Although there is no universal classification of voice problems, voice disorders can be separated into certain categories: organic (structural or neurogenic), functional, neurological (psychogenic) or iatrogenic, for example. [ 31 ]  Depending on the diagnosis and severity of the voice problem, and depending on the category that the voice disorder falls into, there are various treatment methods that can be suggested to the patient. The professional has to keep in mind there is not one universal treatment, but rather the clinical approach must find what  the optimal effective course of action for that particular patient is. [ citation needed ]


There are three main type of treatments: medical treatments, voice therapy and surgical treatments. [ 32 ]  When necessary, certain voice disorders use a combination of treatment approaches. [ 9 ]  A medical treatment involves the use of botulinum toxin (botox) or anti-reflux medicines, for example. Botox is a key treatment for voice disorders such as Spasmodic Dysphonia. [ 33 ]  Voice therapy is mainly used with patients who have an underlying cause of voice misuse or abuse. [ 34 ]  Laryngologists also recommend this type of treatment to patients who have an organic voice disorder - such as vocal fold nodules, cysts or polyps as well as to treat functional dysphonia. [ 9 ]  Certain surgical treatments can be implemented as well - phono microsurgery (removal of vocal fold lesions performed with a microscope), laryngeal framework surgery (the manipulation of the voice box), as well as injection augmentation (injection of substance to vocal folds to improve closure). Surgical treatments may be recommended for patients having an organic dysphonia. [ 35 ] [ 36 ]


A combination of both an indirect treatment method (an approach used to change external factors affecting the vocal folds) [ 37 ]  and a direct  treatment  method (an approach used where the mechanisms functioning during the use of the vocal folds, such as phonation or respiration, are the main focus) [ 37 ]  may be used to treat dysphonia. [ 9 ] [ 12 ] [ 38 ] [ 39 ]


Direct therapies address the physical aspects of vocal production. [ 9 ]  Techniques work to either modify vocal fold contact, manage breathing patterns, and/or change the tension at level of the larynx. [ 9 ]  Notable techniques include, but are not limited to, the  yawn-sigh method ,  optimal pitch ,  laryngeal manipulation , humming, the  accent method , and the  Lee Silverman Voice Treatment . [ 9 ] [ 38 ]  An example of a direct therapy is circumlaryngeal manual therapy, which has been used to reduce tension and massage hyoid-laryngeal muscles. [ 12 ]  This area is often tense from chronic elevation of the larynx. [ 12 ]  Pressure is applied to these areas as the patient hums or sustains a vowel. [ 12 ]  Traditional voice therapy is often used to treat muscular tension dysphonia. [ 12 ]


Indirect therapies take into account external factors that may influence vocal production. [ 9 ]  This incorporates maintenance of vocal hygiene practices, as well as the prevention of harmful vocal behaviours. [ 40 ]  Vocal hygiene includes adequate hydration of the vocal folds, monitoring the amount of voice use and rest, avoidance of vocal abuse (e.g., shouting, clearing of the throat), and taking into consideration lifestyle choices that may affect vocal health (e.g., smoking, sleeping habits). [ 40 ]  Vocal warm-ups and cool-downs may be employed to improve muscle tension and decrease risk of injury before strenuous vocal activities. [ 40 ]  It should be taken into account that vocal hygiene practices alone are minimally effective in treating dysphonia, and thus should be paired with other therapies. [ 40 ]


Medical and surgical treatments have been recommended to treat organic dysphonias. An effective treatment for  spasmodic dysphonia  (hoarseness resulting from periodic breaks in phonation due to hyperadduction of the vocal folds) is  botulinum toxin  injection. [ 8 ] [ 41 ]  The toxin acts by blocking  acetylcholine  release at the thyro-arytenoid muscle. Although the use of botulinum toxin injections is considered relatively safe, patients' responses to treatment differ in the initial stages; some have reported experiencing swallowing problems and breathy voice quality as a side-effect to the injections. [ 8 ] [ 41 ]  Breathiness may last for a longer period of time for males than females. [ 41 ]


Surgeries involve myoectomies of the laryngeal muscles to reduce voice breaks, and laryngoplasties, in which laryngeal cartilage is altered to reduce tension. [ 8 ]


Dysphonia is a general term for voice impairment that is sometimes used synonymously with the  perceptual  voice quality of hoarseness. [ 13 ]  It is the reason for 1% of all visits to primary care providers. [ 13 ]  The  lifetime risk  of hoarse voice complaints among primary care patients is 30%. [ 13 ]  Since hoarseness is a general symptom, it is associated with a number of laryngeal diagnoses. [ 13 ]


There is an interplay of sex and age differences associated with dysphonia. The  point prevalence  of dysphonia in adults under the age of 65 is 6.6%. [ 20 ]  Dysphonia is more common in adult females than males, [ 20 ] [ 42 ]  possibly due to sex-related anatomical differences of the vocal mechanism. [ 4 ]  In childhood, however, dysphonia is more often found in boys than girls. [ 43 ]  As there are no anatomical differences in larynges of boys and girls prior to puberty, it has been proposed that the higher rate of voice impairment found in boys arises from louder social activities, personality factors, or more frequent inappropriate vocal use. [ 43 ]  The most common laryngeal diagnosis among children is  vocal fold nodules , [ 20 ]  a condition known to be associated with vocally damaging behaviours. [ 44 ]  However, a causal relationship has not yet been definitively proven. [ 43 ]  The overall prevalence of dysphonia in children ranges from 3.9% - 23.4%, most commonly affecting children between the ages of 8 - 14. [ 20 ]  Among the elderly, dysphonia is associated with both naturally occurring anatomical and physiological changes as well as higher rates of pathological conditions. [ 42 ]  The point prevalence of dysphonia among the elderly is 29%. [ failed verification ] [ 20 ]  Findings regarding the prevalence of geriatric dysphonia in the general population are very variable, ranging from 4 - 29.1%. [ 42 ]  This variability is likely due to different  methodology  used in obtaining information from participants. [ 20 ]  The most common laryngeal diagnoses among the elderly are polyps,  laryngopharyngeal reflux , muscle tension dysphonia,  vocal fold paresis  or  paralysis , vocal fold mass, glottic insufficiency,  malignant lesions , and neurologic conditions affecting the larynx. [ 42 ]


The  House–Brackmann score  is a score to grade the degree of  nerve  damage in a  facial nerve palsy . The measurement is determined by measuring the upwards (superior) movement of the mid-portion of the top of the  eyebrow , and the outwards (lateral) movement of the angle of the mouth. Each reference point scores 1 point for each 0.25 cm movement, up to a maximum of 1 cm. The scores are then added together, to give a number out of 8. [ 1 ]  The score predicts recovery in those with  Bell's palsy . [ 2 ]


The score carries the name of the Dr John W. House and Dr Derald E. Brackmann, otolaryngologists in Los Angeles, California, who first described the system in 1985. [ 1 ]  It is one of a number of facial nerve scoring systems, such as Burres-Fisch, Nottingham, Sunnybrook, [ 3 ]  and Yanagihara. [ 4 ]  Of these, the Nottingham scale has been identified as possibly being easier and more reproducible. [ 3 ]  A modification of the original House–Brackmann score, called the "Facial Nerve Grading Scale 2.0" (FNGS2.0) was proposed in 2009. [ 4 ]


Human papillomavirus-positive oropharyngeal cancer  ( HPV-positive OPC  or  HPV+OPC ), is a  cancer  ( squamous cell carcinoma ) of the throat caused by the  human papillomavirus  type 16 virus (HPV16). In the past, cancer of the  oropharynx  (throat) was associated with the use of alcohol or tobacco or both, but the majority of cases are now associated with the HPV  virus , acquired by having oral contact with the  genitals  ( oral-genital sex ) of a person who has a genital HPV infection.  Risk factors include having a large number of sexual partners, a history of oral-genital sex or  anal–oral sex , having a female partner with a history of either an abnormal  Pap smear  or  cervical dysplasia , having chronic  periodontitis , and, among men, younger age at first intercourse and a history of  genital warts . HPV-positive OPC is considered a separate disease
from HPV-negative  oropharyngeal cancer  (also called HPV negative-OPC and  HPV-OPC).


HPV-positive OPC presents in one of four ways: as an asymptomatic abnormality in the mouth found by the patient or a health professional such as a dentist; with local symptoms such as pain or infection at the site of the tumor; with difficulties of speech, swallowing, and/or breathing; or as a swelling in the neck if the cancer has spread to local lymph nodes. Detection of a  tumour suppressor protein , known as  p16 , is commonly used to diagnose an HPV-associated OPC. The extent of disease is described in the standard cancer  staging system , using the  AJCC   TNM  system, based on the T stage (size and extent of tumor), N stage (extent of involvement of regional  lymph nodes ) and M stage (whether there is  spread of the disease  outside the region or not), and combined into an overall stage from I–IV. In 2016, a separate staging system was developed for HPV+OPC, distinct from HPV-OPC.


Whereas most  head and neck cancers  have been declining as smoking rates have declined, HPV-positive OPC has been increasing. Compared to HPV-OPC patients, HPV-positive patients tend to be younger, have a higher  socioeconomic status  and are less likely to smoke. In addition, they tend to have smaller tumours, but are more likely to have involvement of the cervical lymph nodes. In the United States and other countries, the number of cases of oropharyngeal cancer has been increasing steadily, with the incidence of HPV-positive OPC increasing faster than the decline in HPV-negative OPC. The increase is seen particularly in young men in  developed  countries, and HPV-positive OPC now accounts for the majority of all OPC cases. Efforts are being made to reduce the incidence of HPV-positive OPC by introducing  vaccination  that includes HPV types 16 and 18, found in 95% of these cancers, before exposure to the virus. Early data suggest a reduction in infection rates.


In the past, the treatment of OPC was radical surgery, with an approach through the neck and splitting of the  jaw bone , which resulted in morbidity and poor survival rates. Later,  radiotherapy  with or without the addition of  chemotherapy , provided a less disfiguring alternative, but with comparable poor outcomes. Now, newer  minimally invasive  surgical techniques through the mouth have improved outcomes; in high-risk cases, this surgery is often followed by radiation and/or chemotherapy. In the absence of   high-quality evidence  regarding which treatment provides the best outcomes, management decisions are often based on one or more of the following: technical factors, likely functional loss, and patient preference. The presence of HPV in the tumour is associated with a better response to treatment and a better outcome, independent of the treatment methods used, and a nearly 60% reduced risk of dying from the cancer. Most recurrence occurs locally and within the first year after treatment. The use of tobacco decreases the chances of survival.


HPV+OPC presents in one of four ways: as an asymptomatic abnormality in the mouth found by the patient or a health professional such as a dentist; with local symptoms such as pain or infection at the site of the tumor; with difficulties of speech, swallowing, and/or breathing; or as a swelling in the neck (if the cancer has spread to lymph nodes). These may be accompanied by more general symptoms such as loss of appetite, weight loss, and weakness. [ 3 ]


Most  mucosal   squamous cell   head and neck cancers , including  oropharyngeal cancer  (OPC), have historically been attributed to tobacco and alcohol use. However, this pattern has changed considerably since the 1980s. It was realised that some cancers occur in the absence of these risk factors and
an association between  human papillomavirus  (HPV) and various squamous cell cancers, including OPC, was first described in 1983. [ 4 ] [ 5 ]  Since then both  molecular  and  epidemiological  evidence has been accumulating, with the  International Agency for Research on Cancer  (IARC) stating that high-risk HPV types 16 and 18 are carcinogenic in humans, in 1995, [ 6 ]  and In 2007 that HPV was a cause for oral cancers. [ 7 ] [ 8 ]   Human papillomavirus  (HPV)-positive cancer (HPV+OPC)  incidence  has been increasing while HPV-negative (HPV-OPC) cancer incidence is declining, a trend that is estimated to increase further in coming years. [ 9 ]  Since there are marked differences in  clinical presentation  and  treatment   relative to HPV status, HPV+OPC is now viewed as a distinct biologic and clinical condition. [ 10 ] [ 11 ] [ 12 ]


Human HPV has long been implicated in the  pathogenesis  of several anogenital cancers including those of the  anus ,  vulva ,  vagina ,  cervix , and  penis . [ 13 ]  In 2007 it was also implicated by both  molecular  and  epidemiological  evidence in cancers arising outside of the anogenital tract, namely oral cancers. HPV infection is common among healthy individuals and is acquired through  oral sex . Although less data is available, the prevalence of HPV infection is at least as common among men as among women, with 2004 estimates of about 27% among US women aged 14–59. [ 8 ]


HPV oral infection precedes the development of HPV+OPC. [ 8 ] [ 5 ]  Slight injuries in the  mucous membrane  serve as an entry gate for HPV, which thus works into the  basal layer  of the  epithelium . [ 14 ] [ 15 ]   People testing positive for HPV type 16 virus (HPV16) oral infection have a 14 times increased risk of developing HPV+OPC. [ 14 ]   Immunosuppression  seems to be an increased risk factor for HPV+OPC. [ 5 ]  Individuals with  TGF-β1  genetic variations, specially T869C, are more likely to have HPV16+OPC. [ 16 ]  TGF-β1 plays an important role in controlling the immune system. In 1993 it was noted that patients with human papillomavirus (HPV)-associated anogenital cancers had a 4-fold increased risk of tonsillar squamous-cell carcinoma. [ 17 ]  Although evidence suggests that HPV16 is the main cause of OPC in humans not exposed to smoking and alcohol, the degree to which tobacco and/or alcohol use may contribute to increasing the risk of HPV+OPC has not always been clear [ 5 ]  but it appears that both smoking and HPV infection are independent and additive risk factors for developing OPC. [ 18 ]  The connection between HPV-infection and oropharyngeal cancer is stronger in regions of lymphoepithelial tissue (base of tongue and palatine tonsils) than in regions of stratified squamous epithelium (soft palate and uvula). [ 19 ]   Human herpesvirus-8  infection can potentiate the effects of HPV-16. [ 20 ]


Risk factors  include a high number of sexual partners (25% increase >= 6 partners), a history of  oral-genital sex  (125% >= 4 partners), or  anal–oral sex , a female partner with a history of either an abnormal  Pap smear  or  cervical dysplasia , [ 21 ]  chronic  periodontitis , [ 22 ] [ 23 ]  and, among men, decreasing age at first intercourse and history of  genital warts . [ 24 ] [ 25 ] [ 26 ] [ 27 ]


Cancers of the oropharynx primarily arise in lingual and palatine tonsil  lymphoid  tissue that is lined by respiratory  squamous   mucosal epithelium, which may be  invaginated  within the lymphoid tissue. Therefore, the tumour first arises in hidden crypts. OPC is graded based on the degree of squamous and  keratin  differentiation into well, moderate, or poorly (high) differentiated grades. Other pathological features include the presence of finger-like invasion,  perineural invasion , depth of invasion, and distance of the tumour from resection margins. Phenotypic variants include  basaloid squamous carcinoma , a high-grade form ( see  Chung Fig. 35-3(C) [ 28 ]  and illustration here). They are most commonly non-keratinising. HPV+OPC also differs from HPV-OPC in being focal rather than multifocal and not being associated with pre-malignant  dysplasia . HPV+OPC patients are therefore at less risk of developing other malignancies in the head and neck region, unlike other head and neck primary tumours that may have associated second neoplasms, that may occur at the same time (synchronous) or a distant time (metachronous), both within the head and neck region or more distantly. This suggests that the oncogenic alterations produced by the virus are spatially limited rather than related to a field defect. [ 29 ] [ 28 ] [ 30 ]


The  oropharynx , at the back of the  mouth , forms a circle and includes the  base of the tongue  (posterior third) below, the  tonsils  on each side, and the  soft palate  above, together with the walls of the  pharynx , including the anterior  epiglottis ,  epiglottic valleculae  and  branchial cleft  at its base.  The oropharynx is one of three divisions of the interior of the pharynx based on their relation to adjacent structures (nasal pharynx ( nasopharynx ), oral pharynx (oropharynx) and laryngeal pharynx ( laryngopharynx  – also referred to as the hypopharynx), from top to bottom). The pharynx is a semicircular fibromuscular tube joining the  nasal cavities  above to the  larynx  (voice box) and  oesophagus  (gullet), below, where the larynx is situated in front of the oesophagus. [ 31 ]


The oropharynx lies between the mouth (oral cavity) to the front, and the laryngopharynx below, which separates it from the larynx. The upper limit of the oropharynx is marked by the soft palate and its lower limit by the epiglottis and root of the tongue. The oropharynx communicates with the mouth, in front through what is known as the oropharyngeal isthmus, or  isthmus of the fauces . The  isthmus  (i.e. connection) is formed above by the soft palate, below by the posterior third of the tongue, and at the sides by the  palatoglossal arches . The posterior third of the tongue or tongue base contains numerous  follicles  of  lymphatic tissue  that form the  lingual tonsils . Adjacent to the tongue base, the lingual surface of the epiglottis, which curves forward, is attached to the tongue by median and lateral  glossoepiglottic folds . The folds form small troughs known as the epiglottic valleculae. The lateral walls are marked by two vertical pillars on each side, the pillars of the fauces, or palatoglossal arches. More properly they are separately named the palatoglossal arch anteriorly and the  palatopharyngeal arch  posteriorly. The anterior arch is named from the  palatoglossal muscle  within, running from the soft palate to the  tongue   ( glossus ), while the posterior arch similarly contains the  palatopharyngeal muscle  running from the soft palate to the lateral pharynx. Between the arches lies a triangular space, the  tonsillar fossa  in which lies the  palatine tonsil , another lymphoid organ.  [ 32 ]


The external pharyngeal walls consisting of the four constrictor muscles form part of the mechanism of  swallowing . The microscopic anatomy is composed of four layers, being from the  lumen  outwards, the  mucosa ,  submucosa , muscles, and the fibrosa, or fibrous layer. The mucosa consists of stratified squamous epithelium, that is generally non-keratinised, except when exposed to chronic irritants such as tobacco smoke. The submucosa contains aggregates of lymphoid tissue. [ 32 ] [ 33 ]


Cancers arising in the tonsillar fossa spread to the  cervical lymph nodes , primarily the subdigastric (upper jugular) lymph nodes (level II), with secondary involvement of the mid (level III) and low (level IV)  jugular nodes  and sometimes the posterior cervical nodes (level V). Base of tongue cancers spread to the subdigastric and mid jugular nodes, and occasionally posterior cervical nodes but being closer to the midline are more likely to have bilateral nodal disease. Tonsillar cancers rarely spread to the contralateral side unless involving the midline. [ 34 ]


HPV-associated cancers are caused by high-risk strains of HPV, mainly HPV-16 and HPV-18. [ 35 ]  HPV is a small  non-enveloped   DNA virus  of the  papillomavirus  family. Its  genome  encodes the early (E)  oncoproteins  E5, E6 and E7 and the late (L)  capsid  proteins L1 and L2. The virus gains access to the mucosa through microlesions, where it infects the  basal layer  of cells, which are still able to proliferate. While the virus does not replicate in these cells,  expression  of its early genes stimulates proliferation and lateral expansion of the basal cells. As this moves the virus particles into the overlying suprabasal layers, late viral gene expression occurs, enabling replication of the circular viral genome ( see  figure) and structural proteins. As these are pushed into the most superficial mucosal layers, complete viral particles are assembled and released. [ 36 ]


An increased risk of HPV+OPC is observed more than 15 years after HPV exposure, [ 8 ]  pointing to a slow development of the disease, similar to that seen in cervical cancer. Relative to HPV-OPC, the  oncogenic  molecular progression of HPV+OPC is poorly understood. [ 28 ]   The two main viral  oncoproteins  of the high risk HPV types are E6 and E7. These are consistently expressed in malignant cell lines, and if their expression is inhibited the malignant  phenotype  of the cancer cells is blocked. Either of these oncoproteins can  immortalise  cell lines, [ 37 ]  but are more efficient when both are expressed since their separate molecular roles are  synergistic . [ 35 ] [ 36 ]  The E6 and E7  oncogenes  become integrated into host-cell DNA, and the oncoproteins they express interfere with a variety of predominantly  antiproliferative   cellular regulatory mechanisms . They bind to and inactivate the best known of these mechanisms, the  tumor suppressor proteins   p53  and  retinoblastoma protein  pRB (pRb) leading to genomic instability and then  cell cycle  deregulation ( see  Chung et al., 2016 Fig. 35.2). [ 28 ]  Further, yet to be elicited, mechanisms are required for the final steps of  malignant transformation  of HPV infected cells. [ 28 ]


HPV- and HPV+OPC are distinguishable at the molecular level. The naturally occurring ( wild type ) p53 is widely involved in  cellular processes , including  autophagy , response to DNA damage, cell cycle regulation, and  senescence ,  apoptosis  and the generation of  adenosine triphosphate  (ATP) through  oxidative phosphorylation . [ 38 ]  The gene encoding p53 is inactivated by E6 at the protein level and is found as the wild type in HPV+OPC but mutated in HPV-OPC. In HPV+OPC  p53  protein undergoes accelerated degradation by E6, drastically reducing its levels, while in HPV-OPC it undergoes  genetic mutation , which may result in  synthesis  of an abnormal p53 protein, that may not only be inactive as a tumour suppressor but can also bind and inactivate any non-mutated wild type p53, with an increase in oncogenic activity. [ 39 ]  Although p53 mutations occur in HPV+OPC, they are far less common than in HPV-OPC (26%  vs  48%), and do not appear to affect clinical outcome. [ 40 ]


The pRb protein is inactivated by E7 in HPV+OPC, but in HPV-OPC it is the p16 tumour suppressor part of the pRb tumour suppressor network that is inactivated. Also the pRb pathway is inactivated by E7 instead of  Cyclin D1  amplification. [ 8 ] [ 41 ]   CDKN2A  is a  tumour suppressor gene  that encodes a tumor suppressor protein,  p16  (cyclin-dependent kinase inhibitor 2A) and inhibits the  kinase  activity of the cyclin-dependent kinases  CDK4  and  CDK6 , which in turn induce cell cycle arrest. [ 38 ]  p16 expression is cell cycle-dependent and is expressed focally in only about 5–10% of normal squamous epithelium. Like most HPV+ cancers, HPV+OPC express p16 but the latter does not function as a tumour-suppressor, because the mechanism by which this is achieved, pRb, has been inactivated by E7. p16 is  upregulated  (over-expressed) due to E7-related loss of pRB with reduced negative feedback, [ 39 ] [ 42 ]  whereas it is downregulated in up to 90% of HPV-OPC. [ 43 ]  This diffuse over-expression in the tumour cells provides a diagnostic marker for HPV involvement. [ 44 ] [ 45 ]  Although HPV E6 and E7 reduce tumour suppressor activity, they do so less than genetic and  epigenetic  processes do in HPV-OPC. [ 46 ] [ 47 ] [ 11 ]


The tonsillar epithelia ( palatine  and  lingual ) share similar  nonkeratinization  characteristics with the  cervix , where HPV infection plays the major role in cases of  cervical cancer . [ 14 ] [ 48 ]  Also E6 and E7 may make HPV+OPC more  immunogenic  than HPV-OPC, since anti-E6 and E7  antibodies  may be detected in these patients. This, in turn, could restrict the malignant behaviour of HPV+OPC and the presence of antibodies has been associated with a better prognosis, while treatment may enhance the immunogenicity of the tumour, and hence improve response, although to what extent is not clear. [ 49 ] [ 11 ]  Outcomes are also associated with improved  adaptive immunity . [ 50 ]


Initial diagnosis requires visualisation of the tumour either through the mouth or  endoscopically  through the nose using a  rhinoscope , illustrated to the right, followed by  biopsy . [ citation needed ]


HPV+OPC is usually diagnosed at a more advanced  stage  than HPV-OPC, [ 8 ]  with 75–90% having involvement of regional lymph nodes. [ 51 ]  Furthermore, HPV+OPC is more likely to be poorly differentiated with nonkeratinized or basaloid cells. [ 52 ] [ 53 ]   [ 54 ]


Genetic signatures of HPV+ and HPV- OPC are different. [ 55 ] [ 56 ] [ 57 ] [ 58 ] [ 59 ]  HPV+OPC is associated with expression level of the  E6/E7 mRNAs  and of  p16 . [ 60 ]   HPV16 E6/E7-positive cases are  histopathologically  characterized by their  verrucous  or papillary ( nipple  like) structure and  koilocytosis  of the adjacent mucosa. Approximately 15% of HNSCCs are caused by HPV16 infection and the subsequent constitutive expression of E6 and E7, and some HPV-initiated tumors may lose their original characteristics during  tumor progression . [ 61 ]  High-risk HPV types may be associated with oral carcinoma, by  cell-cycle  control dysregulation, contributing to oral  carcinogenesis  and the overexpression of mdm2, p27 and cathepsin B. [ 62 ]


HPV+OPC is not merely characterized by the presence of HPV-16: only the expression of viral oncogenes within the tumor cells plus the serum presence of E6 or E7 antibodies is unambiguously conclusive for HPV+OPC. [ 14 ]


There is not a standard HPV testing method in head and neck cancers, [ 63 ]  both  in situ hybridization  (ISH) and  polymerase chain reaction  (PCR) are commonly used. [ 44 ] [ 64 ]  Both methods have comparable performance for HPV detection, however, it is important to use appropriate  sensitivity  controls. [ 65 ]   Immunohistochemistry  (IHC)  staining  of the tissue for p16 is frequently used as a cost-effective surrogate for HPV in OPC, compared to ISH or PCR [ 66 ] [ 67 ] [ 68 ]  but there is a small incidence of HPV-negative p16-positive disease accounting for about 5% of HPV-OPC. [ 66 ]


Staging  is generally by the  UICC / AJCC   TNM  (Tumour, Nodes, Metastases) system. [ 68 ]  Staging is based on  clinical examination ,  diagnostic imaging , and pathology. On imaging, involved lymph nodes may appear  cystic , a characteristic of HPV+OPC. [ 69 ]


HPV+OPC has been treated similarly to stage-matched and site-matched HPV-unrelated OPC, but its unique features, which contrast smoking-related HPV-OPC head and neck cancers, for which patients' demographics, comorbidities, risk factors, and carcinogenesis differ markedly, suggest that a distinct staging system be developed to more appropriately represent the severity of the disease and its prognosis. [ 70 ]  Standard AJCC TNM staging, such as the seventh edition (2009) [ 71 ]  while predictive for HPV-OPC has no prognostic value in HPV+OPC. [ 72 ] [ 73 ] [ 67 ] [ 70 ]  The 8th edition of the  AJCC  TNM Staging Manual (2016) [ 74 ]  incorporates this specific staging for HPV+OPC. [ 75 ]  As of 2018, treatment  guidelines  are evolving to account for the different outcomes observed in HPV+OPC. Consequently, less intensive (de-intensification) use of radiotherapy or chemotherapy, [ 76 ]  as well as specific therapy, is under investigation, enrolling HPV+OPC in  clinical trials  to preserve disease control and minimise  morbidity  in selected groups based on modified TNM staging and smoking status. [ 77 ] [ 78 ] [ 79 ] [ 80 ] [ 81 ]


HPV+ cancer of the oropharynx are staged as (AJCC 8th ed. 2016): [ 75 ]
Tumour stage


Nodal stage


Clinical stage


However, the published literature and ongoing clinical trials use the older seventh edition that does not distinguish between HPV+OPC and HPV-OPC – see  Oropharyngeal Cancer – Stages . [ 82 ] [ 83 ]  The T stages are essentially similar between AJCC 7 and AJCC 8. with two exceptions. Tis ( carcinoma in situ ) has been eliminated and the division of T4 into substages (e.g. T4a) has been removed. The major changes are in the N stages, and hence the overall clinical stage. N0 remains the same, but as with the T stage, substages such as N2a have been eliminated. Extracapsular extension (ECE), also referred to as extranodal extension (ENE), which is invasion by the tumour beyond the capsule of the lymph node has been eliminated as a staging criterion. [ a ]


This results in an HPV+OPC tumour being given a lower stage than if it were HPV-OPC. For instance, a 5 cm tumour with one ipsilateral node involved that is 5 cm in size but has ECE would be considered T3N3bM0 Stage IVB if HPV- but T3N1M0 Stage II if HPV+. [ 75 ]


Prevention of HPV+OPC involves avoiding or reducing exposure to risk factors where possible. [ citation needed ]


About 90% of HPV+OPC carry HPV 16, and another 5% type 18. These two types are both targets of available vaccines.  HPV vaccines  given before exposure can prevent persistent genital infection and the consequent precancerous state. [ 11 ]  Therefore, they have a theoretical potential to prevent oral HPV infection. [ 8 ]  A 2010 review study has found that HPV16 oral infection was rare (1.3%) among the 3,977 healthy subjects analyzed. [ 84 ]


The goals of treatment are to optimise survival and locoregional disease control, and prevent spread to distant areas of the body ( metastasis ), while minimising short- and long-term  morbidity . [ 85 ]  There is no high quality  Level I evidence  from prospective clinical trials in HPV+OPC, therefore treatment guidelines must rely on data from treatment of OPC in general and from some retrospective unplanned  subsetting  of those studies, together with data for head and neck cancer in general. [ 68 ]  Treatment for OPC has traditionally relied on  radiotherapy ,  chemotherapy  and/or other systemic treatments, and surgical resection. Depending on the stage and other factors treatment may include a combination of  modalities . [ 86 ]  The mainstay has been radiotherapy in most cases. [ 67 ]  a pooled analysis of published studies suggested comparable disease control between radiation and surgery, but higher complication rates for surgery +/− radiation. [ 86 ] [ 87 ]  Ideally a single modality approach is preferred since triple modality is associated with much more toxicity and a multidisciplinary team in a large centre with high patient volumes is recommended. [ 68 ] [ 88 ] [ 12 ]


Differences in response to treatment between HPV-OPC and HPV+OPC may include differences in the extent and manner in which cellular growth-regulatory pathways are altered in the two forms of OPC. For instance, in HPV+OPC the HPV E6 and E7 oncogenes merely render the p53 and pRb pathways dormant, leaving open the possibility of reactivation of these pathways by  down-regulating  (reducing) expression of the oncogenes. This is in contrast to the mutant form of p53 found in HPV-OPC which is associated with treatment resistance. [ 11 ]  Furthermore, it is suggested that the effects of E6 and E7 on these pathways render the tumour more radiosensitive, possibly by interference with mechanisms such as  DNA repair , repopulation signalling, and cell-cycle redistribution. [ 89 ] [ 90 ]  The microenvironment is also important, with radiation increasing host  immune response  to viral  antigens  expressed on the tumour. [ 50 ] [ 49 ]  Also, there is an association between an increase in  tumour-infiltrating lymphocytes  and in circulating  white blood cells  in HPV+OPC patients and better prognosis. This implies a role for an  adaptive immune system  in suppressing  tumour progression . [ 91 ] [ 92 ] [ 90 ]


Historically, surgery provided a single approach to head and neck cancer. Surgical management of OPC carried significant morbidity with a transcervical (through the neck) approach, often involving mandibulotomy, in which the jawbone ( mandible ) is split. This is referred to as an open surgical technique. Consequently, surgical approaches declined in favour of radiation. In the United States, the use of surgery declined from 41% of cases in 1998 to 30% by 2009, the year that the  Food and Drug Administration  approved the use of the newer techniques. [ 93 ]


These improvements in surgical techniques have allowed many tumours to be  resected  (removed)  by transoral (through the mouth) surgical approaches (TOS), using transoral  endoscopic  head and neck surgery (HNS). [ 94 ]  Consequently, surgery became used more, increasing to 35% of cases by 2012. [ 93 ]  This approach has proven safety, efficacy and tolerability, and includes two main  minimally invasive  techniques,  transoral robotic surgery  (TORS) [ 95 ] [ 96 ] [ 97 ] [ 98 ] [ 99 ] [ 100 ]  and  transoral laser microsurgery  (TLM). [ 101 ] [ 102 ] [ 103 ]  No direct comparisons of these two techniques have been conducted, and clinical trials in head and neck cancer such as ECOG 3311 allow either. They are associated with substantial postoperative morbidity, depending on the extent of resection but compared to older techniques have a shorter hospital stay, faster recovery, less pain, and less need for  gastrostomy  or  tracheostomy , and less long-term effects, which are minimal in the absence of postoperative radiation (RT), or chemoradiation (CRT). [ 104 ] [ 105 ]  TORS has the practical advantage that angled telescopes and rotating robotic surgical arms provide better line of sight. Outcomes of minimally invasive procedures also compare favourably with more invasive ones. In early-stage disease, including involvement of neck nodes, TORS produces a 2-year survival of 80–90%. [ 106 ]  TLM similarly, is reported to have a five-year survival of 78% and local control rates of 85–97%. [ 107 ] [ 108 ]  In addition to early disease, minimally invasive surgery has been used in advanced cases, with up to 90% local control and disease-specific survival. [ 95 ] [ 108 ]  Postoperative swallowing was excellent in 87%, but long-term dysphagia was associated with larger (T4) cancers, especially if involving the base of the tongue. [ 108 ]   [ 12 ]


The details of the surgical approach depend on the location and size of the primary tumour and its N stage.  Neck dissection  to examine the draining lymph nodes may be carried out simultaneously or as a second staging procedure. For tumours of the tonsil and lateral pharyngeal wall, and clinically node-negative (N0) disease, dissection of the neck typically involves levels 2–4 ( see  diagram in Dubner 2017 )  ipsilaterally . Where nodes are involved clinically, dissection will depend on the location and size of the node or nodes. In the case of tongue base primaries, close to the  midline , bilateral dissection is recommended. [ 12 ]


An advantage of a primary surgical approach is the amount of  pathological  information made available, including grade,  margin status , and degree of involvement of lymph nodes. This may change the staging, as up to 40% of patients may have a different postoperative pathological stage compared to their preoperative clinical stage. In one study, 24% had their stage reduced (downstaged), which may impact subsequent decision making, including a reduction in intensity and morbidity. [ 109 ] [ 12 ]  In the United Kingdom, the  Royal College of Pathologists  (1998) [ 110 ] [ b ]  has standardised the reporting of surgical margins, with two categories, "mucosal" and "deep", and for each created groups based on the microscopic distance from invasive cancer to the margin, as follows: more than 5 mm (clear), 1–5 mm (close) and less than 1 mm (involved). [ 111 ]


Data on the use of postoperative  radiation therapy  (PORT) is largely confined to historical or retrospective studies rather than high quality  randomized clinical trials  and are based on the overall population of patients with head and neck cancer, rather than specific studies of HPV+OPC, which would have formed a very small proportion of the population studied. [ 12 ]  Despite surgical excision, in the more advanced cases local and regional recurrence of the cancer, together with spread outside of the head and neck region ( metastases ) are frequent. The risk of subsequent recurrent disease has been considered highest in those tumours where the pathology shows tumour at the margins of the resection (positive margins), multiple involved regional lymph nodes, and extension of the tumour outside of the capsule of the lymph node (extracapsular extension), based on historical experience with head and neck cancer. [ 112 ]  PORT was introduced in the 1950s in an attempt to reduce treatment failure from surgery alone. [ 113 ]  Although never tested in a controlled setting, PORT has been widely adopted for this purpose. [ 114 ]  In an analysis of surgical treatment failure at  Memorial Sloan-Kettering Cancer Center , patients treated with surgery alone between 1960 and 1970 had failure rates of 39 and 73% for those with negative and positive surgical margins respectively. These were compared to those who received PORT (with or without chemotherapy) from 1975 to 1980. The latter group had lower failure rates of 2% and 11% respectively. [ 115 ]  In addition, one randomised study from the 1970s (RTOG 73–03) compared preoperative radiation to PORT, and found lower failure rates with the latter. [ 114 ] [ 116 ]


The addition of another modality of treatment is referred to as  adjuvant  (literally helping) therapy, compared to its use as the initial (primary) therapy, also referred to as radical therapy. Consequently, many of these patients have been treated with adjuvant radiation, with or without chemotherapy. In the above series of reports of minimally invasive surgery, many (30–80%) patients received adjuvant radiation. However, functional outcomes were worse if radiation was added to surgery and even worse if both radiation and chemotherapy were used. [ 12 ]  Radiation dosage has largely followed that derived for all head and neck cancers, in this setting, based on risk. Historically only one randomised clinical trial has addressed optimal dosage, allocated patients to two dosage levels, stratified by risk, but showed no difference in cancer control between the low and high doses (63 and 68.4 Gy), but a higher incidence of complications at the higher doses. Consequently, the lower dose of 57.6  Gy  was recommended. [ 117 ] [ 118 ]  Because the authors used a fractionation scheme of 1.8 Gy per treatment, this dosage was not widely adopted, practitioners preferring a larger fraction of 2 Gy to produce a shorter treatment time, and a slightly higher dose of 60 Gy in 2 Gy fractions (30 daily treatments). [ 41 ]  Yet 57.6 Gy in 1.8 Gy fractions is equivalent (iso-effective dose) to only 56 Gy in 2 Gy fractions. [ 119 ]  60 Gy corresponds to the 63 Gy used as the low dose in the high-risk group. 60 Gy was also the dose used in RTOG 73–03. Subsequently, there was a tendency to intensify treatment in head and neck cancer, and many centres adopted a dose of 66 Gy, at least for those patients with adverse tumour features. [ 120 ]  The effectiveness of PORT in HPV+OPC receives some support from a  cohort study  (Level 2b), although the number of patients was low, and the number of events (recurrent disease or death) only 7%. [ 121 ]  Another retrospective population-level study (Level 4) of the  SEER  database (1998–2011) concluded that there was an overall survival but not disease-specific survival effect of radiation in 410 patients with a single lymph node involved, but used only  univariate  statistical analysis and contained no information on HPV status. [ 122 ]  A subsequent much larger study on a similar population in the National Cancer Database (2004–2013) of over 9,000 patients found a survival advantage but this was only in HPV-OPC, not in 410 HPV+OPC patients, [ 123 ]  and a subsequent study of 2,500 low and intermediate risk HPV+OPC patients showed similar overall survival whether PORT was given or not. [ 124 ]


While less studies have been completed examining deintensification (de-escalation) in this setting, than in primary radical radiation for this cancer (see below), it is an area of active investigation. [ 125 ]  In one single institution study, a decision was made to reduce the radiation dose in high-risk patients with HPV+OPC from 66 to 60 Gy, corresponding to the actual evidence, and follow-up has shown no decrease in cancer control. [ 120 ]  Current trials, both in North America and Europe (such as ECOG 3311 [ c ]  and PATHOS [ d ] ) use 50 Gy as the comparison arm. [ 127 ]  The comparator of 50 Gy was chosen on the grounds of (i) the exquisite sensitivity of HPV+OPC to radiation, both  in vitro  and  in vivo ; ECOG 1308 showing excellent disease control at 54 Gy; and data [ 128 ]  suggesting that 50 Gy in 1.43 Gy (iso-effective dose 43 Gy in 2.0 Gy) was sufficient to electively treat the neck. [ 126 ]  Other studies, such as MC1273 and DART-HPV have evaluated doses as low as 30–36 Gy. [ 129 ]  Lowering the radiation dose to 54 Gy was identified as one of the important Clinical Cancer Advances of 2018 by the
 American Society of Clinical Oncology , under the general theme of "Less Is More: Preserving Quality of Life With Less
Treatment". [ 130 ]
Chemotherapy has been used concurrently with radiation in this setting, as in primary treatment with radical radiation, particularly where pathological features indicated a higher risk of cancer recurrence. Several studies have suggested that this does not improve local control, but adds toxicity. [ 131 ]


Concerns over the morbidity associated with traditional open surgical en-bloc resection led to exploring alternative approaches using radiation. [ 121 ]  Intensity-modulated radiation therapy ( IMRT ) can provide good control of primary tumours while preserving excellent control rates, with reduced toxicity to salivary and pharyngeal structures relative to earlier technology. HPV+OPC has shown increased sensitivity to radiation with more rapid regression, compared to HPV-OPC. [ 132 ]  Generally, radiation can safely be delivered to the involved side alone (ipsilateral), due to the low rate of recurrent cancer on the opposite side (contralateral), and significantly less toxicity compared to bilateral treatment. [ e ] [ 134 ] [ 133 ]  IMRT has a two-year disease-free survival between 82 and 90%, and a two-year disease-specific survival up to 97% for stage I and II. [ 135 ] [ 136 ]


Reported  toxicities  include dry mouth ( xerostomia ) from  salivary gland  damage, 18% (grade 2); [ f ]  difficulty swallowing ( dysphagia ) from damage to the constrictor muscles, larynx and oesophageal sphincter, 15% (grade 2);  subclinical   aspiration  up to 50% (reported incidence of aspiration pneumonia approximately 14%);  hypothyroidism  28–38% at three years (may be up to 55% depending on amount of the thyroid gland exposed to over 45  Gy  radiation;  esophageal stenosis  5%;  osteonecrosis  of the  mandible  2.5%; and need for a  gastrostomy  tube to be placed at some point during or up to one year after treatment 4% (up to 16% with longer follow up). [ 12 ] [ 138 ] [ 136 ] [ 139 ] [ 140 ]  Concerns have been expressed regarding excessive short- and long-term toxicity, especially dysphagia, and xerostomia, [ 141 ] [ 142 ] [ 143 ]  and hence whether standard doses expose patients with better prognoses are being exposed to overtreatment and unnecessary side effects. [ 144 ] [ 90 ]


The probability of xerostomia at one year increases by 5% for every 1Gy increase in dose to the  parotid gland . Doses above 25–30 Gy are associated with moderate to severe xerostomia. Similar considerations apply to the  submandibular gland , but xerostomia is less common if only one parotid gland is included in the radiated field [ 145 ]  and the contralateral submandibular gland is spared (less than 39 Gy) [ 146 ]  In the same manner, the radiation dose to the  pharyngeal constrictor muscles ,  larynx , and  cricopharyngeal inlet  determine the risk of dysphagia (and hence the dependence on  gastrostomy  tube feeds). The threshold for this toxicity is volume-dependent at 55–60 Gy, [ 147 ] [ 148 ] [ 149 ] [ 90 ]  with moderate to severe impairment of swallowing, including aspiration, stricture and feeding tube dependence above a mean dose of 47 Gy, with a recommended dose to the inferior constrictor of less than 41 Gy. [ 150 ] [ 151 ]  Dose-toxicity relationships for the superior and middle constrictors are steep, with a 20% increase in the probability of dysphagia for each 10 Gy. [ 152 ]  For late dysphagia, threshold mean total constrictor doses, to limit rates of greater than or equal to grade 2 and 3 below 5% were 58 and 61 Gy respectively. For grade 2 dysphagia, the rate increased by 3.4% per Gy. [ 153 ]  Doses above 30 Gy to the thyroid are associated with moderate to severe hypothyroidism. [ 154 ]  Subjective, patient-reported outcomes of  quality of life  also correlate with radiation dose received. [ 142 ]


Altered  fractionation  schemes, such as RTOG 9003   [ g ] [ 141 ]  and RTOG 0129 [ h ]  have not conferred additional benefit. [ 155 ] [ 156 ]  Radiation dose recommendations were largely determined  empirically  in clinical studies with few HPV+OPC patients, and have remained unchanged for half a century, [ 90 ]  making it difficult to determine the optimum dose for this subgroup. A common approach uses 70 Gy bilaterally and anteriorly, such as RTOG 9003 (1991–1997) [ 141 ] [ 155 ]  and RTOG 0129 (2002–2005). [ 157 ] [ 156 ]  For lateralized tonsil cancer unilateral neck radiation is usually prescribed, but for tongue base primaries bilateral neck radiation is more common, but unilateral radiation may be used where tongue base lesions are lateralised. [ 12 ]


Concerns have been expressed regarding excessive short- and long-term toxicity, especially dysphagia and xerostomia, [ 141 ] [ 142 ] [ 143 ]  and hence whether standard doses expose patients with better prognoses to overtreatment and unnecessary side effects. [ 144 ] [ 90 ]  Current toxicities have been described as "not tolerable", [ 158 ]  and hence an intense interest in de-escalation. [ 127 ]


While comparison with historical controls has limited value compared to randomised clinical trials ( phase III ),  phase II  studies using reduced doses of radiation compared to the historical standard of 70 Gy have been carried out. A study using 54–60 Gy (a 15–20% reduction, stratified by response to initial induction chemotherapy) demonstrated comparable levels of disease control with much lower complication rates, [ 90 ]  when compared to similar studies, using 70 Gy, such as ECOG 2399. [ 159 ] [ 160 ]  The percentage of patients alive after 2 years was 95% at the higher dose and 98% at the lower dose. Similarly for the percentage free of disease (86 and 92%). Toxicities were greatly reduced from an incidence of grade 3 or greater dysphagia and mucositis of 54 and 53% respectively, to 9%. A lower incidence and severity of dysphagia also means that fewer patients require gastrostomy feeding. [ 90 ]  A similar comparison can be made with the pooled data from two RTOG studies which utilized 70 Gy (0129 and 0522). [ 161 ]


No new guidelines dealing specifically with HPV+OPC have yet been developed, outside of clinical trials. Indirect data suggests the efficacy of less intense treatment. A retrospective analysis of advanced (N+) HPV+OPC suggested 96% 5-year local control with de-intensified radiation of 54 Gy and concurrent  cisplatin  based chemotherapy. [ 162 ]  The conclusions of the above pair of similar phase II trials have been supported by several other phase II trials. A prospective trial ( ECOG  1308) demonstrated similar locoregional control with 54 Gy, [ 144 ]  and another study, a high pathological complete response rate at 60 Gy. [ 163 ]  The Quarterback trial [ i ]  showed comparable outcomes between 56 and 70 Gy. [ 164 ]  and was followed by Quarterback 2, comparing 50 to 56 Gy. [ j ]  Similarly, the Optima trial showed good disease control with doses between 45 and 50 Gy. [ 165 ]  Ongoing studies, following the experience of the  Mayo Clinic  trial (MC1273), [ 129 ]  such as that the  Memorial Sloan Kettering Cancer Center  are exploring doses as low as 30Gy. [ k ]  These studies all used well below the previous standard dose of 70 Gy. Since long-term toxicity is associated with radiation dose, determining the efficacy of lower and hence less morbid doses of radiation is a priority, since many HPV+ patients can be expected to have long-term survival. [ 12 ]


Radiation is commonly utilised in combination with chemotherapy but also may be used as a single modality, especially in earlier stages, e.g. T1-T2, N0-1, and its use in later stages is being explored in clinical trials such as RTOG 1333 which compares radiation alone to radiation with reduced chemotherapy, in non or light smokers. [ 12 ]


As with the radiotherapy data, most of the available knowledge on the efficacy of chemotherapy derives from the treatment of advanced head and neck cancer rather than specific studies of HPV+OPC. Since 1976, many clinical studies have compared CRT to RT alone in the primary management of locally advanced head and neck cancers and have demonstrated an advantage to CRT in both survival and locoregional control. [ 166 ] [ 167 ]  Cisplatin is considered the standard agent, and a survival advantage was seen for those patients who received radiation with concurrent cisplatin. [ 168 ]  Despite this no trials directly comparing cisplatin with other agents in this context have been conducted. The other agent that is widely used is  Cetuximab , a  monoclonal antibody  directed at the  epidermal growth factor receptor  (EGFR). A 10% survival advantage at three years was noted when cetuximab was given concurrently with radiation (bioradiation). [ 169 ]  Cetuximab trials were completed before knowledge of HPV status. [ 170 ]  Laboratory and clinical studies on the utility of cetuximab in this context are conflicting.  The main toxicity is an  acneiform  rash, but it had not been compared directly to cisplatin in HPV+OPC, until RTOG 1016 ( see Talk ) addressed this question. [ 12 ] [ 164 ]  Analysis of the results three years after the trial was completed demonstrates that cetuximab is inferior to cisplatin. [ 171 ]  Concurrent chemotherapy is also superior to chemotherapy alone ( induction chemotherapy ) followed by radiation. [ 166 ] [ 12 ]  Cetuximab shows no advantage when added to cisplatin in combination with radiation. [ 143 ]  Although chemoradiation became a treatment standard based on clinical trials and in particular,  meta-analyses , a subsequent  population-based study  of patients with OPC, indicated no advantage to the addition of chemotherapy to radiation in either HPV+OPC or HPV-OPC, [ 172 ]  and significant concerns about added toxicity. [ 173 ]


Chemotherapy also has a role, combined with radiation, in the postoperative setting (adjuvant therapy). [ 174 ]  Generally it is used where the  pathology  of the resected specimen indicates features associated with a high risk of locoregional recurrence (e.g. extracapsular extension through involved lymph nodes or very close margins). It has shown improved disease-free survival and locoregional control in two very similar clinical trials in such high-risk patients,  EORTC  22931 (1994–2000) [ 112 ]  and RTOG 9501 (1995–2000). [ l ] [ m ] [ n ] [ 175 ] [ 176 ] [ 177 ]  However, for HPV+OPC patients, such extracapsular spread does not appear to be an adverse factor [ 178 ] [ 179 ] [ 180 ]  and the addition of chemotherapy to radiation in this group provided no further advantage. [ 179 ]  Since the  sample size  to detect a survival advantage is large, given the small number of events in this group, these studies may have been  underpowered  and the question of the utility of adding chemotherapy is being addressed in a randomized clinical trial (ADEPT) with two-year locoregional control and disease-free survival as the endpoint. [ o ]  The addition of chemotherapy to radiation increases acute and late toxicity. In the GORTEC trial, chemotherapy with  docetaxel  provided improved survival and locoregional control in locally advanced OPC but was associated with increased mucositis and need for feeding by gastrostomy. [ 181 ]  Chemotherapy and radiation are associated with a risk of death of 3–4% in this context. [ 182 ]  It is unclear whether the added toxicity of adding chemotherapy to radiation is offset by significant clinical benefits in disease control and survival. [ 12 ]


It is thought that HPV+OPC patients benefit better from radiotherapy and concurrent  cetuximab  treatment than HPV-OPC patients receiving the same treatment, [ 183 ]  and that radiation and cisplatin induce an immune response against an  antigenic  tumour which enhances their effect on the cancer cells. [ 49 ]  Although the incidence of HPV positivity is low (10–20%), an advantage for HPV+OPC was seen in trials of both cetuximab and  panitumumab , a similar anti-EGFR agent, but not a consistent interaction with treatment, although HPV+OPC appears not to benefit to the same extent as HPV-OPC to second line anti-EGFR therapy, possibly due to lower EGFR expression in HPV+OPC. [ 170 ]


In the absence of high-quality evidence comparing a primary surgical approach to other modalities, decisions are based on consideration of factors such as adequate surgical exposure and anatomically favourable features for adequate resection, post-treatment function, and  quality of life . Such patient selection may enable them to avoid the morbidity of additional adjuvant treatment. In the absence of favourable surgical features, the primary treatment of choice remains radiation with or without chemotherapy. Tumor characteristics that favour a non-surgical approach include invasion of the base of the tongue to the extent of requiring resection of 50% or more of the tongue, pterygoid muscle involvement, extension into the  parapharyngeal fat  abutting the  carotid , involvement of the mandible or  maxilla  or invasion of the  prevertebral space . [ 12 ]


The adequacy of surgical  resection  is a major factor in determining the role of postoperative adjuvant therapy. In the presence of a  positive margin  on pathological examination, most radiation oncologists recommend radiation to the primary site, and concurrent chemotherapy. A negative margin is more likely to be treated with lower doses and a smaller treatment volume. Also, the removal of a bulky tumour may allow reduced dosage to adjacent uninvolved pharyngeal structures and hence less effect on normal  swallowing . [ 76 ] [ 12 ]


The cancer outcomes (local control, regional control, and survival) for transoral resection followed by adjuvant therapy are comparable to primary chemoradiation, [ 102 ] [ 98 ] [ 139 ]  so that treatment decisions depend more on treatment-related morbidity, functional outcome, and quality of life. Patient factors also need to be taken into account, including general baseline functionality, smoking history, anesthesia risk, oropharyngeal function, swallowing and airway protection, and potential for rehabilitation. Patient preference is equally important. Many clinical trials are underway focussing on deintensification, often with risk  stratification , e.g. Low, Intermediate and High Risk ( see Fundakowski and Lango, Table I ). [ 12 ] [ p ]


Clinical decisions also take into account morbidities, particularly if cancer outcomes are comparable for instance surgery is associated with a risk of bleeding between 5–10%, and a 0.3% risk of fatal postoperative haemorrhage. [ 103 ] [ 184 ] [ 99 ] [ 100 ]  Surgery may also be complicated by  dysphagia , and while most patients can tolerate a diet on the first postoperative day, long-term use of a feeding tube has been reported as high as 10%. [ 108 ] [ 99 ] [ 100 ]  Patients with larger tumours, involvement of base of the tongue and requiring postoperative adjuvant therapy are more likely to require a long-term feeding tube. [ 185 ] [ 186 ]  Overall, function and quality of life appear relatively similar between surgery with postoperative radiation, and primary chemoradiation, [ 187 ] [ 188 ] [ 12 ]  but HPV+OPC patients tend to have a better quality of life at diagnosis than HPV-OPC but may sustain greater loss following treatment. [ 189 ]


Anatomical considerations may also dictate a preference for surgical or non-surgical approaches. For instance  trismus , a bulky tongue, limited extension of the neck, prominent teeth,  torus mandibularis  (a bony growth on the mandible), or limited width of the mandible would all be relative contraindications to surgery. [ 101 ]  Tumour-related considerations include invasion of the mandible,  base of the skull , and extensive involvement of the larynx or more than half of the base of the tongue. [ 102 ]  Technical considerations in offering surgery as a primary modality include the presumed ability to achieve adequate margins in the resected specimen and the degree of resulting defect, since close or positive margins are likely to result in subsequent adjuvant therapy to achieve disease control, with resultant increased morbidity. Costs are difficult to estimate but one US study, based on estimates of 25% of all OPC patients receiving surgery alone and 75% surgery followed by adjuvant therapy, using the criteria of the  NCCN , found that this approach was less expensive than primary chemoradiation. [ 190 ] [ 191 ] [ 192 ]


Early stage disease [ q ]  is associated with a relatively favourable outcome, for which single modality therapy is recommended, the choice depending on tumour location and accessibility. For instance, unilateral tonsil or tongue base tumours will generally be treated with transoral resection and selective ipsilateral neck dissection. On the other hand, a large midline tongue lesion would require bilateral neck dissection, but in the absence of what are considered adverse pathology (positive margins, extracapsular extension) will likely be treated by surgery alone or radiation including ipsilateral or bilateral neck radiation fields, with surgery for those instances where the likelihood of adjuvant therapy is low. [ 12 ]


But many HPV+OPC present with involvement of the lymph nodes in the neck, and hence a higher stage of disease, generally referred to as locally advanced disease. This group is mostly treated with multimodality therapy, except one of the more favourable subgroups with small primary tumours and lymph node involvement confined to a single node no larger than 3 cm in size, which as noted are considered early-stage disease. The three main options for locally advanced but operable disease are resection, neck dissection, and adjuvant therapy; chemoradiation (with possible  salvage surgery ); induction chemotherapy followed by radiation or chemoradiation. However, the last option has not been supported in clinical trials that tested it. [ r ]  The primary consideration of surgery for locally advanced disease is to obtain adequate negative margins and spare the patient postoperative chemoradiation. But this must be balanced against the morbidity and functional loss from extensive resection, particularly where the tongue base is involved. To avoid such morbidity, primary chemoradiation is preferred. The management of disease within the cervical lymph nodes has to be taken into account in treating locally advanced disease. Guidelines for all OPC dictate that extracapsular extension be given postoperative chemoradiation. Where gross neck disease is evident initially primary chemoradiation is usually given. [ 12 ]


Current guidelines are based on data for OPC as a whole so that patients are generally being treated regardless of HPV status, yet many clinicians and researchers are considering deintensification. [ 195 ]  Treatment of this condition will likely continue to evolve in the direction of deintensification, to minimize loss of function but maintain disease control. [ 196 ]  In the absence of specific clinical trials and guidelines, patient preferences need to be taken into consideration to minimise short- and long-term toxicity and functional loss and optimize quality of life, given the prolonged survival frequently seen. [ 12 ]  This may involve exploring patients' values regarding  trade-offs  of disease control against adverse effects of treatment. Patients who have received CRT as primary treatment for OPC place a high value on survival, and although agreeing that deintensification is desirable, were reluctant to trade off much survival advantage for lower toxicity, though would be more likely to forgo chemotherapy than accept reduced radiation. [ 197 ]


In some situations, HPV+OPC may present with cervical lymph nodes but no evident disease of a primary tumour (T0 N1–3) and is therefore classed as  Squamous Cell Carcinoma of Unknown Primary Origin . This occurs in 2–4% of patients presenting with metastatic cancer in the cervical nodes. The incidence of HPV positivity is increasing at a similar rate to that seen in OPC. In such situations, resection of the lingual and palatine tonsils together with neck dissection may be diagnostic and constitute sufficient intervention, since recurrence rates are low. [ 198 ] [ 199 ] [ 200 ] [ 201 ] [ 202 ] [ 12 ] [ excessive citations ]


The presence of HPV within the tumour has been realised to be an important factor for predicting survival since the 1990s. [ 203 ]


Tumor HPV status is strongly associated with positive therapeutic response and survival compared with HPV-negative cancer, independent of the treatment modality chosen and even after adjustment for the stage. [ 204 ]  While HPV+OPC patients have some favourable  demographic  features compared to HPV-OPC patients, such differences account for only about ten percent of the survival difference seen between the two groups. [ 11 ]  Response rates of over 80% are reported in HPV+ cancer and three-year progression-free survival has been reported as 75–82% and 45–57%, respectively, for HPV+ and HPV- cancer, and improving over increasing time. [ 12 ] [ 205 ] [ 206 ] [ 207 ]  It is likely that HPV+OPC is inherently less malignant than HPV-OPC since patients treated by surgery alone have better survival after adjustment for stage. [ 11 ]


HPV is tested for by the presence of the  biomarker   p16 , which normally increases in the presence of HPV. Some people can have elevated levels of p16 but test negative for HPV and vice versa. This is known as discordant cancer. The 5-year survival for people who test positive for HPV and p16 is 81%, for discordant cancer it is 53 – 55%, and 40% for those who test negative for p16 and HPV. [ 208 ] [ 209 ]


In  RTOG  clinical trial 0129, [ s ]  in which all patients with advanced disease received radiation and chemotherapy, a retrospective analysis ( recursive-partitioning analysis , or RPA) at three years identified three risk groups for survival (low, intermediate, and high) based on HPV status, smoking, T stage, and N stage ( see  Ang et al., Fig. 2). [ 157 ]  HPV status was the major determinant of survival, followed by smoking history and stage. 64% were HPV+ and all were in the low and intermediate-risk groups, with all non-smoking HPV+ patients in the low-risk group. 82% of the HPV+ patients were alive at three years compared to 57% of the HPV- patients, a 58% reduction in the risk of death. [ t ] [ 157 ]  Locoregional failure is also lower in HPV+, being 14% compared to 35% for HPV-. [ 160 ]


HPV positivity confers a 50–60% lower risk of disease progression and death, but the use of tobacco is an independently negative prognostic factor. [ 157 ] [ 210 ]  A pooled analysis of HPV+OPC and HPV-OPC patients with disease progression in RTOG trials 0129 and 0522 showed that although less HPV+OPC experienced disease progression (23 v. 40%), the  median  time to disease progression following treatment was similar (8 months). The majority (65%) of recurrences in both groups occurred within the first year after treatment and were locoregional. Although the rate of failure in the opposite neck following treatment of only one side, is 2.4%, the rate of an isolated recurrence in the opposite neck is 1.7%, and these were mainly where the primary tumour involved the midline. However, the rate of failure in the contralateral neck is also greater for HPV+. [ 211 ]  Of those that recur in this site, nearly all were successfully treated (salvaged) by further local treatment to the opposite neck. [ 133 ]


HPV+ did not reduce the rate of metastases (about 45% of patients experiencing progression), which are predominantly to the lungs (70%), although some studies have reported a lower rate. [ 212 ] [ 161 ]  with 3-year distant recurrence rates of about 10% for patients treated with primary radiation or chemoradiation. [ 213 ]  Even if recurrence or metastases occur, HPV positivity still confers an advantage. [ 12 ] [ 212 ] [ 214 ]
By contrast tobacco usage is an independently negative prognostic factor, with decreased response to therapy, [ 157 ] [ 210 ]  increased disease recurrence rates and decreased survival. [ 215 ]  The negative effects of smoking, increases with the amount smoked, particularly
if greater than 10  pack-years . [ 157 ] [ 210 ]


For patients such as those treated on RTOG 0129 with primary chemoradiation, detailed  nomograms  have been derived from that  dataset  combined with RTOG 0522, enabling prediction of outcome based on a large number of  variables . For instance, a 71-year-old married non-smoking high school graduate with a  performance status  (PS) of 0, and no weight loss or  anaemia  and a T3N1 HPV+OPC would expect to have a  progression-free survival  of 92% at 2 years and 88% at 5 years. A 60-year-old unmarried nonsmoking high school graduate with a PS of 1, weight loss and anaemia, and a T4N2 HPV+OPC  would expect to have a survival of 70% at two years and 48% at five years. [ 216 ]


Less detailed information is available for those treated primarily with surgery, for whom fewer patients are available, [ 121 ]  as well as low rates of recurrence (7–10%), but features that have traditionally been useful in predicting prognosis in other head and neck cancers, appear to be less useful in HPV+OPC. [ 51 ]  These patients are frequently stratified into three risk groups: [ 93 ]


HPV+OPC patients are less likely to develop other cancers, compared to other head and neck cancer patients. [ 30 ]  A possible explanation for the favourable impact of HPV+ is "the lower probability of occurrence of 11q13 gene amplification, which is considered to be a factor underlying faster and more frequent recurrence of the disease" [ 14 ]  Presence of TP53 mutations, a marker for HPV- OPC, is associated with worse prognosis. [ 8 ]  High grade of p16 staining is thought to be better than HPV PCR analysis in predicting radiotherapy response. [ 64 ]


The risk of regional cancer recurrence after neck dissection is often estimated [ 164 ]  from a large series based on all upper aerodigestive squamous cell cancers. In this series, the overall risks at three years by pathological stage (AJCC 7) were: [ 217 ]


In 2015, squamous cell cancer of the head and neck region was the fifth most common cancer other than skin cancer, globally, with an annual incidence of 600,000 cases and about 60,000 cases annually in the United States and Europe. [ 218 ]  The global  incidence  of pharyngeal cancer in 2013 was estimated at 136,000 cases. [ 12 ] [ 219 ] [ 220 ]  For 2008 the  Global Burden of Disease  for OPC in 2008 is estimated at 85,000 cases, of which 22,000 were attributable to HPV, a  population attributable fraction  (PAF) of 26%. Of these, 17,000 were males and 4,400 females, 13,000 (60%) were aged between 50 and 69 years of age, and the majority of cases (15,000) were in  developed regions  compared to  developing regions  (6,400). [ 221 ] [ 2 ]   Age Standardised Incidence Rates  (ASR) differ considerably by region and country ( see  de Martel et al., 2017 Fig. 2b). [ 221 ]  ASRs for 2012 were highest in  Europe (Hungary 3.0) and North America (United States 1.7) but much lower in Africa (≤ 0.3), Asia (≤ 0.6), Latin America (≤ 0.4) and  Oceania  (≤ 0.2) (other than  Australasia , Australia 0.9). [ 222 ] [ 221 ]  Estimated average numbers of cases and ASR for the US in the period 2008–2012 were 15,738 and 4.5 respectively. HPV+OPC was much more common in males than females (12,638, 7.6 and 3,100, 1.7). The highest incidence age group was 60–69 and was higher in  Caucasians  than in other races. [ 223 ]


HPV+OPC patients tend to be younger than HPV- patients in general. [ 224 ]  The clinical presentation is also changing from the "typical" head and neck cancer patient with advanced age and major  substance usage . [ 12 ]  By contrast patients with HPV+ cancer are younger (4th–6th decades), male (ratio 8:1) with no or only a minimum history of smoking, generally Caucasian, reached higher education levels, are married, and have higher income. [ 225 ]  The risk factors for HPV-OPC and HPV+OPC tend to be independent, except for smoking which adversely affects both. [ 11 ]  The presenting features are also different between HPV+ and HPV- OPC. HPV+ tumours have smaller primary lesions (less than 4 cm) but more advanced nodal disease resulting in higher TNM staging. This, in turn, may overestimate the severity of the disease status. [ 226 ] [ 227 ]


There has been a global trend in increasing OPC incidence, particularly in North America and northern Europe, but even in Taiwan, which has a very high rate for all cancers of the head and neck region, OPC rates increased more rapidly between 1995 and 2009 than any other cancer site. [ 228 ] [ 229 ]  The Global Burden of HPV+OPC increased from 22,000 in 2008 to 29,000 by 2012, and the PAF from 26% to 31%, [ 221 ]  and is considered an  epidemic . [ 44 ]  In the United States the estimated number of cases was 12,410 in 2008, [ 230 ]  13,930 in 2013 [ 231 ]  and 17,000 for 2017. [ 232 ]  Of these cases, HPV+ cancer has been increasing compared to HPV- cancer, but the increase in HPV+OPC exceeds the decline in HPV-OPC resulting an overall increase in OPC. [ 11 ]  The rise in pharyngeal cancer incidence contrasts with a marginal decline in other head and neck cancers. [ 233 ]  As a result, the commonest head and neck cancer has shifted from  larynx  to oropharynx. [ 121 ]  A survey of 23 countries between 1983 and 2002 showed an increase in oropharyngeal squamous cell carcinoma that was particularly noticeable in young men in economically  developed  countries. [ 220 ] [ 12 ]  In the United Kingdom the incidence of oral and oropharyngeal cancer in men rose 51%, from 7/100,000 to 11/100,000 between 1989 and 2006. [ 233 ]  In the US there is a growing incidence of HPV associated oropharyngeal cancers, [ 234 ]  In the early 1980s HPV+ accounted for only 7.5% of cases in the US but by 2016 this was 70%, [ 12 ] [ 235 ] [ 236 ] [ 237 ]  perhaps as a result of changing sexual behaviors, decreased popularity of tonsillectomies, improved radiologic and pathologic evaluation, and changes in classification. [ 238 ] [ 239 ] [ 240 ]  Tonsil and oropharyngeal cancers increased in male predominance between 1975 and 2004, despite reductions in smoking. [ 241 ]  HPV-OPC decreased with decreasing smoking rates from 1988 to 2004, while HPV+OPC increased by almost 7.5% per year from about 16% of all cases of OPC in the early 1980s to almost 70% in 2004. [ 225 ] [ 242 ]  The decline in smoking may be linked to the decreasing proportion of HPV negative cancers, while changes in sexual activity may be reflected in increasing proportion of HPV positive cancers. [ 225 ]  Recently, in the US, HPV associated OPC represent about 60% of OPC cases [ 160 ] [ 243 ]  compared with 40% in the previous decade. [ 233 ]  By 2007, in the US,  incidence of general OPC, including non-HPV associated, is 3.2 cases per 100,000 males/year and 1.9 per 100,000 all-sexes/year. [ 244 ]  This makes HPV+OPC one of only five cancers that have increased in incidence in the US since 1975. [ 245 ]  The largest increase in incidence has occurred in patients under age 50. [ 246 ]


The increase in incidence of HPV-associated OPC is also seen in other countries, like  Sweden , with a 2007 incidence of over 80% for cancer in the tonsils, [ 247 ] [ 248 ]   Finland [ 249 ]  and the  Czech Republic . [ 250 ]  Partners of patients with HPV-positive oropharyngeal cancer do not seem to have elevated oral HPV infection compared with the general population. [ 251 ]  In Australia the incidence of HPV-associated OPC was 1.56 cases per 100,000 males/year (2001–2005), rising from 19% (1987–90) to 47% (2001–05) and 63.5% (2006–2010). [ 252 ] [ 253 ]  In Canada the percentage of cases of OPC attributable to HPV increased from 47% in 2000 to 74% in 2012. [ 254 ]


The  hyoid bone  ( lingual bone  or  tongue-bone ) ( / ˈ h aɪ ɔɪ d / [ 2 ] [ 3 ] ) is a  horseshoe-shaped   bone  situated in the anterior midline of the  neck  between the  chin  and the  thyroid cartilage .  At rest, it lies between the base of the  mandible  and the third  cervical vertebra .


Unlike other bones, the hyoid is only distantly  articulated  to other bones by muscles or ligaments. It is the only bone in the human body that is not connected to any other bones. The hyoid is anchored by muscles from the anterior, posterior and inferior directions, and aids in tongue movement and swallowing. The hyoid bone provides attachment to the muscles of the  floor of the mouth  and the tongue above, the  larynx  below, and the  epiglottis  and  pharynx  behind. [ citation needed ]


Its name is derived from  Greek    hyoeides  'shaped like the letter  upsilon  (υ)'. [ 4 ] [ 5 ]


The hyoid bone is classed as an  irregular bone  and consists of a central part called the body, and two pairs of horns, the greater and lesser horns.


The body of the hyoid bone is the central part of the hyoid bone. [ clarification needed ]


The greater and lesser horns ( Latin :  cornua ) are two sections of bone that project from each side of the hyoid.


The greater horns project backward from the outer borders of the body; they are flattened from above downward and taper to their end, which is a bony  tubercle  connecting to the  lateral thyrohyoid ligament . The upper surface of the greater horns are rough and close to its lateral border, and facilitates muscular attachment. The largest of muscles that attach to the upper surface of the greater horns are the  hyoglossus  and the  middle pharyngeal constrictor , which extend along the whole length of the horns; the  digastric muscle  and  stylohyoid muscle  have small insertions in front of these near the junction of the body with the horns. To the medial border, the  thyrohyoid membrane  is attached, while the anterior half of the lateral border gives insertion to the  thyrohyoid muscle . [ citation needed ]


The lesser horns are two small, conical eminences, attached by their bases to the angles of junction between the body and greater horns of the hyoid bone. They are connected to the body of the bone by fibrous tissue, and occasionally to the greater horns by distinct diarthrodial  joints , which usually persist throughout life, but occasionally become  ankylosed . The lesser horns are situated in the line of the transverse ridge on the body and appear to be continuations of it. The apex of each horn gives attachment to the  stylohyoid ligament ; the  chondroglossus  rises from the medial side of the base. [ citation needed ]


The second  pharyngeal arch , also called the hyoid arch, gives rise to the lesser cornu of the hyoid and the upper part of the body of the hyoid. The cartilage of the third pharyngeal arch forms the greater cornu of the hyoid and the lower portion of the body of the hyoid.


The hyoid is  ossified  from six centers: two for the body, and one for each cornu.  Ossification commences in the greater cornua toward the end of  fetal development , in the hyoid body shortly afterward, and in the lesser cornua during the first or second year after birth.  Until middle age, the connection between the body and greater cornu is  fibrous .


In early life, the outer borders of the body are connected to the greater horns by synchondroses; after middle life, usually by bony union.


Blood is supplied to the hyoid bone via the  lingual artery , which runs down from the  tongue  to the greater horns of the bone. The suprahyoid branch of the lingual artery runs along the upper border of the hyoid bone and supplies blood to the attached muscles.


The hyoid bone is present in many  mammals . It allows a wider range of tongue, pharyngeal and laryngeal movements by bracing these structures alongside each other in order to produce variation. [ 6 ]  Its descent in living creatures is not unique to  Homo sapiens , [ 7 ]  and does not allow the production of a wide range of sounds: with a lower larynx, men do not produce a wider range of sounds than women and two-year-old babies. Moreover, the larynx position of Neanderthals was not a handicap to producing speech sounds. [ 8 ]    The discovery of a modern-looking hyoid bone of a  Neanderthal  man in the  Kebara Cave  in  Israel  led its discoverers to argue that the Neanderthals had a descended  larynx , and thus human-like  speech  capabilities. [ 9 ]   However, other researchers have claimed that the morphology of the hyoid is not indicative of the larynx's position. Recent research has indicated that the hyoid bone may have significant involvement in the ability to swallow. It has been hypothesized that the mammalian hyoid bone evolved in conjunction with the development of  lactation , thus allowing babies to suckle milk. [ 10 ]  It is necessary to take into consideration the skull base, the mandible and the cervical vertebrae and a cranial reference plane. [ 11 ] [ 12 ]


A large number of muscles attach to the hyoid: [ 13 ]


The hyoid bone is important to a number of physiological functions, including breathing, swallowing and speech. It is also thought to play a key role in keeping the upper airway open during sleep, [ 14 ] [ 15 ]  and as such, the development and treatment of  obstructive sleep apnea  (OSA; characterized by repetitive collapse of the upper airway during sleep). A mechanistic involvement of the hyoid bone in OSA is supported by numerous studies demonstrating that a more inferiorly positioned hyoid bone is strongly associated with the presence and severity of the disorder. [ 16 ] [ 17 ]  Movement of the hyoid bone is also thought to be important in modifying upper airway properties, which was recently demonstrated in computer model simulations. [ 18 ]  A  surgical procedure  that aims to potentially increase and improve the airway is called  hyoid suspension .


Due to its position, the hyoid bone is not easily susceptible to fracture. In a suspected case of murder or physical abuse of an adult, a  fractured hyoid  strongly indicates throttling or  strangulation . In children and adolescents (in whom the hyoid bone is still flexible because  ossification  is yet to be completed) fracture may not occur even after serious trauma.


The hyoid bone is derived from the lower half of the second  gill arch  in  fish , which separates the first gill slit from the  spiracle , and is often called the  hyoid arch . In many vertebrates, it also incorporates elements of other gill arches, and has a correspondingly greater number of cornua.  Amphibians  and non-avian  reptiles  may have many cornua, while mammals (including humans) have two pairs, and  birds  only one. In birds, and some reptiles, the body of the hyoid is greatly extended forward, creating a solid bony support for the  tongue . [ 19 ]   The howler monkey  Alouatta  has a  pneumatized  hyoid bone, one of the few cases of postcranial pneumatization of bones outside  Saurischia .


In  woodpeckers , the hyoid bone is elongated, with the horns wrapping around the back of the skull. This is part of the system that keeps the brain cushioned and undamaged by the pecking action.


In  mammals , the hyoid often determines whether one can  roar . If the hyoid is incompletely  ossified  (for example:  lions ), it allows the animal to roar, but not purr. If the hyoid is completely ossified (for example:  cheetahs ), it does not allow the animal to roar, but instead will allow the animal to purr and meow, as seen in  house cats  (lions, cheetahs and house cats all belong to the family  Felidae ). [ 20 ]


In veterinary anatomy, the term  hyoid apparatus  is the collective term used to refer to the  bones  of the  tongue —a pair of  stylohyoidea , a pair of  thyrohyoidea , and unpaired  basihyoideum [ 21 ] —and associated, upper- gular  connective tissues. [ 22 ]  In humans, the single hyoid bone is an equivalent of the hyoid apparatus. [ 23 ]


This article incorporates text in the  public domain  from  page 177  of the 20th edition of   Gray's Anatomy   (1918)


The  hypoglossal nerve , also known as the  twelfth cranial nerve ,  cranial nerve XII , or simply  CN XII , is a  cranial nerve  that innervates all the  extrinsic and intrinsic muscles  of the  tongue  except for the  palatoglossus , which is innervated by the  vagus nerve . [ a ]


CN XII is a  nerve with a sole motor function . The nerve arises from the  hypoglossal nucleus  in the  medulla [ 1 ] [ 2 ]  as a number of small rootlets, pass through the  hypoglossal canal  and down through the neck, and eventually passes up again over the tongue muscles it supplies into the tongue.


The nerve is involved in controlling tongue movements required for speech and  swallowing , including sticking out the tongue and moving it from side to side. Damage to the nerve or the neural pathways which control it can affect the ability of the tongue to move and its appearance, with the most common sources of damage being injury from trauma or surgery, and  motor neuron disease . The first recorded description of the nerve was by  Herophilos  in the third century BC. The name hypoglossus springs from the fact that its passage is below the  tongue , from  hypo  ( Greek :  "under" ) and  glossa  ( Greek :  "tongue" ).


The hypoglossal nerve arises as a number of small rootlets from the front of the  medulla , the bottom part of the  brainstem , [ 1 ] [ 2 ]  in the  anterolateral sulcus  which separates the  olive  and the  pyramid . [ 3 ]  The nerve passes through the  subarachnoid space  and pierces the  dura mater  near the  hypoglossal canal , an opening in the  occipital bone  of the skull. [ 2 ] [ 4 ]


After emerging from the hypoglossal canal, the hypoglossal nerve gives off a meningeal branch and picks up a branch from the  anterior   ramus  of  C1 .  It then travels close to the  vagus nerve   and spinal division of the  accessory nerve , [ 2 ]  spirals downwards behind the vagus nerve and passes between the  internal carotid artery  and  internal jugular vein  lying on the  carotid sheath . [ 4 ]


At a point at the level of the  angle of the mandible , the hypoglossal nerve emerges from behind the   posterior  belly of the  digastric muscle . [ 4 ]  It then loops around a branch of the  occipital artery  and travels forward into the region beneath the mandible. [ 4 ]  The hypoglossal nerve moves forward lateral to the  hyoglossus  and medial to the  stylohyoid muscles  and  lingual nerve . [ 5 ]  It continues deep to the  genioglossus muscle  and continues forward to the tip of the tongue. It distributes branches to the intrinsic and extrinsic muscle of the tongue innervates as it passes in this direction, and supplies several muscles (hyoglossus, genioglossus and styloglossus) that it passes. [ 5 ]


The rootlets of the hypoglossal nerve arise from the  hypoglossal nucleus  near the bottom of the  brain stem . [ 1 ]  The hypoglossal nucleus receives input from both the  motor cortices  but the contralateral input is dominant; innervation of the tongue is essentially lateralized. [ 6 ]  Signals from muscle spindles on the tongue travel through the hypoglossal nerve, moving onto the  lingual nerve  which synapses on the  trigeminal   mesencephalic nucleus . [ 2 ]


Neurons of the hypoglossal nucleus are derived from the  basal plate  of the embryonic  medulla oblongata . [ 7 ] [ 8 ]  The musculature they supply develops as the  hypoglossal cord  from the  myotomes  of the first four pairs of occipital somites. [ 9 ] [ 10 ]  The nerve is first visible as a series of roots in the fourth week of development, which have formed a single nerve and link to the tongue by the fifth week. [ 11 ] [ 12 ]


The hypoglossal nerve provides motor control of the extrinsic muscles of the tongue:  genioglossus ,  hyoglossus ,  styloglossus , and the intrinsic muscles of the  tongue . [ 2 ]  These represent all muscles of the tongue except the  palatoglossus muscle , which is innervated by the  vagus nerve . [ 2 ]   The hypoglossal nerve is of a  general somatic efferent  (GSE) type. [ 2 ]


These muscles are involved in moving and manipulating the tongue. [ 2 ]  The left and right genioglossus muscles in particular are responsible for protruding the tongue. The muscles, attached to the underside of the top and back parts of the tongue, cause the tongue to protrude and deviate towards the opposite side. [ 13 ]  The hypoglossal nerve also supplies movements including clearing the mouth of saliva and other involuntary activities. The hypoglossal nucleus interacts with the  reticular formation , involved in the control of several reflexive or automatic motions, and several corticonuclear originating fibers supply innervation aiding in unconscious movements relating to speech and articulation. [ 2 ]


Reports of damage to the hypoglossal nerve are rare. [ 14 ]  The most common causes of injury in one case series were compression by tumours and gunshot wounds. [ 15 ]  A wide variety of other causes can lead to damage of the nerve. These include surgical damage, medullary stroke, multiple sclerosis, Guillain-Barre syndrome, infection, sarcoidosis, and presence of an ectatic vessel in the hypoglossal canal. [ 15 ] [ 16 ]  Damage can be on one or both sides, which will affect symptoms that the damage causes. [ 2 ]  Because of the close proximity of the nerve to other structures including nerves, arteries, and veins, it is rare for the nerve to be damaged in isolation. [ 16 ]  For example, damage to the left and right hypoglossal nerves may occur with damage to the facial and trigeminal nerves as a result of damage from a clot following  arteriosclerosis  of the  vertebrobasilar artery . Such a stroke may result in tight oral musculature, and difficulty speaking, eating and chewing. [ 2 ]


Progressive bulbar palsy , a form of  motor neuron disease , is associated with combined lesions of the hypoglossal nucleus and  nucleus ambiguus  with wasting ( atrophy ) of the motor nerves of the  pons  and medulla. This may cause difficulty with tongue movements, speech, chewing and swallowing caused by dysfunction of several cranial nerve nuclei. [ 2 ]  Motor neuron disease is the most common disease affecting the hypoglossal nerve. [ 17 ]


The hypoglossal nerve is tested by examining the tongue and its movements. At rest, if the nerve is injured a tongue may appear to have the appearance of a "bag of worms" ( fasciculations ) or wasting ( atrophy ). The nerve is then tested by sticking the tongue out. If there is damage to the nerve or its pathways, the tongue will usually but not always deviate to one side, due to the  genioglossus  muscle receiving nerve signals on one side but not the other. [ 6 ] [ 19 ]  When the nerve is damaged, the tongue may feel "thick," "heavy," or "clumsy." Weakness of tongue muscles can result in slurred speech, affecting sounds particularly dependent on the tongue for generation (i.e.,  lateral approximants ,  dental stops ,  alveolar stops ,  velar nasals ,  rhotic consonants  etc.). [ 17 ]  Tongue strength may be tested by poking the tongue against the inside of their cheek, while an examiner feels or presses from the cheek. [ 6 ]


The hypoglossal nerve carries lower motor neurons that  synapse  with upper motor neurons at the  hypoglossal nucleus . Symptoms related to damage will depend on the position of damage in this pathway. If the damage is to the nerve itself (a  lower motor neuron lesion ), the tongue will curve toward the damaged side, owing to weakness of the genioglossus muscle of affected side which action is to deviate the tongue in the contralateral side . [ 19 ] [ 20 ]  If the damage is to the nerve pathway (an  upper motor neuron lesion ) the tongue will curve away from the side of damage, due to action of the affected genioglossus muscle, and will occur without fasciculations or wasting, [ 19 ]  with speech difficulties more evident. [ 6 ]  Damage to the hypoglossal nucleus will lead to wasting of muscles of the tongue and deviation towards the affected side when it is stuck out. This is because of the weaker genioglossal muscle. [ 2 ]


The hypoglossal nerve may be connected ( anastomosed ) to the  facial nerve  to attempt to restore function when the facial nerve is damaged. Attempts at repair by either wholly or partially connecting nerve fibres from the hypoglossal nerve to the facial nerve may be used when there is focal facial nerve damage (for example, from trauma or cancer). [ 21 ] [ 22 ]


The hypoglossal nerve has also been clinically implicated in the treatment of  obstructive sleep apnea . [ 23 ] [ 24 ]  Certain patients with  obstructive sleep apnea  who are deemed eligible candidates (e.g., failed  continuous positive airway pressure  therapy, underwent appropriate testing with  drug induced sleep endoscopy , and meet other criteria as outlined by the  FDA ) [ 25 ]  may be offered the  hypoglossal nerve stimulator  as an alternative. The purpose of the  hypoglossal nerve stimulator  is to relieve  tongue  base obstruction during sleep by stimulating the  tongue  to protrude during inspiration (i.e., inhale).


In this procedure, an electrical stimulator lead is placed around branches of the hypoglossal nerve that control tongue protrusion (e.g.,  genioglossus ) via an incision in the neck. [ 26 ]  A sensor lead is then placed in the chest between the ribs in the layer between the  internal intercostal muscles  and  external intercostal muscles . The stimulator and sensory lead are then connected via a tunneled wire to an implantable pulse generator. When turned on during sleep, the sensory lead in the chest detects the respiratory cycle. During inspiration (i.e., inhale), an electrical signal is fired via the stimulator lead in the neck, stimulating the hypoglossal nerve, and causing the tongue to protrude, thereby alleviating obstruction.


The first recorded description of the hypoglossal nerve was by  Herophilos  (335–280 BC), although it was not named at the time. The first use of the name  hypoglossal  in Latin as  nervi hypoglossi externa  was used by  Winslow  in 1733. This was followed though by several different namings including  nervi indeterminati ,  par lingual ,  par gustatorium ,  great sub-lingual  by different authors, and  gustatory nerve  and  lingual nerve  (by Winslow). It was listed in 1778 as  nerve hypoglossum magnum  by Soemmering. It was then named as the  great hypoglossal nerve  by  Cuvier  in 1800 as a translation of Winslow and finally named in English by  Knox  in 1832. [ 27 ]


The hypoglossal nerve is one of twelve cranial nerves found in  amniotes  including  reptiles ,  mammals  and birds. [ 28 ]  As with humans, damage to the nerve or nerve pathway will result in difficulties moving the tongue or  lap ping water, decreased tongue strength, and generally cause deviation away from the affected side initially, and then to the affected side as contractures develop. [ 29 ]  The evolutionary origins of the nerve have been explored through studies of the nerve in rodents and reptiles. [ 30 ]  The nerve is regarded as arising evolutionarily from nerves of the cervical spine, [ 2 ]  which has been incorporated into a separate nerve over the course of evolution. [ 30 ]


The size of the hypoglossal nerve, as measured by the size of the hypoglossal canal, has been hypothesised to be associated with the progress of evolution of  primates , with reasoning that larger nerves would be associated with improvements in speech associated with evolutionary changes. This hypothesis has been refuted. [ 31 ]


The  hypoglossal nerve stimulator  is a novel strategy for the treatment of  obstructive sleep apnea . [ 1 ] [ 2 ]  It has been gaining popularity over the last few decades and was approved in Europe in 2013 and the  Food and Drug Administration  (FDA) in April 2014. [ 3 ]
The purpose of the hypoglossal nerve stimulator is to relieve  tongue  base obstruction during sleep by stimulating the  tongue  to protrude during inspiration (i.e., inhale). [ 1 ]


Certain patients with  obstructive sleep apnea  who are deemed eligible candidates may be offered the hypoglossal nerve stimulator as an alternative.  FDA -approved hypoglossal nerve neurostimulation is considered medically reasonable and necessary for the treatment of moderate to severe  obstructive sleep apnea  when all of the following criteria are met: [ 4 ]


In this procedure, an electrical stimulator lead is placed around branches of the  hypoglossal nerve  that control tongue protrusion (e.g.,  genioglossus ) via an incision in the neck. [ 5 ]  A sensor lead is then placed in the chest between the  ribs  in the layer between the  internal intercostal muscles  and  external intercostal muscles . The stimulator and sensory lead are then connected via a tunneled wire to an implantable pulse generator. When turned on during sleep, the sensory lead in the chest detects the respiratory cycle. During inspiration (i.e., inhale), an electrical signal is fired via the stimulator lead in the neck, stimulating the hypoglossal nerve, and causing the tongue to protrude, thereby alleviating obstruction. [ 6 ]


Once implanted, the hypoglossal nerve stimulator is typically activated in clinic approximately 4 weeks afterwards. [ 7 ]  The implant may be configured to best accommodate the patient's comfort and sleeping habits (e.g., set a delay based on sleep latency).


The hypoglossal nerve stimulator implantable pulse generator battery life typically lasts 8–12 years, after which the implantable pulse generator may be safely replaced with another surgery. [ 8 ]


In the  human mouth , the  incisive foramen  (also known as: " anterior palatine foramen ", or " nasopalatine foramen ") is the opening of the  incisive canals  on the  hard palate  immediately behind the  incisor teeth . It gives passage to blood vessels and nerves. The incisive foramen is situated within the incisive fossa of the  maxilla .


The incisive foramen is used as an  anatomical landmark  for defining the severity of  cleft lip and cleft palate .


The incisive foramen exists in a variety of species.


The incisive foramen is a funnel-shaped opening in the bone of the oral  hard palate  representing the inferior termination of the  incisive canal . [ citation needed ]  An oral prominence - the incisive papilla - overlies the incisive fossa. [ 1 ]


The incisive foramen is situated immediately behind the  incisor teeth , and in between the two  premaxillae . [ citation needed ]


The incisive foramen allows for blood vessels and nerves to pass. These include:


As many nerves exit the  incisive canal  at the incisive foramen, it may be used for injection of  local anaesthetic . [ 3 ]


When  plain radiographs  are taken of the  mouth , the incisive foramen may be mistaken for a periapical lesion. [ 5 ]


The incisive foramen can be used as a landmark when describing  cleft lip and cleft palate , which can either extend in front of (primary) or behind (secondary) the foramen. [ 6 ] [ 7 ]  It is also important as a  surgical  landmark to avoid damaging its nerves and vascular structures. [ 3 ]


The incisive foramen is also known as the anterior palatine foramen, [ 5 ]  the nasopalatine foramen, and the incisive fossa.


In many other species, the incisive foramina allow for passage of ducts to the  vomeronasal organ . [ 2 ]  It can be found in  cats , [ 6 ]  and  alligators . [ 8 ]


This article incorporates text in the  public domain  from  page 162  of the 20th edition of   Gray's Anatomy   (1918)


The  incus  ( pl. :  incudes ) or  anvil  in the  ear  is one of three small  bones  ( ossicles ) in the  middle ear . The incus receives vibrations from the  malleus , to which it is connected laterally, and transmits these to the  stapes  medially. The incus is named for its resemblance to an  anvil  ( Latin :  incus ).


The incus is the second of three  ossicles , very small bones in the  middle ear  which act to transmit sound. It is shaped like an  anvil , and has a long and short crus extending from the body, which articulates with the  malleus . [ 2 ] : 862   The short crus attaches to the  posterior ligament of the incus . The long crus articulates with the  stapes  at the lenticular process.


The  superior ligament of the incus  attaches at the body of the incus to the roof of the  tympanic cavity .


The incus is  homologous  to the  quadrate bone  found in other tetrapods. [ 3 ]


Vibrations in the  middle ear  are received via the  tympanic membrane . The malleus, resting on the membrane, conveys vibrations to the incus. This in turn conveys vibrations to the  stapes . [ 2 ]