf { a }$ 证据等级）。（）腹盆腔：它对软组织分辨力低，平扫时病变与正常子宫颈密度相近，尤其对局限于宫颈的早期子宫颈癌观察效果差；增强扫描对比度优于平扫，但仍有近 $50 \%$ 病变呈等密度而难以明确范围。一项Meta分析显示评估宫旁受累时诊断宫旁浸润的敏感性MRI为 $74 \%$ ，CT为 $5 5 \%$ ，因此CT对于ⅡB期宫颈癌的诊断准确率不如 $\mathrm { M R I } ^ { [ 2 5 ] }$ 。其优势主要在于显示中晚期病变方面，评价宫颈病变与周围结构（如膀胱、直肠等）的关系、淋巴结转移情况，以及大范围扫描腹盆腔其他器官是否存在转移。对于有核磁禁忌证的患者可选择 CT 检查（ $2 \mathbf { a }$ 证据等级）。（）核医学影像检查：早期全面评估全身肿瘤负荷、掌握预后信息对患者分层和制订个性化治疗方案非常重要。以 ${ } ^ { 1 8 } \mathrm { F } .$ ‑氟代脱氧葡萄糖（ $^ { 1 8 } \mathrm { F }$ ‑fluoro‑2‑deoxy‑D‑glucose， ${ } ^ { 1 8 } \mathrm { F } .$ ‑FDG）为示踪剂的正电子发射断层‑计算机断层扫描（positronemission tomography‑computed tomography，PET‑CT）技术能够同时提供恶性肿瘤分子水平的代谢活性及解剖位置，被指南推荐用于宫颈癌的诊断分期及疗效判定等。然而其对于宫旁有无浸润的判断无独特优势，其优势主要在于评估淋巴结转移及全身转移方面，因此对于接受同步放化疗的患者尤其有必要完善PET‑CT（2a证据等级）。（）胸部射线片及胸部检查：主要目的是为了排除肺转移和纵隔淋巴结转移。胸片只能排除明显的肺转移，无法评估纵隔淋巴结，所以有条件的医院还是应该行胸部 CT 检查。推荐意见：建议在初诊或第1次转诊时由至少2名有经验的高年资妇科医师为患者完善妇科检查并结合肛查（Ⅱa 类推荐）。建议患者完善PET‑CT 或 MRI，有条件者完善 TRUS 检查（Ⅱa类推荐）。 # 二、ⅡB期宫颈癌的放化疗 # （一）根治性同步放化疗传统放疗已被认为是宫颈癌的有效治疗方法［26］。然而，近年来，基于铂类的同步放化疗占据了更大的比例。与传统放疗相比，接受了同步放化疗患者的 OS 和无疾病生存（disease‑free survival，DFS）均得到改善，死亡风险低于传统放疗［27‑31］。同步放化疗的出现将宫颈癌的年率提高了 $6 \%$ （从 $60 \%$ 提高至 $6 6 \%$ ）。因此，1999年之后美国国家癌症研究所建议对晚期宫颈癌和局部晚期宫颈癌病例进行同步放化疗［32］。同步放化疗即盆腔外照射 $^ +$ 含顺铂方案的同步化疗 $^ +$ 近距离治疗。放疗总剂量为 $4 5 { \sim } 5 0 . 4 ~ \mathrm { G y }$ 分25\~28次进行，同时1次/周 $3 0 { \sim } 4 0 ~ \mathrm { m g / m } ^ { 2 }$ 顺铂化疗，随后腔内放疗。顺铂毒性不耐受者可用卡铂替换。一些临床研究中还有顺铂联合方案的同步化疗方案：分别于放疗第 1、29天行顺铂 $5 0 { \sim } 7 0 ~ \mathrm { m g } / \mathrm { m } ^ { 2 }$ 及紫杉醇 $1 3 5 { \sim } 1 7 5 ~ \mathrm { m g / m } ^ { 2 }$ 静脉化疗；顺铂 $^ +$ 紫杉醇周疗：分别于放疗第 $1 、 8 、 1 5 、 2 2 、 2 9 、 3 6$ 天行顺铂 $2 5 \sim$ $3 0 ~ \mathrm { m g / m } ^ { 2 }$ 及紫杉醇 $6 0 { \sim } 8 0 ~ \mathrm { m g / m } ^ { 2 }$ 静脉化疗。需根据患者放化疗的不良反应进行剂量调整，总体原则是不影响放疗正常进行。目前，尚无专门针对期宫颈癌的随机对照试验比较手术与放疗的治疗效果。有几个小型回顾性研究报道根治性全子宫切除加辅助放疗和根治性同步放化疗在ⅡB 期宫颈癌患者的 OS 相近［33‑34］（3a证据等级）。然而，根治性手术的完全切除率较低，大多数患者（ $9 0 . 5 \% { \sim } 1 0 0 \%$ ）由于存在不良预后因素而需要辅助治疗，由此带来了更高的并发症风险，尤其是慢性发病风险，例如小肠梗阻、下肢淋巴水肿和慢性神经性膀胱［6，8，23，35‑38（］ 2a 证据等级）。宫颈癌病理类型中鳞癌占 $8 0 \% { \sim } 9 3 . 7 \%$ ，腺癌占 $2 . 8 \% { \sim } 8 \%$ ，腺鳞癌占 $3 . 1 \% { \sim } 7 . 4 \%$ 。因此，预期术后存在辅助放疗高危因素的患者应避免手术而直接行同步放化疗，以免患者同时承受手术和放疗的双重不良反应。推荐意见：同步放化疗应作为ⅡB期宫颈鳞癌的首选方案（Ⅱa类推荐）。ⅡB期宫颈腺癌或腺鳞癌也可以选择同步放化疗作为根治性治疗方案（Ⅱb类推荐） # （二）同步放化疗的未来展望 1. 化疗药物的改进：铂类同步放化疗已被证明可以成功改善局部晚期宫颈癌患者预后［39‑41］。目前，化疗通常涉及单药顺铂或顺铂加氟尿嘧啶的组合［29，42］。目前有研究正在改进几种化疗方案的剂量和用药时间。一项随机对照试验发现与标准铂类同步放化疗组相比，顺铂 $^ +$ 吉西他滨同步放化疗组的 3 年无进展生存（progression‑free survival，PFS）有所改善 $( 7 4 . 4 \% : 6 5 . 0 \%$ ），OS有所改善（1b证据等级）。然而，3\~4 级中性粒细胞减少症发生率显著增加（ $5 1 . 2 \% : 5 . 9 \%$ ），级血液系统不良反应发生率增加 $( 7 1 . 9 \% : 2 3 . 9 \% ) ^ { 1 3 5 , 4 2 }$ 2］，并有可能导致腹泻增加 $( 1 7 . 7 \% : 4 . 7 \% )$ ）。因此，尽管PFS和OS有所改善，但目前不推荐顺铂 $^ +$ 吉西他滨同步放化疗［6，35］。同步放化疗 $^ +$ 辅助化疗：一项随机对照试验（ACTLACC研究）评估了同步放化疗后联合辅助化疗是否可以改善PFS和OS，结果显示同步放化疗 $^ +$ 辅助化疗组与单纯同步放化疗组的3年PFS、OS率相近［43］（1b证据等级）。另有一项国际随机对照试验（研究）评估了基于标准顺铂的同步放化疗后追加 4 个周期卡铂和紫杉醇化疗是否可以改善OS，结果显示同步放化疗后追加辅助化疗未能进一步改善 $0 \mathrm { S } ^ { [ 4 4 - 4 5 ] }$ （1b证据等级）。目前，尚无单独针对ⅡB 期宫颈癌同步放化疗后追加辅助化疗的前瞻性多中心大样本研究，因此尚无明确的临床证据支持ⅡB期宫颈癌进行同步放化疗后辅助化疗。安全性方面，追加辅助化疗组的3\~4级不良反应发生率显著高于单纯同步放化疗组，最常见的为血液系统3\~4级不良反应。 3. 新辅助化疗 $^ +$ 同步放化疗：一项随机对照期临床试验（研究）证明新辅助化疗联合同步放化疗可以显著改善局部晚期宫颈癌的 PFS和OS，将癌症复发或死亡的风险降低 $3 5 \%$ ；接受了额外新辅助化疗的患者5年PFS提高了 $9 \%$ （新辅助化疗联合同步放化疗组和单纯同步放化疗组的5年PFS率分别为 $73 \%$ 和 $64 \%$ ），5年OS率提高了 $8 \%$ （ $80 \%$ 和 $72 \%$ ）［46］（1b 证据等级）。2023 年度欧洲肿瘤内科学会会议上报道的Ⅲ期临床试验（研究）对比了帕博利珠单抗联合同步放化疗对比安慰剂联合同步放化疗治疗高危局部晚期宫颈癌的疗效（摘要号LBA38），虽然随访时间还很短，但结果看起来很有希望。该研究方案有可能成为患者的另一种治疗选择，但并发症发生率也随之增高。一项系统性综述提示新辅助化疗联合同步放化疗的3\~4级并发症率约为 $2 5 \%$ ，缓解率约为 $70 \%$ 。最常见的3\~4级并发症是中性粒细胞减少症、贫血和腹泻［47］。推荐意见：同步放化疗的化疗药物选择日益增多，但目前仍推荐采用以铂类药物为基础的单药或联合化疗（Ⅱa类推荐）。虽然顺铂 $^ +$ 吉西他滨同步放化疗可以提高生存时间，但其相应带来更高的并发症发生率，因此不予推荐（Ⅱa类推荐）。宫颈癌患者在接受标准的顺铂为基础的同步放化疗后给予卡铂联合紫杉醇方案的辅助化疗未能改善OS，反而增加了短期不良反应，因此辅助化疗不予推荐（Ⅱa类推荐）。尽管有高质量的临床研究提示新辅助化疗联合同步放化疗相比单纯同步放化疗显著提高了局部晚期宫颈癌的生存时间，但治疗者也需考虑随之带来的不良反应（Ⅱb类推荐）。 # 三、期宫颈癌的手术治疗 # （一）ⅡB期宫颈癌手术治疗存在的问题 ⅡB期宫颈癌接受手术治疗的前提是预期可达根治性切除且切缘阴性。然而即使是在有经验的医疗中心，根治手术的完全切除率也通常较低，往往需要辅助治疗［35］。术后放疗，特别是同步放化疗，与治疗相关并发症的风险增加相关，从而增加了手术相关的并发症率［27，48‑49］。有文献报道ⅡB期宫颈癌患者中根治性全子宫切除加辅助同步放化疗组出现3\~4级远期不良反应的风险高于直接同步放化疗组 $( 2 4 . 1 \% \colon 1 0 . 6 \%$ ），并且 OS 未改善（ $( 6 6 . 4 \% : 6 8 . 3 \% ) ^ { [ 5 0 ] }$ 。另有其他研究表明根治性全子宫切除加辅助同步放化疗与 3\~4 级晚期治疗相关并发症的发生率较高相关，且 OS 和 PFS 未改善［37，51］。尽管这些只是小型回顾性研究，但结果均提示根治性全子宫切除加辅助同步放化疗比根治性同步放化疗危害更大，且预后获益尚不明确。 # （二）新辅助化疗 $^ +$ 根治性全子宫切除对比单纯根治性全子宫切除新辅助化疗后根治手术可作为不具备实施同步放化疗的局部晚期宫颈癌的一种替代治疗方法。前期研究报道新辅助化疗可降低术后的病理危险并改善预后［52‑53］。一项 IB‑Ⅲ B 期宫颈癌的分析报告称新辅助化疗 $^ +$ 根治性全子宫切除的OS优于单独手术［54‑58］（2a 证据等级）。然而，另一项研究总结了7项包含ⅡB期患者的随机对照试验，认为新辅助化疗 $^ +$ 根治性全子宫切除的OS与单纯根治性全子宫切除相近［3］（2a证据等级）。这些结论表明术者应仔细筛选新辅助化疗 $^ +$ 根治性全子宫切除的适用人群。一些专家认为新辅助化疗 $^ +$ 根治性全子宫切除仅对选定的高风险病例有益，例如肿瘤直径 ${ > } 4 ~ \mathrm { c m }$ ；组织病理学危险因素，如组织学分级级、淋巴血管受累和血管受累以及疑似淋巴结转移［58］。然而，目前尚无高质量证据表明哪些患者可以从新辅助化疗 $^ +$ 根治性全子宫切除中获益最多。 # （三）新辅助化疗 $^ +$ 根治性全子宫切除对比同步放化疗目前有3项随机对照试验比较新辅助化疗后根治性全子宫切除术与同步放化疗对IB3‑ⅡB期宫颈癌的疗效（均为1b证据等级）。Gupta等［59］的Ⅲ期随机对照临床试验发现，新辅助化疗 $^ +$ 根治性全子宫切除组的5年DFS低于同步放化疗组（新辅助化疗组为 $6 7 . 2 \%$ ，同步放化疗组为 $7 9 . 3 \%$ ），并且5年OS相近。另一项随机对照试验的结果与Gupta等［60］的研究结果相似，新辅助化疗 $^ +$ 根治性全子宫切除组的 DFS 更低，OS 相近（新辅助化疗组为$6 8 . 0 \%$ ，同步放化疗组为 $7 6 . 0 \%$ ）［60］。在并发症方面，新辅助化疗 $^ +$ 根治性全子宫切除组的短期并发症（特别是血液系统并发症）更高，而同步放化疗组的远期并发症（例如小肠和阴道并发症）更常见。Kenter等［60］的研究纳入了IB‑ⅡB的宫颈癌患者，发现新辅助化疗后根治性全子宫切除术与同步放化疗的5年OS相近 $7 2 \% : 7 6 \%$ ）， $53 6 \%$ 的新辅助化疗患者术后仍需要辅助放疗；新辅助化疗后根治性全子宫切除术组更易出现短期不良严重事件（ $41 \%$ ∶$23 \%$ ），而同步放化疗更易出现长期不良严重事件（ $2 1 \% : 1 5 \%$ ）。因此，目前的研究证据还不够支持新辅助化疗 $^ +$ 手术能带来更长DFS和PFS的结论。基于这些结果，笔者认为新辅助化疗 $^ +$ 根治性全子宫切除对于ⅡB期宫颈癌的治疗并不优于同步放化疗（Ⅱa类推荐）。另外，使用顺铂进行化疗可能可以改善新辅助化疗 $^ +$ 根治性全子宫切除的疗效。一项Ⅲ期试验比较了转移性或复发性宫颈癌患者的常规紫杉醇加顺铂方案与紫杉醇加卡铂方案［61］。该研究发现，在既往未接受过以顺铂为基础的化疗的患者中，紫杉醇加卡铂组的中位OS时间比紫杉醇加顺铂组短（13.0 个月∶23.2 个月）［62（］ 1b 证据等级）。推荐意见：宫颈鳞癌患者接受根治性全子宫切除术的前提是预期可达根治性手术且切缘阴性（Ⅱa类推荐）。新辅助化疗可以提高宫颈癌的局部控制率和手术切净率，但不能改善其预后，且术后病理学高危因素易被掩盖，原则上不推荐使用。然而对于肿瘤直径 ${ \bf { > } } 4 ~ { \bf { c m } }$ 的患者可考虑使用新辅助化疗（Ⅲ类推荐）。 # 四、宫颈腺癌及腺鳞癌的治疗由于腺癌属于不常见的组织学类型，目前缺乏针对期宫颈腺癌的多中心前瞻性大样本研究，大多数指南也未根据局部晚期宫颈癌组织学类型对治疗建议进行细分。由于腺鳞癌中的腺癌成分恶性程度高、预后差，因此本指南认为腺鳞癌应等同于腺癌的治疗。腺癌组织学是不良的独立预测因子，远处转移率较高［62‑63］，且对放疗的抵抗较高［64］，对化疗的敏感性也不如鳞癌［65］。宫颈腺癌患者的同步放化疗 OS率比鳞癌患者差（ $5 8 . 6 \%$ ∶$2 6 . 7 \%$ ）［64，66‑67］。已有很多研究提出手术对于腺癌患者的重要意义［68］。有研究认为对于 ${ < } 6 5$ 岁的ⅡB期宫颈腺癌患者应采用手术治疗［69］。也有其他研究提出同步放化疗后行全子宫切除手术在ⅡB期宫颈腺癌中占有优势［70］。还有人认为对于肿瘤直径 ${ > } 4 ~ \mathrm { c m }$ 的腺癌患者可考虑使用新辅助化疗联合根治性手术。根据目前证据，宫颈腺癌手术治疗可能优于同步放化疗。推荐意见：根据目前的证据，我们推荐对ⅡB期宫颈腺癌及腺鳞癌患者进行根治性手术（Ⅱa类推荐）或同步放化疗（Ⅱb类推荐）。声明本共识旨在为ⅡB期宫颈癌的诊断与治疗提出指导性意见，但并非唯一的实践指南，不排除其他共识、意见与建议的合理性专家组成员（按姓氏笔画排序）马晓欣（中国医科大学附属盛京医院），王丹波（辽宁省肿瘤医院），王宁（大连医科大学附属第二医院），王玉东（上海交通大学医学院附属国际和平妇幼保健院），王沂峰（南方医科大学珠江医院），石琨（广州医科大学附属妇女儿童医疗中心），田建辉（上海中医药大学附属市中医医院），史庭燕（复旦大学附属中山医院），孙阳（福建省肿瘤医院），邬素芳（上海交通大学医学院附属第一人民医院），朱滔（浙江省肿瘤医院），米鑫（北京儿童医院顺义妇儿医院），李志刚（南方医科大学附属广东省人民医院），李俊东（中山大学肿瘤防治中心），李娜（遵义医科大学第二附属医院），李斌（中国医学科学院肿瘤医院），李佩玲（哈尔滨医科大学附属第二医院），张丙忠（中山大学孙逸仙纪念医院），张师前（山东大学齐鲁医院），张治宁（宁夏医科大学总医院），张国楠（四川省肿瘤医院），张梅（安徽医科大学第一附属医院），张瑜（中南大学湘雅医院），陆安伟（南方医科大学深圳医院），陈刚（华中科技大学同济医学院附属同济医院），陈默（复旦大学附属妇产科医院），陈德新（四川省妇幼保健院），汪辉（浙江大学医学院附属妇产科医院），孟元光（中国人民解放军总医院），金平（深圳市妇幼保健院），周圣涛（四川大学华西第二医院），姚书忠（中山大学附属第一医院），姜桦（复旦大学附属妇产科医院），柯桂好（复旦大学附属肿瘤医院），赵书君（郑州大学第三附属医院），赵敏（无锡市妇幼保健院），唐均英（重庆医科大学附属第一医院），袁蕾（复旦大学附属妇产科医院），梁志清（陆军军医大学西南医院），程文俊（南京医科大学第一附属医院），曾定元（广州医科大学附属妇女儿童医疗中心柳州医院），彭澎（北京协和医院），蔡丽萍（南昌大学第一附属医院）执笔人姜启迪（复旦大学附属妇产科医院），邹若瑶（复旦大学附属妇产科医院），董戌辉（同济大学附属妇产科医院）利益冲突所有作者声明无利益冲突 # 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c78c34ca954d4d3bb307097d4b393c7a	中华医学会	不孕症诊断指南	·临床指南· # 不孕症诊断指南陈子江1 刘嘉茵2 黄荷凤3 乔杰4 周灿权5 黄国宁6 孙莹璞7 杨冬梓8 梁晓燕 9 郁琦 10 孙赟 11 李铮 11 范立青 12 徐丛剑 13 黄元华 14 张学红 15 杨菁16 卢少明1 崔琳琳1 颜军昊1 林金芳13 1 山东大学附属生殖医院生殖科，济南；2 南京医科大学第一附属医院生殖医学中心；3 上海交通大学医学院附属国际和平妇幼保健院辅助生殖科；4 北京大学第三医院生殖医学中心 100191；5 中山大学附属第一医院妇产科，广州510080；6 重庆市生殖与遗传研究所 400010；7 郑州大学第一附属医院生殖医学中心450003；8 中山大学孙逸仙纪念医院妇产科，广州 510120；9 中山大学附属第六医院生殖医学中心，广州 510655；10中国医学科学院北京协和医院妇产科 100730；11上海交通大学医学院附属仁济医院生殖医学科；12中信湘雅生殖与遗传专科医院精子库，长沙；13复旦大学附属妇产科医院妇科，上海；14海南医学院第一附属医院生殖医学中心，海口；15兰州大学第一医院生殖医学科；16武汉大学人民医院生殖医学中心通信作者：陈子江，Email：chenzijiang@hotmail.com；刘嘉茵，Email：jyliu_nj@126.com；黄荷凤，Email：huanghefg@hotmail.com；乔杰，Email：jie.qiao@263.net 【摘要】不孕症是种低生育力状态，严重危害育龄期女性的生殖健康，指对配偶未采取避孕措施，有规律性生活至少个月未能获得临床妊娠。广义的不孕症包括不能妊娠和不能获得活产两个方面，本指南仅包括不能妊娠的相关内容。本指南是由中华医学会妇产科学分会妇科内分泌学组参考、美国生殖医学学会（）、英国国家卫生和临床医疗优选研究所（）的相关指南，并结合我国临床实践现状，经全国各级医疗机构专家函审最终制定，适用于全国各级各类医疗机构妇产科及男科执业医师对不孕症的诊断。 DOI:10.3760/cma.j.issn.0529‐567x.2019.08.001 # 病因分类不孕症是1种低生育力状态，指1对配偶未采取避孕措施，有规律性生活至少个月未能获得临床妊娠。其中，临床妊娠是指有妊娠的临床征象，并经超声检查证实存在个或以上妊娠囊［1］。异常的临床妊娠包括异位妊娠（包括子宫颈妊娠和瘢痕子宫妊娠）、胚胎停止发育、早期和晚期流产、死胎、早产、过期妊娠、死产，但不包括生化妊娠。广义的不孕症包括不能妊娠和不能获得活产两个方面，本指南仅包括不能妊娠的相关内容。本指南是由中华医学会妇产科学分会妇科内分泌学组起草，经全国90余位各级医疗机构专家函审最终制定，适用于全国各级各类医疗机构妇产科及男科执业医师对不孕症的诊断。本指南中涉及的单病种的诊断参见相应的诊断标准［如多囊卵巢综合征（PCOS）的诊断参见中华人民共和国卫生行业标准［2］］。不孕症根据女方、男方既往有无与配偶的临床妊娠史可分为原发性和继发性不孕症；根据病因，又可分为女性因素不孕症、男性因素不孕症和原因不明不孕症。 # 一、女性因素不孕症女性因素不孕症病因主要包括排卵障碍和盆腔因素两方面，通过影响卵母细胞的生成、发育、排出、运送、受精，或胚胎的早期发育、着床等过程，进而导致不孕。 # （一）排卵障碍常见的原因有：下丘脑性闭经或月经失调，包括：（）进食障碍性闭经；（2）过度肥胖和消瘦、过度运动；（3）特发性低促性腺激素性低性激素性闭经；（4）Kallmann综合征、药物因素等。垂体性闭经或月经失调，包括特发性高催乳素血症、垂体腺瘤、Sheehan综合征、空碟鞍综合征等。 3. 卵巢性闭经或月经失调，包括：（1）早发性卵巢功能不全，由染色体和基因缺陷的遗传因素、自身免疫性疾病、手术和放化疗导致的医源性因素等；（）多囊卵巢综合征，表现为稀发排卵或月经稀发、临床和（或）生化高雄激素血症、代谢紊乱等临床特征；（3）Turner综合征，为45，X及嵌合型染色体异常；（）先天性性腺发育不全；（）功能性卵巢肿瘤，异常分泌雄激素和雌激素的内分泌性肿瘤。其他内分泌疾病，包括先天性肾上腺皮质增生症、Cushing综合征、肾上腺皮质功能减退症、甲状腺功能减退等。 # （二）盆腔因素 # 主要是指：先天性生殖系统畸形：包括苗勒管发育不全等。子宫颈因素：包括子宫颈机能不全、其他子宫颈病变等。3. 子宫体病变：包括子宫内膜病变、子宫肿瘤、宫腔粘连等。输卵管及其周围病变：包括输卵管梗阻、输卵管周围粘连、输卵管积水、盆腔粘连等。 # 5.子宫内膜异位症。 # 二、男性因素不孕症男性因素不孕症主要是由于男性性功能障碍和（或）精液异常所致，后者包括无精子症、少或弱精子症、畸形精子症、单纯性精浆异常。 # （一）无精子症 2\~3 次精液高速离心后沉淀物显微镜检查均未见精子，称无精子症。主要分为两类：原发性无精子症（生精功能障碍性无精子症）和梗阻性无精子症。 # （二）少或弱精子症连续2\~3次的标准精液分析，精子数量或活动力低于参考值下限，为少或弱精子症。根据表现可分为少精子症、弱精子症、少弱精子症和隐匿精子症。隐匿精子症指精液常规检查（使用新鲜标本）未发现精子，但离心后沉淀物检查中可发现精子。 # （三）畸形精子症指正常形态精子的百分率低于参考值下限，推荐使用改良巴氏染色法行精子形态染色。 # （四）单纯性精浆异常表现为精液中精子浓度、活动力、总数和形态正常，但精浆的物理性状、生化性质、细菌内容物异常，多为特发性的，但是与不育的发生缺少足够的证据。常见的导致精液异常的原因有先天性异常、全身性因素、生殖系统病变以及其他因素［3］。 1. 先天性异常：主要是指先天性发育畸形及遗传性疾病。前者常见的有隐睾或睾丸下降不全、先天性输精管精囊缺如、先天性睾丸发育障碍和高促性腺激素性性腺功能减退；后者主要包括染色体核型异常、染色体微缺失、克氏症及嵌合型、唯支持细胞综合征、雄激素受体基因突变和纤毛不动综合征等。 2. 全身性因素：包括疾病相关的常见的内分泌异常，有特发性低促性腺激素性性腺功能减退、Kallmann综合征、高催乳素血症等。免疫性不育目前临床上无明确的诊断标准。其他可能的原因还包括吸烟、过度饮酒、吸毒、环境因素和近期内高热。生殖系统病变：主要包括：（）性交功能障碍和（或）射精功能障碍，如器质性和（或）心理性原因引起勃起不能或不充分、性交频率不足、不射精和逆行射精；（2）继发性睾丸损伤，或医源性损伤；（3）伴有精液参数异常的精索静脉曲张；（）男性附属性腺感染，临床常合并附睾炎、前列腺炎、精囊炎等。 # 三、原因不明不孕症原因不明不孕症是种生育力低下的状态，可能的病因包括隐性子宫输卵管因素、潜在的卵母细胞或精子异常、受精障碍、胚胎发育阻滞、反复胚胎种植失败、免疫性因素等，但应用目前的检查手段无法确定。 # 诊断依据不孕症的各种病因可能同时存在，因此，应根据特定的病史、体格检查、辅助检查结果明确诊断。 # 一、女性因素不孕症 # （一）病史采集主要针对月经情况及相关的影响因素、婚育史、可能影响输卵管通畅度和盆腔环境的高危因素进行询问，初步判断是否存在排卵障碍或盆腔因素可能。（参见文后附表1） # （二）体格检查体格检查包括全身检查和妇科检查。 1. 全身检查：主要是指体格发育及营养状况，如身高、体重、体脂分布特征、嗅觉、第二性征、有无甲状腺肿大、皮肤改变等。 2. 妇科双合诊或三合诊检查：应明确外阴发育、阴毛分布、阴蒂大小、阴道有无异常分泌物；子宫颈是否光滑，有无异常分泌物；子宫位置、大小、形状、质地、活动度；附件区有无增厚、包块和压痛；直肠子宫陷凹及宫骶韧带处有无结节和触痛；下腹有无包块、压痛和反跳痛。 # （三）辅助检查辅助检查需根据病史和体格检查的线索提示进行选择，包括盆腔超声检查、激素检测、输卵管通畅度检查和其他检查。 1. 盆腔超声检查：应作为女性因素不孕症患者的常规检查，推荐使用经阴道超声［4］。检查内容包括：（1）子宫位置、大小、形态、子宫肌层的结构、子宫内膜的厚度和分型： $\textcircled{1}$ 子宫形态或结构异常，提示子宫畸形和发育异常的可能。 $\textcircled{2}$ 子宫壁的占位提示子宫肌瘤或子宫腺肌瘤的可能；占位的大小及与子宫腔的关系，子宫内膜线是否变形或移位，必要时可进行三维超声、MRI或宫腔镜检查。 $\textcircled{3}$ 子宫内膜形态异常或占位提示宫腔粘连、子宫内膜瘢痕化、子宫内膜息肉或黏膜下子宫肌瘤的可能。子宫内膜随卵泡的发育逐渐增厚，在成熟卵泡阶段厚度可达到 $9 \mathrm { m m }$ 。卵泡期的子宫内膜“三线征”清晰，为A型；排卵期的子宫内膜回声增强，“三线”依稀可见，为B型；黄体期的子宫内膜呈高回声征象，为C型。（2）卵巢基础状态的评估： $\textcircled{1}$ 测量卵巢的体积、双侧卵巢内直径 $2 { \sim } 9 \ \mathrm { m m }$ 的窦卵泡计数、优势卵泡的直径。正常双侧卵巢内直径 $2 { \sim } 9 ~ \mathrm { m m }$ 的窦卵泡总数 $^ { \cdot \geqslant 9 }$ 个且单侧均 $^ { < 1 2 }$ 个；1侧或双侧卵巢窦卵泡数≥12个为多囊卵巢的征象；双侧卵巢窦卵泡总数少于5\~7个为卵巢功能减退征象，需要复查并结合其他指标综合判断。 $\textcircled{2}$ 确认卵巢内是否存在异常回声，如存在则需报告其性质、大小、与邻近器官的关系。泥沙样囊液回声提示子宫内膜异位囊肿可能；持续存在或增大的囊性或实性包块提示卵巢肿瘤可能；继发于促排卵周期的包块，需要与卵泡囊肿或黄体鉴别。（3）超声排卵监测：动态监测卵泡发育及排卵情况，并同时进行子宫内膜的动态监测。（4）卵巢外有无异常回声及其性质、形状、大小：卵巢外的腊肠状或串珠状不规则无回声区、内部可见不完全分隔带状强回声提示输卵管积水可能。盆腔积液或包裹性积液提示盆腔粘连可能。此外，还需鉴别输卵管卵巢囊肿、盆腔输卵管脓肿。激素检测：包括血、、催乳素、雌二醇、睾酮、孕酮和促甲状腺素（thyroid stimulatinghormone，TSH），各指标的临床意义不同。（）基础水平反映了卵巢的窦卵泡储备， ${ > } 1 2 \ \mathrm { U } / \mathrm { L }$ 提示卵巢功能减退， ${ \geqslant } 2 5 \mathrm { ~ U } / \mathrm { L }$ 提示卵巢功能不全， ${ \geqslant } 4 0 \mathrm { ~ U / L }$ 提示卵巢功能衰竭， ${ < } 5 \mathrm { ~ U / L }$ 提示血值较低。（2）基础LH水平随卵巢功能减退而逐渐升高；LH/FSH比值 $\geqslant 2$ 提示的可能。（3）基础雌二醇水平一般不高于 $2 9 2 . 8 \ \mathrm { p m o l / L }$ （即 $8 0 \ \mathrm { p g / m l }$ ），升高提示卵巢功能减退可能。卵泡期雌二醇水平随卵泡的生长逐渐升高，卵泡成熟时可达每个卵泡 $1 0 9 8 \mathrm { p m o l } / \mathrm { L }$ （即 $3 0 0 \mathrm { p g / m l }$ ）。（4）如果FSH、LH、雌二醇3种激素的基础水平均偏低，提示低促性腺激素性排卵障碍；如果FSH和LH水平升高，伴雌二醇水平下降，提示高促性腺激素性排卵障碍或卵巢功能减退。（）催乳素水平升高时需要排除干扰因素后复查，必要时行垂体CT或MRI检查排除垂体腺瘤。高催乳素血症伴有月经周期紊乱、闭经、卵泡发育异常、黄体功能不足时，可考虑为不孕症的原因。（）睾酮水平超过医疗机构自己实验室正常值上限的2.0\~2.5倍，提示卵巢或肾上腺存在分泌雄激素的肿瘤可能。（7）黄体期孕酮 ${ > } 9 . 5 1 \ \mathrm { n m o l / L }$ （即 $3 ~ \mathrm { n g / m l }$ ）提示近期有排卵；黄体中期的孕酮水平可反映黄体功能［一般高于 $3 1 . 7 \mathrm { n m o l } / \mathrm { L }$ （即 $1 0 ~ \mathrm { n g / m l }$ ）］，但准确的阈值难以确定。（8）月经周期中期尿LH水平激增间接预示排卵的发生，可动态监测，排卵多出现在LH峰后 $1 { \sim } 2 \mathrm { d }$ 。除上述经典的内分泌指标外，抗苗勒管激素（anti‐Müllerian hormone，AMH）开始逐渐广泛应用于评价卵巢储备，其水平在月经周期的各时期相对稳定，与基础窦卵泡计数有很强的相关性，但由于个体差异较大，目前并没有公认的诊断界值或参考值范围。此外，还需注意应用外源性激素（如口服避孕药、促性腺激素释放激素）、肥胖、低促性腺激素性性腺功能减退可能会影响AMH的检测结果。 3. 输卵管通畅度检查：推荐使用子宫输卵管X线造影作为输卵管通畅度的一线筛查，三维实时超声子宫输卵管造影在一定条件下可以作为诊断依据。造影应在月经、短效口服避孕药使用周期或无排卵周期，阴道流血干净后3\~7 d进行，检查前夫妻避免性生活并排除生殖系统炎症。检查时注意观察宫腔形态，输卵管走行、形态、位置，以及盆腔内造影剂的弥散情况。子宫输卵管造影可以提示宫腔形态异常，如宫腔粘连、宫腔占位和子宫畸形等。输卵管走行僵直、显影中断、造影剂在输卵管内积聚或盆腔弥散欠佳，提示输卵管通畅度异常、梗阻和盆腔粘连的可能；造影剂在输卵管远端膨大积聚提示输卵管积水可能。但需注意子宫输卵管造影属于侵入性操作，因而并不是首选检查，其适于基于男性精液常规分析、盆腔双合诊、排卵监测或治疗性诊断未能明确不孕症病因时的诊断，或拟行人工授精的不孕症患者。 # 4. 其他检查：（）基础体温测定：基础体温测定可作为年轻、试孕阶段、月经失调的女性因素不孕症患者初步的自测方法，可配合其他排卵监测方法同时进行，不能单独作为本周期排卵预测的方法。（）腹腔镜或宫腔镜检查：腹腔镜不作为常规检查，主要适用于有阳性体征而影像学检查无法确定病因，或有其他适应证，或为确立原因不明不孕症诊断的患者。宫腔镜也不属于常规检查，而是用于影像学检查疑似或提示宫腔异常者以进一步明确诊断，可与治疗同时进行。检查应在月经、短效口服避孕药使用周期或无排卵周期，阴道流血干净后3\~7 d进行。（）其他影像学检查：其他影像学检查是指或MRI检查，适用于病史、体格检查和（或）基本辅助检查提示肿瘤或占位性病变等异常的患者，以明确诊断。 # 二、男性因素不孕症 # （一）病史采集男性病史的重点采集内容主要关注性生活情况、婚育史、是否存在可能影响生育能力的全身性疾病、专科疾病或其他危险因素。（参见文后附表2） # （二）体格检查男方体格检查也包含全身检查和生殖系统专科检查两方面。 1. 体格发育及营养状况：包括身高、体重、血压、躯干肢体比例、嗅觉、第二性征（喉结、体毛分布、有无男性乳房女性化等）。生殖系统检查：明确有无包茎或包皮过长；有无尿道下裂、严重阴茎弯曲、瘢痕、硬化斑块、赘生物、溃疡或尿道分泌物；睾丸形状、体积和质地，有无下降不全、异位或回缩；附睾能否触及，有无囊肿、结节及压痛；输精管能否触及，有无中断、增粗、结节及触痛；有无阴囊肿块；有无精索静脉曲张及分级；腹股沟区有无疝、瘢痕或淋巴结肿大；前列腺大小、质地是否均匀、有无结节和压痛；精囊能否触及、有无压痛。 # （三）辅助检查 1. 精液分析：精液分析应作为男性患者的常规检查，需行2\~3次精液分析，以获取基线数据。检查时间为禁欲2\~7 d，每次检查的禁欲时间尽可能恒定。男性的精液性状需要与临床指标结合起来加以分析、理解；无论对于个体或是人群，精液的性状变化较大；因此，其检查结果并不是决定夫妇能否生育的唯一因素，这一参考值范围也只是对男性的生育状态提供参考性指导［5］。低于参考值范围下限的男性并非是绝对不育的［5］。另外，精液质量还存在地区性差异和实验室间的差异，因此，各个实验室应制定自己的参考值范围。（参见文后附表、附表）对于少精子症患者根据精子浓度进行分度，（1）轻中度少精子症：连续2\~3次标准的精液分析，精子浓度在 $5 { \times } 1 0 ^ { 6 } / \mathrm { m l } { \sim } < 1 5 { \times } 1 0 ^ { 6 } / \mathrm { m l }$ 之间；（）严重少精子症：连续2\~3次标准的精液分析，精子浓度在$1 { \times } 1 0 ^ { 6 } / \mathrm { m l } { \sim } { < } 5 { \times } 1 0 ^ { 6 } / \mathrm { m l }$ 之间；（3）极严重少精子症：连续2\~3次标准的精液分析，精子浓度 $< 1 { \times } 1 0 ^ { 6 } / \mathrm { m l }$ ；（4）隐匿精子症：新鲜标本中未观察到精子，但离心后沉淀物检查中可发现精子。表1 男性基础生殖激素水平的临床意义 <table><tr><td>FSH</td><td>LH</td><td>睾酮</td><td>催乳素</td><td>临床意义</td></tr><tr><td>正常</td><td>正常</td><td>正常</td><td>正常</td><td>生精功能正常</td></tr><tr><td>减低</td><td>减低</td><td>减低</td><td>正常</td><td>低促性腺激素性性腺功能减退</td></tr><tr><td>升高或正常</td><td>正常</td><td>正常</td><td>正常</td><td>生精功能障碍a</td></tr><tr><td>升高</td><td>升高</td><td>正常或减低</td><td>正常</td><td>睾丸功能衰竭或高促性腺激素性性腺功能减退</td></tr><tr><td>正常或减低</td><td>正常或减低</td><td>减低</td><td>升高</td><td>分泌催乳素的肿瘤</td></tr></table> 注：a部分生精功能障碍患者可表现为FSH水平正常，但FSH水平升高可明确提示生精功能障碍 2. 激素检测：血清激素检测不是必须项目，如存在以下情况需要测定相关的生殖激素水平：（1）精子浓度低于 $1 0 { \times } 1 0 ^ { 6 } / \mathrm { m l }$ ；（）性功能障碍；（）有其他提示内分泌疾病的临床表现。生殖激素测定应至少包括FSH和睾酮。如睾酮水平降低应复查，并进一步检测LH和催乳素。见表1。生殖系统超声检查：生殖系统检查中有可疑异常发现时可行相关的超声检查，包括前列腺、精囊腺、睾丸、附睾、阴囊内血流、精索等。 # 4. 其他检查：（）性高潮后尿液检查：适用于性高潮后无精液排出或精液量少于 $1 ~ \mathrm { m l }$ 的患者（除外双侧输精管发育不全或有性腺功能减退的临床表现者），以确诊是否存在逆行射精。（）精浆抗精子抗体的测定：考虑是否存在免疫性不育，不作为独立的诊断指标。（3）遗传学筛查：染色体核型分析及Y染色体微缺失检查适用于无精子症或严重少精子症患者、CFTR基因筛查适用于单侧或双侧输精管缺如的无精子症患者，基因筛查适用于疑似综合征的患者。（4）下丘脑‐垂体区域的影像学检查：适用于高催乳素血症及促性腺激素分泌不足的患者。（）诊断性睾丸活检：适用于无精子症患者，以评估睾丸的生精功能、鉴别梗阻性与非梗阻性无精子症。 # 诊断流程不孕症的诊断要点在于病因诊断。对于符合不孕症定义、有影响生育的病史（如月经稀发或闭经，已知或可疑的子宫、卵巢或盆腔病变，期子宫内膜异位症，可疑的男性生育力低下等）、或女方年龄 $\geqslant 3 5$ 岁的夫妇，建议双方同时就诊，分别进行病史采集及体格检查［6］。通过男方精液常规分析、女方盆腔双合诊、超声监测排卵、基础内分泌测定和输卵管通畅度检查，初步评估就诊夫妇的生育能力，明确女性因素（排卵障碍、盆腔因素）、男性因素和原因不明不孕症的病因分类。在此基础上，再结合夫妇特异性的病史和（或）临床表现，进一步选择针对性的辅助检查，完成病因诊断。见图。 # 一、女性因素不孕症 1. 排卵障碍性不孕症：近期心理、进食、体重、环境或生活习惯改变的情况，全身性疾病，药物治疗等有重要的提示意义。月经周期紊乱（周期 $\lvert \geqslant 3 5 \mathrm { ~ d ~ }$ 或 ${ < } 2 6 \mathrm { ~ d ~ } ,$ ）或闭经和排卵功能评估可确定是否存在排卵障碍。对于确诊为排卵障碍者，可结合病史、临床表现及针对性的辅助检查明确病因。盆腔因素不孕症：生殖道、盆腔及腹腔的感染史或手术史，传染病史（如结核、性传播疾病），宫内节育器使用史，孕产史及并发症史等有重要的提示意义。原发疾病的症状（包括盆腹腔疼痛、低热、痛经及伴随症状等）、体征和辅助检查，可确定是否存在盆腔因素。对于存在盆腔因素的患者可通过有针对性的辅助检查（如腹腔镜或宫腔镜检查、CT或MRI检查等）明确病因。 ![](images/0916909a3004a89367c84231ec3ad7a294a14a9861a4f0b5839567d191efdce3.jpg) 图1 不孕症的诊断流程 # 二、男性因素不孕症首先通过病史采集、体格检查明确是否存在男性因素，区分原发性或继发性。再通过精液分析、睾丸组织病理学检查、激素检测、超声检查及其他检查明确病因诊断［7］。 # 三、原因不明不孕症原因不明不孕症属于排除性诊断，精液分析、排卵监测、妇科检查和输卵管通畅性检查未发现异常即可诊断。必要时可施以诊断性腹腔镜检查确诊［6］。对于年轻、卵巢功能正常、不孕时间 $< 3$ 年的原因不明不孕症夫妇，可进行3\~6个周期的夫精宫腔内人工授精，作为治疗性诊断。利益冲突所有作者均声明不存在利益冲突志谢感谢全国余位各级医疗机构函审专家对本指南的指导与支持函审专家名单（按姓氏笔画排序）：丁丽萍（山东省潍坊市妇幼保健院）、马艳萍（云南省第一人民医院）、王卓然（哈尔滨医科大附属第一医院）、王树玉（首都医科大学附属北京市妇产医院）、王恒才（济南市中心医院）、王斌（山东省聊城市人民医院）、王蕊（首都医科大学附属北京天坛医院）、方慧莹（澳门仁伯爵综合医院）、邓晓惠（山东大学齐鲁医院）、卢光琇（中信湘雅生殖与遗传专科医院）、叶虹（重庆市生殖与遗传研究所）、叶碧绿（温州医学院附属第一医院）、田秦杰（中国医学科学院北京协和医院）、丘彦（重庆医科大学附属第一医院）、冯云（上海交通大学医学院附属瑞金医院）、匡延平（上海交通大学医学院附属第九人民医院）、师娟子（陕西省妇幼保健院）、曲文玉（沈阳市妇婴医院）、刚春玲（山东省德州市人民医院）、朱冬沂（山东省临沂市人民医院）、朱桂金（华中科技大学同济医学院附属同济医院）、伍琼芳（江西省妇幼保健院）、全松（南方医科大学南方医院）、庄广伦（中山大学附属第一医院）、刘风华（广东省妇幼保健院）、刘睿智（吉林大学第一医院）、祁秀娟（青岛大学附属医院）、许良智（四川大学华西第二医院）、孙秀芹（济宁医学院附属医院）、孙晓溪（上海集爱遗传与不育诊疗中心）、孙海翔（南京大学医学院附属鼓楼医院）、孙磊（香港养和医院）、纪亚忠（同济大学附属同济医院）、玛依努尔·尼牙孜（新疆维吾尔自治区人民医院）、李大金（复旦大学附属妇产科医院）、李冰（广州妇产科研究所）、李红（苏州市立医院）、李英（山东省菏泽市立医院）、李尚为（四川大学华西第二医院）、李健（厦门市妇幼保健院）、李媛（首都医科大学附属北京朝阳医院）、李慕军（广西医科大学第一附属医院）、连方（山东中医药大学附属医院）、肖红梅（中信湘雅生殖与遗传专科医院）、吴效科（黑龙江中医药大学附属第一医院）、吴瑞芳（北京大学深圳医院）、吴煜（中国福利会国际和平妇幼保健院）、何方方（中国医学科学院北京协和医院）、邹淑花（青岛市妇女儿童医疗保健中心）、沙爱国（厦门大学附属成功医院）、沈浣（北京大学人民医院）、张云山（天津市中心妇产科医院）、张以文（中国医学科学院北京协和医院）、张亦文（山东省威海市妇女儿童医院）、张孝禹（山东省烟台市烟台山医院）、张松英（浙江大学医学院附属邵逸夫医院）、张波（广西壮族自治区妇幼保健院）、张玲（合肥市妇幼保健院）、张菱（济南市妇幼保健院）、陈士岭（南方医科大学南方医院）、陈秀娟（内蒙古医科大学附属医院）、陈贵安（北京大学第三医院）、邵小光（大连市妇产医院）、武学清（山西省妇幼保健院）、林戈（中信湘雅生殖与遗传专科医院）、周从容（贵阳医科大学附属医院）、郑梅玲（山西医科大学第一医院）、郑鹏生（西安交通大学第一附属医院）、赵军招（温州医科大学附属第一医院）、赵君利（宁夏医科大学总医院）、赵晓明（上海交通大学医学院附属仁济医院）、郝翠芳（山东省烟台毓璜顶医院）、钟影（成都市锦江区妇幼保健院）、侯丽辉（黑龙江中医药大学附属第一医院）、姜宏（解放军第一〇五医院）、姚元庆（解放军总医院）、姚康寿（浙江省计划生育科学技术研究所）、党小红（青海省人民医院）、倪亚莉（甘肃省妇幼保健院）、徐仙（宁夏医科大学总医院）、徐永萍（山东大学第二医院）、徐明娟（海军军医大学附属长海医院）、徐素欣（河北医科大学第二医院）、徐耀宏（吉林大学第二医院）、高士友（湖南省妇幼保健院）、黄学锋（温州医科大学附属第一医院）、曹云霞（安徽医科大学）、崔艳国（山东省淄博市妇幼保健院）、鹿群（北京大学人民医院）、章汉旺（华中科技大学同济医学院附属同济医院）、章晓梅（云南省第一人民医院）、曾勇（深圳中山泌尿外科医院）、滕晓明（上海市第一妇婴保健院） # 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DOI: 10.1016/j.fertnstert.2014.12.103. （收稿日期：2019‐04‐18）（本文编辑：沈平虎）附表1 女性病史采集内容 <table><tr><td>类别</td><td>内容说明</td></tr><tr><td>现病史</td><td>不孕年限、性生活状况、避孕方法及使用时间心理、进食、体重改变史</td></tr><tr><td>月经史</td><td>有无发热、盆腹腔疼痛史近期检查、诊疗的经过初潮年龄、周期、经期、经量变化、末次月经时间</td></tr><tr><td>婚育史</td><td>有无痛经及其伴随症状和严重程度、是否进行性加重婚姻情况、孕产史及并发症史</td></tr><tr><td>既往史</td><td>有无盆腔炎症性疾病史、有无盆腔或腹腔手术史有无结核等特殊传染病、性传播疾病史</td></tr><tr><td></td><td>有无甲状腺疾病、自身免疫性疾病等全身性疾病史</td></tr><tr><td></td><td>以及治疗情况有无慢性疾病药物治疗史</td></tr><tr><td></td><td></td></tr><tr><td></td><td></td></tr><tr><td>个人史家族史</td><td>有无过度运动史有无吸烟、酗酒、服用成瘾性药物、吸毒史，职业以及特殊环境、毒物接触史</td></tr></table> 附表2 男性病史采集内容 <table><tr><td>采集项目</td><td></td><td>内容说明</td></tr><tr><td>现病史</td><td colspan="3">不育年限性生活史、性交频率和时间、有无勃起和(或) 射精障碍、曾用过的避孕方法近期不育相关检查及治疗经过、以及未避孕的时间生育史,是否使性伴侣获得妊娠及妊娠结局</td></tr><tr><td>既往史</td><td colspan="3">有无隐睾、青春期延迟或早熟，有无男性乳腺发育、其他先天性发育异常疾病史及相关治疗史，包括性传播疾病、泌尿生殖系统感染、腮腺炎合并睾丸炎、病毒性睾丸炎、慢性呼吸道疾病、肾功能衰竭、肝功能不全、糖尿病、附睾炎、纤维病变、结核、有无放化疗史、有无嗅觉障碍、中线缺陷(腭裂)及其他慢性疾病手术史,包括睾丸手术、腹股沟疝修补术、输精管结扎术、阴囊损伤、睾丸扭转</td></tr><tr><td>个人史</td><td colspan="3">脊柱外伤史职业及习惯，高温、放射和有毒环境暴露史，吸烟、酗酒、吸毒史药物治疗史及药物依赖史，如磺胺类抗生素、合成代谢的类固醇激素、抗肿瘤药物、抗抑郁药、抗精神病类药物、</td></tr><tr><td>家族史</td><td colspan="3">抗高血压药物等特殊饮食史,如长期使用棉籽油等有无近亲婚配，男性家庭成员有无性腺功能减退、隐睾、囊性纤维化</td></tr></table> 附表3 精液质量相关的术语 <table><tr><td>术语</td><td>解释</td></tr><tr><td>无精液症</td><td>没有精液(不射精或逆行射精)</td></tr><tr><td>弱精子症</td><td>前向运动的精子的百分率低于参考值下限</td></tr><tr><td>弱畸精子症</td><td>前向运动和形态正常的精子的百分率</td></tr><tr><td></td><td>均低于参考值下限</td></tr><tr><td>无精子症</td><td>射出的精液中无精子</td></tr><tr><td>隐匿精子症血精症</td><td>新鲜标本中无精子，离心后沉淀物中见精子</td></tr><tr><td>白细胞精子症</td><td>精液中存在红细胞精液中含有的白细胞数量高于正常值下限</td></tr><tr><td>（脓精症）死精子症</td><td></td></tr><tr><td></td><td>精液中精子存活比例低,非运动精子所占比例高于参考值下限</td></tr><tr><td>正常精子症</td><td>精子的总数或浓度a、前向运动和正常形态精子的百分率等于或高于参考值下限</td></tr><tr><td>少弱精子症</td><td>精子的总数或浓度a和前向运动精子的百分率均低于参考值下限</td></tr><tr><td>少弱畸精子症</td><td>精子的总数或浓度前向运动和正常形态精子的百分率均低于参考值下限</td></tr><tr><td>少畸精子症</td><td>精子的总数或浓度"和正常形态精子的百分率均低于参考值下限</td></tr><tr><td>少精子症</td><td>精子的总数或浓度a低于参考值下限</td></tr><tr><td>畸形精子症</td><td>正常形态精子的百分率低于参考值下限</td></tr></table> 注：a推荐使用精子总数，因为浓度是通过总数得出的附表4 WHO精液参数的参考值下限［5］ <table><tr><td>精液参数</td><td>参考值下限(范围)</td></tr><tr><td>精液量(ml)</td><td>≥1.5(1.4~1.7)</td></tr><tr><td>精子总数(10%每次射精)</td><td>≥39(33~46)</td></tr><tr><td>精子浓度(10%ml)</td><td>≥15(12~16)</td></tr><tr><td>精子活动率(PR+NP,%)</td><td>≥40(38~42)</td></tr><tr><td>前向运动精子比率(%)</td><td>≥32(31~34)</td></tr><tr><td>精子存活率(%)</td><td>≥58(55~63)</td></tr><tr><td>正常形态精子比率(%)</td><td>≥4.0(3.0~4.0)</td></tr></table> 注：PR表示前向运动精子；NP表示非前向运动精子 # 2019年8期继续教育题目（单项选择题）： 1.以下哪一项不属于异常妊娠（） A.子宫瘢痕妊娠；B.胚胎停止发育；C.早产；D.生化妊娠2.不孕症分类中不包括以下哪一项（） A.女性因素不孕症；B.男性因素不孕症；C.原因不明不孕症；D.免疫性不孕症 3.以下哪一项属于排卵障碍性不孕症（）双子宫；宫腔粘连；先天性性腺发育不全以下哪一项不属于精液异常（） A.不射精；B.无精子症；C.畸形精子症；D.单纯性精浆异常5.排卵功能检测不包括以下哪一项（）基础体温测定；腹腔镜检查；超声监测；激素测定（继续教育的答题方式及获得学分的方法见插页。答案见下期。）（2019年7期继续教育题目的答案：1.D 2.A 3.E 4.E 5.A）	None	None	None
51023a53b86f47b1a5c2f732dae84a2c	中华医学会	与生育相关的慢性子宫内膜炎诊治专家共识（2025年版）	# 与生育相关的慢性子宫内膜炎诊治专家共识（2025年版）中国优生科学协会女性生殖道疾病诊治分会中华医学会妇产科学分会感染性疾病协作组关键词：慢性子宫内膜炎;专家共识;诊断;治疗 Keywords:chronic endometritis ;expert consensus ;diagnosis ;therapy 中图分类号：R711.33 文献标志码：A 慢性子宫内膜炎(chronic endometritis,CE)是指子宫内膜间质出现浆细胞浸润、充血水肿、密度增加，可伴有腺上皮损伤，子宫内膜上皮与间质发育不同步为主要病理特征的慢性炎症[1-2]。多数CE是由病原体所致的感染性炎症，少数情况下为其他慢性刺激所致。一般认为,CE属于盆腔炎性疾病(pelvic inflammatory disease,PID)的范畴,常因症状轻微、隐匿而被漏诊。近年来,CE对生殖健康的危害，如不孕、反复胚胎种植失败和反复妊娠丢失等备受关注。然而,CE的诊断标准尚未统一，治疗方案有待规范。因此，中国优生科学协会女性生殖道疾病诊治分会和中华医学会妇产科学分会感染性疾病协作组组织专家，经过查阅文献、反复讨论,提取循证证据并形成本共识,旨在帮助妇产科医生提高CE的诊治水平，改善与生育相关慢性子宫内膜炎患者的生育结局。本共识推荐级别及其代表意义。见表1。表1本共识推荐级别及其代表意义 <table><tr><td>推荐级别</td><td>代表意义</td></tr><tr><td>1类</td><td>基于高级别临床研究证据，专家意见高度一致</td></tr><tr><td>2A类</td><td>基于高级别临床研究证据,专家意见基本一致;或基</td></tr><tr><td></td><td>于低级别临床研究证据,专家意见高度一致</td></tr><tr><td>2B类</td><td>基于低级别临床研究证据,专家意见基本一致</td></tr><tr><td>3类</td><td>无论基于何种级别临床研究证据,专家意见明显分歧</td></tr></table> 基金项目：国家重点研发计划（2024YFC2707400）通信作者：薛凤霞，天津医科大学总医院妇产科天津市女性生殖健康与优生重点实验室，天津300052，电子信箱：xuefengxia@tmu.edu.cn;廖秦平,清华大学附属北京清华长庚医院，北京102218,电子信箱:liaoqinping@gmail.com;吕卫国,浙江大学医学院附属妇产科医院,浙江杭州310006,电子信箱：lbwg@zju.edu.cn # 1CE的患病情况及危害由于采用的CE诊断标准及研究人群存在差异，不同研究中报告的CE患病率差异较大。CE的高危因素尚未完全明确,但研究表明，不明原因不孕、反复胚胎种植失败、不明原因反复妊娠丢失、子宫内膜息肉、子宫内膜异位症、其他部位的生殖道感染等与CE的发生存在相关性。 1.1不明原因不孕、反复胚胎种植失败和反复妊娠丢失CE相关研究主要集中在不明原因不孕、反复胚胎种植失败(repeated implantationfailure,RIF)及不明原因反复妊娠丢失(recurrent pregnancy loss,RPL)人群,上述三类人群CE的患病率分别为 $2 . 8 \% { \sim } 5 6 . 8 \% ^ { [ 3 ] }$ $7 . 7 \% \sim 6 6 . 3 \%$ $9 \%$ 2$6 7 . 6 \% ^ { [ 3 , 6 ] }$ 。因CE诊断标准及研究人群差异,上述人群的CE患病率范围较大，本共识针对上述三类人群的患病率进行了Meta分析。共纳入98项研究，其中不孕人群的研究45项（人群总数32644例），CE的合并患病率为 $2 6 . 3 8 \%$ $9 5 \% \mathrm { C I } 2 0 . 9 7 \% { \sim } 3 2 . 1 6 \%$ ；RIF人群的研究36项（人群总数6504例），CE的合并患病率为 $3 6 . 3 2 \%$ （ $9 5 \% \mathrm { C I } \ 3 0 . 7 1 \% \sim$ $4 2 . 1 2 \%$ );RPL人群的研究17项(人群总数3653例)，CE的合并患病率为 $2 9 . 1 9 \% ( 9 5 \% \mathrm { C I } 2 0 . 8 \% \sim 3 9 . 2 9 \% )$ 。有Meta分析将健康女性(个人史及妇科病史正常，或月经规律/内分泌指标正常,或既往有正常孕产史)作为对照组,探讨CE与不良生育结局的关系。共纳入9项研究，结果显示,不孕和RPL患者CE患病率显著高于健康女性$\stackrel { \prime } { O R } = 2 . 9 6 , O R = 3 . 5 9 ) ^ { [ 7 ] }$ 。另有研究表明,合并CE的RIF患者临床妊娠率显著低于不合并CE者[8]。经过抗菌药物治疗后，上述人群的生育结局均能得到不同程度改善[9-10]。故建议对不明原因不孕、RIF和RPL人群进行CE相关检查[1]。 1.2子宫内膜息肉和子宫内膜异位症有Meta分析纳入8项研究,探讨CE与子宫内膜息肉的关系。结果显示，子宫内膜息肉患者CE的患病率为 $2 8 . 7 1 \% { \sim } 9 2 . 5 9 \%$ ,合并患病率为 $5 1 . 3 5 \%$ $9 5 \% \mathrm { C I } 2 7 . 2 4 \% { \sim } 7 5 . 1 3 \%$ ,明显高于无子宫内膜息肉患者( $O R { = } 3 . 0 7$ ${ \geqslant } 3$ 个子宫内膜息肉患者的CE患病率高于单发息肉者( $O R { = } 3 . 4 3$ )[12]。同时,CE还增加子宫内膜息肉切除术后息肉复发的风险[13]。 $3 \% \sim 5 3 \%$ 的子宫内膜异位症患者合并 $\mathrm { C E } ^ { [ 1 4 ] }$ ,子宫内膜异位症患者CE 患病率高于非子宫内膜异位症者( $5 2 . 9 4 \%$ vs. $2 7 . 0 2 \%$ )，同时，CE也增加子宫内膜异位症的患病风险（ $O R { = } 3 . 0 3 7$ [15]。上述研究表明子宫内膜息肉、子宫内膜异位症和CE存在高度相关性，在危害生殖健康方面可能会有相互影响。1.3其他CE与其他部位的生殖道感染关系密切。CE患者的既往生殖道感染史显著多于非CE患者( $2 8 . 5 0 \%$ vs.$1 4 . 1 0 \%$ )[16]。输卵管炎患者CE发生率高[16],输卵管阻塞和输卵管积水者亦然[17-18]。 CE的发生还与经期延长[18]、宫腔粘连[19]、剖宫产瘢痕憩室[20]、流产史及流产或分娩后慢性蜕膜炎[18.21]、妊娠胚物残留[22]等相关。 # 2CE的病原微生物及宫腔菌群既往使用培养法对正常宫腔微生物进行检测,限于培养条件和技术，多数研究无法通过培养获得明确的微生物,因此宫腔曾被认为是无菌的。高通量测序(next genera-tion sequencing,NGS)技术能够检测出整个生境中的微生物，且能够检测低丰度的微生物群，通过NGS发现正常宫腔内有一些微生物存在，这些微生物与正常的子宫内膜组织、子宫内膜周期性的内分泌变化，以及宫腔局部的免疫微环境共同组成了宫腔微生态。目前的研究认为，正常宫腔以乳杆菌为主[23],但宫腔微生物丰度较低，其细菌负荷比阴道低100\~10 000倍[24-25]。使用培养法对CE患者宫腔病原微生物检测发现,最常见的是大肠埃希菌、粪肠球菌、链球菌和葡萄球菌等细菌，占 $5 9 . 7 \%$ ;其次为支原体占 $1 1 . 0 \%$ ;此外还有棒状杆菌、肺炎克雷伯菌、假丝酵母菌等[26-28]。而沙眼衣原体和淋病奈瑟菌检出率很低(分别为 $2 . 8 \%$ 和 $0 . 2 \%$ )[27]。 NGS检测发现，CE宫腔乳杆菌占比降低，非乳杆菌比例上升，且微生物代谢异常，如精氨酸、脯氨酸及视黄醇代谢通路显著上调等[29]。NGS所检测出的宫腔菌群种类繁多,但CE的微生态环境、核心致病菌群并不明确。微生物感染不仅造成子宫内膜炎症和功能受损，并引发一系列局部免疫紊乱，也可能免疫紊乱后发生CE，菌群异常与免疫相互作用，从而导致子宫内膜的容受性发生改变,导致不良生育结局。推荐意见1:CE可导致不良生育结局，对于不明原因不孕、反复胚胎种植失败和反复妊娠丢失者，建议完善CE相关检查(推荐级别:2A类)。推荐意见2：CE的常见致病微生物为细菌感染(推荐级别:2A类)。 # 3CE导致宫腔免疫微环境改变的机制微生物侵入子宫内膜后，免疫细胞在各种细胞因子和趋化因子的作用下到达感染部位，随即进一步释放一系列炎症因子，导致子宫内膜微环境、子宫内膜功能和结构的变化。 3.1正常子宫内膜的免疫微环境子宫内膜的免疫是一个复杂而精密的生物学现象，其免疫微环境在维持生殖功能(如胚胎着床和妊娠保护)与防御病原体入侵之间保持动态平衡。子宫内膜的黏膜免疫分为固有免疫和适应性免疫，对维持女性生殖健康具有关键作用。固有免疫应答包括子宫内膜抵御病原体入侵的机械屏障作用、以巨噬细胞及子宫自然杀伤细胞(uterine natural killer cells,uNK)为主的免疫细胞介导的免疫应答。适应性免疫包括B细胞介导的体液免疫和T细胞介导的细胞免疫[30]。巨噬细胞是一种分布在子宫内膜各层中的免疫细胞，包括M1型和M2型，前者主要分泌促炎性因子[白细胞介素(IL)-1α、IL-1β、IL-6、IL-12、肿瘤坏死因子(TNF)-α、IL-23],参与炎症反应;后者主要通过抑炎因子[IL-10和转化生长因子(TGF)-β]介导免疫耐受和组织重塑[31]。uNK细胞是一群驻留在子宫内膜功能层的免疫耐受细胞，通过诱导T细胞凋亡、抑制免疫应答过度激活、参与妊娠期蜕膜血管生成,促进胚胎着床、滋养细胞的侵蚀和胎盘的形成过程[31-32]。 T细胞主要包括 $\mathrm { C D 4 ^ { + } T }$ 细胞和 $\mathrm { C D 8 ^ { + } T }$ 细胞。根据$\mathrm { C D 4 ^ { + } T }$ 细胞产生的细胞因子不同，可分为辅助性T细胞1(Th1）、辅助性T细胞2(Th2)和调节性T细胞 $\mathrm { ( T r e g ) }$ 。Th1细胞主要分泌IL-1β、IL-6、干扰素(IF $\mathrm { \Delta \ " N } ) { - } \gamma \mathrm { \ 、 T N F - } \alpha$ 发挥促炎作用。Th2细胞主要分泌IL-4、IL-5和IL-10等细胞因子调节子宫内膜对胚胎的免疫耐受，从而有利于胚胎植入和妊娠维持。Treg细胞在母胎免疫耐受的建立和维持中发挥关键作用[3I]。B细胞数量很少,主要分布在子宫内膜基底层[33]。当病原体侵入子宫内膜后,在革兰阴性菌细胞壁成分脂多糖(lipopolysaccharide,LPS)等抗原的刺激下,部分B细胞向子宫内膜间质区迁移、浸润[34],分化成浆细胞,产生IgM、IgA1、IgA2、IgG1和IgG2等免疫球蛋白抗体发挥作用。子宫内膜中以上免疫细胞及其分泌的细胞因子,在免疫调节分子(如雌孕激素)的作用下，与上皮细胞和间质细胞组成子宫内膜的免疫微环境，影响子宫内膜容受性和胚胎着床发育等过程。 3.2CE对免疫和生育的影响及机制CE时免疫细胞分布和功能的变化会引起局部免疫应答异常，影响子宫内膜免疫微环境和母胎界面免疫平衡[35]。 CE时巨噬细胞向M1型极化,M1型细胞数量增加,M1/M2型比例失调,M1型细胞分泌的IL-6、IL-12、IL-23等促炎因子较正常女性子宫内膜显著升高，同时其分泌的TNF- $\mathbf { \nabla } \cdot \mathbf { \alpha } \mathbf { \alpha } \propto$ 和$\mathrm { I F N - } \gamma$ 可进一步诱导Th1介导的免疫应答,对胚胎产生毒性作用[36]。在分泌期及孕早期,CE患者子宫内膜uNK细胞数量减少，不利于母胎免疫耐受的建立，影响受精卵着床[37]。CE发生时,LPS能促进子宫内膜微血管内皮细胞的黏附素E和趋化因子表达增加，诱导B细胞侵入子宫内膜间质及腺体，分化为浆细胞产生免疫球蛋白抗体。RIF合并CE者,其 $\mathrm { I g M } \mathrm { , I g A 1 \mathrm { , I g A 2 \mathrm { , I g G 1 } } }$ 和IgG2表达显著增高,尤其是 $\mathrm { I g } \mathrm { G } 2$ 升高。这些抗体介导的局部免疫应答可能对胚胎植入产生不利影响[34]。 CE 患者分泌期子宫内膜 $\mathrm { C D 8 ^ { + } T }$ 细胞比例升高[38],Th1细胞免疫应答亢进，分泌大量促炎因子IL-1β、IL-6和TNF- $\mathbf { \nabla } \cdot \mathbf { \alpha } \mathbf { \alpha } \propto$ ,促进炎症反应[36.39],Th2及Treg细胞免疫应答受到抑制,抑炎因子IL-10、IL-11、TGF- $\boldsymbol { \cdot } \boldsymbol { \beta }$ 等的表达减少[40],免疫应答向Th1型偏移、Th1/Th2比例增加，这些炎性反应失衡导致母胎免疫耐受失衡，对胚胎产生细胞毒作用，影响胚胎植入。 CE时子宫内膜免疫微环境的变化会干扰妊娠过程，如胎盘血管发育、滋养层细胞侵袭和螺旋动脉重塑，导致RIF、RPL和胎儿生长受限等不良生育结局发生。此外，CE患者的子宫内膜在分泌中期易分化延迟[41-42],改变子宫内膜种植窗，影响子宫内膜容受性，导致受精卵着床失败，引起RIF、RPL。推荐意见：CE导致不良生育结局的机制可能为：引发的炎症反应和局部免疫微环境紊乱，使子宫内膜容受性下降和胚胎着床发育障碍,影响受孕和妊娠维持(推荐级别：3类)。 # 4CE的诊断 CE的诊断需结合患者病史、临床表现、宫腔镜检查和子宫内膜组织病理检查等辅助检查作出诊断。CE患者常合并不明原因不孕、反复胚胎种植失败、不良妊娠史及生殖道感染史。CE多数无明显的临床表现,少数有轻微的非特异性症状,如下腹不适、异常子宫出血(不规则出血、经间期出血、经期延长）、阴道分泌物增多等[1,43]。妇科检查常无阳性发现。辅助检查包括血常规、妇科超声、宫腔镜检查和子宫内膜病理学检查。血常规、妇科超声往往无特异性表现,可用于排除急性感染及其他宫腔异常。宫腔镜检查和子宫内膜病理学检查是重要的辅助检查手段。 4.1宫腔镜检查宫腔镜检查能全面直观地了解宫腔解剖及黏膜情况，在CE诊治中有重要价值。镜下特征不仅能作为诊断依据，而且还能判断子宫内膜炎的严重程度，评估治疗转归。宫腔镜诊断CE目前尚无统一的诊断标准。临床上多使用2019年国际CE标准化工作组提出的CE宫腔镜诊断标准[44],包括以下宫腔镜下特征：(1)草莓征：在弥漫性充血子宫内膜的背景上，可以见到白色点状、散在的腺管开□。(2)子宫内膜局灶性充血：子宫内膜小面积充血。(3)子宫内膜出血点：为局灶性红色区域,边缘清晰且不规则，可能与毛细血管相连。(4)微小息肉(直径 ${ < } 1 \mathrm { m m } ,$ ，具有明显的血管轴,由炎性细胞与小血管和腺体混合而成。(5)子宫内膜间质水肿：指在卵泡期出现子宫内膜不规则增厚和苍白。见图1a\~f。 ![](images/1dd2639bf42463d88c553dc0e7e7021a29f71b6455341a93fd2f7d41d6dde3d5.jpg) 图1慢性子宫内膜炎宫腔镜图像 a.草莓征：在弥散性充血子宫内膜的背景上,可见白色点状、散在的腺管开口;b.子宫内膜局灶性充血：子宫内膜小面积充血;c.子宫内膜出血点：局灶性红色区域,边缘清晰且不规则，可能与毛细血管相连;d.微小息肉(直径 $< 1 \mathrm { m m }$ )：具有明显的血管轴，由炎性细胞与小血管和腺体混合而成;e.子宫内膜大面积充血，合并草莓征;f.子宫内膜水肿,合并微小息肉子宫内膜充血、出血及微小息肉是常见的CE征象，宫腔镜下子宫内膜充血及出血受探宫、扩宫的影响，当需要观察是否存在子宫内膜炎时，宫腔镜检查尽量用外径小的(外径 ${ < } 5 \mathrm { m m }$ )宫腔镜在非探宫和非扩宫情况下进行，对于局灶的子宫内膜异常，应提倡镜下定位活检子宫内膜组织。宫腔镜检查是诊断CE的重要手段，其阴性预测值高达 $9 8 . 8 \% ^ { [ 4 5 ] }$ 。多项宫腔镜特征联合可提高CE诊断的准确率。微小息肉是诊断CE的可靠依据，其敏感度和特异度分别为$54 \%$ 和 $9 9 \%$ ,准确率为 $9 0 \% ^ { [ 4 6 ] }$ ;间质水肿联合子宫内膜充血诊断的准确率为 $9 2 . 7 \% ^ { [ 4 5 ] }$ ;微小息肉、间质水肿、草莓征和（或）子宫内膜充血联合诊断的准确率达 $9 3 . 4 \% \sim$ $9 4 . 7 7 \% ^ { [ 4 5 , 4 7 ] }$ 。另有研究提出结合患者病史和宫腔镜特征赋分后建立宫腔镜评分系统，其敏感度 $6 2 . 8 \%$ ,特异度 $9 1 . 7 \%$ 阳性预测值 $8 8 . 8 \%$ ,阴性预测值 $7 0 . 1 \% ^ { [ 4 8 ] }$ # 4.2病理学检查 4.2.1病理学特征病理学检查是CE的辅助诊断方法。CE的病理特征主要有：子宫内膜间质出现浆细胞浸润、充血水肿、密度增加,可伴有腺上皮损伤,子宫内膜上皮与间质发育不同步。其中，子宫内膜间质浆细胞浸润是CE比较突出的特征。然而,由于浆细胞数量通常较少,并且与间质中的纤维细胞、单核淋巴细胞鉴别困难,常需要借助一些浆细胞生物标志物去识别。CD138在浆细胞膜上表达，免疫组化检测CD138是识别浆细胞常用的方法。但CD138在子宫内膜腺上皮及子宫颈鳞状细胞也有表达,容易造成假阳性。浆细胞特异性核转录因子MUM1可在终末分化阶段活化的浆细胞核显色，可酌情使用CD138/MUM1双染协助识别浆细胞。除关注子宫内膜间质中的浆细胞以外,还应关注子宫内膜间质的其他慢性炎症改变,例如,有无间质密度增加、纤维化、间质水肿、腺上皮损伤及反应性改变、上皮细胞与间质细胞不同步等[49]。 4.2.2结合临床特征进行病理学结果判读CE合并不孕、RIF或RPL的病因病理不尽相同，所以病理检查与病史和宫腔镜检查结合更有临床意义。(1)当宫腔镜和病理检查都提示CE,临床确诊CE。(2)当宫腔镜和病理检查都不支持CE时，临床不诊断CE,患者可能为其他病因导致的不孕或不良生育结局。(3)当病理提示CE,但宫腔镜未提示CE时，临床可以诊断CE,因为宫腔镜检查容易受检查者主观评价和经验的影响，可能发生漏诊。(4)当病理未提示CE，而宫腔镜有CE表现时，临床医生应与病理医生沟通，了解具体病理表现。鉴于宫腔镜下微小息肉联合子宫内膜充血的诊断准确率较高，若患者同时有高危因素和不明原因不孕、RIF、RPL史，临床可以诊断CE,因为子宫内膜取样的方法、位置、深度和月经周期都会影响标本制作和病理结果。可疑CE的患者，宫腔镜检查时尽量不探宫、不扩宫，子宫内膜取样时尽可能定位活检和多点取样相结合。对临床诊断为CE的患者，需给予抗菌药物治疗，有生育需求的患者应在治疗后复查宫腔镜和病理检查。 4.3微生物检测微生物检测方法包括培养法和分子生物学方法,后者又包括聚合酶链反应(polymerase chain re-action,PCR)和高通量测序等。微生物培养不仅能提供客观精确的病因学诊断，而且还能指导临床用药，但假阴性率高，耗时较长，不能及时指导临床治疗。微生物的分子生物学检测可以发现宫腔微生物多样性增加，但核心致病菌群目前仍无法确定，且宫腔取材容易受子宫颈、阴道的污染，临床应用仍受限制。 4.3.1微生物培养对CE致病菌的认识源于子宫内膜微生物培养，其主要微生物为常见细菌和支原体，很少见到沙眼衣原体和淋病奈瑟菌。微生物培养能提供诊断依据并指导抗菌药物治疗，但由于微生物培养基种类有限,部分子宫内膜微生物培养困难,或无法培养,且培养周期长，取材易污染等,该方法对临床的指导价值有限。 4.3.2分子生物学方法PCR仅能针对已知的目标微生物进行检测，对CE的子宫内膜行PCR检测的研究较少。Moreno等[50]对113例CE患者的子宫内膜用PCR方法检测9种常见微生物(大肠埃希菌、肠球菌、链球菌、葡萄球菌等),并与3种诊断方法(宫腔镜检查、病理学检查及微生物培养)进行比较,在3种方法结果均一致的13例样本中(12例3种诊断方法均阳性，1例均阴性),PCR检测的敏感度为$7 5 \%$ ，特异度为 $100 \%$ ，阳性预测值 $100 \%$ ，阴性预测值 $2 5 \%$ 准确率为 $7 6 . 9 2 \%$ 。尚需更多的研究探索使用PCR方法进行CE检测的准确性。高通量测序技术，如16SrRNA测序和宏基因组测序，可以全面检测宫腔内所有微生物,获得细菌相对丰度,有利于鉴别微生物多样性和系统研究宫腔微生态。但目前高通量测序仍未在临床普遍应用，CE的微生态环境、核心致病菌群尚需进一步研究。 CE有多种诊断方法，其优缺点和诊断标准各异，诊断结果差异较大,需要综合考虑。宫腔镜检查结合宫腔镜定位活检后的病理学检查是诊断CE的最佳方法。鉴定CE病原微生物仍较困难,相关技术需要进一步提高。推荐意见1:CE的诊断需结合病史、临床表现、宫腔镜检查和子宫内膜组织病理等辅助检查作出诊断(推荐级别:2A类)。推荐意见2:CE的宫腔镜特征有草莓征、子宫内膜充血、微小息肉和子宫内膜间质水肿,同时出现多项宫腔镜表现可提高诊断准确率。宫腔镜结合病理检查是CE的最佳诊断方法(推荐级别：2B类）。推荐意见3：子宫内膜微生物培养虽阳性率低，但能根据药敏结果指导抗菌药物选择;分子生物学检测方法虽然可提高微生物检测的敏感度，但CE的核心致病菌群尚不明确，临床应用需要进一步探讨(推荐级别:3类)。 # 5CE的治疗 CE多为常见的细菌混合感染，口服抗菌药物是主要治疗方法，且以联合用药居多，可以改善生育结局,但药物的选择、用法、疗程等尚不统一,需要进一步探讨。5.1经验性抗菌药物治疗由于微生物培养和检测的局限性，CE治疗多采用经验性抗菌药物。CE病原体以常见细菌和支原体为主，而非淋病奈瑟菌和衣原体，故常选用多西环素、甲硝唑和环丙沙星等。其中，多西环素具有从细菌到支原体的广泛抗菌谱，是治疗CE的首选药物[28.51-53]。多项研究[28.52]治疗CE的一线方案为：口服多西环素 $1 0 0 \mathrm { m g } , 2$ 次/d,14d,复查未愈者选择二线方案：口服环丙沙星 $2 0 0 { \sim } 5 0 0 \mathrm { m g } , 2$ 次 $/ \mathrm { d } +$ 甲硝唑 $2 5 0 { \sim } 5 0 0 \mathrm { m g } , 2$ 次/d,14d,均获得较高的治愈率。另一项237例CE伴不孕患者的研究,采用基本相同方案(一线仍为多西环素 $1 0 0 \mathrm { m g } , 2$ 次/d,14d,二线方案变为左氧氟沙星 $2 0 0 \mathrm { m g }$ ，2次 $/ \mathrm { d } +$ 甲硝唑$5 0 0 \mathrm { m g }$ ,3次/d,14d)，经过1\~2个周期治疗后总治愈率$8 9 . 0 3 \%$ ,临床妊娠率和活产率也显著提高[53]。另有研究纳入117例RIF合并CE的患者,使用多西环素 $1 0 0 \mathrm { m g } , 2$ 次/d,$1 4 \mathrm { d } +$ 甲硝唑 $5 0 0 \mathrm { m g } , 3$ 次/d,14d,单疗程治愈率为 $7 0 . 9 4 \%$ ，治愈者临床妊娠率、胚胎着床率及活产率均显著升高[54]。也有学者将喹诺酮类 $+$ 硝基咪唑类作为首选方案，分别用氧氟沙星( $4 0 0 \mathrm { m g } , 2$ 次 $/ \mathrm { d } , 1 4 \mathrm { d } ) +$ 甲硝唑( $5 0 0 \mathrm { m g } , 2$ 次/d,14d)和左氧氟沙星 $( 5 0 0 \mathrm { m g } / \mathrm { d } , 1 4 \mathrm { d } ) +$ 替硝唑( $\mathrm { \Omega } \mathrm { [ g / d } , \mathrm { 1 4 d } \mathrm { ) }$ 治疗CE,单疗程治愈率分别为 $73 \%$ 和 $8 9 . 3 \%$ [6,55] 《辅助生殖技术中异常子宫内膜诊疗的中国专家共识》提出,多西环素或氧氟沙星联合甲硝唑可以有效治疗CE并改善生育结局。 5.2针对病原体的抗菌药物治疗针对病原体培养结果用药是最合理的治疗方法。Cicinelli等[56根据CE患者（宫腔镜和病理均证实)的子宫内膜微生物培养结果用药：G菌阳性，口服阿莫西林联合克拉维酸(1g,2次/d,8d); $\mathrm { G } ^ { - }$ 菌阳性，口服环丙沙星( $5 0 0 \mathrm { m g } , 2$ 次/d,10d);若支原体/脲原体阳性，口服交沙霉素( $_ { 1 \mathrm { g } , 2 }$ 次/d,12d),若治疗后复查仍阳性，则口服米诺环素( $1 0 0 \mathrm { m g } , 2$ 次/d,12d);培养阴性者用药方案为：单次肌内注射头孢曲松 $2 5 0 \mathrm { m g + }$ 口服多西环素（ $1 0 0 \mathrm { m g } , 2$ 次 $/ \mathrm { d } , 1 4 \mathrm { d } ) +$ □服甲硝唑( $5 0 0 \mathrm { m g } , 2$ 次/d,14d)。该研究有61例CE伴RIF患者，按上述方案治疗单疗程治愈率 $2 7 . 8 7 \% ( 1 7 / 6 1 )$ ,两个疗程总治愈率为 $5 0 . 8 2 \% \AA \AA 3 1 / 6 1 \AA$ ，三个疗程总治愈率为 $7 5 . 4 1 \% ( 4 6 / 6 1 )$ 。另一项研究采用相同方案，经1\~3个疗程治疗后，CE总治愈率 $8 1 . 2 5 \% ^ { [ 5 7 ] }$ 一项Meta分析[58]研究了796例RIF伴CE患者治疗后的生育结局(2项针对性治疗,3项经验性治疗),结果显示：单疗程抗菌药物治疗后不复查而直接胚胎移植的患者，生育结局无明显改善;复查治愈后再移植的患者较持续CE者的胚胎植入率( $O R { = } 3 . 2 4$ 、临床妊娠率( $O R { = } 4 . 0 2$ 和持续妊娠率( $O R { = } 6 . 8 1$ )均有显著提高，说明抗菌药物治疗可以改善患者生育结局，并且治愈后再助孕对改善预后有重要意义。对于宫腔镜下CE表现显著(如大面积草莓征和微息肉）、或病理检查显示大量浆细胞浸润的患者,提示炎症程度较重，可考虑增加抗菌药物疗程，以提高临床疗效。CE治疗后的复查建议在子宫内膜经过1\~2次更新后进行。疗效评估的主要手段仍是宫腔镜检查结合定点活检行病理检查，有条件的机构推荐微型宫腔镜进行CE的评估，以便于操作且减少损伤。若复查确认CE消退，患者可在后续的月经周期开始备孕或进行胚胎移植。目前尚缺少比较经验性应用抗菌药物和针对性用药疗效的大样本研究。理论上,针对性用药更合理精准,实际上,其治愈率并未优于经验性用药,这可能与微生物培养的局限性和CE多为混合感染有关。治疗效果不佳者可能与服药时间不够、药物不敏感或合并其他病因等有关。治疗后判断治愈的标准、病理复查的间隔和取样方法也会影响治愈率。对于微生物培养阴性的患者,是否用药及如何用药尚无具体方案。而持续性CE患者的用药疗程和途径也有待商榷。此外,CE严重程度与抗菌药物疗程的关系也需要更多循证医学证据支持。 5.3其他治疗方法中西医结合可以提高CE治疗效果。在抗菌药物治疗的基础上，通过辨病辨证辅以中医中药，进行清热活血、理气补虚等，可以降低抗菌药物耐药，改善机体炎症状态[59]。但中医辨证主要依赖个人经验,诊断标准不统一，缺乏高质量大样本随机对照研究支持。针对CE引起的宫腔免疫微环境紊乱问题,有学者发现孕激素能调节母胎界面免疫平衡，避免胎儿被母体排斥，认为孕激素是一种治疗选择[60];泼尼松等免疫调节剂也可改善CE患者的助孕结局[];还有研究发现宫腔灌注富血小板血浆可以改善子宫内膜炎症和容受性[2],上述方法为CE治疗提供了新策略,但安全性和有效性还需大样本研究证实。推荐意见1:CE患者推荐口服抗菌药物治疗，治愈率高，且能改善生育结局(推荐级别：2A类)。推荐意见2：治疗方案可选用多西环素或联合硝基咪唑类药物，也可以选择喹诺酮类联合硝基咪唑类药物。具体疗程可根据CE严重程度决定(推荐级别：2B类）。 # 6结语 CE可导致不良生育结局，其主要机制可能是微生物感染与免疫应答的相互作用。宫腔镜联合病理学检查是诊断CE的最佳方法。对不明原因不孕、RIF或RPL者,宜行CE相关检查,确诊者应合理使用抗菌药物进行治疗。抗菌药物治疗效果不佳者可能为疗程不足或对药物不敏感，可延长抗菌药物治疗时间或结合中医中药等其他治疗方法。虽然此次专家组在CE诊治方面达成一些共识，但有些问题尚需进一步探讨，如CE的发病机制、CE病原学诊断方法的优化、CE的严重程度与抗菌药物疗程、抗菌药物剂量、耐药CE的治疗等。希望妇产科医师及病理医师重视CE,为统一诊断标准、提高疗效提供更多高级别的循证医学证据。利益冲突专家组所有成员均声明不存在利益冲突执笔专家：吕永焕(天津医科大学总医院);薛凤霞(天津医科大学总医院);刘朝晖(首都医科大学附属北京妇产医院);刘从容(北京大学第三医院);张慧英(天津医科大学总医院); 王茜(天津医科大学总医院);闫晔(天津医科大学总医院);张崴(天津中医药大学第二附属医院);廖秦平(清华大学附属北京清华长庚医院);吕卫国(浙江大学医学院附属妇产科医院) 参与共识制定和讨论专家（按姓氏笔画排序）：丁岩(新疆医科大学第一附属医院);马晓欣(中国医科大学附属盛京医院);王玉东(上海交通大学医学院附属国际和平妇幼保健院);王志启(首都医科大学附属北京友谊医院);王沂峰(南方医科大学珠江医院);王建东(首都医科大学北京妇产医院);王悦(河南省人民医院);王晓黎(海南省妇女儿童医学中心);王惠兰(河北医科大学第二医院);王新宇(浙江大学医学院附属第四医院);王颖梅(天津医科大学总医院);冯力民(首都医科大学附属北京天坛医院);田文艳(天津医科大学总医院);刘开江(上海交通大学医学院附属仁济医院）；刘宏伟(四川大学华西第二医院）;刘宏图(中国疾病预防控制中心病毒病预防控制所);刘建华(上海交通大学医学院附属第九人民医院);刘国忠(天津坤如玛丽妇产医院);朱雪琼(温州医科大学附属第二医院);安瑞芳(西安交通大学第一附属医院);孙蓬明(福建省妇幼保健院);刘巍(哈尔滨医科大学附属第二医院);狄文(上海交通大学医学院附属仁济医院);李龙(天津医科大学);陈刚(华中科技大学同济医学院附属同济医院);杨兴升(山东大学齐鲁医院);张师前(山东大学齐鲁医院);陈廷涛(南昌大学);陈芳(潍坊市人民医院);邱丽华(上海交通大学医学院附属仁济医院);汪宏波(华中科技大学同济医学院附属协和医院);汪希鹏(上海交通大学医学院附属新华医院);张岱(北京大学第一医院);张果(北京大学人民医院);张帝开(深圳大学第三附属医院);张茜蒻(天津医科大学总医院);陈晓军(上海市第十人民医院);张晓玲(江西省妇幼保健院);李萍（南京医科大学附属妇产医院);张淑兰(中国医科大学附属盛京医院);李淑霞(天津市中心妇产科医院);张辉(河北医科大学第四医院);李蓉(北京大学第三医院);杨筱凤(西安交通大学第一附属医院);宋殿荣(天津中医药大学第二附属医院);宋静慧(内蒙古医科大学附属医院);宋磊（解放军总医院)；杨毅(中国医学科学院北京协和医学院北京协和医院);杨慧霞(北京大学第一医院);周坚红(浙江大学医学院附属妇产科医院)；郑文欣(美国得克萨斯大学西南医学中心);郑波(北京大学第一医院);郑建华(哈尔滨医科大学附属第一医院);罗海宁(天津市中心妇产科医院);罗新（暨南大学附属第一医院);周颖[中国科学技术大学附属第一医院(安徽省立医院)];胡丽娜(重庆医科大学附属第二医院);郝敏(山西医科大学第二医院);洪颖(南京大学医学院附属鼓楼医院);赵澄泉(美国匹兹堡大学医疗中心);耿力(北京大学第三医院);徐大宝(中南大学湘雅三医院);秦莹莹[山东第一医科大学附属省立医院(山东省立医院)];郭瑞霞(郑州大学第一附属医院);康山(河北医科大学第四医院);隋龙(复旦大学附属妇产科医院);梁旭东(北京大学人民医院);崔满华（吉林大学第二医院）；韩丽萍(郑州大学第一附属医院);谭文华(哈尔滨医科大学附属第二医院);谭布珍(南昌大学第二附属医院);熊正爱(重庆医科大学附属第二医院);樊尚荣(北京大学深圳医院);薛敏(中南大学湘雅三医院);瞿全新(天津市第一中心医院) # 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9242298facc94e8c8cc02d30f5d973d8	中华医学会	中国宫腔镜诊断与手术临床实践指南（2023版）	·临床指南· # 中国宫腔镜诊断与手术临床实践指南（2023 版）中华医学会妇产科学分会妇科内镜学组通信作者：段华，首都医科大学附属北京妇产医院北京妇幼保健院，北京 100006， Email：duanhua@ccmu.edu.cn 【摘要】　宫腔镜手术以其对子宫腔病变定位诊断和精准治疗等优势，被誉为经自然腔道微创手术的“典范”；其在保留子宫、去除病变组织同时，恢复子宫腔形态与功能，实现子宫腔整复手术治疗目的。近年来，随着临床应用的普及开展、手术器械的研发完善、诊疗方法的推陈创新以及围手术期管理的细化规范，使宫腔镜子宫腔整复手术得到了长足发展。2012年“妇科宫腔镜诊治规范”距今已经十余年，为了更好适应当今临床诊疗与发展需求，中华医学会妇产科学分会妇科内镜学组结合国内外最新循证医学证据和我国宫腔镜子宫腔整复手术临床实践，对宫腔镜手术指征、施术前准备、新设备器械的进展、操作要点、术中与术后监护以及手术并发症防治等方面进行了全面更新完善，旨在规范宫腔镜子宫腔整复手术临床应用，提高诊疗效果，造福广大病患。基金项目：国家重点研发计划（2018YFC1004803）宫腔镜是经阴道自然腔道对子宫腔及子宫颈管各类病变进行诊断与微创整复手术的治疗方法，以其直视观察、定位准确、保留器官与保护功能等优势，被誉为子宫腔疾病治疗的“典范”；宫腔镜手术是与开腹手术、经阴道手术和腹腔镜手术并列的妇科手术基本技能。2012年，中华医学会妇产科学分会妇科内镜学组制定发表的“妇科宫腔镜诊治规范”至今已时隔十余年，十余年来，随着宫腔镜子宫腔整复手术临床应用的普及开展、手术器械的研发改良、手术种类的创新拓展以及对围手术期管理的深入细化，使宫腔镜在子宫腔整复手术中的应用得到了进一步发展和完善。结合国内临床应用现状及大量临床研究，对2012年“妇科宫腔镜诊治规范”进行更新完善，以便更好规范宫腔镜子宫腔整复手术的临床应用，提高诊疗效果，惠及广大病患。本指南修订基于近十年国内外相关的循证医学证据结果，参考国际指南并结合我国实际情况，经过多次讨论和修改而制定。指南制定遵循指南研究与评价工具（Appraisal of Guidelines Researchand Evaluation， AGREEⅡ）原则。循证医学等级采用美国预防服务工作组分类系统进行分级。证据等级：Ⅰ级：从至少1个合理设计的随机对照试验中获得的证据。Ⅱ级：从精心设计的队列研究或病例对照分析研究中获得的证据，该研究最好来自1个以上的中心或研究小组；或在干预或不干预下，从多个时间序列获得的证据。在不受干预的试验中产生的重要结果也可以被视为这类证据；或从未随机化的精心设计的对照试验中获得的证据。级：基于临床经验、描述性研究或专家委员会报告的权威人士的意见。推荐等级：A级：基于良好和一致的科学证据，高度确信利明显大于弊；B级：基于有限的或不一致的科学证据，高度确信获益较多或至少中度以上获益较多；C级：基于专家共识，至少中度确信能够有一定的获益［1‑2］。一、宫腔镜诊断与手术的适应证与禁忌证 1. 诊断适应证：（1）各类子宫腔病变所致异常子宫出血的评估；（2）评估不孕症的子宫、子宫颈因素；（）子宫内膜损伤所致宫腔粘连的形态学评估；（4）子宫及下生殖道畸形的分类评估；（5）子宫腔异物及宫内节育器异常的定位评估；（6）各类子宫腔影像学异常的病因评估；（7）子宫内膜癌早期诊断、保留生育功能治疗及随访的评估［3］；（）各类子宫腔手术后的二次探查评估；（9）各类子宫颈及子宫颈管病变的协助诊断；（）顽固性阴道排液的病因检查；（11）幼女阴道异物及占位病变的病因检查。 # 2. 手术适应证：（1）子宫内膜息肉引起各类临床症状；（2）子宫肌瘤影响子宫腔形态并引起相应的临床症状；（）子宫内膜损伤所致宫腔粘连，患者有迫切的生育愿望，或由于粘连导致经血流出受阻；（）子宫及下生殖道畸形影响生育或生理功能；（5）子宫腔异物，包括宫内节育器取出、既往子宫手术残留缝线取出、残留妊娠组织取出等；（）特殊部位妊娠，如妊娠囊位于子宫颈、宫角、剖宫产术后子宫瘢痕部位及子宫肌壁等；（7）剖宫产术后子宫瘢痕憩室（又称剖宫产术后子宫切口缺损）影响生育或生理功能；（8）子宫内膜不典型增生及早期子宫内膜样癌保留生育功能治疗；（9）局灶或囊性子宫腺肌病病灶切除；（10）各类子宫颈管赘生性病变切除；（11）幼女阴道异物、阴道或子宫颈肿瘤活检。 # 3. 禁忌证：（1）绝对禁忌证：严重内、外科合并症不能耐受手术操作。（2）相对禁忌证： $\textcircled{1}$ 盆腔炎症及阴道炎症急性期、或体温 ${ > } 3 7 . 5 \mathrm { ~ } \mathrm { ~ } \mathrm { ~ C ~ }$ ； $\textcircled{2}$ 子宫活跃性大量出血、重度贫血； $\textcircled{3}$ 正常妊娠状态； $\textcircled{4} 3$ 个月内有子宫穿孔史；$\textcircled{5}$ 浸润性子宫颈癌； $\textcircled{6}$ 生殖道结核未经抗结核治疗； $\textcircled{7}$ 子宫腔深度超过 $1 2 \mathrm { { c m } }$ 。 # 二、宫腔镜施术前准备与注意事项 1. 检查项目：宫腔镜施术前需行必要的检查以排除手术禁忌证，包括血常规、阴道分泌物、心电图、传染病系列（乙型肝炎、艾滋病、梅毒等）等，根据病情需要酌情进行盆腔超声等影像学检查。 2. 子宫颈预处理：非妊娠状态的子宫颈管狭窄坚韧、难以扩张，尤其是有子宫颈手术史或绝经期的患者。约一半的宫腔镜手术并发症与困难的子宫颈扩张相关［4］。对于上述子宫颈坚韧、难以扩张的患者进行子宫颈预处理是保障宫腔镜手术成功的关键。子宫颈预处理的方法包括药物预处理、机械预处理及激素类预处理，多中心前瞻性研究证明，前列腺素 $\mathrm { P G F } _ { 2 \alpha }$ 衍生物类如卡前列甲酯栓 $1 ~ \mathrm { m g }$ ，对于子宫颈坚硬患者具有良好的软化效果，可以阴道或直肠给药，简单方便［5‑6（］ Ⅰ级证据，A级推荐）；前列腺素PGE 衍生物米索前列醇也被认为具有子宫颈软化作用，是子宫腔手术中可供选择的子宫颈预处理药物之一。上述药物在使用时应注意如青光眼、哮喘、过敏体质等用药禁忌证［4，7］。机械预处理目前以简易子宫颈扩张棒为主，子宫颈坚硬时有插入失败的风险。雌激素类制剂预处理主要针对绝经期患者，建议在宫腔镜手术前半个月开始用药。证据表明，局部使用普罗雌烯阴道胶丸具有软化子宫颈及阴道组织的作用，局部剂型不通过血液屏障，不影响子宫内膜厚度等［8］。药物预处理对子宫颈扩张困难、置镜疼痛的未生育以及绝经期患者能够有效软化子宫颈组织，显著提高患者满意度［9］。子宫颈预处理的具体方法详见中华医学会妇产科学分会妇科内镜学组年发布的《宫腔镜手术子宫颈预处理临床实践指南》［10］。 3. 子宫肌瘤预处理：对于影响子宫腔形态、体积较大、合并严重贫血的患者提倡酌情使用促性腺激素释放激素激动剂（GnRH‑a）进行术前预处理［11］。GnRH‑a 可通过降低类固醇激素水平、直接抑制肌瘤的细胞增殖、促进肌瘤细胞凋亡、减少瘤体血供等多种机制缩小肌瘤体积，用药3个月，肌瘤体积缩小 $2 0 \% { \sim } 5 0 \% ^ { [ 1 2 ] }$ 。对体积较大的黏膜下肌瘤不仅增加了手术的可行性，同时保障了手术的安全性。随机对照试验证明，0型\~Ⅰ型黏膜下肌瘤接受GnRH‑a预处理后手术时间明显缩短、灌流介质吸收量显著降低［11］。并且，对于合并严重贫血的患者，应用纠正贫血后对于保证手术疗效和手术安全也是至关重要的［13（］ A级推荐）。 4. 膨宫与灌流介质：膨宫与灌流是实施宫腔镜子宫腔整复手术的必备条件。一般情况下，膨宫压力设置为 $8 0 { \sim } 1 0 0 \ \mathrm { m m H g } ( 1 \ \mathrm { m m H g } { = } 0 . 1 3 3 \ \mathrm { k P a } )$ ）或 $\leqslant$ 患者平均动脉压；施术操作前应排空灌流介质连通管道内残存的空气。灌流介质的选择依据手术中使用的电能与非电能系统决定。灌流介质的种类分为非电解质介质（如 $5 \%$ 葡萄糖、 $5 \%$ 甘露醇等）、电解质介质（主要为生理盐水）。目前，国内使用单极电能手术系统时，灌流介质主要为 $5 \%$ 葡萄糖（糖尿病患者可用$5 \%$ 甘露醇）；使用双极电手术系统时，灌流介质常选择生理盐水。需要注意，尽管电解质介质由于含有电解质离子，引起稀释性低钠血症的概率较非电解质介质低［14］，但是，电解质介质过量吸收依然存在体液超负荷及心肺功能衰竭的风险。因此，无论使用电解质还是非电解质灌流介质，手术中均应监测介质的使用量和进入患者体循环的吸收量［15］（Ⅰ级证据，A级推荐）。 # 三、宫腔镜手术设备器械进展近年来，随着光能、电能不同能源形式的研发转化以及对传统手术器械的改良完善，使子宫腔整复手术中可供选择的器械呈现多样化，在一定程度上方便和促进了临床应用，简要介绍如下。 1. 窄带光成像系统（narrow‑band imaging，）：是将氙光源产生的光波进行过滤，筛选波长$4 1 5 \ \mathrm { n m } { \pm } 3 0 \ \mathrm { n m }$ 的蓝光和波长 $5 4 0 ~ \mathrm { n m } { \pm } 3 0 ~ \mathrm { n m }$ 的绿光，增强对黏膜血管网络纹理观察的可视度［16］。在宫腔镜手术中，主要用于对子宫内膜病变如增生性病变及癌变组织血管分布密集部位的观察，对微小病灶组织进行聚焦定位并实施靶向活检及切除治疗［17］。系统评价表明，与普通光成像相比，NBI可明显提高对子宫内膜癌及子宫内膜不典型增生诊断的敏感度［17‑18］（Ⅰ级证据）；对子宫内膜病变识别的特异度能较普通光成像提高 $1 4 . 9 \%$ ，在高危内膜增生的识别方面，其敏感度提高了 $2 0 \% ^ { [ 1 8 ] }$ 。尽管如此，由于 NBI光波对组织的穿透深度仅有 $0 . 1 5 \sim$ $0 . 3 0 \mathrm { n m } ^ { [ 1 9 - 2 0 ] }$ ，因而不能对肥厚内膜及较大病灶深处血管的观察，同时，即使是对子宫内膜表层血管特征的识别，也与施术者的经验和施术技巧有关。 2. 宫腔镜组织旋切系统：目前，高频电能系统仍然是宫腔镜手术的主要能源形式。在此基础上研发的组织旋切系统如 Myosure、IBS 和 Truclear等，其作用原理均是在电能做功的基础上，利用机械旋切实现对病灶组织的切除，粉碎的组织碎屑随灌流介质排出，保持了子宫腔视野的清晰，同时旋切系统粉碎组织时不需要反复进出子宫腔，相对缩短了手术时间，不仅操作简单易学，也在一定程度上降低了灌流介质过量吸收‑体液超负荷综合征的风险［21］。目前组织旋切系统主要应用于已排除恶变的子宫内膜息肉、型型黏膜下肌瘤、残留妊娠组织切除等［14］。使用组织旋切系统需要注意的问题：（1）由于旋切刀头是通过转动粉碎组织，无法电凝止血；（2）粉碎的组织标本细碎影响组织病理学检查，可能存在遗漏癌变组织的风险［22］；（3）旋切刀头与镜体同轴并且隐藏在镜体外鞘之内，无法实现对埋入内膜下方或肌壁内占位病灶的切割，例如对Ⅱ型肌瘤的切除尚缺乏有效的证据支持［14］。激光：激光是较早应用于宫腔镜手术治疗的能源形式之一。临床中使用的激光包括气体激光、掺钕钇铝石榴石（Nd：YAG）激光、半导体激光等［23］。半导体激光是近年来国外研究较多并在临床实际中应用的宫腔镜手术激光，其以 $9 8 0 \mathrm { n m }$ 和$1 ~ 4 7 0 ~ \mathrm { n m }$ 的双波长模式，对病灶组织进行切割的同时产生凝固效应达到止血的效果［24］，其组织效应能够与传统高频电手术相当。在宫腔镜手术中通过半导体激光进行子宫纵隔切开术和子宫内膜息肉切除术是安全有效的，同时也有成功实施黏膜下肌瘤切除术的报道［25］。使用激光作为能源时：（1）需要配备激光设备和激光保护装备；（2）难以获得供组织病理学检查的标本，同样也存在遗漏癌变组织的风险；（）费用相比高频电手术昂贵等。 4. 超细宫腔镜：超细宫腔镜是在传统诊断型宫腔镜镜体外鞘直径 $4 . 5 { \sim } 5 . 5 ~ \mathrm { m m }$ 的基础上，对宫腔镜外鞘进行改良，使外鞘直径缩小、镜体更加纤细，目前临床用于诊断的超细宫腔检查镜外鞘直径 $2 . 7 \sim$ $3 . 1 \mathrm { m m }$ ；附带操作孔道的宫腔检查镜外鞘直径$3 . 8 \mathrm { m m }$ ，内含 $1 . 7 \mathrm { m m }$ 操作孔道，可在诊断的同时用于组织活检、异物取出等［14］。超细手术宫腔电切镜的外鞘直径由传统的 $8 . 5 { \sim } 9 . 0 \ \mathrm { m m } \left( 2 6 { \sim } 2 7 \ \mathrm { F r . } \right)$ ）缩小为 $5 . 3 \ \mathrm { m m } ( \mathrm { 1 6 \ F r . } )$ ），可在无麻醉状态下实施子宫内膜息肉及子宫颈息肉切除手术［26］。超细宫腔镜的优势是在非麻醉状态下更易通过子宫颈管，降低患者在施术操作时的疼痛感。但是，由于：（）无麻醉、在意识清醒状态下施术，患者对疼痛的耐受性可能更低；（2）镜体过细致成像不佳、视野不清；（）微型器械对病灶处理的作用有限，单次手术失败及再次手术的风险增加［27］；因此，在选择使用超细宫腔镜手术时应充分评估手术的可行性。 5. 冷器械：是通过非能量介入方式对组织进行钳夹、分离或剪切等机械操作，尽管使用冷器械无电能源系统介入，但是，由于受机械能做功原理和纤细操作孔道的限制，微型冷器械使用时对病灶组织的钳夹、牵拉及剪切等操作明显受限；对于子宫肌瘤和宫内节育器残留等坚硬组织的钳夹和牵拉，需要通过配置有 $3 { \sim } 4 ~ \mathrm { m m }$ 操作孔道的传统宫腔镜实施手术。与能源系统介导的手术宫腔镜相比，冷器械使用时需要熟悉其工作原理，对于不能完成的手术操作需要及时更换电能手术系统，除此以外，选择冷器械还应客观评估适宜的手术指征、手术操作的可行性，并结合施术者的经验等进行综合评估。 # 四、宫腔镜检查临床应用检查时机的选择：对于月经周期规律的患者，实施宫腔镜检查的最佳时机是月经干净后 $3 \sim$ 7 d（早卵泡期），此时子宫内膜较薄，子宫腔视野相对开阔，便于观察；对于月经周期紊乱的患者，可以安排在任何时候进行检查，但需注意检查前应排除妊娠的可能；对于异常子宫出血的患者，可在出血期间进行检查，明确出血原因并为后续治疗提供依据。需要说明的是，对于急性大量出血的患者是否应立即行宫腔镜检查尚存争议，需要结合患者全身情况及出血原因综合分析，酌情选择［28（］ C级推荐）。传统宫腔镜检查：传统宫腔镜检查对子宫腔形态和病变进行直视观察，已成为子宫腔疾病诊断的经典方法。目前，临床用于诊断的硬管型宫腔镜外鞘直径 $4 . 5 { \sim } 5 . 5 ~ \mathrm { m m }$ ，带有操作孔道的硬管型宫腔镜外鞘直径 $6 . 0 { \sim } 6 . 5 ~ \mathrm { m m }$ ，镜体前视角 $0 { \sim } 3 0 ^ { \circ }$ ，可对子宫腔的全貌进行直视观察与定位活检，明确病变性质并为进一步精准切除病灶、手术治疗奠定基础。阴道内镜检查：阴道内镜检查又称非接触式宫腔镜检査，是指在宫腔镜检査过程中不放置阴道窥具、无需子宫颈钳夹持及扩张子宫颈、也不需要在麻醉状态下完成检查操作。系统评价（纳入项随机对照试验）表明，阴道内镜与传统宫腔镜检查的检查效果无显著差异，但阴道内镜手术时间更短，患者疼痛显著减轻［14］。国内的随机对照试验（ $\scriptstyle n = 4 0 0$ ）证明，阴道内镜检查较传统宫腔镜检查，检查时间、患者疼痛程度均有显著降低，并且阴道内镜检查在术后并发症方面同样显著低于传统宫腔镜检查［29（］ Ⅰ级证据）。阴道内镜技术应用中需要注意的问题：（）镜下寻找、辨别子宫颈外口和进入子宫颈内口尚有一定的技术门槛，施术者经验不足或子宫颈内外口粘连狭窄均有可能导致镜体置入失败；（2）阴道内镜是否增加术后感染也是值得关注的问题，尽管目前尚无相关证据表明阴道内镜技术可能导致术后感染风险的增加，但是仍需强调操作前彻底的阴道消毒以及尽量避免镜体与阴道壁的接触［30］。有鉴于此，目前仍需进行高质量研究以更好地评估阴道内镜技术（大小、角度、刚性柔性）应用于不同类型子宫腔病变诊断的可行性和优势。 4. 门诊或日间宫腔镜治疗：是在门诊进行宫腔镜检查的同时对子宫腔病变部位进行活检或简单的治疗操作，由于是在门诊检查的同时完成治疗，故统称为门诊或日间宫腔镜治疗。近年来，临床为简化手术流程、缩短患者等待住院时间而开展的门诊或日间宫腔镜治疗主要以子宫内膜息肉切除、0型黏膜下肌瘤切除、子宫纵隔切开、宫腔粘连分离、宫腔内残留妊娠组织切除等简单的手术操作为主［31］。与住院实施的宫腔镜手术操作相比，门诊宫腔镜手术在临床应用中存在的问题日渐显现，多中心、随机对照、非劣效性研究（ $\scriptstyle n = 5 0 7$ ）表明，门诊宫腔镜子宫内膜息肉切除的手术失败率高于住院宫腔镜手术，患者对门诊宫腔镜手术的耐受度低于住院宫腔镜手术，门诊宫腔镜手术后仍需再次手术治疗的概率高于住院宫腔镜手术，这与门诊宫腔镜手术使用的微型器械、非能源操作的局限、意识清醒状态下患者的耐受性下降等因素有关［27（］ Ⅰ级证据）。除此以外，由于子宫特殊的解剖学特点和对施术者较高的操作经验要求，也增加了门诊宫腔镜手术的困难。大样本量回顾性研究（ $\scriptstyle n = 3 1 0 5 2$ ）表明，门诊宫腔镜手术失败最常见的原因中疼痛占 $3 2 . 7 \%$ 、子宫颈狭窄占 $4 4 . 3 \%$ 、子宫腔视线不佳占 $4 . 3 \%$ ，门诊宫腔镜手术在绝经后人群中置镜失败的概率也明显高于生育年龄妇女［32］（Ⅱ级证据）。基于现有证据，大规模开展门诊或日间宫腔镜手术应综合考虑影响手术操作的风险因素，对于绝经、子宫颈狭窄、合并严重的全身基础性疾病需要严密进行监测或者对不能在局部麻醉下耐受手术操作的患者、复杂的子宫腔病变，均不建议选择门诊或日间宫腔镜手术。对于符合手术要求的患者，施术前还应充分交代手术失败的可能性、由于疼痛无法耐受手术、病灶切除不全需要二次手术以及严重手术并发症需要转入住院手术室或开腹探查的可能性等［14，27］。此外，鉴于目前在门诊或日间实施的宫腔镜黏膜下肌瘤切除、子宫纵隔切开及宫腔粘连分离等研究多为单中心小样本量研究［31］，仍需大样本量、前瞻性、高质量临床研究证据进一步评价。总之，开展门诊或日间宫腔镜手术应进行详细的病史收集、影像学评估以及对子宫腔病变程度的综合评价预估，最大限度降低手术失败的风险。与此同时，门诊或日间宫腔镜手术必须在具备充分抢救设备及抢救条件的门诊手术室进行、拥有完善的抢救流程、配备专业经验丰富的施术医师和麻醉医师，以保障患者安全为前提［14（］ C级推荐）。五、宫腔镜子宫腔整复手术指征与要点 1. 子宫内膜息肉切除术（hysteroscopicpolypectomy）：是对有症状的子宫内膜息肉诊断与治疗的微创方法。目前，对于有症状的子宫内膜息肉推荐使用宫腔镜从根蒂部完整切除息肉进行组织病理学检查，避免盲视下刮宫术；对绝经后子宫内膜息肉，特别是体积较大或合并子宫出血的患者，不推荐期待观察［33‑34］（A级推荐）。对于无症状的子宫内膜息肉如果存在恶变风险因素如息肉直径 ${ > } 2 \mathrm { c m }$ 、绝经期、伴有代谢综合征、应用他莫昔芬药物等，均建议行息肉切除术［35‑36］（B 级推荐）。对于合并子宫内膜息肉的不孕症患者，息肉切除术后自然妊娠率和辅助生殖治疗成功率均显著增加［37］（Ⅰ级证据）。手术要点与共识：（1）对于有生育要求的子宫内膜息肉患者，手术中应避免损伤基底层子宫内膜；（）对于绝经期及具有恶变风险的子宫内膜息肉患者，手术时应尽可能切除息肉基底部组织，必要时应对息肉周边内膜进行活检。 2. 子宫肌瘤切除术（hysteroscopic）：宫腔镜子宫肌瘤切除术的主要手术指征：（1）0型黏膜下肌瘤；（2）Ⅰ型、Ⅱ型黏膜下肌瘤；（3）部分影响子宫腔形态的Ⅲ型肌瘤。手术要点与共识：（）建议施术前宫腔镜联合B 超检查，通过 STEPW［大小（size）、宫腔部位（topography）、基底宽度占宫壁范围（extension ofthe base）、肌瘤位于肌层的占比（penetration intothe myometrium）、侧壁位置（lateral wall position）］分类系统评估手术的复杂程度、肌瘤完全切除的可能性、手术时间以及发生体液超负荷的风险［38］（Ⅰ级证据，A级推荐）。（2）对于合并严重贫血的患者应进行预处理纠正贫血后再施术。（3）对于肌瘤直径>$4 \mathrm { { c m } }$ 的Ⅱ型黏膜下肌瘤及肌壁间内凸肌瘤应酌情进行施术前GnRH‑a预处理，缩小肌瘤体积，减少肌瘤血供，提高手术安全性。（4）对于有生育要求的肌瘤患者建议使用针状电极在肌瘤凸出表面开窗，通过水压分离使瘤体向子宫腔暴露，便于直视下进行切除或钳夹取出；对于开窗后不能突向子宫腔的肌瘤部分不宜强行向肌壁内深挖，将肌瘤切除至与周围肌壁平齐，肌壁间残留的肌瘤视术后情况酌情二次手术。（）对于有生育要求的多发肌瘤患者，术后个月酌情宫腔镜二次探查评估子宫腔形态并进行相应的备孕指导等处理。 3. 子宫纵隔矫治术（hysteroscopicmytroplasty）：通过宫腔镜切开和（或）切除纵隔组织，恢复子宫腔解剖学形态。手术指征：（1）由于子宫纵隔引起的复发性流产；（2）合并不孕症的子宫纵隔排除其他不孕因素，证据表明，宫腔镜子宫纵隔矫治术能够改善生育结局［39（］ Ⅱ级证据），提高活产率；因此对于有不良孕产史或排除其他因素的不孕症患者，建议酌情手术治疗（B级推荐）。手术要点与共识：（1）子宫纵隔是子宫发育畸形所致的子宫形态学异常，宫腔镜联合腹腔镜是诊断与鉴别诊断的“金标准”方法［40］。（2）宫腔镜联合腹腔镜在手术中不仅能够精准诊断分类、及时发现子宫穿孔和进行及时补救处理，同时，对于合并不孕症的患者还能够明确盆腹腔内其他影响生育的因素并进行同期处理。（）超监护简便、无创伤，但不能直视盆腹腔病灶，不能同时进行子宫穿孔及盆腔共存病灶的处理［41］。（4）无论何种监护方法均应以患者安全作为首选考虑因素，选择何种监护方式应根据患者的具体情况酌情决定。（）宫腔镜纵隔切开或切除至子宫底部时，应注意辨别纵隔组织与子宫肌层组织的分界，避免损伤正常子宫肌壁组织。有限的病例报告报道了子宫纵隔切开或切除术后发生妊娠子宫破裂的病例，考虑与手术损伤子宫肌层组织、术中发生子宫不全穿孔或完全穿孔等因素有关。纵隔切开或切除矫治术后创面愈合需个月的时间，术后个月酌情宫腔镜二次探查确定子宫腔形态并指导患者备孕［42］。 4. 宫腔镜宫腔粘连分离术（hysteroscopicadhesiolysis）：是对由于子宫内膜损伤所致子宫腔形态学破坏实施的子宫腔整复手术。通过宫腔镜直视观察子宫腔形态、内膜损伤程度以及残留子宫内膜分布，是施术前进行评估的首选方法［23，43（］ A级推荐），也是制定个体化手术方案的依据。手术目的：恢复子宫腔解剖学形态及子宫腔容积，治疗相关症状（不孕、疼痛等），预防再粘连形成，促进子宫内膜再生修复，恢复患者生育功能［23，43］。手术指征：（1）有强烈生育愿望的、子宫内膜损伤致宫腔粘连的不孕、月经过少患者；（2）子宫内膜损伤致子宫颈管或宫腔粘连造成的积血、疼痛、闭经及不孕等相关临床症状［44］。手术要点与共识：（1）宫腔粘连分离子宫腔整复手术，是恢复子宫腔解剖学形态的首选治疗方法［23，43］。（2）施术前应进行宫腔镜检查，全面评估子宫腔形态、明确粘连范围与性质、残留内膜多少与分布，制定个体化手术方案与术后综合管理措施［45］。（3）手术中应贯彻切除瘢痕组织、保护残留内膜、恢复子宫腔形态的施术原则［23，43］。（4）手术中酌情选择B超或腹腔镜监护，能够有效减少子宫穿孔并发症的发生［41］；腹腔镜监护可以及时发现并处理子宫穿孔，对盆腹腔存在的疾病和影响生育的因素进行处理。（）预防手术后再粘连是提高手术疗效的重要措施，子宫腔适形支撑球囊通过屏障效应阻隔创面之间的相互贴附，能够降低宫腔粘连分离子宫腔整复手术后再粘连的形成［46‑47］（A级推荐）。（）除了经典的雌孕激素人工周期促进子宫内膜再生修复，目前尚无在临床广为使用的促进子宫内膜再生修复的措施，干细胞、细胞因子及富血小板血浆（PRP）等是近年来尝试使用的促进子宫内膜再生修复的方法，有限的临床证据表明，其对促进子宫内膜再生修复的作用是可行的，但需要多中心、大样本量研究进一步验证、完善［48］。剖宫产术后子宫瘢痕憩室切开术（hysteroscopic repair of cesarean scar diverticulum）：是对剖宫产术后子宫切口愈合缺陷通过宫腔镜治疗的手术方法［49］。手术指征：（1）由于子宫下段愈合缺陷所致异常子宫出血、经药物治疗无效、无再生育要求的患者；（）经影像学精准测量子宫切口缺陷底部距子宫浆膜面的子宫肌层厚度 $\mathrm { \geqslant } 3 ~ \mathrm { m m }$ 。手术要点与共识：（1）施术前应进行影像学与宫腔镜的全面评估，通过精准测量憩室顶端具有足够厚度的肌层组织；（）手术中应切除足够的憩室下方组织，充分引流憩室内潴留的经血，同时，电凝憩室腔炎性内膜组织及增生的血管；（3）建议手术酌情在超声监护下进行［50（］ C级推荐）。剖宫产术后子宫瘢痕妊娠切除术（hysteroscopic resection of cesarean scar pregnancy）：剖宫产术后子宫瘢痕妊娠（CSP）是剖宫产术后远期并发症之一，也是一种特殊类型的异位妊娠，明确诊断后推荐酌情终止妊娠。通过宫腔镜或宫腔镜联合其他方法对CSP进行分型诊断和手术治疗是安全可行的［51］，参照2016年中华医学会《剖宫产术后子宫瘢痕妊娠诊治专家共识》中对CSP的分型标准［52］，通过宫腔镜手术处理CSP应酌情联合B超或腹腔镜，手术指征包括：（1）Ⅰ型、Ⅱ型 CSP；（2）部分未破裂的Ⅲ型CSP。手术要点与共识：（）施术前应进行全面的影像学评估，必要时应选择精准测量妊娠囊与膀胱之间子宫肌层的厚度，明确妊娠组织的范围、血供分布、是否植入肌层等；（2）对Ⅰ型和部分Ⅱ型CSP，宫腔镜联合B超进行妊娠组织切除是安全可行的［53］；（3）对于血供丰富、妊娠囊与膀胱之间子宫肌层菲薄或中断、妊娠组织体积较大的Ⅱ型和Ⅲ型CSP，需要进行充分的施术前准备，通过药物治疗、子宫动脉栓塞或子宫血管阻断等措施进行预处理后再酌情施术；（4）对于需要进行子宫瘢痕部位切除修补的CSP建议联合腹腔镜手术，待宫腔镜切除妊娠组织后，腹腔镜进行子宫瘢痕部位切除修补手术［54‑55］。 7. 子宫腔异物取出术（hysteroscopic removal offoreign body）：是在宫腔镜直视下定位取出残留、嵌顿于宫腔内的异物或妊娠组织。手术指征：（1）宫内节育器残留，包括宫内节育器断裂、部分嵌顿入子宫肌层或被粘连组织包裹等；（2）妊娠组织残留；（3）既往子宫手术缝线暴露。手术要点与共识：（1）宫腔镜取出宫内节育器需根据嵌顿入子宫肌层的程度酌情选择超声或腹腔镜监护；（2）应避免对血流丰富或存在动静脉瘘的妊娠组织即刻实施宫腔镜手术，建议酌情使用药物杀胚或中医药活血化瘀进行预处理后、待血hCG趋于正常、残留妊娠组织缩小以及周围血供不丰富时再酌情处理。六、术中与术后监护宫腔镜子宫腔整复手术特殊的施术环境有别于传统的开放性手术、腹腔镜手术和经阴道手术，由于涉及到膨宫压力与灌流介质，由此可能引起的灌流介质过量吸收‑体液超负荷综合征、气体栓塞以及心肺功能衰竭等致命性手术并发症，严密的术中与术后监护是保障手术安全的必要措施。 1. 生命体征监护：包括呼吸、脉搏、血压、血氧饱和度及心电监护等。 2. 灌流介质监测：依据手术中使用的灌流介质种类进行精确计算及管理使用。主要监测指标为灌流介质负欠量（ $=$ 施术中使用的灌流介质总量-灌流介质流出量）。负欠量是指进入患者体循环的介质量，短时间内灌流介质过快吸收可能在患者体循环特别是末梢循环积聚致使体液超负荷，引发肺水肿与急性左心功能衰竭，对于非电解质介质还有可能引致稀释性低钠血症并由此导致各类临床症状。使用的灌流介质种类不同，发生体液超负荷时的负欠量预警值不同，原则上，当使用非电解质介质时，负欠量一般以 $1 0 0 0 \mathrm { m l }$ 为界，而对于电解质介质，负欠量一般以 $2 5 0 0 \mathrm { m l }$ 为界，超过该数值时应积极采取相关的预防措施、严密监测心肺功能并争取在短时间内结束手术［14］。虽然电解质介质过量吸收所致电解质紊乱的风险相比较非电解质介质低，但是，短时间大量电解质介质进入体循环同样有可能发生体液超负荷的风险，特别是对于患有心血管疾病、肾功能不全以及年长的患者，手术中应由多学科团队（MDT）参与并严密监护灌流介质的负欠量。美国妇产科医师协会和欧洲妇科内镜学会提倡对于疑难复杂的宫腔镜子宫腔整复手术应使用灌流介质自动监测系统，持续动态测量灌流介质的出入量及宫腔内压力，当介质负欠量差值达到预设阈值时即自动停止灌流并报警，以此降低灌流介质过量吸收‑体液超负荷综合征的发生率［14］。腹腔镜与超监护：两者均为宫腔镜子宫腔整复手术常用的监护方法，如何选择需要根据手术的种类、施术者对手术风险的评估以及患者的具体情况决定，具体选择参考上文各类手术方式中的专家观点。术后监护：（）迟发性电解质紊乱稀释性低钠血症，手术后除了生命体征监测以外，最重要的是由于灌流介质过量吸收引起的体液超负荷综合征。对手术中灌流介质用量较多、特别是使用非电解质介质时，术后应酌情检测血电解质离子，并以此为依据，选择静脉补液种类并纠正电解质紊乱。（2）酌情使用抗生素：对于有感染高危因素的患者建议酌情选择抗生素预防感染发生。 # 七、手术并发症预防与处理 1. 子宫穿孔：子宫穿孔是宫腔镜子宫腔整复手术的常见并发症，发生率文献报道不一。子宫穿孔的风险因素包括：（）子宫颈狭窄及子宫颈扩张困难，约 $50 \%$ 的穿孔与此有关；（2）对子宫肌壁切割或破坏过深，特别是子宫腔压力过高时，子宫肌壁厚度变薄；（3）子宫腔形态改变如较大的黏膜下肌瘤、宫腔粘连及子宫畸形等［56］。处理：（1）立即停止手术，明确穿孔部位，并检查是否存在邻近器官损伤并进行相应处理；（2）对于穿孔范围小、无活动性出血和器官损伤者，可给予收缩子宫、止血药物等对症处理；如不能奏效，应酌情放置子宫腔适形球囊压迫止血；（3）对于穿孔合并盆腹腔器官损伤、大出血等，应及时腹腔镜或开腹手术探查，修补损伤的器官并进行相应处理。预防：（）施术前应评估子宫颈状态，对于既往有子宫颈手术史、绝经期、无阴道分娩史以及子宫颈发育不良等特殊人群，应积极进行子宫颈预处理；（）避免暴力扩宫；（）对于穿孔高风险的手术如子宫肌瘤、子宫内膜损伤所致宫腔粘连、子宫畸形等的手术，建议酌情联合 B 超监护或腹腔镜监护，避免对子宫肌层破坏过深，及时发现和避免子宫穿孔发生［57‑59］。大出血：出血量超过 $5 0 0 \mathrm { m l }$ 被视为手术严重并发症之一［60‑61］，术中或术后大出血的原因：（1）子宫肌层破坏过深，如子宫穿孔、Ⅱ型或Ⅲ型黏膜下肌瘤切除、严重宫腔粘连或子宫畸形矫治手术等；（）子宫颈撕裂，与子宫颈预处理不全、暴力扩宫有关；（3）妊娠相关疾病的子宫腔手术，如合并动静脉瘘的胎盘植入、子宫颈妊娠、CSP等［62］；（4）凝血功能障碍性疾病，如凝血因子缺乏、严重肾功能衰竭透析患者等。处理：（1）子宫腔适形球囊压迫是针对手术中或手术后急性大出血的有效止血措施［63］；（2）酌情选择收缩子宫平滑肌的药物，如前列腺素衍生物类药物［6］、缩宫素、垂体后叶素等；（3）上述方法不能奏效时酌情选择子宫动脉栓塞或子宫切除术［14］。预防：对于高危出血风险的手术应充分进行施术前评估，针对具体风险因素制定应对预案，如针对子宫肌瘤应酌情进行预处理，针对子宫颈坚硬的患者提倡子宫颈预处理，对妊娠相关疾病的手术也应充分术前评估、制定预防术中大出血的预案后再实施手术。 3. 灌流介质过量吸收‑体液超负荷综合征：是宫腔镜子宫腔整复手术特有的严重并发症之一，诱发原因可能与下列因素有关：（1）膨宫压力设置过高［64‑65］；（2）手术时间过长；（3）子宫腔创面过大，如子宫内膜损伤致重度宫腔粘连、Ⅱ型及肌壁间肌瘤等手术，对子宫肌壁破坏过深、血窦广泛开放，致使灌流介质大量、快速进入患者体循环。主要临床表现以急性左心功能衰竭、肺水肿等循环障碍为主的一系列症状体征，诊断治疗不及时还可能出现脑水肿、抽搐、心肺功能衰竭甚至死亡。处理：（1）一经确诊应立即停止手术，动态监测血流动力学变化。（）吸氧、利尿、纠正心肺功能、警惕肺水肿、脑水肿的发生。（）纠正电解质紊乱，发生稀释性低钠血症时，计算补钠量，依据下列公式：所需补钠量 ${ } = { }$ （正常血钠值-测得血钠值） $\times 5 2 \% \times$ 体重 $( \mathrm { k g } ) ^ { [ 6 6 ] }$ 。将计算所得补钠量换算为 $3 \%$ 或 $5 \%$ NaCl溶液，开始的补钠量按照计算总量的1/3补给，动态监测尿量及血清电解质变化，酌情增减；切忌快速、高浓度补钠，以免造成暂时性脑内低渗透压状态，使脑组织间的液体转移到血管内，致使脑组织脱水，引发大脑损伤的风险［67］。（4）以生理盐水作为灌流介质时，虽然发生低钠血症的风险降低，但介质吸收过量仍有体液超负荷的风险［65］，此时，频繁使用利尿剂虽有助于改善体液超负荷，但有可能促发低钠血症，此时，需要启动MDT协作诊疗或重症监护病房（ICU）进行全面的体液平衡管理。预防：（）严密监护手术中灌流介质出、入量与负欠量，适时给予利尿剂，静脉补液以含电解质离子的介质为主；（2）避免对子宫肌壁切割过深，对较大或合并贫血的Ⅱ型黏膜下肌瘤或肌壁间肌瘤施术前应进行预处理；（3）避免过高的子宫腔压力，般情况下子宫腔压力设置 ${ \leqslant } 1 0 0 \ \mathrm { m m H } \mathrm { g }$ 或 $\leqslant$ 患者平均动脉压［67］；（）控制手术时间；（）对于年长患者、特别是合并心血管疾病、肾功能衰竭等合并症时，更应严密监测体循环阻力指数（SVRI）、电解质及血浆渗透压；（6）酌情建立灌流介质动态监测控制体系，手术团队应及时报告灌流介质使用量，达到预设阈值时应启动报警提示。气体栓塞：气体栓塞是罕见但严重的并发症，致死率高达 $6 9 . 2 \% ^ { [ 6 6 ] }$ 。诱发因素：（1）手术中宫腔镜反复进出子宫腔，空气经过子宫腔创面开放的血管进入静脉循环；（2）灌流介质管道内的气体排出不全或进入空气；（3）子宫腔压力设置过高等。气体栓塞发病突然，进展快，早期症状包括呼气末$\mathrm { C O } _ { 2 }$ 分压（ $\mathrm { P C O } _ { 2 }$ ）下降、心动过缓、血氧分压（ ${ \displaystyle \mathrm { P O } _ { 2 } }$ ）下降，心前区闻及大水轮音等；继之血流阻力增加、心输出量减少，患者出现紫绀、低血压、呼吸急促、心肺功能衰竭而死亡。处理：气体栓塞一旦发生应立即停止操作，组织进行抢救治疗。（）将患者置于左侧卧位及头低臀高位，可促进空气或气体向右心室尖部漂移，减少右心室流出道梗阻［65］；（）正压吸氧，纠正心肺功能衰竭；（3）输入生理盐水促进血液循环，放置中心静脉导管，监测心肺动脉压［62］。预防：（）施术中应避免头低臀高体位［67］；（）施术前排空灌流介质连通管道内的气体；（）进行子宫颈预处理，避免粗暴扩宫致子宫颈裂伤；（）避免设置过高的子宫腔压力；（）尽量减少手术过程中器械反复进出子宫腔形成“虹吸”效应致使空气进入子宫腔［62］；（6）重视气体栓塞的早期临床表现与识别，加强术中监护与急救处理。宫腔镜子宫腔整复手术严重并发症的抢救流程见图1。 5. 感染：目前尚无高质量的证据证明预防性使用抗生素能有效防止盆腔感染的发生。但如果宫腔镜检查或手术后发生感染致盆腔脓肿时则临床后果严重。因此，施术前需严格掌握手术适应证，生殖系统感染急性期禁忌手术；对于有感染高危因素的患者建议使用抗生素预防感染［68］。 ![](images/aa3eed244ddcee0baa5ab2df8351951f6395cd1ca3b1caccf609d1d67eec947d.jpg) 需要强调的是，宫腔镜子宫腔整复手术是保留子宫和保护生育功能的手术，施术前应充分评估手术的可行性、安全性与治疗效果；治疗失败或症状复发可酌情选择后续治疗，包括二次宫腔镜手术、药物治疗或子宫切除手术；因此，施术前需要重视与患者的告知及知情同意，切忌违反患者意愿强制施术。 # 参与本指南编写的专家：顾问：郎景和（中国医学科学院北京协和医院）、夏恩兰（首都医科大学附属复兴医院）执笔专家：段华（首都医科大学附属北京妇产医院）、张颖（首都医科大学附属北京妇产医院）、郭银树（首都医科大学附属北京妇产医院）通讯专家：段华（首都医科大学附属北京妇产医院）秘书：李博涵（首都医科大学附属北京妇产医院）参加讨论专家（按照姓氏汉语拼音顺序排列）：白文佩（首都医科大学附属北京世纪坛医院）、蔡云朗（东南大学附属中大医院）、陈红（武汉大学中南医院）、池余刚（重庆市妇幼保健院）、狄文（上海交通大学医学院附属仁济医院）、段华（首都医科大学附属北京妇产医院）、冯云（云南省第一人民医院）、高婷（中国科学技术大学附属第一医院安徽省立医院）、郭银树（首都医科大学附属北京妇产医院）、郝敏（山西医科大学第二医院）、花茂芳（连云港市第三人民医院）、金力（中国医学科学院北京协和医院）、李立安（解放军总医院第一医学中心）、李小毛（中山大学附属第三医院）、林凤（温州医科大学附属第一医院）、林元（福建省妇幼保健院）、凌斌（中日友好医院）、刘木彪（珠海市人民医院）、卢美松（哈尔滨医科大学附属第一医院）、罗喜平（广东省妇幼保健院）、马德美（山东大学第二医院）、孟跃进（郑州大学第二附属医院）、牛菊敏（沈阳市妇婴医院）、彭超（北京大学第一医院）、邱剑萍（南京医科大学附属苏州医院）、任琛琛（郑州大学第三附属医院）、荣风年（山东第一医科大学第一附属医院）、石彬（河北医科大学第二医院）、隋龙（复旦大学附属妇产科医院）、孙静（上海市第一妇婴保健院）、谭欣（四川大学华西第二医院）、王敏（中国医科大学附属盛京医院）、王素敏（南京医科大附属妇产医院）、王武亮（郑州大学第二附属医院）、王晓辉（江西省景德镇市第二医院）、王晓雷（山东省威海市妇幼保健院）、王晓黎（海南省妇女儿童医学中心）、王沂峰（南方医科大学珠江医院）、谢晓英（赣南医学院第一附属医院）、徐大宝（中南大学湘雅三医院）、许泓（中国福利会国际和平妇幼保健院）、薛翔（西安交通大学第二附属医院）、杨雯（解放军总医院第一医学中心）、杨欣（北京大学人民医院）、姚书忠（中山大学附属第一医院）、叶海燕（广东省人民医院）、易萍（重庆医科大学附属第三医院）、应小燕（南京医科大学第二附属医院）、袁瑞（重庆医科大学附属第一医院）、张峰（山东省临沂市妇幼保健院）、张松英（浙江大学医学院附属邵逸夫医院）、张晓玲（江西省妇幼保健院）、张信美（浙江大学医学院附属妇产科医院）、张颖（首都医科大学附属北京妇产医院）利益冲突所有作者声明无利益冲突 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[68] 夏恩兰. 宫腔镜术后子宫腔感染的防治及预后[J].中国实用妇科与产科杂志, 2012, 28(6):409‑412. # 《中华妇产科杂志》专业领域内公知公认的缩略语直接使用的说明为了更方便、简洁地使用本专业领域内的名词术语及其缩略语，本刊特公布公知公认的部分缩略语，作者在撰写文章时可以直接使用以下缩略语，而不必再注明其全称。未公布的名词术语，请按照如下规则进行缩写：原词过长（一般为超过 4 个汉字）且在文中多次出现者，若为中文缩略语可于第1次出现时写出全称，在括号内写出缩略语，如：卵巢上皮性癌（卵巢癌）；若为外文缩略语可于第1次出现时写出中文全称，在括号内写出外文全称及其缩略语，如：体重指数（body mass index，BMI）。本说明从2023年第1期开始执行。以下为可直接使用的缩略语，括号内为缩略语的全称。 # 一、英文缩略语 AFP（甲胎蛋白）；AIDS（获得性免疫缺陷综合征）；B超（B型超声）；CA（癌相关抗原，如： $\mathrm { C A } _ { 1 2 5 }$ ）；CD（分化群，如：$\mathrm { C D _ { 4 } ^ { + } }$ T淋巴细胞）；cDNA（互补DNA）；CT（计算机体层摄影）；（弥漫性血管内凝血）；（酶联免疫吸附试验）；ER（雌激素受体）；FSH（卵泡刺激素）； $\mathrm { H B c A g }$ （乙型肝炎病毒核心抗原）； $\mathrm { H B e A g }$ （乙型肝炎病毒 e 抗原）；HBsAg（乙型肝炎病毒表面抗原）； $\mathrm { h C G }$ （人绒毛膜促性腺激素）；HE染色（苏木精‑伊红染色）；综合征（溶血、肝酶升高和低血小板计数综合征）；HIV（人类免疫缺陷病毒）；HPV（人乳头状瘤病毒）；ICU（重症监护病房）；Ig（免疫球蛋白，如：IgA、IgM）；LH（黄体生成素）；MRI（磁共振成像）；mRNA（信使）；（聚合酶链反应）；（孕激素受体）；法（链霉菌抗生物素蛋白‑过氧化物酶连接法）；TORCH（弓形体病、其他病毒、风疹、巨细胞病毒、单纯疱疹病毒）。 # 二、中文缩略语彩超（彩色多普勒超声）；查体（体格检查）；电镜（电子显微镜）；放疗（放射治疗）；肛查（肛门检查）；光镜（光学显微镜）；化疗（化学药物治疗）；活检（活组织检查）；免疫组化（免疫组织化学）；胸片（胸部X线片）；诊刮（诊断性刮宫）。	None	None	None
b26a4f4690b04611b7b65857e286591e	中华医学会	中国年轻乳腺癌诊疗专家共识（2022）	·标准与规范· # 中国年轻乳腺癌诊疗专家共识（2022）中国临床肿瘤学会乳腺癌专家委员会中国抗癌协会乳腺癌专业委员会中华医学会外科学分会乳腺外科学组通信作者：刘强，中山大学附属孙逸仙纪念医院，广州 510120，Email：liuq77@mail.sysu.edu.cn 【摘要】　年轻乳腺癌患者具有相对高危的临床病理特征和较差的预后，存在独特的医疗和心理社会需求，需要在临床上特别关注。近年来，年轻乳腺癌在全球范围内逐渐增多，已有多个国际组织针对其管理形成一定共识。中国年轻乳腺癌比例更高、发病年龄更低，面临的临床问题也有所不同，不少问题尚缺乏明确的循证医学证据和指南。基于中国年轻乳腺癌患者的特点和诊疗现状，100多位来自外科、内科、放疗科、妇科和生殖科的专家们针对BRCA1/2基因胚系突变、化疗、内分泌治疗、生育力保护和妇科问题等热点进行了深入探讨，以国内外临床研究进展为基础，结合中国的临床实践，形成了《中国年轻乳腺癌诊疗专家共识（版）》，旨在规范和优化中国年轻乳腺癌的诊疗，促进相关临床研究的开展，以进一步改善年轻乳腺癌患者的预后和生活质量。【关键词】　乳腺肿瘤；　年轻；　共识 # Expert consensus on the diagnosis and treatment of young breast cancer in China (2022 Edition) Chinese Society of Clinical Oncology, Experts Committee on Breast Cancer; China Anti-Cancer Association, the Society of Breast Cancer; Chinese Medical Association, Chinese Society of Breast Surgery Corresponding author: Liu Qiang, Sun Yat‑sen Memorial Hospital, Sun Yat‑sen University, Guangzhou 510120,China, Email:liuq77@mail.sysu.edu.cn 【Abstract】 Young breast cancer patients are associated with high‑risk clinicopathological features and poor prognosis, leading to unique medical and psychosocial needs and calling for special attention in clinical practice. In recent years, the incidence of young breast cancer has gradually increased worldwide, and several international committees have formed some consensuses on young breast cancer management. In China, there is a higher proportion of young breast cancer patients with younger age of onset and different clinical problems, lacking clear evidence‑based medicine and guidelines. Based on the characteristics of young breast cancer and present situation of diagnosis and treatment in China, more than 100 experts from multiple specialities including surgery, internal medicine, radiotherapy, gynecology and reproduction had a deep discussion around the hot topics in young breast cancer, involving germline BRCA1/2 gene mutation, chemotherapy, endocrine therapy, fertility preservation and gynecological conditions, and formulated the 'Expert consensus on the diagnosis and treatment of young breast cancer in China (2022 Edition)'. This consensus is made according to the progress of clinical research worldwide and combined with the clinical practice in China, with the aims of standardizing and optimizing the diagnosis and treatment of young breast cancer in China, promoting the development of relevant clinical research, and further improving the prognosis and quality of life of young breast cancer patients. 【Key words】 Breast neoplasms; Young; Consensus 随着生活方式的改变和筛查诊断技术的提高，年轻乳腺癌患者在全球有逐渐增多的趋势［1‑2］。年轻乳腺癌患者有着独特的医疗和心理社会需求，包括生育、卵巢保护、生活质量等，需要在临床上加以特殊关注。对年轻乳腺癌患者的管理，欧洲肿瘤内科学会（European Society for Medical Oncology，ESMO）、欧洲乳腺癌专科学会（European Society ofBreast Cancer Specialists，EUSOMA）、美国临床肿瘤学会（American Society of Clinical Oncology，ASCO）等多个组织已形成相关共识［3‑5］。然而，与欧美不同的是，中国的年轻乳腺癌比例明显更高，发病年龄更低，面临的临床诊疗问题也有所区别，不少情况都缺乏明确的临床证据和指引。为规范和优化中国年轻女性乳腺癌的诊疗，中国年轻乳腺癌（Young Breast Cancer in China，YBCC）专家组就临床诊疗相关问题进行了深入探讨，并以专家投票形式形成诊疗专家共识。 YBCC专家组由来自中国乳腺外科、肿瘤内科、放疗科、妇科、生殖科的137名专家组成，旨在规范患者的临床诊疗，促进基础和临床研究的开展，并改善其预后和生活质量。共识投票前，YBCC 专家组中 42 位乳腺领域专家结合特点，就相关临床重点关注问题进行了次会议探讨，并最终选定 50 个投票问题。第一届共识大会于年月日在广州举行，大会邀请了国内外多位专家对YBCC的相关问题举办讲座及讨论，随后专家组就诊疗相关的50个问题进行了讨论和投票，并在许多问题上形成了共识，其中有两个问题因不同专家理解的差异可能引起歧义暂时搁置，与会专家针对个问题的投票结果详见附录（查看附录请扫描本文首页二维码）。 # 一、YBCC概况 2020年，乳腺癌已经成为全球最常见的恶性肿瘤，也是全球女性发病率和死亡率最高的恶性肿瘤。在中国，乳腺癌是女性恶性肿瘤发病率之首，2020年新发病例达 42万［6］。乳腺癌患者的年龄分布在东西方存在明显差异。美国乳腺癌的中位发病年龄为岁， ${ < } 4 0$ 岁的乳腺癌仅占所有乳腺癌的 $4 . 9 \%$ ；而在中国等东亚国家，乳腺癌的中位发病年龄约为 45\~49岁［7‑8］。复旦大学肿瘤医院在2007—2020年登记的66 201例乳腺癌患者的数据显示，我国 ${ < } 4 0$ 岁乳腺癌患者占所有乳腺癌的$1 4 . 9 \%$ ， ${ < } 3 5$ 岁者占 $6 . 5 \% ^ { [ 9 ] }$ 。此外，复旦大学肿瘤医院登记的 ${ < } 4 0$ 岁新诊断乳腺癌患者占所有新诊断患者的比例有逐年增加的趋势，由1999年的 $1 1 . 4 \%$ 上升至年的 $1 6 . 4 \% ^ { [ 1 0 ] }$ 。而中山大学孙逸仙纪念医院的 39 378 例早期乳腺癌多中心数据库则显示， $\leqslant 4 0$ 岁乳腺癌患者由2015年的 $1 7 . 7 \%$ 增长至2021 年的 $2 2 . 3 \%$ ，占全部患者的 $1 9 . 9 \%$ ， $\leqslant 3 5$ 岁者占$9 . 4 \%$ 。关于的发病趋势， $45 \%$ 的专家组基于临床经验认为年轻乳腺癌的发病率近年有上升趋势，而另外 $43 \%$ 的专家认为近年来年轻乳腺癌发病人数有所增加，但主要是由于整体乳腺癌的发病率在升高，年轻患者总体乳腺癌的比例并没有明显增高。目前国际上对年轻乳腺癌的年龄定义尚未统一，有的研究界定在岁，而更多的研究界定在40岁［11］。考虑到40岁以下乳腺癌患者面临较差的乳腺癌特异性生存率、生育力保护和妊娠等特殊问题，国际年轻乳腺癌共识专家组（Breast Cancer in，）将岁以下患者定义为年轻乳腺癌［3‑4］。由于中国乳腺癌患者的平均发病年龄为 45\~49 岁， $62 \%$ 的YBCC专家认为应将40岁以下定义为年轻乳腺癌，而 $32 \%$ 和 $6 \%$ 的YBCC专家则分别认为应定为岁和岁以下，因此专家组将岁作为年轻乳腺癌的界限取得共识。与年长患者相比，年轻乳腺癌患者复发转移风险较高、总体生存较差。中国 ${ < } 4 0$ 岁的乳腺癌患者年无病生存率和年总生存率分别为 $8 5 . 5 \%$ 和$8 5 . 0 \%$ ，而40\~49岁患者分别为 $8 8 . 1 \%$ 和 $8 8 . 7 \% ^ { [ 9 ] }$ 。这种差异可能与年轻乳腺癌较强的侵袭性生物学行为相关，研究显示，年轻乳腺癌的组织学分级更高，Ki‑67高表达比例更高，脉管浸润的比例更高，三阴性乳腺癌比例更高。因此年轻乳腺癌倾向于具有更高复发风险的特征［12‑14］。此外，约 $70 \%$ 的乳腺癌患者为激素受体（hormone receptor，HR）阳性［10］，年轻患者由于卵巢功能活跃导致体内雌激素水平较高，可能刺激 HR 阳性的乳腺癌细胞生长，从而与年长患者相比有更高的复发风险。2003年国际乳腺癌研究组（IBCSG）发起的 SOFT/TEXT研究结果显示，绝经前中高危阳性乳腺癌患者，使用促性腺激素释放激素激动剂（gonadotropin‑releasing hormone agonist，GnRHa）进行卵巢功能抑制（ovarian function suppression，），可明显降低其复发风险［15‑16］。年轻乳腺癌患者不仅在治疗和预后方面具有鲜明特点，在康复后的生活质量等方面也有独特的需求。由于发病时年龄尚轻，治愈后有更多参与职场的机会和需求，承担的社会和家庭角色功能更多更复杂，对生活质量的要求也更高。在抗肿瘤治疗的同时，年轻乳腺癌患者有着生育力保护、保留乳房外形等个性化需求，需在临床实践中加以关注。以往报道的中国乳腺癌患者平均保乳率为 $1 4 . 6 \% \sim$ $2 1 . 1 \%$ ，大多数医院的保乳率为 $1 0 \% { \sim } 3 0 \% ^ { [ 1 7 . 1 9 ] }$ 。$69 \%$ 的YBCC专家表示所在医院的保乳率为 $10 \% \sim$ $30 \%$ ， $2 5 \%$ 的专家所在医院保乳率为 $30 \% { \sim } 5 0 \%$ ，反映了近年来中国的保乳率有所提高，但仍有上升的空间。目前关于中国年轻乳腺癌的保乳率数据有限，复旦大学肿瘤医院数据显示， ${ < } 4 0$ 岁的乳腺癌患者保乳率为 $3 1 . 5 \%$ ，高于总体乳腺癌患者的保乳率 $( 2 0 . 5 \%$ ）［9］。中山大学孙逸仙纪念医院的数据则显示， — 年期间 $\leqslant 4 0$ 岁的乳腺癌患者保乳率是 $5 5 . 7 \%$ ，而 ${ > } 4 0$ 岁患者保乳率是 $4 5 . 7 \%$ ，显示年轻乳腺癌患者的保乳率明显更高，且其随访数据显示，保乳患者与切乳患者具有相似的远期预后，证实了保乳手术在中国女性乳腺癌患者中的安全性和有效性［20］。 # 二、BRCA1/2基因胚系突变与年轻乳腺癌年轻乳腺癌患者更易存在乳腺癌易感基因的胚系致病突变，最常见的是基因胚系突变［21］。北京大学肿瘤医院在2003—2015年间对8 085例未经选择的乳腺癌患者进行了乳腺癌易感基因胚系致病突变研究，所有患者的易感基因总突变率为 $9 . 2 \%$ ，其中BRCA1/2基因胚系突变最为常见，突变率为 $5 . 3 \%$ ；在没有乳腺癌或卵巢癌家族史的40岁以下年轻乳腺癌患者中，易感基因总突变率为 $1 3 . 2 \%$ ，其中 BRCA1/2 基因胚系突变率为$8 . 7 \%$ ；在有乳腺癌或卵巢癌家族史的患者中，BRCA1/2 基因胚系突变率上升至 $1 8 . 1 \%$ ，在年轻且有家族史的患者中，BRCA1/2基因胚系突变率高达$2 8 . 4 \% ^ { [ 2 2 ] }$ 。BRCA1/2基因胚系突变与乳腺癌分子分型存在显著相关性［23］，三阴性乳腺癌BRCA1/2基因的胚系突变频率最高，其中BRCA1基因胚系突变率为 $7 . 4 \%$ ，BRCA2基因胚系突变率为 $3 . 8 \%$ ；在HR阳性、人表皮生长因子受体 2（human epidermalgrowth factor receptor 2，HER2）阴性乳腺癌中，BRCA1基因胚系突变率为 $1 . 1 \%$ ，BRCA2基因胚系突变率为 $4 . 3 \%$ ；HER2 阳性乳腺癌 BRCA1 和基因的胚系突变频率较低，分别为 $0 . 6 \%$ 和基于国内外的流行病学证据，YBCC专家组针对乳腺癌患者推荐行BRCA1/2基因胚系突变检测的指征进行了投票。对于有乳腺癌或卵巢癌等相关家族史、三阴性乳腺癌和40岁以下的年轻乳腺癌患者，由于其BRCA1/2基因胚系突变频率较高，分别有 $9 7 \% . 9 1 \%$ 和 $6 3 \%$ 的YBCC专家推荐其行BRCA1/2基因胚系突变检测，而 $3 5 \%$ 的专家推荐将BRCA1/2基因胚系检测的年龄延后至 ${ < } 4 5$ 岁，另有$2 9 \%$ 的专家推荐美国国立综合癌症网络（NationalComprehensive Cancer Network，NCCN）指南的BRCA1/2基因胚系检测指征：需要化疗的HER2阴性乳腺癌患者。以上投票结果显示，YBCC专家对于推荐BRCA1/2基因胚系检测的适应证选择上较欧美专家更为谨慎，因为45岁以下和需要化疗的HER2阴性乳腺癌患者在中国乳腺癌人群中占比都比较多。既往研究在基因胚系突变是否会影响早期乳腺癌患者预后结论并不一致。一项包含个研究例患者的荟萃分析结果显示：BRCA1基因胚系致病突变的乳腺癌患者相较于散发乳腺癌患者具有更差的总体生存（overallsurvival，OS）和更差的乳腺癌特异性生存；而基因胚系突变的乳腺癌患者与非突变的患者相比无明显差异［24］。但另一项对基因胚系突变的年轻乳腺癌患者预后的前瞻性队列研究显示：BRCA1/2基因胚系突变的患者与非突变患者相比在、和年的预后分析中均未见差异［25］。北京大学肿瘤医院的研究也显示，BRCA1基因胚系突变患者的无病生存和乳腺癌特异生存更差；但在校正了年龄、肿瘤大小、淋巴结和组织学分级等因素后，基因胚系突变对患者生存没有显著影响，而 BRCA2 基因胚系突变对生存的影响更小［22］。 BRCA1/2基因胚系突变是否会影响同侧或对侧乳房的乳腺癌发生率是早期乳腺癌患者选择保乳或全切手术的重要因素，其最佳的手术方式仍存在争议。北京大学肿瘤医院的一项中位随访时间达80个月的回顾性研究显示，BRCA1/2基因胚系突变组同侧乳腺癌复发率（ipsilateral breast tumorrecurrence，IBTR）为 $3 . 9 \%$ ，未显著高于非突变组的$2 . 0 \% ^ { [ 2 6 ] }$ 。另一项包含10项研究2 846例患者的荟萃分析则显示，IBTR在术后7年内BRCA1/2基因胚系突变组未显著高于非突变组，BRCA1/2致病突变导致的风险在年后开始出现，随访时间高于7年的亚组分析提示IBTR在BRCA1/2基因胚系突变组更高［27］。此外，多项研究显示BRCA1/2基因胚系突变的乳腺癌患者行保乳与切乳相比，乳腺癌特异生存和OS均差异无统计学意义［28‑29］。不过对侧乳腺癌10年累积风险在BRCA1/2基因胚系突变患者中为 $1 5 \% { \sim } 2 6 \%$ ，显著高于非突变患者的 $3 \% ^ { [ 3 0 - 3 1 ] }$ 。基于以上研究结果，NCCN指南指出BRCA1/2基因胚系致病突变不是保乳术的绝对禁忌证或相对禁忌证。对于BRCA1/2基因胚系致病突变的乳腺癌患者，可考虑行患乳切乳联合对侧预防性切乳手术。而对于已经行保乳术或切乳术后，不建议对健乳行二次预防性切乳［32］。ASCO 2020 与 BCY 指南4均建议综合评估BRCA1/2基因胚系突变患者的风险，包括发病年龄、家族史、分子分型等，决定是否行切乳或对侧预防性切乳或双侧附件切除术。若不行预防性切除手术，则需密切随访［3，33］。 YBCC专家组针对BRCA1/2基因胚系突变检测与手术时机、基因胚系突变与手术方式选择的相关问题进行了投票。无论对于有乳腺癌或卵巢癌家族史的年轻乳腺癌患者，还是患有三阴性乳腺癌的年轻患者，均有超过半数专家（分别为$53 \%$ 和 $52 \%$ ）不推荐其等待基因检测结果再决定手术方式。对于术前已知携带BRCA1/2基因胚系致病突变的年轻乳腺癌患者，如果具备保乳条件， $72 \%$ 的专家认为需与患者充分沟通患侧复发和对侧新发乳腺癌的风险，并充分考虑患者年龄、家族史及个人意愿等条件后再决定是否保乳，而$2 5 \%$ 的专家推荐其选择保乳治疗。目前已知BRCA1/2基因胚系致病突变会显著增加对侧乳腺癌风险。北京大学肿瘤医院的数据显示，BRCA1和BRCA2基因胚系突变乳腺癌患者对侧乳腺癌的10年累积发病风险分别为 $1 5 . 5 \%$ 和$1 7 . 5 \%$ ，显著高于非携带者的 $3 . 2 \%$ ；在年轻乳腺癌患者中，和基因胚系突变携带者对侧乳腺癌的年累积发病风险分别上升至 $2 1 . 5 \%$ 和 $2 0 . 2 \%$ ；在有乳腺癌家族史的患者中，BRCA1和BRCA2基因胚系突变携带者对侧乳腺癌的10年累积发病风险分别高达 $2 7 . 5 \%$ 和 $2 7 . 1 \%$ ，提示有家族史患者的BRCA1/2基因胚系突变致病率更高［31］。对于携带致病BRCA1/2基因胚系突变的年轻乳腺癌患者，如患侧选择皮下腺体切除 $^ +$ 假体植入， $6 6 \%$ 的专家认为需与患者充分沟通健侧新发风险，并充分考虑患者年龄、家族史及个人意愿等条件后，再决定是否行对侧预防性切除，而 $20 \%$ 和$13 \%$ 的专家则分别不建议或建议患者同时行对侧乳房预防性切除。对于患侧保乳或未进行预防性对侧切除的基因胚系突变患者， $8 2 \% . 7 1 \%$ 和 $87 \%$ 的YBCC专家分别推荐术后采用B超、钼靶和MRI方式密切监测乳腺情况，正电子发射计算机断层扫描（PET‑CT）不是推荐的常规复查项目。与会专家特别指出，不建议单独使用X线检查随访，因X线对40岁以下及致密乳腺诊断的准确性欠佳；强烈推荐乳腺联合超的检查手段，因对致密乳腺具有高敏感性，有助于发现其他手段不能发现的多灶和多中心肿瘤［34］。 TNT研究显示，卡铂在BRCA1/2基因胚系突变晚期三阴性乳腺癌患者中的疗效优于紫杉醇（客观缓解率分别为 $6 8 . 2 \%$ 和 $3 3 . 3 \%$ ，无进展生存时间分别为 6.8和 4.4个月），CBCSG006研究在我国人群中也得出类似结论，因此铂类在晚期乳腺癌中可以作为BRCA1/2基因胚系突变患者的优选化疗药物［35‑36］。然而，BRCA1/2基因胚系突变患者辅助治疗阶段的最佳化疗方案尚无定论。在中国9个中心开展的PATTERN研究显示，与传统蒽环紫杉联合方案相比，紫杉联合卡铂辅助化疗可以改善三阴性乳腺癌患者的无病生存（5 年无病生存率 $8 6 . 5 \%$ 与 $8 0 . 3 \%$ ，风险比 $0 . 6 5 , P { = } 0 . 0 3$ ），且在BRCA1/2基因胚系突变亚组中观察到相似的生存获益［37］。尽管如此，对于需要化疗的携带致病基因胚系突变的年轻乳腺癌患者的辅助化疗是否应考虑包含铂类，YBCC专家组未能达成一致共识，分别有$3 9 \%$ 和 $40 \%$ 的专家推荐或不推荐含铂方案，另外的$20 \%$ 专家选择不确定，认为铂类在基因胚系突变的年轻乳腺癌辅助化疗中的应用仍需积累更多长期生存获益数据。基因胚系突变患者卵巢癌的发病风险亦有所增加。北京大学肿瘤医院一项纳入例乳腺癌的家系研究显示，和BRCA2基因胚系突变患者70岁卵巢癌累积风险分别为 $1 5 . 3 \%$ 和 $5 . 5 \%$ ，远高于非携带者的 $0 . 4 \%$ ；基因胚系突变携带者卵巢癌发病年龄大多在 40 岁之后，BRCA2 基因胚系突变携带者卵巢癌发病年龄大多在 45 岁之后；合并卵巢癌的患者很少具有卵巢癌家族史，提示对于没有卵巢癌家族史的患者，亦需要警惕合并卵巢癌的可能［38］。中山大学孙逸仙纪念医院的数据显示，有卵巢癌家族史的 BRCA1/2基因胚系突变乳腺癌患者有 $1 2 . 5 \%$ 的比例会患卵巢癌。因此对于有卵巢癌家族史的突变乳腺癌患者可能更要积极处理卵巢的问题。对于携带致病BRCA1/2基因胚系突变的年轻乳腺癌患者，预防性卵巢切除的时机目前尚无定论，YBCC专家组对此进行了投票。由于过早切除卵巢会显著影响年轻乳腺癌患者的生活质量， $72 \%$ 的专家选择根据患者的突变类型、家族史和个人意愿等因素，决定是否行预防性双侧卵巢输卵管切除和切除时机。仅 $3 5 \%$ 的与会专家认可BCY‑4指南的推荐，即 BRCA1携带者在 35\~40岁，BRCA2携带者在 40\~45 岁进行预防性卵巢切除［3］；亦有专家指出，中国患者卵巢癌发病年龄较晚，可酌情推迟预防性卵巢切除的时机。对于没有卵巢癌家族史的患者， $26 \%$ 的与会专家认为可密切观察，待自然绝经后再行卵巢切除，还有 $21 \%$ 的与会专家认为可以考虑不切除卵巢，可以选择一直观察。 # 三、年轻乳腺癌患者的化疗化疗是乳腺癌综合治疗的重要组成部分，目前针对年轻乳腺癌最佳化疗策略的研究很少，因此，年轻乳腺癌化疗方案的选择应参考现行临床诊疗指南推荐。目前临床常用的化疗方案是含紫杉或蒽环的方案，早期乳腺癌试验者协作组（EBCTCG）荟萃分析对比了不同化疗方案的长期生存结果，结果显示接受含紫杉或蒽环方案治疗的早期乳腺癌，死亡风险未受年龄影响［39］，对于阳性乳腺癌患者，抗治疗获益和患者早期复发风险亦与年龄无关。Luminal型患者选择化疗方案必须考虑疾病对化疗的敏感性与复发风险［40‑41］。一项汇总分析纳入了项乳腺癌新辅助化疗的前瞻性随机对照研究，年龄 ${ < } 4 0$ 岁患者人群与年龄 $\geqslant 4 0$ 岁的人群相比，病理学完全缓解（pathologic completeremission，pCR）率在年轻患者中明显更高，主要是因为年轻乳腺癌患者中三阴性乳腺癌和HR阳性HER2 阴性人群的 pCR 率显著提高，但年龄仅是阳性阴性人群独立的生存预后因素，在三阴性乳腺癌和HR阴性HER2阳性人群中未发现二者的相关性［42］。虽然年轻乳腺癌患者相对复发转移风险较高，但专家组分别有 $44 \%$ 和 $46 \%$ 的专家选择或不选择针对年轻患者常规推荐比普通患者更强化疗方案。因此，年轻患者应与年长患者一样，基于其疾病分期和分子分型等因素合理选择化疗方案，仅考虑年龄因素进行更强的化疗决策可能存在过度治疗的风险。随着多基因检测技术研究的不断深入，一些多基因检测工具如 21 基因检测（Oncotype $\mathrm { D X } ^ { \mathbb { \left( B \right) } }$ ）、70 基因检测（MammaPrint® ）、50 基因检测（Prosigna® ）、Endopredict®和乳腺癌指数（BCI）已在欧美作为 $\mathrm { H R + / H E R - }$ 早期乳腺癌患者预后的评估工具甚至辅助化疗治疗决策的重要依据［32，43］。但值得注意的是，TAILORx和MINDACT研究结果均显示，Oncotype 和 MammaPrint 检测在 50 岁以下患者的预测价值不如50岁以上的患者［44‑45］。而在迄今为止开展的多基因检测临床研究中，入组人群主要为欧美患者，40岁以下患者比例很低。因此对于HR阳性HER2阴性乳腺癌患者，根据正规的基因检测结果（如21基因或Mammaprint等）选择是否化疗的适用年龄范围， $5 2 \% , 3 9 \%$ 或 $3 5 \%$ 的YBCC专家分别选择 50 岁以上、45\~50 岁或不确定，仅$2 5 \%$ 或 $22 \%$ 的专家选择35\~40岁或35岁以下，因此依据多基因检测结果指导YBCC患者是否选择辅助化疗仍需慎重。肿瘤化疗药物在杀死肿瘤细胞的同时，对人体的正常细胞难免有一定的不良反应。关于年轻乳腺癌患者主要担心的化疗不良反应，高达 $91 \%$ 的专家选择了脱发，显示年轻乳腺癌患者对于外表的重视程度相当高，可能与年轻患者担任的社会角色有关。此外，还有 $6 8 \% , 6 3 \%$ 和 $61 \%$ 的专家分别选择了心脏毒性、血液学毒性和胃肠道反应作为主要担心的不良反应。蒽环类药物早在年代即取得了乳腺癌化疗药物的基石地位，但由于其有一定的心脏毒性［46］，近年来乳腺癌的化疗方案有逐渐“去蒽环”的趋势。 $8 3 \%$ 的YBCC专家认为“去蒽环”化疗方案相对含蒽环方案的优势是更少的心脏不良反应。蒽环心脏毒性相关的危险因素有年龄（>65岁）、纵隔辐射、较高的蒽环类药物累积剂量、先前存在的心脏病和其他心脏危险因素（如高血压）［47‑48］。而相比于欧美国家，中国乳腺癌患者更年轻，心脏基础状况较好，一般使用心脏毒性较低的蒽环类药物如表柔比星，因此引发心脏不良事件的发生率较低。此外，年轻乳腺癌患者治愈后预期寿命较长，尤其对于中高危患者，治疗方案的选择需要很好平衡治愈率和心脏毒性的风险。 $56 \%$ 的YBCC专家反对年轻乳腺癌患者需要化疗时优选“去蒽环”化疗， $3 5 \%$ 的专家表示不确定，仅 $9 \%$ 的专家支持年轻乳腺癌的化疗优选“去蒽环”方案。对于HER2阳性乳腺癌患者，曲妥珠单抗和帕妥珠单抗等靶向治疗大幅度提高了化疗的疗效，已有一些研究证实乳腺癌“去蒽环”方案是可行的策略［49‑51］，但蒽环类药物在阳性乳腺癌中也有突出的疗效［52］，投票时 $43 \%$ 的YBCC专家认为年轻乳腺癌如为HER2阳性，可优选“去蒽环”方案，但在中高危（Ⅱ期或Ⅲ期淋巴结阳性）HER2阳性乳腺癌患者的优选辅助化疗方案中， $84 \%$ 的 YBCC 专家选择了4周期多柔比星 $^ +$ 环磷酰胺/表柔比星 $+$ 环磷酰胺（AC/EC）‑序贯4周期紫杉类 $\left( \mathrm { T H P } \right) +$ 曲妥珠单抗 $^ +$ 帕妥珠单抗，还有 $70 \%$ 的专家选择了6周期多西他赛 $^ +$ 卡铂 $^ +$ 曲妥珠单抗 $^ +$ 帕妥珠单抗（TCbHP）。而对于HER2阴性乳腺癌，多项研究证实含蒽环方案相比非蒽环方案疗效更优［53］，尤其是中高危的患者使用非蒽环方案的获益尚不明确，因此对于中高危（Ⅱ期或Ⅲ期淋巴结阳性）HER2阴性乳腺癌患者的优选辅助化疗方案，高达 $9 5 \%$ 的 YBCC专家选择了周期序贯周期紫杉类，还有$2 5 \%$ 的专家选择了6周期多西他赛 $^ +$ 多柔比星 $^ +$ 环磷酰胺/多西他赛 $^ +$ 表柔比星 $^ +$ 环磷酰胺（TAC/TEC），其他化疗方案的选择均低于 $20 \%$ 。对于三阴性乳腺癌新辅助治疗，GeparSixto研究、CALGB40603 研究和 BRIGHTNESS 研究和研究均提示在蒽环和（或）紫杉基础上联合铂类可显著提高新辅助治疗pCR率［53‑56］，但对是否延长生存仍无法得出一致结论。因此，对于中高危年轻乳腺癌 HER2 阳性或三阴患者， $71 \%$ 的YBCC专家反对常规考虑含铂方案来取代含蒽环的辅助化疗方案， $21 \%$ 的专家不确定，仅 $8 \%$ 的专家支持。通常认为蒽环类药物的累积剂量是引起心脏毒性的主要原因［57］，传统蒽环类药物多柔比星和表柔比星的最大累积剂量分别是 $5 5 0 ~ \mathrm { m g } / \mathrm { m } ^ { 2 }$ 和 $9 0 0 \sim$ $\mathrm { 1 ~ 0 0 0 ~ m g / m } ^ { 2 }$ 。脂质体多柔比星是一类新型的蒽环类药物，由于有脂质体包裹且经聚乙二醇化修饰，在心肌的分布和累积浓度较低，与多柔比星相比心脏毒性显著降低［58］，有研究证实，其与曲妥珠单抗在晚期HER2阳性乳腺癌联合使用具有良好的疗效和心脏安全性［59］。 $60 \%$ 的YBCC专家认为，对于需要蒽环化疗的年轻乳腺癌患者，可考虑心脏和脱发等毒性更小的脂质体阿霉素来代替传统蒽环。不过专家们也指出，脂质体阿霉素在早期乳腺癌的数据还很有限，需要谨慎使用。 # 四、年轻乳腺癌的内分泌治疗 HR阳性年轻乳腺癌患者辅助内分泌治疗有多种选择：他莫昔芬、联合他莫昔芬、联合芳香化酶抑制剂（aromatase inhibitor，AI）和 CDK4/6 抑制剂阿贝西利联合标准辅助内分泌治疗。选择性雌激素受体调节剂（selective estrogen，）他莫昔芬是低复发风险乳腺癌患者的标准治疗方案，同样适用于低复发风险的年轻患者。尽管他莫昔芬可能反馈刺激雌二醇升高［60］，尚无证据表明他莫昔芬引起的雌二醇升高是否影响患者预后或子宫内膜厚度，也没有证据提示针对他莫昔芬引起的雌二醇升高是否应给予何种处理。因此， $89 \%$ 的专家不建议服用他莫昔芬单药治疗的患者监测雌二醇水平。他莫昔芬需要通过CYP2D6酶代谢成为活性产物吲哚昔芬，才能有效发挥阻断雌激素受体（estrogen receptor，ER）的作用。而 CYP2D6 基因多态性影响CYP2D6酶的活性，在CYP2D6弱或中等代谢型人群中，他莫昔芬的活性代谢产物吲哚昔芬有所减少，从而影响他莫昔芬的疗效［61］。托瑞米芬是另一种SERM类药物，不经过CYP2D6酶代谢，因此不受CYP2D6基因代谢亚型的影响。中国医学科学院肿瘤医院开展的一项单中心回顾性研究显示，托瑞米芬较他莫昔芬可以改善患者的无病生存（5年无病生存率 $8 9 . 6 \%$ 比 $8 0 . 9 \%$ ， $P { = } 0 . 0 0 9$ ），中国大约有 $20 \%$ 的患者为 $\mathrm { C Y P 2 D 6 ^ { * } 1 0 T / T }$ 基因型（突变纯合子型），在这些弱代谢患者中，托瑞米芬较他莫昔芬的获益更加显著（5 年无病生存率 $9 0 . 9 \%$ 与$6 7 . 9 \% , P { = } 0 . 0 3 1 ) ^ { [ 6 2 ] }$ 。不过由于相关研究较少且证据级别偏低，随机对照研究尚在进行中， $52 \%$ 的专家反对在临床工作中相同可及条件下优选托瑞米芬，另外 $34 \%$ 的专家相较他莫昔芬会优选托瑞米芬。绝经前女性下丘脑分泌促性腺激素释放激素，使垂体释放黄体生成素和卵泡刺激素，从而作用于卵巢并释放雌激素，而雌激素能促进阳性的乳腺癌细胞生长。GnRHa可以通过持续刺激垂体，抑制垂体分泌黄体生成素和卵泡刺激素，进而下调绝经前患者体内雌激素水平，起到的作用，进而抑制乳腺癌的生长［63］。在SOFT和TEXT研究的联合分析中，研究者将传统的临床病理特征［患者年龄、肿瘤大小、分级、淋巴结状态、、孕激素受体（）和表达］合并成一个连续性变量，称为“复合风险”，随着复合风险的增加，联合OFS治疗可以带来更加显著的获益［64］。对于高复发风险的绝经前 HR 阳性阴性乳腺癌患者，联合类药物依西美坦对比OFS联合他莫昔芬或他莫昔芬单药治疗的8年无远处复发率绝对获益为 $10 \% { \sim } 1 5 \%$ ；对于中等复发风险的患者，OFS联合AI至少可以降低 $5 \%$ 的复发风险［64］。在研究未接受化疗的患者中，OFS联合AI相对他莫昔芬带来 $5 . 2 \%$ 的无病生存获益；接受化疗的患者从OFS联合AI中的无病生存获益高达 $9 . 0 \% ^ { [ 4 0 ] }$ 。与其他年龄组患者相比， ${ < } 3 5$ 岁的年轻女性从的治疗中获益最大，联合较他莫昔芬单药可使 ${ < } 3 5$ 岁患者的远处复发风险相对降低 $5 5 \%$ ，使35\~49岁患者的远处复发风险相对降低 $1 3 \% { \sim } 2 6 \% ^ { [ 6 4 ] }$ 。OFS联合AI可以在OFS联合他莫昔芬的基础上进一步降低复发风险，与联合他莫昔芬相比，OFS联合AI显示出无病生存持续的改善，8年无病生存的绝对获益为 $4 \%$ ，8年无远处转移生存的绝对获益为 $2 . 1 \% ^ { [ 4 0 ] }$ 。基于和研究，专家组建议中高复发风险的绝经前阳性乳腺癌患者（尤其是年轻、需要接受化疗的患者）接受包含OFS的内分泌治疗，并对几种特定情形是否适用卵巢抑制进行了投票。对于接受化疗的ER阳性年轻患者，在化疗后仍有月经、化疗后停经且高危、化疗后停经且中危的 3 种情况下，分别有 $8 3 \% . 8 1 \% . 6 4 \%$ 的YBCC专家认为适用OFS治疗。对于无需化疗的阳性年轻患者，也有 $56 \%$ 的专家认为其适用OFS治疗，显示专家们对于OFS在年轻乳腺癌的使用接受度很高。对于化疗后停经的ER阳性围绝经期患者， $67 \%$ 的YBCC专家认为高危患者应使用OFS，而 $3 8 \%$ 的专家认为中危患者也应使用OFS。有专家指出应根据化疗前的月经状态判断是否适用，不建议根据化疗后是否停经干扰的选择。类药物可以分为甾体类和非甾体类，两者的作用机制有所不同。甾体类的代表药物为型芳香化酶灭活剂依西美坦，其可以导致芳香化酶永久性灭活、芳香化酶水平降低；非甾体类AI的代表药物为Ⅱ型芳香化酶抑制剂，其可以导致芳香化酶暂时性失活、芳香化酶水平升高。有多项研究显示，在自然绝经的患者中，甾体类和非甾体类AI的疗效相似［65‑66］。不过年轻患者接受 OFS 后的人工绝经并不能完全模拟自然绝经，自然绝经患者的多个内分泌器官都存在衰老现象，而人工绝经的患者仅卵巢功能被抑制，其肾上腺等器官仍处于年轻状态。一项系统分析显示，在绝经后乳腺癌患者中，患者的体质指数不会影响 AI 的疗效［67］；而ABCSG12研究则显示，随着体质指数的增加，绝经前患者接受GnRHa联合AI治疗的复发风险亦显著增加［68］；提示自然绝经患者中的证据不一定适用于人工绝经的年轻患者。但是，目前尚无明确证据显示甾体类和非甾体类AI应用于年轻乳腺癌患者有不同的疗效，因此，尽管SOFT和TEXT研究中绝经前患者所采用的AI均为依西美坦，临床上也常采用联合非甾体类来曲唑和阿那曲唑进行辅助内分泌治疗。对于OFS是否应联合甾体类AI作为年轻乳腺癌辅助内分泌治疗的优选， $58 \%$ 的YBCC专家认为非甾体类AI与甾体类AI疗效相当，均可做为OFS联合AI时的选择， $34 \%$ 的专家则认为甾体类AI应为优选。有个月或个月给药剂型，两者的生理和临床结局相似。多项研究表明，3个月与1个月剂型GnRHa均可有效降低雌激素水平，达到卵巢抑制的效果［69‑72］。项纳入222例绝经前乳腺癌患者的随机对照研究显示，个月和个月剂型GnRHa 在降低雌激素方面有相同的作用［69］。此外，3个月和1个月剂型 $\mathrm { G n R H a }$ 均能快速持久降雌，可以在周内快速降低雌二醇水平，在周时将雌二醇降至 $3 0 ~ \mathrm { { n g / L } }$ 以下，并且在整个治疗期间使患者维持在绝经后水平［72‑73］。3 个月和 1 个月剂型 $\mathrm { G n R H a }$ 的降雌作用均是可逆的， $8 5 \%$ 的患者可以在停药后2年恢复月经，患者越年轻恢复月经的概率越大［74‑75］。多项研究报告了两种剂型GnRHa的卵巢逃逸率，3个月剂型GnRHa的卵巢逃逸率为$4 . 8 0 \% { \sim } 9 . 3 8 \% ,$ ，1个月剂型的卵巢逃逸率为 $3 . 6 0 \% \sim$ $1 2 . 2 0 \%$ ，尚无证据表明两种剂型的卵巢逃逸率差异具有统计学意义［70，73，76‑78］。从长期预后来看，3个月剂型GnRHa治疗的5年无病生存率为 $9 0 . 4 \%$ ，与其他报道中个月剂型的年无病生存率$8 9 . 8 \%$ 相当［69，79］。安全性方面，两项头对头研究证实，3个月和 1个月剂型 GnRHa均具有良好的安全性［72‑73］。复旦大学肿瘤医院基于真实世界数据比较了个月剂型亮丙瑞林和个月剂型戈舍瑞林的成本差异，结果显示，3个月剂型的直接非医疗成本（包括交通费、食宿费）和间接成本（包括患者劳动力损失、家属或陪护者劳动力损失）均显著低于1个月剂型［80］。3个月剂型GnRHa可减少患者往返医院的次数和花费，可能提高患者的治疗依从性。因此，3个月剂型GnRHa也是临床上常见的选择，可以满足患者的个性化需求。针对的剂型选择， $81 \%$ 的专家认为 3 个月剂型和 1 个月剂型均可作为卵巢抑制与SERM类药物联用， $56 \%$ 的专家认为两种剂型可以与AI类药物联用且无需考虑患者年龄。亦有接近$50 \%$ 的专家认为，因为年轻患者卵巢功能更强，相对更容易产生OFS逃逸，对于年轻患者联合AI时使用 GnRHa 应更谨慎，可能需更多监测雌激素水平。总体而言，YBCC专家组支持3个月剂型和1个月剂型GnRHa均可作为OFS的选择。 AI能够特异性抑制芳香化酶失活，抑制雌激素生成，降低血液中雌激素水平；如果将AI用于绝经前女性，其引起的雌激素水平降低可刺激下丘脑垂体通路，进而导致血浆雌二醇水平的升高［81］。在既往研究中，GnRHa联合AI方案中AI的启动时机有所不同，多在开始GnRHa治疗6周后开始AI治疗，或在开始GnRHa后立即开始，或在化疗完成后进行，目前尚缺乏上述启动时机与患者预后的相关性分析［72‑73］。已知需要周才能将雌二醇降低至绝经后水平［72‑73］，不过在开始GnRHa治疗后，AI刺激下丘脑垂体通路进而导致雌二醇水平升高的作用有限；因此，早期同步启动和治疗，也是可以接受的。 $53 \%$ 的专家认为，对于未绝经的乳腺癌患者， $\mathrm { G n R H a }$ 可以与AI同时启用。另有 $43 \%$ 的专家则认为需在开始GnRHa治疗并确认后，才可以开始治疗，以尽可能避免刺激下丘脑垂体通路进而导致雌二醇水平升高，尤其对于少部分OFS逃逸患者，过早使用AI可能有不良反应。如前所述，3个月剂型和1个月剂型GnRHa均有一定的卵巢逃逸率，各研究报道的卵巢逃逸率为$3 . 6 0 \% { \sim } 1 2 . 2 0 \% ^ { [ 7 0 , 7 3 , 7 6 - 7 8 ] }$ 。卵巢逃逸的发生与患者年龄显著相关，患者越年轻发生卵巢逃逸的可能性越大，接受过化疗的患者卵巢逃逸率较低，卵巢逃逸率随GnRHa治疗时间的延长而下降［82‑83］。但是，目前尚缺乏卵巢逃逸与患者预后的相关性分析，现有研究采用的卵巢逃逸阈值不统一，医疗机构所采用的性激素检测技术和参考范围也并不一致［84］。因此，在 GnRHa 应用期间监测雌激素水平的临床价值仍不明确。 $45 \%$ 的YBCC专家认为不需要监测雌激素， $31 \%$ 的专家认为刚开始时需要、确认后无需监测，仅 $11 \%$ 的专家认为在整个使用过程中需要定期监测。GnRHa 联合 AI 类药物时， $28 \%$ 的专家认为需要监测雌激素以反映卵巢逃逸情况； $\mathrm { G n R H a }$ 联合SERM类药物时，仅 $5 \%$ 的专家认为需要监测雌激素。临床中如选择监测，YBCC专家对于选择何种固定检测频率未达成一致共识， $28 \%$ 的专家建议年轻乳腺癌患者使用OFS时每3个月监测1次，其他频率监测的支持率均在 $10 \%$ 左右或以下。专家们指出，OFS期间需警惕某些可能提示卵巢功能恢复的生理变化，如不明原因的阴道流血或重新出现更年期症状的周期性波动等。五、年轻乳腺癌患者的生育问题肿瘤治疗的进步改善了乳腺癌患者的长期生存，中国乳腺癌患者的发病年龄更早，加之现代社会生育年龄的延后，很多乳腺癌患者在确诊后仍有强烈的生育愿望。我国计划生育政策的逐渐放开进一步提升了乳腺癌患者的生育需求。中国医学科学院肿瘤医院在 — 年间开展的一项横断面调查显示， $2 6 . 3 \%$ 的年轻乳腺癌患者在乳腺癌治疗后仍有生育需求，但仅 $1 . 9 \%$ 的患者接受了生育力保护治疗［85］。四川省肿瘤医院在年开展的一项问卷调查显示，年轻乳腺癌患者对化疗影响生育力和生育力保护有一定认识，超过 $30 \%$ 的年轻乳腺癌患者接受了生育力保护［86］。然而，国外一项基于人群的调查研究显示，经治乳腺癌患者的妊娠率仅 $3 \%$ ，比一般人群的妊娠率低 $4 0 \%$ 。由此可见，尽管乳腺癌患者在确诊后有较高的生育需求，但由于化疗对卵巢的损伤作用和长达5\~10年的辅助内分泌治疗对最佳妊娠时机的延误，加之部分肿瘤科医师和患者对生育问题仍存在顾虑以及生育力保护措施的缺位，年轻乳腺癌患者的生育现状仍有待改善［88］。为了改善年轻乳腺癌患者的生育管理现状，应该提高肿瘤科医师和患者对生育力保护的认识，加强对患者进行生育力保护的宣教，并建立和完善乳腺癌多学科诊疗团队，为患者提供及时而准确的妇产科、生殖内分泌专家的指导［89］。目前没有证据显示生育会降低乳腺癌患者的预后［90‑92］。欧洲一项多中心回顾性研究显示，妊娠不会影响乳腺癌患者的无病生存，无论其乳腺癌为ER阳性或ER阴性［92］。建议所有年轻女性乳腺癌患者在确诊乳腺癌之后、制定抗肿瘤方案之前接受生育咨询，明确是否有生育要求，尽早与患者及其配偶讨论治疗方案对生育力的影响、生育力保护的可行性及其对乳腺癌治疗的影响。环磷酰胺是辅助治疗常用的化疗药物，同时也是导致卵巢功能衰竭的高风险化疗药物［93］。复旦大学附属肿瘤医院在ER阳性乳腺癌患者中开展的一项期随机对照研究显示，无环磷酰胺辅助化疗方案的1年月经恢复率更高（ $6 3 . 1 \%$ 与 $4 8 . 3 \%$ ）、4年成功妊娠率更高（ $9 . 6 \%$ 与 $2 . 7 \%$ ），无病生存和OS差异无统计学意义［94］。中山大学孙逸仙纪念医院乳腺肿瘤中心团队开展了一项荟萃分析，汇总2 633 例来自 5 项临床试验的乳腺癌患者数据，结果证实了含环磷酰胺的化疗方案相比无环磷酰胺化疗方案显著提高化疗相关的闭经［95］。因此，对于有生育需求的年轻乳腺癌患者，可尽量避免使用含环磷酰胺的化疗方案。此外，建议年轻乳腺癌患者在确诊后尽早选择合适的生育力保护方案。目前较为广泛使用的方案包括：生育力保存技术和化疗期间应用GnRHa保护卵巢功能。目前已有较多研究证实了生育力保护技术的安全性和有效性。欧洲一项队列研究显示，在乳腺癌诊断后接受生育力保存技术的患者，其5年和年累积死亡风险低于未接受生育力保存技术的患者（年累积死亡风险 $5 . 3 \%$ 与 $1 1 . 1 \%$ ，年累积死亡风险 $1 3 . 8 \%$ 与 $2 3 . 2 \%$ ），5年和10年累积分娩率则大幅度增加（5 年累积分娩率 $1 9 . 4 \%$ 与 $8 . 6 \%$ ，10 年累积分娩率 $4 0 . 7 \%$ 与 $1 5 . 8 \%$ ）［96］。目前，可选择的生育力保存技术有胚胎冻存、卵母细胞冻存、未成熟卵母细胞体外培养成熟技术（invitromaturation，IVM）、卵巢组织的冻存与移植等［32］。胚胎冻存、卵母细胞冻存前需要进行卵巢刺激，为降低卵巢刺激方案造成的体内雌激素水平升高，推荐乳腺癌患者采用添加来曲唑的控制性卵巢刺激方案，该方案可以降低外源性卵泡刺激素的用量，降低体内雌激素水平，并增加排卵数目及成熟卵子数目［97］。多项研究表明，卵巢刺激和后续妊娠无论对于 ER 阳性或 ER 阴性乳腺癌患者均不会增加其肿瘤复发风险，亦不会增加BRCA1/2突变患者卵巢癌的发病风险［98‑100］。此外，生殖科专家认为年龄 ${ > } 3 5$ 岁患者原则上不推荐卵母细胞冻存，因为成功率偏低。YBCC 专家组针对人工辅助生殖常需用到激素刺激是否影响患者复发风险进行了投票，对于ER阳性或阴性的中高危年轻乳腺癌患者，$49 \%$ 或 $53 \%$ 的专家选择了不确定，而 $32 \%$ 或 $46 \%$ 的专家认为其复发风险不受影响，反映了YBCC专家对使用激素刺激的辅助生殖技术对乳腺癌复发风险的影响仍持谨慎态度。进行，不会延误抗肿瘤治疗的启动，也不会增加体内雌激素水平，还可以减少患者进行超促排卵方案的时间和经济花费，避免卵巢过度刺激综合征的发生。IVM和卵巢冻存技术的联合应用可以提高生育力保存的成功率，但由于技术复杂，仅在部分先进的辅助生殖技术中心开展。生育力保护技术一般应在全身治疗前进行，如果允许实施生育力保护技术的时间窗较长（例如，超过 2 周），可以考虑在联合来曲唑的卵巢刺激后进行卵母细胞冻存或胚胎冻存；如果允许的时间窗较短，可以直接选择IVM和卵巢冻存。 GnRHa兼具卵巢抑制和卵巢保护的双重调控作用，一方面，GnRHa 可以竞争性结合 GnRHa 受体，抑制或下调GnRHa分泌，最终下调雌激素水平，抑制乳腺癌细胞生长；另一方面，可以通过暂时抑制卵巢功能，或抑制卵巢血管生成，减少化疗药物随血液进入卵巢，直接或间接地保护卵巢功能［101］。化疗期间应用GnRHa进行卵巢保护是一种易于实施且经济成本较低的生育力保护方案，其有效性和安全性已被多项研究证实，适用于对生育或完成所有辅助治疗后卵巢功能有要求的年轻患者的辅助化疗阶段［102‑105］。北京大学人民医院开展的一项前瞻性队列研究纳入了例阳性或阴性的乳腺癌患者，探索化疗期间应用进行卵巢保护对卵巢储备功能指标抗苗勒管激素（anti‑mullerian hormone，AMH）恢复率的影响，相比对照组，可显著提高患者恢复率（ $4 6 . 5 \%$ 与 $2 1 . 8 \%$ ， $P { = } 0 . 0 0 2 { \mathrm { ~ } }$ ），各亚组的获益趋势一致［106］。上海市第六人民医院开展的EGOFACT研究同样证实， $\mathrm { G n R H a }$ 可以显著降低化疗后闭经的发生率，提高化疗后 AMH 恢复率［107］。欧美一项纳入873例ER阳性或阴性乳腺癌患者的系统综述表明，化疗期间应用 $\mathrm { G n R H a }$ 可以显著降低化疗后闭经的发生率（ $1 4 . 1 \%$ 与 $3 0 . 9 \%$ ， $P { < } 0 . 0 0 1$ ），提高治疗后的妊娠率（ $1 0 . 3 \%$ 与 $5 . 5 \% , P { = } 0 . 0 3$ ）。但如单独使用 $\mathrm { G n R H a }$ ，妊娠成功率较低，因此如有较强的生育愿望，建议联合其他的辅助生殖措施以尽可能提高妊娠成功率。无论ER阳性或ER阴性乳腺癌患者，化疗期间应用 $\mathrm { G n R H a }$ 均不会影响患者的无病生存和 $\mathrm { O S ^ { [ 1 0 3 ] } }$ 。 YBCC专家组对于卵巢保护与OFS的异同和适用人群达成了一致共识。卵巢保护与OFS均使用药物，卵巢保护以减少化疗期间药物对卵巢损伤为目的，应用于对生育或完成所有辅助治疗后卵巢功能有要求的年轻患者的辅助化疗阶段；以抑制卵巢功能和降低阳性乳腺癌复发或进展为目的，主要用于绝经前患者的辅助内分泌治疗阶段。卵巢保护与患者乳腺癌的 ER 状态无关，适用于所有希望或需要治疗后保留卵巢功能的患者；OFS与患者乳腺癌的ER状态有关，主要用于ER阳性的乳腺癌患者。美国一项在健康受试者中开展的研究显示，GnRHa治疗1周即可导致卵泡雌激素、雌激素和孕激素水平的显著下降，治疗周即可导致促黄体生成素水平的显著下降［108］。用于卵巢保护的关键研究均采用在化疗前1\~2周开始给药的策略，在化疗期间每4周1次，持续至最后一剂化疗前或化疗后 2 周［102，105］。建议在化疗前 2 周即开始使用$\mathrm { G n R H a }$ ，每月1次，直至化疗结束后2周给予最后一剂药物。尽管目前GnRHa用于卵巢保护的研究多采用1 个月剂型 $\mathrm { { G n R H a } } ^ { [ 1 0 2 , 1 0 5 ] }$ ，但是目前已有不少证据表明3个月剂型GnRHa与1个月剂型具有相似的卵巢保护效果。福建医科大学在100例接受化疗的乳腺癌患者中评价了3个月或1个月剂型亮丙瑞林的卵巢保护作用，结果显示，个月和个月剂型在化疗结束后6个月和12个月的AMH恢复率相当；此外，无论根据化疗方案分组还是年龄分组，两种剂型的水平和月经状态恢复水平差异均无统计学意义［109］。因此，3个月剂型 $\mathrm { G n R H a }$ 也是卵巢保护的一种选择， $84 \%$ 的YBCC专家支持3个月剂型和1个月剂型的 $\mathrm { G n R H a }$ 均可用于卵巢保护。具体生育力保护方法及时机需要针对每例患者的实际情况讨论，需要寻求专业生殖内分泌专家的指导与帮助。推荐所有具有生育需求或希望保护卵巢功能的年轻乳腺癌患者在化疗期间应用GnRHa保护卵巢，无论是否已经采用其他生育力保存技术。对于有强烈生育需求的中高危年轻乳腺癌患者，YBCC专家一致支持在化疗前接受卵子冷冻、胚胎冷冻、卵巢组织冷冻等辅助生殖技术，同时推荐在化疗期间GnRHa保护卵巢，以提高未来成功妊娠及生育的可能性。对于可能有生育需求的中高危年轻乳腺癌患者，与会专家对辅助生殖技术的支持率有所下降，但更多专家仍然强调了化疗期间GnRHa保护卵巢的价值。合考虑年轻乳腺癌患者的身体状况、肿瘤的病理特点和复发风险［92］。建议年轻乳腺癌患者尽可能在复发高峰年限过后再考虑妊娠。虽然乳腺癌辅助内分泌治疗会导致年轻患者进一步推迟妊娠时间，甚至错过最佳生育时机，但是不建议患者为生育而中断规范的内分泌治疗［110］。一项探索内分泌治疗中断后怀孕的安全性的前瞻性研究（IBCSG 48‑14/BIG 8‑13，NCT02308085）正在进行中，其结果将为因怀孕中断内分泌治疗与乳腺癌复发风险是否相关提供证据。 # 六、年轻乳腺癌患者的妇科问题 # （一）子宫内膜癌风险及子宫内膜厚度监测服用他莫昔芬可使子宫内膜癌的发病风险增加2\~8倍，且其概率呈剂量和时间依赖性［111‑112］。ATLAS研究显示，他莫昔芬5年治疗组的患者在第年的子宫内膜癌发病率为 $1 . 6 \%$ ，他莫昔芬10年治疗组的患者在第5\~14年的子宫内膜癌发病率上升至 $3 . 1 \% ^ { [ 1 1 3 ] }$ 。 NSABP P‑1 研究显示，尽管他莫昔芬与安慰剂相比显著增加了子宫内膜癌的发病率（ $1 . 3 \%$ 与 $0 . 5 \%$ ），但主要发生于岁及以上的人群，50岁以下者使用他莫昔芬与安慰剂相比的子宫内膜癌发病风险无明显差异，NSABP B‑14研究观察到了同样的趋势［111‑112］。中山大学孙逸仙纪念医院的一项SEER数据库分析研究亦显示，40岁以上的激素受体阳性或阴性的乳腺癌患者发生第二原发子宫内膜癌风险均比正常人群增加［114］。韩国一项纳入60 545例乳腺癌患者的全国性研究进一步证实，在 ${ < } 4 0$ 岁的乳腺癌患者中，他莫昔芬并未增加子宫内膜癌风险，且子宫内膜癌在 ${ < } 4 0$ 岁患者中的发病率极低，为 $( 0 . 3 4 { \sim } 0 . 6 2 ) / 1 \ 0 0 0$ 例每年［115］。此外，在 SOFT/TEXT 研究中， $\mathrm { G n R H a }$ 联合他莫昔芬组并未发现子宫内膜增厚现象［116］，这可能与GnRHa抑制人子宫内膜细胞的增殖和诱导凋亡有关［117］。因此，绝经前乳腺癌患者使用他莫昔芬是较为安全的，尤其是联合GnRHa的患者。 $48 \%$ 的专家表示从未接诊过他莫昔芬导致子宫内膜癌的患者，还有 $39 \%$ 的专家表示仅接诊过1\~3例此类患者。由于发病率很低，大多数专家表示根据其临床经验无法准确估计中国他莫昔芬治疗患者发生子宫内膜癌的概率。对于绝经前患者， $47 \%$ 的专家认为服用他莫昔芬内分泌治疗不会增加其子宫内膜癌风险，另外 $2 7 \%$ 的专家不确定；对于围绝经期或绝经后患者， $90 \%$ 的与会专家认为服用他莫昔芬内分泌治疗会增加子宫内膜癌风险。妇科B超检查子宫内膜厚度是服用他莫昔芬患者术后随访的一种常用手段，年轻患者的雌激素水平较高和他莫昔芬对子宫内膜起到弱激动剂的作用，服用他莫昔芬的年轻乳腺癌患者发生子宫内膜增厚的可能性较大［115］，因此临床上因子宫内膜增厚而反复行诊断性刮宫的患者不少见。对于服用他莫昔芬的绝经前患者， $67 \%$ 的 YBCC 专家推荐其定期监测子宫内膜厚度。而对于服用他莫昔芬的围绝经期或绝经后患者，由于子宫内膜癌风险相对较高， $91 \%$ 的专家支持定期监测子宫内膜厚度。对于接受他莫昔芬治疗的无症状的绝经后患者，多项研究分别报道了以 $5 { \sim } 1 5 ~ \mathrm { m m }$ 的子宫内膜厚度作为诊断子宫内膜病变的临界值，但具体标准在妇科学界尚未达成共识［118‑121］。北京协和医院在— 年间对例治疗期间行子宫内膜活检的患者进行了回顾性分析，发现当子宫内膜厚度 $< 1 5 ~ \mathrm { m m }$ 时，绝经前患者发生子宫内膜病变的概率不高［122］。针对子宫内膜厚度问题， $53 \%$ 的YBCC 专家认为子宫内膜厚度 ${ > } 1 0 ~ \mathrm { m m }$ 即需要临床关注或密切随访， $39 \%$ 的专家认为可放宽至$1 6 ~ \mathrm { m m }$ ，还有 $6 4 \%$ 的专家则认为对于有规律月经的患者无需关注其子宫内膜厚度。专家们进一步针对何时需要诊断性刮宫这一问题进行了投票，对于有不规则阴道流血或子宫内膜不平或息肉的患者，分别有 $7 9 \%$ 和 $76 \%$ 的专家建议诊断性刮宫；对于子宫内膜厚度 $> 1 6 ~ \mathrm { m m }$ 的患者， $40 \%$ 的专家认为需要诊断性刮宫；而对于有规律月经者， $44 \%$ 的专家认为无论子宫内膜多厚都无需诊断性刮宫。因此，不推荐单纯根据子宫内膜厚度判断年轻患者是否需要活检。相较于子宫内膜厚度，异常的超声表现（例如子宫内膜不均或内膜增厚伴丰富血流）或出现异常子宫出血，是更加明确的子宫内膜活检的指征［122］。 # （二）避孕药物和孕激素节育器一项基于亚洲人群的研究显示，人工流产是乳腺癌的独立危险因素［123］。因此，建议所有性生活活跃的年轻乳腺癌患者应采取适当的避孕措施。没有生育需求的患者可以考虑男性或女性绝育。多项研究表明激素类避孕方式与乳腺癌发病或复发风险升高有关。我国一项系统分析提示，口服避孕药可能会增加中国女性乳腺癌的发病风险（随机效应模型比值比 1.46）［124］。另有来自欧美的研究显示，外源性激素使用是乳腺导管原位癌患者术后复发的高危因素之一（5年局部复发率 $8 . 7 \%$ 与 $5 . 2 \%$ ），在诊断乳腺癌后继续使用孕激素节育环将增加乳腺癌的复发风险（未校正风险比3.39）［125‑126］。对于尚未患有乳腺癌的 BRCA1 突变基因携带者，建议避免在年轻时服用激素类避孕药。加拿大一项纳入2 492例BRCA1突变携带者的病例对照研究表明，在25岁之前服用过口服避孕药者（即使只有1次），其在40岁之前发生乳腺癌的风险显著增加（比值比 1.19\~1.45）［127］。孕激素节育器除了避孕外，还经常被用来治疗子宫内膜增厚，包括可能会用于他莫昔芬引起的子宫内膜增厚。但既往在HR阳性和HR阴性患者中开展的研究表明，孕激素节育器可能会增加乳腺癌患者的复发风险［125］。尽管相关研究结论不完全一致［128‑129］，对乳腺癌患者使用孕激素节育器（如曼月乐环）处理子宫内膜病变还是应持谨慎态度。与会专家针对乳腺癌患者是否可以放置含孕激素的宫内节育器如曼月乐环、是否可以长期服用口服避孕药均未能达成共识。为了尽量减少乳腺癌复发，无论HR状态如何，建议年轻乳腺癌患者首选屏障避孕法或不含激素的宫内节育器，尽量避免长期使用激素类避孕方法。此外，紧急避孕药对于任何女性而言都不适合作为常规避孕方式，乳腺癌患者同样应做好其他高效避孕措施。 # 中国年轻乳腺癌诊疗专家共识撰写组成员顾问（按姓氏汉语拼音排序）：江泽飞（解放军总医院肿瘤医学部）；刘荫华（北京大学第一医院）；任国胜（重庆医科大学附属第一医院）；邵志敏（复旦大学附属肿瘤医院）；宋尔卫（中山大学附属孙逸仙纪念医院）；吴炅（复旦大学附属肿瘤医院）；徐兵河（中国医学科学院肿瘤医院）执笔人：刘强（中山大学附属孙逸仙纪念医院） YBCC专家组成员（按姓氏汉语拼音排序）：陈波（中国医科大学附属第一医院）；陈佳艺（上海交通大学医学院附属瑞金医院）；陈凯（中山大学附属孙逸仙纪念医院）；陈前军（广东省中医院）; 陈蓉（北京协和医院）；陈文艳（南昌市第三医院）; 陈益定（浙江大学医学院附属第二医院）；陈占红（浙江省肿瘤医院）；程晶（华中科技大学同济医学院附属协和医院）；杜彩文（中国医学科学院肿瘤医院深圳医院）;段学宁（北京大学第一医院）；范蕾（复旦大学附属肿瘤医院）；范照青（北京大学肿瘤医院）；范志民（吉林大学第一医院）;冯继锋（江苏省肿瘤医院）；傅芳萌（福建医科大学附属协和医院）; 傅佩芬（浙江大学医学院附属第一医院）;葛睿（复旦大学附属华东医院）; 耿翠芝（河北医科大学第四医院）；龚畅（中山大学附属孙逸仙纪念医院）；管晓翔（江苏省人民医院）；郭宝良（哈尔滨医科大学附属第二医院）；郝春芳（天津市肿瘤医院）；何劲松（北京大学深圳医院）;胡夕春（复旦大学附属肿瘤医院）；黄建（浙江大学医学院附属第二医院）；黄晓波（中山大学附属孙逸仙纪念医院）;冀学宁（大连大学附属中山医院）；金锋（中国医科大学附属第一医院）；金丽（复旦大学附属妇产科医院）；李恒宇（上海长海医院）；李卉（四川省肿瘤医院）；李惠平（北京大学肿瘤医院）；李俊杰（复旦大学附属肿瘤医院）；李曼（大连医科大学附属第二医院）; 李南林（解放军空军军医大学西京医院）；李炘正（山西省肿瘤医院）; 李兴睿（华中科技大学同济医学院附属同济医院）；李志高（哈尔滨医科大学附属肿瘤医院）；厉红元（重庆医科大学附属第一医院）; 梁晓燕（中山大学附属第六医院）；廖宁（广东省人民医院）；林颖（中山大学附属第一医院）；凌瑞（解放军空军军医大学西京医院）；刘彩刚（中国医科大学附属盛京医院）; 刘红（天津医科大学肿瘤医院）；刘健（福建省肿瘤医院）；刘洁琼（中山大学附属孙逸仙纪念医院）；刘仁斌（中山大学附属第三医院）；刘蜀（贵州医科大学附属医院）；刘晓安（江苏省人民医院）；刘运江（河北医科大学第四医院）；刘真真(河南省肿瘤医院）；柳光宇（复旦大学附属肿瘤医院）; 陆劲松（上海交通大学医学院仁济医院）；罗婷（四川大学华西医院）;马斌林（新疆医科大学附属肿瘤医院）；马杰（唐山市人民医院）；马力（河北医科大学第四医院）; 毛大华（贵州医科大学附属乌当医院）；聂建云（云南省肿瘤医院）；欧江华（新疆医科大学附属肿瘤医院）；欧阳取长（湖南省肿瘤医院）；潘跃银（中国科学技术大学附属第一医院）；彭培建（中山大学附属第五人民医院）；齐晓伟（陆军军医大学附属第一医院）；钱立元（中南大学湘雅三医院）；盛湲（上海市长海医院）；史艳侠（中山大学肿瘤防治中心）；宋传贵（福建医科大学附属协和医院）；宋国红（北京大学肿瘤医院）；宋玉华（青岛大学附属医院）；孙刚（新疆医科大学附属肿瘤医院）；孙涛（辽宁省肿瘤医院）；孙正魁（江西省肿瘤医院）；唐金海（江苏省人民医院）；唐鹏（陆军军医大学第一附属医院）; 滕月娥（中国医科大学附属第一医院）佟仲生（天津医科大学肿瘤医院）；王碧芸（复旦大学附属肿瘤医院）；王海波（青岛大学附属医院）；王红霞（上海交通大学附属第一人民医院）；王建东（解放军总医院第一医学中心）；王坤（广东省人民医院）；王墨培（北京大学第三医院）；王瓯晨（温州医科大学附属第一医院）；王守满（中南大学湘雅医院）；王殊（北京大学人民医院）;王树森（中山大学肿瘤防治中心）;王水（江苏省人民医院）; 王涛（解放军总医院肿瘤医学部）；王廷（解放军空军军医大学西京医院）；王曦（中山大学肿瘤防治中心）; 王先明（深圳市第二人民医院）；王翔（中国医学科学院肿瘤医院）；王晓稼（浙江省肿瘤医院）; 王昕（中国医学科学院肿瘤医院）；王永胜（山东省肿瘤医院）；韦伟（北京大学深圳医院）；吴智勇（汕头市中心医院）；谢梅青（中山大学附属孙逸仙纪念医院）；解云涛（北京大学肿瘤医院）；熊慧华（华中科技大学同济医学院附属同济医院）；徐莹莹（中国医科大学附属第一医院）；薛妍（西安国际医学中心肿瘤医院）杨红健（中国科学院大学附属肿瘤医院）；杨华伟（广西医科大学附属肿瘤医院）；杨谨（西安交通大学第一附属医院）杨雅平（中山大学附属孙逸仙纪念医院）；姚峰（武汉大学人民医院）；叶松青（福建省立医院）；易文君（中南大学湘雅二医院）；殷咏梅（江苏省人民医院）；余科达（复旦大学附属肿瘤医院）；余之刚（山东大学第二医院）；袁芃（中国医学科学院肿瘤医院）；曾晓华（重庆大学附属肿瘤医院）；张安秦（广东省妇幼保健院）；张建国（哈尔滨医科大学附属第二医院）；张剑（复旦大学附属肿瘤医院）；张瑾（天津市肿瘤医院）；张强（辽宁省肿瘤医院）；张清学（中山大学附属孙逸仙纪念医院）；张清媛（哈尔滨医科大学附属肿瘤医院）；张少华（解放军总医院肿瘤医学部）；张毅（陆军军医大学西南医院）；郑莹（复旦大学附属肿瘤医院）；周文斌（江苏省妇幼保健院）；朱丽（上海交通大学附属第一人民医院）利益冲突所有作者均声明不存在利益冲突 # 参考文献 [1] Wang H, Tsai YH, Dong YH, et al. 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c66e7f0f4287480a9d726d98896ca9df	中华医学会	人乳头瘤病毒相关的非宫颈疾病早期预防专家共识（2025版）	·标准与规范· # 人乳头瘤病毒相关的非宫颈疾病早期预防专家共识（2025版）中华预防医学会肿瘤预防与控制专业委员会中华预防医学会疫苗与免疫分会通信作者：赵方辉，国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院流行病学研究室，北京 100021，Email：zhaofangh@cicams.ac.cn；王华庆，中国疾病预防控制中心免疫规划中心，北京 100050，Email $:$ wanghq@chinacdc.cn；张海增，国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院结直肠外科，北京 100021，Email：haizengzhang@163.com 【摘要】　人乳头瘤病毒（）相关疾病已成为严重威胁人类健康的公共卫生问题。然而，目前仅宫颈癌已具备较为完善的以HPV疫苗接种和筛查为主的预防手段，但对于HPV相关的非宫颈疾病如外阴癌、阴道癌、阴茎癌、肛门癌、头颈部恶性肿瘤、尖锐湿疣、复发性呼吸道乳头状瘤病等，国内尚未有指南和共识系统指导其早期预防策略和措施。为此，中华预防医学会肿瘤预防与控制专业委员会与中华预防医学会疫苗与免疫分会全面总结病原学和流行病学、相关非宫颈疾病的疾病负担以及早期预防证据并形成条推荐意见，旨在为相关疾病防控、妇幼保健、临床诊治、卫生管理、政策制定等相关人员提供建议和参考依据，进而减少HPV感染风险，促进HPV相关非宫颈疾病的早诊早治，降低疾病负担。【关键词】　人乳头瘤病毒；　一级预防；　二级预防；　人乳头瘤病毒疫苗；　早期诊断基金项目：中国医学科学院医学健康科技创新工程（）实践指南注册：国际实践指南注册与透明化平台（PREPARE‑2025CN914） # Expert consensus on the early prevention of human papillomavirus related non‑cervical diseases (2025 edition) Cancer Prevention and Control Committee, Chinese Preventive Medicine Association; Vaccine and Immunization Branch, Chinese Preventive Medicine Association Corresponding authors: Zhao Fanghui, Department of Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China, Email: zhaofangh@cicams. ac. cn; Wang Huaqing, National Immunization Program, Chinese Center for Disease Control and Prevention, Beijing 100050, China, Email: wanghq@chinacdc. cn; Zhang Haizeng, Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China, Email: haizengzhang@163. com 【Abstract】 Human papillomavirus (HPV)‑related diseases have become a significant public health issue, posing a serious threat to human health. However, currently, only cervical cancer has well‑established prevention measures, primarily based on HPV vaccination and screening. For other HPV‑related non‑cervical diseases such as vulvar cancer, vaginal cancer, penile cancer, anal cancer, head and neck cancer, genital warts, and recurrent respiratory papillomatosis, there are no specific guidelines or consensus to systematically guide their early prevention strategies and measures in China. Therefore, Cancer Prevention and Control Committee, Chinese Preventive Medicine Association and Vaccine and Immunization Branch, Chinese Preventive Medicine Association comprehensively summarized the etiology and epidemiology of HPV, the disease burden of HPV‑related non‑cervical diseases, and the evidence for early prevention, and formed 13 recommendations. This consensus aims to comprehensively summarize the etiology and epidemiology of HPV infection, the disease burden of HPV‑related non‑cervical diseases, and the evidence for early prevention, providing recommendations and references for relevant personnel in disease prevention and control, maternal and child health care, clinical diagnosis and treatment, health management, policy‑making, etc., and finally, reducing the risk of HPV infection, promoting early diagnosis and treatment of HPV‑related non‑cervical diseases, and decreasing the disease burden. 【Key words】 Human papillomavirus; Primary prevention; Secondary prevention; Human papillomavirus vaccines; Early diagnosis Fund program: Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021‑I2M‑1‑004) Practice guideline registration: Practice Guideline Registration for Transparency (PREPARE‑2025CN914) 人乳头瘤病毒（）是一种嗜上皮组织的无包膜双链环状小DNA病毒，可引起人体皮肤/黏膜上皮发生一系列增生性病变［1］。不同型别的感染可引起不同疾病，低危型（）通常可引起尖锐湿疣或复发性呼吸道乳头状瘤病（）等良性疾病［1］，而高危型（）的持续感染则与子宫颈、肛门、生殖器和口腔、口咽等头颈部位的多种恶性肿瘤与癌前病变相关［2］。目前在HPV相关疾病的预防管理中，仅宫颈癌已具备较为完善的以疫苗接种、筛查和早诊早治为主的预防措施。在相关非宫颈部位疾病预防方面，一级预防多通过健康教育、健康促进以及HPV疫苗接种为主。在健康教育与健康促进方面，当前公众对HPV相关疾病的认知大多集中于宫颈癌和女性防控，对非宫颈疾病防控的了解有限；在疫苗接种方面，我国目前接种群体以女性为主，但适龄女性HPV疫苗接种覆盖率偏低［3］。一些国际指南共识中虽建议将男女均纳入疫苗接种对象［4］，但尚未系统梳理男性接种HPV疫苗预防HPV相关疾病的研究证据。在二级预防方面，我国缺乏指南共识明确针对HPV相关非宫颈疾病的筛查和早诊早治策略与措施［5‑7］。综上，亟需制定系统、全面的早期预防策略，以减少感染在人群中的影响［8］。基于此，中华预防医学会肿瘤预防与控制专业委员会与中华预防医学会疫苗与免疫分会邀请领域内专家，就HPV病原学和流行病学、相关非宫颈疾病的流行病学以及早期预防策略和措施等相关问题进行分析整理和深入探讨，形成本共识。 # 第一部分共识制订方法学 # 一、共识发起机构与专家组成员本共识由中华预防医学会肿瘤预防与控制专业委员会与中华预防医学会疫苗与免疫分会牵头，专家组由来自公共卫生与预防医学（流行病学、公共卫生等）、临床医学（肿瘤学、传染病、皮肤病、妇产科、耳鼻喉、头颈外科、泌尿科）等领域的34名专家组成。 # 二、共识目的和目标人群本共识旨在规范和优化HPV相关非宫颈疾病的早期预防策略和措施，减少HPV感染风险，促进相关非宫颈疾病的筛查和早诊早治，进而降低疾病负担。本共识面向的目标人群为从事 HPV相关非宫颈疾病早期预防的疾病防控、妇幼保健、临床诊疗（妇产科、皮肤科、儿科、耳鼻喉科、泌尿科、男科、肿瘤科、感染科等）、基础研究、卫生管理、政策制定等相关人员。 # 三、文献检索和共识形成过程本共识自2024年10月起开始筹备，起草组在、中国知网、万方医学等数据库全面检索了2014年1月至2025年4月HPV相关非宫颈疾病防控的文献，重点关注黏膜型HPV型别相关非宫颈疾病的早期预防，主要包括外阴癌、阴道癌、阴茎癌、肛门癌、头颈部恶性肿瘤、尖锐湿疣、RRP的早期预防。所使用关键词主要包括：humanpapillomavirus、 HPV、 infection、 epidemiology、burden、 incidence、 prevalence、 mortality、 vulvarintraepithelial neoplasia、vulvar neoplasm、cancer ofthe vulva、vaginal intraepithelial neoplasia、vaginalneoplasm、cancer of the vagina、penile neoplasm、penis cancer、cancer of the penis、head and neckneoplasm、cancer of head and neck、oropharyngealcancer、cancer of the oropharyn $\setminus$ 、oral cancer、cancer oforal cavity、 hypopharyngeal cancer、 cancer ofhypopharyn、laryngeal cancer、cancer of the larynx、anal intraepithelial neoplasia、anus neoplasm、analneoplasm、 condyloma acuminatum、 genitalcondyloma、 anogenital condyloma、 recurrentrespiratory papillomatosis、HPV vaccine、vaccination、screening、 early diagnosis、 prevention、 healtheducation、health promotion、人乳头瘤病毒、人乳头瘤病毒感染、流行病学、负担、发病率、患病率、死亡率、外阴上皮内瘤变、外阴肿瘤、外阴癌、阴道上皮内瘤变、阴道肿瘤、阴道癌、阴茎肿瘤、阴茎癌、头颈部肿瘤、口咽癌、口腔癌、下咽癌、喉癌、肛门癌、肛管癌、肛门部位肿瘤、肛门上皮内瘤变、尖锐湿疣、肛门生殖疣、复发性呼吸道乳头状瘤病、HPV疫苗、疫苗接种、筛查、早期诊断、预防、健康教育、健康促进等。 # 四、共识推荐程度本共识使用目前国际上较为权威且应用范围较广的卫生系统中证据推荐分级的评估、制订与评价（GRADE）系统（表1）［9］。其中，证据水平A为高等水平证据，来源于结果一致的多项随机临床试验或荟萃分析；证据水平B为中等水平证据，来源于单项随机临床试验或多项非随机对照研究；证据水平为低等水平证据，仅为专家共识意见和（或）回顾性研究。专家组对初稿进行次会议研讨，采用线上投票的形式，对每一条推荐意见及其强度勾选“强推荐”“弱推荐”或“不推荐”。针对单条推荐意见，获得“强推荐”的票数达到或超过投票专家数的2/3，则确定为强推荐；“弱推荐” $^ +$ “强推荐”的票数超过2/3，则确定为弱推荐；否则不达成共识。 # 第二部分 HPV病原学和流行病学 # 一、HPV病原学是一种嗜上皮组织的无包膜双链环状小DNA 病毒，其直径为 $5 0 { \sim } 5 5 ~ \mathrm { n m }$ ，病毒基因组约$8 ~ \mathrm { k b }$ ，具有上皮细胞趋向性，可感染皮肤和黏膜。HPV基因组可分为3个区域：早期区域（包含开放阅读框、、、、、）、晚期区域（包含开放阅读框和），以及非编码上游调节区，又称为长控制区域［10］。L1开放阅读框是HPV基因组中个最保守的序列，因此被广泛用于新型HPV病毒的鉴定。HPV型别的区分主要基于一个位于L1 开放阅读框架基因上 $2 9 1 ~ \mathrm { b p }$ 的片段，如 HPV 基因组序列存在 $10 \%$ 及以上的差异，即为不同的基因型别［11‑12］。目前已发现并分离鉴定出多种HPV型别，根据主要感染部位，可分为皮肤型和黏膜型；根据其诱发癌症的潜力，可分为HR‑HPV与LR‑HPV。HR‑HPV主要包括16、18、31、33、35、39、45、51、52、56、58、59、66、68 型等，被公认可能致癌；LR‑HPV 主要包括 6、11、40、42、43、44、54、61、、、型等，可能引起尖锐湿疣、或其他良性病变［10］。 C # 二、HPV感染流行病学 # （一）HPV传染原、传播途径、易感人群 HPV的传染源为HPV感染者，传播途径包括：（）性传播途径：主要通过同性或异性性行为中的黏膜接触造成感染，是最主要的传播途径；表1 GRADE证据的推荐质量分级与定义 <table><tr><td>项目</td><td>内容</td></tr><tr><td>证据等级</td><td></td></tr><tr><td>高（A）</td><td>非常有把握：观察值接近真实值</td></tr><tr><td>中(B）</td><td>对观察值有中等把握：观察值有可能接近真实值,但仍有可能差别很大</td></tr><tr><td>低（C）</td><td>对观察值的把握有限：观察值可能与真实值有较大差别</td></tr><tr><td>极低(D）</td><td>对观察值几乎无把握：观察值与真实值可能有极大差别</td></tr><tr><td>推荐等级</td><td></td></tr><tr><td>强(1）</td><td>明确显示干预措施利大于弊或弊大于利</td></tr><tr><td>弱(2）</td><td>利弊不确定或无论治疗高低的证据均显示利弊相当</td></tr></table> 注：GRADE为证据推荐分级的评估、制订与评价（2）皮肤黏膜接触：可通过直接接触感染者的皮肤或黏膜而传播，其感染风险相对较低，但当皮肤或黏膜存在微小损伤时，感染风险将显著增加；（）母婴传播：常见于生殖道感染的母亲在分娩过程中传给新生儿，如儿童 RRP 可能是患儿在分娩过程中从阴道分泌物获得 HPV‑6/11 感染所致；（4）其他传播途径：如医源性传播，该传播方式较为罕见，但在医疗过程中，若医务人员未严格遵守无菌操作原则，或使用的医疗器械未经充分消毒，也可能导致HPV的医源性传播。感染人体后主要通过两个通路引发疾病：（）感染扩增通路：病毒在人体内完成病毒复制的生命周期，通常不会引起癌变；（2）转化通路：HR‑HPV病毒基因整合进人基因组，E6和E7癌蛋白过度表达，进而引发癌症［13］。多数HPV感染为一过性感染，超过 $80 \%$ 的感染可在个月内被机体自然清除，仅有少数HR‑HPV持续感染可发展为癌前病变和癌症［14］。LR‑HPV感染上皮细胞之后，会导致细胞出现异常的增殖与分化现象，最终逐渐形成疣体。除一般人群之外，HPV感染的高风险人群主要可分为以下几类：（1）免疫缺陷人群：具有遗传或获得性免疫功能受损的群体，主要包括原发性免疫缺陷病患者、人类免疫缺陷病毒（HIV）感染者、艾滋病（AIDS）患者、实体器官移植受者、造血干细胞移植受者、正接受化学治疗的恶性肿瘤患者、因风湿免疫性疾病等接受糖皮质激素长期治疗者、正在接受其他免疫抑制剂治疗者等［15‑16］；（）具有以下性行为的人群：包括男男性行为人群（MSM）、多性伴人群、性生活频繁者、初次性生活年龄低的女性等［17‑18］；（3）具有其他HPV感染高危因素的人群：包括多孕多产、吸烟、长期口服避孕药、营养失衡等行为因素、生物学因素（主要包括细菌、病毒和衣原体等各种微生物感染）等，上述因素均可能增加HPV感染风险［13，19］。 # （二）一般人群HPV感染特征一项多中心流行病学研究数据显示，在我国女性健康体检人群中，宫颈部位 HPV 感染率为$1 7 . 7 0 \%$ ，其中感染率为 $1 3 . 1 2 \%$ ,LR-HPV感染率为 $4 . 5 8 \%$ 。中，感染最为常见，感染率达 $4 . 4 0 \%$ ，随后依次为HPV‑58（ $2 . 6 5 \%$ ）、16（ $2 . 1 5 \%$ ）等；LR‑HPV 中，HPV‑61（ $1 . 7 5 \%$ ）、81（ $1 . 7 4 \%$ ）、42（ $1 . 6 4 \%$ ）是常见的感染型别［20］。一项广东和河北的研究显示，在口腔部位女性年龄标准化HPV感染率为 $2 . 7 \% ^ { [ 2 1 ] }$ ；在外阴部位，我国女性HPV感染率为 $2 2 . 3 2 \%$ ，其中HR‑HPV感染率为$1 7 . 6 9 \%$ ，感染率为 $5 . 1 3 \% ^ { [ 2 2 ] }$ 。对于男性感染率，一项纳入项研究的荟萃分析显示，中国男性门诊就诊人群中HPV感染率为 $5 2 . 4 5 \%$ ，其中最常见的亚型为HPV-6( $1 9 . 0 6 \%$ ）、 $. 1 1 ( 1 3 . 7 1 \%$ ）和 $1 6 ( 8 . 2 9 \% )$ ）。具体部位中，门诊男性肛门部位、头颈部位、生殖器部位的任一型别HPV感染率分别为 $4 6 . 4 0 \% , 3 1 . 9 4 \%$ 、$6 6 . 2 5 \%$ 。在健康体检男性人群中HPV感染率为$7 . 8 9 \%$ ，其中感染率最高的亚型为 $\mathrm { H P V } { - } 1 6 \big ( 3 . 6 6 \% \big )$ 、5 $2 ( 1 . 3 7 \%$ ）和 $5 8 \ : ( 1 . 1 9 \%$ ）。在健康体检男性人群中，肛门部位、头颈部位、生殖器部位的任一型别HPV感染率分别为 $5 . 3 4 \% . 3 . 4 2 \%$ 及 $8 . 4 3 \% ^ { [ 2 3 ] }$ 。在感染年龄分布方面，女性宫颈部位HPV感染的年龄分布通常呈双峰模式，感染高峰年龄分别为 $\leqslant 2 0$ 和 $5 6 { \sim } 6 0$ 岁，在 26\~50 岁人群中呈现较低水平（ $\leqslant 1 7 \%$ ）；而男性外生殖器部位HPV感染则未发现明显的年龄高峰［24］。 # （三） HPV易感人群的感染特征在免疫缺陷的个体中（如阳性人群），免疫功能异常可能导致HPV的持续感染和广泛感染，引起难治性皮肤和肛门生殖器疣或癌前病变，并可能增加 HPV相关恶性肿瘤的发生风险［15］。一项基于中国人群的荟萃分析研究显示，中国 HIV/AIDS者的HPV感染率为 $5 2 . 5 4 \%$ ，男性HIV/AIDS者HPV感染率 $( 7 4 . 6 \%$ ）高于女性 $( 4 1 . 0 \%$ ），HR‑HPV感染率$( 3 9 . 0 \%$ ）高于感染率（ $( 2 3 . 9 \%$ ）［25］。由于的性行为方式特殊，女性接种疫苗所形成的免疫屏障无法对这一人群起到保护作用，所以该人群属于HPV易感人群。一项荟萃分析显示，中国MSM的肛门HPV感染率约为 $8 5 . 1 \%$ （HIV 阳性）、 $5 3 . 6 \%$ （HIV阴性）和 $5 9 . 2 \%$ （未知HIV状态），其中 HPV 基因型以 HPV‑6、11、16、18、52 和 58 为主［17］。初次性行为年龄过早、多个性伴侣等因素均能增加生殖道HPV感染的机会。有研究显示，初次性生活年龄 ${ \leqslant } 1 9$ 岁的女性以及性伴侣数目 $\geqslant 2$ 人的女性宫颈HPV感染率分别为 $1 7 . 8 \%$ 和 $1 5 . 7 \%$ ，显著高于初次性生活年龄 ${ \displaystyle > } 1 9$ 岁女性（ $1 2 . 5 \%$ ）以及性伴侣数为1人的女性（ $1 2 . 4 \%$ ）感染率［26］。一项纳入4 026名男性的横断面研究显示，当前吸烟者的外生殖器感染率 $( 4 2 . 1 \%$ ）显著高于既往吸烟者（ $( 3 7 . 3 \%$ ）和从不吸烟者 $( 3 4 . 9 \% ) ^ { [ 2 7 ] }$ 。HPV感染常合并其他生殖道病原体感染，这些病原体进一步增加了生殖道对HPV的易感性。研究显示，宫颈炎症、滴虫感染人群的 HPV 阳性率显著高于未感染人群［28］。（四）相关的非宫颈疾病流行病学相关的非宫颈疾病负担及其变化趋势：近年来，HPV相关非宫颈疾病的发生率不断上涨。根据2022年世界卫生组织（WHO）发布的全球癌症统计报告（以下数据中统计的病例不区分感染状态），女性人群的外阴癌和阴道癌的年龄标准化发病率（ASIR）分别为 0.83/10 万和 0.36/10 万，年龄标准化死亡率（ASMR）分别为 0.30/10万和 0.15/万［29］。男性人群中，阴茎癌和分别为 0.79/10 万和 0.28/10 万［30］。目前关于外阴癌、阴道癌和阴茎癌的全球总体 5 年生存率报道较少。欧洲一项大型研究显示，外阴癌和阴道癌患者5年生存率分别为 $62 \%$ 和 $4 0 \% ^ { [ 3 1 ] }$ ；美国和欧洲的数据显示阴茎癌患者的年生存率分别为 $6 3 \%$ 和 $7 0 \% ^ { [ 3 2 ] }$ 。中国人群中，女性外阴癌和阴道癌的 ASIR 分别为万和万，分别为万和0.08/10 万［29］；外阴癌患者 5 年生存率约为$6 0 . 5 \% ^ { [ 3 3 ] }$ ，阴道癌患者5年生存率约为 $7 9 . 0 \% ^ { [ 3 4 ] }$ 。男性阴茎癌的 ASIR 和 ASMR 分别为 0.49/10 万和0.18/10 万［29］，基于超过 1 000 例中国男性阴茎癌患者的预后研究显示，其5年生存率约为 $6 7 . 3 \% ^ { [ 3 5 ] }$ 。男女共患病则涉及多种疾病，包括肛门癌、头颈部恶性肿瘤、尖锐湿疣以及等。年全球的肛门、口腔、口咽的恶性肿瘤 ASIR 分别为 $0 . 5 4 /$ 10 万、4.00/10 万和 1.10/10 万，ASMR 分别为 $0 . 2 1 /$ 10 万、1.90/10 万和 0.53/10 万［29］；美国监测、流行病学和结果数据库（SEER）数据显示，肛门癌以及口腔/口咽癌的 5 年相对生存率分别为 $7 1 . 3 \%$ 、$6 9 . 5 \% ^ { [ 3 6 . 3 7 ] }$ 。中国的肛门、口腔、口咽的恶性肿瘤ASIR 分别为 0.22/10 万、1.50/10 万和 0.33/10 万，ASMR 分别为 0.15/10 万、0.78/10 万和 $0 . 1 9 / 1 0$ 万［29］；根据我国华南地区的一项多中心研究，我国肛门癌患者5年生存率约为 $8 2 . 8 \% ^ { [ 3 8 ] }$ ；全国口腔/口咽癌患者 5 年生存率约为 $4 7 . 0 \% ^ { [ 3 9 ] }$ 。一项 HPV 相关疾病负担研究显示，2007—2015年中国HPV相关癌症的新发病例数每年增加 $3 . 8 \%$ ，ASIR 增幅为$3 . 0 \% ^ { [ 4 0 ] }$ ；女性人群中，肛门癌和外阴癌新发病例每年分别增加 $6 . 5 \%$ 和 $3 . 7 \%$ ；男性疾病中，肛门癌、口咽癌病例每年分别增加 $7 . 5 \%$ 和 $4 . 4 \%$ ，预计到2030 年，中国 HPV 相关肿瘤的 ASIR 预计达 $9 . 3 5 /$ 10万人［40］。我国HPV相关良性疾病的流行病学数据相对较少且差异较大：2008—2016年尖锐湿疣报告发病率为 24.65/10 万\~29.47/10 万，其中男性发病率为 25.91/10 万 \~28.97/10 万，女性为 23.30/万万［41］。目前我国尚无相关流行病学数据，但其在全球发病率为 0.02/10 万 $\sim 2 . 8 0 /$ 10 万［42］。归因风险及不同疾病人群中感染情况：研究显示，肛门癌、阴道癌、阴茎癌、口咽癌、外阴癌、喉癌和口腔癌归因于HPV感染的人群归因分值（PAF）分别为 $8 8 . 0 \% . 7 8 . 0 \% . 4 8 . 0 \% . 2 9 . 0 \% .$ 、$2 4 . 1 \% . 4 . 6 \%$ 和 $4 . 3 \% ^ { [ 4 3 ] }$ 。不同疾病中的 HPV 感染型别存在差异。女性疾病中，外阴癌以HPV‑16（ $78 . 1 \%$ ）和 $\mathrm { H P V } { - } 3 3 \left( 7 . 5 \% \right)$ 为主［44］，阴道癌则以 HPV‑16（ $4 9 . 4 \%$ ）和 HPV‑52（ $1 5 . 2 \%$ ）为主［45］。男性阴茎癌中以 HPV‑16（64/74， $8 6 . 5 \%$ ）和HPV-18 $( 6 / 7 4 , 8 . 1 \% )$ ）为主［46］。在肛门癌中，HPV‑16占所有HPV阳性肛门癌的 $73 \%$ ；HPV‑18是第二常见类型，约占 $5 \% ^ { [ 4 7 ] }$ 。头颈部恶性肿瘤则与和关系密切。一项荟萃分析显示，头颈部肿瘤病例中的总感染率为 $2 4 . 7 \%$ ，其中口咽癌为 $3 1 . 6 \%$ ，喉癌为 $2 8 . 5 \%$ ，口腔癌为$1 4 . 9 \% ^ { [ 4 8 ] }$ ； $\mathrm { H P V } { - } 1 8$ 总感染率为 $6 . 0 \%$ ，其中喉癌为$3 1 . 2 \%$ ，口腔癌为 $7 . 2 \%$ ，口咽癌为 $0 . 6 \% ^ { [ 4 9 ] }$ 。在上述肿瘤中，与感染相关的组织病理学类型以鳞状细胞癌为主。HPV良性疾病中的HPV型别则多为低危型：在尖锐湿疣中，LR‑HPV感染、多种型别感染、感染的检出率分别为 $4 9 . 4 8 \%$ 、$2 4 . 9 2 \%$ 和 $5 . 9 7 \%$ ；其中，和是主要的感染型别，感染率分别为 $3 5 . 2 0 \%$ 和 $2 2 . 5 2 \%$ ，且多为单一感染［50］。中国儿童 RRP 患者 HPV 总感染率为$9 2 . 0 \%$ ，以和为主，感染率分别为 $4 2 . 4 \%$ 和 $7 2 . 3 \% ^ { [ 5 1 ] }$ 。 # （五）早期预防策略和措施的证据及循证的推荐推荐意见及说明根据疾病发生发展过程以及健康影响因素的特点，可把预防策略按等级分类，称为三级预防。因本共识强调HPV相关的非宫颈疾病的早期预防，且相关疾病的第三级预防（又称临床防治，是在疾病的临床期为了减少疾病的危害而采取的措施，可以防止伤残和促进功能恢复，提高生活质量）已有规范的临床诊疗指南参考，故本共识着重对HPV相关的非宫颈疾病一级和二级预防进行介绍。一级预防：指在疾病尚未发生时，针对病因或危险因素采取措施，以降低 HPV暴露的水平，增强个体对抗HPV暴露的能力，从而预防HPV相关疾病的发生，具体措施包括健康教育和健康促进、HPV疫苗接种等。二级预防：是指在疾病尚处于临床前期或无症状的阶段，通过早期发现、早期诊断和早期治疗 HPV感染相关疾病，阻止疾病进展和恶化，具体包括针对高危人群定期进行临床检查（如细胞学检查、HPV检测等），对发现的良性病变及癌前病变及时采取局部治疗，阻断疾病进展。 1.外阴癌及阴道癌：外阴癌是一种少见的妇科恶性肿瘤，可发生于外阴的皮肤、黏膜及其附件组织，主要病理学类型有鳞癌、恶性黑色素瘤、腺癌、基底细胞癌、肉瘤及转移性癌。外阴癌占所有女性生殖系统恶性肿瘤的 $2 \% \sim 5 \%$ ，多发生于绝经后妇女［5］。阴道癌是指癌灶局限于阴道壁，无子宫颈癌、外阴癌的组织学证据的阴道恶性肿瘤，也可继发于邻近器官恶性肿瘤，如子宫颈、外阴、直肠等。大多数阴道癌的组织学类型为鳞状细胞癌，但也有黑色素瘤、肉瘤、腺癌及其他组织学类型［6］。与外阴癌相似，阴道癌也是较为少见的妇科恶性肿瘤，占成年妇科恶性肿瘤的 $1 \% \sim 2 \%$ ，占女童妇科恶性肿瘤的 $4 . 5 \% ^ { [ 6 }$ ］。（1）一级预防：因外阴癌、阴道癌在一般人群中的发病率均处于较低水平，故其预防策略和措施主要基于高风险人群进行。绝经后妇女罹患外阴癌的风险更高，此外，HPV感染者、免疫缺陷人群、吸烟人群、外阴慢性炎症疾病人群均具有更高的外阴癌发生风险［52］。对于阴道癌来说，除 HPV感染者、免疫缺陷人群、绝经后女性的发病风险较高之外，子宫切除史、阴道壁反复损伤、盆腔放疗史、母亲妊娠期间口服雌激素（己烯雌酚）、有宫颈癌病史的患者等人群的阴道癌发病风险也高于普通人群［53］。应对上述高风险人群进行积极健康教育，并可指导此类人群进行外阴自检操作，在出现疑似表现或症状时积极就诊。同时，对于相关外阴及阴道癌高风险人群，应注意保持健康的生活习惯（如戒烟、健康饮食、合理运动等），提高自身免疫力。研究证据表明，性生活活跃女性的性伴侣持续使用安全套可以显著避免女性的宫颈和外阴/阴道部位HPV感染［54］。因此，对于性伴侣进行安全性行为教育，引导其进行安全性行为（如佩戴安全套）可以有助于预防女性HPV感染，以降低外阴/阴道部位癌症和癌前病变发生风险。近年间，陆续有研究显示，二价、四价、九价疫苗均对外阴和阴道癌前病变有较好的预防效果［55‑56］。一项汇总了已发表 HPV 疫苗临床试验的荟萃分析研究显示，在未感染或未感染疫苗包含型别的年轻女性（岁）中，接种疫苗对感染相关高级别外阴和阴道病变的保护效力超过 $90 \%$ ，与HPV疫苗对宫颈癌及癌前病变的保护效力相当［57］。丹麦一项纳入514 537名17\~26岁女性的调查研究显示，与未接种疫苗的女性相比，岁之前接种疫苗的女性阴道高级别鳞状上皮内病变风险降低了 $84 \%$ ；对于17\~26岁接种疫苗的女性，阴道高级别鳞状上皮内病变的发生风险与未接种疫苗女性类似，提示疫苗接种年龄越小，对阴道高级别鳞状上皮内病变的保护效力可能越好［58］。美国一项报道显示，引入HPV疫苗后的17年内，15\~19岁女性的阴道癌前病变发病率每年下降 $1 9 . 1 \%$ ，高级别外阴癌前病变发病率每年下降$2 1 . 0 \% ^ { [ 5 9 ] }$ 。此外，HPV疫苗接种对外阴和阴道浸润性癌症也可能存在保护效果。一项研究对 $1 6 \sim$ 17岁接种二价或四价HPV疫苗的3 341名女性（接种组）及16 526名年龄与接种组分布一致、来源于般人群的未接种HPV疫苗女性（对照组）进行随访，发现接种组未出现任何HPV阳性浸润性癌症（宫颈癌、阴道癌、外阴癌等），而对照组发生17例，证明疫苗保护效力为 $1 0 0 \% ^ { [ 5 6 ] }$ 。综上，适龄女性尽早接种HPV疫苗，在预防宫颈癌的同时，可以最大程度降低外阴/阴道部位癌前病变和癌症的风险。（2）二级预防：鉴于外阴癌、阴道癌发病率低，对其进行大规模筛查的成本效益比较低，故不推荐对全人群进行外阴癌及阴道癌常规筛查，但在女性行常规宫颈癌筛查时可同时加强外阴和阴道的检查，以实现外阴和阴道部位病变的发现和早期诊断。国际妇产科联盟（）发布的癌症报告中的外阴癌诊治指南部分鼓励硬化性苔藓（一种与外阴癌发生发展有关的疾病）患者进行自检；对有多年外阴瘙痒史并伴有外阴白斑或经久不愈的糜烂、外阴结节、乳头状瘤、尖锐湿疣及溃疡等可疑病变的患者，应及时进行组织病理学活检；已确诊宫颈、肛门部位鳞状上皮内病变的女性在阴道镜随访中必须同时检查外阴和阴道部位［60‑61］。 FIGO 2021癌症报告中的阴道癌诊治指南部分以及我国阴道恶性肿瘤诊断与治疗指南（2021 年版）均指出，多次宫颈锥切术后仍持续有宫颈高级别鳞状上皮内病变或持续HR‑HPV阳性的女性，推荐采用细胞学检查、阴道镜长期随访阴道情况。目前的横断面和回顾性研究均显示，有阴道癌筛查指征的人群，HPV、细胞学检查可作为主要筛查手段以助于发现阴道早期病变［6，62］。因此，对具有阴道癌高危因素的人群可定期进行联合细胞学检查，异常者及时转诊阴道镜检查，以实现阴道癌或阴道癌前病变早期诊断并加以干预［6，63‑64］，但目前尚缺乏大规模前瞻性随机对照研究进一步验证其筛查效果。推荐意见1：对具有外阴癌和阴道癌高危因素的女性加强健康教育，包括自检方式、健康生活方式以及安全性行为教育，同时应重视其性伴侣的安全性行为教育；推荐无接种禁忌证的适龄女性尽早接种疫苗，在预防宫颈癌的同时预防相关外阴/阴道癌及癌前病变。（A级证据，强推荐）推荐意见2：推荐行常规宫颈癌筛查时行常规外阴检查，对外阴癌高危人群推荐自检，已确诊宫颈、肛门部位鳞状上皮内病变的女性在阴道镜检查中应常规检查外阴部位。（B级证据，强推荐）推荐意见3：推荐行常规宫颈癌筛查时同时加强阴道检查，有阴道癌筛查指征的人群应定期进行联合细胞学检查。（级证据，弱推荐） 2.阴茎癌：阴茎癌为起源于阴茎头、包皮、冠状沟、阴茎体部的恶性肿瘤［65］，其中 $9 5 \%$ 的组织学类型为鳞状细胞癌。阴茎癌是一种非常少见的恶性疾病，其在男性癌症新发病例中占比不足 $1 \%$ 。（）一级预防：感染、包茎、慢性阴茎炎症（与包茎有关的龟头包皮炎）、硬化性苔藓病、吸烟、多个性伴侣等均与较高的阴茎癌发病率呈正相关，而包皮环切术是阴茎癌的主要保护因素，尤其是包茎患者［65‑66］。一项荟萃分析报告，在儿童时期接受包皮环切将降低 $67 \%$ 的阴茎癌发病风险［67］。此外，全球性数据显示，包皮环切率越高的地区，其阴茎癌发病率越低，二者在地区层面呈显著负相关［67］。应对存在上述高危因素的人群进行日常健康教育，同时倡导此类人群养成健康生活习惯，如戒烟、注意局部卫生（尤其是未行包皮环切术的人群）、使用安全套、减少性伴侣数量等。同时，具有上述危险因素的人群应警惕阴茎头皮肤溃疡、红斑、硬结、异常分泌物等表现，如出现疑似症状或体征时应及时就诊。目前关于疫苗接种对阴茎癌保护作用的研究证据有限［68］。一项Ⅲ期临床试验显示，相比未接种HPV疫苗者，接种者HPV‑6、11、16和18型相关的外生殖器病变（尖锐湿疣、阴茎、肛门和肛门上皮内瘤变，或阴茎、肛门癌症）的发生率约下降 $7 8 . 9 \% ^ { [ 6 9 ] }$ 。另一项全球性系统综述显示，四价HPV疫苗预防HPV‑6、11、16或18型男性相关外生殖器病变（包括外生殖器尖锐湿疣、阴茎上皮内瘤变、会阴上皮内瘤变、阴茎和会阴癌）的有效率为$9 1 . 8 \% ^ { [ 7 0 ] }$ 。（2）二级预防：因阴茎癌发病率较低，且目前国内外发布的阴茎癌相关诊疗指南中均未提供可用于阴茎癌的筛查措施，故不推荐对全人群进行阴茎癌筛查［71］。然而，由于阴茎癌与 HPV 具有较强的关联性，欧洲泌尿外科学会（EAU）、美国临床肿瘤协会（ASCO）、欧洲肿瘤内科学会（ESMO）等发布的阴茎癌诊疗指南指出，对于可疑的阴茎病变需进行组织病理学活检，且阴茎部位标本的病理学评估需包括对HPV感染状态的评估［71‑72］。推荐意见4：推荐对具有阴茎癌高危因素的男性加强健康教育，包括包茎患者行包皮环切术、健康生活方式、安全性行为教育、注意局部卫生等；推荐无接种禁忌证的适龄男性接种HPV疫苗以预防相关阴茎癌。（级证据，强推荐）推荐意见5：推荐可疑的阴茎病变应进行组织病理学活检，病理学评估应包括对HPV感染状态的评估。（C级证据，弱推荐） 3.肛门癌：肛门包括肛管和肛周。肛管可分为解剖学肛管和外科学肛管，其中解剖学肛管指肛缘至齿状线的部分，平均长度约 $2 \mathrm { c m }$ ；外科学肛管指肛缘至肛管直肠环平面部分 $3 { \sim } 5 ~ \mathrm { c m } ^ { [ 7 3 ] }$ 。由于解剖学边界重叠、组织学特征交叉和临床指南演变等原因，肛管癌和肛周肿瘤的定义标准不一。分类以齿状线为界区分肛管与肛周，美国国立综合癌症网络（NCCN）指南将肛缘肿瘤单独列出，并将肛管癌严格限定为齿状线至肛缘病变。美国癌症联合委员会（）分期系统中将肛管癌分期独立于肛周癌（后者按皮肤癌分期）。肛门癌根据病理类型可分为鳞状细胞癌、恶性黑色素瘤、基底细胞癌、间质瘤等，其中 $9 5 \%$ 的组织学类型为鳞状细胞癌，其他组织学类型较为少见。（1）一级预防：肛门癌常见危险因素包括HPV感染史、性传播疾病史、多个性伴侣、肛交、免疫缺陷、吸烟等。MSM，尤其是HIV感染的MSM的肛门癌发病风险显著高于普通人群。应对上述高风险人群进行健康教育，告知 HPV 感染的风险以及可能症状，并建议该部分人群避免高危性行为，科学使用安全套，以减少肛周皮肤损伤风险，若出现可疑症状及时就诊。此外，高危人群应通过改变生活方式，如戒烟、戒酒、合理膳食（如减少红肉类及腌制品摄入、注重植物饮食、增加粗粮蔬菜水果摄入、根据排便状况调整饮食）、保持良好的精神状态等预防肛门癌的发生。目前肛门癌的诊疗指南中仍以HPV疫苗接种作为HPV相关肛门上皮内瘤变和肛门癌首选的预防手段。现有的疫苗均可有效预防男、女性肛门上皮内瘤变（）和肛门感染，特别是对于 ${ \leqslant } 2 6$ 岁未感染HIV的人群，接种HPV疫苗可有效预防新发肛门HPV感染［74］。一项荟萃分析显示，疫苗对男性的保护效力为 $9 1 . 1 \% \cdot$ \~$9 3 . 1 \%$ ，对和肛门癌的保护效力为 $8 9 . 6 \%sim$ $9 1 . 7 \% ^ { [ 7 5 ] }$ 。此外，在肛门癌高危人群如MSM人群中也观察到了HPV疫苗的显著保护效力。一项基于16\~26岁性活跃MSM的随机对照试验研究结果显示，疫苗接种可以有效预防肛门部位疫苗相关型别的HPV感染和相关的 $\mathrm { A I N } ^ { [ 7 6 ] }$ 。综上，适龄人群应接种HPV疫苗以预防HPV相关肛门癌、AIN和肛门部位HPV感染。（2）二级预防：目前国内外指南尚不推荐对一般人群进行常规肛门癌筛查，但对于 HIV 感染者、MSM、长期肛交史、广泛下生殖道癌前病变者、免疫缺陷人群、长期使用激素治疗人群以及长期接受免疫抑制治疗人群等肛门癌高危人群，有必要进行肛门癌筛查［7，77‑78］。目前推荐的主要筛查方法为肛门细胞学检查和肛门直肠指检，以高分辨率肛门镜检查进行早期诊断。而国际肛门瘤变协会（IANS）提出了肛门细胞学和 HR‑HPV 检测作为主要筛查方式［78‑79］。基于大型前瞻性队列的研究证实，通过不同初筛 $^ +$ 分流等组合将肛门细胞学和高危HPV检查联合使用，相比于单独使用肛门细胞学检查或HR‑HPV 检测，其检出 AIN 的特异性将显著提高，而敏感性仅轻微下降［79‑80］，并可以减少高分辨率肛门镜的转诊。国内肛门上皮内瘤变诊治专家共识中明确了高分辨率肛门镜的检查指征，建议对于肛门细胞学异常者（意义不明确的不典型鳞状细胞及以上者）、肛门HPV‑16或18阳性、临床可疑肛门癌前病变者（如外阴、阴道或子宫颈癌前病变可疑累及肛门者等）进行高分辨率肛门镜检查。推荐意见6：对具有肛门癌高危因素的人群加强健康教育，倡导其通过科学使用安全套、避免高危性行为、戒烟、戒酒、合理膳食等方式预防肛门癌；推荐无接种禁忌证的适龄人群通过接种疫苗预防 HPV 相关肛门癌、AIN 和肛门部位 HPV 感染。（A级证据，强推荐）推荐意见7：针对肛门癌高危人群推荐采用肛门细胞学和（或）检测进行筛查，细胞学异常、HPV‑16或18型阳性、临床可疑肛门癌前病变者需转诊高分辨率肛门镜检查。（B级证据，弱推荐） 4.头颈部恶性肿瘤：头颈部恶性肿瘤是位于锁骨以上区域的恶性肿瘤的合称，上界为颅底、后界为颈椎。国际上通用分类标准系按肿瘤原发部位将头颈部肿瘤分为：唇、口腔；咽；喉；唾液腺；鼻腔、鼻窦；甲状腺等六大区域。头颈部的组织器官密集，解剖结构比较复杂，这些器官发生的肿瘤类型繁多，病理类型复杂。头颈部恶性肿瘤约占所有癌症病例的 $4 . 8 \% ^ { [ 8 1 ] }$ ，最常见的组织病理学类型为鳞状细胞癌。其中，与HPV感染相关的头颈部恶性肿瘤主要包括口腔、口咽等部位的鳞状细胞癌。（）一级预防：头颈部恶性肿瘤的发生与吸烟、饮酒密切相关［82‑84］。此外，诸如、病毒、单纯疱疹病毒等感染人群、免疫缺陷人群、性活跃人群（尤其是多性伴侣人群与口交性行为人群）、咀嚼槟榔人群等的头颈部肿瘤发生风险较高［85］。应对上述高危人群进行健康教育，倡导健康的生活方式，如戒烟、戒酒、戒槟榔等。对于存在口交性行为人群，应同时加强对性伴侣的健康性行为教育，如尽量避免口交性行为、在性生活中使用安全套等，以减少HPV感染和相关疾病发生风险。目前已有部分研究证明HPV疫苗对口咽鳞状细胞癌以及口腔HPV感染可能存在保护效果。芬兰发起的一项社区随机试验验证了疫苗对口咽鳞状细胞癌的保护作用，并且对疫苗以外型别的口咽鳞状细胞癌表现出保护性［86］。一项基于非随机对照试验的综述结果表明，与接种疫苗者相比，未接种疫苗者口咽鳞状细胞癌的风险增加了19倍［87］。哥斯达黎加进行的一项双盲随机对照试验研究结果显示，与对照组相比，接种二价疫苗组的口腔和感染率在年内减少了$9 3 . 3 \% ^ { [ 8 8 ] }$ 。一项纳入6项研究的荟萃分析显示，接种疫苗可使发生口腔HPV感染风险降低 $46 \%$ ，口腔HPV‑16型感染风险可显著降低 $8 0 \%$ 。通过以上证据可见疫苗接种可以预防口腔感染，并降低以口咽鳞状细胞癌为主的相关头颈部鳞状细胞癌的发病率。（2）二级预防：目前尚无研究证据支持全人群进行头颈部恶性肿瘤筛查的获益情况［82，90］，但已有充足的证据证实，鼻咽癌、下咽癌、上颌窦癌等如能获得早期诊断，仅用单一、创伤较小的治疗方式即可获得满意的生存率、功能保留率以及较高的生活质量［91］。头颈部恶性肿瘤的早期诊断主要依靠影像学评估。近年来，内镜窄带成像（NBI）等技术在早期黏膜病变的检测中显示出一定潜力，且有助于炎性反应和瘢痕与恶性病变的初步鉴别，在鼻咽癌、喉癌和下咽癌的早期诊断中，相较于普通白光内镜在敏感性和特异性方面有所提高，但其对内镜医师的专业技术能力依赖性较高［91‑92］。推荐意见8：推荐对具有头颈部恶性肿瘤高危因素的人群加强健康教育，倡导其戒烟、戒酒、戒槟榔、尽量避免口交性行为；推荐无接种禁忌证的适龄人群通过接种HPV疫苗预防口腔HPV感染及相关口咽鳞状细胞癌。（A级证据，强推荐）推荐意见9：推荐使用内镜检查等影像学检查技术实现头颈部恶性肿瘤的早期诊断。（级证据，强推荐）尖锐湿疣：尖锐湿疣是由感染引起的以皮肤黏膜疣状增生性病变为主的性传播疾病，多发于生殖器、肛门或肛周部位的皮肤、黏膜上，也可累及腹股沟或会阴等区域［93］。被动肛交者皮损可发生于肛周、肛管和直肠，口交者可出现在口腔。除疣体本身外，多数疣无明显症状，少数患者可能出现瘙痒、出血或疼痛等症状［93］，根据皮损类型可分为典型尖锐湿疣、丘疹状疣、扁平状疣等。（1）一级预防：尖锐湿疣的高危人群主要包括性活跃人群、MSM、免疫缺陷人群等［93］。针对上述高风险人群，应加强健康教育，普及安全性行为知识，强调 HPV传播途径及潜在危害，并鼓励高危人群在出现疑似症状或异常皮损时及时就医。此外，此类高危人群应采取安全性行为（如使用安全套）、注意个人卫生、避免与他人共用洗浴及卫生物品等，从而避开传染源、切断传播途径。此外，对于存在尖锐湿疣的孕产妇人群需加强管理，降低HPV的母婴垂直传播风险［93‑94］。现有研究表明，四价或九价疫苗接种可预防 $9 0 \% { \sim } 9 5 \%$ 的尖锐湿疣，并可显著降低 $89 \%$ 尖锐湿疣的复发率［93，95‑97］。此外，HPV疫苗对尖锐湿疣的保护效果也因接种年龄而异。 ${ \leqslant } 1 5$ 岁接种4价疫苗可使尖锐湿疣发生率降低约 $80 \%$ ，而随着疫苗接种年龄的增加，保护效果急剧下降［98］。一项荟萃分析了14个高收入国家的全国或地区性监测数据、行政健康数据的一般人群资料，涵盖约6 000 万例青少年和年轻成年人群。研究显示，在接种HPV疫苗5\~8年后，15\~19岁女性尖锐湿疣诊断率下降了 $67 \%$ ，20\~24岁女性诊断率下降了 $54 \%$ ，岁女性诊断率下降了 $31 \%$ ；岁男性诊断率下降了 $48 \%$ ，岁男性诊断率下降了$3 2 \% ^ { [ 8 ] }$ 。综上，建议适龄人群应尽早接种HPV疫苗预防尖锐湿疣。（2）二级预防：国内外现有指南中均未制定尖锐湿疣相关的筛查策略［93‑94，97，99］。对于具有多性伴、高危性行为、性伴感染史、与尖锐湿疣患者有密切接触史等高危人群，建议定期进行临床评估，根据临床表现结合病史进行诊断；若出现不典型皮损和特殊部位的皮损，可结合辅助检查（皮肤镜、阴道窥器、阴道镜、肛门镜、直肠镜、尿道镜、组织病理活检）进行诊断［93‑94，97，99］。推荐意见10：对尖锐湿疣高危人群加强健康教育，倡导其进行安全性行为、注意个人卫生等方式预防尖锐湿疣；推荐无接种禁忌证的适龄人群尽早接种HPV疫苗预防尖锐湿疣。（A级证据，强推荐）推荐意见11：推荐尖锐湿疣高危人群定期评估疾病发生风险，若出现不典型皮损和特殊部位的皮损，可结合辅助检查进行诊断。（C级证据，弱推荐） 6.RRP：RRP 是呼吸道常见的良性肿瘤，主要由感染尤其是和感染引起的上呼吸道疾病。RRP有两个典型高发年龄段，一是2岁左右幼儿期和7岁以内的学龄前期儿童，另一个是40\~50岁左右的中年期，临床上因此分为幼年型和成人型 $\mathrm { R R P ^ { [ 1 0 0 ] } }$ 。主要表现为呼吸道内多发疣状突起新生物，可引起声音嘶哑、呼吸困难和窒息等。成人型RRP可自发癌变，或在吸烟、合并多种病毒感染、机体的免疫状态低下、咽喉反流等因素刺激下发生癌变，国外报道的 RRP 恶变率为$3 . 0 \% { \sim } 6 . 2 \% ^ { [ 1 0 0 ] }$ 。相比于成人RRP，儿童RRP一般无癌变风险，但侵袭性和复发率更高［101‑102］。（1）一级预防：儿童多通过垂直传播途径感染引发。因此，儿童预防多以其父母的健康教育和孕产期保健为主。备孕男性和女性人群均应接受相关的健康教育，了解 HPV 相关知识和预防手段，以避免母体HPV感染及通过垂直传播导致的新生儿感染。如父母或家庭成员患尖锐湿疣，应避免与婴幼儿共用毛巾、浴盆等物品，接触婴儿前严格洗手。有研究表明，成人型RRP患者具有口交性行为的比例更高［103］，因此应尽量避免口交性行为，在性生活中使用安全套以减少HPV感染风险和RRP发生风险［104］。此外，吸烟与成人型RRP的发生、复发相关，因此，应积极提倡戒烟等健康生活方式以降低成人型RRP的发生和复发风险［105］。美国一项研究对比分析了不同疫苗接种率地区的幼年型复发性呼吸道乳头状瘤病（JORRP）发病率，结果显示，HPV疫苗接种率较高地区的发病率下降幅度显著低于接种率较低的地区［106］。 — 年，澳大利亚广泛开展了岁女性四价疫苗接种计划，此后的监测数据显示 JORRP 发病率逐年下降，发病率从年的万下降至年的万［107］。美国一项基于患儿的调查研究显示，所有可检测到 HPV标本的 HPV基因型均为HPV疫苗可预防的HPV基因型，而母体接种HPV疫苗有助于预防阴道分娩过程中的垂直传播［108］。HPV疫苗有可能预防成人RRP的发生，但目前尚无相关数据支持［100］。（）二级预防：现有国内外指南尚未推荐针对的全人群筛查，《中国幼年型复发性呼吸道乳头状瘤病诊断与治疗指南（）》推荐，对于声音嘶哑、症状持续个月以上或声音嘶哑进行性加重者需重点关注；此外，对所有声嘶合并喘鸣、喉梗阻或呼吸困难的儿童，在生命体征平稳时，可结合临床具体情况选择性进行软性咽喉内镜检查，同时对高危人群可采取针对性监测策略［42］。推荐意见12：对儿童高危人群的父母及家庭成员加强健康教育，倡导父母进行安全性行为、加强孕产期保健等，同时鼓励家庭成员注意保持良好卫生行为以预防儿童发生RRP；对成年RRP高危人群加强健康教育，倡导其进行安全性行为、保持健康生活方式以预防；推荐无接种禁忌证的适龄人群接种疫苗以降低其子女发生的风险。（C级证据，弱推荐）推荐意见13：对于有声音嘶哑等症状的儿童需重点关注，如存在喘鸣、喉梗阻或呼吸困难，可在生命体征平稳时，推荐结合临床具体情况选择性进行软性咽喉内镜检查。（A级证据，强推荐） # 第三部分未来工作建议 # 一、加强健康教育与健康促进公众的健康意识和知识水平对HPV相关疾病的防控成效具有决定性影响。当前，我国公众对HPV 相关疾病的认知大多集中于宫颈癌和女性防控，对HPV相关非宫颈疾病的了解有限，且对不同受众人群通常缺乏有针对性的健康教育和科普模式。因此，对于不同的受众群体，应采取针对性健康教育策略。例如，针对青少年群体，可将HPV防治知识纳入中小学健康教育课程中；对于适龄儿童家长，可通过“家长学校”等创新渠道开展认知干预。感染人群、同性性行为人群等特殊群体通常是HPV相关疾病的高发群体。为提高上述人群获得公平可及的健康服务机会，减少污名化和歧视现象，可通过动员基于上述群体的公益组织、“红丝带”友好门诊等渠道开展针对性健康教育。在对HPV相关疾病的高危人群开展健康教育时，也应同时加强其性伴侣的健康教育。相比于女性，男性通常对HPV引发的疾病和自身感染风险的认识度不足［93‑94，109］，在未来的HPV健康宣传科普中应进一步加强男性高危人群的关注［95］。此外，随着我国新媒体的迅猛发展，信息传播渠道日益多样化。在此趋势下，HPV相关疾病的健康教育与科普也应紧跟自媒体发展的趋势，在保证健康教育和科普质量的条件下进行创新，建立多维度防治知识传播体系，例如通过“线上 $+$ 线下”双轨模式开展科普宣传：线上利用短视频平台、医疗机构公众号等新媒体渠道，制作可视化科普内容等；线下在医院候诊区设置智能导览屏，定期举办社区健康讲堂等，重点解读HPV感染与相关疾病的关联。 # 二、HPV疫苗接种策略提出的《加速消除宫颈癌全球战略》呼吁年全球所有国家实现“ ”的战略目标，即 $90 \%$ 的女孩在15岁之前完成HPV疫苗接种，$70 \%$ 的女性在35和45岁之前接受高效检测方法筛查， $90 \%$ 确诊宫颈疾病的女性得到治疗。截至年月，全球已有个国家或地区将疫苗纳入免疫规划［110‑111］。我国自2016年批准首个预防宫颈癌的 HPV 疫苗上市至今已有 9 年，截至年月，我国已有个省份出台了疫苗接种政策。然而，年我国岁适龄女性的首剂HPV疫苗接种覆盖率仅为 $1 0 . 1 5 \% ^ { [ 3 ] }$ ，这可能与我国尚未将HPV疫苗纳入免疫规划、当前多数地区实行自愿自费接种有关。我国可借鉴国际经验，依托国家免疫规划专家咨询委员会等循证机制，开展调研和技术论证，通过将HPV疫苗纳入国家免疫规划来保障HPV疫苗的可及性，提高整体人群的接种覆盖率。此外，年全球已有个国家采取了不分性别接种的策略，即向适龄男女同等推广HPV疫苗接种［111］，我国也分别于2025年1和4月批准四价和九价HPV疫苗扩展至男性接种，以预防HPV引起的肛门癌、AIN以及尖锐湿疣，但当前仍缺乏HPV疫苗在我国男性的保护效力和效果数据。因此，未来还需大力开展HPV疫苗预防男性HPV相关疾病的临床研究、真实世界研究以及卫生经济学等研究，为我国扩大HPV疫苗预防适应证和覆盖人群提供高质量证据。 # 三、HPV相关的非宫颈疾病筛查和早期诊断因HPV相关非宫颈疾病的发病率、死亡率较低，基于一般人群的大规模筛查可能不具有成本效益，因此，HPV相关非宫颈疾病的筛查和早期诊断体系应针对高危人群构建。首先，对于存在HPV持续感染、免疫缺陷人群、性生活过早或多个性伴侣等高危因素的人群需重点关注，尤其是已患宫颈癌、肛门癌等疾病时，应重点关注HPV感染相关其他生殖器疾病的发生风险，并定期进行相关检查（如细胞学检查、HPV检测等），以实现早发现、早诊断、早治疗。其次，对于已确诊HPV相关癌前病变的患者，应根据疾病进展情况采取积极的治疗措施，使尽可能多的癌变前期或癌症患者得到有效治疗或管理。患者经治疗症状缓解后，临床医师应根据患者个体复发及转移风险制订随访计划，定期监测HPV感染情况，出现复发或转移时尽早就医。 # 四、总结与展望本共识仅反映多学科专家团队基于国内外相关指南、最新研究进展及我国HPV相关非宫颈疾病早期预防实际情况形成的一致意见，不具备法律约束性质。共识的内容代表该领域的阶段性认识，未来将根据新的临床及公共卫生实践证据进行及时更新。为最大程度保护我国人群免受HPV引发非宫颈疾病的危害，社会各界需要共同努力，创新医防协同机制，大力倡导男女共防，执行和完善HPV引发非宫颈疾病的早期预防策略，减少HPV感染风险，促进HPV相关非宫颈疾病的早诊早治，降低疾病负担。 # 本共识制订专家组成员编写顾问（按姓氏汉语拼音排序）：乔友林（北京协和医学院群医学及公共卫生学院）；魏丽惠（北京大学人民医院妇产科）；郎景和（国家妇产疾病临床医学研究中心中国医学科学院北京协和医学院北京协和医院妇产科）执笔专家：赵方辉（国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院流行病学研究室）；王华庆（中国疾病预防控制中心免疫规划中心）；张海增（国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院结直肠外科）；胡尚英（国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院流行病学研究室）；张莉（北京协和医学院群医学及公共卫生学院）；赵雪莲（国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院流行病学研究室）；杨欢（国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院流行病学研究室）编写专家名单（按姓氏汉语拼音排序）：陈飞（国家妇产疾病临床医学研究中心中国医学科学院北京协和医学院北京协和医院妇产科）；丁超（国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院麻醉科）；樊静洁（南方医科大学深圳妇幼保健院预防保健科）；韩光（湖北省肿瘤医院华中科技大学同济医学院附属湖北肿瘤医院放疗中心）；洪颖（南京大学医学院附属鼓楼医院妇产科）；胡尚英（国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院流行病学研究室）；姜太一（首都医科大学附属北京佑安医院感染与免疫医学科）；郎景和（国家妇产疾病临床医学研究中心中国医学科学院北京协和医学院北京协和医院妇产科）；刘青（首都医科大学附属北京佑安医院妇科）；马丽晶（首都医科大学附属北京同仁医院耳鼻咽喉头颈外科）；齐淑贞（中国医学科学院皮肤病医院性病科）；乔友林（北京协和医学院群医学及公共卫生学院）；寿建忠（国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院泌尿外科）；隋龙（复旦大学附属妇产科医院宫颈疾病诊治中心宫腔疾病诊治中心）；汪习成（云南省传染病医院感染科）；王华庆（中国疾病预防控制中心免疫规划中心）；王军（首都医科大学附属北京同仁医院耳鼻咽喉头颈外科）；王俊玲（兰州大学公共卫生学院）；王临虹（中国疾病预防控制中心妇幼保健中心）；魏丽惠（北京大学人民医院妇产科）；吴昊（首都医科大学附属北京佑安医院感染中心）；徐金华（复旦大学附属华山医院皮肤科）；杨欢（国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院流行病学研究室）；杨慧（四川大学华西医院耳鼻咽喉头颈外科）；张海增（国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院结直肠外科）；张莉（北京协和医学院群医学及公共卫生学院）；张路坤（深圳第三人民医院感染与免疫科）；张韶凯（河南省肿瘤医院肿瘤防治研究办公室）；张媛媛（国家癌症中心中国医学科学院肿瘤医院妇科）；赵方辉（国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院流行病学研究室）；赵更力（北京大学第一医院妇产科）；赵雪莲（国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院流行病学研究室）；赵昀（北京大学人民医院妇产科）；朱志强（首都医科大学附属北京佑安医院泌尿外科）编写组秘书：郑启健（兰州大学公共卫生学院）；钟盼亮（北京协和医学院群医学及公共卫生学院）；杜翰霖（北京协和医学院群医学及公共卫生学院）利益冲突所有作者声明不存在利益冲突 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c3e91b4d60db4ae8be0988a95c709d4c	中华医学会	保留盆腔自主神经的子宫颈癌根治性手术中国专家共识	指南与规范 # 保留盆腔自主神经的子宫颈癌根治性手术中国专家共识中国医师协会妇产科医师分会妇科肿瘤学组通信作者：李斌，国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院妇科 100021， Email： libin $@$ cicams．ac．cn；向阳，中国医学科学院北京协和医院妇科肿瘤中心 100730， Email： xiangy $@$ pumch．cn 【摘要】子宫颈癌是妇科常见恶性肿瘤针对早期患者的子宫颈癌根治性手术会对盆腔自主神经造成损伤导致术后排尿排便及性功能障碍为了提高患者术后生活质量国际分型推荐将保留盆腔自主神经的子宫颈癌根治性手术型手术作为主要术式开展中国医师协会妇产科医师分会妇科肿瘤学组邀请多名中国妇科肿瘤领域专家基于当前相关研究现状对保留盆腔自主神经的子宫颈癌根治性手术的解剖基础手术指征技术要点术后评估等诸多关键性问题进行深入探讨最终达成保留盆腔自主神经的子宫颈癌根治性手术中国专家共识以指导型手术在中国的规范化应用。【主题词】子宫颈肿瘤根治性子宫切除盆腔自主神经生活质量临床应用专家共识基金项目：北京市科技计划DOI： 10．3760 ／ cma．j．cn112152⁃20210525⁃00411 # Chinese expert consensus on nerve⁃sparing radical hysterectomy for cervical cancer Gynecologic Oncology Group， Chinese Obstetricians and Gynecologists AssociationCorresponding authors： Li Bin， Department of Gynecologic Oncology， National Cancer Center ／ NationalClinical Research Center for Cancer ／ Cancer Hospital， Chinese Academy of Medical Sciences and Peking UnionMedical College， Beijing 100021， China， Email： libin＠ cicams．ac．cn； Xiang Yang， Gynecologic OncologyCenter， Chinese Academy of Medical Sciences and Peking Union Medical College Hospital， Beijing 100730，China， Email： xiangy＠ pumch．cn 【Abstract】 Cervical cancer is the most common gynecologic malignancy． Radical hysterectomy for early⁃stage cervical cancer could cause damage to pelvic autonomic nerves， leading to postoperative urination， defecation and sexual dysfunction． In order to improve the postoperative quality of life， the international Querleu⁃Morrow （ Q⁃M） surgical classification system recommends the nerve⁃sparing radical hysterectomy （type⁃C1） as the mainstay operation． The Gynecologic Oncology Group affiliated to Chinese Obstetricians and Gynecologists Association has invited a number of domestic specialists and conducted in⁃ depth discussions on key issues such as anatomical basis， surgical indications， techniques， postoperative evaluation for nerve⁃sparing radical hysterectomy． Finally， the specialists reach a consensus to guide the standardized application of this procedure in China．【Subject words】 Uterine cervical neoplasms； Radical hysterectomy； Pelvic autonomic nerves；Quality of life； Clinical application； Expert consensusFund program： Beijing Municipal Commission of Science and Technology （Z171100001017115）DOI： 10．3760 ／ cma．j．cn112152⁃20210525⁃00411 子宫颈癌是世界上危及女性健康的重大疾病年中国新发子宫颈癌病例数为例死亡例数为 34 000 例［1］。子宫颈癌根治性手术一直是期国际妇产科联盟分期患者的主要治疗手段［2］子宫颈癌根治性手术中大范围切除宫旁组织的同时会对盆腔自主神经造成损伤可导致术后排尿排便和性功能障碍影响患者的术后生活质量。如何减少子宫颈癌根治性手术并发症，是妇科医师们一直关注的热点问题。年日本学者首先提出了保留盆腔自主神经的子宫颈癌根治性手术（ nerve⁃sparing radical［3］该术式于年被命名为东京术式的技术要点是将极为细小的盆腔自主神经结构交感神经副交感神经从周围组织中做精细辨识和分离以达到保留的目的我国学者吴义勋等于世纪年代开始尝试在子宫颈癌根治术中保留盆腔自主神经丛的临床实践［4］世纪以来国外学者对应用于早期子宫颈癌进行了深入探讨，初步肯定了其改善排尿、排便功能障碍以及提高患者术后生活质量的效果［5⁃9］。年国外学者提出的子宫颈癌国际手术分型分型系统中被归为型［10］年Q⁃M 分型推荐将 C1 型手术作为子宫颈癌根治性手术的主要术式在全球推行［11］。国内已有多家医学中心开展了子宫颈癌型手术［12⁃16］但目前仍存在手术解剖不清晰步骤不统一等问题，影响 C1 型手术的普及应用。为了进一步明确型手术的解剖标志建立规范化的操作步骤保证手术质量中国医师协会妇产科医师分会妇科肿瘤学组邀请国内多名妇科肿瘤学专家进行了深入研讨在尊重循证医学证据的基础上参考大量国内外文献并汇聚专家经验形成了保留盆腔自主神经的子宫颈癌根治性手术中国专家共识本文凝练了专家们对当前型手术关键问题包括解剖学基础、手术指征、技术要点、术后评估等方面）达成的一致性意见，同时也不回避相关的争议与分歧，以此推动 C1 型手术的临床规范化应用。 # 一盆腔自主神经解剖学基础盆腔自主神经解剖及功能盆腔自主神经结构复杂熟悉其解剖学特点和生理功能是型手术成功实施的前提。盆腔自主神经系统由腹下神经、盆腔内脏神经、下腹下神经丛及其发出的直肠支子宫支膀胱支及阴道之组成支配相应的脏器腹下神经（交感神经）主干由上腹下神经丛汇集而成，起源于胸 11 至腰 2 的交感神经，于腹主动脉前方交织成上腹下神经丛沿髂总血管向下走行至骶岬水平发出左右腹下神经各一束腹下神经紧贴直肠系膜，于宫骶韧带外侧，行走于输尿管背侧，到达子宫动脉水平与骶交感神经节的节后纤维融合并与子宫深静脉背侧的来自第对骶神经的盆腔内脏神经（副交感神经）汇合，形成下腹下神经丛下腹下神经丛发出直肠支子宫支膀胱支及阴道支这些分支内均含有交感神经及副交感神经成分支配直肠子宫膀胱和阴道的生理功能［17⁃19］直肠支通过控制结直肠的活跃度和肛门内外括约肌来控制排便子宫支可以控制子宫收缩等生理功能膀胱支控制膀胱括约肌及逼尿肌功能感知膀胱容量变化并调节储尿和排尿阴道支控制阴道血管平滑肌的舒缩调节性唤起阶段阴道充血及润滑［19］。专家共识：专家们高度认同盆腔自主神经解剖和功能的经典理论，并一致认为掌握盆腔自主神经解剖学理论知识是规范化开展 C1 型手术的前提。盆腔自主神经解剖新认知盆腔自主神经结构细小呈丛状分布与周围组织难以分离这也是造成型手术难度的主要原因解剖学研究显示盆腔自主神经结构位于一矢状位的平面内这一平面由输尿管系膜及其延伸部分所构成解剖上定义为侧脐韧带的膜样返折属于骶前盆腔脏层筋膜的内侧致密部分神经平面位于输尿管的背侧并与输尿管相连［20⁃22］，组织胚胎发生方面，子宫、阴道及宫旁组织位于苗勒氏形态发生单元内，而盆腔自主神经平面则位于不同的形态发生单元内存在整体保留的可能性［9］。盆腔自主神经平面与宫旁组织存在固有间隙即外侧的直肠侧间隙膀胱侧间隙及内侧的冈林间隙阴道侧间隙充分利用解剖学间隙可减少分离神经结构的难度使型手术易于实施［20⁃21］。有研究显示，盆腔自主神经平面与输尿管的关系密切输尿管周围分布的一些腹下交感神经束并不汇入下腹下神经丛而是沿着神经平面直达膀胱三角部位对膀胱进行支配［23］神经平面内的一些神经也会对输尿管起支配作用保留盆腔自主神经平面可以同时将这些神经结构保留［24］。解剖新理念为型手术简化提供了重要的理论依据。专家共识：专家们尊重当前盆腔自主神经解剖的新观点，并认为这些新认知可以为 C1 型手术的简化提供理论基础。 # 二、手术适应证与禁忌证适应证应根据肿瘤临床分期病理类型肿瘤分化程度等不同决定行型或者型手术但2017年Q⁃M分型的更新版本强调了C1型手术为子宫颈癌根治性手术的主要术式只有在不适合保留盆腔自主神经的情况下才选择型手术［11］年美国国立综合癌症网络（ National Comprehensive CancerNetwork， NCCN）指南认可 Q⁃M 分型的新观点，推荐型手术适用于 $\mathrm { ~ I ~ B 1 \sim ~ I ~ B 2 ~ }$ 期的患者也可选择$\mathrm { ~ I ~ B 3 \sim I I ~ A 1 }$ 期患者［25］多项关于型手术的研究中纳入了局部晚期患者（ⅠB3 期和ⅡA2 期，肿瘤直径 ${ > } 4 \ \mathrm { c m }$ ）和ⅡB 期患者，结果显示，C1 型手术不影响预后并有利于提高患者的术后生活质量［26⁃29］。因此，有学者主张接受过新辅助化疗的局部晚期患者也可作为型手术的适应证但是另有学者强调型手术适应证应趋于保守主张选择肿瘤直径 $\leqslant 4 ~ \mathrm { c m }$ 的期无淋巴结转移等危险因素者实施型手术以保证肿瘤治疗的安全性［30⁃31］。 C1 型手术中可能会出现一侧盆腔自主神经保留失败的问题。有研究表明，C1 型手术中，保留单侧自主神经对于促进术后膀胱功能恢复效果肯定［8，31］。专家共识：在缺乏足够的前瞻性临床研究证据的情况下，专家建议对肿瘤直径 $\leqslant 4 \ \mathbf { c m }$ 的ⅠB 期、无宫颈深间质浸润、无淋巴⁃脉管间隙受侵、无阴道受侵、无淋巴结转移的危险因素者实施 C1 型手术。如遇到阴道受侵的ⅡA1 期患者，可以根据情况保留没有阴道侵犯的一侧盆腔自主神经，以兼顾患者生活质量及肿瘤治疗的安全性。 2．禁忌证：神经周围侵犯（ perineural invasion，又称嗜神经侵袭指肿瘤细胞入侵三层神经鞘膜中的任意一层或肿瘤细胞聚集包绕神经周径并沿神经浸润转移的现象是肿瘤的一种特殊的转移方式其特点是肿瘤细胞沿着神经通路体神经及自主神经快速播散受神经与肿瘤细胞之间信号传导调节其具体机制尚未明确PNI 在早期子宫颈癌中的发生率为 $7 . 0 \% \sim 3 5 . 1 \%$ ，与患者预后有关，故认为 PNI 为 C1 型手术的禁忌证［32］。虽然术前影像及术中冰冻病理检查有助于发现但其价值有限不能及时指导术式的选择。 PNI 的诊断主要依靠术后病理形态学观察及免疫组化染色结果。 PNI 与肿瘤体积大、宫颈深间质浸润淋巴脉管间隙受侵阴道受累淋巴结转移密切相关有学者主张应加强术前评估排除与相关的危险因素再选择型手术［16，32］ # 专家共识：当宫颈活检或者宫颈锥切提示有PNI 的相关情况时，应视为 C1 型手术的禁忌证。 # 三、手术技术 # （一）C1 型手术的基本技术要点型手术要求在大范围切除宫旁组织时对盆腔自主神经结构的各部分进行精细的解剖分离及保留，其中最关键的是对盆腔自主神经丛膀胱支的保留［5⁃9，12⁃16］。技术要点如下。侧方宫旁组织切除及盆腔内脏神经保留于起始端切断子宫动脉及子宫浅静脉进而向输尿管上方翻起将侧方宫旁组织主韧带于髂内静脉内侧切除，于起始部切断子宫深静脉时注意保留其背侧的盆腔内脏神经背侧宫旁组织切除及腹下神经保留于宫骶韧带外侧识别、分离腹下神经，给予保留。将宫骶韧带及阴道直肠韧带切除至直肠水平腹侧宫旁组织切除及下腹下神经丛的识别打开膀胱宫颈韧带浅层，彻底游离输尿管至膀胱入口处。游离子宫深静脉主干及其分支，将子宫深静脉于髂内静脉处切断，提起断端向子宫颈方向牵拉，在子宫深静脉的背侧识别腹下神经骶交感神经节发出的神经纤维与盆腔内脏神经汇合形成的下腹下神经丛并识别其发出的子宫支及走行在膀胱宫颈韧带深层内的膀胱支切断膀胱宫颈韧带深层中的膀胱中静脉和膀胱下静脉注意保护膀胱中静脉和膀胱下静脉外侧及背侧的下腹下神经丛膀胱支。阴道旁组织切除及膀胱支保留在阴道旁组织内寻找下腹下神经丛子宫支与膀胱支的交汇处于交汇处切断子宫支保留膀胱支并向外侧推开再完成子宫广泛切除。专家共识：对于 C1 型手术的基本技术要点需要规范。专家们强调应注重精细化解剖操作，并按照关键的解剖标志来完成盆腔自主神经各部分的保留，并不强调处理子宫各个韧带的顺序。 # （二）C1 型手术的简化型手术中系统地解剖盆腔自主神经丛是导致操作复杂的主要原因对细小自主神经结构的分离操作本身也会造成其损伤影响术后器官功能因此建立型手术的简化方法符合目前临床需求，也是今后的发展方向。研究者充分利用盆腔固有间隙来降低型手术分离神经操作的难度如利用冈林间隙分离腹下神经后切除宫骶韧带［6⁃8］利用阴道侧间隙分离下腹下神经丛膀胱支后切除阴道旁组织［13⁃14，26，28］，这些操作可使型手术操作有所简化另有医学中心基于对盆腔自主神经解剖的新认知提出整体保留神经平面的方法［33］。保留神经平面的方法以输尿管为清晰解剖标志充分利用盆腔固有间隙外侧的直肠侧间隙及膀胱侧间隙内侧的冈林间隙及阴道侧间隙）将神经平面（输尿管系膜及向膀胱延伸部分）整体保留。保留神经平面的方法避免了对具体自主神经结构的分离，可使手术进一步简化［33］。专家共识：充分利用盆腔间隙可以降低 C1 型手术的操作难度，神经平面的整体保留则为简化 C1型手术提供了新思路。 # （三）C1 型手术的特殊技术方法盆腔自主神经结构细小术中辨识及分离困难使用术前盆腔自主神经结构显像［34］术中神经导航［26，35］腹腔镜及手术放大镜［7，36⁃37］等特殊方法可能有助于术中神经结构的辨识与分离此外能量手术器械如单极双极等容易对盆腔自主神经结构造成电热损伤从而造成术后功能障碍因此型手术操作应尽量选择无能量手术器械如冷刀止血钳血管夹等或低能量如超声刀手术器械来进行分离神经相关操作可以减少能量器械造成的电热损伤有助于保护术后盆腔自主神经功能［38］。有研究者借助外科超声吸引装置（ cavitron［5，39⁃40］或水刀［41］来完成 C1 型手术，这两种特殊器械均可以特异性清除自主神经束周围的脂肪组织使神经束和血管得到清晰地显露在处理血管时更好地保留盆腔自主神经结构此外和水刀均不产生热能从而减少对自主神经功能造成的影响。专家共识：如条件具备，可借助特殊设备及器械辅助完成 C1 型手术。在盆腔自主神经分离与保留操作中，应尽量使用无能量或低能量手术器械，避免对神经的电热损伤。 # 四型手术效果评估 # （一）肿瘤治疗安全性评价型手术在保留盆腔自主神经丛时会在一定程度上造成阴道旁组织切除范围的缩小这是否影响肿瘤治疗效果是学者们普遍关注的问题组织胚胎学研究显示盆腔自主神经结构与宫颈属于不同的苗勒氏发生单元，保留盆腔自主神经理论上不会对子宫颈癌根治性手术造成影响［9］已有多项单中心多中心回顾性队列研究和分析结果证实，C1 型手术不影响子宫颈癌患者预后，也不增加盆腔局部复发率［42⁃46］。小样本前瞻性随机对照研究显示型手术与常规子宫颈癌根治术比较年预后差异无统计学意义从而肯定了型手术的肿瘤治疗安全性［47］。但仍有待开展多中心、大样本的期临床试验对型手术的肿瘤治疗安全性进行最终评价 # （二）手术可操作性评价由于手术技术的进步及特殊外科器械的应用型手术的时间较前有所缩短费时问题基本得到解决［14⁃15，40］。 C1 型手术操作精细度高，对自主神经邻近的静脉分支做单独处理从而有效减少了术中出血［42］。精细化操作也避免了手术副损伤的发生，不会增加患者的并发症［42］。 # 三盆腔器官功能评价改善术后盆腔器官功能提高患者生活质量是实施 C1 型手术的最主要目的。 C1 型手术重点保留支配膀胱的盆腔自主神经丛膀胱支因此能否改善术后膀胱排尿功能障碍是评估手术效果的关键此外，C1 型手术对盆腔自主神经丛的精细分离也可能减少对盆腔自主神经丛直肠支及阴道支的损伤手术效果评估也应兼顾术后直肠排便功能及性功能两个方面围手术期尿动力学检查和直肠动力学检查尿动力学检查和直肠动力学检查是准确反映盆腔自主神经保留效果的客观方法尿动力学检查的主要判读指标包括膀胱顺应性逼尿肌顺应性最大逼尿肌压力最大尿流率平均尿流率初始尿意最强尿意及残余尿等［16，35，41，48］尿动力学检查应在术前完成作为基线数据与术后对比术后定期随诊时通过尿动力学检测可以客观评价排尿功能的恢复情况。有研究显示，接受 C1 型手术的患者术后尿动力学指标均优于常规手术患者而且指标恢复正常的时间较短［16，26，35，47⁃49］。虽然尿动力学方法检查准确但其检查不够便捷影响其应用判读指标不统一也是其面临的问题与尿动力学检查类似具备条件的医院也可对型术后患者进行直肠动力学检查，来客观评估直肠功能恢复情况。 2．术后近期膀胱功能评价：评价 C1 型术后近期膀胱排尿功能的方法主要为残余尿测定残余尿量的标准并不统一残余尿量 $< 5 0 \mathrm { ~ m l }$ 或 $< 1 0 0 \mathrm { ~ m l }$ 作为膀胱功能恢复的标准［7⁃8］残余尿量评估也需结合患者膀胱有充盈感及自主排尿的满意情况［7］各项研究之间关于术后拔除尿管及首次测定残余尿的时间有很大差别，时间为术后 $2 \sim 1 4 \mathrm { ~ d ~ }$ 不等［15，49］。对于未能恢复膀胱排尿功能患者的处理方法也有不同包括自导尿耻骨上膀胱造瘘间断开放尿管膀胱训练及留置尿管保持开放［15，40，42，47，49⁃51］。尽管各项研究中学者采用的研究方法不同但对型手术能够显著缩短术后导尿时间促进术后近期膀胱功能恢复，学者们保持一致观点［15，42，49⁃51］。术后远期生活质量评价盆腔自主神经受损后会对患者的术后远期生活质量造成影响包括膀胱功能、直肠功能和性功能障碍［28，47，51⁃52］。远期器官功能是反映型手术效果最有价值的指标生活质量调查则是主要的评价方法相关研究均显示，接受 C1 型手术的患者较常规手术患者发生远期膀胱功能障碍的概率明显下降膀胱储尿功能和排空功能均有改善［42，44，53⁃54］。此外，有研究显示，C1型手术能够明显减少患者便秘的症状但对其能否改善远期直肠功能并不明确［54⁃55］。性功能方面，有学者通过客观测量发现，C1 型手术术后患者性唤起阶段阴道血流有所增加提示型手术对于改善患者术后性功能障碍可能有益［56］但相关问卷调查研究结果却显示型手术不能改善患者性交困难、阴道润滑度下降、高潮障碍等症状［57⁃58］。因此，学者认为型手术只对改善远期膀胱功能效果是肯定的。专家共识：在选择合适指征的前提下，C1 型手术安全、可行，可以有效减少患者术后的膀胱排尿功能障碍的发生，有助于提高生活质量，但对减少术后直肠排便功能障碍及性功能障碍并不确定。 # 五其他相关问题微创技术的应用微创手术腹腔镜及机器人手术术野清晰操作精细止血高效放大效果有利于盆腔自主神经的辨识和分离已有研究显示腹腔镜型手术较开腹型手术出血少术后膀胱功能恢复更快［59］目前还缺乏关于腹腔镜C1 型手术远期预后的研究报道。目前，NCCN 指南推荐开腹作为子宫颈癌根治术的标准入路［25］但也有研究显示腹腔镜型手术仍适用于肿瘤 ${ \leqslant } 4 ~ \mathrm { c m }$ 的期患者前提是放弃举宫操作［60］。国内专家对子宫颈癌腹腔镜手术已达成共识认为在严格遵循无瘤操作的基础上对于局部肿瘤 ${ \leqslant } 2 \ \mathrm { c m }$ 无危险因素的患者适用腹腔镜手术［61］学习曲线问题型手术为一种复杂的手术方式高度依赖术者的技能而掌握相应的技能需要较长的学习曲线［15］这要求术者在能够熟练完成常规子宫颈癌根治性手术的基础上充分掌握分型新理念并对盆腔自主神经的解剖与生理功能有透彻的理解建立简化的型手术可能对术者克服学习曲线问题有一定帮助参与编写本共识专家一致认为应接受 Q⁃M 分型建议，对早期子宫颈癌患者开展 C1 型手术，以提高患者的生活质量但首先要对型手术进行规范化经过多轮讨论专家们对型手术的多个关键性问题达成共识并倡导开展多中心合作完善型手术标准化的技术流程指导临床规范应用在此基础上，应充分结合解剖学新认知，寻求简化的手术方法以促进型手术今后的普及和推广学术指导郎景和中国医学科学院北京协和医院妇产科执笔专家李斌国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院妇科向阳中国医学科学院北京协和医院妇科肿瘤中心张国楠电子科技大学医学院附属肿瘤医院四川省肿瘤医院妇科肿瘤中心梁志清陆军军医大学第一附属医院重庆市西南医院妇产科）、王泽华（华中科技大学同济医学院附属协和医院妇产科参加编写及讨论专家（按姓氏汉语拼音字母排序）曹冬焱中国医学科学院北京协和医学院妇科肿瘤中心陈春林南方医科大学南方医院妇产科程文俊南京医科大学第一附属医院江苏省人民医院妇科）、崔竹梅（青岛大学附属医院妇科）、狄文（上海交通大学医学院附属仁济医院妇产科郭瑞霞郑州大学第一附属医院妇科胡元晶天津市中心妇产科医院南开大学附属妇产医院妇瘤科华克勤复旦大学附属妇产科医院妇科肿瘤科康山河北医科大学第四医院妇科孔北华山东大学齐鲁医院妇产科李斌国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院妇科梁志清陆军军医大学第一附属医院重庆市西南医院妇产科）、刘崇东（首都医科大学北京朝阳医院妇产科）、刘开江（上海交通大学医学院附属仁济医院妇瘤科）、陆安伟（南方医科大学深圳医院妇科）、孟元光（解放军总医院第七医学中心妇产医学部米鑫北京市顺义区妇幼保健院妇产科任彤中国医学科学院北京协和医院妇科肿瘤中心宋磊解放军总医院第七医学中心妇产医学部王刚四川省妇幼保健院妇产科王建六北京大学人民医院妇产科）、王世军（首都医科大学宣武医院妇产科）、王玉东上海交通大学医学院附属国际和平妇幼保健院妇瘤科王泽华华中科技大学同济医学院附属协和医院妇产科向阳中国医学科学院北京协和医院妇科肿瘤中心杨隽钧中国医学科学院北京协和医院妇科肿瘤中心姚书忠中山大学附属第一医院妇产科张国楠电子科技大学医学院附属肿瘤医院四川省肿瘤医院妇科肿瘤中心赵丹国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院妇科学术秘书：赵丹国家癌症中心国家肿瘤临床医学研究中心中国医学科学院北京协和医学院肿瘤医院妇科利益冲突所有作者均声明不存在利益冲突 # 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ec1b31269c4b41d1a8557c2d103aee9a	中华医学会	功能失调性子宫出血临床诊断治疗指南(草案)	·临床指南· # 功能失调性子宫出血临床诊断治疗指南(草案) 中华医学会妇产科学分会内分泌学组中华医学会妇产科学分会绝经学组正常妇女的月经周期为 $2 4 \sim 3 5 \mathrm { ~ d ~ }$ ，经期持续2\~7d,平均失血量为 $2 0 \sim 6 0 ~ \mathrm { m l }$ 。凡不符合上述标准的均属异常子宫出血（abnormal uterinebleeding)。异常子宫出血涵盖的范围较大,既包括器质性疾病所致的异常子宫出血也包括功能失调性子宫出血(功血)。功血有多种月经紊乱形式,且其内分泌机制不同。目前,功血的临床处理方法多样,且略显繁杂，因而就这一妇科常见病提出规范化诊断治疗原则十分必要。 # 一、功血的定义及分类功血是由于生殖内分泌轴功能紊乱造成的异常子宫出血。分为无排卵型功血和有排卵型功血两大类。 1.无排卵型功血：青春期及绝经过渡期常见。因下丘脑-垂体-卵巢轴发育不完善或卵巢功能下降导致无周期性排卵，临床表现为出血失去规律性（周期性），间隔时长时短,出血量不能预计，一般出血时间长,不易自止。出血频繁或出血多者可引起严重贫血甚至休克。 19 2.有排卵型功血：有周期性排卵，因此临床上仍有可辨认的月经周期。有排卵型功血常表现为：（1)月经过多：指月经周期规则、经期正常,但经量 $> 8 0 \ m \ l$ 。常因子宫内膜纤溶酶活性过高或前列腺素等血管舒缩因子分泌失调所致。(2)月经间期出血：又可分为： $\textcircled{1}$ 黄体功能异常：分黄体萎缩不全及黄体功能不全两类。前者由于黄体萎缩过程延长引起子宫内膜不规则脱落，临床表现为经期延长，常在点滴出血后才有正式月经来潮，以后又常淋漓数日；后者因黄体期孕酮分泌不足，黄体期缩短，临床表现为周期缩短,经量可稍增多。黄体功能异常者常合并不孕或者流产。 $\textcircled{2}$ 围排卵期出血：原因不明,可能与排卵前后激素水平波动有关。出血期 $\leqslant 7 \mathrm { \ d }$ ，出血停止数天后又出血，量少，多数持续1\~3d,时有时无。目前，国内尚无大样本量的关于功血的流行病学统计资料，国外资料则集中在月经过多方面。WHO资料显示，在育龄期女性中， $19 \%$ 有月经过多。由于相关资料尚不多，有待更全面的临床观察和相应的流行病学研究。 # 二、功血的诊断 # (一)诊断依据功血的诊断须根据病史、身体检查和相应的辅助检查综合得出。 1.病史：包括患者的年龄、月经史、婚育史、避孕措施、是否存在引起月经失调的内分泌疾病或凝血功能障碍性疾病病史，以及近期有无服用干扰排卵的药物或抗凝药物等，还应包括已进行过的检查和治疗情况。仔细询问患者的月经情况,了解出血类型是鉴别功血与其他异常子宫出血的最主要依据。 2.身体检查：检查有无贫血、甲状腺功能低减、甲状腺功能亢进、多囊卵巢综合征及出血性疾病的阳性体征。妇科检查应排除阴道、宫颈及宫体病变;注意出血来自宫颈柱状上皮异位面局部还是来自宫颈管内。 3.辅助检查：根据病史及临床表现常可做出功血的初步诊断。辅助检查的目的是鉴别诊断和确定病情严重程度及是否有合并症。辅助检查主要包括：(1)全血细胞计数：确定有无贫血及血小板减少。(2)凝血功能检查：凝血酶原时间、活化部分凝血活酶时间、血小板计数、出凝血时间等，排除凝血功能障碍性疾病。(3)尿妊娠试验或血人绒毛膜促性腺激素 $\beta$ 亚单位( $\beta$ -hCG)检测：除外妊娠。(4)盆腔超声检查：了解子宫内膜厚度及回声，以明确有无宫腔占位性病变及其他生殖道器质性病变等。（5)基础体温(BBT)测定：不仅有助于判断有无排卵，还可提示黄体功能不全（体温升高天数 $\leqslant 1 1 \ \mathrm { d }$ ）、黄体萎缩不全(高相期体温下降缓慢伴经前期出血)。当BBT呈双相，月经间期出现不规则出血时，可鉴别出血是发生在卵泡期、排卵期或黄体期。(6)激素水平测定：适时测定孕酮水平可确定有无排卵及黄体功能,测定甲状腺素水平可迅速排除甲状腺功能异常,测定催乳素及其他内分泌激素水平以利于鉴别诊断。(7)诊断性刮宫或宫腔镜下刮宫：当异常子宫出血病程超过半年,或超声检查发现子宫内膜厚度 $> 1 2 \ \mathrm { m m }$ ,或患者年龄 $> 4 0$ 岁时,首次就诊可考虑采用诊断性刮宫或宫腔镜下刮宫，以了解子宫内膜情况。 # (二)诊断流程功血的诊断应按照下列步骤进行。见图1。 1.确定异常子宫出血的模式：月经周期、经期、经量都异常为不规则出血。月经间期出血是指两次正常月经之间有点滴出血,可分为卵泡期出血、围排卵期出血和黄体期出血。 2.除外器质性疾病：这是诊断功血的关键。功血应该与所有引起异常子宫出血的器质性疾病,包括生殖道、非生殖道、全身性疾病以及医源性出血相鉴别。少数情况下功血也可与无症状的子宫肌瘤并存。 ![](images/61dfce687a5253c4e9242a4a550d7fc093746b0419978a2447a6f2088676a7df.jpg) 图1功血的诊断流程 3.鉴别有无排卵及无排卵的病因：有排卵型功血与无排卵型功血的病理、生理变化及处理原则都有很大的不同。根据BBT、出血前5～9d的孕酮水平或适时取子宫内膜进行病理检查即可鉴别。 # 三、功血的治疗 # (一)无排卵型功血的治疗 1.止血 (1)性激素：无排卵型功血的治疗首选应用性激素。 1)孕激素：孕激素治疗也称"子宫内膜脱落法"或“药物刮宫”，停药后短期内即有撤退性出血,适用于血红蛋白 $>$ $8 0 ~ \mathrm { g / L }$ 、生命体征稳定的患者。具体用法如下： $\textcircled{1}$ 黄体酮：$2 0 \sim 4 0 ~ \mathrm { m g }$ ，肌内注射,每日1次，共 $3 \sim 5 \mathrm { ~ d ~ }$ $\textcircled{2}$ 地屈孕酮（其他名称：达芙通）： $1 0 ~ \mathrm { m g }$ ,口服，每日2次，共 $1 0 \mathrm { ~ d ~ }$ 。 $\textcircled{3}$ 微粒化黄体酮胶囊（其他名称：琪宁）： $2 0 0 \sim 3 0 0 ~ \mathrm { m g }$ ,口服,每日1次，共 $1 0 \mathrm { ~ d ~ } _ { \varsigma }$ 。 $\textcircled{4}$ 醋酸甲羟孕酮（MPA）： $6 \sim 1 0 ~ \mathrm { m g }$ ，口服，每日1次,共 $1 0 \mathrm { ~ d ~ }$ 。 2)雌激素：雌激素治疗也称"子宫内膜修复法”，适用于出血时间长、量多致血红蛋白 $< 8 0 ~ \bf \delta g / L$ 的青春期患者。具体用法如下： $\textcircled{1}$ 苯甲酸雌二醇：初始剂量 $3 \sim 4 \mathrm { \ m g / d }$ ,分2\~3次肌内注射,若出血明显减少,则维持;若出血量未见减少，则加量,也可从 $6 \sim 8 \mathrm { \ m g / d }$ 开始,每日最大量一般不超过 $1 2 { \mathrm { ~ m g } } _ { }$ 出血停止3d后开始减量，通常以每3天递减1/3量为宜。 $\textcircled{2}$ 结合雌激素： $2 5 { \mathrm { ~ m g } }$ ,静脉注射，可 $4 \sim 6 \mathrm { ~ h ~ }$ 重复1次，一般用药 $2 \sim$ 3次;次日应给予结合雌激素（其他名称：倍美力） $3 . 7 5 \sim 7 . 5 ~ \mathrm { m g / d }$ ，口服，并按每3天递减1/3量为宜。也可在 $2 4 \sim 4 8 \mathrm { ~ h ~ }$ 内开始用口服避孕药。 $\textcircled{3}$ 结合雌激素：每次$1 , 2 5 ~ \mathrm { m g }$ 或戊酸雌二醇(其他名称：补佳乐)每次 $2 ~ \mathrm { m g }$ ,口服,每4\~6小时1次，血止3d后按每3天递减1/3量为宜。各种雌激素治疗过程中，当血红蛋白增加至 $9 0 ~ \mathbf { g } / \mathbf { L }$ 以上后，均必须加用孕激素治疗,以达到撤退性出血的目的。 3)复方短效口服避孕药：适用于长期而严重的无排卵出血。目前使用的是第3代短效口服避孕药，如去氧孕烯-炔雌醇（其他名称:妈富隆）、孕二烯酮-炔雌醇(其他名称:敏定偶)或复方醋酸环丙孕酮(其他名称：达英-35),用法为每次1\~2片，每8\~12小时1次，血止3d后逐渐减量至每天1片，维持至第21天本周期结束。‘ 4)高效合成孕激素：高效合成孕激素可使子宫内膜萎缩,从而达到内膜萎缩和止血目的,此法不适用于青春期患者。炔诺酮(其他名称：妇康片， $0 . 6 2 5 \mathrm { \ m g / }$ 片)治疗出血量较多的功血时，首剂量为 $5 \ \mathrm { m g }$ ，每8小时1次，血止2\~3d后，每3天递减1/3量，直至维持量为每天 $2 . 5 \sim$ $5 . 0 ~ \mathrm { m g }$ ;持续用至血止后21d停药，停药后3\~7d发生撤退性出血。也可用左炔诺孕酮 $1 . 5 \sim 2 . 2 5 ~ \mathrm { m g / d }$ ,血止后按同样原则减量。 (2)刮宫术：刮宫可迅速止血，并具有诊断价值，可了解子宫内膜病理变化,除外恶性病变。对于绝经过渡期及病程长的育龄期妇女应首先考虑使用刮宫术，对未婚、无性生活史的青少年，除非要除外内膜病变,不轻易选择刮宫术，仅适于大量出血且药物治疗无效需立即止血，或需要行子宫内膜组织病理学检查者。对于B超检查提示宫腔内异常者可在宫腔镜下刮宫，以提高诊断的准确率。 (3)辅助治疗：一般止血药包括氨甲环酸(其他名称：妥塞敏）每次 $_ { 1 \mathrm { ~ g ~ } }$ ，每天2\~3次，或酚磺乙胺(其他名称：止血敏）、维生素K等。1)丙酸睾酮：具有对抗雌激素的作用，可减少盆腔充血和增加子宫张力,减少子宫出血,并有协助止血作用。2)矫正凝血功能：出血严重时可补充凝血因子，如纤维蛋白原、血小板、新鲜冻干血浆或新鲜血。3)矫正贫血：对中、重度贫血患者在上述治疗的同时，可给予铁剂和叶酸治疗，必要时输血。4)抗炎治疗：对出血时间长,贫血严重，抵抗力差或有合并感染临床征象者，应及时应用抗生素。 # 2.调节月经周期采用上述方法达到止血目的后，因病因并未去除，停药后多数患者可复发，需采取措施控制周期，防止功血再次发生。 (1)孕激素：可于撤退性出血第15天起，使用地屈孕酮$1 0 \sim 2 0 ~ \mathrm { m g / d }$ ,共10d,或微粒化黄体酮胶囊 $2 0 0 \sim 3 0 0 ~ \mathrm { m g / d }$ ，共10d,或MPA $4 \sim 1 2 ~ \mathrm { m g / d }$ ,分2\~3次口服，共 $1 0 \sim 1 4 ~ \mathrm { d } _ { \varsigma }$ 酌情应用3\~6个周期。 (2)口服避孕药：口服避孕药可很好地控制周期，尤其适用于有避孕需求的患者。一般在止血用药撤退性出血后，周期性使用口服避孕药3个周期,病情反复者可酌情延长至6个周期。应用口服避孕药的潜在风险应予注意，有血栓性疾病、心脑血管疾病高危因素及40岁以上吸烟的女性不宜应用。 (3)雌、孕激素序贯疗法：如孕激素治疗后不出现撤退性出血，考虑是否内源性雌激素水平不足，可用雌、孕激素序贯疗法。绝经过渡期患者伴有绝经症状且单纯孕激素定期撤退不能缓解者，按《绝经过渡期和绝经后激素治疗临床应用指南修订草案(2006版)》[]处理。 (4)左炔诺孕酮宫内缓释系统：可有效治疗功血，原理为在宫腔内局部释放左炔诺孕酮,抑制子宫内膜生长。 # 3.手术治疗对于药物治疗效果不佳或不宜用药、无生育要求的患者，尤其是不易随访的年龄较大者及内膜病理为癌前病变或癌变者，应考虑手术治疗。 S (1)子宫内膜去除术：适用于激素等药物治疗无效或复发者，尤其适用于无生育要求的有排卵型月经过多患者，并可同时剔除黏膜下子宫肌瘤。 (2)子宫全切除术。 # (二)有排卵型功血的治疗 # 1．月经过多的治疗 (1)药物治疗：1)止血药：氨甲环酸口服每次 $_ { \mathrm { ~ 1 ~ g ~ } }$ ，每天2\~3次，可减少经量 $54 \%$ ；经量 $< 2 0 0 \ \mathrm { m l }$ 者，应用后 $92 \%$ 的患者经量 $< 8 0 \mathrm { ~ m l }$ ，无栓塞性疾病增加的报道。不良反应为轻度恶心、头晕、头痛等。也可应用酚碘乙胺、维生素K等。2)宫腔放置左炔诺孕酮宫内缓释系统：放置后，该系统可在宫腔内释放左炔诺孕酮 $2 0 ~ \mu \mathrm { g } / \mathrm { d }$ ,有效期一般为5年。使用该系统过程中，经量可明显减少， $2 0 \% \sim 3 0 \%$ 的使用者可出现闭经，但使用的最初6个月可能发生突破性出血。左炔诺孕酮宫内缓释系统副作用少。3)高效合成孕激素：使用高效合成孕激素可使子宫内膜萎缩。 (2)手术治疗：子宫内膜去除术、子宫全切除术或子宫动脉栓塞术。 # 2.月经间期出血的治疗建议先对患者进行1\~2个周期的观察,测定BBT,明确出血类型，排除器质性病变，再进行干预。 (1)围排卵期出血：止血等对症治疗。 (2)经前期出血：出血前补充孕激素或hCG，卵泡期应用枸橡酸氯米酚促排卵以改善卵泡发育及黄体功能。 (3)月经期延长：周期第5～7天，给予小剂量雌激素帮助修复子宫内膜,或枸橡酸氯米酚促卵泡正常发育，或在前个周期的黄体期应用孕激素促进子宫内膜脱落。 (4)口服避孕药：可适用于上述各种月经间期出血，口服避孕药可很好地控制周期，尤其适用于有避孕需求的患者。一般于月经第1～5天开始,周期性使用口服避孕药3个周期，病情反复者可酌情延长至6个周期。 # 参考文献 [1］中华医学会妇产科学分会绝经学组．绝经过渡期和绝经后激素治疗临床应用指南修订草案(2006版)．中华妇产科杂志， 2008,43:396-398. （收稿日期：2008-12-25）（本文编辑：潘伟） ·消息· # 第13届全国经阴道子宫系列手术及盆底重建学习班通知由广东省佛山市妇幼保健院主办的全国经阴道子宫系列手术培训项目，经卫生部批准列入2009年国家级继续医学教育项目（编号：2008-05-01-029〈国>），现定于2009 年5月6至10日在佛山市举办"第13届全国经阴道子宫系列手术及盆底重建学习班”。学习班将重点讨论经阴道子宫全切除术（包括非脱垂子宫和脱垂子宫）、子宫次全切除术、子宫肌瘤剔除术、广泛性子宫切除术及盆底重建等手术的适应证、禁忌证、操作技巧、并发症的防治等。并将邀请国内著名专家郎景和、沈铿、宋磊、姚元庆、朱兰、王建六、杨冬梓、王沂峰、张晓薇、罗新、陆安伟、谢庆煌、柳晓春等教授进行专题讲座和手术演示，并备有相关手术VCD及阴式手术专用器械。与会者颁发国家级I类继续教育学分10分。有意参加学习班者，请与广东省佛山市妇幼保健院谢庆煌、贾德勤联系，电话：谢庆煌：13809814853、贾德勤：0757-82969772；传真：0757-82969936。也可通过电子邮箱（kejiaoke $@$ fsfy.com）报名，正式会议通知可从网站（http://www.fsfy.com）下载，也可来电索取。	None	None	None
3ec1e4675251475185b5605fbb36ef1f	中华医学会	多囊卵巢综合征的诊断和治疗专家共识	·临床指南· # 多囊卵巢综合征的诊断和治疗专家共识 # 中华医学会妇产科学分会内分泌学组多囊卵巢综合征（polycystic ovary syndrome,PCOS）是妇科内分泌临床常见的疾病，在我国有着庞大的患者群。PCOS临床表现呈异质性，不但严重影响患者的生殖功能，而且雌激素依赖性肿瘤如子宫内膜癌发病率增加，相关的代谢失调包括高雄激素血症、胰岛素抵抗、糖代谢异常、脂代谢异常、心血管疾病风险也增加。PCOS至今病因尚不明确，诊断标准不统一，治疗药物的使用方案混乱,对远期并发症也缺乏合理的防治措施,因此,制定诊治规范迫在眉睫。中华医学会妇产科学分会内分泌学组于2006年11月18日在重庆召开了妇科内分泌学专家扩大会议，会议经过热烈的讨论，初步达成了目前中国的PCOS 诊断和治疗专家共识,经过1年多40余场关于PCOS诊断和治疗专家共识的全国巡讲，广泛征求各界意见,2007年11月24日中华医学会妇产科学分会内分泌学组在海南省三亚市召开了PCOS 诊断和治疗专家共识临床问题解答专家会，最终产生了适合目前中国情况的PCOS 诊断和治疗专家共识。 # 一、PCOS 概述 PCOS 在生育年龄妇女中的发病率为 $5 \% \sim 1 0 \%$ （中国尚无确切患病率报道)，占无排卵性不孕症患者的 $30 \%$ \~$60 \%$ 。目前,我国尚缺少全国性、大样本、多中心的研究结果。PCOS 的确切病因尚不清楚,有研究认为,其可能是由于某些遗传基因与环境因素相互作用引起的。不 1．遗传因素：PCOS有家族聚集现象，被推测为一种多基因病，目前的候选基因研究涉及胰岛素作用相关基因、高雄激素相关基因和慢性炎症因子等。 2.环境因素:宫内高雄激素环境、抗癫痫药物、地域、营养和生活方式等,可能是PCOS 发病的危险因素或易患因素,尚需进行流行病学调查后，完善环境与PCOS关系的认识。 # 二、PCOS 的诊断在现阶段，推荐2003年欧洲人类生殖与胚胎学会和美国生殖医学会专家会议推荐的标准在中国使用,待中国国内的流行病学调查和相关研究有了初步结果之后,再斟酌是否对此诊断标准进行修正。 1.PCOS诊断标准：(1)稀发排卵或无排卵;(2)雄激素水平升高的临床表现和(或)高雄激素血症；(3)卵巢多囊性改变；(4)上述3条中符合2条,并排除其他致雄激素水平升高的病因,包括先天性肾上腺皮质增生、Cushing 综合征、分泌雄激素的肿瘤等，以及其他引起排卵障碍的疾病，如高催乳素血症，卵巢早衰和垂体或下丘脑性闭经，以及甲状腺功能异常。 2.标准的判断：(1)稀发排卵或无排卵： $\textcircled{1}$ 初潮2\~3年不能建立规律月经;闭经(停经时间超过3个以往月经周期或 $\geqslant 6$ 个月)；月经稀发，即周期 $\geqslant 3 5 \ { \mathrm { \textbf { d } } }$ 及每年 $\geqslant 3$ 个月不排卵者（WHOⅡ类无排卵）； $\textcircled{2}$ 月经规律并不能做为判断有排卵的证据； $\textcircled{3}$ 基础体温（BBT)、B超监测排卵、月经后半期孕酮测定等方法有助于判断是否有排卵；(2)雄激素水平升高的临床表现：痤疮(复发性痤疮，常位于额、双颊、鼻及下颌等部位）、多毛(上唇、下颌、乳晕周围、下腹正中线等部位出现粗硬毛发);(3)雄激素水平升高的生化指标：总睾酮、游离睾酮指数或游离睾酮水平高于实验室参考正常值；(4)多囊卵巢(PCO)诊断标准：一侧或双侧卵巢中直径 $2 \sim 9 \ \mathrm { m m }$ 的卵泡 $\geqslant 1 2$ 个，和(或)卵巢体积 $\geqslant 1 0 \ m l$ 。 3.PCOS 诊断的排除标准：排除标准是诊断 PCOS 的必须条件，如催乳素水平明显升高，应排除垂体瘤， $2 0 \% \sim 3 5 \%$ 的PCOS患者可伴有催乳素水平轻度升高;如存在稀发排卵或无排卵，应测定卵泡刺激素(FSH)和雌二醇水平,排除卵巢早衰和中枢性闭经等;测定甲状腺功能,以排除由于甲状腺功能低下所致的月经稀发；如出现高雄激素血症或明显的雄激素水平升高的临床表现，应排除非典型性肾上腺皮质增生（NCAH）、Cushing综合征、分泌雄激素的卵巢肿瘤等。 4.青春期 PCOS 诊断标准：由于难以鉴别生理状态与PCOS状态,且尚缺乏循证医学的证据，目前尚没有对青春期PCOS统一的诊断标准。 # 三、PCOS 的合并症 PCOS常伴有肥胖[1-2]、代谢综合征[34]和胰岛素抵抗[5.] # 四、PCOS 的治疗 PCOS 患者无论是否有生育要求，首先均应进行生活方式调整，戒烟、戒酒。肥胖患者通过低热量饮食和耗能锻炼，降低全部体重的 $5 \%$ 或更多,就能改变或减轻月经紊乱、多毛、痤疮等症状并有利于不孕的治疗。减轻体重至正常范围,可以改善胰岛素抵抗,阻止PCOS长期发展的不良后果，如糖尿病、高血压、高血脂和心血管疾病等代谢综合征。 # (一)调整月经周期 PCOS 患者的月经不规律可以表现为月经周期不规律、月经稀发、量少或闭经,还有一些阴道出血是不可预测的。调整月经周期,可以保护子宫内膜,减少子宫内膜癌的发生。 1.口服避孕药：可选择各种短效口服避孕药,其中，孕激素可使子宫内膜转换,从而减少子宫内膜癌的发生。常规用法是在自然月经期或撤退性出血的第5天开始服用，每日1片,连续服用21d,停药约5d开始撤退性出血，撤退性出血第5天重新开始用药，或停药7d后重复启用。至少3～6个月，可重复使用。口服避孕药可纠正高雄激素血症，改善雄激素水平升高的临床表现;同时可有效避孕,周期性撤退性出血还可改善子宫内膜状态，预防子宫内膜癌的发生。但需特别注意的是，PCOS患者是特殊人群，常常存在糖、脂代谢紊乱,用药期间应监测血糖、血脂变化;对于青春期女性应用口服避孕药前应进行充分的知情同意;服药前需排除口服避孕药的禁忌证。 2.孕激素：对无明显雄激素水平升高的临床和实验室表现，且无明显胰岛素抵抗的无排卵患者，可单独采用定期孕激素治疗，以周期性撤退性出血改善子宫内膜状态。常用的孕激素有醋酸甲羟孕酮、黄体酮(其他名称：琪宁）、地屈孕酮(其他名称：达芙通)等。常规用法是在月经周期后半期醋酸甲羟孕酮 $6 \ m g / \mathrm { d }$ ，或黄体酮 $2 0 0 \mathrm { \ m g / d }$ ，或地屈孕酮$1 0 \sim 2 0 ~ \mathrm { m g / d }$ ，每月 $^ { 1 0 \mathrm { ~ d ~ } }$ ，至少每两个月撤退性出血1次；撤退性出血也可以肌内注射黄体酮5\~7d,如长期应用仍需肌内注射 $^ { 1 0 \mathrm { ~ d ~ } }$ 以上才能保护子宫内膜。使用孕激素的优点是：(1)调整月经周期，保护子宫内膜，预防子宫内膜癌的发生；(2)可能通过减慢黄体生成素(LH)脉冲式分泌频率，在一定程度上降低雄激素水平；(3)适用于无严重高雄激素血症和代谢紊乱的患者。 10 # (二)高雄激素血症的治疗各种短效口服避孕药均可用于高雄激素血症的治疗，以复方醋酸环丙孕酮(其他名称：达英-35)为首选；其可通过抑制下丘脑-垂体LH分泌，而抑制卵泡膜细胞高水平雄激素的生成。通常，痤疮需治疗3个月，多毛需治疗6个月，但停药后雄激素水平升高的症状将恢复。会 # (三)胰岛素抵抗的治疗二甲双胍适用于治疗肥胖或有胰岛素抵抗的患者。二甲双胍通过增强周围组织对葡萄糖的摄入、抑制肝糖原产生，并在受体后水平增强胰岛素敏感性、减少餐后胰岛素分泌，改善胰岛素抵抗，预防代谢综合征的发生。常规用法是：$5 0 0 ~ \mathrm { m g }$ ，每日2\~3次，治疗时每3\~6个月复诊1次，了解月经和排卵恢复情况，有无不良反应，复查血清胰岛素水平。如果月经不恢复，仍须加用孕激素调经。二甲双胍为B类药，药品说明上并未将妊娠后妇女列为适应人群，妊娠后是否继续应用，需根据患者具体情况和内分泌科医生建议慎重决定。二甲双胍的副作用最常见的是胃肠道反应,如腹胀、恶心、呕吐及腹泻，这些症状为剂量依赖性的,2～3周逐渐加至足量及餐中服用药物可减少副作用。严重的副作用是可能发生肾功能损害和乳酸性酸中毒，须定期复查肾功能。 # (四)促排卵治疗为促使无排卵的患者达到排卵及获得正常妊娠，常需进行促排卵治疗。 1．一线促排卵治疗：枸橡酸氯米芬：从自然月经或撤退性出血(黄体酮 $2 0 \ m g / \mathrm { d }$ ，肌内注射 $\times 3 \mathrm { ~ d ~ }$ 的第5天开始，$5 0 ~ \mathrm { m g / d }$ ,共5d,如无排卵则每周期增加 $5 0 \ \mathrm { m g / d }$ ，直至150$\mathbf { m g / d }$ 。有满意排卵者不必增加剂量，如卵泡期长或黄体期短说明剂量可能低，可适当增加剂量;疗效判断可测试和记录BBT，但为防止过多卵泡生长或观察确切疗效也可采用经阴道或直肠B超监测卵泡发育。枸橡酸氯米芬具有弱的抗雌激素作用，可影响宫颈黏液，精子不宜生存与穿透;还可影响输卵管蠕动及子宫内膜发育，不利于胚胎着床，可于近排卵期适量加用戊酸雌二醇等天然雌激素；另外，枸橼酸氯米芬还可引起血管舒缩性潮热、腹部膨胀或不适、胸部疼痛、恶心和呕吐、头痛和视觉症状，偶有患者不能耐受此药。 2.二线促排卵治疗：(1)促性腺激素：常用的促性腺激素为人绝经期促性腺激素（hMG）、高纯度FSH(HP-FSH)和基因重组FSH(r-FSH)。适用于耐枸橡酸氯米芬的无排卵的不孕患者(已除外其他不孕原因)；具备盆腔超声及雌激素监测的技术条件，并具有治疗卵巢过度刺激综合征(OHSS)和减胎技术的医院。禁忌证包括：血FSH水平升高的卵巢性无排卵患者；无监测卵泡发育和排卵技术条件的医院。用法：低剂量逐渐递增的FSH方案和逐渐减少的方案。使用促性腺激素的并发症有：多胎妊娠、OHSS。故在使用促性腺激素的过程中，需要反复超声和雌激素水平监测。文献报道，直径 $> 1 6 \mathrm { \ m m }$ 的卵泡 $\geqslant 4$ 个时，发生多胎妊娠和OHSS 的可能性增加，应取消该周期。（2)腹腔镜下卵巢打孔术（laparoscopic ovarian drilling,LOD）[8-9]：主要用于枸橡酸氯米芬抵抗、因其他疾病需腹腔镜检查盆腔、随诊条件差、不能进行促性腺激素治疗监测者，建议选择体重指数（BMI) $\leqslant$ $3 4 \mathrm { ~ k g } / \mathrm { m } ^ { 2 }$ $\mathrm { L H } > 1 0 ~ \mathrm { U } / \mathrm { L }$ ,游离睾酮水平高的患者做为治疗对象。LOD的促排卵机制为，破坏产生雄激素的卵巢间质，间接调节垂体-卵巢轴，使血清LH及睾酮水平下降,增加妊娠机会，并可能降低流产的危险。LOD可能出现的问题有，治疗无效、盆腔粘连、卵巢功能低下。 3．体外受精-胚胎移植：(1)适应证：以上方法促排卵治疗失败的患者。(2)机制：通过促性腺激素释放激素降调节垂体,抑制内源性FSH和LH分泌，降低高水平LH的不良作用，改善卵巢对hMG或FSH的反应。（3）可能出现的问题及解决方法：获得的卵子数多、质量不佳、成功率低、OHSS发生率高[10-I],解决方法是取卵受精后可不在本周期雌激素水平高时移植胚胎,冷冻保存后在下个自然周期移植，或行未成熟卵母细胞的体外成熟。 # 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[2］Zhou BF. Predictive values of body mass index and waist circumference for risk factors of certain related diseases in Chinese adults study on optimal cut-off points of body mass index and waist circumference in Chinese adults.Biomed Environ Sci,2O02,15： 83-96. [3]International Diabetes Federation（IDF）．The IDF consensus worldwide definition of the metabolic syndrome[DB/OL]．http:// www.idf.org/home. ［4］中华医学会糖尿病分会代谢综合征研究协作组．中华医学会糖尿病学分会关于代谢综合征的建议．中华糖尿病杂志， 2004,12:156-161. [5]Fronzo RA，Andres R，Andres R.Glucose clamp technique：a method for quantifying insulin secretion and resistance.Am J Physiol,1979,237:214-223. [6]Matthews DR,Hosker JP,Rudenski AS,et al.Homeostasis model assessment:insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 1985,28:412-419. [7]Katz A,Nambi SS，Mather K,et al．Quantitative insulin sensitivity check index：a simple，accurate method for assessing insulin sensitivity in humans.J Clin Endocrinol Metab,2Oo0,85： 2402-2410. [8]Amer SA,Li TC,Cooke ID.Laparoscopic ovarian diathermy in women with polycystic ovarian syndrome：a retrospective study on the influence of the amount of energy used on the outcome.Hum Reprod,2002,17:1046-1051. [9]Amer SA，Li TC，Ledger WLOvulation induction using laparoscopic ovarian drilling in women with polycystic ovarian syndrome：predictors of success.Hum Reprod，2004,19:1719- 1724. [10]Golan A,Ron-el R,Herman A,et al.Ovarian hyperstimulation syndrome：an update review. Obstet Gynecol Surv,1989,44:430- 440. [11]Navot D,Bergh PA,Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies：prevention and treatment. Fertil Steril,1992,58:249-261. （收稿日期：2008-04-15）（本文编辑：潘伟） ·消息· # 2008年国际妇科肿瘤论坛(中国·无锡)通知妇科肿瘤是目前育龄女性的常见疾病，严重危害女性的健康。为进一步推动本地区妇科肿瘤治疗的发展，推广肿瘤个体化和综合治疗的理念，江苏省医学会、复旦大学附属肿瘤医院、无锡市医院管理中心、无锡肿瘤医院共同主办的“2008年国际妇科肿瘤论坛（中国·无锡）"定于2008年10月31日一11月2日中下旬在无锡市举办。届时将邀请美国安德森癌症中心、新加坡妇产科医院、日本东京大学医学部附属病院及我国香港大学医学院等著名的妇科肿瘤专家和北京、上海等国内多位著名专家讲演，展示目前国内外妇科肿瘤多学科综合治疗的最新研究成果，并为参与本次大会的广大妇科肿瘤专业人士提供交流、学习、协作的机会。我们真诚地期待您的参加。参会者将授予省继续教育I类学分8分。联系人：江苏省无锡市第四人民医院蒋平；电话：0510-88683005;Email:lightframe_3@163.com # “拜耳先灵杯”补佳乐临床应用论文有奖征集补佳乐(戊酸雌二醇片)是一种天然雌激素，每片补佳乐含戊酸雌二醇 $1 ~ \mathrm { m g }$ 。戊酸雌二醇是由植物、大豆提取而成，是目前最接近人体雌激素，且活性最高的天然雌激素。补佳乐进人人体后，立即变为雌二醇，然后按照雌二醇的典型途径进行代谢，因此非常安全和容易检测。自补佳乐上市以来，其在治疗功能失调性子宫出血、体外受精治疗中的内膜准备、调经、绝经期妇女的激素治疗、产后回奶、子宫粘连预防和治疗、人工流产术后的子宫内膜生长等方面的确切而安全的作用，已经得到广大妇产科医生的认可和推崇。为了更好地交流补佳乐的临床应用经验，《中华妇产科杂志》编委会与拜耳医药保健公司女性健康事业部联合举办“拜耳先灵杯”补佳乐临床应用论文评奖活动。（1)征文内容：补佳乐用于治疗因雌激素缺乏引起的各种疾病及症状,包括功能失调性子宫出血、体外受精治疗中的内膜准备、调经、绝经期妇女的激素治疗、产后回奶、子宫粘连的预防和治疗、人工流产术后的子宫内膜生长等方面的研究。观察病例要求最少30例,观察随访时间不少于3个周期。(2)征文要求：征文内容侧重于临床应用,在病例选择、治疗方案、疗效观察方面应设对照组，有统计学分析。写作规范参见《中华妇产科杂志》稿约。论文要求4000 字以内并附中英文摘要，请注明作者姓名、单位及科室、地址和邮政编码。（3)评选方法：根据论文的科学性、真实性、设计水平等进行评审。前瞻性论文优先考虑。由《中华妇产科杂志》编委会组织妇产科专家组成的评审委员会对论文进行评审，评选出：特等奖1名（奖金7000元)；一等奖2名(奖金5000元)；二等奖3名（奖金3000元)；三等奖8名(奖金1000元)。获奖论文经审核符合录用标准的将被推荐在《中华妇产科杂志》刊登。所有符合要求的论文将编人《中华妇产科杂志》编委会与拜耳医药保健公司女性健康事业部共同出版的《补佳乐临床应用文集》。（4)截稿日期：2009年4月30日。来稿请寄《中华妇产科杂志》编辑部(地址：北京东四西大街42号，邮政编码：100710)；投稿同时请务必附论文的软盘，并请在信封上注明“补佳乐征文"字样,也可将论文以Word 格式Email发给以下地址：zhaoxiaowen $@$ cma.org.cn。论文请自留底稿，恕不退稿。	None	None	None
07133c49d574492a945f3e84645c947a	中华医学会	女性慢性盆腔痛诊治中国专家共识	·专家共识· # 女性慢性盆腔痛诊治中国专家共识贺豪杰1 陈娟2 侯征1 段华3 张鹏4 路桂军5 刘红菊6 王立杰7 马彩玲8 薛艳 9 王建六 10 黄向华 11 赵霞 12 郝敏 13 哈春芳 14 韩劲松 1 王莎 1 李水清 15 梁志清 16 林井副 17 凌斌 18 路静 19 万有 20 许泓 21 张信美22 周应芳23 朱根海24 朱兰2 郭红燕1 1 北京大学第三医院妇产科国家妇产疾病临床医学研究中心，北京；2 中国医学科学院北京协和医院妇产科国家妇产疾病临床医学研究中心，北京 100730；3 首都医科大学附属北京妇产医院妇科微创诊治中心，北京 100006；4 中国康复研究中心泌尿科，北京；5 清华大学附属北京清华长庚医院疼痛科，北京；6 中国医学科学院北京协和医院疼痛科，北京 100730；7 山东大学齐鲁医院妇产科，济南 250012；8 新疆医科大学附属第一医院妇产科，乌鲁木齐 830054；9 北京大学第三医院消化科，北京 100191；10北京大学人民医院妇产科，北京 100044；11河北医科大学第二医院妇产科，石家庄 050000；12四川大学华西第二医院妇产科，成都 610041；13山西医科大学第二医院妇产科，太原 030001；14宁夏医科大学总医院妇产科，银川 750004；15北京大学第三医院疼痛科，北京 100191；16陆军军医大学第一附属医院妇产科，重庆 430038；17解放军总医院放射科，北京 100853；18中日友好医院妇产科，北京 100029；19新疆维吾尔自治区乌鲁木齐市妇幼保健院妇科，乌鲁木齐；20北京大学基础医学院北京大学神经科学研究所，北京 100191；21上海交通大学医学院附属国际和平妇幼保健院妇科，上海；22浙江大学医学院附属妇产科医院妇科，杭州；23北京大学第一医院妇产科，北京 100034；24海南省人民医院妇产科，海口 570311通信作者：朱兰， Email：zhu_julie@vip.sina.com；郭红燕， Email：bysyghy@163.com 【摘要】　女性慢性盆腔痛（）是定位于盆腔的持续个月以上的疼痛，患病率高，病因涉及多个器官、系统，常伴有心理变化，严重影响患者的身心健康，诊治极为复杂，目前国内尚缺乏相应的诊治指南。本共识是在参考国际指南的基础上，结合国内的临床实践经验，由妇科、泌尿科、消化科、疼痛科、影像科、心理学及基础神经生物学等多学科专家共同讨论制定，详细阐述了CPP的评估（包括详细询问病史、系统全面查体、针对性的辅助检查以及疼痛、心理评估）、诊断和治疗（包括患者教育、药物治疗、康复治疗、介入治疗、手术治疗、补充和替代治疗、精神心理治疗和多学科综合治疗）等方面，并给出了19条推荐意见，旨在为这一复杂病症提供诊治思路以及为临床工作提供指导。慢性盆腔痛（chronic pelvic pain，CPP）病因繁复、诊治棘手，涉及到包括妇科在内的多个相关学科，国内缺乏相关的诊治指南，为此国内相关领域的妇科、泌尿科、消化科、疼痛科、影像科、心理学以及基础神经生物学专家经过讨论，并参考研究证据、国际指南以及中国的临床实际，制定了《女性慢性盆腔痛诊治中国专家共识》，旨在为临床提供诊治思路以及实际工作指导。 # 一、定义迄今为止，CPP尚无国际通用的统一定义［1］，尤其是在疼痛部位、持续时间以及是否具有周期性等问题上。国际上较为公认的标准为：定位于盆腔的，包括腹壁、盆腔器官、会阴区域、腰骶部、臀部，持续6个月以上的非周期性疼痛；如果周期性疼痛对生活和心理造成严重影响也归为范畴［2］。需要强调的是，疼痛是一种主观感觉，即使检查未见异常并不能否定CPP的诊断。按上述定义，女性CPP的发病率为 $5 . 7 \% { \sim } 2 6 . 6 \% ^ { [ 3 ] }$ ，影响人群广泛，且对患者的生命质量影响大。 # 二、病因及分类 2020 年，美国妇产科医师协会（AmericanCollege of Obstetricians and Gynecologists，ACOG）共识［2］将的病因分为器官疾病、神经肌肉骨骼异常及心理社会因素三大类。本共识主要采用此分类，同时结合了 2015 年国际妇产科心身医学会（International Society of Psychosomatics in Obstetrics& Gynecology，ISPOG）CPP 共识的病因分类［4］，具体见表1。器官疾病产生的疼痛主要为内脏神经痛，其特点包括：疼痛弥散、定位不准、界限不清；对牵拉、缺血、炎症敏感；常常伴有自主神经症状，包括出汗、生命体征异常或胃肠道症状。器官疾病的分类包括女性生殖系统、泌尿系统及消化系统疾病，其中，既包括炎症、肿瘤、结石等特定疾病，也包括病因不明、需排他性诊断的综合征，需进行细致的鉴别诊断。最易引起的器官疾病、综合征包括：子宫内膜异位症、间质性膀胱炎及所致膀胱疼痛综合征（interstitial cystitis/bladder painsyndrome，IC/BPS）、肠易激综合征（irritable bowelsyndrome，IBS）［5］。神经肌肉疼痛与长期微损伤、姿势不良、手术创伤造成肌肉筋膜产生扳机点或神经血管卡压有关，其特点为查体触及相关肌肉群可复现的疼痛。精神社会因素在各种疼痛中均起着重要作用，影响疼痛的严重程度及预后。需要强调的是器官疾病可以同时合并神经肌肉疼痛及精神社会因素。表1 慢性盆腔痛病因分类（参考2020年ACOG共识［2］及2015年ISPOG共识［4］） <table><tr><td colspan="2"></td><td>器官疾病原因</td><td></td><td></td><td>神经肌肉原因</td><td>精神社会原因</td></tr><tr><td colspan="2">生殖系统</td><td></td><td>IEDICAL:AS</td><td></td><td>纤维肌痛</td><td>虐待</td></tr><tr><td colspan="2">子宫内膜异位症及子宫腺肌病盆腔炎症性疾病及其后遗症</td><td></td><td></td><td></td><td>姿势综合征肌筋膜痛综合征</td><td>药物依赖</td></tr><tr><td colspan="2">残留卵巢综合征(residual ovary syndrome)及卵巢残余物综合征(ovarian remnant syndrome)</td><td></td><td></td><td></td><td>尾骨痛</td><td>躯体症状障碍抑郁症</td></tr><tr><td colspan="2">盆腔综合征中華器学</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2"></td><td></td><td></td><td></td><td>腹旺综肌综合征</td><td>焦神疗裂症</td></tr><tr><td colspan="2">妇科恶性肿瘤</td><td></td><td></td><td></td><td>肌肉损伤</td><td></td></tr><tr><td colspan="2">附件肿物</td><td></td><td></td><td></td><td>扳机点</td><td></td></tr><tr><td colspan="2">子宫肌瘤</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">外阴前庭炎</td><td></td><td></td><td></td><td>神经源性</td><td></td></tr><tr><td colspan="2"></td><td></td><td></td><td></td><td>腹型癫痫</td><td></td></tr><tr><td colspan="2">盆腔器官脱垂及其手术后并发症</td><td></td><td></td><td></td><td>腹型偏头痛</td><td></td></tr><tr><td colspan="2">生殖系统畸形</td><td></td><td></td><td></td><td>神经病理性疼痛</td><td></td></tr><tr><td colspan="2">泌尿系统</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">间质性膀胱炎/膀胱疼痛综合征</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">膀胱肿瘤及其治疗并发症</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">泌尿系统慢性感染性疾病</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">尿道综合征</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">泌尿系统结石</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">尿道憩室</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">膀胱功能紊乱</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">消化系统</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2"></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">肠易激综合征</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">炎症性肠病、慢性阑尾炎</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">结直肠肿瘤及其治疗并发症</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">乳糜泻</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">结肠憩室</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2">慢性不全肠梗阻</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="2"></td><td></td><td></td><td></td><td></td><td></td></tr></table> 注：ACOG表示美国妇产科医师协会；ISPOG表示国际妇产科心身医学会 # 三、评估流程 CPP需要通过详细询问病史、系统全面的查体以及有的放矢的辅助检查进行临床评估，从而确定发病器官及病因［6］。 1. 临床病史采集：因CPP病史复杂且特殊，临床病史采集需要足够的时间和耐心，认真倾听并引导患者陈述。推荐采用填写问卷的方式获得完整病史，推荐国际盆腔痛学会（International Pelvic Pain Society，IPPS）在其网站（www.pelvicpain.org）公布的盆腔疼痛评估问卷，内容包括患者的基本信息、疼痛的描述及诱因、不同情况下疼痛的评分、疼痛的人体定位图、月经史、消化道症状、健康习惯、排尿症状、疼痛性质、治疗措施及效果、手术及术中所见以及心理状况等。在问卷的基础上，还要再次详细补充询问病史，以获得更翔实的记录。参考表2作为CPP问诊提纲进行初筛。在初筛的基础上再进一步询问相关问题。如果疼痛与月经相关，需详细了解具体的发生时间（月经期、排卵期或月经后疼痛）。对于性交痛，需了解是性交时痛还是性交后痛、持续时间以及具体的疼痛部位（阴道口痛、深部阴道痛或下腹痛），如：子宫内膜异位症往往是性交时阴道深部或下腹痛；阴部神经痛经常是性交开始时的阴道口或阴道内疼痛，疼痛一旦被激发，常持续至性交后数小时甚至数天，坐位时疼痛加重；盆腔炎症性疾病（pelvicinflammatory disease，PID）及 IC/BPS 常表现为性交后下腹痛。如果疼痛与排尿相关，应具体询问有无尿频、尿痛、夜尿增多等，有无诱发因素（如辛辣饮食），是否使用过抗生素治疗、是否有效等，以区分泌尿系统感染及。病史询问，可以帮助初步界定复杂的器官源性，有些患者通过询问病史甚至可以达到初步诊断；重要的是，为下一步的查体和辅助检查的选择提供了依据和方向。 2. 查体：目的是了解疼痛的部位及特征，为进一步诊断的可能原因提供最直接的依据。因病因可能涉及盆腔以外器官，查体需包括站立位、坐位、卧位及膀胱截石位等不同体位且应为多系统的全面查体。最好在疼痛发作的时候进行检查，通过检查疼痛及压痛位置复现疼痛，描绘疼痛“地图”。站立位观察患者的站姿、步态，观察脊柱有无侧弯，双侧骶髂关节是否对称、是否有压痛，脊柱及脊椎旁肌肉是否有压痛，是否有腹壁疝、切口疝，单腿站立试验，扭髋运动及前屈、后仰是否受限，耻骨联合是否有压痛，以及腰背部肌肉筋膜的压痛点等来判断是否有肌肉骨骼系统的异常。坐位注意观察患者的坐姿，如：阴部神经痛患者可能坐位会加重疼痛，患者往往站立就医或坐位时以健侧臀部着力以避免压迫患侧阴部神经而诱发疼痛。卧位重点为腹部检查，检查有无触痛和扳机点；推荐对腹壁扳机点进行Carnett试验［7］，阳性结果是指在肌肉收缩时腹壁压痛点疼痛加重或不缓解，提示疼痛位于腹壁，而非盆腹腔器官。如果疼痛与体位、劳累、体育锻炼有关，除行上述检查外，应行腰大肌试验、闭孔肌试验、“ ”字试验、直腿抬高试验以除外骶髂关节、腰椎以及肌肉筋膜疾患。腹部查体还应关注肌张力、有无压痛、反跳痛、腹膜刺激征等，阳性往往提示盆腔器官相关疼痛。另外，需注意检查腹股沟区有无疝、淋巴结增大等。以膀胱截石位进行外生殖器检查，特别是有外阴、阴道疼痛以及性交痛的患者，除了关注外阴皮肤、黏膜有无红肿、溃疡、异常分泌物等之外，须注意有无皮肤捏痛、前庭部位触痛，以及行棉签或牙签试验来判断是否有阴部神经支配区域的神经敏感体征。注意阴道检查强调先用单指检查，依次检查阴道前壁（膀胱、尿道）有无压痛、盆底肌肉的肌力及肌张力以及有无扳机点、坐骨棘内侧有无触痛。阴道前壁的压痛和憋尿感是 IC/BPS 的特征之一；而坐骨棘内侧触痛或闭孔内肌下方的阴部神经管触痛往往是阴部神经痛的体征；盆底肌肉触痛往往提示伴发盆底肌肉筋膜炎。描述时需要描述检查的体位、路径（经阴道或经肛门检查），扳机点触痛的位置、肌肉群，触痛的程度及是否有放射［8］。表2 慢性盆腔痛初步问诊提纲 <table><tr><td>一般问题</td><td>何时开始疼痛,疼痛如何发作,有何诱因;疼痛发作的性质、部位、持续时间;是否有发热;疼痛一旦开始是否有扩散或放射;使疼痛加重或缓解的因素</td></tr><tr><td>生殖系统相关</td><td>疼痛是否与月经周期有关;是否有性交痛;是否有阴道分泌物增多</td></tr><tr><td>泌尿系统相关</td><td>疼痛是否与排尿相关,是否有尿频、憋尿时疼痛加重、夜尿增多、尿道口痛</td></tr><tr><td>消化系统相关</td><td>是否有便秘、腹泻、便血或其他与胃肠道相关的症状;排便前疼痛是否加重,排便后是否减轻</td></tr><tr><td>伴随的皮肤、肌肉症状</td><td>疼痛是否与皮肤(疼痛、瘙痒、烧灼感)及姿势、运动相关,是否与肌肉关节有关</td></tr><tr><td>伴随的精神状态</td><td>疼痛是否引起情绪异常如焦虑或抑郁;睡眠状况</td></tr><tr><td>疼痛治疗情况及效果</td><td>曾采取过什么措施、药物来缓解疼痛,是否有效</td></tr><tr><td>患者对于疼痛的关注点</td><td>患者认为疼痛的原因是什么;对于疼痛,患者最关注什么</td></tr></table> 中华量学會杂志社最后进行窥具检查及双合诊盆腔检查，检查有无子宫颈举摆痛，宫骶韧带是否增粗、有无触痛，子宫后壁、阴道后穹隆有无触痛结节，是否有肿物及盆腔器官活动度等来辅助诊断PID、子宫内膜异位症等妇科原因引起的CPP。为避免遗漏，建议查体完毕立即填写IPPS疼痛评估问卷的体格检查部分。辅助检查：在填写问卷、问诊、全面查体后，初步判断CPP的病因，再有的放矢进行相关的辅助检查。CT、MRI检查不作为常规检查方法。诊断性腹腔镜检查尚存争议。见表3。疼痛、心理状态评估：除了问诊、查体外，对于慢性疼痛的患者需要进行疼痛、心理状态的评估。有关疼痛强度的评估方法主要包括视觉模拟评分法（visual analog scale， VAS）、口述分级评分法（verbal rating scale，VRS）、面部表情疼痛量表（faces pain scale，FPS）等［9］；综合评估疼痛性质及强度的评估量表常用 McGill 疼痛问卷（McGill pain）［10］。另外，对生命质量的评估较常采用的是健康调查简表（the medical outcomes study36‑item short form health survey，SF‑36）［11‑12］。 CPP可引起心理疾患，同时，其共存的心理问题也影响疼痛的感知及促进慢性疼痛的发展。在CPP 患者中，常伴有焦虑及抑郁情绪［2］。可借鉴一些心理筛查量表对患者心理状态进行评估，如：患者健康问卷抑郁量表（patient health questionnare‑9，PHQ‑9）、患者健康问卷躯体症状群量表（patienthealth questionnare‑15，PHQ‑15）［13］进行筛查，若可疑有焦虑抑郁问题或怀疑焦虑抑郁引起躯体化症状，需要专业精神心理医生会诊。 # 四、治疗疼痛外周敏化及中枢敏化理论与早治疗：如果疼痛或引起疼痛的病因持续存在，可造成外周和中枢水平的炎性因子、受体、突触、信号通路等异常表达，门控钠通道或钙通道等异常开放，中枢的调控能力下降；内源性血清素、去甲肾上腺素、内源性阿片类物质等释放异常，导致患者痛阈下降，出现痛觉超敏，同时容易并发心理和睡眠障碍［13］。基于上述疼痛敏化的理论，建议患者早诊断、早治疗。 2. 患者教育：患者教育包括解释疼痛的病因，消除对未知病因的焦虑情绪。鼓励特殊病因的患者自我管理。如：患者的饮食及生活习惯建议，阴部神经痛患者建议“马桶型”坐垫避免压迫阴部神经，以及盆底肌筋膜痛患者的放松治疗、姿势纠正等建议。 3. 药物治疗：（1）止痛药：推荐首选非阿片类止痛药［2］。对乙酰氨基酚是一类耐受性良好的止痛药，为非处方药，有中枢性解热镇痛效果，并能抑制下行羟色胺能通路及抑制一氧化氮合成而发挥解热镇痛作用，不作用于外周环氧合酶（cyclooxygenase， COX）受体，抗炎作用弱。镇痛效果在个体间差异较大，需要根据患者的治疗效果决定是否可长期应用。不良反应主要包括出汗、胃肠道反应及皮疹。每天剂量不超过 $2 \ { \underline { { \mathbf { g } } } } ^ { [ 1 3 ] }$ 。非甾体类抗炎药（non‑steroidalanti‑inflammatory drugs， NSAID）通过抑制 COX，减少前列腺素的产生而发挥作用，对于外周及炎症相关疼痛有效。NSAID是治疗类风湿关节炎、骨性关节炎、痛风以及各类轻中度疼痛的一线用药，尤其是急、慢性炎性疼痛。有两种异构体，即和，对和作用的不同是NSAID 药理作用和不良反应的主要原因，对表3 慢性盆腔痛辅助检查推荐 <table><tr><td>月经相关疼痛</td><td>基本检查：血CA125、妇科超声检查。诊断困难或合并排尿、排便症状、高度可疑特殊部位子宫内膜异位症者行盆腔 MRI检查</td></tr><tr><td>泌尿系统相关疼痛</td><td>尿常规、中段尿培养、泌尿系统超声检查;可疑占位性病变,行泌尿系统CT及膀胱镜检查;高度可疑IC/BPS,行钾离子膀胱灌注试验、膀胱镜下水扩张术</td></tr><tr><td>消化道相关疼痛</td><td>消化内镜、消化道造影、盆腹腔CT、直肠电生理等检查,也需除外炎症性肠病及消化道肿瘤[6]</td></tr><tr><td>阴部神经相关疼痛</td><td>查体有坐骨棘或阴部神经管压痛，阴部神经阻滞可作为治疗性诊断</td></tr><tr><td>盆底肌肉筋膜相关疼痛</td><td>盆底电生理、X线、MRI检查</td></tr></table> COX1的抑制作用越强，导致消化道反应的不良反应越大，非选择性NSAID如布洛芬、双氯芬酸、吲哚美辛，长期使用需注意其消化道溃疡等不良反应。选择性抑制剂如塞来昔布，主要用于骨性关节炎、风湿性关节炎、强直性脊柱炎以及痛经等疼痛患者。由于其选择性作用于COX2受体，消化道溃疡不良反应发生率降低。用法 $1 0 0 { \sim } 2 0 0 ~ \mathrm { m g }$ 口服，每天2次。磺胺类过敏、荨麻疹及冠心病者禁用。同对乙酰氨基酚，NSAID药物也需权衡其镇痛效果及不良反应来综合评价此类药物针对个体是否适合长期应用。不同于急性疼痛，阿片类止痛药不推荐作为非癌性CPP的常规及一线用药。而且，阿片类药物不能与苯二氮䓬类药物如地西泮等一起使用。长期使用阿片类止痛药有呼吸抑制、便秘、口干、恶心、呕吐、嗜睡、谵妄、躯体依赖及戒断症状等不良反应［14］。若已开始使用阿片类药物，建议逐渐减量，具体应在疼痛科等专科医生指导下进行。（）抗抑郁药物：可以提高中枢神经系统中羟色胺、去甲肾上腺素及多巴胺等的浓度进而抑制兴奋性神经递质的释放，起到钝化痛觉通路的作用。可用于神经肌肉原因引起的CPP以及IC/BPS，尤其是对于合并中重度抑郁的患者，建议心理治疗的同时加用抗抑郁药物治疗，可同时改善疼痛及抑郁症状，并可增强神经源性疼痛物理治疗的效用。常用药物为三环类抗抑郁药及选择性5‑羟色胺去甲肾上腺素再摄取抑制剂（selective serotoninand norepinephrine reuptake inhibitors，SSNRI）［15］。阿米替林是最常用的三环类抗抑郁药，用量：$1 2 . 5 { \sim } 2 5 ~ \mathrm { m g }$ ，每天 3 次，一般最大剂量不超过$1 5 0 \mathrm { m g / d }$ ，不良反应有抗胆碱能反应如口干、嗜睡、便秘等。严重心脏病、青光眼、麻痹性肠梗阻、甲状腺机能亢进、有癫痫病史患者禁用。度洛西汀、文拉法辛是SSNRI的代表药物。度洛西汀用于外周神经源性疼痛及纤维肌痛的推荐剂量为 $6 0 \mathrm { m g / d }$ 。另外，度洛西汀是唯一被美国食品药品管理局（FDA）批准用于治疗肌肉骨骼疼痛的抗抑郁药。对度洛西汀过敏、病情未控制的闭角型青光眼患者禁用，且禁止与单胺氧化酶抑制剂如异烟肼等合用，25 岁以下及肝肾功能异常者不推荐使用。（3）钙离子通道 $\alpha 2 \delta$ 配体药物：钙离子通道 $\alpha 2 \delta$ 配体药物（抗惊厥药）中，加巴喷丁及普瑞巴林是治疗 CPP 的常用药物。推荐其用于骨骼肌肉及神经源性 $\mathrm { C P P } ^ { [ 2 , 1 6 ] }$ 。加巴喷丁建议从 $3 0 0 \mathrm { m g / d }$ 逐渐加量至 $9 0 0 { \sim } 1 ~ 2 0 0 ~ \mathrm { m g / d }$ ，每天不超过 $2 . 4 \ \mathrm { g }$ ，其常见不良反应为头晕、困倦、外周水肿，持续用药后不良反应可减轻。除推荐用于上述神经源性及骨骼肌肉疼痛外，加巴喷丁也可用于IC/BPS。普瑞巴林的用量推荐 $3 0 0 \mathrm { m g / d }$ ，其不良反应与加巴喷丁相似。用药均需要遵循夜间起始、缓慢加量及逐渐减量的原则。（）抗生素：在患者中是否应用抗生素尚有争议。推荐在PID患者中应用抗生素，以缓解症状及保护生殖生育功能［17］。根据经验选择广谱抗生素以覆盖可能的病原体，包括淋病奈瑟菌、沙眼衣原体、支原体、厌氧菌和需氧菌等。根据严重程度决定静脉给药或非静脉给药以及是否需要住院治疗［18］。口服药物可选择二代或三代头孢菌素类药物（如头孢唑肟、头孢噻肟等），或氧氟沙星 $0 . 4 \ \mathrm { g } / 1 2 \ \mathrm { h }$ ，或左氧氟沙星 $0 . 5 \ \mathrm { g / d }$ ，共 $1 4 \textup { d }$ 。如果所选口服药物不覆盖厌氧菌，需加用硝基咪唑类药物，如：甲硝唑$0 . 4 \ \mathrm { g } / 1 2 \ \mathrm { h }$ ，口服。为治疗非典型病原微生物，可加用多西环素 $0 . 1 \ \mathrm { g } / 1 2 \ \mathrm { h }$ 口服（或米诺环素 $0 . 1 \ \mathrm { g } / 1 2 \ \mathrm { h }$ 口服）；或阿奇霉素 $0 . 5 \ \mathrm { g } / \mathrm { d }$ ，口服，1\~2 d 后改为$0 . 2 5 ~ \mathrm { g / d }$ ，共 $5 \mathrm { \sim } 7 \mathrm { ~ d } ^ { [ 1 8 ] }$ 。（5）性激素类药物：这类药物种类较多，常用于子宫内膜异位症和子宫腺肌病的长期管理，包括短效复方口服避孕药（combined oral contraceptives，COC）、促性腺激素释放激素激动剂（gonadotropin‑releasing hormone agonist，GnRH‑a）、孕激素及其衍生物等。其在控制痛经的同时，对子宫内膜异位症引起的CPP以及原因不明的CPP均有一定效果。长期应用需注意各种药物的适用人群以及应用注意事项和不良反应。 $\textcircled{1}$ ：有效缓解痛经、子宫内膜异位症相关疼痛，同时可以规律月经，减少月经量［19‑21］。40岁以上或有高危因素（如糖尿病、高血压、血栓史及吸烟）的患者慎用，须警惕血栓风险。 $\textcircled{2}$ GnRH‑a：GnRH‑a 作用较 COC 更强，但极低的雌激素水平会导致其长期应用受限；其主要不良反应是低雌激素相关的潮热、阴道干涩、骨质丢失、情绪变化、睡眠不良等。可以采用低剂量雌激素“反向添加疗法”，在改善症状的同时疗效仍有保障［22］。另外，观察性研究显示，GnRH‑a可用于治疗及诊断与残留卵巢综合征相关的 $\mathrm { C P P } ^ { [ 2 3 ] }$ 。 $\textcircled{3}$ 孕激素及其衍生物：孕激素治疗与子宫内膜异位症相关的有效，其机制主要通过子宫内膜蜕膜化进而使内膜萎缩。用于治疗的孕激素包括醋酸甲羟孕酮（medroxyprogesterone acetate）、左炔诺孕酮宫内释放系统（levonorgestrel‑releasing，）、去甲睾酮衍生物（如炔诺酮及地诺孕素）［19，24‑25］。地诺孕素是同时具有19‑去甲睾酮和孕酮衍生物特性的新型人工合成孕激素，在缓解子宫内膜异位症相关疼痛方面，地诺孕素及GnRH‑a同样有效，且可以长期用药，潮热方面的不良反应少于 GnRH‑a，主要不良反应为子宫不规则出血［25］。（6）针对IC/BPS的药物：IC是膀胱无菌性炎症，发病与膀胱黏膜糖胺聚糖缺失及肥大细胞作用相关，以尿频、尿急、夜尿增多、膀胱充盈时耻骨上区域疼痛为主要症状，有时也可出现尿道及会阴部疼痛，在排尿后得到缓解。较顽固，临床疗效不确切，容易出现治疗后症状反复。常用的治疗方法为药物治疗和膀胱灌注治疗，保守治疗无效可考虑骶神经调节治疗及手术治疗。 $\textcircled{1}$ 戊聚糖多硫酸盐：戊聚糖多硫酸盐是唯一由FDA批准用于 IC/BPS治疗的口服药物［26‑28］，其机制主要是纠正膀胱上皮的糖胺聚糖缺失，可缓解疼痛、尿急、尿频，但对夜尿增多无效果。用量：$1 0 0 ~ \mathrm { m g }$ 口服，每天次。用药周有 $50 \%$ 的患者有效。对于效果不明显的患者，可加用肝素治疗［29‑30］。 $\textcircled{2}$ 抗组胺药物：肥大细胞释放组胺类物质在中发挥作用，所以抗组胺药物对遗传性过敏性或活检组织中有肥大细胞明显聚集的患者有效。常用的抗组胺药物羟嗪［26‑27］通过阻断H1受体起作用，用量：羟嗪 $2 5 { \sim } 7 5 \ \mathrm { m g / d }$ ，主要不良反应为嗜睡、眩晕。 $\textcircled{3}$ 免疫抑制剂：由于其免疫抑制作用，需慎重选用。环孢素通过抑制T淋巴细胞激活、稳定肥大细胞而起作用，常用剂量： $1 . 5 ~ \mathrm { m g / k g }$ ，每天2次。环孢素有止痛效果，但对尿频、尿急症状的效果有限。糖皮质激素由于缺乏证据而不推荐使用［28］。对于合并自身免疫性疾病（如系统性红斑狼疮）的IC/BPS患者，激素治疗及免疫抑制剂治疗需遵循风湿免疫科专科意见。 $\textcircled{4}$ 膀胱灌注药物：推荐采用多种药物的“鸡尾酒”法膀胱灌注，常用药物包括局部麻醉药如利多卡因 $( 1 \% )$ ）、二甲亚砜（ $50 \%$ 溶液 $5 0 ~ \mathrm { m l }$ ）、肝素（10 000 U）、透明质酸（ $\mathrm { 4 0 ~ m g }$ ）及硫酸软骨素$( 0 . 2 \% { \sim } 2 \% )$ ）等。单用或多种药物混合膀胱灌注 1\~ 3次/周，持续6\~8周，对于膀胱疼痛、尿频、尿急症状有效。透明质酸及硫酸软骨素膀胱灌注可能修复糖胺聚糖缺失，但现有的临床试验由于缺乏对照组而证据有限［28］。（）针对药物［31］：是一组持续或间歇发作，以腹痛、腹胀、排便习惯和（或）大便性状改变为临床表现，且排除消化道器质性病变的肠道功能紊乱性疾病。推荐目前国际公认的罗马诊断标准：反复发作的腹痛或不适（即感觉不舒服而非疼痛），最近3个月内每个月至少有3 d出现症状，合并以下2条或多条： $\textcircled{1}$ 排便后症状缓解； $\textcircled{2}$ 发作时伴有排便频率改变； $\textcircled{3}$ 发作时伴有大便性状（外观）改变。IBS的治疗主要是饮食及生活习惯调节。解痉剂如匹维溴铵 $5 0 ~ \mathrm { m g }$ 、每天3次，可以缓解腹痛症状［32］。止泻药物如蒙脱石、洛哌丁胺可缓解 IBS患者的腹泻症状［33‑34］。利那洛肽是鸟苷酸环化酶激动剂，是治疗 IBS伴发便秘的有效药物［35］。肠道不吸收的抗生素（主要是利福昔明）可以改善非便秘型IBS患者的疼痛症状及腹胀、腹泻症状［36］。渗透性泻剂如聚乙二醇 $1 0 \ \mathrm { g } \mathrm { , } 1 { \sim } 2$ 次，可用于缓解便秘型IBS患者的便秘症状［37］，乳果糖由于可能增加腹胀症状而不推荐使用［38］。益生菌如双歧杆菌、乳杆菌对改善IBS疼痛症状有一定的疗效［36］。抗焦虑抑郁药可试用于的治疗，中医药可能对改善IBS症状有一定的效果。 4. 康复治疗：CPP的康复治疗主要针对神经肌肉原因引起的疼痛，较为典型的且与妇科关系密切的是盆底肌筋膜痛综合征（myofascial pelvic painsyndrome，MPPS），其疼痛来源于缩短、紧绷且有触痛的盆底肌肉和筋膜，伴有高度敏感的扳机点，临床表现为骨盆、阴道、外阴、直肠或膀胱等部位的疼痛。欧洲泌尿学会指南［28］推荐康复治疗是 MPPS的首选治疗方案，也可辅助用于各类 CPP；包括肌肉筋膜手法治疗（myofascial physical treatment）、生物反馈治疗（biofeedback）和电刺激疗法（electricalstimulation therapy）等［28］。ACOG 共识［2］也提出盆底物理治疗及认知行为疗法可用于治疗肌肉筋膜及社会心理原因所引起的CPP。（）肌肉筋膜手法治疗：主要包括肌肉筋膜放松治疗和按摩扳机点治疗，肌肉筋膜放松治疗的原理是对痉挛的肌肉筋膜进行拉伸和脱敏，可以使挛缩的肌肉舒展，恢复供血，缓解疼痛。按摩扳机点治疗可以提高肌肉筋膜内感受器的痛觉阈值，减轻疼痛的敏感性，起到疼痛脱敏的效果。（2）生物反馈治疗：盆底生物反馈治疗是将盆底肌肉运动信号转换成声音或视觉等患者可以感知的信号，通过这些反馈信息，指导患者进行正确的盆底肌训练。目的是纠正盆底肌肉的过度活动和功能失调，放松紧张的肌肉筋膜，重新建立大脑与盆底肌肉之间的反射通路。（）电刺激疗法：基于疼痛的阀门控制理论，通过皮肤表面电极之间传导电流，达到镇痛的目的。目前多用的是经皮电刺激疗法（transcutaneouselectrical nerve stimulation）及经阴道电刺激疗法。介入治疗：（）神经阻滞治疗：是指使用药物或物理措施，阻断局部感觉神经纤维的传导功能，以达到缓解或消除疼痛的目的。多用局部麻醉药或局部麻醉药联合糖皮质激素类药物进行神经阻滞。针对常用的神经阻滞治疗，包括髂腹下神经阻滞、髂腹股沟神经阻滞，主要适用于下腹腹壁肌肉筋膜或髂腹下神经、髂腹股沟神经支配区域的疼痛；阴部神经阻滞，适用于盆底肌筋膜痛及阴部神经支配区域（阴阜、外阴、阴道及肛周区域）的疼痛；上腹下丛阻滞，用于直肠、子宫等器官疼痛的治疗；奇神经节阻滞，针对盆腔交感神经疼痛。神经阻滞治疗适应证的选择、长期效果、不良反应均需慎重评估。（2）扳机点药物注射（trigger point injection）：推荐扳机点药物注射用于治疗肌肉筋膜源性 $\mathrm { C P P } ^ { [ 2 ] }$ ，比单纯缺血性按摩有效［39］，尤其适用于物理治疗和药物治疗无效的盆底肌肉痉挛患者。注射药物多采用布比卡因或罗哌卡因、激素类药物、阿片类药物，单用或联合应用。常用药物： $0 . 5 \%$ 或 $1 \%$ 利多卡因及 $0 . 1 2 5 \%$ 布比卡因混合溶液每个扳机点注射$1 { \sim } 2 ~ \mathrm { m l }$ 。禁忌证为感染、凝血功能障碍，注意避免麻醉剂进入血液循环及局部血肿形成。肉毒毒素（botulinum neurotoxin）是由肉毒梭菌产生的细菌外毒素，肉毒毒素注射治疗主要用于物理治疗失败的肌肉筋膜源性疼痛患者［40‑41］。（）神经调节（）：包括脊髓刺激（spinal cord stimulation）、骶神经根刺激、背根神经节刺激及周围神经刺激。由于价格昂贵，仅适用于对药物等保守治疗无效的患者，并且在放入永久调节器之前先有试验刺激阶段［42］。目前，有小样本量的初步研究［42］，尚需大样本量的临床研究进一步证实其疗效。手术治疗：（）子宫内膜异位症病灶切除术：CPP患者中明确有子宫内膜异位症病灶，尤其是药物治疗效果欠佳者，建议手术切除异位病灶，术后给予药物治疗。具体的手术治疗措施需综合考虑患者的年龄、疾病状况及生育要求等因素［20］。（）粘连松解术：不推荐对患者常规进行粘连松解术［2］。排除子宫内膜异位症、子宫腺肌病和附件疾病等妇科病因后，腹腔镜粘连松解术对于治疗无效，并且增加了手术并发症的风险，增加了额外的医疗费用［43］。但是，对于粘连引起肠狭窄导致的CPP，粘连松解术有一定的作用。（3）子宫切除术：仅对明确由子宫病因（如子宫腺肌病）造成盆腔疼痛的患者可以行子宫切除术，且应考虑患者的年龄及生育计划［20］。须警惕术后一些患者仍会存在CPP的相应症状。（4）骶前神经切断术及子宫神经切断术：不推荐将骶前神经切断及子宫神经切断术作为的常规治疗方法［20］。骶前神经切断术可能对子宫内膜异位症引起的中线型痛经有效，但对性交痛等并无改善，子宫神经切断术已有明确证据无治疗疼痛的效果［19］。（）针对的手术：包括膀胱镜检查及膀胱镜下水扩张术、A型肉毒毒素注射、经尿道切除膀胱上皮病变、电凝及激光手术、膀胱切除手术［28］。尽管膀胱镜下水扩张术对是一种常用的治疗方法，但尚缺乏充分的科学依据，可作为诊断性评估方法及除外隐匿的膀胱肿瘤，但对治疗作用有限，尤其不建议反复施行。对Hurner溃疡行电凝、激光等治疗对疼痛有效。型肉毒毒素膀胱壁注射可通过对膀胱的传入通路的抗伤害作用，从而改善症状及尿动力学，但需警惕尿潴留。膀胱切除术用于对上述保守治疗无效的患者。（6）神经减压术：在治疗CPP方面，神经减压术及神经调节尚处于试验性治疗阶段，如骶棘韧带及骶结节韧带或阴部神经管狭窄造成的阴部神经卡压，保守治疗无效或反复复发者，可进行阴部神经减压术。其效果及安全性尚需要进一步的证据［2］。补充和替代治疗：包括利用生物源性物质的天然成分进行治疗（如大麻素、中药）、精神‑躯体疗法（如瑜伽、太极）以及针灸等疗法。补充和替代治疗对神经肌肉疼痛有效［2，44］。针灸可显著减轻疼痛及减少阿片类药物的用量［44］。瑜伽、放松、太极、按摩及手法治疗显示有效，但证据级别均较低［2］。 8. 精神心理治疗：对于CPP，精神心理治疗与病因治疗同等重要。基本的心身护理应该从诊治开始就包含在的治疗理念中。认知行为疗法是一种以目标为导向的疗法，当与药物和物理治疗结合时，其优势在于缓解抑郁和疼痛对人际关系和其他方面的影响。证据显示，认知行为疗法与不治疗相比有少到中等的益处［2］。多学科综合治疗：的多学科综合治疗涉及疼痛科、妇科、泌尿科、消化科、普外科、肛肠科、康复科、影像科、神经科、精神心理科、物理治疗等。何时寻求多学科诊治则需要根据患者病情的复杂性、首诊医生的专业性以及获得多学科诊治资源的便利性来个体化进行［2］。综上所述，是一种相对常见而临床诊治棘手的症候群，需要充分评估、全面认识才能够对其给予准确有效的治疗。多学科团队在其中起着至关重要的作用。治疗手段的多样性需要临床医生在多种方法中选择对患者最有效的方法，并采用多维度分层次的规范化、个体化治疗。 # 五、推荐意见汇总本共识参照2001年英国牛津循证医学中心的证据分级与推荐意见强度，将证据分为1、2、3、4、共个级别，推荐等级分为、、、共个等级。见表4。 # 1. A级推荐：（1）不推荐阿片类药物作为治疗CPP的一线药物（1/A）。（2）不推荐常规腹腔镜粘连松解术用于治疗CPP（1/A）。（3）解痉剂可改善 IBS 症状，对腹痛有效（1/A）。 # 2. B级推荐：（1）推荐多学科综合治疗用于 $\mathbf { C P P } ( 2 / \mathbf { B } )$ 。（2）推荐针灸用于治疗 $\mathbf { C P P } ( 2 / \mathbf { B } )$ 。（3）戊聚糖多硫酸盐用于治疗IC/BPS （2/B）。（4）推荐三环类抗抑郁药阿米替林可用于治疗IC/BPS（2/B）。（5）推荐钙离子通道 $\mathbf { \alpha } \mathbf { \alpha } \mathbf { 2 } \hat { \mathbf { 0 } }$ 配体药物加巴喷丁用于治疗IC/BPS所致 $\mathbf { C P P } ( 2 / \mathbf { B } )$ 。（6）膀胱灌注（“鸡尾酒”法）用于治疗IC/BPS引起的 $\mathbf { C P P } ( 2 / \mathbf { B } )$ 。（7）膀胱镜下水扩张术用于诊断治疗IC/BPS（3/B）。（8）扳机点注射麻醉药和激素等的混合制剂可用于治疗肌肉筋膜源性 $\mathbf { C P P } ( 2 / \mathbf { B } )$ 。（9）肌肉筋膜手法治疗可用于治疗MPPS（2/B）。（10）盆底神经电刺激疗法可用于治疗MPPS（2/B）。（11）子宫内膜异位病灶切除术用于治疗子宫内膜异位症相关疼痛（3/B）。（12）COC、孕激素及其衍生物及GnRH‑a可用于治疗子宫内膜异位症相关疼痛，但GnRH‑a不宜长期使用（2/B）。（13）促分泌剂如利那洛肽可改善便秘型IBS腹痛症状（2/B）。 # 3. C级推荐：（1）推荐三环类抗抑郁药阿米替林、SSNRI（度洛西汀、文拉法辛）用于治疗神经肌肉筋膜相关的 CPP，其中文拉法辛安慰剂效应较强（4/C）。（2）益生菌可改善IBS疼痛症状（4/C）。（3）骶神经调节用于治疗IC/BPS （4/C）。利益冲突所有作者声明无利益冲突 # 参考文献 [1] Williams RE, Hartmann KE, Steege JF. 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DOI: 10.1213/ ANE.0000000000002579. 表4 本共识使用的证据级别和推荐等级 <table><tr><td>等级划分标准</td><td>证据级别</td><td>推荐等级</td></tr><tr><td>同质RCT的系统评价或单个RCT</td><td>1</td><td>A</td></tr><tr><td>同质队列研究的系统评价或单个队列研究(包括低质量RCT,如：随访率<80%)</td><td>2</td><td>B</td></tr><tr><td>同质病例对照研究的系统评价或单个病例对照研究</td><td>3</td><td>B</td></tr><tr><td>病例系列研究(包括低质量的队列研究和病例对照研究)</td><td>4</td><td>C</td></tr><tr><td>无明确证据的专家意见</td><td>5</td><td>D</td></tr></table> 注：RCT表示随机对照试验 # 2024年10期继续教育题目（单项选择题）： 1. 关女性慢性盆腔痛的病因，下列说法哪项是错误的：（） A. 涉及多个系统 B. 常多种病因共存 C. 妇科炎症是最主要病因 D. 病因复杂，往往需要多学科联合诊治 2. 女性慢性盆腔痛的止痛药物治疗首选：（） A. 阿片类药物B. 非阿片类药物C. 吗啡D. 芬太尼皮贴对可疑间质性膀胱炎的患者可进行以下检查协助诊疗，除了（）。尿常规及尿培养 B. 泌尿系统超声 C. 钾离子试验 D. 腹腔镜检查 E. 膀胱镜检查及水扩张试验 4. 关于阿片类药物的不良反应，下列哪项说法是错误的：可能出现恶心、呕吐等消化道反应 B. 不会成瘾 C. 可能出现呼吸抑制 D. 可能出现戒断症状 5. 下列慢性盆腔痛治疗方法中，不推荐的是（）。对慢性盆腔痛患者首先进行腹腔镜探查术以发现病因和进行粘连松解术 B. 对慢性盆腔痛患者进行多学科联合诊治 C. 对慢性盆腔痛患者中有焦虑抑郁情绪的可在专业医师指导下口服抗焦虑药物治疗慢性盆腔痛的治疗包括药物、康复、介入、补充治疗等多种治疗手段（继续教育的答题方式及获得学分的方法见“编后”。答案见下期）（2024年9期继续教育题目的答案：1.C 2.D 3.B 4.C 5.D）【编后】经全国继续医学教育委员会批准,本刊开设继教专栏,每年从第1期至第10期共刊发篇继教文章文后附道单选题读者阅读后可扫描标签二维码答题每篇可免费获得类继教学分0.5分,全年最多可获5分。	None	None	None
f2a93763bf474a0d9ae79b5ceebf17a4	中华医学会	妇科单孔腹腔镜手术技术的专家意见	·临床指南· # 妇科单孔腹腔镜手术技术的专家意见中华医学会妇产科学分会妇科单孔腹腔镜手术技术协助组外科学发展至今，进入了微创外科的时代，其是以最小的创伤达到最大的治疗效果。妇科腹腔镜手术发展至今技术日臻完善，但也面临着如何追求更加体现微创理念、带给患者更多人文关怀的问题。单孔腹腔镜手术技术（laparoendoscopic singlesite surgery，LESS）是基于近年来兴起的自然孔道内镜手术（natural orifice transluminal endoscopicsurgery，NOTES）的基本理念，即减少或隐藏手术瘢痕、减轻术后疼痛、促进术后康复而开展起来的。经脐单孔腹腔镜手术技术（transumbilicallaparoendoscopic single site surgery，TU-LESS），将手术切口隐藏于脐孔或脐周，利用人类先天残留的自然瘢痕，使手术几乎不留瘢痕，具有突出的美容优势，也是对传统腹腔镜技术的发展和有益补充[1]。综合国内外发展的状况，LESS在妇科领域具有广阔的应用前景，有必要在现阶段作客观的认识。 # 一、命名对于该类手术的称谓，由于可以应用于多学科的原因、历史原因及国别原因，目前国内外对于“单孔腹腔镜手术”的命名尚不统一[2]。为了便于研究和回顾，列出如下：腹腔镜内镜单切口手术（laparoendoscopic single site surgery，LESS）、胚胎期自然腔道内镜手术(embryonic natural orificetransumbilical endoscopic surgery，E-NOTES)、单切口腹腔镜手术（single incision laparoscopic surgery，SILS）、单孔入路手术（single port access surgery，SPA）、单通道手术（single access surgery，SAS）、单通道脐部手术（one port umbilical surgery，OPUS）、经脐内镜手术（transumbilical endoscopic surgery，TUES）、自然孔道经脐手术（natural orifice transumbilicalsurgery，NOTUS）等。我们建议将该技术称为“单孔腹腔镜手术”，英文表述为“laparoendoscopic single site surgery”，英文缩写为“LESS”，理由如下：（1）此名称在国内已普遍应用，在能检索到的中文文献中，大多数使用此名称；（2）符合国际通用的表述习惯，2008年，国际单孔腹腔镜手术研究与评估协会（LESSCAR），确定了“LESS”的称谓，并已得到国际内镜协会（NOSCAR）的批准；（3）得到国内外科专家的认可，2010年，中华医学会外科学分会腹腔镜与内镜外科学组进行了论证，确定并推荐使用此名称。 # 二、定义原则上只要是满足单孔道多通路的手术，均可称为 LESS。 LESS 包含了单一入路通道（single-entry portal），腹腔、盆腔、胸腔（abdomen,pelvis, thorax）手术部位，腹腔镜、内窥镜、机器人（laparoscopic, endoscopic or robotic surgery）手术方式，经脐或脐外（umbilical or extra-umbilical）的手术，不经内腔或经内腔（extraluminal or transluminalsurgery）的手术等内容[2]。“经脐单孔腹腔镜手术技术”将手术切口隐藏于脐孔或脐周，利用人类先天残留的自然瘢痕，使手术几乎不留瘢痕，具有突出的美容优势，在妇科领域，多数LESS采用经脐入路，故中文可称为“经脐单孔腹腔镜手术”，英文表述为“transumbilical laparoendoscopic single sitesurgery”，英文缩写为“TU-LESS”。建议今后在国内学术期刊发表有关“单孔腹腔镜手术”的论文时，应统一称谓，以便交流和检索。 # 三、LESS的适应证与传统腹腔镜手术的适应证相同，只是受到目前技术的限制，LESS的适应证应该更加严格，包括：（1）卵巢囊肿剔除术；（2）输卵管切除术；（3）附件切除术；（4）子宫肌瘤剔除术；（5）子宫全切除术；（6）盆腔粘连分解术；（7）人工阴道成形术（腹膜法）。随着技术的发展和条件的改善，也可以逐步开展盆底手术如阴道骶骨固定术等，以及恶性肿瘤的手术，包括：（1）盆腔和腹主动脉旁淋巴结切除术；（2）早期子宫内膜癌分期手术；（3）子宫颈癌根治性手术等[3-4]。另外，单孔腹腔镜经脐入路也为妇科手术同时行阑尾或胆囊切除提供了方便。但是，由于LESS目前还处于临床探索阶段，尚无充分的循证医学证据证实其安全性和有效性[5]。因此，我们建议手术适应证应遵循以下原则：（1）现阶段良性疾病应是LESS的主要适应证；（2）有条件的单位和有相应资质的医师，可以有选择地对妇科恶性肿瘤的LESS治疗进行积极、稳妥、慎重的探索性临床研究；（3）所选择的病例应是临床分期早的子宫或子宫颈恶性肿瘤：（）应积极探索机器人辅助的 LESS；（5）在克服镜下缝合等难题的前提下，审慎开展LESS下的盆底修复手术。四、LESS的禁忌证与传统腹腔镜手术的禁忌证相同，但禁忌证是相对的；包括粘连严重，如严重的子宫内膜异位症、有多次腹部手术史或术中发现手术部分粘连严重者，与传统腹腔镜类似，在这样的病例中，操作空间小和操作困难可能会妨碍LESS的实施，也会增加中转开腹的可能，或需要多孔才能完成[5]。在单孔腹腔镜子宫全切除术中，子宫体积大小可能成为1个限制因素，随着子宫体积增大，中转为开腹手术或传统腹腔镜手术的概率增大[6]。依据目前的技术条件，以下情况应列为LESS的禁忌证：（1）晚期恶性肿瘤；（2）全身情况不能耐受麻醉；（3）巨大盆腔肿物；（4）凝血功能障碍；（5）腹腔严重感染；（6）脐部发育异常。手术医师需注意的是，无论采用何种手术方式，手术的目标和原则是不变的。手术是否能够在单孔腹腔镜下完成，既取决于医师的能力和技巧，也需要有合适的器械和光源设备。手术医师需要充分评估患者的病情、自身的能力和技巧，以及是否有得力的器械，以便选择最适合的手术方式。 # 五、LESS技术及设备入路切口的选择：应该在已有的、成熟规范的腹腔镜手术术式的基础上进行。从LESS的定义来说，原则上只要是满足单孔道多通路的手术，均可称为LESS，但在妇科手术领域，几乎全部采用经脐入路方式；从脐部解剖而言，经脐入路方式最适合妇科手术。 2. 入路平台：依照外科手术原理，LESS经脐切口的入路平台，大致可以归纳为3类：（1）使用传统腹腔镜经脐入路平台：依然使用传统腹腔镜的经脐的穿刺套管（trocar）通道，在腹腔镜中增加沿着主轴的侧槽通道，可以通过专用的手术操作器械，如分离钳、剪刀、单极电凝切器、输卵管套环器等，用来完成相对简单的手术，此平台已广泛应用于输卵管绝育手术。（2）皮肤单一切口配合多个筋膜切口：此种平台方法的基本原理是，皮肤为单一切口，而通过此切口分别穿过筋膜插入多个 $5 \sim 1 0 ~ \mathrm { m m }$ 的trocar 进入腹腔，其优点是可以使用传统的 trocar，不需要增加设备，缺点是各筋膜切口之间的“桥梁”被削减，可能导致筋膜减弱，也可能导致术中漏气，气腹形成不良。（3）LESS的专用入路平台：医疗商用设备厂商开发了多种LESS的专用入路平台，并获得了临床使用许可证，在临床上得以广泛应用；基本是通过单一平台有多个通道进入腹腔。在发表有关LESS的论文时，作者应详细说明切口方式，并提供腹部切口照片，照片应包括上自剑突水平下至耻骨联合上缘范围内的腹部图像。 3. 光学系统：传统腹腔镜的光源设备和摄像系统均可用于LESS，目前常用的是 $1 0 \ : \mathrm { m m } \ : 0 ^ { \circ }$ 前视镜和 $3 0 ^ { \circ }$ 前斜视镜镜头。前者视野较窄，不能进行多角度的观察，只能前视，应用于LESS增加了手术视野的限制，可用于简单的单孔腹腔镜探查及手术。后者可通过调节按钮或体外转动光缆而获得多角度的视野，更适合应用于单孔腹腔镜的各类手术。使用 $5 \mathrm { m m } 3 0 ^ { \circ }$ 超长镜头，可通过镜头的旋转调整视野角度，避免器械遮挡视野；一定程度可减少镜头和手术器械之间的相互干扰，增加了手术操作稳定性。另外，目前已经有多种可弯曲或可变角度及$4 5 ^ { \circ }$ 导光束接口镜头以及3D影像系统在临床使用。 4. 手术操作器械：为解决器械之间、器械与镜头之间的平行进出以及操作“三角”丧失等问题，现LESS的主流器械被设计成弯曲直行再弯曲、直行再弧形等形状以及关节连动杆多自由度器械以利于手术操作。我们建议：（1）利用入路平台多通道的特点，当术中遇到操作困难时，要及时转换到不同的通道进入器械，以便操作。（2）弯器械和直器械配合使用，提高手术效率。（3）较大通道可以进入较粗大的手术器械，使牵拉和夹持更有力，尤其是切除子宫时更为重要。（4）可使用智能能量器械，电凝、电切相结合的器械，可减少手术器械的进出，增加操作稳定性，更便捷。（5）需要配备合适的举宫器，能够获得良好的子宫操纵，便于暴露手术部位。 5. LESS的缝合及打结：单孔腹腔镜下腔内缝合使用传统的器械缝合和打结难度较大，且耗时，但可以通过以下几种方法解决这个问题，（1）使用免打结的倒刺缝线；（2）使用预先滑结抽紧方法；（3）使用关节连动杆器械和直器械配合进行缝合、打结；（4）使用腔内带腕关节自动归位的持针器；（5）使用自动缝合器；（6）子宫全切除术后的阴道残端可经阴道进行缝合[7]。六、LESS的难点及手术技能培训难点：（）手术器械及光学系统的相互干扰是主要问题，由于所有器械均由单个切口进入腹腔，使得在体外操作的手柄相互干扰，操纵杆在腹壁套管中拥挤牵绊，难以在腹腔内展开，所谓的“筷子效应”。（2）由于同轴操纵，违背了传统的三角分布原则，在一定程度上影响术者对深度和距离的判断，从而使得操作的精准度下降。（3）由于LESS是直线视野（inline vision），画面立体感差，镜头在腹腔内外易与手术器械相互干扰，画面稳定性差。与传统腹腔镜相比，LESS对于操作者的技术和熟练程度要求较高，难度较大，要求术者不但要有良好的传统腹腔镜手术基础和镜下空间感，并需要能够熟练地掌握单孔腹腔镜特有的曲状器械的使用（或与传统器械的混合使用）。在选择患者时更应该严格把握手术适应证和禁忌证；充分术前沟通，取得患者的充分配合[8]。 LESS的学习曲线较为特殊，既要求有一定的腹腔镜手术基础，又需要长期、反复的练习，增强手术技巧和熟练程度，以取得更好的微创和美容效果。根据目前的条件，建议经过以下培训：（1）熟练掌握传统腹腔镜的操作；（2）单孔腹腔镜模拟器体外训练；（3）对动物进行LESS操作训练；（4）在有LESS经验医师的指导下逐步开展LESS[9]。 # 七、结语 LESS是微创手术的一种，现阶段，已经可以完成部分妇科手术，主要优势是美容和减轻疼痛。掌握LESS的关键是要在传统腹腔镜手术的基础上，积累操作经验，使用特殊的手术器械；LESS的发展速度依赖于手术器械的进步和医师观念的改变[10]。目前，国内外关于LESS的研究均为病例报告或回顾性病例分析研究，尚无关于单孔腹腔镜与传统腹腔镜手术的大样本量、多中心前瞻性随机对照研究，来确定患者是否能从LESS获益。我们提倡有条件的单位积极开展此类研究，以获得确切的循证医学证据，进一步评价LESS的安全性及有效性。中华医学会妇产科学分会妇科单孔腹腔镜手术技术协助组专家名单：郎景和（中国医学科学院北京协和医院）、孙大为（中国医学科学院北京协和医院）、张俊吉（中国医学科学院北京协和医院）、刘海元（中国医学科学院北京协和医院）、张震宇（首都医科大学附属北京朝阳医院）、孟元光（解放军总医院）、刘开江（上海交通大学医学院附属仁济医院）、梁志清（第三军医大学西南医院）、康山（河北医科大学第四医院）、段华（首都医科大学附属北京妇产医院）、卢美松（哈尔滨医科大学附属第一医院）、杨清（中国医科大学附属盛京医院）、王光伟（中国医科大学附属盛京医院）、石刚（四川大学华西第二医院）、陈捷（福建省人民医院）、王沂峰（南方医科大学珠江医院）、冯力民（首都医科大学附属北京天坛医院）、郝敏（山西医科大学第二医院）、王建（第四军医大学西京医院）、王世军（首都医科大学宣武医院）、邓锁（哈尔滨医科大学附属第一医院）、刘木彪（广东省人民医院）、姚书忠（中山大学附属第一医院）、马彩铃（新疆医科大学第一附属医院）、赵仁峰（广西壮族自治区人民医院）。本专家意见整理专家：孙大为（中国医学科学院北京协和医院）、张俊吉（中国医学科学院北京协和医院）、刘海元（中国医学科学院北京协和医院） # 参考文献 [1] Goebel K, Goldberg JM. Women′ s preference of cosmetic results after gynecologic surgery[J]. J Minim Invasive Gynecol, 2014, 21(1):64-67. DOI: 10.1016/j.jmig.2013.05.004. [2] 孙大为. 正确认识单孔腹腔镜手术在妇科的应用[J]. 中华腔镜外科杂志:电子版, 2012, 5(4): 168-172. DOI: 10.3877/ cma.j.issn.1674-6899.2012.04.001. [3] Boruta DM, Fagotti A, Bradford LS, et al. Laparoendoscopic single-site radical hysterectomy with pelvic lymphadenectomy: initial multi-institutional experience for treatment of invasive cervical cancer[J]. J Minim Invasive Gynecol, 2014,21(3): 394-398. DOI: 10.1016/j.jmig.2013.10.005. [4] Fagotti A, Boruta DM, Scambia G, et al. First 100 early endometrial cancer cases treated with laparoendoscopic single-site surgery: a multicentric retrospective study[J]. Am J Obstet Gynecol, 2012,206(4):353.e1-6. DOI: 10.1016/j. ajog.2012.01.031. [5] Park HS, Kim TJ, Song T, et al. Single-port access (SPA) laparoscopic surgery in gynecology: a surgeon′ s experience with an initial 200 cases[J]. Eur J Obstet Gynecol Reprod Biol, 2011, 154(1):81-84. DOI: 10.1016/j.ejogrb.2010.09.004. [6] Park JY, Kim TJ, Kang HJ, et al. Laparoendoscopic single site (LESS) surgery in benign gynecology: perioperative and late complications of 515 cases[J]. Eur J Obstet Gynecol Reprod Biol, 2013, 167(2):215-218. DOI: 10.1016/j.ejogrb.2012.11. 027. [7] Matos-Azevedo AM,Diaz-Guémes MI,Pérez-Duarte FJ, et al Comparison of single access devices during cut and suturing tasks on simulator[J]. J Surg Res, 2014,192(2):356-367. DOI: 10.1016/j.jss.2014.06.017. [8] Uppal S, Frumovitz M, Escobar P, et al. Laparoendoscopic single-site surgery in gynecology: review of literature and available technology[J]. J Minim Invasive Gynecol, 2011,18(1): 12-23. DOI: 10.1016/j.jmig.2010.07.013. [9] Kommu SS. Ex-vivo training model for laparoendoscopic single-site surgery[J]. J Minim Access Surg, 2011,7(1): 104-108. DOI: 10.4103/0972-9941.72398. [10] Bradford LS, Boruta DM. Laparoendoscopic single-site surgery in gynecology: a review of the literature, tools, and techniques[J]. Obstet Gynecol Surv, 2013,68(4):295-304. DOI: 10.1097/OGX.0b013e318286f673.	None	None	None

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