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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pain'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary embolism'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal injury'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Somnolence'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Systemic mycosis'. | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | ACYCLOVIR, BLINATUMOMAB, CASPOFUNGIN, CEFTRIAXONE, GENTAMICIN, MEROPENEM, MORPHINE SULFATE, TEICOPLANIN | DrugsGivenReaction | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
What was the administration route of drug 'MORPHINE SULFATE'? | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
What was the dosage of drug 'MORPHINE SULFATE'? | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | UNK (MAX. 15 MCG/KG PER HOUR) | DrugDosageText | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
What was the outcome of reaction 'Systemic mycosis'? | Fulminant Rhizomucor pusillus mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.
This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
1 Introduction
Rhizomucor pusillus is a mucormycete that can induce fatal, opportunistic infections in immunocompromised patients. Despite being the third most common invasive fungal infection after aspergillosis and candidiasis, mucormycosis is still a rare disease. Mucormycetes can be found in soil and decaying organic structures all over the world. Infections by Rhizomucor spp. are rare in humans, but mostly caused by R. pusillus [1]. There are 28 (10 pediatric) published cases of mucormycosis associated with R. pusillus [2,3]. The hyphae are highly angio-invasive and can cause hemorrhage, thrombosis, infarction and necrosis in any organ [1]. The overall mortality rate of mucormycosis is very high, at roughly 47% in all patients and up to 80% in hematopoietic stem cell transplantation (HSCT) recipients. The outcome depends on the underlying disease, the location of infection and the time to diagnosis and treatment [1,4,5].
Mucormycosis can cause fatal, opportunistic infections in immunocompromised hosts such as transplant recipients, patients with hematological or malignant diseases [6]. Immunocompetent persons are hardly infected [1,4,7]. In the special risk group of HSCT recipients pretreatment with antifungal medication not suitable against mucormycosis is related to an even higher risk of infection [5].
A 70% increase in the appearance of mucormycosis between 1940 and 2000 is described, especially among patients with hemato-oncological underlying diseases or after HSCT [1,5]. The incidence in allogeneic HSCT recipients is stated at roughly 0.3% up to 2.5% [5].
The most frequent locations of infection are rhino-orbito-cerebral and pulmonary [2]. The course of the disease is progressive and rapidly invasive, with often no more than a few days between diagnosis and death [1]. Considering the fast progression of the disease, early diagnosis and treatment are vital for best outcomes. Mucormycosis is difficult to diagnose and identifying the fungus is often challenging. Thus, many cases are only identified after an autopsy has been performed.
To date, the best treatment is the combination of surgery and antifungal medication. The gold standard for drug therapy is liposomal amphotericin B [2]. Most azoles are not effective against mucormycosis, except for posaconazole [1,5,8]. In high-risk pediatric patients (with cancer or after HSCT) high-dose liposomal amphotericin B (5–10 mg per kg BW) or liposomal amphotericin B in combination with caspofungin or with posaconazole are suggested according to the guidelines for treatment of invasive fungal disease in pediatric oncology patients [9]. There are promising results with isavuconazole which might play a more prominent role in the future [2].
Generally, data concerning treatment options in mucormycosis substantially relies on retrospective case reports, animal models and in vitro studies. There is a lack of prospective clinical trials, especially in children. This is the first published case report of a child with a second relapse of acute lymphatic leukemia (ALL) developing a fulminant mucormycosis during blinatumomab treatment. Blinatumomab is a monoclonal antibody with dual specificity for CD3+ cells (T cells) and CD19+ cells (B cells). This immunologic binding leads to T-cell mediated apoptosis in B cells. Destroying all B cells and causing neutropenia frequently blinatumomab is associated with a risk of infections such as mucormycosis although it is less immune-suppressing than standard chemotherapy. The unique addition of this case report to the few existing descriptions is the rapid sequence of unfortunate events and circumstances resulting in a fatal situation. Therefore, it is the aim of this case report to increase clinicians’ awareness of this lethal disease and the need for immediate action.
2 Case
A seven-year-old boy was referred to the University Children's Hospital Tuebingen for treatment with a monoclonal bi-specific T-cell engager (blinatumomab) after a second relapse of pre-B-ALL. The first relapse had been treated with allogeneic HSCT from an unrelated HLA-compatible donor. Upon admission (day 0), his blood values were already compromised (hemoglobin 8.5 g/dl, thrombocytes 13.000/μl and WBC (white blood cells) 940/μl with 50/μl neutrophils, CRP (C-reactive protein) 6.83 mg/dl, ferritin 182 μg/dl). The patient was presented in a chronically reduced general condition with cachexia, dry skin, pallor, multiple hematomas and a hepatosplenomegaly. Antibiotic, antiviral, and antifungal chemoprophylaxis was performed with ceftriaxone, teicoplanin, acyclovir and caspofungin. Even prior to the antibody treatment, the patient complained about pain in the left flank which had to be treated with continuous infusion of morphine (max. 15 μg/kg BW per hour). The pain aggravated on day +5 of blinatumomab treatment. The ultrasound scan did not show any pathology apart from the known hepatosplenomegaly. Suddenly on day +6 the boy seemed somnolent and sleepy. First an overdose of morphine was assumed.
However, even after dose reduction the boy reacted with delay and only opened his eyes when addressed. Hence, a cerebral side effect of blinatumomab was presumed. On the same evening, the neurological condition of the patient worsened again. A cerebral CT scan as well as an MRI scan was performed. The imaging showed multiple cerebral hemorrhages (Fig. 1). Due to cardio-respiratory decompensation, the boy was transferred to the intensive care unit, where he received mechanical ventilation and catecholamine therapy. Blinatumomab treatment was stopped. At the time, the blood count had dropped considerably (hemoglobin 6.7 g/dl, thrombocytes 49.000/μl and WBC 120/μl with 20/μl neutrophils) and the CRP had risen to 23.13 mg/dl (ferritin 1439 μg/dl). The echocardiography showed multiple thrombi in the left and right ventricle. Thus, thromboembolic events were presumed as the cause of the cerebral lesions. An endocarditis with multiple septic embolisms was suspected, since the boy had suffered an endocarditis earlier. Consequently, the antibiotic regimen was intensified with meropenem, teicoplanin, and gentamicin. The antimycotic treatment (caspofungin 1 × 50 mg/day) was continued. CT scans of the thorax, abdomen and pelvis were performed 12 h later. They revealed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in both lungs, the heart, both kidneys, the liver, the intestines and in multiple muscles (Fig. 2). A bone marrow aspiration showed bone marrow aplasia with lymphatic blasts. Cerebral pressure was rising. The etiology of the lesions was still unknown at that time. A few hours later, the patient succumbed to cerebral herniation. The patient died in the intensive care unit seven days after starting blinatumomab treatment (day +7) and about 24 hours after the first neurological symptoms appeared. The autopsy showed an invasive mycosis of R. pusillus as the cause of death (Fig. 3, Fig. 4, Fig. 5). The macroscopic and microscopic examination of several organs including the lungs led to the suspicion of a systemic fungal infection. R. pusillus was then identified via PCR-based methods.Fig. 1 Cerebral infiltration of the mucormycosis.
Head MRI (a + b, transversal FLAIR – fluid-attenuated inversion recovery) reflecting the cerebral lesions due to septic embolic infarctions and bleeding.
Fig. 1Fig. 2 Imaging of the disseminated mucormycosis
CT images in portal venous phase (a + b transversal reformations, c + d coronal reformation) illustrate huge right and left ventricular thrombi (*) in the heart and multiple septic embolic infarctions in the myocardium, liver, pancreas, spleen and both kidneys. Furthermore, there are focal areas of consolidation with surrounding ground-glass opacity (halo sign) in both lungs (white arrows) and attendant atelectasis of left lower lobe (white arrowhead) as radiological manifestations of pulmonary mucormycosis.
Fig. 2Fig. 3 Autopsy of the heart.
a) Macroscopy view of the left ventricle with aortic valve and origin of the right coronary artery. Note a parietal thrombus in the endocardium (*), locally infiltrating the myocardium (*). b) Myocardium with a vascular occlusion of coronary artery. c) Grocott stain demonstrates a coronary artery containing many fungal hyphae within the vessel-forming thrombosis. The culture revealed the presence of R. pusillus.
Fig. 3Fig. 4 Autopsy of abdominal organs (kidney).
a) Macroscopic view of the left kidney with multiple infarcts. b) H&E stain of the kidney showing extensive tubular necrosis secondary to hemorrhagic infarct and one occluded artery (*). c) Higher magnification revealing many fungal hyphae within the vessel producing a thrombus. d) Grocott stain highlights the fungal hyphae.
Fig. 4Fig. 5 Autopsy of abdominal organs (stomach, colon).
a) Macroscopic view of the stomach. b) Colon segment showing multiple ulcerations.
Fig. 5
3 Discussion
Mucormycosis is an emerging, severe infection in immunocompromised patients characterized by high mortality. Today's knowledge about the disease is mainly based on retrospective analyses, case reports and literature reviews.
In the first literature review summarizing the published information on mucormycosis in children with underlying hemato-oncological diseases, 82 cases were identified (1958–2007). Around 90% of the presented children suffered from leukemia, as did the boy in this case report. Looking at the development of mortality rates, an encouraging decrease from 100% (1950–1959) to 25.8% (2000–2007) can be observed. Disseminated disease was associated with a worse outcome and surgical treatment with better prognosis. Rhizomucor was identified in 9.1% of the cases. Neutropenia and steroid treatment were identified as risk factors [10].
Twelve pediatric cases from Germany and Austria were reported to the Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) between 2004 and 2008. Eight children suffered from an underlying hematological disease or had received HSCT. Half of them had been treated with steroids, six of eleven patients had been neutropenic and one-third of the affected children had received antifungal medication with caspofungin or voriconazole prior to the infection. The overall mortality rate was stated at 67%. All children with disseminated disease died [11].
In a report from two registries on mucormycosis in children (2005–2014, 15 countries, 63 cases) the results seem to be similar. 46% suffered from hematological malignancies (55% ALL) and 15.9% were HSCT recipients. Almost half of the children suffered from neutropenia and the lungs were the most common location of infection (19%), whereas dissemination was recorded in 38.1% of the cases. The overall mortality in these children was 33.3%. Patients with HSCT, dissemination and an age of less than one year, were associated with higher risk of death [12].
Looking more closely only at the mucormycosis caused by R. pusillus, an analysis of 22 cases shows that the rate of immunocompromised patients is even higher in this subgroup (91%) [13]. Disseminated infection was reported in 40.9% of these cases, with a mortality of 78% (overall mortality rate in R. pusillus infections: 46%) [13]. Interestingly, in 68% of the R. pusillus cases, a nosocomial or health care-related infection (e.g. associated with IV catheters, injection sites, construction work) could not be excluded and had been described previously [8,13,14].
Table 1 provides an overview of pediatric case reports of mucormycosis caused by R. pusillus and underlying hemato-oncological disorder (Table 1).Table 1 Published pediatric case reports of mucormycosis caused by R. pusillus with underlying hematological disease.
Table 1patient underlying disease location treatment outcome reference
girl,
14 years ALL, after HSCT, neutropenia disseminated intracardial thrombus, infectious emboli of multiple organs fluconazole, caspofungin, voriconazole, amphotericin B died [15]
girl,
12 years hemophagocytic lymphohistiocytosis disseminated antibiotics died [3]
girl,
10 years severe aplastic anemia disseminated, thromboembolisms of several organs prophylactic fluconazole died [7]
boy,
19 years acute myeloid leukemia relapse liver local surgery, amphotericin B, posaconazole, deferasirox survived [16]
boy,
16 years acute myeloid leukemia disseminated antifungal therapy died [6]
boy,
15 years ALL soft tissues, rhino-cerebral amphotericin B, posaconazole survived [8]
boy,
11 years ALL nasal, sinus tissues amphotericin B survived [14]
boy,
3 years ALL, second relapse (after HSCT) perineum, cerebral amphotericin B, voriconazole died [17]
boy,
18 years acute leukemia lung, kidney amphotericin B died [18]
boy,
21 months ALL soft tissues amphotericin B, debridement, rifampicin survived [19]
Comparing this data to the case presented here, it can be concluded that the patient was part of the typical high-risk group for a deadly mucormycosis (ALL, neutropenia, disseminated disease). Consistent with the literature, the diagnosis in the presented case was not identified until an autopsy was performed. Universal fungal PCR of the tracheal secretion could not detect any fungal infection, even on the day the patient died. This emphasizes the diagnostic challenges associated with mucormycosis. In the post-mortem, molecular pathological analyses revealed a disseminated infection with proof of R. pusillus in the lungs and other organs.
As the lungs are the most common location in patients with malignancies, one might speculate that the lungs were the original location of the infection. However, the source of infection in the boy remains unclear. A health care-related infection cannot be excluded either.
Due to lack of awareness of the deadly infection, the patient discussed in this case report did not receive standard treatment for mucormycosis (liposomal amphotericin B ± surgery). Instead, the boy was treated with caspofungin as an antifungal prophylaxis for candidiasis and aspergillosis, as the most common invasive fungal infection after HSCT [17]. Caspofungin is not suitable for the treatment of mucormycosis as monotreatment. There are several descriptions of breakthrough filamentous fungal infections (one out of four with R. pusillus) in pediatric oncological patients receiving caspofungin [17]. By using caspofungin or voriconazole as a prophylactic treatment, resistant fungi such as R. pusillus can cause severe infections as in the described case [15]. Since posaconazole seems to be effective in mucormycosis, a general switch from caspofungin, voriconazole or fluconazole to posaconazole as the standard prophylactic antimycotic treatment should be considered. However, there are also reports about breakthrough infections under prophylaxis with posaconazole [5].
In the ECMM report, 39% of the cases were treated with amphotericin B, 7% with posaconazole and 21% with both. In 2011, the mortality rate was stated at 47% (27% in children), which is an improvement compared to 66–76% in 1990 and 94% prior to 1970 [4]. In ECMM's study, one of the factors associated with mortality was treatment with caspofungin prior to diagnosis [4]. Furthermore, delay of amphotericin B treatment (more than 6 days, resulting in a two-fold mortality increase), cytopenia, and active malignancy are also associated with higher mortality. Retrospectively, all of these factors were present in the current case and might have contributed to the fatal outcome.
To the best of our knowledge, this is the first case of a child developing a fulminant mucormycosis during blinatumomab treatment. The combination of targeted therapy (blinatumomab) and reduced immunocompetence after HSCT resulted in an increased vulnerability to opportunistic infections. Furthermore, this case draws attention to one key factor that mucormycosis is a life-threatening and progressive infection. Since 2017, the blinatumomab treatment has been part of the standard treatment of ALL in the AIEOP-BFM-2017 protocol.
Knowledge about associated invasive fungal infections is limited. In three trials invasive fungal diseases were stated in 8 of 501 patients (fusarium n=2, aspergillus n=1, candida n=1, mucor n=1, pneumocystis n=1, unspecified n=2) [20]. To the best of our knowledge there is no data concerning invasive fungal infections in pediatric patients during blinatumomab treatment.
Unfortunately, there is a lack of prospective studies regarding antifungal prophylaxis in new targeted therapies such as blinatumomab. It is important that clinicians take into consideration opportunistic and difficult-to-treat infections such as mucormycosis to increase the chances of patients’ survival. Consequently, prophylactic treatment with an antimycotic medication covering mucormycetes (liposomal amphotericin B) should be considered in high-risk patients.
Declaration of competing interest
No conflicts of interest are declared. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.
Acknowledgements
None. | Fatal | ReactionOutcome | CC BY-NC-ND | 33489743 | 19,721,335 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Disseminated Mycobacterium abscessus infection and native valve endocarditis.
Mycobacterium abscessus is a rapidly growing mycobacterium. It rarely causes disseminated infection or endocarditis. A 55-year-old male with a history of hepatitis C, liver cirrhosis, intravenous drug use (last use was four years ago), and chronic back pain presented with a three-week history of a right calf nodular lesion. He did not have a fever, chills, rash, dyspnea, or cough. Laboratory data showed mild leukocytosis. Computed tomography of the chest revealed bilateral cavitating nodules. Skin biopsy, sputum, and blood cultures grew Mycobacterium abscessus. Therapy with meropenem, tigecycline, and amikacin was initiated. He was re-admitted with worsening lower back pain. A lumbar magnetic resonance imaging showed destructive changes of L4 and L5 vertebral bodies concerning for osteomyelitis. Blood culture and bone biopsy grew Mycobacterium abscessus again. An echocardiogram was performed due to persistent bacteremia, which revealed large vegetation on the tricuspid valve and small vegetation on the mitral valve. Therapy was changed to eight weeks of amikacin, with cefoxitin and imipenem for twelve months based on drug susceptibility. Treatment of disseminated Mycobacterium abscessus is challenging due to antibiotic resistance. Typically, multidrug therapy is warranted with at least three active drugs. In severe valvular endocarditis, valve replacement may be required.
1 Introduction
Mycobacterium abscessus complex are rapidly growing mycobacteria, which are ubiquitous to the environment. They have a very low incidence of infection and are mostly described in the immunocompromised population with reduced CD4 count and complement levels [1]. Immunocompetent individuals with indwelling vascular catheters or disruption of normal anatomic barriers are at risk for developing disseminated infection [2].
2 Case presentation
A 55-year-old male with a history of hepatitis C, liver cirrhosis, intravenous drug use (last use was four years ago), and chronic back pain presented with a three-week history of a right calf nodular lesion. He denied fevers, chills, rash, dyspnea, or cough. He was unsuccessfully treated with a course of doxycycline as an outpatient. Of note, one month prior, he was on a prednisone taper for three weeks for back pain exacerbation. On presentation, he was afebrile with a blood pressure of 163/89 mmHg, heart rate of 92/minute, respiratory rate of 20 breaths/minute, and saturating 98% on ambient air. There was a right calf nodular lesion with peripheral induration, central ulceration with a black base, and mild serous discharge.
Laboratory data showed mild leukocytosis. Computed tomography of the chest revealed bilateral cavitating nodules, the largest in the superior segment of the left lower lobe (Fig. 1A). Skin biopsy, blood, and sputum cultures were obtained. Given skin and cavitary lung lesions, there was concern about methicillin-resistant Staphylococcus aureus (MRSA) infection, and empiric vancomycin was initiated. Skin biopsy, blood, and sputum cultures grew acid-fast bacilli, but Mycobacterium tuberculosis polymerase chain reaction assay was negative. The final result showed Mycobacterium abscessus. The human immunodeficiency virus antibody screen was negative. Therapy with meropenem, tigecycline, and amikacin was initiated after infectious diseases consultation, and he was discharged to a rehabilitation facility. After three months, he was re-admitted for evaluation of worsening lower back pain. A lumbar magnetic resonance imaging revealed destructive changes of L4 and L5 vertebral bodies concerning for osteomyelitis. Bone biopsy and blood cultures grew Mycobacterium abscessus again. Due to persistent bacteremia, an echocardiogram was performed, which revealed large mobile vegetation on the tricuspid valve and small vegetation on the mitral valve consistent with endocarditis (Fig. 1B). Based on drug susceptibility, he was discharged on amikacin for eight weeks, with cefoxitin and imipenem for twelve months. During follow-up after a month, he had been clinically doing well with a near-complete resolution of skin rash.Fig. 1 (A) Is computed tomography of the chest in an axial view showing a cavitary lesion in the superior segment of the left lower lobe and (B) is an echocardiogram showing large tricuspid valve vegetation (arrow) and small mitral valve vegetation (arrowhead) in an apical 4-chamber view (RV, right ventricle; TV, tricuspid valve; RA, right atrium; LV, left ventricle; MV, mitral valve; LA, left atrium and interventricular septum denoted by a curved arrow).
Fig. 1
3 Discussion
Mycobacterium abscessus complex includes M. chelonae, and M. abscessus. M. abscessus is the most prevalent microorganism in the rapidly-growing mycobacteria group causing pulmonary infections [3]. Disseminated M. abscessus is rare, and mycobacterial endocarditis is rarer. Prosthetic valves are commonly infected, and among native valves, aortic and mitral valves are the most frequently affected [4]. Risk factors include indwelling vascular catheters, cardiac catheterization, intravenous drug users, immunocompromised due to human immunodeficiency virus, hematological malignancies, or immunosuppressive agent use due to organ transplants. Recent corticosteroid use may have been the risk factor for our patient. Patients can present with non-specific symptoms or be asymptomatic. The most common presenting symptom is usually fever presenting as pyrexia of unknown origin, followed by chest pain or dyspnea. Blood cultures are highly sensitive, especially in cases of native valve endocarditis. Acid-fast bacilli stain of sputum, and histological sections (if available like skin biopsy, prosthetic valve) should be performed [4]. Echocardiography should be performed in patients with persistently positive blood cultures or radiological findings of pulmonary septic emboli. In a literature review of mycobacterial endocarditis, 15 out of 46 patients had a cardiac murmur at presentation, and echocardiography was used to confirm the presence of vegetations [4,5]. Treatment of Mycobacterium abscessus is challenging due to antibiotic resistance, including macrolides, aminoglycosides, rifamycins, tetracyclines, and β-lactams [3]. Evidence-based management of disseminated M. abscessus infection and endocarditis lacks due to the rarity of the condition. Usually, empiric treatment is started based on the in vitro susceptibility data, and later targeted therapy is employed when drug susceptibilities are available [6]. Drugs with in vitro activity include clarithromycin, amikacin, tigecycline, imipenem, and cefoxitin [5]. Treatment of pulmonary disease involves a multidrug regimen with at least three active drugs. Treatment duration ranges from 4 to 12 months depending on the severity of illness, and in refractory cases, surgical debridement may be required. Therefore, expert consultation is recommended [7]. Treatment of infective endocarditis requires a multidrug regimen for 6–12 months and is usually refractory, requiring early surgical intervention, especially in severe valvular endocarditis [4,8].
Declaration of competing interest
The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. | PREDNISOLONE | DrugsGivenReaction | CC BY-NC-ND | 33489744 | 19,456,432 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Osteomyelitis'. | Disseminated Mycobacterium abscessus infection and native valve endocarditis.
Mycobacterium abscessus is a rapidly growing mycobacterium. It rarely causes disseminated infection or endocarditis. A 55-year-old male with a history of hepatitis C, liver cirrhosis, intravenous drug use (last use was four years ago), and chronic back pain presented with a three-week history of a right calf nodular lesion. He did not have a fever, chills, rash, dyspnea, or cough. Laboratory data showed mild leukocytosis. Computed tomography of the chest revealed bilateral cavitating nodules. Skin biopsy, sputum, and blood cultures grew Mycobacterium abscessus. Therapy with meropenem, tigecycline, and amikacin was initiated. He was re-admitted with worsening lower back pain. A lumbar magnetic resonance imaging showed destructive changes of L4 and L5 vertebral bodies concerning for osteomyelitis. Blood culture and bone biopsy grew Mycobacterium abscessus again. An echocardiogram was performed due to persistent bacteremia, which revealed large vegetation on the tricuspid valve and small vegetation on the mitral valve. Therapy was changed to eight weeks of amikacin, with cefoxitin and imipenem for twelve months based on drug susceptibility. Treatment of disseminated Mycobacterium abscessus is challenging due to antibiotic resistance. Typically, multidrug therapy is warranted with at least three active drugs. In severe valvular endocarditis, valve replacement may be required.
1 Introduction
Mycobacterium abscessus complex are rapidly growing mycobacteria, which are ubiquitous to the environment. They have a very low incidence of infection and are mostly described in the immunocompromised population with reduced CD4 count and complement levels [1]. Immunocompetent individuals with indwelling vascular catheters or disruption of normal anatomic barriers are at risk for developing disseminated infection [2].
2 Case presentation
A 55-year-old male with a history of hepatitis C, liver cirrhosis, intravenous drug use (last use was four years ago), and chronic back pain presented with a three-week history of a right calf nodular lesion. He denied fevers, chills, rash, dyspnea, or cough. He was unsuccessfully treated with a course of doxycycline as an outpatient. Of note, one month prior, he was on a prednisone taper for three weeks for back pain exacerbation. On presentation, he was afebrile with a blood pressure of 163/89 mmHg, heart rate of 92/minute, respiratory rate of 20 breaths/minute, and saturating 98% on ambient air. There was a right calf nodular lesion with peripheral induration, central ulceration with a black base, and mild serous discharge.
Laboratory data showed mild leukocytosis. Computed tomography of the chest revealed bilateral cavitating nodules, the largest in the superior segment of the left lower lobe (Fig. 1A). Skin biopsy, blood, and sputum cultures were obtained. Given skin and cavitary lung lesions, there was concern about methicillin-resistant Staphylococcus aureus (MRSA) infection, and empiric vancomycin was initiated. Skin biopsy, blood, and sputum cultures grew acid-fast bacilli, but Mycobacterium tuberculosis polymerase chain reaction assay was negative. The final result showed Mycobacterium abscessus. The human immunodeficiency virus antibody screen was negative. Therapy with meropenem, tigecycline, and amikacin was initiated after infectious diseases consultation, and he was discharged to a rehabilitation facility. After three months, he was re-admitted for evaluation of worsening lower back pain. A lumbar magnetic resonance imaging revealed destructive changes of L4 and L5 vertebral bodies concerning for osteomyelitis. Bone biopsy and blood cultures grew Mycobacterium abscessus again. Due to persistent bacteremia, an echocardiogram was performed, which revealed large mobile vegetation on the tricuspid valve and small vegetation on the mitral valve consistent with endocarditis (Fig. 1B). Based on drug susceptibility, he was discharged on amikacin for eight weeks, with cefoxitin and imipenem for twelve months. During follow-up after a month, he had been clinically doing well with a near-complete resolution of skin rash.Fig. 1 (A) Is computed tomography of the chest in an axial view showing a cavitary lesion in the superior segment of the left lower lobe and (B) is an echocardiogram showing large tricuspid valve vegetation (arrow) and small mitral valve vegetation (arrowhead) in an apical 4-chamber view (RV, right ventricle; TV, tricuspid valve; RA, right atrium; LV, left ventricle; MV, mitral valve; LA, left atrium and interventricular septum denoted by a curved arrow).
Fig. 1
3 Discussion
Mycobacterium abscessus complex includes M. chelonae, and M. abscessus. M. abscessus is the most prevalent microorganism in the rapidly-growing mycobacteria group causing pulmonary infections [3]. Disseminated M. abscessus is rare, and mycobacterial endocarditis is rarer. Prosthetic valves are commonly infected, and among native valves, aortic and mitral valves are the most frequently affected [4]. Risk factors include indwelling vascular catheters, cardiac catheterization, intravenous drug users, immunocompromised due to human immunodeficiency virus, hematological malignancies, or immunosuppressive agent use due to organ transplants. Recent corticosteroid use may have been the risk factor for our patient. Patients can present with non-specific symptoms or be asymptomatic. The most common presenting symptom is usually fever presenting as pyrexia of unknown origin, followed by chest pain or dyspnea. Blood cultures are highly sensitive, especially in cases of native valve endocarditis. Acid-fast bacilli stain of sputum, and histological sections (if available like skin biopsy, prosthetic valve) should be performed [4]. Echocardiography should be performed in patients with persistently positive blood cultures or radiological findings of pulmonary septic emboli. In a literature review of mycobacterial endocarditis, 15 out of 46 patients had a cardiac murmur at presentation, and echocardiography was used to confirm the presence of vegetations [4,5]. Treatment of Mycobacterium abscessus is challenging due to antibiotic resistance, including macrolides, aminoglycosides, rifamycins, tetracyclines, and β-lactams [3]. Evidence-based management of disseminated M. abscessus infection and endocarditis lacks due to the rarity of the condition. Usually, empiric treatment is started based on the in vitro susceptibility data, and later targeted therapy is employed when drug susceptibilities are available [6]. Drugs with in vitro activity include clarithromycin, amikacin, tigecycline, imipenem, and cefoxitin [5]. Treatment of pulmonary disease involves a multidrug regimen with at least three active drugs. Treatment duration ranges from 4 to 12 months depending on the severity of illness, and in refractory cases, surgical debridement may be required. Therefore, expert consultation is recommended [7]. Treatment of infective endocarditis requires a multidrug regimen for 6–12 months and is usually refractory, requiring early surgical intervention, especially in severe valvular endocarditis [4,8].
Declaration of competing interest
The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. | PREDNISOLONE | DrugsGivenReaction | CC BY-NC-ND | 33489744 | 19,456,432 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Disseminated Mycobacterium abscessus infection and native valve endocarditis.
Mycobacterium abscessus is a rapidly growing mycobacterium. It rarely causes disseminated infection or endocarditis. A 55-year-old male with a history of hepatitis C, liver cirrhosis, intravenous drug use (last use was four years ago), and chronic back pain presented with a three-week history of a right calf nodular lesion. He did not have a fever, chills, rash, dyspnea, or cough. Laboratory data showed mild leukocytosis. Computed tomography of the chest revealed bilateral cavitating nodules. Skin biopsy, sputum, and blood cultures grew Mycobacterium abscessus. Therapy with meropenem, tigecycline, and amikacin was initiated. He was re-admitted with worsening lower back pain. A lumbar magnetic resonance imaging showed destructive changes of L4 and L5 vertebral bodies concerning for osteomyelitis. Blood culture and bone biopsy grew Mycobacterium abscessus again. An echocardiogram was performed due to persistent bacteremia, which revealed large vegetation on the tricuspid valve and small vegetation on the mitral valve. Therapy was changed to eight weeks of amikacin, with cefoxitin and imipenem for twelve months based on drug susceptibility. Treatment of disseminated Mycobacterium abscessus is challenging due to antibiotic resistance. Typically, multidrug therapy is warranted with at least three active drugs. In severe valvular endocarditis, valve replacement may be required.
1 Introduction
Mycobacterium abscessus complex are rapidly growing mycobacteria, which are ubiquitous to the environment. They have a very low incidence of infection and are mostly described in the immunocompromised population with reduced CD4 count and complement levels [1]. Immunocompetent individuals with indwelling vascular catheters or disruption of normal anatomic barriers are at risk for developing disseminated infection [2].
2 Case presentation
A 55-year-old male with a history of hepatitis C, liver cirrhosis, intravenous drug use (last use was four years ago), and chronic back pain presented with a three-week history of a right calf nodular lesion. He denied fevers, chills, rash, dyspnea, or cough. He was unsuccessfully treated with a course of doxycycline as an outpatient. Of note, one month prior, he was on a prednisone taper for three weeks for back pain exacerbation. On presentation, he was afebrile with a blood pressure of 163/89 mmHg, heart rate of 92/minute, respiratory rate of 20 breaths/minute, and saturating 98% on ambient air. There was a right calf nodular lesion with peripheral induration, central ulceration with a black base, and mild serous discharge.
Laboratory data showed mild leukocytosis. Computed tomography of the chest revealed bilateral cavitating nodules, the largest in the superior segment of the left lower lobe (Fig. 1A). Skin biopsy, blood, and sputum cultures were obtained. Given skin and cavitary lung lesions, there was concern about methicillin-resistant Staphylococcus aureus (MRSA) infection, and empiric vancomycin was initiated. Skin biopsy, blood, and sputum cultures grew acid-fast bacilli, but Mycobacterium tuberculosis polymerase chain reaction assay was negative. The final result showed Mycobacterium abscessus. The human immunodeficiency virus antibody screen was negative. Therapy with meropenem, tigecycline, and amikacin was initiated after infectious diseases consultation, and he was discharged to a rehabilitation facility. After three months, he was re-admitted for evaluation of worsening lower back pain. A lumbar magnetic resonance imaging revealed destructive changes of L4 and L5 vertebral bodies concerning for osteomyelitis. Bone biopsy and blood cultures grew Mycobacterium abscessus again. Due to persistent bacteremia, an echocardiogram was performed, which revealed large mobile vegetation on the tricuspid valve and small vegetation on the mitral valve consistent with endocarditis (Fig. 1B). Based on drug susceptibility, he was discharged on amikacin for eight weeks, with cefoxitin and imipenem for twelve months. During follow-up after a month, he had been clinically doing well with a near-complete resolution of skin rash.Fig. 1 (A) Is computed tomography of the chest in an axial view showing a cavitary lesion in the superior segment of the left lower lobe and (B) is an echocardiogram showing large tricuspid valve vegetation (arrow) and small mitral valve vegetation (arrowhead) in an apical 4-chamber view (RV, right ventricle; TV, tricuspid valve; RA, right atrium; LV, left ventricle; MV, mitral valve; LA, left atrium and interventricular septum denoted by a curved arrow).
Fig. 1
3 Discussion
Mycobacterium abscessus complex includes M. chelonae, and M. abscessus. M. abscessus is the most prevalent microorganism in the rapidly-growing mycobacteria group causing pulmonary infections [3]. Disseminated M. abscessus is rare, and mycobacterial endocarditis is rarer. Prosthetic valves are commonly infected, and among native valves, aortic and mitral valves are the most frequently affected [4]. Risk factors include indwelling vascular catheters, cardiac catheterization, intravenous drug users, immunocompromised due to human immunodeficiency virus, hematological malignancies, or immunosuppressive agent use due to organ transplants. Recent corticosteroid use may have been the risk factor for our patient. Patients can present with non-specific symptoms or be asymptomatic. The most common presenting symptom is usually fever presenting as pyrexia of unknown origin, followed by chest pain or dyspnea. Blood cultures are highly sensitive, especially in cases of native valve endocarditis. Acid-fast bacilli stain of sputum, and histological sections (if available like skin biopsy, prosthetic valve) should be performed [4]. Echocardiography should be performed in patients with persistently positive blood cultures or radiological findings of pulmonary septic emboli. In a literature review of mycobacterial endocarditis, 15 out of 46 patients had a cardiac murmur at presentation, and echocardiography was used to confirm the presence of vegetations [4,5]. Treatment of Mycobacterium abscessus is challenging due to antibiotic resistance, including macrolides, aminoglycosides, rifamycins, tetracyclines, and β-lactams [3]. Evidence-based management of disseminated M. abscessus infection and endocarditis lacks due to the rarity of the condition. Usually, empiric treatment is started based on the in vitro susceptibility data, and later targeted therapy is employed when drug susceptibilities are available [6]. Drugs with in vitro activity include clarithromycin, amikacin, tigecycline, imipenem, and cefoxitin [5]. Treatment of pulmonary disease involves a multidrug regimen with at least three active drugs. Treatment duration ranges from 4 to 12 months depending on the severity of illness, and in refractory cases, surgical debridement may be required. Therefore, expert consultation is recommended [7]. Treatment of infective endocarditis requires a multidrug regimen for 6–12 months and is usually refractory, requiring early surgical intervention, especially in severe valvular endocarditis [4,8].
Declaration of competing interest
The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. | AMIKACIN, CEFOXITIN SODIUM, CILASTATIN SODIUM\IMIPENEM | DrugsGivenReaction | CC BY-NC-ND | 33489744 | 18,872,799 | 2021 |
What was the dosage of drug 'PREDNISOLONE'? | Disseminated Mycobacterium abscessus infection and native valve endocarditis.
Mycobacterium abscessus is a rapidly growing mycobacterium. It rarely causes disseminated infection or endocarditis. A 55-year-old male with a history of hepatitis C, liver cirrhosis, intravenous drug use (last use was four years ago), and chronic back pain presented with a three-week history of a right calf nodular lesion. He did not have a fever, chills, rash, dyspnea, or cough. Laboratory data showed mild leukocytosis. Computed tomography of the chest revealed bilateral cavitating nodules. Skin biopsy, sputum, and blood cultures grew Mycobacterium abscessus. Therapy with meropenem, tigecycline, and amikacin was initiated. He was re-admitted with worsening lower back pain. A lumbar magnetic resonance imaging showed destructive changes of L4 and L5 vertebral bodies concerning for osteomyelitis. Blood culture and bone biopsy grew Mycobacterium abscessus again. An echocardiogram was performed due to persistent bacteremia, which revealed large vegetation on the tricuspid valve and small vegetation on the mitral valve. Therapy was changed to eight weeks of amikacin, with cefoxitin and imipenem for twelve months based on drug susceptibility. Treatment of disseminated Mycobacterium abscessus is challenging due to antibiotic resistance. Typically, multidrug therapy is warranted with at least three active drugs. In severe valvular endocarditis, valve replacement may be required.
1 Introduction
Mycobacterium abscessus complex are rapidly growing mycobacteria, which are ubiquitous to the environment. They have a very low incidence of infection and are mostly described in the immunocompromised population with reduced CD4 count and complement levels [1]. Immunocompetent individuals with indwelling vascular catheters or disruption of normal anatomic barriers are at risk for developing disseminated infection [2].
2 Case presentation
A 55-year-old male with a history of hepatitis C, liver cirrhosis, intravenous drug use (last use was four years ago), and chronic back pain presented with a three-week history of a right calf nodular lesion. He denied fevers, chills, rash, dyspnea, or cough. He was unsuccessfully treated with a course of doxycycline as an outpatient. Of note, one month prior, he was on a prednisone taper for three weeks for back pain exacerbation. On presentation, he was afebrile with a blood pressure of 163/89 mmHg, heart rate of 92/minute, respiratory rate of 20 breaths/minute, and saturating 98% on ambient air. There was a right calf nodular lesion with peripheral induration, central ulceration with a black base, and mild serous discharge.
Laboratory data showed mild leukocytosis. Computed tomography of the chest revealed bilateral cavitating nodules, the largest in the superior segment of the left lower lobe (Fig. 1A). Skin biopsy, blood, and sputum cultures were obtained. Given skin and cavitary lung lesions, there was concern about methicillin-resistant Staphylococcus aureus (MRSA) infection, and empiric vancomycin was initiated. Skin biopsy, blood, and sputum cultures grew acid-fast bacilli, but Mycobacterium tuberculosis polymerase chain reaction assay was negative. The final result showed Mycobacterium abscessus. The human immunodeficiency virus antibody screen was negative. Therapy with meropenem, tigecycline, and amikacin was initiated after infectious diseases consultation, and he was discharged to a rehabilitation facility. After three months, he was re-admitted for evaluation of worsening lower back pain. A lumbar magnetic resonance imaging revealed destructive changes of L4 and L5 vertebral bodies concerning for osteomyelitis. Bone biopsy and blood cultures grew Mycobacterium abscessus again. Due to persistent bacteremia, an echocardiogram was performed, which revealed large mobile vegetation on the tricuspid valve and small vegetation on the mitral valve consistent with endocarditis (Fig. 1B). Based on drug susceptibility, he was discharged on amikacin for eight weeks, with cefoxitin and imipenem for twelve months. During follow-up after a month, he had been clinically doing well with a near-complete resolution of skin rash.Fig. 1 (A) Is computed tomography of the chest in an axial view showing a cavitary lesion in the superior segment of the left lower lobe and (B) is an echocardiogram showing large tricuspid valve vegetation (arrow) and small mitral valve vegetation (arrowhead) in an apical 4-chamber view (RV, right ventricle; TV, tricuspid valve; RA, right atrium; LV, left ventricle; MV, mitral valve; LA, left atrium and interventricular septum denoted by a curved arrow).
Fig. 1
3 Discussion
Mycobacterium abscessus complex includes M. chelonae, and M. abscessus. M. abscessus is the most prevalent microorganism in the rapidly-growing mycobacteria group causing pulmonary infections [3]. Disseminated M. abscessus is rare, and mycobacterial endocarditis is rarer. Prosthetic valves are commonly infected, and among native valves, aortic and mitral valves are the most frequently affected [4]. Risk factors include indwelling vascular catheters, cardiac catheterization, intravenous drug users, immunocompromised due to human immunodeficiency virus, hematological malignancies, or immunosuppressive agent use due to organ transplants. Recent corticosteroid use may have been the risk factor for our patient. Patients can present with non-specific symptoms or be asymptomatic. The most common presenting symptom is usually fever presenting as pyrexia of unknown origin, followed by chest pain or dyspnea. Blood cultures are highly sensitive, especially in cases of native valve endocarditis. Acid-fast bacilli stain of sputum, and histological sections (if available like skin biopsy, prosthetic valve) should be performed [4]. Echocardiography should be performed in patients with persistently positive blood cultures or radiological findings of pulmonary septic emboli. In a literature review of mycobacterial endocarditis, 15 out of 46 patients had a cardiac murmur at presentation, and echocardiography was used to confirm the presence of vegetations [4,5]. Treatment of Mycobacterium abscessus is challenging due to antibiotic resistance, including macrolides, aminoglycosides, rifamycins, tetracyclines, and β-lactams [3]. Evidence-based management of disseminated M. abscessus infection and endocarditis lacks due to the rarity of the condition. Usually, empiric treatment is started based on the in vitro susceptibility data, and later targeted therapy is employed when drug susceptibilities are available [6]. Drugs with in vitro activity include clarithromycin, amikacin, tigecycline, imipenem, and cefoxitin [5]. Treatment of pulmonary disease involves a multidrug regimen with at least three active drugs. Treatment duration ranges from 4 to 12 months depending on the severity of illness, and in refractory cases, surgical debridement may be required. Therefore, expert consultation is recommended [7]. Treatment of infective endocarditis requires a multidrug regimen for 6–12 months and is usually refractory, requiring early surgical intervention, especially in severe valvular endocarditis [4,8].
Declaration of competing interest
The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. | UNK, TAPER FOR 3 WEEKS | DrugDosageText | CC BY-NC-ND | 33489744 | 19,456,432 | 2021 |
What was the dosage of drug 'PREDNISONE'? | Disseminated Mycobacterium abscessus infection and native valve endocarditis.
Mycobacterium abscessus is a rapidly growing mycobacterium. It rarely causes disseminated infection or endocarditis. A 55-year-old male with a history of hepatitis C, liver cirrhosis, intravenous drug use (last use was four years ago), and chronic back pain presented with a three-week history of a right calf nodular lesion. He did not have a fever, chills, rash, dyspnea, or cough. Laboratory data showed mild leukocytosis. Computed tomography of the chest revealed bilateral cavitating nodules. Skin biopsy, sputum, and blood cultures grew Mycobacterium abscessus. Therapy with meropenem, tigecycline, and amikacin was initiated. He was re-admitted with worsening lower back pain. A lumbar magnetic resonance imaging showed destructive changes of L4 and L5 vertebral bodies concerning for osteomyelitis. Blood culture and bone biopsy grew Mycobacterium abscessus again. An echocardiogram was performed due to persistent bacteremia, which revealed large vegetation on the tricuspid valve and small vegetation on the mitral valve. Therapy was changed to eight weeks of amikacin, with cefoxitin and imipenem for twelve months based on drug susceptibility. Treatment of disseminated Mycobacterium abscessus is challenging due to antibiotic resistance. Typically, multidrug therapy is warranted with at least three active drugs. In severe valvular endocarditis, valve replacement may be required.
1 Introduction
Mycobacterium abscessus complex are rapidly growing mycobacteria, which are ubiquitous to the environment. They have a very low incidence of infection and are mostly described in the immunocompromised population with reduced CD4 count and complement levels [1]. Immunocompetent individuals with indwelling vascular catheters or disruption of normal anatomic barriers are at risk for developing disseminated infection [2].
2 Case presentation
A 55-year-old male with a history of hepatitis C, liver cirrhosis, intravenous drug use (last use was four years ago), and chronic back pain presented with a three-week history of a right calf nodular lesion. He denied fevers, chills, rash, dyspnea, or cough. He was unsuccessfully treated with a course of doxycycline as an outpatient. Of note, one month prior, he was on a prednisone taper for three weeks for back pain exacerbation. On presentation, he was afebrile with a blood pressure of 163/89 mmHg, heart rate of 92/minute, respiratory rate of 20 breaths/minute, and saturating 98% on ambient air. There was a right calf nodular lesion with peripheral induration, central ulceration with a black base, and mild serous discharge.
Laboratory data showed mild leukocytosis. Computed tomography of the chest revealed bilateral cavitating nodules, the largest in the superior segment of the left lower lobe (Fig. 1A). Skin biopsy, blood, and sputum cultures were obtained. Given skin and cavitary lung lesions, there was concern about methicillin-resistant Staphylococcus aureus (MRSA) infection, and empiric vancomycin was initiated. Skin biopsy, blood, and sputum cultures grew acid-fast bacilli, but Mycobacterium tuberculosis polymerase chain reaction assay was negative. The final result showed Mycobacterium abscessus. The human immunodeficiency virus antibody screen was negative. Therapy with meropenem, tigecycline, and amikacin was initiated after infectious diseases consultation, and he was discharged to a rehabilitation facility. After three months, he was re-admitted for evaluation of worsening lower back pain. A lumbar magnetic resonance imaging revealed destructive changes of L4 and L5 vertebral bodies concerning for osteomyelitis. Bone biopsy and blood cultures grew Mycobacterium abscessus again. Due to persistent bacteremia, an echocardiogram was performed, which revealed large mobile vegetation on the tricuspid valve and small vegetation on the mitral valve consistent with endocarditis (Fig. 1B). Based on drug susceptibility, he was discharged on amikacin for eight weeks, with cefoxitin and imipenem for twelve months. During follow-up after a month, he had been clinically doing well with a near-complete resolution of skin rash.Fig. 1 (A) Is computed tomography of the chest in an axial view showing a cavitary lesion in the superior segment of the left lower lobe and (B) is an echocardiogram showing large tricuspid valve vegetation (arrow) and small mitral valve vegetation (arrowhead) in an apical 4-chamber view (RV, right ventricle; TV, tricuspid valve; RA, right atrium; LV, left ventricle; MV, mitral valve; LA, left atrium and interventricular septum denoted by a curved arrow).
Fig. 1
3 Discussion
Mycobacterium abscessus complex includes M. chelonae, and M. abscessus. M. abscessus is the most prevalent microorganism in the rapidly-growing mycobacteria group causing pulmonary infections [3]. Disseminated M. abscessus is rare, and mycobacterial endocarditis is rarer. Prosthetic valves are commonly infected, and among native valves, aortic and mitral valves are the most frequently affected [4]. Risk factors include indwelling vascular catheters, cardiac catheterization, intravenous drug users, immunocompromised due to human immunodeficiency virus, hematological malignancies, or immunosuppressive agent use due to organ transplants. Recent corticosteroid use may have been the risk factor for our patient. Patients can present with non-specific symptoms or be asymptomatic. The most common presenting symptom is usually fever presenting as pyrexia of unknown origin, followed by chest pain or dyspnea. Blood cultures are highly sensitive, especially in cases of native valve endocarditis. Acid-fast bacilli stain of sputum, and histological sections (if available like skin biopsy, prosthetic valve) should be performed [4]. Echocardiography should be performed in patients with persistently positive blood cultures or radiological findings of pulmonary septic emboli. In a literature review of mycobacterial endocarditis, 15 out of 46 patients had a cardiac murmur at presentation, and echocardiography was used to confirm the presence of vegetations [4,5]. Treatment of Mycobacterium abscessus is challenging due to antibiotic resistance, including macrolides, aminoglycosides, rifamycins, tetracyclines, and β-lactams [3]. Evidence-based management of disseminated M. abscessus infection and endocarditis lacks due to the rarity of the condition. Usually, empiric treatment is started based on the in vitro susceptibility data, and later targeted therapy is employed when drug susceptibilities are available [6]. Drugs with in vitro activity include clarithromycin, amikacin, tigecycline, imipenem, and cefoxitin [5]. Treatment of pulmonary disease involves a multidrug regimen with at least three active drugs. Treatment duration ranges from 4 to 12 months depending on the severity of illness, and in refractory cases, surgical debridement may be required. Therefore, expert consultation is recommended [7]. Treatment of infective endocarditis requires a multidrug regimen for 6–12 months and is usually refractory, requiring early surgical intervention, especially in severe valvular endocarditis [4,8].
Declaration of competing interest
The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. | TAPER FOR 3 WEEKS | DrugDosageText | CC BY-NC-ND | 33489744 | 19,400,677 | 2021 |
What was the outcome of reaction 'Osteomyelitis'? | Disseminated Mycobacterium abscessus infection and native valve endocarditis.
Mycobacterium abscessus is a rapidly growing mycobacterium. It rarely causes disseminated infection or endocarditis. A 55-year-old male with a history of hepatitis C, liver cirrhosis, intravenous drug use (last use was four years ago), and chronic back pain presented with a three-week history of a right calf nodular lesion. He did not have a fever, chills, rash, dyspnea, or cough. Laboratory data showed mild leukocytosis. Computed tomography of the chest revealed bilateral cavitating nodules. Skin biopsy, sputum, and blood cultures grew Mycobacterium abscessus. Therapy with meropenem, tigecycline, and amikacin was initiated. He was re-admitted with worsening lower back pain. A lumbar magnetic resonance imaging showed destructive changes of L4 and L5 vertebral bodies concerning for osteomyelitis. Blood culture and bone biopsy grew Mycobacterium abscessus again. An echocardiogram was performed due to persistent bacteremia, which revealed large vegetation on the tricuspid valve and small vegetation on the mitral valve. Therapy was changed to eight weeks of amikacin, with cefoxitin and imipenem for twelve months based on drug susceptibility. Treatment of disseminated Mycobacterium abscessus is challenging due to antibiotic resistance. Typically, multidrug therapy is warranted with at least three active drugs. In severe valvular endocarditis, valve replacement may be required.
1 Introduction
Mycobacterium abscessus complex are rapidly growing mycobacteria, which are ubiquitous to the environment. They have a very low incidence of infection and are mostly described in the immunocompromised population with reduced CD4 count and complement levels [1]. Immunocompetent individuals with indwelling vascular catheters or disruption of normal anatomic barriers are at risk for developing disseminated infection [2].
2 Case presentation
A 55-year-old male with a history of hepatitis C, liver cirrhosis, intravenous drug use (last use was four years ago), and chronic back pain presented with a three-week history of a right calf nodular lesion. He denied fevers, chills, rash, dyspnea, or cough. He was unsuccessfully treated with a course of doxycycline as an outpatient. Of note, one month prior, he was on a prednisone taper for three weeks for back pain exacerbation. On presentation, he was afebrile with a blood pressure of 163/89 mmHg, heart rate of 92/minute, respiratory rate of 20 breaths/minute, and saturating 98% on ambient air. There was a right calf nodular lesion with peripheral induration, central ulceration with a black base, and mild serous discharge.
Laboratory data showed mild leukocytosis. Computed tomography of the chest revealed bilateral cavitating nodules, the largest in the superior segment of the left lower lobe (Fig. 1A). Skin biopsy, blood, and sputum cultures were obtained. Given skin and cavitary lung lesions, there was concern about methicillin-resistant Staphylococcus aureus (MRSA) infection, and empiric vancomycin was initiated. Skin biopsy, blood, and sputum cultures grew acid-fast bacilli, but Mycobacterium tuberculosis polymerase chain reaction assay was negative. The final result showed Mycobacterium abscessus. The human immunodeficiency virus antibody screen was negative. Therapy with meropenem, tigecycline, and amikacin was initiated after infectious diseases consultation, and he was discharged to a rehabilitation facility. After three months, he was re-admitted for evaluation of worsening lower back pain. A lumbar magnetic resonance imaging revealed destructive changes of L4 and L5 vertebral bodies concerning for osteomyelitis. Bone biopsy and blood cultures grew Mycobacterium abscessus again. Due to persistent bacteremia, an echocardiogram was performed, which revealed large mobile vegetation on the tricuspid valve and small vegetation on the mitral valve consistent with endocarditis (Fig. 1B). Based on drug susceptibility, he was discharged on amikacin for eight weeks, with cefoxitin and imipenem for twelve months. During follow-up after a month, he had been clinically doing well with a near-complete resolution of skin rash.Fig. 1 (A) Is computed tomography of the chest in an axial view showing a cavitary lesion in the superior segment of the left lower lobe and (B) is an echocardiogram showing large tricuspid valve vegetation (arrow) and small mitral valve vegetation (arrowhead) in an apical 4-chamber view (RV, right ventricle; TV, tricuspid valve; RA, right atrium; LV, left ventricle; MV, mitral valve; LA, left atrium and interventricular septum denoted by a curved arrow).
Fig. 1
3 Discussion
Mycobacterium abscessus complex includes M. chelonae, and M. abscessus. M. abscessus is the most prevalent microorganism in the rapidly-growing mycobacteria group causing pulmonary infections [3]. Disseminated M. abscessus is rare, and mycobacterial endocarditis is rarer. Prosthetic valves are commonly infected, and among native valves, aortic and mitral valves are the most frequently affected [4]. Risk factors include indwelling vascular catheters, cardiac catheterization, intravenous drug users, immunocompromised due to human immunodeficiency virus, hematological malignancies, or immunosuppressive agent use due to organ transplants. Recent corticosteroid use may have been the risk factor for our patient. Patients can present with non-specific symptoms or be asymptomatic. The most common presenting symptom is usually fever presenting as pyrexia of unknown origin, followed by chest pain or dyspnea. Blood cultures are highly sensitive, especially in cases of native valve endocarditis. Acid-fast bacilli stain of sputum, and histological sections (if available like skin biopsy, prosthetic valve) should be performed [4]. Echocardiography should be performed in patients with persistently positive blood cultures or radiological findings of pulmonary septic emboli. In a literature review of mycobacterial endocarditis, 15 out of 46 patients had a cardiac murmur at presentation, and echocardiography was used to confirm the presence of vegetations [4,5]. Treatment of Mycobacterium abscessus is challenging due to antibiotic resistance, including macrolides, aminoglycosides, rifamycins, tetracyclines, and β-lactams [3]. Evidence-based management of disseminated M. abscessus infection and endocarditis lacks due to the rarity of the condition. Usually, empiric treatment is started based on the in vitro susceptibility data, and later targeted therapy is employed when drug susceptibilities are available [6]. Drugs with in vitro activity include clarithromycin, amikacin, tigecycline, imipenem, and cefoxitin [5]. Treatment of pulmonary disease involves a multidrug regimen with at least three active drugs. Treatment duration ranges from 4 to 12 months depending on the severity of illness, and in refractory cases, surgical debridement may be required. Therefore, expert consultation is recommended [7]. Treatment of infective endocarditis requires a multidrug regimen for 6–12 months and is usually refractory, requiring early surgical intervention, especially in severe valvular endocarditis [4,8].
Declaration of competing interest
The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. | Recovered | ReactionOutcome | CC BY-NC-ND | 33489744 | 19,456,432 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute respiratory distress syndrome'. | Propofol-Induced Severe Necrotizing Pancreatitis.
Propofol is a widely used sedative for gastrointestinal endoscopic procedures. Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition. Propofol-induced pancreatitis is an extremely rare phenomenon. We present a 22-year-old healthy man who underwent esophagogastroduodenoscopy with propofol as a sedative. Soon after, he developed acute upper gastrointestinal symptoms and was diagnosed with pancreatitis. His prolonged hospital course was complicated with necrotizing pancreatitis, acute respiratory distress syndrome, septic shock, and other end-organ damages. We hope to increase awareness of a life-threatening adverse event of a commonly used anesthetic such as propofol.
INTRODUCTION
Propofol, 2,6-diisopropylphenol, is a commonly used agent for induction and maintenance of anesthesia. It has also gained wide-spread popularity for gastrointestinal (GI) endoscopic procedures because it is short-acting and has fewer side effects.1,2 Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition.3 However, propofol-induced pancreatitis has been reported, although a seemingly rare phenomenon.3 We present a case of severe necrotizing pancreatitis with multiorgan failure, attributed to delayed reaction after receiving propofol for an elective esophagogastroduodenoscopy (EGD) procedure.
CASE REPORT
A 22-year-old white man with a medical history of gastroesophageal reflux disease and past cholecystectomy underwent EGD evaluation for intermittent esophageal dysphagia of many years. His only home medication was omeprazole. He had no EGD, previous exposure to propofol, or known drug and environmental allergies. He did not use tobacco, drink alcohol, or use any illicit drugs. He had no family history of significant medical conditions. EGD was accomplished without any immediate complications. For procedural sedation, he received a total of 150 mg of intravenous propofol. EGD revealed mild esophageal stricture at the esophagogastric junction, which was dilated to 20 mm using a balloon dilator. Esophageal mucosal changes, including ringed esophagus, feline appearance, and longitudinal furrows, were also found in the middle and lower third of the esophagus. Biopsies were taken from the esophagus which showed eosinophilic esophagitis. The remainder examined upper GI tract was otherwise unremarkable.
He tolerated the procedure and anesthesia well. However, about 90 minutes after his discharge, he called and reported a sudden onset of severe epigastric pain and several episodes of emesis that started after a meal. He was instructed to go to the emergency department immediately for further evaluation. In the emergency department, he was found to have marked elevation of his lipase at about 14,000 U/L and a total leukocyte count of 30,000 cells per liter with no eosinophilia, high neutrophils, and normal lymphocyte counts. His triglycerides level was 79 mg/dL. Initial abdominal and pelvic computed tomography showed peripancreatic fluid without any evidence of cyst, abscess, or necrosis. He was initially admitted to the general medical floor for intravenous fluid hydration and pain control but was soon transferred to the intensive care unit (ICU) because of deterioration and development of hypoxia and hemodynamic instability.
In the ICU, he developed acute hypoxic respiratory failure due to acute respiratory distress syndrome requiring intubation and mechanical ventilation. Subsequently, he developed septic shock, requiring vasopressor support and broad-spectrum antibacterial and antifungal agents; significant pleural effusion, requiring thoracentesis and chest tube placement; and acute kidney injury that improved gradually without the need for dialysis. Repeat abdominal and pelvic computed tomography 10 days later demonstrated pancreatic necrosis with extensive peripancreatic fluid extending to post-pararenal space along with retroperitoneal fluid collection, requiring percutaneous drain placement and ultimately pancreatic necrosectomy (Figure 1). To complicate matters further, the patient also developed severe ischemic colitis because of shock, requiring a subtotal colectomy. The patient had had a prolonged course of hospitalization, mostly in the ICU setting at 2 tertiary care centers for over 6 months, receiving cares from multiple medical and surgical specialties. He was then transferred to rehab facility and is currently doing well.
Figure 1. Abdominal displaying pancreatitis with peripancreatic fluid collection (red arrows).
Exhaustive diagnostic workup had been performed to exclude other causes of pancreatitis. This patient had a cholecystectomy 2 years ago. His initial abdominal imaging and laboratory work ruled out gallstone pancreatitis and pancreatic divisum. He had no history of alcohol use. Extensive and repeated laboratory tests and microbiology excluded common infectious pathogens. A nasopharyngeal respiratory viral polymerase chain reaction testing was positive for human rhinovirus; however, serum testing was negative, which rules out a viral cause for the patient's pancreatitis. Autoimmune etiology was ruled out because immunoglobulin levels were normal. He had initial unremarkable blood work, including normal serum triglyceride level, except for elevated lipase level and total white count at presentation. His only home medication was omeprazole that he had been taking for multiple years. He had no previous trauma or exposure to drugs or toxins. Testing for rare causes such as cystic fibrosis and myotonic dystrophy was also negative. He had no history of vascular disease or vasculitis. He had no known history of drug or environmental allergies. Given the chronological association of propofol administration and immediate development of acute pancreatitis without any other causes, it was concluded that the patient had propofol-induced severe necrotizing pancreatitis.
DISCUSSION
Propofol is lipophilic and a global central nervous depressant with a rapid onset of sedation, dose-related hypnotic effect, and a quick recovery profile.4 Although extensive use of propofol has increased patient satisfaction and acceptability in GI procedures, risks of over-sedation and complications are not negligible.5,6 Deeper sedation levels can increase the risk of procedural hypotension, colonic perforation, and aspiration pneumonia.5,7,8 Moreover, propofol may lead to increase in mortality and morbidity from cardiopulmonary complications in elderly compared with younger patients probably because of reduced renal clearance.9
Case reports have been published over the years that showed propofol as a rare causative agent for pancreatitis.1,4,10–13 The mechanism of this drug-induced pancreatitis is largely unknown, although propofol-induced hypertriglyceridemia, hypersensitivity, or direct pancreatic toxicity had been suggested as possible culprit.3,14 We present a case of severe necrotizing pancreatitis within hours of after single dosage of propofol exposure that ultimately led to multiorgan failure. Initial triglyceride levels were normal, and all other causes of pancreatitis were systematically ruled out. Hence, the mechanism of propofol-induced pancreatitis in our case remains unidentified, suggesting an idiosyncratic reaction.
Although propofol-induced pancreatitis is a rare phenomenon, the exact incidence is unclear and potentially much higher due in part to possible poor recognition, especially for mild cases. We hope that this case report will help increase pancreatitis awareness as a potentially life-threatening adverse event associated with propofol sedation and not assume postprocedural abdominal pain to be secondary to abdominal dilation from periprocedural air insufflation. The debate is likely to continue as to the cost, risks, and benefits of ever-popular propofol-induced deep sedation vs conventional benzodiazepines and opioid-induced conscious sedation for GI endoscopic procedures. We would like to make the clinicians aware of the rare but potentially fatal complication of propofol, and they should consider other alternative sedatives.
DISCLOSURES
Author contributions: All authors contributed equally to this manuscript. H. Zhang is the article guarantor.
Financial disclosure: None to report.
Previous presentation: This case was presented at the Michigan Osteopathic Association, May 17, 2019; Southfield, Michigan.
Informed consent was obtained for this case report. | OMEPRAZOLE, PROPOFOL | DrugsGivenReaction | CC BY-NC-ND | 33490299 | 20,919,114 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Multiple organ dysfunction syndrome'. | Propofol-Induced Severe Necrotizing Pancreatitis.
Propofol is a widely used sedative for gastrointestinal endoscopic procedures. Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition. Propofol-induced pancreatitis is an extremely rare phenomenon. We present a 22-year-old healthy man who underwent esophagogastroduodenoscopy with propofol as a sedative. Soon after, he developed acute upper gastrointestinal symptoms and was diagnosed with pancreatitis. His prolonged hospital course was complicated with necrotizing pancreatitis, acute respiratory distress syndrome, septic shock, and other end-organ damages. We hope to increase awareness of a life-threatening adverse event of a commonly used anesthetic such as propofol.
INTRODUCTION
Propofol, 2,6-diisopropylphenol, is a commonly used agent for induction and maintenance of anesthesia. It has also gained wide-spread popularity for gastrointestinal (GI) endoscopic procedures because it is short-acting and has fewer side effects.1,2 Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition.3 However, propofol-induced pancreatitis has been reported, although a seemingly rare phenomenon.3 We present a case of severe necrotizing pancreatitis with multiorgan failure, attributed to delayed reaction after receiving propofol for an elective esophagogastroduodenoscopy (EGD) procedure.
CASE REPORT
A 22-year-old white man with a medical history of gastroesophageal reflux disease and past cholecystectomy underwent EGD evaluation for intermittent esophageal dysphagia of many years. His only home medication was omeprazole. He had no EGD, previous exposure to propofol, or known drug and environmental allergies. He did not use tobacco, drink alcohol, or use any illicit drugs. He had no family history of significant medical conditions. EGD was accomplished without any immediate complications. For procedural sedation, he received a total of 150 mg of intravenous propofol. EGD revealed mild esophageal stricture at the esophagogastric junction, which was dilated to 20 mm using a balloon dilator. Esophageal mucosal changes, including ringed esophagus, feline appearance, and longitudinal furrows, were also found in the middle and lower third of the esophagus. Biopsies were taken from the esophagus which showed eosinophilic esophagitis. The remainder examined upper GI tract was otherwise unremarkable.
He tolerated the procedure and anesthesia well. However, about 90 minutes after his discharge, he called and reported a sudden onset of severe epigastric pain and several episodes of emesis that started after a meal. He was instructed to go to the emergency department immediately for further evaluation. In the emergency department, he was found to have marked elevation of his lipase at about 14,000 U/L and a total leukocyte count of 30,000 cells per liter with no eosinophilia, high neutrophils, and normal lymphocyte counts. His triglycerides level was 79 mg/dL. Initial abdominal and pelvic computed tomography showed peripancreatic fluid without any evidence of cyst, abscess, or necrosis. He was initially admitted to the general medical floor for intravenous fluid hydration and pain control but was soon transferred to the intensive care unit (ICU) because of deterioration and development of hypoxia and hemodynamic instability.
In the ICU, he developed acute hypoxic respiratory failure due to acute respiratory distress syndrome requiring intubation and mechanical ventilation. Subsequently, he developed septic shock, requiring vasopressor support and broad-spectrum antibacterial and antifungal agents; significant pleural effusion, requiring thoracentesis and chest tube placement; and acute kidney injury that improved gradually without the need for dialysis. Repeat abdominal and pelvic computed tomography 10 days later demonstrated pancreatic necrosis with extensive peripancreatic fluid extending to post-pararenal space along with retroperitoneal fluid collection, requiring percutaneous drain placement and ultimately pancreatic necrosectomy (Figure 1). To complicate matters further, the patient also developed severe ischemic colitis because of shock, requiring a subtotal colectomy. The patient had had a prolonged course of hospitalization, mostly in the ICU setting at 2 tertiary care centers for over 6 months, receiving cares from multiple medical and surgical specialties. He was then transferred to rehab facility and is currently doing well.
Figure 1. Abdominal displaying pancreatitis with peripancreatic fluid collection (red arrows).
Exhaustive diagnostic workup had been performed to exclude other causes of pancreatitis. This patient had a cholecystectomy 2 years ago. His initial abdominal imaging and laboratory work ruled out gallstone pancreatitis and pancreatic divisum. He had no history of alcohol use. Extensive and repeated laboratory tests and microbiology excluded common infectious pathogens. A nasopharyngeal respiratory viral polymerase chain reaction testing was positive for human rhinovirus; however, serum testing was negative, which rules out a viral cause for the patient's pancreatitis. Autoimmune etiology was ruled out because immunoglobulin levels were normal. He had initial unremarkable blood work, including normal serum triglyceride level, except for elevated lipase level and total white count at presentation. His only home medication was omeprazole that he had been taking for multiple years. He had no previous trauma or exposure to drugs or toxins. Testing for rare causes such as cystic fibrosis and myotonic dystrophy was also negative. He had no history of vascular disease or vasculitis. He had no known history of drug or environmental allergies. Given the chronological association of propofol administration and immediate development of acute pancreatitis without any other causes, it was concluded that the patient had propofol-induced severe necrotizing pancreatitis.
DISCUSSION
Propofol is lipophilic and a global central nervous depressant with a rapid onset of sedation, dose-related hypnotic effect, and a quick recovery profile.4 Although extensive use of propofol has increased patient satisfaction and acceptability in GI procedures, risks of over-sedation and complications are not negligible.5,6 Deeper sedation levels can increase the risk of procedural hypotension, colonic perforation, and aspiration pneumonia.5,7,8 Moreover, propofol may lead to increase in mortality and morbidity from cardiopulmonary complications in elderly compared with younger patients probably because of reduced renal clearance.9
Case reports have been published over the years that showed propofol as a rare causative agent for pancreatitis.1,4,10–13 The mechanism of this drug-induced pancreatitis is largely unknown, although propofol-induced hypertriglyceridemia, hypersensitivity, or direct pancreatic toxicity had been suggested as possible culprit.3,14 We present a case of severe necrotizing pancreatitis within hours of after single dosage of propofol exposure that ultimately led to multiorgan failure. Initial triglyceride levels were normal, and all other causes of pancreatitis were systematically ruled out. Hence, the mechanism of propofol-induced pancreatitis in our case remains unidentified, suggesting an idiosyncratic reaction.
Although propofol-induced pancreatitis is a rare phenomenon, the exact incidence is unclear and potentially much higher due in part to possible poor recognition, especially for mild cases. We hope that this case report will help increase pancreatitis awareness as a potentially life-threatening adverse event associated with propofol sedation and not assume postprocedural abdominal pain to be secondary to abdominal dilation from periprocedural air insufflation. The debate is likely to continue as to the cost, risks, and benefits of ever-popular propofol-induced deep sedation vs conventional benzodiazepines and opioid-induced conscious sedation for GI endoscopic procedures. We would like to make the clinicians aware of the rare but potentially fatal complication of propofol, and they should consider other alternative sedatives.
DISCLOSURES
Author contributions: All authors contributed equally to this manuscript. H. Zhang is the article guarantor.
Financial disclosure: None to report.
Previous presentation: This case was presented at the Michigan Osteopathic Association, May 17, 2019; Southfield, Michigan.
Informed consent was obtained for this case report. | OMEPRAZOLE, PROPOFOL | DrugsGivenReaction | CC BY-NC-ND | 33490299 | 20,919,114 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pancreatitis necrotising'. | Propofol-Induced Severe Necrotizing Pancreatitis.
Propofol is a widely used sedative for gastrointestinal endoscopic procedures. Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition. Propofol-induced pancreatitis is an extremely rare phenomenon. We present a 22-year-old healthy man who underwent esophagogastroduodenoscopy with propofol as a sedative. Soon after, he developed acute upper gastrointestinal symptoms and was diagnosed with pancreatitis. His prolonged hospital course was complicated with necrotizing pancreatitis, acute respiratory distress syndrome, septic shock, and other end-organ damages. We hope to increase awareness of a life-threatening adverse event of a commonly used anesthetic such as propofol.
INTRODUCTION
Propofol, 2,6-diisopropylphenol, is a commonly used agent for induction and maintenance of anesthesia. It has also gained wide-spread popularity for gastrointestinal (GI) endoscopic procedures because it is short-acting and has fewer side effects.1,2 Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition.3 However, propofol-induced pancreatitis has been reported, although a seemingly rare phenomenon.3 We present a case of severe necrotizing pancreatitis with multiorgan failure, attributed to delayed reaction after receiving propofol for an elective esophagogastroduodenoscopy (EGD) procedure.
CASE REPORT
A 22-year-old white man with a medical history of gastroesophageal reflux disease and past cholecystectomy underwent EGD evaluation for intermittent esophageal dysphagia of many years. His only home medication was omeprazole. He had no EGD, previous exposure to propofol, or known drug and environmental allergies. He did not use tobacco, drink alcohol, or use any illicit drugs. He had no family history of significant medical conditions. EGD was accomplished without any immediate complications. For procedural sedation, he received a total of 150 mg of intravenous propofol. EGD revealed mild esophageal stricture at the esophagogastric junction, which was dilated to 20 mm using a balloon dilator. Esophageal mucosal changes, including ringed esophagus, feline appearance, and longitudinal furrows, were also found in the middle and lower third of the esophagus. Biopsies were taken from the esophagus which showed eosinophilic esophagitis. The remainder examined upper GI tract was otherwise unremarkable.
He tolerated the procedure and anesthesia well. However, about 90 minutes after his discharge, he called and reported a sudden onset of severe epigastric pain and several episodes of emesis that started after a meal. He was instructed to go to the emergency department immediately for further evaluation. In the emergency department, he was found to have marked elevation of his lipase at about 14,000 U/L and a total leukocyte count of 30,000 cells per liter with no eosinophilia, high neutrophils, and normal lymphocyte counts. His triglycerides level was 79 mg/dL. Initial abdominal and pelvic computed tomography showed peripancreatic fluid without any evidence of cyst, abscess, or necrosis. He was initially admitted to the general medical floor for intravenous fluid hydration and pain control but was soon transferred to the intensive care unit (ICU) because of deterioration and development of hypoxia and hemodynamic instability.
In the ICU, he developed acute hypoxic respiratory failure due to acute respiratory distress syndrome requiring intubation and mechanical ventilation. Subsequently, he developed septic shock, requiring vasopressor support and broad-spectrum antibacterial and antifungal agents; significant pleural effusion, requiring thoracentesis and chest tube placement; and acute kidney injury that improved gradually without the need for dialysis. Repeat abdominal and pelvic computed tomography 10 days later demonstrated pancreatic necrosis with extensive peripancreatic fluid extending to post-pararenal space along with retroperitoneal fluid collection, requiring percutaneous drain placement and ultimately pancreatic necrosectomy (Figure 1). To complicate matters further, the patient also developed severe ischemic colitis because of shock, requiring a subtotal colectomy. The patient had had a prolonged course of hospitalization, mostly in the ICU setting at 2 tertiary care centers for over 6 months, receiving cares from multiple medical and surgical specialties. He was then transferred to rehab facility and is currently doing well.
Figure 1. Abdominal displaying pancreatitis with peripancreatic fluid collection (red arrows).
Exhaustive diagnostic workup had been performed to exclude other causes of pancreatitis. This patient had a cholecystectomy 2 years ago. His initial abdominal imaging and laboratory work ruled out gallstone pancreatitis and pancreatic divisum. He had no history of alcohol use. Extensive and repeated laboratory tests and microbiology excluded common infectious pathogens. A nasopharyngeal respiratory viral polymerase chain reaction testing was positive for human rhinovirus; however, serum testing was negative, which rules out a viral cause for the patient's pancreatitis. Autoimmune etiology was ruled out because immunoglobulin levels were normal. He had initial unremarkable blood work, including normal serum triglyceride level, except for elevated lipase level and total white count at presentation. His only home medication was omeprazole that he had been taking for multiple years. He had no previous trauma or exposure to drugs or toxins. Testing for rare causes such as cystic fibrosis and myotonic dystrophy was also negative. He had no history of vascular disease or vasculitis. He had no known history of drug or environmental allergies. Given the chronological association of propofol administration and immediate development of acute pancreatitis without any other causes, it was concluded that the patient had propofol-induced severe necrotizing pancreatitis.
DISCUSSION
Propofol is lipophilic and a global central nervous depressant with a rapid onset of sedation, dose-related hypnotic effect, and a quick recovery profile.4 Although extensive use of propofol has increased patient satisfaction and acceptability in GI procedures, risks of over-sedation and complications are not negligible.5,6 Deeper sedation levels can increase the risk of procedural hypotension, colonic perforation, and aspiration pneumonia.5,7,8 Moreover, propofol may lead to increase in mortality and morbidity from cardiopulmonary complications in elderly compared with younger patients probably because of reduced renal clearance.9
Case reports have been published over the years that showed propofol as a rare causative agent for pancreatitis.1,4,10–13 The mechanism of this drug-induced pancreatitis is largely unknown, although propofol-induced hypertriglyceridemia, hypersensitivity, or direct pancreatic toxicity had been suggested as possible culprit.3,14 We present a case of severe necrotizing pancreatitis within hours of after single dosage of propofol exposure that ultimately led to multiorgan failure. Initial triglyceride levels were normal, and all other causes of pancreatitis were systematically ruled out. Hence, the mechanism of propofol-induced pancreatitis in our case remains unidentified, suggesting an idiosyncratic reaction.
Although propofol-induced pancreatitis is a rare phenomenon, the exact incidence is unclear and potentially much higher due in part to possible poor recognition, especially for mild cases. We hope that this case report will help increase pancreatitis awareness as a potentially life-threatening adverse event associated with propofol sedation and not assume postprocedural abdominal pain to be secondary to abdominal dilation from periprocedural air insufflation. The debate is likely to continue as to the cost, risks, and benefits of ever-popular propofol-induced deep sedation vs conventional benzodiazepines and opioid-induced conscious sedation for GI endoscopic procedures. We would like to make the clinicians aware of the rare but potentially fatal complication of propofol, and they should consider other alternative sedatives.
DISCLOSURES
Author contributions: All authors contributed equally to this manuscript. H. Zhang is the article guarantor.
Financial disclosure: None to report.
Previous presentation: This case was presented at the Michigan Osteopathic Association, May 17, 2019; Southfield, Michigan.
Informed consent was obtained for this case report. | OMEPRAZOLE, PROPOFOL | DrugsGivenReaction | CC BY-NC-ND | 33490299 | 20,919,114 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Septic shock'. | Propofol-Induced Severe Necrotizing Pancreatitis.
Propofol is a widely used sedative for gastrointestinal endoscopic procedures. Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition. Propofol-induced pancreatitis is an extremely rare phenomenon. We present a 22-year-old healthy man who underwent esophagogastroduodenoscopy with propofol as a sedative. Soon after, he developed acute upper gastrointestinal symptoms and was diagnosed with pancreatitis. His prolonged hospital course was complicated with necrotizing pancreatitis, acute respiratory distress syndrome, septic shock, and other end-organ damages. We hope to increase awareness of a life-threatening adverse event of a commonly used anesthetic such as propofol.
INTRODUCTION
Propofol, 2,6-diisopropylphenol, is a commonly used agent for induction and maintenance of anesthesia. It has also gained wide-spread popularity for gastrointestinal (GI) endoscopic procedures because it is short-acting and has fewer side effects.1,2 Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition.3 However, propofol-induced pancreatitis has been reported, although a seemingly rare phenomenon.3 We present a case of severe necrotizing pancreatitis with multiorgan failure, attributed to delayed reaction after receiving propofol for an elective esophagogastroduodenoscopy (EGD) procedure.
CASE REPORT
A 22-year-old white man with a medical history of gastroesophageal reflux disease and past cholecystectomy underwent EGD evaluation for intermittent esophageal dysphagia of many years. His only home medication was omeprazole. He had no EGD, previous exposure to propofol, or known drug and environmental allergies. He did not use tobacco, drink alcohol, or use any illicit drugs. He had no family history of significant medical conditions. EGD was accomplished without any immediate complications. For procedural sedation, he received a total of 150 mg of intravenous propofol. EGD revealed mild esophageal stricture at the esophagogastric junction, which was dilated to 20 mm using a balloon dilator. Esophageal mucosal changes, including ringed esophagus, feline appearance, and longitudinal furrows, were also found in the middle and lower third of the esophagus. Biopsies were taken from the esophagus which showed eosinophilic esophagitis. The remainder examined upper GI tract was otherwise unremarkable.
He tolerated the procedure and anesthesia well. However, about 90 minutes after his discharge, he called and reported a sudden onset of severe epigastric pain and several episodes of emesis that started after a meal. He was instructed to go to the emergency department immediately for further evaluation. In the emergency department, he was found to have marked elevation of his lipase at about 14,000 U/L and a total leukocyte count of 30,000 cells per liter with no eosinophilia, high neutrophils, and normal lymphocyte counts. His triglycerides level was 79 mg/dL. Initial abdominal and pelvic computed tomography showed peripancreatic fluid without any evidence of cyst, abscess, or necrosis. He was initially admitted to the general medical floor for intravenous fluid hydration and pain control but was soon transferred to the intensive care unit (ICU) because of deterioration and development of hypoxia and hemodynamic instability.
In the ICU, he developed acute hypoxic respiratory failure due to acute respiratory distress syndrome requiring intubation and mechanical ventilation. Subsequently, he developed septic shock, requiring vasopressor support and broad-spectrum antibacterial and antifungal agents; significant pleural effusion, requiring thoracentesis and chest tube placement; and acute kidney injury that improved gradually without the need for dialysis. Repeat abdominal and pelvic computed tomography 10 days later demonstrated pancreatic necrosis with extensive peripancreatic fluid extending to post-pararenal space along with retroperitoneal fluid collection, requiring percutaneous drain placement and ultimately pancreatic necrosectomy (Figure 1). To complicate matters further, the patient also developed severe ischemic colitis because of shock, requiring a subtotal colectomy. The patient had had a prolonged course of hospitalization, mostly in the ICU setting at 2 tertiary care centers for over 6 months, receiving cares from multiple medical and surgical specialties. He was then transferred to rehab facility and is currently doing well.
Figure 1. Abdominal displaying pancreatitis with peripancreatic fluid collection (red arrows).
Exhaustive diagnostic workup had been performed to exclude other causes of pancreatitis. This patient had a cholecystectomy 2 years ago. His initial abdominal imaging and laboratory work ruled out gallstone pancreatitis and pancreatic divisum. He had no history of alcohol use. Extensive and repeated laboratory tests and microbiology excluded common infectious pathogens. A nasopharyngeal respiratory viral polymerase chain reaction testing was positive for human rhinovirus; however, serum testing was negative, which rules out a viral cause for the patient's pancreatitis. Autoimmune etiology was ruled out because immunoglobulin levels were normal. He had initial unremarkable blood work, including normal serum triglyceride level, except for elevated lipase level and total white count at presentation. His only home medication was omeprazole that he had been taking for multiple years. He had no previous trauma or exposure to drugs or toxins. Testing for rare causes such as cystic fibrosis and myotonic dystrophy was also negative. He had no history of vascular disease or vasculitis. He had no known history of drug or environmental allergies. Given the chronological association of propofol administration and immediate development of acute pancreatitis without any other causes, it was concluded that the patient had propofol-induced severe necrotizing pancreatitis.
DISCUSSION
Propofol is lipophilic and a global central nervous depressant with a rapid onset of sedation, dose-related hypnotic effect, and a quick recovery profile.4 Although extensive use of propofol has increased patient satisfaction and acceptability in GI procedures, risks of over-sedation and complications are not negligible.5,6 Deeper sedation levels can increase the risk of procedural hypotension, colonic perforation, and aspiration pneumonia.5,7,8 Moreover, propofol may lead to increase in mortality and morbidity from cardiopulmonary complications in elderly compared with younger patients probably because of reduced renal clearance.9
Case reports have been published over the years that showed propofol as a rare causative agent for pancreatitis.1,4,10–13 The mechanism of this drug-induced pancreatitis is largely unknown, although propofol-induced hypertriglyceridemia, hypersensitivity, or direct pancreatic toxicity had been suggested as possible culprit.3,14 We present a case of severe necrotizing pancreatitis within hours of after single dosage of propofol exposure that ultimately led to multiorgan failure. Initial triglyceride levels were normal, and all other causes of pancreatitis were systematically ruled out. Hence, the mechanism of propofol-induced pancreatitis in our case remains unidentified, suggesting an idiosyncratic reaction.
Although propofol-induced pancreatitis is a rare phenomenon, the exact incidence is unclear and potentially much higher due in part to possible poor recognition, especially for mild cases. We hope that this case report will help increase pancreatitis awareness as a potentially life-threatening adverse event associated with propofol sedation and not assume postprocedural abdominal pain to be secondary to abdominal dilation from periprocedural air insufflation. The debate is likely to continue as to the cost, risks, and benefits of ever-popular propofol-induced deep sedation vs conventional benzodiazepines and opioid-induced conscious sedation for GI endoscopic procedures. We would like to make the clinicians aware of the rare but potentially fatal complication of propofol, and they should consider other alternative sedatives.
DISCLOSURES
Author contributions: All authors contributed equally to this manuscript. H. Zhang is the article guarantor.
Financial disclosure: None to report.
Previous presentation: This case was presented at the Michigan Osteopathic Association, May 17, 2019; Southfield, Michigan.
Informed consent was obtained for this case report. | OMEPRAZOLE, PROPOFOL | DrugsGivenReaction | CC BY-NC-ND | 33490299 | 20,919,114 | 2021-01 |
What was the administration route of drug 'PROPOFOL'? | Propofol-Induced Severe Necrotizing Pancreatitis.
Propofol is a widely used sedative for gastrointestinal endoscopic procedures. Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition. Propofol-induced pancreatitis is an extremely rare phenomenon. We present a 22-year-old healthy man who underwent esophagogastroduodenoscopy with propofol as a sedative. Soon after, he developed acute upper gastrointestinal symptoms and was diagnosed with pancreatitis. His prolonged hospital course was complicated with necrotizing pancreatitis, acute respiratory distress syndrome, septic shock, and other end-organ damages. We hope to increase awareness of a life-threatening adverse event of a commonly used anesthetic such as propofol.
INTRODUCTION
Propofol, 2,6-diisopropylphenol, is a commonly used agent for induction and maintenance of anesthesia. It has also gained wide-spread popularity for gastrointestinal (GI) endoscopic procedures because it is short-acting and has fewer side effects.1,2 Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition.3 However, propofol-induced pancreatitis has been reported, although a seemingly rare phenomenon.3 We present a case of severe necrotizing pancreatitis with multiorgan failure, attributed to delayed reaction after receiving propofol for an elective esophagogastroduodenoscopy (EGD) procedure.
CASE REPORT
A 22-year-old white man with a medical history of gastroesophageal reflux disease and past cholecystectomy underwent EGD evaluation for intermittent esophageal dysphagia of many years. His only home medication was omeprazole. He had no EGD, previous exposure to propofol, or known drug and environmental allergies. He did not use tobacco, drink alcohol, or use any illicit drugs. He had no family history of significant medical conditions. EGD was accomplished without any immediate complications. For procedural sedation, he received a total of 150 mg of intravenous propofol. EGD revealed mild esophageal stricture at the esophagogastric junction, which was dilated to 20 mm using a balloon dilator. Esophageal mucosal changes, including ringed esophagus, feline appearance, and longitudinal furrows, were also found in the middle and lower third of the esophagus. Biopsies were taken from the esophagus which showed eosinophilic esophagitis. The remainder examined upper GI tract was otherwise unremarkable.
He tolerated the procedure and anesthesia well. However, about 90 minutes after his discharge, he called and reported a sudden onset of severe epigastric pain and several episodes of emesis that started after a meal. He was instructed to go to the emergency department immediately for further evaluation. In the emergency department, he was found to have marked elevation of his lipase at about 14,000 U/L and a total leukocyte count of 30,000 cells per liter with no eosinophilia, high neutrophils, and normal lymphocyte counts. His triglycerides level was 79 mg/dL. Initial abdominal and pelvic computed tomography showed peripancreatic fluid without any evidence of cyst, abscess, or necrosis. He was initially admitted to the general medical floor for intravenous fluid hydration and pain control but was soon transferred to the intensive care unit (ICU) because of deterioration and development of hypoxia and hemodynamic instability.
In the ICU, he developed acute hypoxic respiratory failure due to acute respiratory distress syndrome requiring intubation and mechanical ventilation. Subsequently, he developed septic shock, requiring vasopressor support and broad-spectrum antibacterial and antifungal agents; significant pleural effusion, requiring thoracentesis and chest tube placement; and acute kidney injury that improved gradually without the need for dialysis. Repeat abdominal and pelvic computed tomography 10 days later demonstrated pancreatic necrosis with extensive peripancreatic fluid extending to post-pararenal space along with retroperitoneal fluid collection, requiring percutaneous drain placement and ultimately pancreatic necrosectomy (Figure 1). To complicate matters further, the patient also developed severe ischemic colitis because of shock, requiring a subtotal colectomy. The patient had had a prolonged course of hospitalization, mostly in the ICU setting at 2 tertiary care centers for over 6 months, receiving cares from multiple medical and surgical specialties. He was then transferred to rehab facility and is currently doing well.
Figure 1. Abdominal displaying pancreatitis with peripancreatic fluid collection (red arrows).
Exhaustive diagnostic workup had been performed to exclude other causes of pancreatitis. This patient had a cholecystectomy 2 years ago. His initial abdominal imaging and laboratory work ruled out gallstone pancreatitis and pancreatic divisum. He had no history of alcohol use. Extensive and repeated laboratory tests and microbiology excluded common infectious pathogens. A nasopharyngeal respiratory viral polymerase chain reaction testing was positive for human rhinovirus; however, serum testing was negative, which rules out a viral cause for the patient's pancreatitis. Autoimmune etiology was ruled out because immunoglobulin levels were normal. He had initial unremarkable blood work, including normal serum triglyceride level, except for elevated lipase level and total white count at presentation. His only home medication was omeprazole that he had been taking for multiple years. He had no previous trauma or exposure to drugs or toxins. Testing for rare causes such as cystic fibrosis and myotonic dystrophy was also negative. He had no history of vascular disease or vasculitis. He had no known history of drug or environmental allergies. Given the chronological association of propofol administration and immediate development of acute pancreatitis without any other causes, it was concluded that the patient had propofol-induced severe necrotizing pancreatitis.
DISCUSSION
Propofol is lipophilic and a global central nervous depressant with a rapid onset of sedation, dose-related hypnotic effect, and a quick recovery profile.4 Although extensive use of propofol has increased patient satisfaction and acceptability in GI procedures, risks of over-sedation and complications are not negligible.5,6 Deeper sedation levels can increase the risk of procedural hypotension, colonic perforation, and aspiration pneumonia.5,7,8 Moreover, propofol may lead to increase in mortality and morbidity from cardiopulmonary complications in elderly compared with younger patients probably because of reduced renal clearance.9
Case reports have been published over the years that showed propofol as a rare causative agent for pancreatitis.1,4,10–13 The mechanism of this drug-induced pancreatitis is largely unknown, although propofol-induced hypertriglyceridemia, hypersensitivity, or direct pancreatic toxicity had been suggested as possible culprit.3,14 We present a case of severe necrotizing pancreatitis within hours of after single dosage of propofol exposure that ultimately led to multiorgan failure. Initial triglyceride levels were normal, and all other causes of pancreatitis were systematically ruled out. Hence, the mechanism of propofol-induced pancreatitis in our case remains unidentified, suggesting an idiosyncratic reaction.
Although propofol-induced pancreatitis is a rare phenomenon, the exact incidence is unclear and potentially much higher due in part to possible poor recognition, especially for mild cases. We hope that this case report will help increase pancreatitis awareness as a potentially life-threatening adverse event associated with propofol sedation and not assume postprocedural abdominal pain to be secondary to abdominal dilation from periprocedural air insufflation. The debate is likely to continue as to the cost, risks, and benefits of ever-popular propofol-induced deep sedation vs conventional benzodiazepines and opioid-induced conscious sedation for GI endoscopic procedures. We would like to make the clinicians aware of the rare but potentially fatal complication of propofol, and they should consider other alternative sedatives.
DISCLOSURES
Author contributions: All authors contributed equally to this manuscript. H. Zhang is the article guarantor.
Financial disclosure: None to report.
Previous presentation: This case was presented at the Michigan Osteopathic Association, May 17, 2019; Southfield, Michigan.
Informed consent was obtained for this case report. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33490299 | 20,919,114 | 2021-01 |
What was the outcome of reaction 'Multiple organ dysfunction syndrome'? | Propofol-Induced Severe Necrotizing Pancreatitis.
Propofol is a widely used sedative for gastrointestinal endoscopic procedures. Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition. Propofol-induced pancreatitis is an extremely rare phenomenon. We present a 22-year-old healthy man who underwent esophagogastroduodenoscopy with propofol as a sedative. Soon after, he developed acute upper gastrointestinal symptoms and was diagnosed with pancreatitis. His prolonged hospital course was complicated with necrotizing pancreatitis, acute respiratory distress syndrome, septic shock, and other end-organ damages. We hope to increase awareness of a life-threatening adverse event of a commonly used anesthetic such as propofol.
INTRODUCTION
Propofol, 2,6-diisopropylphenol, is a commonly used agent for induction and maintenance of anesthesia. It has also gained wide-spread popularity for gastrointestinal (GI) endoscopic procedures because it is short-acting and has fewer side effects.1,2 Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition.3 However, propofol-induced pancreatitis has been reported, although a seemingly rare phenomenon.3 We present a case of severe necrotizing pancreatitis with multiorgan failure, attributed to delayed reaction after receiving propofol for an elective esophagogastroduodenoscopy (EGD) procedure.
CASE REPORT
A 22-year-old white man with a medical history of gastroesophageal reflux disease and past cholecystectomy underwent EGD evaluation for intermittent esophageal dysphagia of many years. His only home medication was omeprazole. He had no EGD, previous exposure to propofol, or known drug and environmental allergies. He did not use tobacco, drink alcohol, or use any illicit drugs. He had no family history of significant medical conditions. EGD was accomplished without any immediate complications. For procedural sedation, he received a total of 150 mg of intravenous propofol. EGD revealed mild esophageal stricture at the esophagogastric junction, which was dilated to 20 mm using a balloon dilator. Esophageal mucosal changes, including ringed esophagus, feline appearance, and longitudinal furrows, were also found in the middle and lower third of the esophagus. Biopsies were taken from the esophagus which showed eosinophilic esophagitis. The remainder examined upper GI tract was otherwise unremarkable.
He tolerated the procedure and anesthesia well. However, about 90 minutes after his discharge, he called and reported a sudden onset of severe epigastric pain and several episodes of emesis that started after a meal. He was instructed to go to the emergency department immediately for further evaluation. In the emergency department, he was found to have marked elevation of his lipase at about 14,000 U/L and a total leukocyte count of 30,000 cells per liter with no eosinophilia, high neutrophils, and normal lymphocyte counts. His triglycerides level was 79 mg/dL. Initial abdominal and pelvic computed tomography showed peripancreatic fluid without any evidence of cyst, abscess, or necrosis. He was initially admitted to the general medical floor for intravenous fluid hydration and pain control but was soon transferred to the intensive care unit (ICU) because of deterioration and development of hypoxia and hemodynamic instability.
In the ICU, he developed acute hypoxic respiratory failure due to acute respiratory distress syndrome requiring intubation and mechanical ventilation. Subsequently, he developed septic shock, requiring vasopressor support and broad-spectrum antibacterial and antifungal agents; significant pleural effusion, requiring thoracentesis and chest tube placement; and acute kidney injury that improved gradually without the need for dialysis. Repeat abdominal and pelvic computed tomography 10 days later demonstrated pancreatic necrosis with extensive peripancreatic fluid extending to post-pararenal space along with retroperitoneal fluid collection, requiring percutaneous drain placement and ultimately pancreatic necrosectomy (Figure 1). To complicate matters further, the patient also developed severe ischemic colitis because of shock, requiring a subtotal colectomy. The patient had had a prolonged course of hospitalization, mostly in the ICU setting at 2 tertiary care centers for over 6 months, receiving cares from multiple medical and surgical specialties. He was then transferred to rehab facility and is currently doing well.
Figure 1. Abdominal displaying pancreatitis with peripancreatic fluid collection (red arrows).
Exhaustive diagnostic workup had been performed to exclude other causes of pancreatitis. This patient had a cholecystectomy 2 years ago. His initial abdominal imaging and laboratory work ruled out gallstone pancreatitis and pancreatic divisum. He had no history of alcohol use. Extensive and repeated laboratory tests and microbiology excluded common infectious pathogens. A nasopharyngeal respiratory viral polymerase chain reaction testing was positive for human rhinovirus; however, serum testing was negative, which rules out a viral cause for the patient's pancreatitis. Autoimmune etiology was ruled out because immunoglobulin levels were normal. He had initial unremarkable blood work, including normal serum triglyceride level, except for elevated lipase level and total white count at presentation. His only home medication was omeprazole that he had been taking for multiple years. He had no previous trauma or exposure to drugs or toxins. Testing for rare causes such as cystic fibrosis and myotonic dystrophy was also negative. He had no history of vascular disease or vasculitis. He had no known history of drug or environmental allergies. Given the chronological association of propofol administration and immediate development of acute pancreatitis without any other causes, it was concluded that the patient had propofol-induced severe necrotizing pancreatitis.
DISCUSSION
Propofol is lipophilic and a global central nervous depressant with a rapid onset of sedation, dose-related hypnotic effect, and a quick recovery profile.4 Although extensive use of propofol has increased patient satisfaction and acceptability in GI procedures, risks of over-sedation and complications are not negligible.5,6 Deeper sedation levels can increase the risk of procedural hypotension, colonic perforation, and aspiration pneumonia.5,7,8 Moreover, propofol may lead to increase in mortality and morbidity from cardiopulmonary complications in elderly compared with younger patients probably because of reduced renal clearance.9
Case reports have been published over the years that showed propofol as a rare causative agent for pancreatitis.1,4,10–13 The mechanism of this drug-induced pancreatitis is largely unknown, although propofol-induced hypertriglyceridemia, hypersensitivity, or direct pancreatic toxicity had been suggested as possible culprit.3,14 We present a case of severe necrotizing pancreatitis within hours of after single dosage of propofol exposure that ultimately led to multiorgan failure. Initial triglyceride levels were normal, and all other causes of pancreatitis were systematically ruled out. Hence, the mechanism of propofol-induced pancreatitis in our case remains unidentified, suggesting an idiosyncratic reaction.
Although propofol-induced pancreatitis is a rare phenomenon, the exact incidence is unclear and potentially much higher due in part to possible poor recognition, especially for mild cases. We hope that this case report will help increase pancreatitis awareness as a potentially life-threatening adverse event associated with propofol sedation and not assume postprocedural abdominal pain to be secondary to abdominal dilation from periprocedural air insufflation. The debate is likely to continue as to the cost, risks, and benefits of ever-popular propofol-induced deep sedation vs conventional benzodiazepines and opioid-induced conscious sedation for GI endoscopic procedures. We would like to make the clinicians aware of the rare but potentially fatal complication of propofol, and they should consider other alternative sedatives.
DISCLOSURES
Author contributions: All authors contributed equally to this manuscript. H. Zhang is the article guarantor.
Financial disclosure: None to report.
Previous presentation: This case was presented at the Michigan Osteopathic Association, May 17, 2019; Southfield, Michigan.
Informed consent was obtained for this case report. | Recovered | ReactionOutcome | CC BY-NC-ND | 33490299 | 20,924,999 | 2021-01 |
What was the outcome of reaction 'Pancreatitis necrotising'? | Propofol-Induced Severe Necrotizing Pancreatitis.
Propofol is a widely used sedative for gastrointestinal endoscopic procedures. Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition. Propofol-induced pancreatitis is an extremely rare phenomenon. We present a 22-year-old healthy man who underwent esophagogastroduodenoscopy with propofol as a sedative. Soon after, he developed acute upper gastrointestinal symptoms and was diagnosed with pancreatitis. His prolonged hospital course was complicated with necrotizing pancreatitis, acute respiratory distress syndrome, septic shock, and other end-organ damages. We hope to increase awareness of a life-threatening adverse event of a commonly used anesthetic such as propofol.
INTRODUCTION
Propofol, 2,6-diisopropylphenol, is a commonly used agent for induction and maintenance of anesthesia. It has also gained wide-spread popularity for gastrointestinal (GI) endoscopic procedures because it is short-acting and has fewer side effects.1,2 Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition.3 However, propofol-induced pancreatitis has been reported, although a seemingly rare phenomenon.3 We present a case of severe necrotizing pancreatitis with multiorgan failure, attributed to delayed reaction after receiving propofol for an elective esophagogastroduodenoscopy (EGD) procedure.
CASE REPORT
A 22-year-old white man with a medical history of gastroesophageal reflux disease and past cholecystectomy underwent EGD evaluation for intermittent esophageal dysphagia of many years. His only home medication was omeprazole. He had no EGD, previous exposure to propofol, or known drug and environmental allergies. He did not use tobacco, drink alcohol, or use any illicit drugs. He had no family history of significant medical conditions. EGD was accomplished without any immediate complications. For procedural sedation, he received a total of 150 mg of intravenous propofol. EGD revealed mild esophageal stricture at the esophagogastric junction, which was dilated to 20 mm using a balloon dilator. Esophageal mucosal changes, including ringed esophagus, feline appearance, and longitudinal furrows, were also found in the middle and lower third of the esophagus. Biopsies were taken from the esophagus which showed eosinophilic esophagitis. The remainder examined upper GI tract was otherwise unremarkable.
He tolerated the procedure and anesthesia well. However, about 90 minutes after his discharge, he called and reported a sudden onset of severe epigastric pain and several episodes of emesis that started after a meal. He was instructed to go to the emergency department immediately for further evaluation. In the emergency department, he was found to have marked elevation of his lipase at about 14,000 U/L and a total leukocyte count of 30,000 cells per liter with no eosinophilia, high neutrophils, and normal lymphocyte counts. His triglycerides level was 79 mg/dL. Initial abdominal and pelvic computed tomography showed peripancreatic fluid without any evidence of cyst, abscess, or necrosis. He was initially admitted to the general medical floor for intravenous fluid hydration and pain control but was soon transferred to the intensive care unit (ICU) because of deterioration and development of hypoxia and hemodynamic instability.
In the ICU, he developed acute hypoxic respiratory failure due to acute respiratory distress syndrome requiring intubation and mechanical ventilation. Subsequently, he developed septic shock, requiring vasopressor support and broad-spectrum antibacterial and antifungal agents; significant pleural effusion, requiring thoracentesis and chest tube placement; and acute kidney injury that improved gradually without the need for dialysis. Repeat abdominal and pelvic computed tomography 10 days later demonstrated pancreatic necrosis with extensive peripancreatic fluid extending to post-pararenal space along with retroperitoneal fluid collection, requiring percutaneous drain placement and ultimately pancreatic necrosectomy (Figure 1). To complicate matters further, the patient also developed severe ischemic colitis because of shock, requiring a subtotal colectomy. The patient had had a prolonged course of hospitalization, mostly in the ICU setting at 2 tertiary care centers for over 6 months, receiving cares from multiple medical and surgical specialties. He was then transferred to rehab facility and is currently doing well.
Figure 1. Abdominal displaying pancreatitis with peripancreatic fluid collection (red arrows).
Exhaustive diagnostic workup had been performed to exclude other causes of pancreatitis. This patient had a cholecystectomy 2 years ago. His initial abdominal imaging and laboratory work ruled out gallstone pancreatitis and pancreatic divisum. He had no history of alcohol use. Extensive and repeated laboratory tests and microbiology excluded common infectious pathogens. A nasopharyngeal respiratory viral polymerase chain reaction testing was positive for human rhinovirus; however, serum testing was negative, which rules out a viral cause for the patient's pancreatitis. Autoimmune etiology was ruled out because immunoglobulin levels were normal. He had initial unremarkable blood work, including normal serum triglyceride level, except for elevated lipase level and total white count at presentation. His only home medication was omeprazole that he had been taking for multiple years. He had no previous trauma or exposure to drugs or toxins. Testing for rare causes such as cystic fibrosis and myotonic dystrophy was also negative. He had no history of vascular disease or vasculitis. He had no known history of drug or environmental allergies. Given the chronological association of propofol administration and immediate development of acute pancreatitis without any other causes, it was concluded that the patient had propofol-induced severe necrotizing pancreatitis.
DISCUSSION
Propofol is lipophilic and a global central nervous depressant with a rapid onset of sedation, dose-related hypnotic effect, and a quick recovery profile.4 Although extensive use of propofol has increased patient satisfaction and acceptability in GI procedures, risks of over-sedation and complications are not negligible.5,6 Deeper sedation levels can increase the risk of procedural hypotension, colonic perforation, and aspiration pneumonia.5,7,8 Moreover, propofol may lead to increase in mortality and morbidity from cardiopulmonary complications in elderly compared with younger patients probably because of reduced renal clearance.9
Case reports have been published over the years that showed propofol as a rare causative agent for pancreatitis.1,4,10–13 The mechanism of this drug-induced pancreatitis is largely unknown, although propofol-induced hypertriglyceridemia, hypersensitivity, or direct pancreatic toxicity had been suggested as possible culprit.3,14 We present a case of severe necrotizing pancreatitis within hours of after single dosage of propofol exposure that ultimately led to multiorgan failure. Initial triglyceride levels were normal, and all other causes of pancreatitis were systematically ruled out. Hence, the mechanism of propofol-induced pancreatitis in our case remains unidentified, suggesting an idiosyncratic reaction.
Although propofol-induced pancreatitis is a rare phenomenon, the exact incidence is unclear and potentially much higher due in part to possible poor recognition, especially for mild cases. We hope that this case report will help increase pancreatitis awareness as a potentially life-threatening adverse event associated with propofol sedation and not assume postprocedural abdominal pain to be secondary to abdominal dilation from periprocedural air insufflation. The debate is likely to continue as to the cost, risks, and benefits of ever-popular propofol-induced deep sedation vs conventional benzodiazepines and opioid-induced conscious sedation for GI endoscopic procedures. We would like to make the clinicians aware of the rare but potentially fatal complication of propofol, and they should consider other alternative sedatives.
DISCLOSURES
Author contributions: All authors contributed equally to this manuscript. H. Zhang is the article guarantor.
Financial disclosure: None to report.
Previous presentation: This case was presented at the Michigan Osteopathic Association, May 17, 2019; Southfield, Michigan.
Informed consent was obtained for this case report. | Recovered | ReactionOutcome | CC BY-NC-ND | 33490299 | 20,924,999 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pancreatitis'. | Empagliflozin-Associated Pancreatitis: A Consideration for SGLT2 Inhibitors.
Empagliflozin belongs to a class of sodium-glucose cotransporter-2 inhibitors, a medication approved by the US Food and Drug Administration in 2014 for the treatment of type 2 diabetes mellitus. Well-known side effects of this medication include symptomatic hypotension, hypoglycemia, and urinary tract infections among others. We present a case of severe epigastric abdominal pain consistent with acute pancreatitis in the setting of empagliflozin use, suggesting a possible drug-induced acute pancreatitis.
INTRODUCTION
Empagliflozin is a drug in the new class of diabetic medications sodium-glucose cotransporter-2 (SGLT2) inhibitors, indicated for treating type 2 diabetes mellitus. The mechanism of action of empagliflozin is to reduce renal reabsorption of glucose and increase its urinary excretion.1 Well-known side effects of this class of medications include symptomatic hypotension through the drug's ability to cause intravascular volume contraction, hypoglycemia when used with insulin, urinary tract infections, and mycotic infections such as vulvitis and vulvovaginal candidiasis.1 In the review of the current literature, although rare in occurrence (less than 0.1%), drug-induced acute pancreatitis (DIAP) should be considered an adverse effect in patients treated with SGLT2 inhibitors. DIAP is a rare entity, with more than 500 drugs being listed as having DIAP as an adverse effect by the World Health Organization and more than 180 drugs have been implicated to directly cause DIAP.2,3 To our knowledge, there are very few reported cases of empagliflozin-induced pancreatitis.4,5 In addition, canagliflozin, an SGLT2 inhibitor, is known to rarely cause pancreatitis with an incidence <1%.6–10 We report a case of a 47-year-old man who presented with severe epigastric abdominal pain found to have DIAP in the setting of empagliflozin use.
CASE REPORT
A 47-year-old man with a history of abdominal aortic aneurysm status after stent placement, hypertension, and type 2 diabetes mellitus presented with a complaint of severe, epigastric abdominal pain associated with nausea and vomiting for 2 days duration. The patient denied a history of pancreatitis, consuming alcohol, narcotic use, recent trauma, surgical procedures, or exposure to venomous animals. The patient was admitted for management of pancreatitis. Social history including was negative for smoking history, alcohol ingestion, illicit drug use, or cannabis use. His home medications included empagliflozin (initiated 2 months before), atenolol, and hydrochlorothiazide (HCTZ). He had no known significant family history.
On admission, the patient's vital signs were within normal limits. Physical examination was significant for epigastric tenderness without organomegaly and absence of skin rash or scleral icterus. Laboratory workup revealed an elevated lipase of 220 mg/dL. Other laboratory findings were unremarkable, including the absence of eosinophilia, triglyceride level of 123 mg/dL (drawn fasting 1 day after admission), normal electrolyte levels, and liver function tests. Abdominal computed tomography angiography was obtained to evaluate the aortic stent and the pancreas, which revealed fat stranding and findings consistent with pancreatic inflammation located within the head of the pancreas (Figure 1). The gall bladder was unremarkable on abdominal ultrasound without evidence of cholelithiasis or other intraabdominal processes.
Figure 1. Abdominal computed tomography angiography—pancreatic fat stranding around the head of the pancreas consistent with acute pancreatitis (white arrow). Normal gallbladder without the presence of gallstones (red arrow).
The patient was treated with conservative management, including intravenous hydration and pain management. Empagliflozin was held because of suspicion of pancreatitis caused by this medication because of the absence of other inciting causes. The patient was subsequently discharged after 2 days and instructed to discontinue empagliflozin along with follow-up with his primary care physician. The patient refused endoscopic ultrasound. The patient has not had any further episodes of pancreatitis or gastrointestinal complaints at the 2-month outpatient follow-up.
DISCUSSION
The true incidence of DIAP is unknown because there are few population-based studies available, and the quality of available evidence is limited. Although gallstones (35%–40% of cases) and alcohol use (30% of cases) are been considered the most common causes of acute pancreatitis, other causes are extensive and include idiopathic pancreatitis, genetic causes among others.11 In recent literature, the PRSS1, SPINK1, CFTR, CTRC, and CASR genetic variants have been confirmed as chronic pancreatitis-associated genetic factors.12
Empagliflozin is a relatively new diabetic medication in the class of SGLT2 inhibitors, with very few case reports describing its known potential for causing pancreatitis.8 Badalov et al created a classification system that assesses the likelihood that certain drugs are associated with DIAP; the classifications are based on the number of case reports, rechallenge data, consistent latency period, and the ability to exclude other causes of AP.13 Based on the Badalov classification, empagliflozin would be characterized as Class III with at least 2 case reports published without rechallenge data or a consistent latency period. We implemented the use of the Adverse Drug Reaction Probability Scale—a method by which to assess whether there is a causal relationship between an identified clinical event and a drug; scores range from −4 to +13 and interpreted to reflect the strength of the causal relationship.14
Our patient received a score of 6—further supporting the temporal relationship between empagliflozin therapy and DIAP. He, all other likely causes of pancreatitis, were ruled out. The likelihood of HCTZ causing our patient's pancreatitis is unlikely because he had been on this medication without complications for many years before presentation. Our patient also did not present with hypercalcemia or hypertriglyceridemia, which are the assumed mechanisms of HCTZ-induced pancreatitis. In reviewing a recent case report by McIntire and Bayne, empagliflozin-induced pancreatitis occurred at day 104.4 As mentioned above, our patient had been started on empagliflozin therapy approximately 60 days before presentation. We believe that this timeframe further supports the likelihood of a causal relationship. A drug rechallenge is defined as the readministration of a suspected drug that had been previously withdrawn; this may provide valuable information to assess causality between the medication and the reaction.15 This case demonstrates that SGLT2 inhibitors, although a rare cause, should be considered an important part of a clinician's differential when other common etiologies of pancreatitis have been excluded.
Our case emphasizes the importance of the general gastroenterologist and clinician increased awareness of new classes of diabetic medications, especially, but not limited to empagliflozin within the class of SGLT2 inhibitors and their untoward side effects of acute pancreatitis. The clinician should be cognizant that certain medications have more robust evidence than others to associate the drug to DIAP. Larger case-control studies on DIAP are needed to study the true potential these drugs.
DISCLOSURES
Author contributions: All authors contributed equally to this manuscript. KN Dziadkowiec is the article guarantor.
Financial disclosure: None to report.
Informed consent was obtained for this case report. | ATENOLOL, EMPAGLIFLOZIN, HYDROCHLOROTHIAZIDE | DrugsGivenReaction | CC BY-NC-ND | 33490300 | 18,872,884 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood 1,25-dihydroxycholecalciferol increased'. | Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia.
Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A 68Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases.
1 Introduction
Osteomalacia is the progressive softening of bones due to decreased mineralization of calcium and phosphates at sites of bone remodeling and growth, commonly resulting in bone pain and muscle weakness (Michigami, 2019). Fibroblast Growth Factor 23 (FGF23) is a protein secreted by osteocytes mainly in response to calcitriol and phosphate (Martin et al., 2012). FGF23 regulates plasma phosphate concentration predominately by reducing serum calcitriol which mediates intestinal phosphate absorption and by reducing NPT2-mediated phosphate reabsorption in the kidney. Tumor-Induced Osteomalacia (TIO) is a rare paraneoplastic disease in which a phosphaturic mesenchymal tumor (PMT) secretes significant amounts of FGF23 into the bloodstream, leading to downstream osteomalacia through renal phosphate wasting and defective Vitamin D metabolism (Yin et al., 2018). While less than 500 cases of TIO have been reported worldwide, and formal epidemiological studies of the disease have not been performed, surgical resection offers a potentially curative treatment in contrast to similarly presenting disorders (Folpe, 2019).
X-linked hypophosphatemia (XLH) is a phosphate wasting disorder caused by mutations in the PHEX gene which expresses the enzyme phosphate-regulating neutral endopeptidase (PHEX). Studies suggest that the PHEX enzyme may be involved in the regulation of FGF23 (Beck-Nielsen et al., 2019; Liu et al., 2003). Importantly, diagnosing phosphate wasting disorders based purely on clinical criteria is confounded by the similarity of clinical and radiological presentations of this family of disorders. Knowing the distinct genetic basis for a patient's phosphate wasting disorder often allows clinicians to tailor their treatment/management strategy accordingly, potentially saving years of hardship for affected patients. As such, recent emphasis has been placed on using gene panels to accelerate clinicians' diagnosis of these disorders.
In particular, a potential for misdiagnosis of TIO as XLH exists because FGF23 levels are increased in both, PMT tumors are notoriously difficult to find due to their small size and variable location, and (albeit still rare) the incidence of XLH far exceeds that of TIO (Yin et al., 2018; Carpenter, 1997). Here, we present a 41-year-old female in whom a 26-year delayed TIO diagnosis and concurrent misdiagnosis of XLH was identified via a negative hypophosphatemia gene panel and corrected to TIO through identification of a PMT of her 9th right rib. Surgical resection resulted in biochemical and clinical symptom improvement. Histological analysis was positive for FGF23 (CISH) and the FN1-FGFR1 transcriptional marker. Finally, we highlight recent key advances in diagnosing phosphate wasting disorders, molecular characterization of PMTs, and TIO treatment and management.
2 Case presentation
A 41-year-old woman with a prior clinical diagnosis of hypophosphatemic rickets presented to our institution with a 26-year history of low phosphorus, bone pain, proximal muscle weakness, gait abnormalities, and multiple traumatic and insufficiency fractures of the hip, humerus, and spine (Fig. 1, Fig. 7). She had no history of hearing loss. She had lost all her secondary teeth (edentulous). The patient reported no family history of hypophosphatemia, including her 8-year-old male child and 17-year-old female child, neither of whom showed clinical or laboratory indications of musculoskeletal conditions or phosphate wasting disorders. Her maximum height was 5′2″ but she presented to us at 4′8″ due to progressive spine deformities.
Despite intermittent treatment with conventional therapy with phosphorus supplements and calcitriol during her teens and 20s, she developed progressive gait abnormalities and decreased hip strength and ultimately sustained bilateral hip fractures (Fig. 1A) and small fractures throughout her spine (Fig. 1B-C).Fig. 1 Patient musculoskeletal radiology. X-ray AP Pelvis (A) shows evidence of prior bilateral obturator ring fractures with bilateral femoral head/neck angular deformities. X-ray Spine Total AP/Lateral (B-C) shows normal trabecular bone with vertebral body alignments and interspacing intact, but there is mild flattening of the mid vertebral body at multiple levels. There is evidence of previous insufficiency fractures.
Fig. 1
Despite treatment, the patient's symptoms deteriorated further in her 20s, when she had stability rods and screws placed bilaterally in her femurs and hips, respectively (Fig. 1A). Ten years later, the patient presented with a traumatic left humerus fracture, for which she underwent surgery (Figure 7). Post-operatively, the patient was placed on the osteoporosis medication teriparatide.
Teriparatide therapy failed to prevent more spinal fractures (Fig. 1B-C), bone pain, and muscle weakness over the next year, and the patient was eventually confined to a wheelchair. Orthopedic physicians reevaluated her history, officially diagnosed her with X-linked Hypophosphatemia (XLH) (although patient claims having an “unofficial” XLH diagnosis years prior by previous physicians), and started her on Burosumab (60 mg subcutaneous injection every 28 days) - the monoclonal antibody targeted against FGF23. Unfortunately, laboratory values relevant to phosphate wasting (e.g. TmP/GFR, FGF23) were not reported prior to initiation of Burosumab therapy or referral to our institution for further evaluation and treatment.
The patient remained on Burosumab for 3 months. While on Burosumab, the patient reported mild symptomatic improvement with no reported adverse effects, but still had severe limitations in mobility (difficulty from sit to stand, Video 1), fatigue, and pain. On therapy, FGF23 levels were 33,900 RU/mL (normal <180RU/mL) and 36,900 RU/mL two months later as measured by ELISA (Quidel Corporation). Other notable preoperative laboratory values include a normal serum phosphorus, normal calcium, normal total vitamin D, elevated 1,25 dihydroxyvitamin D (333 pg/mL; normal 19.9–79.3 pg/mL), high alkaline phosphatase (168 U/mL; normal 40–150 U/mL), and high PTH (189 pg/mL, normal 16–77 pg/mL) (Table 2). These findings are abnormal for a patient with TIO, but they should be viewed in the context of Burosumab therapy. After discontinuation, her total FGF23 declined to 1532 RU/mL after discontinuing Burosumab but before excision of her PMT which was still considerably elevated above reference range.
At our clinic, areal bone density of the lumbar spine and left forearm (bone density of the femurs could not be performed due to bilateral hip prostheses) were assessed by dual-energy X-ray absorptiometry (DXA) using a GE Lunar Prodigy Advanced densitometer. Densitometry revealed normal bone density in the spine and significantly lower than expected density in the forearm (Fig. 2A-B). A renal ultrasound showed a 4-mm non-obstructing calculus in the lower pole of the right kidney, indicating nephrolithiasis, a well-documented complication of long-term phosphorus and calcitriol therapy (Jan de Beur, 2005).Fig. 2 Pre-operative DXA scans measuring bone mineral density (BMD). (A) Pre-operative bone density of the lumbar spine, (L1-L4): 1.202 g per square cm, T-score (SD of peak BMD): 0.1 Z-score (SD of age-matched BMD): 0.1. (B) Pre-operative bone density of the left forearm (radius 33%) is: 0.694 g per square cm T-score (SD of peak BMD): −2.1 Z-score (SD of age-matched BMD): −2.1. Bone density of the femurs could not be performed due to bilateral hip prostheses.
Fig. 2
Additionally, a 13-gene Invitae hypophosphatemia panel (https://www.invitae.com/en/hypophosphatemia) (Table 1) was performed to adjudicate her clinical diagnosis of XLH. No pathogenic variants were detected prompting our team to suspect TIO and re-evaluate her previous XLH diagnosis.Table 1 Genes tested on the Invitae hypophosphatemia next-generation sequencing panel (https://www.invitae.com/en/hypophosphatemia), with associated localization, diseases, and pathological mutations (Lloyd et al., 1996; Priante et al., 2017; Root, 2018). Panel is sensitive to deletions, insertions, duplications and copy number variants, and single-nucleotide polymorphisms (SNPs). AD = autosomal dominant, AR = autosomal recessive, VDDR = Vitamin D-dependent rickets.
Table 1Gene Primary location(s) of expression Type of mutation precipitating disease Associated hypophosphatemic/osteomalacic disease
ALPL Osteoblasts Loss of function Hypophosphatasia
CLCN5 Proximal renal tubule Loss of function X-linked recessive hypophosphatemic rickets
CYP27B1 Many cell types Loss of function AR VDDR type 1A
CYP2R1 Hepatocytes Loss of function AR VDDR type 1B
DMP1 Osteoblasts, osteocytes Loss of function AR hypophosphatemic rickets
ENPP1 Chondrocytes, osteocytes, plasma cells Loss of function AR hypophosphatemic rickets
FAH Hepatocytes Loss of function AR tyrosinemia type 1
FAM20C Osteoblasts, osteocytes Loss of function AR osteosclerotic bone dysplasia (Raine syndrome)
FGF23 Osteoblasts, osteocytes Gain of function AD hypophosphatemic rickets
FGFR1 Many cell types Gain of function AD type 1 Pfeiffer syndrome and osteoglophonic dysplasia; synthesis upregulated in many TIO-associated tumors
PHEX Osteoblasts Loss of function, X-linked XLH, increased FGF23 secretion
SLC34A3 Proximal renal tubule Loss of function AR hypophosphatemic rickets with hypercalciuria
VDR Loss of function Calcitriol resistance, VDDR type 2A
Due to suspected TIO, a combined 68Ga-DOTATATE PET/CT scan was performed. The CT Scan (Fig. 3A) revealed an unusual lesion in her 9th lateral right rib; PET scan (Fig. 3B) showed that this lesion had high activity; and a 68Ga-DOTATATE scan (an indirect measure of somatostatin receptors which are highly expressed in most TIO-causing tumors) demonstrated activity in the same region (Fig. 3C-D).Fig. 3 Diagnostic radiologic characterization of the right rib mass. (A) CT (white arrows = mass). (B) PET (white arrows = activity). (C) 68 Ga-DOTATE Scan Axial (red arrows = activity). (D) 68 Ga-DOTATE Scan Coronal (A/P) (red arrows = activity).
Fig. 3
Some TIO patients with unresectable or unidentifiable PMTs have benefited greatly from Burosumab therapy (Jan De Beur et al., 2019). However, the accessibility of our patient's tumor prompted us to refer her to Thoracic Surgery for complete resection of the tumor and rib. Further, Burosumab therapy was discontinued prior to measuring baseline laboratory values due to potential confounding, especially with the FGF23 level.
Intra-operatively, surgeons identified a more concerning lesion on the patient's 10th right rib (Fig. 4A) that had no imaging correlate. This lesion was removed, and the surgeons deferred removal of the 9th right rib to ensure the 10th right rib lesion was not the culprit of her TIO symptoms or other pathology warranting alternative intervention. The patient's hypophosphatemia persisted post-operatively. 4-months after surgery, notable lab values included low serum phosphorus (1.4 mg/dL; normal 2.3–4.7 mg/dL), low 1,25 dihydroxyvitamin D (15 pg/mL; 19.9–79.3 pg/mL), normal total vitamin D (38 ng/mL; 25–80 ng/mL), and elevated total FGF23 (1532 RU/mL; <180 RU/mL). Histopathology of the 10th right rib mass showed only non-specific reactive changes, possibly representing an old fracture site.Fig. 4 Gross appearance of surgical specimens. (A) Intra-operative image of 10th right rib mass (no imaging correlate) removed during the first, unsuccessful surgery. White star (*) denotes the large abnormality that prompted surgeons to remove the 10th rib mass. (B-C) Post-operative images of 9th right rib removed during the second, successful surgery. (B) White stars (*) denote the two areas of abnormality, red arrow denotes the primary lesion of concern for PMT shown in Fig. 5, Fig. 6. (C) Significant thickening observed in the 9th right rib.
Fig. 4
These findings further implicated the active 9th rib lesion in her pathology (Figure 3), prompting Thoracic Surgery to remove the 9th right rib (Fig. 4B-C) 5 months after the first unsuccessful surgery. Gross appearance of the 9th right rib showed two areas of abnormality with one denoting the PMT lesion (Fig. 4B) and significant rib thickening along the lateral surface (Fig. 4C). Histological sections of the 9th right rib showed a morphologically classical phosphaturic mesenchymal tumor, consisting of bland spindled cells in a highly vascular background, with unusually hyalinized to occasionally calcified matrix (Fig. 5). Chromogenic in situ hybridization (CISH) of the tumor and RNA-sequencing for the presence of rearrangements in 138 target genes were pursued using methods previously published (Martinez et al., 2019; Carter et al., 2015). FGF23 CISH was strongly positive (Fig. 6). Sequencing was positive for the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1). Taken together, these results are characteristic of a typical PMT.Fig. 5 Histological appearance of 9th right rib phosphaturic mesenchymal tumor (PMT). A) Lower magnification showing infiltration of rib bone (pink, paucicellular) by the PMT. B) Higher magnification (black box of A) of the PMT specifically showing proliferation of uniform short spindle to ovoid cells with a rich vascular background and cystic changes. C) Low magnification of the PMT from a different depth of sectioning.
Fig. 5Fig. 6 FGF23 chromogenic in situ hybridization (CISH) of 9th right rib phosphaturic mesenchymal tumor (PMT).
Fig. 6Fig. 7 Post-operative portable chest X-ray after rib removal (second successful surgery). A left humeral rod and right chest tube are observed. No pneumothorax is seen. The lungs appear clear except for volume loss related to the overlying thoracic deformity. Extensive bone deformities identified, and multiple performed ribs are seen bilaterally but both appear similar to pre-operative radiographs.
Fig. 7Table 2 Longitudinal patient laboratory values. Op 1 denotes the first unsuccessful 10th rib removal operation. Op 2 denotes the second successful 9th rib removal operation. PTH = parathyroid hormone. Note = Pre-Op 1 labs were taken while the patient was on Burosumab, all other labs were taken while the patient was off Burosumab, and Post-Op 2 labs were taken 3 months after resection.
Table 2Laboratory value Normal range Pre-Op 1 (on Burosumab) Post-Op 1, Pre-Op 2 Post-Op 2 (3 months after 9th right rib resection)
Serum phosphorus 2.3–4.7 mg/dL 2.5 1.4 3.7
Calcium 8.4–10.5 mg/dL 9.7 9.3 10.4
Total vitamin D 25–80 ng/mL 40 38 35
1,25 dihydroxyvitamin D 19.9–79.3 pg/mL 333 15 327
Alkaline phosphatase 40–150 U/L 168 111 130
Chloride 96–106 mmol/L 108 109 105
PTH 16–77 pg/mL 189 Not collected 194
FGF23 <180 RU/mL 36,900 1532 245
3 months post-resection, chest x-rays showed no pneumothorax and no significant changes compared to prior radiographs (Fig. 7). FGF23 levels decreased again but remained slightly elevated (245 RU/mL), serum phosphorus normalized (3.7 mg/dL), alkaline phosphatase normalized (130 U/mL), and total vitamin D was 35 ng/mL. Parathyroid hormone remained elevated (194 pg/mL) (Table 2). Clinical assessments of mobility markedly improved (Video 1, Video 2), and the patient has stated she is in less pain and is more active and feels stronger than ever. She will continue to follow up longitudinally in our Endocrinology clinic.
3 Discussion
TIO is a paraneoplastic disease resulting in elevated FGF23, renal phosphate wasting, defective Vitamin D metabolism, and subsequent osteomalacia. Clinically, patients with TIO present with progressive bone pain, muscle weakness, fatigue, and sporadic insufficiency fractures (Yin et al., 2018). TIO can be suggested by serum hypophosphatemia, hyperphosphaturia, and low or inappropriately normal calcitriol levels, but the identification of a phosphaturic mesenchymal tumor (PMT) in the soft tissue or bone is necessary for definitive diagnosis (Feng et al., 2017). Here, we presented a 41-year-old woman suffering from TIO with a 26-year delay in diagnosis with a concurrent misdiagnosis of XLH.
Diagnosing TIO is often complicated by small tumor size and similar initial clinical presentation to more common phosphate wasting disorders such as XLH. A retrospective study of 144 TIO cases found that TIO was misdiagnosed in over 95% (137/144) of cases, with intervertebral disc herniation, spondyloarthritis, and osteoporosis being the most common misdiagnoses (Feng et al., 2017). In this case, our patient was misdiagnosed for 26 years with little symptomatic improvement with either conventional therapy or Burosumab, and subsequent gene paneling at our institution revealed no genetic evidence of her XLH diagnosis.
Patients who present with bone pain, muscle weakness, and multiple fractures should be evaluated for hypophosphatemia, and TMP/GFR should be performed for hypophosphatemic patients. While diagnostically burdensome, a low TMP/GFR is a powerful indicator of renal phosphate wasting in the absence of secondary hyperthyroidism (Jagtap et al., 2012). Though less sensitive than TMP/GFR, calculating a percent tubular reabsorption of phosphate (TRP) is a more easily collected alternative (Takeda et al., 2015). Additionally, 24-h urine phosphorus and calcium can differentiate between malabsorption and phosphate wasting disorders (Payne, 1998).
Patient FGF23 levels and family/personal histories are also important tools for differentiating between phosphate wasting disorders (Table 3). As discussed in our previous report, TIO distinguishes itself from other FGF23-high phosphate wasting disorders in that it often presents with rapid symptom onset later in life, often with a negative family history. On the other hand, XLH is usually inherited as an X-linked dominant inherited disorder that typically presents in early childhood (MD, 2012). As such, genetic testing and associated costs can often be avoided if a clear X-linked pattern is identified by pedigree. That said, XLH can still occur due to de novo mutations, so absence of a family history should not entirely rule out XLH (Durmaz et al., 2013).Table 3 Phosphate wasting disorder differential diagnosis. A differential diagnosis table (not extensive) for phosphate wasting disorders, including TIO, distinguished by serum FGF23 level, reproduced from Colazo et al. (n.d.), Imel and Econs (2012), and Zoller et al. (2017).
Table 3Phosphate wasting disorders with low FGF23 Phosphate wasting disorders with high or “inappropriately normal” FGF23
Fanconi syndrome X-linked hypophosphatemia (XLH)
Hyperparathyroidism Tumor-induced osteomalacia (TIO)
Diuretics (e.g. acetazolamide) Autosomal dominant/autosomal recessive rickets
Myeloma McCune Albright syndrome
Copper disorders (Menkes) Cutaneous-skeletal hypophosphatemia syndrome (CSHS) (e.g., epidermal nevus syndromes)
Alcohol consumption Iron use (iron polymaltose infusions)
Genetic disorders (e.g. Npt2a mutations)
Finally, in the absence of genetic data, indication of several bone and calcification disorders can help distinguish XLH from TIO, though these criteria are highly variable. Enthesopathy (calcification of the joint capsule, tendon insertions, and ligaments) is a common feature of XLH but not of TIO and results in increased apparent BMD (Beck-Nielsen et al., 2019). By contrast, typical TIO patients have remarkably low BMD, often being labelled osteoporotic. Dentition is another clinical differentiator, in that patients with XLH can have recurrent abscesses and dental loss, while dentition in TIO is usually normal (Lee et al., 2017). However, the patient presented here was edentulous, demonstrating that TIO should not be ruled out based on these features.
Suspected TIO should prompt an investigation for active PMTs in the hands, feet, ribs, nasal cavities, and brain (Colazo et al., n.d). In recent literature, a full body 68Ga-DOTATATE scan has been shown to be a specific imaging test for identifying culprit tumors in osteomalacia (Zhang et al., 2015). The 68Ga-DOTATATE scan works by utilizing 68Gallium (68Ga) conjugated to somatostatin peptide analogues, which allows for somatostatin receptor imaging by PET scan. DOTATATE scans are most often used for diagnosing somatostatin-receptor positive neuroendocrine tumors, but PMTs preferentially express somatostatin type 2 receptors (Houang et al., 2013). Hence, this technique allows for targeted imaging of TIO-causing lesions. That said, false positivity can still occur in hypersplenism, fractures, sarcoidosis, or vertebral hemangiomas (Hofman et al., 2015). If very small and/or multiple tumors of unknown significance are present, selective FGF23 venous sampling has shown promise in deciphering the FGF23-producing tumor (Colazo et al., n.d.; Schober et al., 2017). In this case, since two suspicious lesions were encountered, FGF23 venous sampling could have been utilized, but the anatomical location and proximity of both lesions to each other would have made the process difficult to perform and most likely futile.
Misdiagnosis can also occur after tumor identification, especially in cases in which non-PMT tumors morphologically mimic PMTs in the context of hypophosphatemia (Lee et al., 2016). Recent studies have identified novel gene fusions FN1-FGF1 and FN1-FGFR1 that are transcribed and synthesized by the majority of PMTs. The fusion of FN1 and FGFR1 leads to constitutive overexpression of the 3′ portion of FGFR1 through constitutive activation of the FN1 promoter, and the fusion protein products have suspected roles in autocrine signaling (Lee et al., 2016). These fusion products can be detected by RNA sequencing or FISH of the tumor, and several emerging FGF/R inhibitors have been shown to be therapeutically beneficial in relapsing TIO (Hartley et al., 2020).
While diagnosis of TIO depends solely on postoperative biochemical resolution of laboratory abnormalities, the classification of the resected tumor can be helpful. Our patient's tumor tested positive for FN1-FGFR1 by RNAseq and for FGF23 by chromogenic in situ hybridization (CISH), further suggesting PMT (Martinez et al., 2019; Carter et al., 2015). These results support the use of FN1-FGF1/R1 gene fusions and FGF23 CISH as an additional diagnostic tool for TIO and can be used for comparison between the original and a recurrent tumor.
To date, surgical PMT resection is the only curative therapy for TIO. To mitigate risk of recurrence or metastasis, resection should be performed with wide margins where possible, and patients should be monitored longitudinally post-operatively (Hautmann et al., 2015). Here, our patient had dramatic improvements 3 months post-resection in symptoms and mobility (Video 1, Video 2), as well as in serum FGF23, phosphate, and Vitamin D levels (Table 2). Patients with unresectable or undetectable tumors have historically been placed on supplemental phosphate and calcitriol; however, Burosumab is a novel human anti-FGF23 monoclonal antibody initially approved by the FDA to treat XLH that has been recently approved for treatment of such complex TIO presentations (Carpenter et al., 2016; Day et al., 2020). In particular, Kyowa Kirin and Ultragenyx's Crysvita (burosumab-twza) has been approved for the treatment of TIO associated with PMTs that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older. Burosumab has been shown to improve serum phosphate levels and histomorphology of bone biopsies in patients with TIO, but mild side effects have been reported, including reactive overproduction of FGF23 and consequent Vitamin D deficiency (Day et al., 2020). For these reasons, monitoring FGF23 levels is not a reliable way to monitor patients on Burosumab; clinicians should focus on serum phosphorous, Alkaline phosphatase, renal phosphate wasting, 1,25 Dihydroxyvitamin D, and clinical signs/symptoms.
Indeed, in the 3 months prior to tumor identification, our patient was placed on Burosumab therapy and enjoyed mild symptomatic improvement and stable lab values (notably a normal serum phosphorus, see Table 2). While no labs were taken pre-induction, her condition deteriorated while off Burosumab between her two rib resections, indicating a positive impact of Burosumab on her condition. Her marked post-operative improvement supports the use of PMT resection when possible.
In this report, we have demonstrated the utility of two powerful genetic tools – gene paneling and RNA sequencing – at guiding clinicians to a challenging diagnosis of a non-heritable condition. In the 26-year history of this patient's disease, genetic tools have become increasingly cost-effective, sensitive, and precise. A lack of available tests at initial presentation motivated a diagnosis of XLH (a germline genetic condition) based on clinical evidence alone. The similar clinical presentations of many phosphate wasting disorders, the uniqueness of their genetic identifiers like FN1-FGFR1 or PHEX, and the illumination of known, curative therapies through such tests all support the expanded use of gene paneling and tumor sequencing alongside clinical reasoning around phosphate wasting disorders. This fact is further evidenced by the requirement of genetic diagnosis for enrollment in most clinical trials targeting phosphate wasting disorders. Additionally, the advancements in the field over the past 3 decades may warrant the re-evaluation of poorly managed, long-term diagnoses through the lens of a gene panel or specific genetic marker.
4 Conclusion
Tumor-induced osteomalacia (TIO) is a paraneoplastic disease driven by hypersecretion of Fibroblast Growth Factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). In this case report, we present a patient with what we believe to be the longest history of a delayed TIO diagnosis reported in the literature, outlined current diagnostic strategies, and demonstrated the increasing utility of genetic testing in the diagnosis of phosphate wasting disorders.
We highlight the importance of the personal and family histories, as well as potential pitfalls of using exclusively clinical criteria in diagnosing phosphate wasting disorders, as our patient had several clinical findings suggestive of XLH yet had a negative family history of phosphate wasting disorders. Further, we stress the utility of full body imaging, especially a 68Ga-DOTATATE PET/CT scan, in probing cases of high clinical suspicion for TIO, and we applied novel genetic screening methods (i.e. gene paneling and tumor RNA sequencing) to confirm our diagnosis. When possible, performing these tests provides powerful support for a TIO diagnosis. Finally, while our patient has enjoyed a marked recovery 3 months post-surgical resection, we discuss Burosumab, an emerging therapeutic antibody against FGF23 that may be an attractive treatment for undetectable or unresectable tumors in TIO.
The following are the supplementary data related to this article.Video 1
Pre-operative functionality of patient
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Post-operative functionality of patient
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Acknowledgments
Two of the authors (JMC, JAD) are supported by NIGMS of the National Institutes of Health under award number T32GM007347. The content in this report is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The Transparency document associated with this article can be found, in online version. | BUROSUMAB-TWZA | DrugsGivenReaction | CC BY-NC-ND | 33490314 | 18,819,395 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood alkaline phosphatase increased'. | Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia.
Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A 68Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases.
1 Introduction
Osteomalacia is the progressive softening of bones due to decreased mineralization of calcium and phosphates at sites of bone remodeling and growth, commonly resulting in bone pain and muscle weakness (Michigami, 2019). Fibroblast Growth Factor 23 (FGF23) is a protein secreted by osteocytes mainly in response to calcitriol and phosphate (Martin et al., 2012). FGF23 regulates plasma phosphate concentration predominately by reducing serum calcitriol which mediates intestinal phosphate absorption and by reducing NPT2-mediated phosphate reabsorption in the kidney. Tumor-Induced Osteomalacia (TIO) is a rare paraneoplastic disease in which a phosphaturic mesenchymal tumor (PMT) secretes significant amounts of FGF23 into the bloodstream, leading to downstream osteomalacia through renal phosphate wasting and defective Vitamin D metabolism (Yin et al., 2018). While less than 500 cases of TIO have been reported worldwide, and formal epidemiological studies of the disease have not been performed, surgical resection offers a potentially curative treatment in contrast to similarly presenting disorders (Folpe, 2019).
X-linked hypophosphatemia (XLH) is a phosphate wasting disorder caused by mutations in the PHEX gene which expresses the enzyme phosphate-regulating neutral endopeptidase (PHEX). Studies suggest that the PHEX enzyme may be involved in the regulation of FGF23 (Beck-Nielsen et al., 2019; Liu et al., 2003). Importantly, diagnosing phosphate wasting disorders based purely on clinical criteria is confounded by the similarity of clinical and radiological presentations of this family of disorders. Knowing the distinct genetic basis for a patient's phosphate wasting disorder often allows clinicians to tailor their treatment/management strategy accordingly, potentially saving years of hardship for affected patients. As such, recent emphasis has been placed on using gene panels to accelerate clinicians' diagnosis of these disorders.
In particular, a potential for misdiagnosis of TIO as XLH exists because FGF23 levels are increased in both, PMT tumors are notoriously difficult to find due to their small size and variable location, and (albeit still rare) the incidence of XLH far exceeds that of TIO (Yin et al., 2018; Carpenter, 1997). Here, we present a 41-year-old female in whom a 26-year delayed TIO diagnosis and concurrent misdiagnosis of XLH was identified via a negative hypophosphatemia gene panel and corrected to TIO through identification of a PMT of her 9th right rib. Surgical resection resulted in biochemical and clinical symptom improvement. Histological analysis was positive for FGF23 (CISH) and the FN1-FGFR1 transcriptional marker. Finally, we highlight recent key advances in diagnosing phosphate wasting disorders, molecular characterization of PMTs, and TIO treatment and management.
2 Case presentation
A 41-year-old woman with a prior clinical diagnosis of hypophosphatemic rickets presented to our institution with a 26-year history of low phosphorus, bone pain, proximal muscle weakness, gait abnormalities, and multiple traumatic and insufficiency fractures of the hip, humerus, and spine (Fig. 1, Fig. 7). She had no history of hearing loss. She had lost all her secondary teeth (edentulous). The patient reported no family history of hypophosphatemia, including her 8-year-old male child and 17-year-old female child, neither of whom showed clinical or laboratory indications of musculoskeletal conditions or phosphate wasting disorders. Her maximum height was 5′2″ but she presented to us at 4′8″ due to progressive spine deformities.
Despite intermittent treatment with conventional therapy with phosphorus supplements and calcitriol during her teens and 20s, she developed progressive gait abnormalities and decreased hip strength and ultimately sustained bilateral hip fractures (Fig. 1A) and small fractures throughout her spine (Fig. 1B-C).Fig. 1 Patient musculoskeletal radiology. X-ray AP Pelvis (A) shows evidence of prior bilateral obturator ring fractures with bilateral femoral head/neck angular deformities. X-ray Spine Total AP/Lateral (B-C) shows normal trabecular bone with vertebral body alignments and interspacing intact, but there is mild flattening of the mid vertebral body at multiple levels. There is evidence of previous insufficiency fractures.
Fig. 1
Despite treatment, the patient's symptoms deteriorated further in her 20s, when she had stability rods and screws placed bilaterally in her femurs and hips, respectively (Fig. 1A). Ten years later, the patient presented with a traumatic left humerus fracture, for which she underwent surgery (Figure 7). Post-operatively, the patient was placed on the osteoporosis medication teriparatide.
Teriparatide therapy failed to prevent more spinal fractures (Fig. 1B-C), bone pain, and muscle weakness over the next year, and the patient was eventually confined to a wheelchair. Orthopedic physicians reevaluated her history, officially diagnosed her with X-linked Hypophosphatemia (XLH) (although patient claims having an “unofficial” XLH diagnosis years prior by previous physicians), and started her on Burosumab (60 mg subcutaneous injection every 28 days) - the monoclonal antibody targeted against FGF23. Unfortunately, laboratory values relevant to phosphate wasting (e.g. TmP/GFR, FGF23) were not reported prior to initiation of Burosumab therapy or referral to our institution for further evaluation and treatment.
The patient remained on Burosumab for 3 months. While on Burosumab, the patient reported mild symptomatic improvement with no reported adverse effects, but still had severe limitations in mobility (difficulty from sit to stand, Video 1), fatigue, and pain. On therapy, FGF23 levels were 33,900 RU/mL (normal <180RU/mL) and 36,900 RU/mL two months later as measured by ELISA (Quidel Corporation). Other notable preoperative laboratory values include a normal serum phosphorus, normal calcium, normal total vitamin D, elevated 1,25 dihydroxyvitamin D (333 pg/mL; normal 19.9–79.3 pg/mL), high alkaline phosphatase (168 U/mL; normal 40–150 U/mL), and high PTH (189 pg/mL, normal 16–77 pg/mL) (Table 2). These findings are abnormal for a patient with TIO, but they should be viewed in the context of Burosumab therapy. After discontinuation, her total FGF23 declined to 1532 RU/mL after discontinuing Burosumab but before excision of her PMT which was still considerably elevated above reference range.
At our clinic, areal bone density of the lumbar spine and left forearm (bone density of the femurs could not be performed due to bilateral hip prostheses) were assessed by dual-energy X-ray absorptiometry (DXA) using a GE Lunar Prodigy Advanced densitometer. Densitometry revealed normal bone density in the spine and significantly lower than expected density in the forearm (Fig. 2A-B). A renal ultrasound showed a 4-mm non-obstructing calculus in the lower pole of the right kidney, indicating nephrolithiasis, a well-documented complication of long-term phosphorus and calcitriol therapy (Jan de Beur, 2005).Fig. 2 Pre-operative DXA scans measuring bone mineral density (BMD). (A) Pre-operative bone density of the lumbar spine, (L1-L4): 1.202 g per square cm, T-score (SD of peak BMD): 0.1 Z-score (SD of age-matched BMD): 0.1. (B) Pre-operative bone density of the left forearm (radius 33%) is: 0.694 g per square cm T-score (SD of peak BMD): −2.1 Z-score (SD of age-matched BMD): −2.1. Bone density of the femurs could not be performed due to bilateral hip prostheses.
Fig. 2
Additionally, a 13-gene Invitae hypophosphatemia panel (https://www.invitae.com/en/hypophosphatemia) (Table 1) was performed to adjudicate her clinical diagnosis of XLH. No pathogenic variants were detected prompting our team to suspect TIO and re-evaluate her previous XLH diagnosis.Table 1 Genes tested on the Invitae hypophosphatemia next-generation sequencing panel (https://www.invitae.com/en/hypophosphatemia), with associated localization, diseases, and pathological mutations (Lloyd et al., 1996; Priante et al., 2017; Root, 2018). Panel is sensitive to deletions, insertions, duplications and copy number variants, and single-nucleotide polymorphisms (SNPs). AD = autosomal dominant, AR = autosomal recessive, VDDR = Vitamin D-dependent rickets.
Table 1Gene Primary location(s) of expression Type of mutation precipitating disease Associated hypophosphatemic/osteomalacic disease
ALPL Osteoblasts Loss of function Hypophosphatasia
CLCN5 Proximal renal tubule Loss of function X-linked recessive hypophosphatemic rickets
CYP27B1 Many cell types Loss of function AR VDDR type 1A
CYP2R1 Hepatocytes Loss of function AR VDDR type 1B
DMP1 Osteoblasts, osteocytes Loss of function AR hypophosphatemic rickets
ENPP1 Chondrocytes, osteocytes, plasma cells Loss of function AR hypophosphatemic rickets
FAH Hepatocytes Loss of function AR tyrosinemia type 1
FAM20C Osteoblasts, osteocytes Loss of function AR osteosclerotic bone dysplasia (Raine syndrome)
FGF23 Osteoblasts, osteocytes Gain of function AD hypophosphatemic rickets
FGFR1 Many cell types Gain of function AD type 1 Pfeiffer syndrome and osteoglophonic dysplasia; synthesis upregulated in many TIO-associated tumors
PHEX Osteoblasts Loss of function, X-linked XLH, increased FGF23 secretion
SLC34A3 Proximal renal tubule Loss of function AR hypophosphatemic rickets with hypercalciuria
VDR Loss of function Calcitriol resistance, VDDR type 2A
Due to suspected TIO, a combined 68Ga-DOTATATE PET/CT scan was performed. The CT Scan (Fig. 3A) revealed an unusual lesion in her 9th lateral right rib; PET scan (Fig. 3B) showed that this lesion had high activity; and a 68Ga-DOTATATE scan (an indirect measure of somatostatin receptors which are highly expressed in most TIO-causing tumors) demonstrated activity in the same region (Fig. 3C-D).Fig. 3 Diagnostic radiologic characterization of the right rib mass. (A) CT (white arrows = mass). (B) PET (white arrows = activity). (C) 68 Ga-DOTATE Scan Axial (red arrows = activity). (D) 68 Ga-DOTATE Scan Coronal (A/P) (red arrows = activity).
Fig. 3
Some TIO patients with unresectable or unidentifiable PMTs have benefited greatly from Burosumab therapy (Jan De Beur et al., 2019). However, the accessibility of our patient's tumor prompted us to refer her to Thoracic Surgery for complete resection of the tumor and rib. Further, Burosumab therapy was discontinued prior to measuring baseline laboratory values due to potential confounding, especially with the FGF23 level.
Intra-operatively, surgeons identified a more concerning lesion on the patient's 10th right rib (Fig. 4A) that had no imaging correlate. This lesion was removed, and the surgeons deferred removal of the 9th right rib to ensure the 10th right rib lesion was not the culprit of her TIO symptoms or other pathology warranting alternative intervention. The patient's hypophosphatemia persisted post-operatively. 4-months after surgery, notable lab values included low serum phosphorus (1.4 mg/dL; normal 2.3–4.7 mg/dL), low 1,25 dihydroxyvitamin D (15 pg/mL; 19.9–79.3 pg/mL), normal total vitamin D (38 ng/mL; 25–80 ng/mL), and elevated total FGF23 (1532 RU/mL; <180 RU/mL). Histopathology of the 10th right rib mass showed only non-specific reactive changes, possibly representing an old fracture site.Fig. 4 Gross appearance of surgical specimens. (A) Intra-operative image of 10th right rib mass (no imaging correlate) removed during the first, unsuccessful surgery. White star (*) denotes the large abnormality that prompted surgeons to remove the 10th rib mass. (B-C) Post-operative images of 9th right rib removed during the second, successful surgery. (B) White stars (*) denote the two areas of abnormality, red arrow denotes the primary lesion of concern for PMT shown in Fig. 5, Fig. 6. (C) Significant thickening observed in the 9th right rib.
Fig. 4
These findings further implicated the active 9th rib lesion in her pathology (Figure 3), prompting Thoracic Surgery to remove the 9th right rib (Fig. 4B-C) 5 months after the first unsuccessful surgery. Gross appearance of the 9th right rib showed two areas of abnormality with one denoting the PMT lesion (Fig. 4B) and significant rib thickening along the lateral surface (Fig. 4C). Histological sections of the 9th right rib showed a morphologically classical phosphaturic mesenchymal tumor, consisting of bland spindled cells in a highly vascular background, with unusually hyalinized to occasionally calcified matrix (Fig. 5). Chromogenic in situ hybridization (CISH) of the tumor and RNA-sequencing for the presence of rearrangements in 138 target genes were pursued using methods previously published (Martinez et al., 2019; Carter et al., 2015). FGF23 CISH was strongly positive (Fig. 6). Sequencing was positive for the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1). Taken together, these results are characteristic of a typical PMT.Fig. 5 Histological appearance of 9th right rib phosphaturic mesenchymal tumor (PMT). A) Lower magnification showing infiltration of rib bone (pink, paucicellular) by the PMT. B) Higher magnification (black box of A) of the PMT specifically showing proliferation of uniform short spindle to ovoid cells with a rich vascular background and cystic changes. C) Low magnification of the PMT from a different depth of sectioning.
Fig. 5Fig. 6 FGF23 chromogenic in situ hybridization (CISH) of 9th right rib phosphaturic mesenchymal tumor (PMT).
Fig. 6Fig. 7 Post-operative portable chest X-ray after rib removal (second successful surgery). A left humeral rod and right chest tube are observed. No pneumothorax is seen. The lungs appear clear except for volume loss related to the overlying thoracic deformity. Extensive bone deformities identified, and multiple performed ribs are seen bilaterally but both appear similar to pre-operative radiographs.
Fig. 7Table 2 Longitudinal patient laboratory values. Op 1 denotes the first unsuccessful 10th rib removal operation. Op 2 denotes the second successful 9th rib removal operation. PTH = parathyroid hormone. Note = Pre-Op 1 labs were taken while the patient was on Burosumab, all other labs were taken while the patient was off Burosumab, and Post-Op 2 labs were taken 3 months after resection.
Table 2Laboratory value Normal range Pre-Op 1 (on Burosumab) Post-Op 1, Pre-Op 2 Post-Op 2 (3 months after 9th right rib resection)
Serum phosphorus 2.3–4.7 mg/dL 2.5 1.4 3.7
Calcium 8.4–10.5 mg/dL 9.7 9.3 10.4
Total vitamin D 25–80 ng/mL 40 38 35
1,25 dihydroxyvitamin D 19.9–79.3 pg/mL 333 15 327
Alkaline phosphatase 40–150 U/L 168 111 130
Chloride 96–106 mmol/L 108 109 105
PTH 16–77 pg/mL 189 Not collected 194
FGF23 <180 RU/mL 36,900 1532 245
3 months post-resection, chest x-rays showed no pneumothorax and no significant changes compared to prior radiographs (Fig. 7). FGF23 levels decreased again but remained slightly elevated (245 RU/mL), serum phosphorus normalized (3.7 mg/dL), alkaline phosphatase normalized (130 U/mL), and total vitamin D was 35 ng/mL. Parathyroid hormone remained elevated (194 pg/mL) (Table 2). Clinical assessments of mobility markedly improved (Video 1, Video 2), and the patient has stated she is in less pain and is more active and feels stronger than ever. She will continue to follow up longitudinally in our Endocrinology clinic.
3 Discussion
TIO is a paraneoplastic disease resulting in elevated FGF23, renal phosphate wasting, defective Vitamin D metabolism, and subsequent osteomalacia. Clinically, patients with TIO present with progressive bone pain, muscle weakness, fatigue, and sporadic insufficiency fractures (Yin et al., 2018). TIO can be suggested by serum hypophosphatemia, hyperphosphaturia, and low or inappropriately normal calcitriol levels, but the identification of a phosphaturic mesenchymal tumor (PMT) in the soft tissue or bone is necessary for definitive diagnosis (Feng et al., 2017). Here, we presented a 41-year-old woman suffering from TIO with a 26-year delay in diagnosis with a concurrent misdiagnosis of XLH.
Diagnosing TIO is often complicated by small tumor size and similar initial clinical presentation to more common phosphate wasting disorders such as XLH. A retrospective study of 144 TIO cases found that TIO was misdiagnosed in over 95% (137/144) of cases, with intervertebral disc herniation, spondyloarthritis, and osteoporosis being the most common misdiagnoses (Feng et al., 2017). In this case, our patient was misdiagnosed for 26 years with little symptomatic improvement with either conventional therapy or Burosumab, and subsequent gene paneling at our institution revealed no genetic evidence of her XLH diagnosis.
Patients who present with bone pain, muscle weakness, and multiple fractures should be evaluated for hypophosphatemia, and TMP/GFR should be performed for hypophosphatemic patients. While diagnostically burdensome, a low TMP/GFR is a powerful indicator of renal phosphate wasting in the absence of secondary hyperthyroidism (Jagtap et al., 2012). Though less sensitive than TMP/GFR, calculating a percent tubular reabsorption of phosphate (TRP) is a more easily collected alternative (Takeda et al., 2015). Additionally, 24-h urine phosphorus and calcium can differentiate between malabsorption and phosphate wasting disorders (Payne, 1998).
Patient FGF23 levels and family/personal histories are also important tools for differentiating between phosphate wasting disorders (Table 3). As discussed in our previous report, TIO distinguishes itself from other FGF23-high phosphate wasting disorders in that it often presents with rapid symptom onset later in life, often with a negative family history. On the other hand, XLH is usually inherited as an X-linked dominant inherited disorder that typically presents in early childhood (MD, 2012). As such, genetic testing and associated costs can often be avoided if a clear X-linked pattern is identified by pedigree. That said, XLH can still occur due to de novo mutations, so absence of a family history should not entirely rule out XLH (Durmaz et al., 2013).Table 3 Phosphate wasting disorder differential diagnosis. A differential diagnosis table (not extensive) for phosphate wasting disorders, including TIO, distinguished by serum FGF23 level, reproduced from Colazo et al. (n.d.), Imel and Econs (2012), and Zoller et al. (2017).
Table 3Phosphate wasting disorders with low FGF23 Phosphate wasting disorders with high or “inappropriately normal” FGF23
Fanconi syndrome X-linked hypophosphatemia (XLH)
Hyperparathyroidism Tumor-induced osteomalacia (TIO)
Diuretics (e.g. acetazolamide) Autosomal dominant/autosomal recessive rickets
Myeloma McCune Albright syndrome
Copper disorders (Menkes) Cutaneous-skeletal hypophosphatemia syndrome (CSHS) (e.g., epidermal nevus syndromes)
Alcohol consumption Iron use (iron polymaltose infusions)
Genetic disorders (e.g. Npt2a mutations)
Finally, in the absence of genetic data, indication of several bone and calcification disorders can help distinguish XLH from TIO, though these criteria are highly variable. Enthesopathy (calcification of the joint capsule, tendon insertions, and ligaments) is a common feature of XLH but not of TIO and results in increased apparent BMD (Beck-Nielsen et al., 2019). By contrast, typical TIO patients have remarkably low BMD, often being labelled osteoporotic. Dentition is another clinical differentiator, in that patients with XLH can have recurrent abscesses and dental loss, while dentition in TIO is usually normal (Lee et al., 2017). However, the patient presented here was edentulous, demonstrating that TIO should not be ruled out based on these features.
Suspected TIO should prompt an investigation for active PMTs in the hands, feet, ribs, nasal cavities, and brain (Colazo et al., n.d). In recent literature, a full body 68Ga-DOTATATE scan has been shown to be a specific imaging test for identifying culprit tumors in osteomalacia (Zhang et al., 2015). The 68Ga-DOTATATE scan works by utilizing 68Gallium (68Ga) conjugated to somatostatin peptide analogues, which allows for somatostatin receptor imaging by PET scan. DOTATATE scans are most often used for diagnosing somatostatin-receptor positive neuroendocrine tumors, but PMTs preferentially express somatostatin type 2 receptors (Houang et al., 2013). Hence, this technique allows for targeted imaging of TIO-causing lesions. That said, false positivity can still occur in hypersplenism, fractures, sarcoidosis, or vertebral hemangiomas (Hofman et al., 2015). If very small and/or multiple tumors of unknown significance are present, selective FGF23 venous sampling has shown promise in deciphering the FGF23-producing tumor (Colazo et al., n.d.; Schober et al., 2017). In this case, since two suspicious lesions were encountered, FGF23 venous sampling could have been utilized, but the anatomical location and proximity of both lesions to each other would have made the process difficult to perform and most likely futile.
Misdiagnosis can also occur after tumor identification, especially in cases in which non-PMT tumors morphologically mimic PMTs in the context of hypophosphatemia (Lee et al., 2016). Recent studies have identified novel gene fusions FN1-FGF1 and FN1-FGFR1 that are transcribed and synthesized by the majority of PMTs. The fusion of FN1 and FGFR1 leads to constitutive overexpression of the 3′ portion of FGFR1 through constitutive activation of the FN1 promoter, and the fusion protein products have suspected roles in autocrine signaling (Lee et al., 2016). These fusion products can be detected by RNA sequencing or FISH of the tumor, and several emerging FGF/R inhibitors have been shown to be therapeutically beneficial in relapsing TIO (Hartley et al., 2020).
While diagnosis of TIO depends solely on postoperative biochemical resolution of laboratory abnormalities, the classification of the resected tumor can be helpful. Our patient's tumor tested positive for FN1-FGFR1 by RNAseq and for FGF23 by chromogenic in situ hybridization (CISH), further suggesting PMT (Martinez et al., 2019; Carter et al., 2015). These results support the use of FN1-FGF1/R1 gene fusions and FGF23 CISH as an additional diagnostic tool for TIO and can be used for comparison between the original and a recurrent tumor.
To date, surgical PMT resection is the only curative therapy for TIO. To mitigate risk of recurrence or metastasis, resection should be performed with wide margins where possible, and patients should be monitored longitudinally post-operatively (Hautmann et al., 2015). Here, our patient had dramatic improvements 3 months post-resection in symptoms and mobility (Video 1, Video 2), as well as in serum FGF23, phosphate, and Vitamin D levels (Table 2). Patients with unresectable or undetectable tumors have historically been placed on supplemental phosphate and calcitriol; however, Burosumab is a novel human anti-FGF23 monoclonal antibody initially approved by the FDA to treat XLH that has been recently approved for treatment of such complex TIO presentations (Carpenter et al., 2016; Day et al., 2020). In particular, Kyowa Kirin and Ultragenyx's Crysvita (burosumab-twza) has been approved for the treatment of TIO associated with PMTs that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older. Burosumab has been shown to improve serum phosphate levels and histomorphology of bone biopsies in patients with TIO, but mild side effects have been reported, including reactive overproduction of FGF23 and consequent Vitamin D deficiency (Day et al., 2020). For these reasons, monitoring FGF23 levels is not a reliable way to monitor patients on Burosumab; clinicians should focus on serum phosphorous, Alkaline phosphatase, renal phosphate wasting, 1,25 Dihydroxyvitamin D, and clinical signs/symptoms.
Indeed, in the 3 months prior to tumor identification, our patient was placed on Burosumab therapy and enjoyed mild symptomatic improvement and stable lab values (notably a normal serum phosphorus, see Table 2). While no labs were taken pre-induction, her condition deteriorated while off Burosumab between her two rib resections, indicating a positive impact of Burosumab on her condition. Her marked post-operative improvement supports the use of PMT resection when possible.
In this report, we have demonstrated the utility of two powerful genetic tools – gene paneling and RNA sequencing – at guiding clinicians to a challenging diagnosis of a non-heritable condition. In the 26-year history of this patient's disease, genetic tools have become increasingly cost-effective, sensitive, and precise. A lack of available tests at initial presentation motivated a diagnosis of XLH (a germline genetic condition) based on clinical evidence alone. The similar clinical presentations of many phosphate wasting disorders, the uniqueness of their genetic identifiers like FN1-FGFR1 or PHEX, and the illumination of known, curative therapies through such tests all support the expanded use of gene paneling and tumor sequencing alongside clinical reasoning around phosphate wasting disorders. This fact is further evidenced by the requirement of genetic diagnosis for enrollment in most clinical trials targeting phosphate wasting disorders. Additionally, the advancements in the field over the past 3 decades may warrant the re-evaluation of poorly managed, long-term diagnoses through the lens of a gene panel or specific genetic marker.
4 Conclusion
Tumor-induced osteomalacia (TIO) is a paraneoplastic disease driven by hypersecretion of Fibroblast Growth Factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). In this case report, we present a patient with what we believe to be the longest history of a delayed TIO diagnosis reported in the literature, outlined current diagnostic strategies, and demonstrated the increasing utility of genetic testing in the diagnosis of phosphate wasting disorders.
We highlight the importance of the personal and family histories, as well as potential pitfalls of using exclusively clinical criteria in diagnosing phosphate wasting disorders, as our patient had several clinical findings suggestive of XLH yet had a negative family history of phosphate wasting disorders. Further, we stress the utility of full body imaging, especially a 68Ga-DOTATATE PET/CT scan, in probing cases of high clinical suspicion for TIO, and we applied novel genetic screening methods (i.e. gene paneling and tumor RNA sequencing) to confirm our diagnosis. When possible, performing these tests provides powerful support for a TIO diagnosis. Finally, while our patient has enjoyed a marked recovery 3 months post-surgical resection, we discuss Burosumab, an emerging therapeutic antibody against FGF23 that may be an attractive treatment for undetectable or unresectable tumors in TIO.
The following are the supplementary data related to this article.Video 1
Pre-operative functionality of patient
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Post-operative functionality of patient
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Acknowledgments
Two of the authors (JMC, JAD) are supported by NIGMS of the National Institutes of Health under award number T32GM007347. The content in this report is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The Transparency document associated with this article can be found, in online version. | BUROSUMAB-TWZA | DrugsGivenReaction | CC BY-NC-ND | 33490314 | 18,819,395 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood parathyroid hormone increased'. | Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia.
Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A 68Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases.
1 Introduction
Osteomalacia is the progressive softening of bones due to decreased mineralization of calcium and phosphates at sites of bone remodeling and growth, commonly resulting in bone pain and muscle weakness (Michigami, 2019). Fibroblast Growth Factor 23 (FGF23) is a protein secreted by osteocytes mainly in response to calcitriol and phosphate (Martin et al., 2012). FGF23 regulates plasma phosphate concentration predominately by reducing serum calcitriol which mediates intestinal phosphate absorption and by reducing NPT2-mediated phosphate reabsorption in the kidney. Tumor-Induced Osteomalacia (TIO) is a rare paraneoplastic disease in which a phosphaturic mesenchymal tumor (PMT) secretes significant amounts of FGF23 into the bloodstream, leading to downstream osteomalacia through renal phosphate wasting and defective Vitamin D metabolism (Yin et al., 2018). While less than 500 cases of TIO have been reported worldwide, and formal epidemiological studies of the disease have not been performed, surgical resection offers a potentially curative treatment in contrast to similarly presenting disorders (Folpe, 2019).
X-linked hypophosphatemia (XLH) is a phosphate wasting disorder caused by mutations in the PHEX gene which expresses the enzyme phosphate-regulating neutral endopeptidase (PHEX). Studies suggest that the PHEX enzyme may be involved in the regulation of FGF23 (Beck-Nielsen et al., 2019; Liu et al., 2003). Importantly, diagnosing phosphate wasting disorders based purely on clinical criteria is confounded by the similarity of clinical and radiological presentations of this family of disorders. Knowing the distinct genetic basis for a patient's phosphate wasting disorder often allows clinicians to tailor their treatment/management strategy accordingly, potentially saving years of hardship for affected patients. As such, recent emphasis has been placed on using gene panels to accelerate clinicians' diagnosis of these disorders.
In particular, a potential for misdiagnosis of TIO as XLH exists because FGF23 levels are increased in both, PMT tumors are notoriously difficult to find due to their small size and variable location, and (albeit still rare) the incidence of XLH far exceeds that of TIO (Yin et al., 2018; Carpenter, 1997). Here, we present a 41-year-old female in whom a 26-year delayed TIO diagnosis and concurrent misdiagnosis of XLH was identified via a negative hypophosphatemia gene panel and corrected to TIO through identification of a PMT of her 9th right rib. Surgical resection resulted in biochemical and clinical symptom improvement. Histological analysis was positive for FGF23 (CISH) and the FN1-FGFR1 transcriptional marker. Finally, we highlight recent key advances in diagnosing phosphate wasting disorders, molecular characterization of PMTs, and TIO treatment and management.
2 Case presentation
A 41-year-old woman with a prior clinical diagnosis of hypophosphatemic rickets presented to our institution with a 26-year history of low phosphorus, bone pain, proximal muscle weakness, gait abnormalities, and multiple traumatic and insufficiency fractures of the hip, humerus, and spine (Fig. 1, Fig. 7). She had no history of hearing loss. She had lost all her secondary teeth (edentulous). The patient reported no family history of hypophosphatemia, including her 8-year-old male child and 17-year-old female child, neither of whom showed clinical or laboratory indications of musculoskeletal conditions or phosphate wasting disorders. Her maximum height was 5′2″ but she presented to us at 4′8″ due to progressive spine deformities.
Despite intermittent treatment with conventional therapy with phosphorus supplements and calcitriol during her teens and 20s, she developed progressive gait abnormalities and decreased hip strength and ultimately sustained bilateral hip fractures (Fig. 1A) and small fractures throughout her spine (Fig. 1B-C).Fig. 1 Patient musculoskeletal radiology. X-ray AP Pelvis (A) shows evidence of prior bilateral obturator ring fractures with bilateral femoral head/neck angular deformities. X-ray Spine Total AP/Lateral (B-C) shows normal trabecular bone with vertebral body alignments and interspacing intact, but there is mild flattening of the mid vertebral body at multiple levels. There is evidence of previous insufficiency fractures.
Fig. 1
Despite treatment, the patient's symptoms deteriorated further in her 20s, when she had stability rods and screws placed bilaterally in her femurs and hips, respectively (Fig. 1A). Ten years later, the patient presented with a traumatic left humerus fracture, for which she underwent surgery (Figure 7). Post-operatively, the patient was placed on the osteoporosis medication teriparatide.
Teriparatide therapy failed to prevent more spinal fractures (Fig. 1B-C), bone pain, and muscle weakness over the next year, and the patient was eventually confined to a wheelchair. Orthopedic physicians reevaluated her history, officially diagnosed her with X-linked Hypophosphatemia (XLH) (although patient claims having an “unofficial” XLH diagnosis years prior by previous physicians), and started her on Burosumab (60 mg subcutaneous injection every 28 days) - the monoclonal antibody targeted against FGF23. Unfortunately, laboratory values relevant to phosphate wasting (e.g. TmP/GFR, FGF23) were not reported prior to initiation of Burosumab therapy or referral to our institution for further evaluation and treatment.
The patient remained on Burosumab for 3 months. While on Burosumab, the patient reported mild symptomatic improvement with no reported adverse effects, but still had severe limitations in mobility (difficulty from sit to stand, Video 1), fatigue, and pain. On therapy, FGF23 levels were 33,900 RU/mL (normal <180RU/mL) and 36,900 RU/mL two months later as measured by ELISA (Quidel Corporation). Other notable preoperative laboratory values include a normal serum phosphorus, normal calcium, normal total vitamin D, elevated 1,25 dihydroxyvitamin D (333 pg/mL; normal 19.9–79.3 pg/mL), high alkaline phosphatase (168 U/mL; normal 40–150 U/mL), and high PTH (189 pg/mL, normal 16–77 pg/mL) (Table 2). These findings are abnormal for a patient with TIO, but they should be viewed in the context of Burosumab therapy. After discontinuation, her total FGF23 declined to 1532 RU/mL after discontinuing Burosumab but before excision of her PMT which was still considerably elevated above reference range.
At our clinic, areal bone density of the lumbar spine and left forearm (bone density of the femurs could not be performed due to bilateral hip prostheses) were assessed by dual-energy X-ray absorptiometry (DXA) using a GE Lunar Prodigy Advanced densitometer. Densitometry revealed normal bone density in the spine and significantly lower than expected density in the forearm (Fig. 2A-B). A renal ultrasound showed a 4-mm non-obstructing calculus in the lower pole of the right kidney, indicating nephrolithiasis, a well-documented complication of long-term phosphorus and calcitriol therapy (Jan de Beur, 2005).Fig. 2 Pre-operative DXA scans measuring bone mineral density (BMD). (A) Pre-operative bone density of the lumbar spine, (L1-L4): 1.202 g per square cm, T-score (SD of peak BMD): 0.1 Z-score (SD of age-matched BMD): 0.1. (B) Pre-operative bone density of the left forearm (radius 33%) is: 0.694 g per square cm T-score (SD of peak BMD): −2.1 Z-score (SD of age-matched BMD): −2.1. Bone density of the femurs could not be performed due to bilateral hip prostheses.
Fig. 2
Additionally, a 13-gene Invitae hypophosphatemia panel (https://www.invitae.com/en/hypophosphatemia) (Table 1) was performed to adjudicate her clinical diagnosis of XLH. No pathogenic variants were detected prompting our team to suspect TIO and re-evaluate her previous XLH diagnosis.Table 1 Genes tested on the Invitae hypophosphatemia next-generation sequencing panel (https://www.invitae.com/en/hypophosphatemia), with associated localization, diseases, and pathological mutations (Lloyd et al., 1996; Priante et al., 2017; Root, 2018). Panel is sensitive to deletions, insertions, duplications and copy number variants, and single-nucleotide polymorphisms (SNPs). AD = autosomal dominant, AR = autosomal recessive, VDDR = Vitamin D-dependent rickets.
Table 1Gene Primary location(s) of expression Type of mutation precipitating disease Associated hypophosphatemic/osteomalacic disease
ALPL Osteoblasts Loss of function Hypophosphatasia
CLCN5 Proximal renal tubule Loss of function X-linked recessive hypophosphatemic rickets
CYP27B1 Many cell types Loss of function AR VDDR type 1A
CYP2R1 Hepatocytes Loss of function AR VDDR type 1B
DMP1 Osteoblasts, osteocytes Loss of function AR hypophosphatemic rickets
ENPP1 Chondrocytes, osteocytes, plasma cells Loss of function AR hypophosphatemic rickets
FAH Hepatocytes Loss of function AR tyrosinemia type 1
FAM20C Osteoblasts, osteocytes Loss of function AR osteosclerotic bone dysplasia (Raine syndrome)
FGF23 Osteoblasts, osteocytes Gain of function AD hypophosphatemic rickets
FGFR1 Many cell types Gain of function AD type 1 Pfeiffer syndrome and osteoglophonic dysplasia; synthesis upregulated in many TIO-associated tumors
PHEX Osteoblasts Loss of function, X-linked XLH, increased FGF23 secretion
SLC34A3 Proximal renal tubule Loss of function AR hypophosphatemic rickets with hypercalciuria
VDR Loss of function Calcitriol resistance, VDDR type 2A
Due to suspected TIO, a combined 68Ga-DOTATATE PET/CT scan was performed. The CT Scan (Fig. 3A) revealed an unusual lesion in her 9th lateral right rib; PET scan (Fig. 3B) showed that this lesion had high activity; and a 68Ga-DOTATATE scan (an indirect measure of somatostatin receptors which are highly expressed in most TIO-causing tumors) demonstrated activity in the same region (Fig. 3C-D).Fig. 3 Diagnostic radiologic characterization of the right rib mass. (A) CT (white arrows = mass). (B) PET (white arrows = activity). (C) 68 Ga-DOTATE Scan Axial (red arrows = activity). (D) 68 Ga-DOTATE Scan Coronal (A/P) (red arrows = activity).
Fig. 3
Some TIO patients with unresectable or unidentifiable PMTs have benefited greatly from Burosumab therapy (Jan De Beur et al., 2019). However, the accessibility of our patient's tumor prompted us to refer her to Thoracic Surgery for complete resection of the tumor and rib. Further, Burosumab therapy was discontinued prior to measuring baseline laboratory values due to potential confounding, especially with the FGF23 level.
Intra-operatively, surgeons identified a more concerning lesion on the patient's 10th right rib (Fig. 4A) that had no imaging correlate. This lesion was removed, and the surgeons deferred removal of the 9th right rib to ensure the 10th right rib lesion was not the culprit of her TIO symptoms or other pathology warranting alternative intervention. The patient's hypophosphatemia persisted post-operatively. 4-months after surgery, notable lab values included low serum phosphorus (1.4 mg/dL; normal 2.3–4.7 mg/dL), low 1,25 dihydroxyvitamin D (15 pg/mL; 19.9–79.3 pg/mL), normal total vitamin D (38 ng/mL; 25–80 ng/mL), and elevated total FGF23 (1532 RU/mL; <180 RU/mL). Histopathology of the 10th right rib mass showed only non-specific reactive changes, possibly representing an old fracture site.Fig. 4 Gross appearance of surgical specimens. (A) Intra-operative image of 10th right rib mass (no imaging correlate) removed during the first, unsuccessful surgery. White star (*) denotes the large abnormality that prompted surgeons to remove the 10th rib mass. (B-C) Post-operative images of 9th right rib removed during the second, successful surgery. (B) White stars (*) denote the two areas of abnormality, red arrow denotes the primary lesion of concern for PMT shown in Fig. 5, Fig. 6. (C) Significant thickening observed in the 9th right rib.
Fig. 4
These findings further implicated the active 9th rib lesion in her pathology (Figure 3), prompting Thoracic Surgery to remove the 9th right rib (Fig. 4B-C) 5 months after the first unsuccessful surgery. Gross appearance of the 9th right rib showed two areas of abnormality with one denoting the PMT lesion (Fig. 4B) and significant rib thickening along the lateral surface (Fig. 4C). Histological sections of the 9th right rib showed a morphologically classical phosphaturic mesenchymal tumor, consisting of bland spindled cells in a highly vascular background, with unusually hyalinized to occasionally calcified matrix (Fig. 5). Chromogenic in situ hybridization (CISH) of the tumor and RNA-sequencing for the presence of rearrangements in 138 target genes were pursued using methods previously published (Martinez et al., 2019; Carter et al., 2015). FGF23 CISH was strongly positive (Fig. 6). Sequencing was positive for the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1). Taken together, these results are characteristic of a typical PMT.Fig. 5 Histological appearance of 9th right rib phosphaturic mesenchymal tumor (PMT). A) Lower magnification showing infiltration of rib bone (pink, paucicellular) by the PMT. B) Higher magnification (black box of A) of the PMT specifically showing proliferation of uniform short spindle to ovoid cells with a rich vascular background and cystic changes. C) Low magnification of the PMT from a different depth of sectioning.
Fig. 5Fig. 6 FGF23 chromogenic in situ hybridization (CISH) of 9th right rib phosphaturic mesenchymal tumor (PMT).
Fig. 6Fig. 7 Post-operative portable chest X-ray after rib removal (second successful surgery). A left humeral rod and right chest tube are observed. No pneumothorax is seen. The lungs appear clear except for volume loss related to the overlying thoracic deformity. Extensive bone deformities identified, and multiple performed ribs are seen bilaterally but both appear similar to pre-operative radiographs.
Fig. 7Table 2 Longitudinal patient laboratory values. Op 1 denotes the first unsuccessful 10th rib removal operation. Op 2 denotes the second successful 9th rib removal operation. PTH = parathyroid hormone. Note = Pre-Op 1 labs were taken while the patient was on Burosumab, all other labs were taken while the patient was off Burosumab, and Post-Op 2 labs were taken 3 months after resection.
Table 2Laboratory value Normal range Pre-Op 1 (on Burosumab) Post-Op 1, Pre-Op 2 Post-Op 2 (3 months after 9th right rib resection)
Serum phosphorus 2.3–4.7 mg/dL 2.5 1.4 3.7
Calcium 8.4–10.5 mg/dL 9.7 9.3 10.4
Total vitamin D 25–80 ng/mL 40 38 35
1,25 dihydroxyvitamin D 19.9–79.3 pg/mL 333 15 327
Alkaline phosphatase 40–150 U/L 168 111 130
Chloride 96–106 mmol/L 108 109 105
PTH 16–77 pg/mL 189 Not collected 194
FGF23 <180 RU/mL 36,900 1532 245
3 months post-resection, chest x-rays showed no pneumothorax and no significant changes compared to prior radiographs (Fig. 7). FGF23 levels decreased again but remained slightly elevated (245 RU/mL), serum phosphorus normalized (3.7 mg/dL), alkaline phosphatase normalized (130 U/mL), and total vitamin D was 35 ng/mL. Parathyroid hormone remained elevated (194 pg/mL) (Table 2). Clinical assessments of mobility markedly improved (Video 1, Video 2), and the patient has stated she is in less pain and is more active and feels stronger than ever. She will continue to follow up longitudinally in our Endocrinology clinic.
3 Discussion
TIO is a paraneoplastic disease resulting in elevated FGF23, renal phosphate wasting, defective Vitamin D metabolism, and subsequent osteomalacia. Clinically, patients with TIO present with progressive bone pain, muscle weakness, fatigue, and sporadic insufficiency fractures (Yin et al., 2018). TIO can be suggested by serum hypophosphatemia, hyperphosphaturia, and low or inappropriately normal calcitriol levels, but the identification of a phosphaturic mesenchymal tumor (PMT) in the soft tissue or bone is necessary for definitive diagnosis (Feng et al., 2017). Here, we presented a 41-year-old woman suffering from TIO with a 26-year delay in diagnosis with a concurrent misdiagnosis of XLH.
Diagnosing TIO is often complicated by small tumor size and similar initial clinical presentation to more common phosphate wasting disorders such as XLH. A retrospective study of 144 TIO cases found that TIO was misdiagnosed in over 95% (137/144) of cases, with intervertebral disc herniation, spondyloarthritis, and osteoporosis being the most common misdiagnoses (Feng et al., 2017). In this case, our patient was misdiagnosed for 26 years with little symptomatic improvement with either conventional therapy or Burosumab, and subsequent gene paneling at our institution revealed no genetic evidence of her XLH diagnosis.
Patients who present with bone pain, muscle weakness, and multiple fractures should be evaluated for hypophosphatemia, and TMP/GFR should be performed for hypophosphatemic patients. While diagnostically burdensome, a low TMP/GFR is a powerful indicator of renal phosphate wasting in the absence of secondary hyperthyroidism (Jagtap et al., 2012). Though less sensitive than TMP/GFR, calculating a percent tubular reabsorption of phosphate (TRP) is a more easily collected alternative (Takeda et al., 2015). Additionally, 24-h urine phosphorus and calcium can differentiate between malabsorption and phosphate wasting disorders (Payne, 1998).
Patient FGF23 levels and family/personal histories are also important tools for differentiating between phosphate wasting disorders (Table 3). As discussed in our previous report, TIO distinguishes itself from other FGF23-high phosphate wasting disorders in that it often presents with rapid symptom onset later in life, often with a negative family history. On the other hand, XLH is usually inherited as an X-linked dominant inherited disorder that typically presents in early childhood (MD, 2012). As such, genetic testing and associated costs can often be avoided if a clear X-linked pattern is identified by pedigree. That said, XLH can still occur due to de novo mutations, so absence of a family history should not entirely rule out XLH (Durmaz et al., 2013).Table 3 Phosphate wasting disorder differential diagnosis. A differential diagnosis table (not extensive) for phosphate wasting disorders, including TIO, distinguished by serum FGF23 level, reproduced from Colazo et al. (n.d.), Imel and Econs (2012), and Zoller et al. (2017).
Table 3Phosphate wasting disorders with low FGF23 Phosphate wasting disorders with high or “inappropriately normal” FGF23
Fanconi syndrome X-linked hypophosphatemia (XLH)
Hyperparathyroidism Tumor-induced osteomalacia (TIO)
Diuretics (e.g. acetazolamide) Autosomal dominant/autosomal recessive rickets
Myeloma McCune Albright syndrome
Copper disorders (Menkes) Cutaneous-skeletal hypophosphatemia syndrome (CSHS) (e.g., epidermal nevus syndromes)
Alcohol consumption Iron use (iron polymaltose infusions)
Genetic disorders (e.g. Npt2a mutations)
Finally, in the absence of genetic data, indication of several bone and calcification disorders can help distinguish XLH from TIO, though these criteria are highly variable. Enthesopathy (calcification of the joint capsule, tendon insertions, and ligaments) is a common feature of XLH but not of TIO and results in increased apparent BMD (Beck-Nielsen et al., 2019). By contrast, typical TIO patients have remarkably low BMD, often being labelled osteoporotic. Dentition is another clinical differentiator, in that patients with XLH can have recurrent abscesses and dental loss, while dentition in TIO is usually normal (Lee et al., 2017). However, the patient presented here was edentulous, demonstrating that TIO should not be ruled out based on these features.
Suspected TIO should prompt an investigation for active PMTs in the hands, feet, ribs, nasal cavities, and brain (Colazo et al., n.d). In recent literature, a full body 68Ga-DOTATATE scan has been shown to be a specific imaging test for identifying culprit tumors in osteomalacia (Zhang et al., 2015). The 68Ga-DOTATATE scan works by utilizing 68Gallium (68Ga) conjugated to somatostatin peptide analogues, which allows for somatostatin receptor imaging by PET scan. DOTATATE scans are most often used for diagnosing somatostatin-receptor positive neuroendocrine tumors, but PMTs preferentially express somatostatin type 2 receptors (Houang et al., 2013). Hence, this technique allows for targeted imaging of TIO-causing lesions. That said, false positivity can still occur in hypersplenism, fractures, sarcoidosis, or vertebral hemangiomas (Hofman et al., 2015). If very small and/or multiple tumors of unknown significance are present, selective FGF23 venous sampling has shown promise in deciphering the FGF23-producing tumor (Colazo et al., n.d.; Schober et al., 2017). In this case, since two suspicious lesions were encountered, FGF23 venous sampling could have been utilized, but the anatomical location and proximity of both lesions to each other would have made the process difficult to perform and most likely futile.
Misdiagnosis can also occur after tumor identification, especially in cases in which non-PMT tumors morphologically mimic PMTs in the context of hypophosphatemia (Lee et al., 2016). Recent studies have identified novel gene fusions FN1-FGF1 and FN1-FGFR1 that are transcribed and synthesized by the majority of PMTs. The fusion of FN1 and FGFR1 leads to constitutive overexpression of the 3′ portion of FGFR1 through constitutive activation of the FN1 promoter, and the fusion protein products have suspected roles in autocrine signaling (Lee et al., 2016). These fusion products can be detected by RNA sequencing or FISH of the tumor, and several emerging FGF/R inhibitors have been shown to be therapeutically beneficial in relapsing TIO (Hartley et al., 2020).
While diagnosis of TIO depends solely on postoperative biochemical resolution of laboratory abnormalities, the classification of the resected tumor can be helpful. Our patient's tumor tested positive for FN1-FGFR1 by RNAseq and for FGF23 by chromogenic in situ hybridization (CISH), further suggesting PMT (Martinez et al., 2019; Carter et al., 2015). These results support the use of FN1-FGF1/R1 gene fusions and FGF23 CISH as an additional diagnostic tool for TIO and can be used for comparison between the original and a recurrent tumor.
To date, surgical PMT resection is the only curative therapy for TIO. To mitigate risk of recurrence or metastasis, resection should be performed with wide margins where possible, and patients should be monitored longitudinally post-operatively (Hautmann et al., 2015). Here, our patient had dramatic improvements 3 months post-resection in symptoms and mobility (Video 1, Video 2), as well as in serum FGF23, phosphate, and Vitamin D levels (Table 2). Patients with unresectable or undetectable tumors have historically been placed on supplemental phosphate and calcitriol; however, Burosumab is a novel human anti-FGF23 monoclonal antibody initially approved by the FDA to treat XLH that has been recently approved for treatment of such complex TIO presentations (Carpenter et al., 2016; Day et al., 2020). In particular, Kyowa Kirin and Ultragenyx's Crysvita (burosumab-twza) has been approved for the treatment of TIO associated with PMTs that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older. Burosumab has been shown to improve serum phosphate levels and histomorphology of bone biopsies in patients with TIO, but mild side effects have been reported, including reactive overproduction of FGF23 and consequent Vitamin D deficiency (Day et al., 2020). For these reasons, monitoring FGF23 levels is not a reliable way to monitor patients on Burosumab; clinicians should focus on serum phosphorous, Alkaline phosphatase, renal phosphate wasting, 1,25 Dihydroxyvitamin D, and clinical signs/symptoms.
Indeed, in the 3 months prior to tumor identification, our patient was placed on Burosumab therapy and enjoyed mild symptomatic improvement and stable lab values (notably a normal serum phosphorus, see Table 2). While no labs were taken pre-induction, her condition deteriorated while off Burosumab between her two rib resections, indicating a positive impact of Burosumab on her condition. Her marked post-operative improvement supports the use of PMT resection when possible.
In this report, we have demonstrated the utility of two powerful genetic tools – gene paneling and RNA sequencing – at guiding clinicians to a challenging diagnosis of a non-heritable condition. In the 26-year history of this patient's disease, genetic tools have become increasingly cost-effective, sensitive, and precise. A lack of available tests at initial presentation motivated a diagnosis of XLH (a germline genetic condition) based on clinical evidence alone. The similar clinical presentations of many phosphate wasting disorders, the uniqueness of their genetic identifiers like FN1-FGFR1 or PHEX, and the illumination of known, curative therapies through such tests all support the expanded use of gene paneling and tumor sequencing alongside clinical reasoning around phosphate wasting disorders. This fact is further evidenced by the requirement of genetic diagnosis for enrollment in most clinical trials targeting phosphate wasting disorders. Additionally, the advancements in the field over the past 3 decades may warrant the re-evaluation of poorly managed, long-term diagnoses through the lens of a gene panel or specific genetic marker.
4 Conclusion
Tumor-induced osteomalacia (TIO) is a paraneoplastic disease driven by hypersecretion of Fibroblast Growth Factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). In this case report, we present a patient with what we believe to be the longest history of a delayed TIO diagnosis reported in the literature, outlined current diagnostic strategies, and demonstrated the increasing utility of genetic testing in the diagnosis of phosphate wasting disorders.
We highlight the importance of the personal and family histories, as well as potential pitfalls of using exclusively clinical criteria in diagnosing phosphate wasting disorders, as our patient had several clinical findings suggestive of XLH yet had a negative family history of phosphate wasting disorders. Further, we stress the utility of full body imaging, especially a 68Ga-DOTATATE PET/CT scan, in probing cases of high clinical suspicion for TIO, and we applied novel genetic screening methods (i.e. gene paneling and tumor RNA sequencing) to confirm our diagnosis. When possible, performing these tests provides powerful support for a TIO diagnosis. Finally, while our patient has enjoyed a marked recovery 3 months post-surgical resection, we discuss Burosumab, an emerging therapeutic antibody against FGF23 that may be an attractive treatment for undetectable or unresectable tumors in TIO.
The following are the supplementary data related to this article.Video 1
Pre-operative functionality of patient
Video 1 Video 2
Post-operative functionality of patient
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Acknowledgments
Two of the authors (JMC, JAD) are supported by NIGMS of the National Institutes of Health under award number T32GM007347. The content in this report is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The Transparency document associated with this article can be found, in online version. | BUROSUMAB-TWZA | DrugsGivenReaction | CC BY-NC-ND | 33490314 | 18,819,395 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fibroblast growth factor 23 increased'. | Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia.
Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A 68Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases.
1 Introduction
Osteomalacia is the progressive softening of bones due to decreased mineralization of calcium and phosphates at sites of bone remodeling and growth, commonly resulting in bone pain and muscle weakness (Michigami, 2019). Fibroblast Growth Factor 23 (FGF23) is a protein secreted by osteocytes mainly in response to calcitriol and phosphate (Martin et al., 2012). FGF23 regulates plasma phosphate concentration predominately by reducing serum calcitriol which mediates intestinal phosphate absorption and by reducing NPT2-mediated phosphate reabsorption in the kidney. Tumor-Induced Osteomalacia (TIO) is a rare paraneoplastic disease in which a phosphaturic mesenchymal tumor (PMT) secretes significant amounts of FGF23 into the bloodstream, leading to downstream osteomalacia through renal phosphate wasting and defective Vitamin D metabolism (Yin et al., 2018). While less than 500 cases of TIO have been reported worldwide, and formal epidemiological studies of the disease have not been performed, surgical resection offers a potentially curative treatment in contrast to similarly presenting disorders (Folpe, 2019).
X-linked hypophosphatemia (XLH) is a phosphate wasting disorder caused by mutations in the PHEX gene which expresses the enzyme phosphate-regulating neutral endopeptidase (PHEX). Studies suggest that the PHEX enzyme may be involved in the regulation of FGF23 (Beck-Nielsen et al., 2019; Liu et al., 2003). Importantly, diagnosing phosphate wasting disorders based purely on clinical criteria is confounded by the similarity of clinical and radiological presentations of this family of disorders. Knowing the distinct genetic basis for a patient's phosphate wasting disorder often allows clinicians to tailor their treatment/management strategy accordingly, potentially saving years of hardship for affected patients. As such, recent emphasis has been placed on using gene panels to accelerate clinicians' diagnosis of these disorders.
In particular, a potential for misdiagnosis of TIO as XLH exists because FGF23 levels are increased in both, PMT tumors are notoriously difficult to find due to their small size and variable location, and (albeit still rare) the incidence of XLH far exceeds that of TIO (Yin et al., 2018; Carpenter, 1997). Here, we present a 41-year-old female in whom a 26-year delayed TIO diagnosis and concurrent misdiagnosis of XLH was identified via a negative hypophosphatemia gene panel and corrected to TIO through identification of a PMT of her 9th right rib. Surgical resection resulted in biochemical and clinical symptom improvement. Histological analysis was positive for FGF23 (CISH) and the FN1-FGFR1 transcriptional marker. Finally, we highlight recent key advances in diagnosing phosphate wasting disorders, molecular characterization of PMTs, and TIO treatment and management.
2 Case presentation
A 41-year-old woman with a prior clinical diagnosis of hypophosphatemic rickets presented to our institution with a 26-year history of low phosphorus, bone pain, proximal muscle weakness, gait abnormalities, and multiple traumatic and insufficiency fractures of the hip, humerus, and spine (Fig. 1, Fig. 7). She had no history of hearing loss. She had lost all her secondary teeth (edentulous). The patient reported no family history of hypophosphatemia, including her 8-year-old male child and 17-year-old female child, neither of whom showed clinical or laboratory indications of musculoskeletal conditions or phosphate wasting disorders. Her maximum height was 5′2″ but she presented to us at 4′8″ due to progressive spine deformities.
Despite intermittent treatment with conventional therapy with phosphorus supplements and calcitriol during her teens and 20s, she developed progressive gait abnormalities and decreased hip strength and ultimately sustained bilateral hip fractures (Fig. 1A) and small fractures throughout her spine (Fig. 1B-C).Fig. 1 Patient musculoskeletal radiology. X-ray AP Pelvis (A) shows evidence of prior bilateral obturator ring fractures with bilateral femoral head/neck angular deformities. X-ray Spine Total AP/Lateral (B-C) shows normal trabecular bone with vertebral body alignments and interspacing intact, but there is mild flattening of the mid vertebral body at multiple levels. There is evidence of previous insufficiency fractures.
Fig. 1
Despite treatment, the patient's symptoms deteriorated further in her 20s, when she had stability rods and screws placed bilaterally in her femurs and hips, respectively (Fig. 1A). Ten years later, the patient presented with a traumatic left humerus fracture, for which she underwent surgery (Figure 7). Post-operatively, the patient was placed on the osteoporosis medication teriparatide.
Teriparatide therapy failed to prevent more spinal fractures (Fig. 1B-C), bone pain, and muscle weakness over the next year, and the patient was eventually confined to a wheelchair. Orthopedic physicians reevaluated her history, officially diagnosed her with X-linked Hypophosphatemia (XLH) (although patient claims having an “unofficial” XLH diagnosis years prior by previous physicians), and started her on Burosumab (60 mg subcutaneous injection every 28 days) - the monoclonal antibody targeted against FGF23. Unfortunately, laboratory values relevant to phosphate wasting (e.g. TmP/GFR, FGF23) were not reported prior to initiation of Burosumab therapy or referral to our institution for further evaluation and treatment.
The patient remained on Burosumab for 3 months. While on Burosumab, the patient reported mild symptomatic improvement with no reported adverse effects, but still had severe limitations in mobility (difficulty from sit to stand, Video 1), fatigue, and pain. On therapy, FGF23 levels were 33,900 RU/mL (normal <180RU/mL) and 36,900 RU/mL two months later as measured by ELISA (Quidel Corporation). Other notable preoperative laboratory values include a normal serum phosphorus, normal calcium, normal total vitamin D, elevated 1,25 dihydroxyvitamin D (333 pg/mL; normal 19.9–79.3 pg/mL), high alkaline phosphatase (168 U/mL; normal 40–150 U/mL), and high PTH (189 pg/mL, normal 16–77 pg/mL) (Table 2). These findings are abnormal for a patient with TIO, but they should be viewed in the context of Burosumab therapy. After discontinuation, her total FGF23 declined to 1532 RU/mL after discontinuing Burosumab but before excision of her PMT which was still considerably elevated above reference range.
At our clinic, areal bone density of the lumbar spine and left forearm (bone density of the femurs could not be performed due to bilateral hip prostheses) were assessed by dual-energy X-ray absorptiometry (DXA) using a GE Lunar Prodigy Advanced densitometer. Densitometry revealed normal bone density in the spine and significantly lower than expected density in the forearm (Fig. 2A-B). A renal ultrasound showed a 4-mm non-obstructing calculus in the lower pole of the right kidney, indicating nephrolithiasis, a well-documented complication of long-term phosphorus and calcitriol therapy (Jan de Beur, 2005).Fig. 2 Pre-operative DXA scans measuring bone mineral density (BMD). (A) Pre-operative bone density of the lumbar spine, (L1-L4): 1.202 g per square cm, T-score (SD of peak BMD): 0.1 Z-score (SD of age-matched BMD): 0.1. (B) Pre-operative bone density of the left forearm (radius 33%) is: 0.694 g per square cm T-score (SD of peak BMD): −2.1 Z-score (SD of age-matched BMD): −2.1. Bone density of the femurs could not be performed due to bilateral hip prostheses.
Fig. 2
Additionally, a 13-gene Invitae hypophosphatemia panel (https://www.invitae.com/en/hypophosphatemia) (Table 1) was performed to adjudicate her clinical diagnosis of XLH. No pathogenic variants were detected prompting our team to suspect TIO and re-evaluate her previous XLH diagnosis.Table 1 Genes tested on the Invitae hypophosphatemia next-generation sequencing panel (https://www.invitae.com/en/hypophosphatemia), with associated localization, diseases, and pathological mutations (Lloyd et al., 1996; Priante et al., 2017; Root, 2018). Panel is sensitive to deletions, insertions, duplications and copy number variants, and single-nucleotide polymorphisms (SNPs). AD = autosomal dominant, AR = autosomal recessive, VDDR = Vitamin D-dependent rickets.
Table 1Gene Primary location(s) of expression Type of mutation precipitating disease Associated hypophosphatemic/osteomalacic disease
ALPL Osteoblasts Loss of function Hypophosphatasia
CLCN5 Proximal renal tubule Loss of function X-linked recessive hypophosphatemic rickets
CYP27B1 Many cell types Loss of function AR VDDR type 1A
CYP2R1 Hepatocytes Loss of function AR VDDR type 1B
DMP1 Osteoblasts, osteocytes Loss of function AR hypophosphatemic rickets
ENPP1 Chondrocytes, osteocytes, plasma cells Loss of function AR hypophosphatemic rickets
FAH Hepatocytes Loss of function AR tyrosinemia type 1
FAM20C Osteoblasts, osteocytes Loss of function AR osteosclerotic bone dysplasia (Raine syndrome)
FGF23 Osteoblasts, osteocytes Gain of function AD hypophosphatemic rickets
FGFR1 Many cell types Gain of function AD type 1 Pfeiffer syndrome and osteoglophonic dysplasia; synthesis upregulated in many TIO-associated tumors
PHEX Osteoblasts Loss of function, X-linked XLH, increased FGF23 secretion
SLC34A3 Proximal renal tubule Loss of function AR hypophosphatemic rickets with hypercalciuria
VDR Loss of function Calcitriol resistance, VDDR type 2A
Due to suspected TIO, a combined 68Ga-DOTATATE PET/CT scan was performed. The CT Scan (Fig. 3A) revealed an unusual lesion in her 9th lateral right rib; PET scan (Fig. 3B) showed that this lesion had high activity; and a 68Ga-DOTATATE scan (an indirect measure of somatostatin receptors which are highly expressed in most TIO-causing tumors) demonstrated activity in the same region (Fig. 3C-D).Fig. 3 Diagnostic radiologic characterization of the right rib mass. (A) CT (white arrows = mass). (B) PET (white arrows = activity). (C) 68 Ga-DOTATE Scan Axial (red arrows = activity). (D) 68 Ga-DOTATE Scan Coronal (A/P) (red arrows = activity).
Fig. 3
Some TIO patients with unresectable or unidentifiable PMTs have benefited greatly from Burosumab therapy (Jan De Beur et al., 2019). However, the accessibility of our patient's tumor prompted us to refer her to Thoracic Surgery for complete resection of the tumor and rib. Further, Burosumab therapy was discontinued prior to measuring baseline laboratory values due to potential confounding, especially with the FGF23 level.
Intra-operatively, surgeons identified a more concerning lesion on the patient's 10th right rib (Fig. 4A) that had no imaging correlate. This lesion was removed, and the surgeons deferred removal of the 9th right rib to ensure the 10th right rib lesion was not the culprit of her TIO symptoms or other pathology warranting alternative intervention. The patient's hypophosphatemia persisted post-operatively. 4-months after surgery, notable lab values included low serum phosphorus (1.4 mg/dL; normal 2.3–4.7 mg/dL), low 1,25 dihydroxyvitamin D (15 pg/mL; 19.9–79.3 pg/mL), normal total vitamin D (38 ng/mL; 25–80 ng/mL), and elevated total FGF23 (1532 RU/mL; <180 RU/mL). Histopathology of the 10th right rib mass showed only non-specific reactive changes, possibly representing an old fracture site.Fig. 4 Gross appearance of surgical specimens. (A) Intra-operative image of 10th right rib mass (no imaging correlate) removed during the first, unsuccessful surgery. White star (*) denotes the large abnormality that prompted surgeons to remove the 10th rib mass. (B-C) Post-operative images of 9th right rib removed during the second, successful surgery. (B) White stars (*) denote the two areas of abnormality, red arrow denotes the primary lesion of concern for PMT shown in Fig. 5, Fig. 6. (C) Significant thickening observed in the 9th right rib.
Fig. 4
These findings further implicated the active 9th rib lesion in her pathology (Figure 3), prompting Thoracic Surgery to remove the 9th right rib (Fig. 4B-C) 5 months after the first unsuccessful surgery. Gross appearance of the 9th right rib showed two areas of abnormality with one denoting the PMT lesion (Fig. 4B) and significant rib thickening along the lateral surface (Fig. 4C). Histological sections of the 9th right rib showed a morphologically classical phosphaturic mesenchymal tumor, consisting of bland spindled cells in a highly vascular background, with unusually hyalinized to occasionally calcified matrix (Fig. 5). Chromogenic in situ hybridization (CISH) of the tumor and RNA-sequencing for the presence of rearrangements in 138 target genes were pursued using methods previously published (Martinez et al., 2019; Carter et al., 2015). FGF23 CISH was strongly positive (Fig. 6). Sequencing was positive for the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1). Taken together, these results are characteristic of a typical PMT.Fig. 5 Histological appearance of 9th right rib phosphaturic mesenchymal tumor (PMT). A) Lower magnification showing infiltration of rib bone (pink, paucicellular) by the PMT. B) Higher magnification (black box of A) of the PMT specifically showing proliferation of uniform short spindle to ovoid cells with a rich vascular background and cystic changes. C) Low magnification of the PMT from a different depth of sectioning.
Fig. 5Fig. 6 FGF23 chromogenic in situ hybridization (CISH) of 9th right rib phosphaturic mesenchymal tumor (PMT).
Fig. 6Fig. 7 Post-operative portable chest X-ray after rib removal (second successful surgery). A left humeral rod and right chest tube are observed. No pneumothorax is seen. The lungs appear clear except for volume loss related to the overlying thoracic deformity. Extensive bone deformities identified, and multiple performed ribs are seen bilaterally but both appear similar to pre-operative radiographs.
Fig. 7Table 2 Longitudinal patient laboratory values. Op 1 denotes the first unsuccessful 10th rib removal operation. Op 2 denotes the second successful 9th rib removal operation. PTH = parathyroid hormone. Note = Pre-Op 1 labs were taken while the patient was on Burosumab, all other labs were taken while the patient was off Burosumab, and Post-Op 2 labs were taken 3 months after resection.
Table 2Laboratory value Normal range Pre-Op 1 (on Burosumab) Post-Op 1, Pre-Op 2 Post-Op 2 (3 months after 9th right rib resection)
Serum phosphorus 2.3–4.7 mg/dL 2.5 1.4 3.7
Calcium 8.4–10.5 mg/dL 9.7 9.3 10.4
Total vitamin D 25–80 ng/mL 40 38 35
1,25 dihydroxyvitamin D 19.9–79.3 pg/mL 333 15 327
Alkaline phosphatase 40–150 U/L 168 111 130
Chloride 96–106 mmol/L 108 109 105
PTH 16–77 pg/mL 189 Not collected 194
FGF23 <180 RU/mL 36,900 1532 245
3 months post-resection, chest x-rays showed no pneumothorax and no significant changes compared to prior radiographs (Fig. 7). FGF23 levels decreased again but remained slightly elevated (245 RU/mL), serum phosphorus normalized (3.7 mg/dL), alkaline phosphatase normalized (130 U/mL), and total vitamin D was 35 ng/mL. Parathyroid hormone remained elevated (194 pg/mL) (Table 2). Clinical assessments of mobility markedly improved (Video 1, Video 2), and the patient has stated she is in less pain and is more active and feels stronger than ever. She will continue to follow up longitudinally in our Endocrinology clinic.
3 Discussion
TIO is a paraneoplastic disease resulting in elevated FGF23, renal phosphate wasting, defective Vitamin D metabolism, and subsequent osteomalacia. Clinically, patients with TIO present with progressive bone pain, muscle weakness, fatigue, and sporadic insufficiency fractures (Yin et al., 2018). TIO can be suggested by serum hypophosphatemia, hyperphosphaturia, and low or inappropriately normal calcitriol levels, but the identification of a phosphaturic mesenchymal tumor (PMT) in the soft tissue or bone is necessary for definitive diagnosis (Feng et al., 2017). Here, we presented a 41-year-old woman suffering from TIO with a 26-year delay in diagnosis with a concurrent misdiagnosis of XLH.
Diagnosing TIO is often complicated by small tumor size and similar initial clinical presentation to more common phosphate wasting disorders such as XLH. A retrospective study of 144 TIO cases found that TIO was misdiagnosed in over 95% (137/144) of cases, with intervertebral disc herniation, spondyloarthritis, and osteoporosis being the most common misdiagnoses (Feng et al., 2017). In this case, our patient was misdiagnosed for 26 years with little symptomatic improvement with either conventional therapy or Burosumab, and subsequent gene paneling at our institution revealed no genetic evidence of her XLH diagnosis.
Patients who present with bone pain, muscle weakness, and multiple fractures should be evaluated for hypophosphatemia, and TMP/GFR should be performed for hypophosphatemic patients. While diagnostically burdensome, a low TMP/GFR is a powerful indicator of renal phosphate wasting in the absence of secondary hyperthyroidism (Jagtap et al., 2012). Though less sensitive than TMP/GFR, calculating a percent tubular reabsorption of phosphate (TRP) is a more easily collected alternative (Takeda et al., 2015). Additionally, 24-h urine phosphorus and calcium can differentiate between malabsorption and phosphate wasting disorders (Payne, 1998).
Patient FGF23 levels and family/personal histories are also important tools for differentiating between phosphate wasting disorders (Table 3). As discussed in our previous report, TIO distinguishes itself from other FGF23-high phosphate wasting disorders in that it often presents with rapid symptom onset later in life, often with a negative family history. On the other hand, XLH is usually inherited as an X-linked dominant inherited disorder that typically presents in early childhood (MD, 2012). As such, genetic testing and associated costs can often be avoided if a clear X-linked pattern is identified by pedigree. That said, XLH can still occur due to de novo mutations, so absence of a family history should not entirely rule out XLH (Durmaz et al., 2013).Table 3 Phosphate wasting disorder differential diagnosis. A differential diagnosis table (not extensive) for phosphate wasting disorders, including TIO, distinguished by serum FGF23 level, reproduced from Colazo et al. (n.d.), Imel and Econs (2012), and Zoller et al. (2017).
Table 3Phosphate wasting disorders with low FGF23 Phosphate wasting disorders with high or “inappropriately normal” FGF23
Fanconi syndrome X-linked hypophosphatemia (XLH)
Hyperparathyroidism Tumor-induced osteomalacia (TIO)
Diuretics (e.g. acetazolamide) Autosomal dominant/autosomal recessive rickets
Myeloma McCune Albright syndrome
Copper disorders (Menkes) Cutaneous-skeletal hypophosphatemia syndrome (CSHS) (e.g., epidermal nevus syndromes)
Alcohol consumption Iron use (iron polymaltose infusions)
Genetic disorders (e.g. Npt2a mutations)
Finally, in the absence of genetic data, indication of several bone and calcification disorders can help distinguish XLH from TIO, though these criteria are highly variable. Enthesopathy (calcification of the joint capsule, tendon insertions, and ligaments) is a common feature of XLH but not of TIO and results in increased apparent BMD (Beck-Nielsen et al., 2019). By contrast, typical TIO patients have remarkably low BMD, often being labelled osteoporotic. Dentition is another clinical differentiator, in that patients with XLH can have recurrent abscesses and dental loss, while dentition in TIO is usually normal (Lee et al., 2017). However, the patient presented here was edentulous, demonstrating that TIO should not be ruled out based on these features.
Suspected TIO should prompt an investigation for active PMTs in the hands, feet, ribs, nasal cavities, and brain (Colazo et al., n.d). In recent literature, a full body 68Ga-DOTATATE scan has been shown to be a specific imaging test for identifying culprit tumors in osteomalacia (Zhang et al., 2015). The 68Ga-DOTATATE scan works by utilizing 68Gallium (68Ga) conjugated to somatostatin peptide analogues, which allows for somatostatin receptor imaging by PET scan. DOTATATE scans are most often used for diagnosing somatostatin-receptor positive neuroendocrine tumors, but PMTs preferentially express somatostatin type 2 receptors (Houang et al., 2013). Hence, this technique allows for targeted imaging of TIO-causing lesions. That said, false positivity can still occur in hypersplenism, fractures, sarcoidosis, or vertebral hemangiomas (Hofman et al., 2015). If very small and/or multiple tumors of unknown significance are present, selective FGF23 venous sampling has shown promise in deciphering the FGF23-producing tumor (Colazo et al., n.d.; Schober et al., 2017). In this case, since two suspicious lesions were encountered, FGF23 venous sampling could have been utilized, but the anatomical location and proximity of both lesions to each other would have made the process difficult to perform and most likely futile.
Misdiagnosis can also occur after tumor identification, especially in cases in which non-PMT tumors morphologically mimic PMTs in the context of hypophosphatemia (Lee et al., 2016). Recent studies have identified novel gene fusions FN1-FGF1 and FN1-FGFR1 that are transcribed and synthesized by the majority of PMTs. The fusion of FN1 and FGFR1 leads to constitutive overexpression of the 3′ portion of FGFR1 through constitutive activation of the FN1 promoter, and the fusion protein products have suspected roles in autocrine signaling (Lee et al., 2016). These fusion products can be detected by RNA sequencing or FISH of the tumor, and several emerging FGF/R inhibitors have been shown to be therapeutically beneficial in relapsing TIO (Hartley et al., 2020).
While diagnosis of TIO depends solely on postoperative biochemical resolution of laboratory abnormalities, the classification of the resected tumor can be helpful. Our patient's tumor tested positive for FN1-FGFR1 by RNAseq and for FGF23 by chromogenic in situ hybridization (CISH), further suggesting PMT (Martinez et al., 2019; Carter et al., 2015). These results support the use of FN1-FGF1/R1 gene fusions and FGF23 CISH as an additional diagnostic tool for TIO and can be used for comparison between the original and a recurrent tumor.
To date, surgical PMT resection is the only curative therapy for TIO. To mitigate risk of recurrence or metastasis, resection should be performed with wide margins where possible, and patients should be monitored longitudinally post-operatively (Hautmann et al., 2015). Here, our patient had dramatic improvements 3 months post-resection in symptoms and mobility (Video 1, Video 2), as well as in serum FGF23, phosphate, and Vitamin D levels (Table 2). Patients with unresectable or undetectable tumors have historically been placed on supplemental phosphate and calcitriol; however, Burosumab is a novel human anti-FGF23 monoclonal antibody initially approved by the FDA to treat XLH that has been recently approved for treatment of such complex TIO presentations (Carpenter et al., 2016; Day et al., 2020). In particular, Kyowa Kirin and Ultragenyx's Crysvita (burosumab-twza) has been approved for the treatment of TIO associated with PMTs that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older. Burosumab has been shown to improve serum phosphate levels and histomorphology of bone biopsies in patients with TIO, but mild side effects have been reported, including reactive overproduction of FGF23 and consequent Vitamin D deficiency (Day et al., 2020). For these reasons, monitoring FGF23 levels is not a reliable way to monitor patients on Burosumab; clinicians should focus on serum phosphorous, Alkaline phosphatase, renal phosphate wasting, 1,25 Dihydroxyvitamin D, and clinical signs/symptoms.
Indeed, in the 3 months prior to tumor identification, our patient was placed on Burosumab therapy and enjoyed mild symptomatic improvement and stable lab values (notably a normal serum phosphorus, see Table 2). While no labs were taken pre-induction, her condition deteriorated while off Burosumab between her two rib resections, indicating a positive impact of Burosumab on her condition. Her marked post-operative improvement supports the use of PMT resection when possible.
In this report, we have demonstrated the utility of two powerful genetic tools – gene paneling and RNA sequencing – at guiding clinicians to a challenging diagnosis of a non-heritable condition. In the 26-year history of this patient's disease, genetic tools have become increasingly cost-effective, sensitive, and precise. A lack of available tests at initial presentation motivated a diagnosis of XLH (a germline genetic condition) based on clinical evidence alone. The similar clinical presentations of many phosphate wasting disorders, the uniqueness of their genetic identifiers like FN1-FGFR1 or PHEX, and the illumination of known, curative therapies through such tests all support the expanded use of gene paneling and tumor sequencing alongside clinical reasoning around phosphate wasting disorders. This fact is further evidenced by the requirement of genetic diagnosis for enrollment in most clinical trials targeting phosphate wasting disorders. Additionally, the advancements in the field over the past 3 decades may warrant the re-evaluation of poorly managed, long-term diagnoses through the lens of a gene panel or specific genetic marker.
4 Conclusion
Tumor-induced osteomalacia (TIO) is a paraneoplastic disease driven by hypersecretion of Fibroblast Growth Factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). In this case report, we present a patient with what we believe to be the longest history of a delayed TIO diagnosis reported in the literature, outlined current diagnostic strategies, and demonstrated the increasing utility of genetic testing in the diagnosis of phosphate wasting disorders.
We highlight the importance of the personal and family histories, as well as potential pitfalls of using exclusively clinical criteria in diagnosing phosphate wasting disorders, as our patient had several clinical findings suggestive of XLH yet had a negative family history of phosphate wasting disorders. Further, we stress the utility of full body imaging, especially a 68Ga-DOTATATE PET/CT scan, in probing cases of high clinical suspicion for TIO, and we applied novel genetic screening methods (i.e. gene paneling and tumor RNA sequencing) to confirm our diagnosis. When possible, performing these tests provides powerful support for a TIO diagnosis. Finally, while our patient has enjoyed a marked recovery 3 months post-surgical resection, we discuss Burosumab, an emerging therapeutic antibody against FGF23 that may be an attractive treatment for undetectable or unresectable tumors in TIO.
The following are the supplementary data related to this article.Video 1
Pre-operative functionality of patient
Video 1 Video 2
Post-operative functionality of patient
Video 2
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Acknowledgments
Two of the authors (JMC, JAD) are supported by NIGMS of the National Institutes of Health under award number T32GM007347. The content in this report is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The Transparency document associated with this article can be found, in online version. | BUROSUMAB-TWZA | DrugsGivenReaction | CC BY-NC-ND | 33490314 | 18,819,395 | 2021-06 |
What was the administration route of drug 'BUROSUMAB-TWZA'? | Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia.
Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A 68Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases.
1 Introduction
Osteomalacia is the progressive softening of bones due to decreased mineralization of calcium and phosphates at sites of bone remodeling and growth, commonly resulting in bone pain and muscle weakness (Michigami, 2019). Fibroblast Growth Factor 23 (FGF23) is a protein secreted by osteocytes mainly in response to calcitriol and phosphate (Martin et al., 2012). FGF23 regulates plasma phosphate concentration predominately by reducing serum calcitriol which mediates intestinal phosphate absorption and by reducing NPT2-mediated phosphate reabsorption in the kidney. Tumor-Induced Osteomalacia (TIO) is a rare paraneoplastic disease in which a phosphaturic mesenchymal tumor (PMT) secretes significant amounts of FGF23 into the bloodstream, leading to downstream osteomalacia through renal phosphate wasting and defective Vitamin D metabolism (Yin et al., 2018). While less than 500 cases of TIO have been reported worldwide, and formal epidemiological studies of the disease have not been performed, surgical resection offers a potentially curative treatment in contrast to similarly presenting disorders (Folpe, 2019).
X-linked hypophosphatemia (XLH) is a phosphate wasting disorder caused by mutations in the PHEX gene which expresses the enzyme phosphate-regulating neutral endopeptidase (PHEX). Studies suggest that the PHEX enzyme may be involved in the regulation of FGF23 (Beck-Nielsen et al., 2019; Liu et al., 2003). Importantly, diagnosing phosphate wasting disorders based purely on clinical criteria is confounded by the similarity of clinical and radiological presentations of this family of disorders. Knowing the distinct genetic basis for a patient's phosphate wasting disorder often allows clinicians to tailor their treatment/management strategy accordingly, potentially saving years of hardship for affected patients. As such, recent emphasis has been placed on using gene panels to accelerate clinicians' diagnosis of these disorders.
In particular, a potential for misdiagnosis of TIO as XLH exists because FGF23 levels are increased in both, PMT tumors are notoriously difficult to find due to their small size and variable location, and (albeit still rare) the incidence of XLH far exceeds that of TIO (Yin et al., 2018; Carpenter, 1997). Here, we present a 41-year-old female in whom a 26-year delayed TIO diagnosis and concurrent misdiagnosis of XLH was identified via a negative hypophosphatemia gene panel and corrected to TIO through identification of a PMT of her 9th right rib. Surgical resection resulted in biochemical and clinical symptom improvement. Histological analysis was positive for FGF23 (CISH) and the FN1-FGFR1 transcriptional marker. Finally, we highlight recent key advances in diagnosing phosphate wasting disorders, molecular characterization of PMTs, and TIO treatment and management.
2 Case presentation
A 41-year-old woman with a prior clinical diagnosis of hypophosphatemic rickets presented to our institution with a 26-year history of low phosphorus, bone pain, proximal muscle weakness, gait abnormalities, and multiple traumatic and insufficiency fractures of the hip, humerus, and spine (Fig. 1, Fig. 7). She had no history of hearing loss. She had lost all her secondary teeth (edentulous). The patient reported no family history of hypophosphatemia, including her 8-year-old male child and 17-year-old female child, neither of whom showed clinical or laboratory indications of musculoskeletal conditions or phosphate wasting disorders. Her maximum height was 5′2″ but she presented to us at 4′8″ due to progressive spine deformities.
Despite intermittent treatment with conventional therapy with phosphorus supplements and calcitriol during her teens and 20s, she developed progressive gait abnormalities and decreased hip strength and ultimately sustained bilateral hip fractures (Fig. 1A) and small fractures throughout her spine (Fig. 1B-C).Fig. 1 Patient musculoskeletal radiology. X-ray AP Pelvis (A) shows evidence of prior bilateral obturator ring fractures with bilateral femoral head/neck angular deformities. X-ray Spine Total AP/Lateral (B-C) shows normal trabecular bone with vertebral body alignments and interspacing intact, but there is mild flattening of the mid vertebral body at multiple levels. There is evidence of previous insufficiency fractures.
Fig. 1
Despite treatment, the patient's symptoms deteriorated further in her 20s, when she had stability rods and screws placed bilaterally in her femurs and hips, respectively (Fig. 1A). Ten years later, the patient presented with a traumatic left humerus fracture, for which she underwent surgery (Figure 7). Post-operatively, the patient was placed on the osteoporosis medication teriparatide.
Teriparatide therapy failed to prevent more spinal fractures (Fig. 1B-C), bone pain, and muscle weakness over the next year, and the patient was eventually confined to a wheelchair. Orthopedic physicians reevaluated her history, officially diagnosed her with X-linked Hypophosphatemia (XLH) (although patient claims having an “unofficial” XLH diagnosis years prior by previous physicians), and started her on Burosumab (60 mg subcutaneous injection every 28 days) - the monoclonal antibody targeted against FGF23. Unfortunately, laboratory values relevant to phosphate wasting (e.g. TmP/GFR, FGF23) were not reported prior to initiation of Burosumab therapy or referral to our institution for further evaluation and treatment.
The patient remained on Burosumab for 3 months. While on Burosumab, the patient reported mild symptomatic improvement with no reported adverse effects, but still had severe limitations in mobility (difficulty from sit to stand, Video 1), fatigue, and pain. On therapy, FGF23 levels were 33,900 RU/mL (normal <180RU/mL) and 36,900 RU/mL two months later as measured by ELISA (Quidel Corporation). Other notable preoperative laboratory values include a normal serum phosphorus, normal calcium, normal total vitamin D, elevated 1,25 dihydroxyvitamin D (333 pg/mL; normal 19.9–79.3 pg/mL), high alkaline phosphatase (168 U/mL; normal 40–150 U/mL), and high PTH (189 pg/mL, normal 16–77 pg/mL) (Table 2). These findings are abnormal for a patient with TIO, but they should be viewed in the context of Burosumab therapy. After discontinuation, her total FGF23 declined to 1532 RU/mL after discontinuing Burosumab but before excision of her PMT which was still considerably elevated above reference range.
At our clinic, areal bone density of the lumbar spine and left forearm (bone density of the femurs could not be performed due to bilateral hip prostheses) were assessed by dual-energy X-ray absorptiometry (DXA) using a GE Lunar Prodigy Advanced densitometer. Densitometry revealed normal bone density in the spine and significantly lower than expected density in the forearm (Fig. 2A-B). A renal ultrasound showed a 4-mm non-obstructing calculus in the lower pole of the right kidney, indicating nephrolithiasis, a well-documented complication of long-term phosphorus and calcitriol therapy (Jan de Beur, 2005).Fig. 2 Pre-operative DXA scans measuring bone mineral density (BMD). (A) Pre-operative bone density of the lumbar spine, (L1-L4): 1.202 g per square cm, T-score (SD of peak BMD): 0.1 Z-score (SD of age-matched BMD): 0.1. (B) Pre-operative bone density of the left forearm (radius 33%) is: 0.694 g per square cm T-score (SD of peak BMD): −2.1 Z-score (SD of age-matched BMD): −2.1. Bone density of the femurs could not be performed due to bilateral hip prostheses.
Fig. 2
Additionally, a 13-gene Invitae hypophosphatemia panel (https://www.invitae.com/en/hypophosphatemia) (Table 1) was performed to adjudicate her clinical diagnosis of XLH. No pathogenic variants were detected prompting our team to suspect TIO and re-evaluate her previous XLH diagnosis.Table 1 Genes tested on the Invitae hypophosphatemia next-generation sequencing panel (https://www.invitae.com/en/hypophosphatemia), with associated localization, diseases, and pathological mutations (Lloyd et al., 1996; Priante et al., 2017; Root, 2018). Panel is sensitive to deletions, insertions, duplications and copy number variants, and single-nucleotide polymorphisms (SNPs). AD = autosomal dominant, AR = autosomal recessive, VDDR = Vitamin D-dependent rickets.
Table 1Gene Primary location(s) of expression Type of mutation precipitating disease Associated hypophosphatemic/osteomalacic disease
ALPL Osteoblasts Loss of function Hypophosphatasia
CLCN5 Proximal renal tubule Loss of function X-linked recessive hypophosphatemic rickets
CYP27B1 Many cell types Loss of function AR VDDR type 1A
CYP2R1 Hepatocytes Loss of function AR VDDR type 1B
DMP1 Osteoblasts, osteocytes Loss of function AR hypophosphatemic rickets
ENPP1 Chondrocytes, osteocytes, plasma cells Loss of function AR hypophosphatemic rickets
FAH Hepatocytes Loss of function AR tyrosinemia type 1
FAM20C Osteoblasts, osteocytes Loss of function AR osteosclerotic bone dysplasia (Raine syndrome)
FGF23 Osteoblasts, osteocytes Gain of function AD hypophosphatemic rickets
FGFR1 Many cell types Gain of function AD type 1 Pfeiffer syndrome and osteoglophonic dysplasia; synthesis upregulated in many TIO-associated tumors
PHEX Osteoblasts Loss of function, X-linked XLH, increased FGF23 secretion
SLC34A3 Proximal renal tubule Loss of function AR hypophosphatemic rickets with hypercalciuria
VDR Loss of function Calcitriol resistance, VDDR type 2A
Due to suspected TIO, a combined 68Ga-DOTATATE PET/CT scan was performed. The CT Scan (Fig. 3A) revealed an unusual lesion in her 9th lateral right rib; PET scan (Fig. 3B) showed that this lesion had high activity; and a 68Ga-DOTATATE scan (an indirect measure of somatostatin receptors which are highly expressed in most TIO-causing tumors) demonstrated activity in the same region (Fig. 3C-D).Fig. 3 Diagnostic radiologic characterization of the right rib mass. (A) CT (white arrows = mass). (B) PET (white arrows = activity). (C) 68 Ga-DOTATE Scan Axial (red arrows = activity). (D) 68 Ga-DOTATE Scan Coronal (A/P) (red arrows = activity).
Fig. 3
Some TIO patients with unresectable or unidentifiable PMTs have benefited greatly from Burosumab therapy (Jan De Beur et al., 2019). However, the accessibility of our patient's tumor prompted us to refer her to Thoracic Surgery for complete resection of the tumor and rib. Further, Burosumab therapy was discontinued prior to measuring baseline laboratory values due to potential confounding, especially with the FGF23 level.
Intra-operatively, surgeons identified a more concerning lesion on the patient's 10th right rib (Fig. 4A) that had no imaging correlate. This lesion was removed, and the surgeons deferred removal of the 9th right rib to ensure the 10th right rib lesion was not the culprit of her TIO symptoms or other pathology warranting alternative intervention. The patient's hypophosphatemia persisted post-operatively. 4-months after surgery, notable lab values included low serum phosphorus (1.4 mg/dL; normal 2.3–4.7 mg/dL), low 1,25 dihydroxyvitamin D (15 pg/mL; 19.9–79.3 pg/mL), normal total vitamin D (38 ng/mL; 25–80 ng/mL), and elevated total FGF23 (1532 RU/mL; <180 RU/mL). Histopathology of the 10th right rib mass showed only non-specific reactive changes, possibly representing an old fracture site.Fig. 4 Gross appearance of surgical specimens. (A) Intra-operative image of 10th right rib mass (no imaging correlate) removed during the first, unsuccessful surgery. White star (*) denotes the large abnormality that prompted surgeons to remove the 10th rib mass. (B-C) Post-operative images of 9th right rib removed during the second, successful surgery. (B) White stars (*) denote the two areas of abnormality, red arrow denotes the primary lesion of concern for PMT shown in Fig. 5, Fig. 6. (C) Significant thickening observed in the 9th right rib.
Fig. 4
These findings further implicated the active 9th rib lesion in her pathology (Figure 3), prompting Thoracic Surgery to remove the 9th right rib (Fig. 4B-C) 5 months after the first unsuccessful surgery. Gross appearance of the 9th right rib showed two areas of abnormality with one denoting the PMT lesion (Fig. 4B) and significant rib thickening along the lateral surface (Fig. 4C). Histological sections of the 9th right rib showed a morphologically classical phosphaturic mesenchymal tumor, consisting of bland spindled cells in a highly vascular background, with unusually hyalinized to occasionally calcified matrix (Fig. 5). Chromogenic in situ hybridization (CISH) of the tumor and RNA-sequencing for the presence of rearrangements in 138 target genes were pursued using methods previously published (Martinez et al., 2019; Carter et al., 2015). FGF23 CISH was strongly positive (Fig. 6). Sequencing was positive for the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1). Taken together, these results are characteristic of a typical PMT.Fig. 5 Histological appearance of 9th right rib phosphaturic mesenchymal tumor (PMT). A) Lower magnification showing infiltration of rib bone (pink, paucicellular) by the PMT. B) Higher magnification (black box of A) of the PMT specifically showing proliferation of uniform short spindle to ovoid cells with a rich vascular background and cystic changes. C) Low magnification of the PMT from a different depth of sectioning.
Fig. 5Fig. 6 FGF23 chromogenic in situ hybridization (CISH) of 9th right rib phosphaturic mesenchymal tumor (PMT).
Fig. 6Fig. 7 Post-operative portable chest X-ray after rib removal (second successful surgery). A left humeral rod and right chest tube are observed. No pneumothorax is seen. The lungs appear clear except for volume loss related to the overlying thoracic deformity. Extensive bone deformities identified, and multiple performed ribs are seen bilaterally but both appear similar to pre-operative radiographs.
Fig. 7Table 2 Longitudinal patient laboratory values. Op 1 denotes the first unsuccessful 10th rib removal operation. Op 2 denotes the second successful 9th rib removal operation. PTH = parathyroid hormone. Note = Pre-Op 1 labs were taken while the patient was on Burosumab, all other labs were taken while the patient was off Burosumab, and Post-Op 2 labs were taken 3 months after resection.
Table 2Laboratory value Normal range Pre-Op 1 (on Burosumab) Post-Op 1, Pre-Op 2 Post-Op 2 (3 months after 9th right rib resection)
Serum phosphorus 2.3–4.7 mg/dL 2.5 1.4 3.7
Calcium 8.4–10.5 mg/dL 9.7 9.3 10.4
Total vitamin D 25–80 ng/mL 40 38 35
1,25 dihydroxyvitamin D 19.9–79.3 pg/mL 333 15 327
Alkaline phosphatase 40–150 U/L 168 111 130
Chloride 96–106 mmol/L 108 109 105
PTH 16–77 pg/mL 189 Not collected 194
FGF23 <180 RU/mL 36,900 1532 245
3 months post-resection, chest x-rays showed no pneumothorax and no significant changes compared to prior radiographs (Fig. 7). FGF23 levels decreased again but remained slightly elevated (245 RU/mL), serum phosphorus normalized (3.7 mg/dL), alkaline phosphatase normalized (130 U/mL), and total vitamin D was 35 ng/mL. Parathyroid hormone remained elevated (194 pg/mL) (Table 2). Clinical assessments of mobility markedly improved (Video 1, Video 2), and the patient has stated she is in less pain and is more active and feels stronger than ever. She will continue to follow up longitudinally in our Endocrinology clinic.
3 Discussion
TIO is a paraneoplastic disease resulting in elevated FGF23, renal phosphate wasting, defective Vitamin D metabolism, and subsequent osteomalacia. Clinically, patients with TIO present with progressive bone pain, muscle weakness, fatigue, and sporadic insufficiency fractures (Yin et al., 2018). TIO can be suggested by serum hypophosphatemia, hyperphosphaturia, and low or inappropriately normal calcitriol levels, but the identification of a phosphaturic mesenchymal tumor (PMT) in the soft tissue or bone is necessary for definitive diagnosis (Feng et al., 2017). Here, we presented a 41-year-old woman suffering from TIO with a 26-year delay in diagnosis with a concurrent misdiagnosis of XLH.
Diagnosing TIO is often complicated by small tumor size and similar initial clinical presentation to more common phosphate wasting disorders such as XLH. A retrospective study of 144 TIO cases found that TIO was misdiagnosed in over 95% (137/144) of cases, with intervertebral disc herniation, spondyloarthritis, and osteoporosis being the most common misdiagnoses (Feng et al., 2017). In this case, our patient was misdiagnosed for 26 years with little symptomatic improvement with either conventional therapy or Burosumab, and subsequent gene paneling at our institution revealed no genetic evidence of her XLH diagnosis.
Patients who present with bone pain, muscle weakness, and multiple fractures should be evaluated for hypophosphatemia, and TMP/GFR should be performed for hypophosphatemic patients. While diagnostically burdensome, a low TMP/GFR is a powerful indicator of renal phosphate wasting in the absence of secondary hyperthyroidism (Jagtap et al., 2012). Though less sensitive than TMP/GFR, calculating a percent tubular reabsorption of phosphate (TRP) is a more easily collected alternative (Takeda et al., 2015). Additionally, 24-h urine phosphorus and calcium can differentiate between malabsorption and phosphate wasting disorders (Payne, 1998).
Patient FGF23 levels and family/personal histories are also important tools for differentiating between phosphate wasting disorders (Table 3). As discussed in our previous report, TIO distinguishes itself from other FGF23-high phosphate wasting disorders in that it often presents with rapid symptom onset later in life, often with a negative family history. On the other hand, XLH is usually inherited as an X-linked dominant inherited disorder that typically presents in early childhood (MD, 2012). As such, genetic testing and associated costs can often be avoided if a clear X-linked pattern is identified by pedigree. That said, XLH can still occur due to de novo mutations, so absence of a family history should not entirely rule out XLH (Durmaz et al., 2013).Table 3 Phosphate wasting disorder differential diagnosis. A differential diagnosis table (not extensive) for phosphate wasting disorders, including TIO, distinguished by serum FGF23 level, reproduced from Colazo et al. (n.d.), Imel and Econs (2012), and Zoller et al. (2017).
Table 3Phosphate wasting disorders with low FGF23 Phosphate wasting disorders with high or “inappropriately normal” FGF23
Fanconi syndrome X-linked hypophosphatemia (XLH)
Hyperparathyroidism Tumor-induced osteomalacia (TIO)
Diuretics (e.g. acetazolamide) Autosomal dominant/autosomal recessive rickets
Myeloma McCune Albright syndrome
Copper disorders (Menkes) Cutaneous-skeletal hypophosphatemia syndrome (CSHS) (e.g., epidermal nevus syndromes)
Alcohol consumption Iron use (iron polymaltose infusions)
Genetic disorders (e.g. Npt2a mutations)
Finally, in the absence of genetic data, indication of several bone and calcification disorders can help distinguish XLH from TIO, though these criteria are highly variable. Enthesopathy (calcification of the joint capsule, tendon insertions, and ligaments) is a common feature of XLH but not of TIO and results in increased apparent BMD (Beck-Nielsen et al., 2019). By contrast, typical TIO patients have remarkably low BMD, often being labelled osteoporotic. Dentition is another clinical differentiator, in that patients with XLH can have recurrent abscesses and dental loss, while dentition in TIO is usually normal (Lee et al., 2017). However, the patient presented here was edentulous, demonstrating that TIO should not be ruled out based on these features.
Suspected TIO should prompt an investigation for active PMTs in the hands, feet, ribs, nasal cavities, and brain (Colazo et al., n.d). In recent literature, a full body 68Ga-DOTATATE scan has been shown to be a specific imaging test for identifying culprit tumors in osteomalacia (Zhang et al., 2015). The 68Ga-DOTATATE scan works by utilizing 68Gallium (68Ga) conjugated to somatostatin peptide analogues, which allows for somatostatin receptor imaging by PET scan. DOTATATE scans are most often used for diagnosing somatostatin-receptor positive neuroendocrine tumors, but PMTs preferentially express somatostatin type 2 receptors (Houang et al., 2013). Hence, this technique allows for targeted imaging of TIO-causing lesions. That said, false positivity can still occur in hypersplenism, fractures, sarcoidosis, or vertebral hemangiomas (Hofman et al., 2015). If very small and/or multiple tumors of unknown significance are present, selective FGF23 venous sampling has shown promise in deciphering the FGF23-producing tumor (Colazo et al., n.d.; Schober et al., 2017). In this case, since two suspicious lesions were encountered, FGF23 venous sampling could have been utilized, but the anatomical location and proximity of both lesions to each other would have made the process difficult to perform and most likely futile.
Misdiagnosis can also occur after tumor identification, especially in cases in which non-PMT tumors morphologically mimic PMTs in the context of hypophosphatemia (Lee et al., 2016). Recent studies have identified novel gene fusions FN1-FGF1 and FN1-FGFR1 that are transcribed and synthesized by the majority of PMTs. The fusion of FN1 and FGFR1 leads to constitutive overexpression of the 3′ portion of FGFR1 through constitutive activation of the FN1 promoter, and the fusion protein products have suspected roles in autocrine signaling (Lee et al., 2016). These fusion products can be detected by RNA sequencing or FISH of the tumor, and several emerging FGF/R inhibitors have been shown to be therapeutically beneficial in relapsing TIO (Hartley et al., 2020).
While diagnosis of TIO depends solely on postoperative biochemical resolution of laboratory abnormalities, the classification of the resected tumor can be helpful. Our patient's tumor tested positive for FN1-FGFR1 by RNAseq and for FGF23 by chromogenic in situ hybridization (CISH), further suggesting PMT (Martinez et al., 2019; Carter et al., 2015). These results support the use of FN1-FGF1/R1 gene fusions and FGF23 CISH as an additional diagnostic tool for TIO and can be used for comparison between the original and a recurrent tumor.
To date, surgical PMT resection is the only curative therapy for TIO. To mitigate risk of recurrence or metastasis, resection should be performed with wide margins where possible, and patients should be monitored longitudinally post-operatively (Hautmann et al., 2015). Here, our patient had dramatic improvements 3 months post-resection in symptoms and mobility (Video 1, Video 2), as well as in serum FGF23, phosphate, and Vitamin D levels (Table 2). Patients with unresectable or undetectable tumors have historically been placed on supplemental phosphate and calcitriol; however, Burosumab is a novel human anti-FGF23 monoclonal antibody initially approved by the FDA to treat XLH that has been recently approved for treatment of such complex TIO presentations (Carpenter et al., 2016; Day et al., 2020). In particular, Kyowa Kirin and Ultragenyx's Crysvita (burosumab-twza) has been approved for the treatment of TIO associated with PMTs that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older. Burosumab has been shown to improve serum phosphate levels and histomorphology of bone biopsies in patients with TIO, but mild side effects have been reported, including reactive overproduction of FGF23 and consequent Vitamin D deficiency (Day et al., 2020). For these reasons, monitoring FGF23 levels is not a reliable way to monitor patients on Burosumab; clinicians should focus on serum phosphorous, Alkaline phosphatase, renal phosphate wasting, 1,25 Dihydroxyvitamin D, and clinical signs/symptoms.
Indeed, in the 3 months prior to tumor identification, our patient was placed on Burosumab therapy and enjoyed mild symptomatic improvement and stable lab values (notably a normal serum phosphorus, see Table 2). While no labs were taken pre-induction, her condition deteriorated while off Burosumab between her two rib resections, indicating a positive impact of Burosumab on her condition. Her marked post-operative improvement supports the use of PMT resection when possible.
In this report, we have demonstrated the utility of two powerful genetic tools – gene paneling and RNA sequencing – at guiding clinicians to a challenging diagnosis of a non-heritable condition. In the 26-year history of this patient's disease, genetic tools have become increasingly cost-effective, sensitive, and precise. A lack of available tests at initial presentation motivated a diagnosis of XLH (a germline genetic condition) based on clinical evidence alone. The similar clinical presentations of many phosphate wasting disorders, the uniqueness of their genetic identifiers like FN1-FGFR1 or PHEX, and the illumination of known, curative therapies through such tests all support the expanded use of gene paneling and tumor sequencing alongside clinical reasoning around phosphate wasting disorders. This fact is further evidenced by the requirement of genetic diagnosis for enrollment in most clinical trials targeting phosphate wasting disorders. Additionally, the advancements in the field over the past 3 decades may warrant the re-evaluation of poorly managed, long-term diagnoses through the lens of a gene panel or specific genetic marker.
4 Conclusion
Tumor-induced osteomalacia (TIO) is a paraneoplastic disease driven by hypersecretion of Fibroblast Growth Factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). In this case report, we present a patient with what we believe to be the longest history of a delayed TIO diagnosis reported in the literature, outlined current diagnostic strategies, and demonstrated the increasing utility of genetic testing in the diagnosis of phosphate wasting disorders.
We highlight the importance of the personal and family histories, as well as potential pitfalls of using exclusively clinical criteria in diagnosing phosphate wasting disorders, as our patient had several clinical findings suggestive of XLH yet had a negative family history of phosphate wasting disorders. Further, we stress the utility of full body imaging, especially a 68Ga-DOTATATE PET/CT scan, in probing cases of high clinical suspicion for TIO, and we applied novel genetic screening methods (i.e. gene paneling and tumor RNA sequencing) to confirm our diagnosis. When possible, performing these tests provides powerful support for a TIO diagnosis. Finally, while our patient has enjoyed a marked recovery 3 months post-surgical resection, we discuss Burosumab, an emerging therapeutic antibody against FGF23 that may be an attractive treatment for undetectable or unresectable tumors in TIO.
The following are the supplementary data related to this article.Video 1
Pre-operative functionality of patient
Video 1 Video 2
Post-operative functionality of patient
Video 2
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Acknowledgments
Two of the authors (JMC, JAD) are supported by NIGMS of the National Institutes of Health under award number T32GM007347. The content in this report is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The Transparency document associated with this article can be found, in online version. | Subcutaneous | DrugAdministrationRoute | CC BY-NC-ND | 33490314 | 18,819,395 | 2021-06 |
What was the outcome of reaction 'Blood 1,25-dihydroxycholecalciferol increased'? | Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia.
Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A 68Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases.
1 Introduction
Osteomalacia is the progressive softening of bones due to decreased mineralization of calcium and phosphates at sites of bone remodeling and growth, commonly resulting in bone pain and muscle weakness (Michigami, 2019). Fibroblast Growth Factor 23 (FGF23) is a protein secreted by osteocytes mainly in response to calcitriol and phosphate (Martin et al., 2012). FGF23 regulates plasma phosphate concentration predominately by reducing serum calcitriol which mediates intestinal phosphate absorption and by reducing NPT2-mediated phosphate reabsorption in the kidney. Tumor-Induced Osteomalacia (TIO) is a rare paraneoplastic disease in which a phosphaturic mesenchymal tumor (PMT) secretes significant amounts of FGF23 into the bloodstream, leading to downstream osteomalacia through renal phosphate wasting and defective Vitamin D metabolism (Yin et al., 2018). While less than 500 cases of TIO have been reported worldwide, and formal epidemiological studies of the disease have not been performed, surgical resection offers a potentially curative treatment in contrast to similarly presenting disorders (Folpe, 2019).
X-linked hypophosphatemia (XLH) is a phosphate wasting disorder caused by mutations in the PHEX gene which expresses the enzyme phosphate-regulating neutral endopeptidase (PHEX). Studies suggest that the PHEX enzyme may be involved in the regulation of FGF23 (Beck-Nielsen et al., 2019; Liu et al., 2003). Importantly, diagnosing phosphate wasting disorders based purely on clinical criteria is confounded by the similarity of clinical and radiological presentations of this family of disorders. Knowing the distinct genetic basis for a patient's phosphate wasting disorder often allows clinicians to tailor their treatment/management strategy accordingly, potentially saving years of hardship for affected patients. As such, recent emphasis has been placed on using gene panels to accelerate clinicians' diagnosis of these disorders.
In particular, a potential for misdiagnosis of TIO as XLH exists because FGF23 levels are increased in both, PMT tumors are notoriously difficult to find due to their small size and variable location, and (albeit still rare) the incidence of XLH far exceeds that of TIO (Yin et al., 2018; Carpenter, 1997). Here, we present a 41-year-old female in whom a 26-year delayed TIO diagnosis and concurrent misdiagnosis of XLH was identified via a negative hypophosphatemia gene panel and corrected to TIO through identification of a PMT of her 9th right rib. Surgical resection resulted in biochemical and clinical symptom improvement. Histological analysis was positive for FGF23 (CISH) and the FN1-FGFR1 transcriptional marker. Finally, we highlight recent key advances in diagnosing phosphate wasting disorders, molecular characterization of PMTs, and TIO treatment and management.
2 Case presentation
A 41-year-old woman with a prior clinical diagnosis of hypophosphatemic rickets presented to our institution with a 26-year history of low phosphorus, bone pain, proximal muscle weakness, gait abnormalities, and multiple traumatic and insufficiency fractures of the hip, humerus, and spine (Fig. 1, Fig. 7). She had no history of hearing loss. She had lost all her secondary teeth (edentulous). The patient reported no family history of hypophosphatemia, including her 8-year-old male child and 17-year-old female child, neither of whom showed clinical or laboratory indications of musculoskeletal conditions or phosphate wasting disorders. Her maximum height was 5′2″ but she presented to us at 4′8″ due to progressive spine deformities.
Despite intermittent treatment with conventional therapy with phosphorus supplements and calcitriol during her teens and 20s, she developed progressive gait abnormalities and decreased hip strength and ultimately sustained bilateral hip fractures (Fig. 1A) and small fractures throughout her spine (Fig. 1B-C).Fig. 1 Patient musculoskeletal radiology. X-ray AP Pelvis (A) shows evidence of prior bilateral obturator ring fractures with bilateral femoral head/neck angular deformities. X-ray Spine Total AP/Lateral (B-C) shows normal trabecular bone with vertebral body alignments and interspacing intact, but there is mild flattening of the mid vertebral body at multiple levels. There is evidence of previous insufficiency fractures.
Fig. 1
Despite treatment, the patient's symptoms deteriorated further in her 20s, when she had stability rods and screws placed bilaterally in her femurs and hips, respectively (Fig. 1A). Ten years later, the patient presented with a traumatic left humerus fracture, for which she underwent surgery (Figure 7). Post-operatively, the patient was placed on the osteoporosis medication teriparatide.
Teriparatide therapy failed to prevent more spinal fractures (Fig. 1B-C), bone pain, and muscle weakness over the next year, and the patient was eventually confined to a wheelchair. Orthopedic physicians reevaluated her history, officially diagnosed her with X-linked Hypophosphatemia (XLH) (although patient claims having an “unofficial” XLH diagnosis years prior by previous physicians), and started her on Burosumab (60 mg subcutaneous injection every 28 days) - the monoclonal antibody targeted against FGF23. Unfortunately, laboratory values relevant to phosphate wasting (e.g. TmP/GFR, FGF23) were not reported prior to initiation of Burosumab therapy or referral to our institution for further evaluation and treatment.
The patient remained on Burosumab for 3 months. While on Burosumab, the patient reported mild symptomatic improvement with no reported adverse effects, but still had severe limitations in mobility (difficulty from sit to stand, Video 1), fatigue, and pain. On therapy, FGF23 levels were 33,900 RU/mL (normal <180RU/mL) and 36,900 RU/mL two months later as measured by ELISA (Quidel Corporation). Other notable preoperative laboratory values include a normal serum phosphorus, normal calcium, normal total vitamin D, elevated 1,25 dihydroxyvitamin D (333 pg/mL; normal 19.9–79.3 pg/mL), high alkaline phosphatase (168 U/mL; normal 40–150 U/mL), and high PTH (189 pg/mL, normal 16–77 pg/mL) (Table 2). These findings are abnormal for a patient with TIO, but they should be viewed in the context of Burosumab therapy. After discontinuation, her total FGF23 declined to 1532 RU/mL after discontinuing Burosumab but before excision of her PMT which was still considerably elevated above reference range.
At our clinic, areal bone density of the lumbar spine and left forearm (bone density of the femurs could not be performed due to bilateral hip prostheses) were assessed by dual-energy X-ray absorptiometry (DXA) using a GE Lunar Prodigy Advanced densitometer. Densitometry revealed normal bone density in the spine and significantly lower than expected density in the forearm (Fig. 2A-B). A renal ultrasound showed a 4-mm non-obstructing calculus in the lower pole of the right kidney, indicating nephrolithiasis, a well-documented complication of long-term phosphorus and calcitriol therapy (Jan de Beur, 2005).Fig. 2 Pre-operative DXA scans measuring bone mineral density (BMD). (A) Pre-operative bone density of the lumbar spine, (L1-L4): 1.202 g per square cm, T-score (SD of peak BMD): 0.1 Z-score (SD of age-matched BMD): 0.1. (B) Pre-operative bone density of the left forearm (radius 33%) is: 0.694 g per square cm T-score (SD of peak BMD): −2.1 Z-score (SD of age-matched BMD): −2.1. Bone density of the femurs could not be performed due to bilateral hip prostheses.
Fig. 2
Additionally, a 13-gene Invitae hypophosphatemia panel (https://www.invitae.com/en/hypophosphatemia) (Table 1) was performed to adjudicate her clinical diagnosis of XLH. No pathogenic variants were detected prompting our team to suspect TIO and re-evaluate her previous XLH diagnosis.Table 1 Genes tested on the Invitae hypophosphatemia next-generation sequencing panel (https://www.invitae.com/en/hypophosphatemia), with associated localization, diseases, and pathological mutations (Lloyd et al., 1996; Priante et al., 2017; Root, 2018). Panel is sensitive to deletions, insertions, duplications and copy number variants, and single-nucleotide polymorphisms (SNPs). AD = autosomal dominant, AR = autosomal recessive, VDDR = Vitamin D-dependent rickets.
Table 1Gene Primary location(s) of expression Type of mutation precipitating disease Associated hypophosphatemic/osteomalacic disease
ALPL Osteoblasts Loss of function Hypophosphatasia
CLCN5 Proximal renal tubule Loss of function X-linked recessive hypophosphatemic rickets
CYP27B1 Many cell types Loss of function AR VDDR type 1A
CYP2R1 Hepatocytes Loss of function AR VDDR type 1B
DMP1 Osteoblasts, osteocytes Loss of function AR hypophosphatemic rickets
ENPP1 Chondrocytes, osteocytes, plasma cells Loss of function AR hypophosphatemic rickets
FAH Hepatocytes Loss of function AR tyrosinemia type 1
FAM20C Osteoblasts, osteocytes Loss of function AR osteosclerotic bone dysplasia (Raine syndrome)
FGF23 Osteoblasts, osteocytes Gain of function AD hypophosphatemic rickets
FGFR1 Many cell types Gain of function AD type 1 Pfeiffer syndrome and osteoglophonic dysplasia; synthesis upregulated in many TIO-associated tumors
PHEX Osteoblasts Loss of function, X-linked XLH, increased FGF23 secretion
SLC34A3 Proximal renal tubule Loss of function AR hypophosphatemic rickets with hypercalciuria
VDR Loss of function Calcitriol resistance, VDDR type 2A
Due to suspected TIO, a combined 68Ga-DOTATATE PET/CT scan was performed. The CT Scan (Fig. 3A) revealed an unusual lesion in her 9th lateral right rib; PET scan (Fig. 3B) showed that this lesion had high activity; and a 68Ga-DOTATATE scan (an indirect measure of somatostatin receptors which are highly expressed in most TIO-causing tumors) demonstrated activity in the same region (Fig. 3C-D).Fig. 3 Diagnostic radiologic characterization of the right rib mass. (A) CT (white arrows = mass). (B) PET (white arrows = activity). (C) 68 Ga-DOTATE Scan Axial (red arrows = activity). (D) 68 Ga-DOTATE Scan Coronal (A/P) (red arrows = activity).
Fig. 3
Some TIO patients with unresectable or unidentifiable PMTs have benefited greatly from Burosumab therapy (Jan De Beur et al., 2019). However, the accessibility of our patient's tumor prompted us to refer her to Thoracic Surgery for complete resection of the tumor and rib. Further, Burosumab therapy was discontinued prior to measuring baseline laboratory values due to potential confounding, especially with the FGF23 level.
Intra-operatively, surgeons identified a more concerning lesion on the patient's 10th right rib (Fig. 4A) that had no imaging correlate. This lesion was removed, and the surgeons deferred removal of the 9th right rib to ensure the 10th right rib lesion was not the culprit of her TIO symptoms or other pathology warranting alternative intervention. The patient's hypophosphatemia persisted post-operatively. 4-months after surgery, notable lab values included low serum phosphorus (1.4 mg/dL; normal 2.3–4.7 mg/dL), low 1,25 dihydroxyvitamin D (15 pg/mL; 19.9–79.3 pg/mL), normal total vitamin D (38 ng/mL; 25–80 ng/mL), and elevated total FGF23 (1532 RU/mL; <180 RU/mL). Histopathology of the 10th right rib mass showed only non-specific reactive changes, possibly representing an old fracture site.Fig. 4 Gross appearance of surgical specimens. (A) Intra-operative image of 10th right rib mass (no imaging correlate) removed during the first, unsuccessful surgery. White star (*) denotes the large abnormality that prompted surgeons to remove the 10th rib mass. (B-C) Post-operative images of 9th right rib removed during the second, successful surgery. (B) White stars (*) denote the two areas of abnormality, red arrow denotes the primary lesion of concern for PMT shown in Fig. 5, Fig. 6. (C) Significant thickening observed in the 9th right rib.
Fig. 4
These findings further implicated the active 9th rib lesion in her pathology (Figure 3), prompting Thoracic Surgery to remove the 9th right rib (Fig. 4B-C) 5 months after the first unsuccessful surgery. Gross appearance of the 9th right rib showed two areas of abnormality with one denoting the PMT lesion (Fig. 4B) and significant rib thickening along the lateral surface (Fig. 4C). Histological sections of the 9th right rib showed a morphologically classical phosphaturic mesenchymal tumor, consisting of bland spindled cells in a highly vascular background, with unusually hyalinized to occasionally calcified matrix (Fig. 5). Chromogenic in situ hybridization (CISH) of the tumor and RNA-sequencing for the presence of rearrangements in 138 target genes were pursued using methods previously published (Martinez et al., 2019; Carter et al., 2015). FGF23 CISH was strongly positive (Fig. 6). Sequencing was positive for the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1). Taken together, these results are characteristic of a typical PMT.Fig. 5 Histological appearance of 9th right rib phosphaturic mesenchymal tumor (PMT). A) Lower magnification showing infiltration of rib bone (pink, paucicellular) by the PMT. B) Higher magnification (black box of A) of the PMT specifically showing proliferation of uniform short spindle to ovoid cells with a rich vascular background and cystic changes. C) Low magnification of the PMT from a different depth of sectioning.
Fig. 5Fig. 6 FGF23 chromogenic in situ hybridization (CISH) of 9th right rib phosphaturic mesenchymal tumor (PMT).
Fig. 6Fig. 7 Post-operative portable chest X-ray after rib removal (second successful surgery). A left humeral rod and right chest tube are observed. No pneumothorax is seen. The lungs appear clear except for volume loss related to the overlying thoracic deformity. Extensive bone deformities identified, and multiple performed ribs are seen bilaterally but both appear similar to pre-operative radiographs.
Fig. 7Table 2 Longitudinal patient laboratory values. Op 1 denotes the first unsuccessful 10th rib removal operation. Op 2 denotes the second successful 9th rib removal operation. PTH = parathyroid hormone. Note = Pre-Op 1 labs were taken while the patient was on Burosumab, all other labs were taken while the patient was off Burosumab, and Post-Op 2 labs were taken 3 months after resection.
Table 2Laboratory value Normal range Pre-Op 1 (on Burosumab) Post-Op 1, Pre-Op 2 Post-Op 2 (3 months after 9th right rib resection)
Serum phosphorus 2.3–4.7 mg/dL 2.5 1.4 3.7
Calcium 8.4–10.5 mg/dL 9.7 9.3 10.4
Total vitamin D 25–80 ng/mL 40 38 35
1,25 dihydroxyvitamin D 19.9–79.3 pg/mL 333 15 327
Alkaline phosphatase 40–150 U/L 168 111 130
Chloride 96–106 mmol/L 108 109 105
PTH 16–77 pg/mL 189 Not collected 194
FGF23 <180 RU/mL 36,900 1532 245
3 months post-resection, chest x-rays showed no pneumothorax and no significant changes compared to prior radiographs (Fig. 7). FGF23 levels decreased again but remained slightly elevated (245 RU/mL), serum phosphorus normalized (3.7 mg/dL), alkaline phosphatase normalized (130 U/mL), and total vitamin D was 35 ng/mL. Parathyroid hormone remained elevated (194 pg/mL) (Table 2). Clinical assessments of mobility markedly improved (Video 1, Video 2), and the patient has stated she is in less pain and is more active and feels stronger than ever. She will continue to follow up longitudinally in our Endocrinology clinic.
3 Discussion
TIO is a paraneoplastic disease resulting in elevated FGF23, renal phosphate wasting, defective Vitamin D metabolism, and subsequent osteomalacia. Clinically, patients with TIO present with progressive bone pain, muscle weakness, fatigue, and sporadic insufficiency fractures (Yin et al., 2018). TIO can be suggested by serum hypophosphatemia, hyperphosphaturia, and low or inappropriately normal calcitriol levels, but the identification of a phosphaturic mesenchymal tumor (PMT) in the soft tissue or bone is necessary for definitive diagnosis (Feng et al., 2017). Here, we presented a 41-year-old woman suffering from TIO with a 26-year delay in diagnosis with a concurrent misdiagnosis of XLH.
Diagnosing TIO is often complicated by small tumor size and similar initial clinical presentation to more common phosphate wasting disorders such as XLH. A retrospective study of 144 TIO cases found that TIO was misdiagnosed in over 95% (137/144) of cases, with intervertebral disc herniation, spondyloarthritis, and osteoporosis being the most common misdiagnoses (Feng et al., 2017). In this case, our patient was misdiagnosed for 26 years with little symptomatic improvement with either conventional therapy or Burosumab, and subsequent gene paneling at our institution revealed no genetic evidence of her XLH diagnosis.
Patients who present with bone pain, muscle weakness, and multiple fractures should be evaluated for hypophosphatemia, and TMP/GFR should be performed for hypophosphatemic patients. While diagnostically burdensome, a low TMP/GFR is a powerful indicator of renal phosphate wasting in the absence of secondary hyperthyroidism (Jagtap et al., 2012). Though less sensitive than TMP/GFR, calculating a percent tubular reabsorption of phosphate (TRP) is a more easily collected alternative (Takeda et al., 2015). Additionally, 24-h urine phosphorus and calcium can differentiate between malabsorption and phosphate wasting disorders (Payne, 1998).
Patient FGF23 levels and family/personal histories are also important tools for differentiating between phosphate wasting disorders (Table 3). As discussed in our previous report, TIO distinguishes itself from other FGF23-high phosphate wasting disorders in that it often presents with rapid symptom onset later in life, often with a negative family history. On the other hand, XLH is usually inherited as an X-linked dominant inherited disorder that typically presents in early childhood (MD, 2012). As such, genetic testing and associated costs can often be avoided if a clear X-linked pattern is identified by pedigree. That said, XLH can still occur due to de novo mutations, so absence of a family history should not entirely rule out XLH (Durmaz et al., 2013).Table 3 Phosphate wasting disorder differential diagnosis. A differential diagnosis table (not extensive) for phosphate wasting disorders, including TIO, distinguished by serum FGF23 level, reproduced from Colazo et al. (n.d.), Imel and Econs (2012), and Zoller et al. (2017).
Table 3Phosphate wasting disorders with low FGF23 Phosphate wasting disorders with high or “inappropriately normal” FGF23
Fanconi syndrome X-linked hypophosphatemia (XLH)
Hyperparathyroidism Tumor-induced osteomalacia (TIO)
Diuretics (e.g. acetazolamide) Autosomal dominant/autosomal recessive rickets
Myeloma McCune Albright syndrome
Copper disorders (Menkes) Cutaneous-skeletal hypophosphatemia syndrome (CSHS) (e.g., epidermal nevus syndromes)
Alcohol consumption Iron use (iron polymaltose infusions)
Genetic disorders (e.g. Npt2a mutations)
Finally, in the absence of genetic data, indication of several bone and calcification disorders can help distinguish XLH from TIO, though these criteria are highly variable. Enthesopathy (calcification of the joint capsule, tendon insertions, and ligaments) is a common feature of XLH but not of TIO and results in increased apparent BMD (Beck-Nielsen et al., 2019). By contrast, typical TIO patients have remarkably low BMD, often being labelled osteoporotic. Dentition is another clinical differentiator, in that patients with XLH can have recurrent abscesses and dental loss, while dentition in TIO is usually normal (Lee et al., 2017). However, the patient presented here was edentulous, demonstrating that TIO should not be ruled out based on these features.
Suspected TIO should prompt an investigation for active PMTs in the hands, feet, ribs, nasal cavities, and brain (Colazo et al., n.d). In recent literature, a full body 68Ga-DOTATATE scan has been shown to be a specific imaging test for identifying culprit tumors in osteomalacia (Zhang et al., 2015). The 68Ga-DOTATATE scan works by utilizing 68Gallium (68Ga) conjugated to somatostatin peptide analogues, which allows for somatostatin receptor imaging by PET scan. DOTATATE scans are most often used for diagnosing somatostatin-receptor positive neuroendocrine tumors, but PMTs preferentially express somatostatin type 2 receptors (Houang et al., 2013). Hence, this technique allows for targeted imaging of TIO-causing lesions. That said, false positivity can still occur in hypersplenism, fractures, sarcoidosis, or vertebral hemangiomas (Hofman et al., 2015). If very small and/or multiple tumors of unknown significance are present, selective FGF23 venous sampling has shown promise in deciphering the FGF23-producing tumor (Colazo et al., n.d.; Schober et al., 2017). In this case, since two suspicious lesions were encountered, FGF23 venous sampling could have been utilized, but the anatomical location and proximity of both lesions to each other would have made the process difficult to perform and most likely futile.
Misdiagnosis can also occur after tumor identification, especially in cases in which non-PMT tumors morphologically mimic PMTs in the context of hypophosphatemia (Lee et al., 2016). Recent studies have identified novel gene fusions FN1-FGF1 and FN1-FGFR1 that are transcribed and synthesized by the majority of PMTs. The fusion of FN1 and FGFR1 leads to constitutive overexpression of the 3′ portion of FGFR1 through constitutive activation of the FN1 promoter, and the fusion protein products have suspected roles in autocrine signaling (Lee et al., 2016). These fusion products can be detected by RNA sequencing or FISH of the tumor, and several emerging FGF/R inhibitors have been shown to be therapeutically beneficial in relapsing TIO (Hartley et al., 2020).
While diagnosis of TIO depends solely on postoperative biochemical resolution of laboratory abnormalities, the classification of the resected tumor can be helpful. Our patient's tumor tested positive for FN1-FGFR1 by RNAseq and for FGF23 by chromogenic in situ hybridization (CISH), further suggesting PMT (Martinez et al., 2019; Carter et al., 2015). These results support the use of FN1-FGF1/R1 gene fusions and FGF23 CISH as an additional diagnostic tool for TIO and can be used for comparison between the original and a recurrent tumor.
To date, surgical PMT resection is the only curative therapy for TIO. To mitigate risk of recurrence or metastasis, resection should be performed with wide margins where possible, and patients should be monitored longitudinally post-operatively (Hautmann et al., 2015). Here, our patient had dramatic improvements 3 months post-resection in symptoms and mobility (Video 1, Video 2), as well as in serum FGF23, phosphate, and Vitamin D levels (Table 2). Patients with unresectable or undetectable tumors have historically been placed on supplemental phosphate and calcitriol; however, Burosumab is a novel human anti-FGF23 monoclonal antibody initially approved by the FDA to treat XLH that has been recently approved for treatment of such complex TIO presentations (Carpenter et al., 2016; Day et al., 2020). In particular, Kyowa Kirin and Ultragenyx's Crysvita (burosumab-twza) has been approved for the treatment of TIO associated with PMTs that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older. Burosumab has been shown to improve serum phosphate levels and histomorphology of bone biopsies in patients with TIO, but mild side effects have been reported, including reactive overproduction of FGF23 and consequent Vitamin D deficiency (Day et al., 2020). For these reasons, monitoring FGF23 levels is not a reliable way to monitor patients on Burosumab; clinicians should focus on serum phosphorous, Alkaline phosphatase, renal phosphate wasting, 1,25 Dihydroxyvitamin D, and clinical signs/symptoms.
Indeed, in the 3 months prior to tumor identification, our patient was placed on Burosumab therapy and enjoyed mild symptomatic improvement and stable lab values (notably a normal serum phosphorus, see Table 2). While no labs were taken pre-induction, her condition deteriorated while off Burosumab between her two rib resections, indicating a positive impact of Burosumab on her condition. Her marked post-operative improvement supports the use of PMT resection when possible.
In this report, we have demonstrated the utility of two powerful genetic tools – gene paneling and RNA sequencing – at guiding clinicians to a challenging diagnosis of a non-heritable condition. In the 26-year history of this patient's disease, genetic tools have become increasingly cost-effective, sensitive, and precise. A lack of available tests at initial presentation motivated a diagnosis of XLH (a germline genetic condition) based on clinical evidence alone. The similar clinical presentations of many phosphate wasting disorders, the uniqueness of their genetic identifiers like FN1-FGFR1 or PHEX, and the illumination of known, curative therapies through such tests all support the expanded use of gene paneling and tumor sequencing alongside clinical reasoning around phosphate wasting disorders. This fact is further evidenced by the requirement of genetic diagnosis for enrollment in most clinical trials targeting phosphate wasting disorders. Additionally, the advancements in the field over the past 3 decades may warrant the re-evaluation of poorly managed, long-term diagnoses through the lens of a gene panel or specific genetic marker.
4 Conclusion
Tumor-induced osteomalacia (TIO) is a paraneoplastic disease driven by hypersecretion of Fibroblast Growth Factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). In this case report, we present a patient with what we believe to be the longest history of a delayed TIO diagnosis reported in the literature, outlined current diagnostic strategies, and demonstrated the increasing utility of genetic testing in the diagnosis of phosphate wasting disorders.
We highlight the importance of the personal and family histories, as well as potential pitfalls of using exclusively clinical criteria in diagnosing phosphate wasting disorders, as our patient had several clinical findings suggestive of XLH yet had a negative family history of phosphate wasting disorders. Further, we stress the utility of full body imaging, especially a 68Ga-DOTATATE PET/CT scan, in probing cases of high clinical suspicion for TIO, and we applied novel genetic screening methods (i.e. gene paneling and tumor RNA sequencing) to confirm our diagnosis. When possible, performing these tests provides powerful support for a TIO diagnosis. Finally, while our patient has enjoyed a marked recovery 3 months post-surgical resection, we discuss Burosumab, an emerging therapeutic antibody against FGF23 that may be an attractive treatment for undetectable or unresectable tumors in TIO.
The following are the supplementary data related to this article.Video 1
Pre-operative functionality of patient
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Post-operative functionality of patient
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Acknowledgments
Two of the authors (JMC, JAD) are supported by NIGMS of the National Institutes of Health under award number T32GM007347. The content in this report is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The Transparency document associated with this article can be found, in online version. | Not recovered | ReactionOutcome | CC BY-NC-ND | 33490314 | 18,819,395 | 2021-06 |
What was the outcome of reaction 'Blood alkaline phosphatase increased'? | Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia.
Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A 68Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases.
1 Introduction
Osteomalacia is the progressive softening of bones due to decreased mineralization of calcium and phosphates at sites of bone remodeling and growth, commonly resulting in bone pain and muscle weakness (Michigami, 2019). Fibroblast Growth Factor 23 (FGF23) is a protein secreted by osteocytes mainly in response to calcitriol and phosphate (Martin et al., 2012). FGF23 regulates plasma phosphate concentration predominately by reducing serum calcitriol which mediates intestinal phosphate absorption and by reducing NPT2-mediated phosphate reabsorption in the kidney. Tumor-Induced Osteomalacia (TIO) is a rare paraneoplastic disease in which a phosphaturic mesenchymal tumor (PMT) secretes significant amounts of FGF23 into the bloodstream, leading to downstream osteomalacia through renal phosphate wasting and defective Vitamin D metabolism (Yin et al., 2018). While less than 500 cases of TIO have been reported worldwide, and formal epidemiological studies of the disease have not been performed, surgical resection offers a potentially curative treatment in contrast to similarly presenting disorders (Folpe, 2019).
X-linked hypophosphatemia (XLH) is a phosphate wasting disorder caused by mutations in the PHEX gene which expresses the enzyme phosphate-regulating neutral endopeptidase (PHEX). Studies suggest that the PHEX enzyme may be involved in the regulation of FGF23 (Beck-Nielsen et al., 2019; Liu et al., 2003). Importantly, diagnosing phosphate wasting disorders based purely on clinical criteria is confounded by the similarity of clinical and radiological presentations of this family of disorders. Knowing the distinct genetic basis for a patient's phosphate wasting disorder often allows clinicians to tailor their treatment/management strategy accordingly, potentially saving years of hardship for affected patients. As such, recent emphasis has been placed on using gene panels to accelerate clinicians' diagnosis of these disorders.
In particular, a potential for misdiagnosis of TIO as XLH exists because FGF23 levels are increased in both, PMT tumors are notoriously difficult to find due to their small size and variable location, and (albeit still rare) the incidence of XLH far exceeds that of TIO (Yin et al., 2018; Carpenter, 1997). Here, we present a 41-year-old female in whom a 26-year delayed TIO diagnosis and concurrent misdiagnosis of XLH was identified via a negative hypophosphatemia gene panel and corrected to TIO through identification of a PMT of her 9th right rib. Surgical resection resulted in biochemical and clinical symptom improvement. Histological analysis was positive for FGF23 (CISH) and the FN1-FGFR1 transcriptional marker. Finally, we highlight recent key advances in diagnosing phosphate wasting disorders, molecular characterization of PMTs, and TIO treatment and management.
2 Case presentation
A 41-year-old woman with a prior clinical diagnosis of hypophosphatemic rickets presented to our institution with a 26-year history of low phosphorus, bone pain, proximal muscle weakness, gait abnormalities, and multiple traumatic and insufficiency fractures of the hip, humerus, and spine (Fig. 1, Fig. 7). She had no history of hearing loss. She had lost all her secondary teeth (edentulous). The patient reported no family history of hypophosphatemia, including her 8-year-old male child and 17-year-old female child, neither of whom showed clinical or laboratory indications of musculoskeletal conditions or phosphate wasting disorders. Her maximum height was 5′2″ but she presented to us at 4′8″ due to progressive spine deformities.
Despite intermittent treatment with conventional therapy with phosphorus supplements and calcitriol during her teens and 20s, she developed progressive gait abnormalities and decreased hip strength and ultimately sustained bilateral hip fractures (Fig. 1A) and small fractures throughout her spine (Fig. 1B-C).Fig. 1 Patient musculoskeletal radiology. X-ray AP Pelvis (A) shows evidence of prior bilateral obturator ring fractures with bilateral femoral head/neck angular deformities. X-ray Spine Total AP/Lateral (B-C) shows normal trabecular bone with vertebral body alignments and interspacing intact, but there is mild flattening of the mid vertebral body at multiple levels. There is evidence of previous insufficiency fractures.
Fig. 1
Despite treatment, the patient's symptoms deteriorated further in her 20s, when she had stability rods and screws placed bilaterally in her femurs and hips, respectively (Fig. 1A). Ten years later, the patient presented with a traumatic left humerus fracture, for which she underwent surgery (Figure 7). Post-operatively, the patient was placed on the osteoporosis medication teriparatide.
Teriparatide therapy failed to prevent more spinal fractures (Fig. 1B-C), bone pain, and muscle weakness over the next year, and the patient was eventually confined to a wheelchair. Orthopedic physicians reevaluated her history, officially diagnosed her with X-linked Hypophosphatemia (XLH) (although patient claims having an “unofficial” XLH diagnosis years prior by previous physicians), and started her on Burosumab (60 mg subcutaneous injection every 28 days) - the monoclonal antibody targeted against FGF23. Unfortunately, laboratory values relevant to phosphate wasting (e.g. TmP/GFR, FGF23) were not reported prior to initiation of Burosumab therapy or referral to our institution for further evaluation and treatment.
The patient remained on Burosumab for 3 months. While on Burosumab, the patient reported mild symptomatic improvement with no reported adverse effects, but still had severe limitations in mobility (difficulty from sit to stand, Video 1), fatigue, and pain. On therapy, FGF23 levels were 33,900 RU/mL (normal <180RU/mL) and 36,900 RU/mL two months later as measured by ELISA (Quidel Corporation). Other notable preoperative laboratory values include a normal serum phosphorus, normal calcium, normal total vitamin D, elevated 1,25 dihydroxyvitamin D (333 pg/mL; normal 19.9–79.3 pg/mL), high alkaline phosphatase (168 U/mL; normal 40–150 U/mL), and high PTH (189 pg/mL, normal 16–77 pg/mL) (Table 2). These findings are abnormal for a patient with TIO, but they should be viewed in the context of Burosumab therapy. After discontinuation, her total FGF23 declined to 1532 RU/mL after discontinuing Burosumab but before excision of her PMT which was still considerably elevated above reference range.
At our clinic, areal bone density of the lumbar spine and left forearm (bone density of the femurs could not be performed due to bilateral hip prostheses) were assessed by dual-energy X-ray absorptiometry (DXA) using a GE Lunar Prodigy Advanced densitometer. Densitometry revealed normal bone density in the spine and significantly lower than expected density in the forearm (Fig. 2A-B). A renal ultrasound showed a 4-mm non-obstructing calculus in the lower pole of the right kidney, indicating nephrolithiasis, a well-documented complication of long-term phosphorus and calcitriol therapy (Jan de Beur, 2005).Fig. 2 Pre-operative DXA scans measuring bone mineral density (BMD). (A) Pre-operative bone density of the lumbar spine, (L1-L4): 1.202 g per square cm, T-score (SD of peak BMD): 0.1 Z-score (SD of age-matched BMD): 0.1. (B) Pre-operative bone density of the left forearm (radius 33%) is: 0.694 g per square cm T-score (SD of peak BMD): −2.1 Z-score (SD of age-matched BMD): −2.1. Bone density of the femurs could not be performed due to bilateral hip prostheses.
Fig. 2
Additionally, a 13-gene Invitae hypophosphatemia panel (https://www.invitae.com/en/hypophosphatemia) (Table 1) was performed to adjudicate her clinical diagnosis of XLH. No pathogenic variants were detected prompting our team to suspect TIO and re-evaluate her previous XLH diagnosis.Table 1 Genes tested on the Invitae hypophosphatemia next-generation sequencing panel (https://www.invitae.com/en/hypophosphatemia), with associated localization, diseases, and pathological mutations (Lloyd et al., 1996; Priante et al., 2017; Root, 2018). Panel is sensitive to deletions, insertions, duplications and copy number variants, and single-nucleotide polymorphisms (SNPs). AD = autosomal dominant, AR = autosomal recessive, VDDR = Vitamin D-dependent rickets.
Table 1Gene Primary location(s) of expression Type of mutation precipitating disease Associated hypophosphatemic/osteomalacic disease
ALPL Osteoblasts Loss of function Hypophosphatasia
CLCN5 Proximal renal tubule Loss of function X-linked recessive hypophosphatemic rickets
CYP27B1 Many cell types Loss of function AR VDDR type 1A
CYP2R1 Hepatocytes Loss of function AR VDDR type 1B
DMP1 Osteoblasts, osteocytes Loss of function AR hypophosphatemic rickets
ENPP1 Chondrocytes, osteocytes, plasma cells Loss of function AR hypophosphatemic rickets
FAH Hepatocytes Loss of function AR tyrosinemia type 1
FAM20C Osteoblasts, osteocytes Loss of function AR osteosclerotic bone dysplasia (Raine syndrome)
FGF23 Osteoblasts, osteocytes Gain of function AD hypophosphatemic rickets
FGFR1 Many cell types Gain of function AD type 1 Pfeiffer syndrome and osteoglophonic dysplasia; synthesis upregulated in many TIO-associated tumors
PHEX Osteoblasts Loss of function, X-linked XLH, increased FGF23 secretion
SLC34A3 Proximal renal tubule Loss of function AR hypophosphatemic rickets with hypercalciuria
VDR Loss of function Calcitriol resistance, VDDR type 2A
Due to suspected TIO, a combined 68Ga-DOTATATE PET/CT scan was performed. The CT Scan (Fig. 3A) revealed an unusual lesion in her 9th lateral right rib; PET scan (Fig. 3B) showed that this lesion had high activity; and a 68Ga-DOTATATE scan (an indirect measure of somatostatin receptors which are highly expressed in most TIO-causing tumors) demonstrated activity in the same region (Fig. 3C-D).Fig. 3 Diagnostic radiologic characterization of the right rib mass. (A) CT (white arrows = mass). (B) PET (white arrows = activity). (C) 68 Ga-DOTATE Scan Axial (red arrows = activity). (D) 68 Ga-DOTATE Scan Coronal (A/P) (red arrows = activity).
Fig. 3
Some TIO patients with unresectable or unidentifiable PMTs have benefited greatly from Burosumab therapy (Jan De Beur et al., 2019). However, the accessibility of our patient's tumor prompted us to refer her to Thoracic Surgery for complete resection of the tumor and rib. Further, Burosumab therapy was discontinued prior to measuring baseline laboratory values due to potential confounding, especially with the FGF23 level.
Intra-operatively, surgeons identified a more concerning lesion on the patient's 10th right rib (Fig. 4A) that had no imaging correlate. This lesion was removed, and the surgeons deferred removal of the 9th right rib to ensure the 10th right rib lesion was not the culprit of her TIO symptoms or other pathology warranting alternative intervention. The patient's hypophosphatemia persisted post-operatively. 4-months after surgery, notable lab values included low serum phosphorus (1.4 mg/dL; normal 2.3–4.7 mg/dL), low 1,25 dihydroxyvitamin D (15 pg/mL; 19.9–79.3 pg/mL), normal total vitamin D (38 ng/mL; 25–80 ng/mL), and elevated total FGF23 (1532 RU/mL; <180 RU/mL). Histopathology of the 10th right rib mass showed only non-specific reactive changes, possibly representing an old fracture site.Fig. 4 Gross appearance of surgical specimens. (A) Intra-operative image of 10th right rib mass (no imaging correlate) removed during the first, unsuccessful surgery. White star (*) denotes the large abnormality that prompted surgeons to remove the 10th rib mass. (B-C) Post-operative images of 9th right rib removed during the second, successful surgery. (B) White stars (*) denote the two areas of abnormality, red arrow denotes the primary lesion of concern for PMT shown in Fig. 5, Fig. 6. (C) Significant thickening observed in the 9th right rib.
Fig. 4
These findings further implicated the active 9th rib lesion in her pathology (Figure 3), prompting Thoracic Surgery to remove the 9th right rib (Fig. 4B-C) 5 months after the first unsuccessful surgery. Gross appearance of the 9th right rib showed two areas of abnormality with one denoting the PMT lesion (Fig. 4B) and significant rib thickening along the lateral surface (Fig. 4C). Histological sections of the 9th right rib showed a morphologically classical phosphaturic mesenchymal tumor, consisting of bland spindled cells in a highly vascular background, with unusually hyalinized to occasionally calcified matrix (Fig. 5). Chromogenic in situ hybridization (CISH) of the tumor and RNA-sequencing for the presence of rearrangements in 138 target genes were pursued using methods previously published (Martinez et al., 2019; Carter et al., 2015). FGF23 CISH was strongly positive (Fig. 6). Sequencing was positive for the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1). Taken together, these results are characteristic of a typical PMT.Fig. 5 Histological appearance of 9th right rib phosphaturic mesenchymal tumor (PMT). A) Lower magnification showing infiltration of rib bone (pink, paucicellular) by the PMT. B) Higher magnification (black box of A) of the PMT specifically showing proliferation of uniform short spindle to ovoid cells with a rich vascular background and cystic changes. C) Low magnification of the PMT from a different depth of sectioning.
Fig. 5Fig. 6 FGF23 chromogenic in situ hybridization (CISH) of 9th right rib phosphaturic mesenchymal tumor (PMT).
Fig. 6Fig. 7 Post-operative portable chest X-ray after rib removal (second successful surgery). A left humeral rod and right chest tube are observed. No pneumothorax is seen. The lungs appear clear except for volume loss related to the overlying thoracic deformity. Extensive bone deformities identified, and multiple performed ribs are seen bilaterally but both appear similar to pre-operative radiographs.
Fig. 7Table 2 Longitudinal patient laboratory values. Op 1 denotes the first unsuccessful 10th rib removal operation. Op 2 denotes the second successful 9th rib removal operation. PTH = parathyroid hormone. Note = Pre-Op 1 labs were taken while the patient was on Burosumab, all other labs were taken while the patient was off Burosumab, and Post-Op 2 labs were taken 3 months after resection.
Table 2Laboratory value Normal range Pre-Op 1 (on Burosumab) Post-Op 1, Pre-Op 2 Post-Op 2 (3 months after 9th right rib resection)
Serum phosphorus 2.3–4.7 mg/dL 2.5 1.4 3.7
Calcium 8.4–10.5 mg/dL 9.7 9.3 10.4
Total vitamin D 25–80 ng/mL 40 38 35
1,25 dihydroxyvitamin D 19.9–79.3 pg/mL 333 15 327
Alkaline phosphatase 40–150 U/L 168 111 130
Chloride 96–106 mmol/L 108 109 105
PTH 16–77 pg/mL 189 Not collected 194
FGF23 <180 RU/mL 36,900 1532 245
3 months post-resection, chest x-rays showed no pneumothorax and no significant changes compared to prior radiographs (Fig. 7). FGF23 levels decreased again but remained slightly elevated (245 RU/mL), serum phosphorus normalized (3.7 mg/dL), alkaline phosphatase normalized (130 U/mL), and total vitamin D was 35 ng/mL. Parathyroid hormone remained elevated (194 pg/mL) (Table 2). Clinical assessments of mobility markedly improved (Video 1, Video 2), and the patient has stated she is in less pain and is more active and feels stronger than ever. She will continue to follow up longitudinally in our Endocrinology clinic.
3 Discussion
TIO is a paraneoplastic disease resulting in elevated FGF23, renal phosphate wasting, defective Vitamin D metabolism, and subsequent osteomalacia. Clinically, patients with TIO present with progressive bone pain, muscle weakness, fatigue, and sporadic insufficiency fractures (Yin et al., 2018). TIO can be suggested by serum hypophosphatemia, hyperphosphaturia, and low or inappropriately normal calcitriol levels, but the identification of a phosphaturic mesenchymal tumor (PMT) in the soft tissue or bone is necessary for definitive diagnosis (Feng et al., 2017). Here, we presented a 41-year-old woman suffering from TIO with a 26-year delay in diagnosis with a concurrent misdiagnosis of XLH.
Diagnosing TIO is often complicated by small tumor size and similar initial clinical presentation to more common phosphate wasting disorders such as XLH. A retrospective study of 144 TIO cases found that TIO was misdiagnosed in over 95% (137/144) of cases, with intervertebral disc herniation, spondyloarthritis, and osteoporosis being the most common misdiagnoses (Feng et al., 2017). In this case, our patient was misdiagnosed for 26 years with little symptomatic improvement with either conventional therapy or Burosumab, and subsequent gene paneling at our institution revealed no genetic evidence of her XLH diagnosis.
Patients who present with bone pain, muscle weakness, and multiple fractures should be evaluated for hypophosphatemia, and TMP/GFR should be performed for hypophosphatemic patients. While diagnostically burdensome, a low TMP/GFR is a powerful indicator of renal phosphate wasting in the absence of secondary hyperthyroidism (Jagtap et al., 2012). Though less sensitive than TMP/GFR, calculating a percent tubular reabsorption of phosphate (TRP) is a more easily collected alternative (Takeda et al., 2015). Additionally, 24-h urine phosphorus and calcium can differentiate between malabsorption and phosphate wasting disorders (Payne, 1998).
Patient FGF23 levels and family/personal histories are also important tools for differentiating between phosphate wasting disorders (Table 3). As discussed in our previous report, TIO distinguishes itself from other FGF23-high phosphate wasting disorders in that it often presents with rapid symptom onset later in life, often with a negative family history. On the other hand, XLH is usually inherited as an X-linked dominant inherited disorder that typically presents in early childhood (MD, 2012). As such, genetic testing and associated costs can often be avoided if a clear X-linked pattern is identified by pedigree. That said, XLH can still occur due to de novo mutations, so absence of a family history should not entirely rule out XLH (Durmaz et al., 2013).Table 3 Phosphate wasting disorder differential diagnosis. A differential diagnosis table (not extensive) for phosphate wasting disorders, including TIO, distinguished by serum FGF23 level, reproduced from Colazo et al. (n.d.), Imel and Econs (2012), and Zoller et al. (2017).
Table 3Phosphate wasting disorders with low FGF23 Phosphate wasting disorders with high or “inappropriately normal” FGF23
Fanconi syndrome X-linked hypophosphatemia (XLH)
Hyperparathyroidism Tumor-induced osteomalacia (TIO)
Diuretics (e.g. acetazolamide) Autosomal dominant/autosomal recessive rickets
Myeloma McCune Albright syndrome
Copper disorders (Menkes) Cutaneous-skeletal hypophosphatemia syndrome (CSHS) (e.g., epidermal nevus syndromes)
Alcohol consumption Iron use (iron polymaltose infusions)
Genetic disorders (e.g. Npt2a mutations)
Finally, in the absence of genetic data, indication of several bone and calcification disorders can help distinguish XLH from TIO, though these criteria are highly variable. Enthesopathy (calcification of the joint capsule, tendon insertions, and ligaments) is a common feature of XLH but not of TIO and results in increased apparent BMD (Beck-Nielsen et al., 2019). By contrast, typical TIO patients have remarkably low BMD, often being labelled osteoporotic. Dentition is another clinical differentiator, in that patients with XLH can have recurrent abscesses and dental loss, while dentition in TIO is usually normal (Lee et al., 2017). However, the patient presented here was edentulous, demonstrating that TIO should not be ruled out based on these features.
Suspected TIO should prompt an investigation for active PMTs in the hands, feet, ribs, nasal cavities, and brain (Colazo et al., n.d). In recent literature, a full body 68Ga-DOTATATE scan has been shown to be a specific imaging test for identifying culprit tumors in osteomalacia (Zhang et al., 2015). The 68Ga-DOTATATE scan works by utilizing 68Gallium (68Ga) conjugated to somatostatin peptide analogues, which allows for somatostatin receptor imaging by PET scan. DOTATATE scans are most often used for diagnosing somatostatin-receptor positive neuroendocrine tumors, but PMTs preferentially express somatostatin type 2 receptors (Houang et al., 2013). Hence, this technique allows for targeted imaging of TIO-causing lesions. That said, false positivity can still occur in hypersplenism, fractures, sarcoidosis, or vertebral hemangiomas (Hofman et al., 2015). If very small and/or multiple tumors of unknown significance are present, selective FGF23 venous sampling has shown promise in deciphering the FGF23-producing tumor (Colazo et al., n.d.; Schober et al., 2017). In this case, since two suspicious lesions were encountered, FGF23 venous sampling could have been utilized, but the anatomical location and proximity of both lesions to each other would have made the process difficult to perform and most likely futile.
Misdiagnosis can also occur after tumor identification, especially in cases in which non-PMT tumors morphologically mimic PMTs in the context of hypophosphatemia (Lee et al., 2016). Recent studies have identified novel gene fusions FN1-FGF1 and FN1-FGFR1 that are transcribed and synthesized by the majority of PMTs. The fusion of FN1 and FGFR1 leads to constitutive overexpression of the 3′ portion of FGFR1 through constitutive activation of the FN1 promoter, and the fusion protein products have suspected roles in autocrine signaling (Lee et al., 2016). These fusion products can be detected by RNA sequencing or FISH of the tumor, and several emerging FGF/R inhibitors have been shown to be therapeutically beneficial in relapsing TIO (Hartley et al., 2020).
While diagnosis of TIO depends solely on postoperative biochemical resolution of laboratory abnormalities, the classification of the resected tumor can be helpful. Our patient's tumor tested positive for FN1-FGFR1 by RNAseq and for FGF23 by chromogenic in situ hybridization (CISH), further suggesting PMT (Martinez et al., 2019; Carter et al., 2015). These results support the use of FN1-FGF1/R1 gene fusions and FGF23 CISH as an additional diagnostic tool for TIO and can be used for comparison between the original and a recurrent tumor.
To date, surgical PMT resection is the only curative therapy for TIO. To mitigate risk of recurrence or metastasis, resection should be performed with wide margins where possible, and patients should be monitored longitudinally post-operatively (Hautmann et al., 2015). Here, our patient had dramatic improvements 3 months post-resection in symptoms and mobility (Video 1, Video 2), as well as in serum FGF23, phosphate, and Vitamin D levels (Table 2). Patients with unresectable or undetectable tumors have historically been placed on supplemental phosphate and calcitriol; however, Burosumab is a novel human anti-FGF23 monoclonal antibody initially approved by the FDA to treat XLH that has been recently approved for treatment of such complex TIO presentations (Carpenter et al., 2016; Day et al., 2020). In particular, Kyowa Kirin and Ultragenyx's Crysvita (burosumab-twza) has been approved for the treatment of TIO associated with PMTs that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older. Burosumab has been shown to improve serum phosphate levels and histomorphology of bone biopsies in patients with TIO, but mild side effects have been reported, including reactive overproduction of FGF23 and consequent Vitamin D deficiency (Day et al., 2020). For these reasons, monitoring FGF23 levels is not a reliable way to monitor patients on Burosumab; clinicians should focus on serum phosphorous, Alkaline phosphatase, renal phosphate wasting, 1,25 Dihydroxyvitamin D, and clinical signs/symptoms.
Indeed, in the 3 months prior to tumor identification, our patient was placed on Burosumab therapy and enjoyed mild symptomatic improvement and stable lab values (notably a normal serum phosphorus, see Table 2). While no labs were taken pre-induction, her condition deteriorated while off Burosumab between her two rib resections, indicating a positive impact of Burosumab on her condition. Her marked post-operative improvement supports the use of PMT resection when possible.
In this report, we have demonstrated the utility of two powerful genetic tools – gene paneling and RNA sequencing – at guiding clinicians to a challenging diagnosis of a non-heritable condition. In the 26-year history of this patient's disease, genetic tools have become increasingly cost-effective, sensitive, and precise. A lack of available tests at initial presentation motivated a diagnosis of XLH (a germline genetic condition) based on clinical evidence alone. The similar clinical presentations of many phosphate wasting disorders, the uniqueness of their genetic identifiers like FN1-FGFR1 or PHEX, and the illumination of known, curative therapies through such tests all support the expanded use of gene paneling and tumor sequencing alongside clinical reasoning around phosphate wasting disorders. This fact is further evidenced by the requirement of genetic diagnosis for enrollment in most clinical trials targeting phosphate wasting disorders. Additionally, the advancements in the field over the past 3 decades may warrant the re-evaluation of poorly managed, long-term diagnoses through the lens of a gene panel or specific genetic marker.
4 Conclusion
Tumor-induced osteomalacia (TIO) is a paraneoplastic disease driven by hypersecretion of Fibroblast Growth Factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). In this case report, we present a patient with what we believe to be the longest history of a delayed TIO diagnosis reported in the literature, outlined current diagnostic strategies, and demonstrated the increasing utility of genetic testing in the diagnosis of phosphate wasting disorders.
We highlight the importance of the personal and family histories, as well as potential pitfalls of using exclusively clinical criteria in diagnosing phosphate wasting disorders, as our patient had several clinical findings suggestive of XLH yet had a negative family history of phosphate wasting disorders. Further, we stress the utility of full body imaging, especially a 68Ga-DOTATATE PET/CT scan, in probing cases of high clinical suspicion for TIO, and we applied novel genetic screening methods (i.e. gene paneling and tumor RNA sequencing) to confirm our diagnosis. When possible, performing these tests provides powerful support for a TIO diagnosis. Finally, while our patient has enjoyed a marked recovery 3 months post-surgical resection, we discuss Burosumab, an emerging therapeutic antibody against FGF23 that may be an attractive treatment for undetectable or unresectable tumors in TIO.
The following are the supplementary data related to this article.Video 1
Pre-operative functionality of patient
Video 1 Video 2
Post-operative functionality of patient
Video 2
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Transparency document.
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Acknowledgments
Two of the authors (JMC, JAD) are supported by NIGMS of the National Institutes of Health under award number T32GM007347. The content in this report is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The Transparency document associated with this article can be found, in online version. | Recovered | ReactionOutcome | CC BY-NC-ND | 33490314 | 18,819,395 | 2021-06 |
What was the outcome of reaction 'Blood parathyroid hormone increased'? | Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia.
Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A 68Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases.
1 Introduction
Osteomalacia is the progressive softening of bones due to decreased mineralization of calcium and phosphates at sites of bone remodeling and growth, commonly resulting in bone pain and muscle weakness (Michigami, 2019). Fibroblast Growth Factor 23 (FGF23) is a protein secreted by osteocytes mainly in response to calcitriol and phosphate (Martin et al., 2012). FGF23 regulates plasma phosphate concentration predominately by reducing serum calcitriol which mediates intestinal phosphate absorption and by reducing NPT2-mediated phosphate reabsorption in the kidney. Tumor-Induced Osteomalacia (TIO) is a rare paraneoplastic disease in which a phosphaturic mesenchymal tumor (PMT) secretes significant amounts of FGF23 into the bloodstream, leading to downstream osteomalacia through renal phosphate wasting and defective Vitamin D metabolism (Yin et al., 2018). While less than 500 cases of TIO have been reported worldwide, and formal epidemiological studies of the disease have not been performed, surgical resection offers a potentially curative treatment in contrast to similarly presenting disorders (Folpe, 2019).
X-linked hypophosphatemia (XLH) is a phosphate wasting disorder caused by mutations in the PHEX gene which expresses the enzyme phosphate-regulating neutral endopeptidase (PHEX). Studies suggest that the PHEX enzyme may be involved in the regulation of FGF23 (Beck-Nielsen et al., 2019; Liu et al., 2003). Importantly, diagnosing phosphate wasting disorders based purely on clinical criteria is confounded by the similarity of clinical and radiological presentations of this family of disorders. Knowing the distinct genetic basis for a patient's phosphate wasting disorder often allows clinicians to tailor their treatment/management strategy accordingly, potentially saving years of hardship for affected patients. As such, recent emphasis has been placed on using gene panels to accelerate clinicians' diagnosis of these disorders.
In particular, a potential for misdiagnosis of TIO as XLH exists because FGF23 levels are increased in both, PMT tumors are notoriously difficult to find due to their small size and variable location, and (albeit still rare) the incidence of XLH far exceeds that of TIO (Yin et al., 2018; Carpenter, 1997). Here, we present a 41-year-old female in whom a 26-year delayed TIO diagnosis and concurrent misdiagnosis of XLH was identified via a negative hypophosphatemia gene panel and corrected to TIO through identification of a PMT of her 9th right rib. Surgical resection resulted in biochemical and clinical symptom improvement. Histological analysis was positive for FGF23 (CISH) and the FN1-FGFR1 transcriptional marker. Finally, we highlight recent key advances in diagnosing phosphate wasting disorders, molecular characterization of PMTs, and TIO treatment and management.
2 Case presentation
A 41-year-old woman with a prior clinical diagnosis of hypophosphatemic rickets presented to our institution with a 26-year history of low phosphorus, bone pain, proximal muscle weakness, gait abnormalities, and multiple traumatic and insufficiency fractures of the hip, humerus, and spine (Fig. 1, Fig. 7). She had no history of hearing loss. She had lost all her secondary teeth (edentulous). The patient reported no family history of hypophosphatemia, including her 8-year-old male child and 17-year-old female child, neither of whom showed clinical or laboratory indications of musculoskeletal conditions or phosphate wasting disorders. Her maximum height was 5′2″ but she presented to us at 4′8″ due to progressive spine deformities.
Despite intermittent treatment with conventional therapy with phosphorus supplements and calcitriol during her teens and 20s, she developed progressive gait abnormalities and decreased hip strength and ultimately sustained bilateral hip fractures (Fig. 1A) and small fractures throughout her spine (Fig. 1B-C).Fig. 1 Patient musculoskeletal radiology. X-ray AP Pelvis (A) shows evidence of prior bilateral obturator ring fractures with bilateral femoral head/neck angular deformities. X-ray Spine Total AP/Lateral (B-C) shows normal trabecular bone with vertebral body alignments and interspacing intact, but there is mild flattening of the mid vertebral body at multiple levels. There is evidence of previous insufficiency fractures.
Fig. 1
Despite treatment, the patient's symptoms deteriorated further in her 20s, when she had stability rods and screws placed bilaterally in her femurs and hips, respectively (Fig. 1A). Ten years later, the patient presented with a traumatic left humerus fracture, for which she underwent surgery (Figure 7). Post-operatively, the patient was placed on the osteoporosis medication teriparatide.
Teriparatide therapy failed to prevent more spinal fractures (Fig. 1B-C), bone pain, and muscle weakness over the next year, and the patient was eventually confined to a wheelchair. Orthopedic physicians reevaluated her history, officially diagnosed her with X-linked Hypophosphatemia (XLH) (although patient claims having an “unofficial” XLH diagnosis years prior by previous physicians), and started her on Burosumab (60 mg subcutaneous injection every 28 days) - the monoclonal antibody targeted against FGF23. Unfortunately, laboratory values relevant to phosphate wasting (e.g. TmP/GFR, FGF23) were not reported prior to initiation of Burosumab therapy or referral to our institution for further evaluation and treatment.
The patient remained on Burosumab for 3 months. While on Burosumab, the patient reported mild symptomatic improvement with no reported adverse effects, but still had severe limitations in mobility (difficulty from sit to stand, Video 1), fatigue, and pain. On therapy, FGF23 levels were 33,900 RU/mL (normal <180RU/mL) and 36,900 RU/mL two months later as measured by ELISA (Quidel Corporation). Other notable preoperative laboratory values include a normal serum phosphorus, normal calcium, normal total vitamin D, elevated 1,25 dihydroxyvitamin D (333 pg/mL; normal 19.9–79.3 pg/mL), high alkaline phosphatase (168 U/mL; normal 40–150 U/mL), and high PTH (189 pg/mL, normal 16–77 pg/mL) (Table 2). These findings are abnormal for a patient with TIO, but they should be viewed in the context of Burosumab therapy. After discontinuation, her total FGF23 declined to 1532 RU/mL after discontinuing Burosumab but before excision of her PMT which was still considerably elevated above reference range.
At our clinic, areal bone density of the lumbar spine and left forearm (bone density of the femurs could not be performed due to bilateral hip prostheses) were assessed by dual-energy X-ray absorptiometry (DXA) using a GE Lunar Prodigy Advanced densitometer. Densitometry revealed normal bone density in the spine and significantly lower than expected density in the forearm (Fig. 2A-B). A renal ultrasound showed a 4-mm non-obstructing calculus in the lower pole of the right kidney, indicating nephrolithiasis, a well-documented complication of long-term phosphorus and calcitriol therapy (Jan de Beur, 2005).Fig. 2 Pre-operative DXA scans measuring bone mineral density (BMD). (A) Pre-operative bone density of the lumbar spine, (L1-L4): 1.202 g per square cm, T-score (SD of peak BMD): 0.1 Z-score (SD of age-matched BMD): 0.1. (B) Pre-operative bone density of the left forearm (radius 33%) is: 0.694 g per square cm T-score (SD of peak BMD): −2.1 Z-score (SD of age-matched BMD): −2.1. Bone density of the femurs could not be performed due to bilateral hip prostheses.
Fig. 2
Additionally, a 13-gene Invitae hypophosphatemia panel (https://www.invitae.com/en/hypophosphatemia) (Table 1) was performed to adjudicate her clinical diagnosis of XLH. No pathogenic variants were detected prompting our team to suspect TIO and re-evaluate her previous XLH diagnosis.Table 1 Genes tested on the Invitae hypophosphatemia next-generation sequencing panel (https://www.invitae.com/en/hypophosphatemia), with associated localization, diseases, and pathological mutations (Lloyd et al., 1996; Priante et al., 2017; Root, 2018). Panel is sensitive to deletions, insertions, duplications and copy number variants, and single-nucleotide polymorphisms (SNPs). AD = autosomal dominant, AR = autosomal recessive, VDDR = Vitamin D-dependent rickets.
Table 1Gene Primary location(s) of expression Type of mutation precipitating disease Associated hypophosphatemic/osteomalacic disease
ALPL Osteoblasts Loss of function Hypophosphatasia
CLCN5 Proximal renal tubule Loss of function X-linked recessive hypophosphatemic rickets
CYP27B1 Many cell types Loss of function AR VDDR type 1A
CYP2R1 Hepatocytes Loss of function AR VDDR type 1B
DMP1 Osteoblasts, osteocytes Loss of function AR hypophosphatemic rickets
ENPP1 Chondrocytes, osteocytes, plasma cells Loss of function AR hypophosphatemic rickets
FAH Hepatocytes Loss of function AR tyrosinemia type 1
FAM20C Osteoblasts, osteocytes Loss of function AR osteosclerotic bone dysplasia (Raine syndrome)
FGF23 Osteoblasts, osteocytes Gain of function AD hypophosphatemic rickets
FGFR1 Many cell types Gain of function AD type 1 Pfeiffer syndrome and osteoglophonic dysplasia; synthesis upregulated in many TIO-associated tumors
PHEX Osteoblasts Loss of function, X-linked XLH, increased FGF23 secretion
SLC34A3 Proximal renal tubule Loss of function AR hypophosphatemic rickets with hypercalciuria
VDR Loss of function Calcitriol resistance, VDDR type 2A
Due to suspected TIO, a combined 68Ga-DOTATATE PET/CT scan was performed. The CT Scan (Fig. 3A) revealed an unusual lesion in her 9th lateral right rib; PET scan (Fig. 3B) showed that this lesion had high activity; and a 68Ga-DOTATATE scan (an indirect measure of somatostatin receptors which are highly expressed in most TIO-causing tumors) demonstrated activity in the same region (Fig. 3C-D).Fig. 3 Diagnostic radiologic characterization of the right rib mass. (A) CT (white arrows = mass). (B) PET (white arrows = activity). (C) 68 Ga-DOTATE Scan Axial (red arrows = activity). (D) 68 Ga-DOTATE Scan Coronal (A/P) (red arrows = activity).
Fig. 3
Some TIO patients with unresectable or unidentifiable PMTs have benefited greatly from Burosumab therapy (Jan De Beur et al., 2019). However, the accessibility of our patient's tumor prompted us to refer her to Thoracic Surgery for complete resection of the tumor and rib. Further, Burosumab therapy was discontinued prior to measuring baseline laboratory values due to potential confounding, especially with the FGF23 level.
Intra-operatively, surgeons identified a more concerning lesion on the patient's 10th right rib (Fig. 4A) that had no imaging correlate. This lesion was removed, and the surgeons deferred removal of the 9th right rib to ensure the 10th right rib lesion was not the culprit of her TIO symptoms or other pathology warranting alternative intervention. The patient's hypophosphatemia persisted post-operatively. 4-months after surgery, notable lab values included low serum phosphorus (1.4 mg/dL; normal 2.3–4.7 mg/dL), low 1,25 dihydroxyvitamin D (15 pg/mL; 19.9–79.3 pg/mL), normal total vitamin D (38 ng/mL; 25–80 ng/mL), and elevated total FGF23 (1532 RU/mL; <180 RU/mL). Histopathology of the 10th right rib mass showed only non-specific reactive changes, possibly representing an old fracture site.Fig. 4 Gross appearance of surgical specimens. (A) Intra-operative image of 10th right rib mass (no imaging correlate) removed during the first, unsuccessful surgery. White star (*) denotes the large abnormality that prompted surgeons to remove the 10th rib mass. (B-C) Post-operative images of 9th right rib removed during the second, successful surgery. (B) White stars (*) denote the two areas of abnormality, red arrow denotes the primary lesion of concern for PMT shown in Fig. 5, Fig. 6. (C) Significant thickening observed in the 9th right rib.
Fig. 4
These findings further implicated the active 9th rib lesion in her pathology (Figure 3), prompting Thoracic Surgery to remove the 9th right rib (Fig. 4B-C) 5 months after the first unsuccessful surgery. Gross appearance of the 9th right rib showed two areas of abnormality with one denoting the PMT lesion (Fig. 4B) and significant rib thickening along the lateral surface (Fig. 4C). Histological sections of the 9th right rib showed a morphologically classical phosphaturic mesenchymal tumor, consisting of bland spindled cells in a highly vascular background, with unusually hyalinized to occasionally calcified matrix (Fig. 5). Chromogenic in situ hybridization (CISH) of the tumor and RNA-sequencing for the presence of rearrangements in 138 target genes were pursued using methods previously published (Martinez et al., 2019; Carter et al., 2015). FGF23 CISH was strongly positive (Fig. 6). Sequencing was positive for the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1). Taken together, these results are characteristic of a typical PMT.Fig. 5 Histological appearance of 9th right rib phosphaturic mesenchymal tumor (PMT). A) Lower magnification showing infiltration of rib bone (pink, paucicellular) by the PMT. B) Higher magnification (black box of A) of the PMT specifically showing proliferation of uniform short spindle to ovoid cells with a rich vascular background and cystic changes. C) Low magnification of the PMT from a different depth of sectioning.
Fig. 5Fig. 6 FGF23 chromogenic in situ hybridization (CISH) of 9th right rib phosphaturic mesenchymal tumor (PMT).
Fig. 6Fig. 7 Post-operative portable chest X-ray after rib removal (second successful surgery). A left humeral rod and right chest tube are observed. No pneumothorax is seen. The lungs appear clear except for volume loss related to the overlying thoracic deformity. Extensive bone deformities identified, and multiple performed ribs are seen bilaterally but both appear similar to pre-operative radiographs.
Fig. 7Table 2 Longitudinal patient laboratory values. Op 1 denotes the first unsuccessful 10th rib removal operation. Op 2 denotes the second successful 9th rib removal operation. PTH = parathyroid hormone. Note = Pre-Op 1 labs were taken while the patient was on Burosumab, all other labs were taken while the patient was off Burosumab, and Post-Op 2 labs were taken 3 months after resection.
Table 2Laboratory value Normal range Pre-Op 1 (on Burosumab) Post-Op 1, Pre-Op 2 Post-Op 2 (3 months after 9th right rib resection)
Serum phosphorus 2.3–4.7 mg/dL 2.5 1.4 3.7
Calcium 8.4–10.5 mg/dL 9.7 9.3 10.4
Total vitamin D 25–80 ng/mL 40 38 35
1,25 dihydroxyvitamin D 19.9–79.3 pg/mL 333 15 327
Alkaline phosphatase 40–150 U/L 168 111 130
Chloride 96–106 mmol/L 108 109 105
PTH 16–77 pg/mL 189 Not collected 194
FGF23 <180 RU/mL 36,900 1532 245
3 months post-resection, chest x-rays showed no pneumothorax and no significant changes compared to prior radiographs (Fig. 7). FGF23 levels decreased again but remained slightly elevated (245 RU/mL), serum phosphorus normalized (3.7 mg/dL), alkaline phosphatase normalized (130 U/mL), and total vitamin D was 35 ng/mL. Parathyroid hormone remained elevated (194 pg/mL) (Table 2). Clinical assessments of mobility markedly improved (Video 1, Video 2), and the patient has stated she is in less pain and is more active and feels stronger than ever. She will continue to follow up longitudinally in our Endocrinology clinic.
3 Discussion
TIO is a paraneoplastic disease resulting in elevated FGF23, renal phosphate wasting, defective Vitamin D metabolism, and subsequent osteomalacia. Clinically, patients with TIO present with progressive bone pain, muscle weakness, fatigue, and sporadic insufficiency fractures (Yin et al., 2018). TIO can be suggested by serum hypophosphatemia, hyperphosphaturia, and low or inappropriately normal calcitriol levels, but the identification of a phosphaturic mesenchymal tumor (PMT) in the soft tissue or bone is necessary for definitive diagnosis (Feng et al., 2017). Here, we presented a 41-year-old woman suffering from TIO with a 26-year delay in diagnosis with a concurrent misdiagnosis of XLH.
Diagnosing TIO is often complicated by small tumor size and similar initial clinical presentation to more common phosphate wasting disorders such as XLH. A retrospective study of 144 TIO cases found that TIO was misdiagnosed in over 95% (137/144) of cases, with intervertebral disc herniation, spondyloarthritis, and osteoporosis being the most common misdiagnoses (Feng et al., 2017). In this case, our patient was misdiagnosed for 26 years with little symptomatic improvement with either conventional therapy or Burosumab, and subsequent gene paneling at our institution revealed no genetic evidence of her XLH diagnosis.
Patients who present with bone pain, muscle weakness, and multiple fractures should be evaluated for hypophosphatemia, and TMP/GFR should be performed for hypophosphatemic patients. While diagnostically burdensome, a low TMP/GFR is a powerful indicator of renal phosphate wasting in the absence of secondary hyperthyroidism (Jagtap et al., 2012). Though less sensitive than TMP/GFR, calculating a percent tubular reabsorption of phosphate (TRP) is a more easily collected alternative (Takeda et al., 2015). Additionally, 24-h urine phosphorus and calcium can differentiate between malabsorption and phosphate wasting disorders (Payne, 1998).
Patient FGF23 levels and family/personal histories are also important tools for differentiating between phosphate wasting disorders (Table 3). As discussed in our previous report, TIO distinguishes itself from other FGF23-high phosphate wasting disorders in that it often presents with rapid symptom onset later in life, often with a negative family history. On the other hand, XLH is usually inherited as an X-linked dominant inherited disorder that typically presents in early childhood (MD, 2012). As such, genetic testing and associated costs can often be avoided if a clear X-linked pattern is identified by pedigree. That said, XLH can still occur due to de novo mutations, so absence of a family history should not entirely rule out XLH (Durmaz et al., 2013).Table 3 Phosphate wasting disorder differential diagnosis. A differential diagnosis table (not extensive) for phosphate wasting disorders, including TIO, distinguished by serum FGF23 level, reproduced from Colazo et al. (n.d.), Imel and Econs (2012), and Zoller et al. (2017).
Table 3Phosphate wasting disorders with low FGF23 Phosphate wasting disorders with high or “inappropriately normal” FGF23
Fanconi syndrome X-linked hypophosphatemia (XLH)
Hyperparathyroidism Tumor-induced osteomalacia (TIO)
Diuretics (e.g. acetazolamide) Autosomal dominant/autosomal recessive rickets
Myeloma McCune Albright syndrome
Copper disorders (Menkes) Cutaneous-skeletal hypophosphatemia syndrome (CSHS) (e.g., epidermal nevus syndromes)
Alcohol consumption Iron use (iron polymaltose infusions)
Genetic disorders (e.g. Npt2a mutations)
Finally, in the absence of genetic data, indication of several bone and calcification disorders can help distinguish XLH from TIO, though these criteria are highly variable. Enthesopathy (calcification of the joint capsule, tendon insertions, and ligaments) is a common feature of XLH but not of TIO and results in increased apparent BMD (Beck-Nielsen et al., 2019). By contrast, typical TIO patients have remarkably low BMD, often being labelled osteoporotic. Dentition is another clinical differentiator, in that patients with XLH can have recurrent abscesses and dental loss, while dentition in TIO is usually normal (Lee et al., 2017). However, the patient presented here was edentulous, demonstrating that TIO should not be ruled out based on these features.
Suspected TIO should prompt an investigation for active PMTs in the hands, feet, ribs, nasal cavities, and brain (Colazo et al., n.d). In recent literature, a full body 68Ga-DOTATATE scan has been shown to be a specific imaging test for identifying culprit tumors in osteomalacia (Zhang et al., 2015). The 68Ga-DOTATATE scan works by utilizing 68Gallium (68Ga) conjugated to somatostatin peptide analogues, which allows for somatostatin receptor imaging by PET scan. DOTATATE scans are most often used for diagnosing somatostatin-receptor positive neuroendocrine tumors, but PMTs preferentially express somatostatin type 2 receptors (Houang et al., 2013). Hence, this technique allows for targeted imaging of TIO-causing lesions. That said, false positivity can still occur in hypersplenism, fractures, sarcoidosis, or vertebral hemangiomas (Hofman et al., 2015). If very small and/or multiple tumors of unknown significance are present, selective FGF23 venous sampling has shown promise in deciphering the FGF23-producing tumor (Colazo et al., n.d.; Schober et al., 2017). In this case, since two suspicious lesions were encountered, FGF23 venous sampling could have been utilized, but the anatomical location and proximity of both lesions to each other would have made the process difficult to perform and most likely futile.
Misdiagnosis can also occur after tumor identification, especially in cases in which non-PMT tumors morphologically mimic PMTs in the context of hypophosphatemia (Lee et al., 2016). Recent studies have identified novel gene fusions FN1-FGF1 and FN1-FGFR1 that are transcribed and synthesized by the majority of PMTs. The fusion of FN1 and FGFR1 leads to constitutive overexpression of the 3′ portion of FGFR1 through constitutive activation of the FN1 promoter, and the fusion protein products have suspected roles in autocrine signaling (Lee et al., 2016). These fusion products can be detected by RNA sequencing or FISH of the tumor, and several emerging FGF/R inhibitors have been shown to be therapeutically beneficial in relapsing TIO (Hartley et al., 2020).
While diagnosis of TIO depends solely on postoperative biochemical resolution of laboratory abnormalities, the classification of the resected tumor can be helpful. Our patient's tumor tested positive for FN1-FGFR1 by RNAseq and for FGF23 by chromogenic in situ hybridization (CISH), further suggesting PMT (Martinez et al., 2019; Carter et al., 2015). These results support the use of FN1-FGF1/R1 gene fusions and FGF23 CISH as an additional diagnostic tool for TIO and can be used for comparison between the original and a recurrent tumor.
To date, surgical PMT resection is the only curative therapy for TIO. To mitigate risk of recurrence or metastasis, resection should be performed with wide margins where possible, and patients should be monitored longitudinally post-operatively (Hautmann et al., 2015). Here, our patient had dramatic improvements 3 months post-resection in symptoms and mobility (Video 1, Video 2), as well as in serum FGF23, phosphate, and Vitamin D levels (Table 2). Patients with unresectable or undetectable tumors have historically been placed on supplemental phosphate and calcitriol; however, Burosumab is a novel human anti-FGF23 monoclonal antibody initially approved by the FDA to treat XLH that has been recently approved for treatment of such complex TIO presentations (Carpenter et al., 2016; Day et al., 2020). In particular, Kyowa Kirin and Ultragenyx's Crysvita (burosumab-twza) has been approved for the treatment of TIO associated with PMTs that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older. Burosumab has been shown to improve serum phosphate levels and histomorphology of bone biopsies in patients with TIO, but mild side effects have been reported, including reactive overproduction of FGF23 and consequent Vitamin D deficiency (Day et al., 2020). For these reasons, monitoring FGF23 levels is not a reliable way to monitor patients on Burosumab; clinicians should focus on serum phosphorous, Alkaline phosphatase, renal phosphate wasting, 1,25 Dihydroxyvitamin D, and clinical signs/symptoms.
Indeed, in the 3 months prior to tumor identification, our patient was placed on Burosumab therapy and enjoyed mild symptomatic improvement and stable lab values (notably a normal serum phosphorus, see Table 2). While no labs were taken pre-induction, her condition deteriorated while off Burosumab between her two rib resections, indicating a positive impact of Burosumab on her condition. Her marked post-operative improvement supports the use of PMT resection when possible.
In this report, we have demonstrated the utility of two powerful genetic tools – gene paneling and RNA sequencing – at guiding clinicians to a challenging diagnosis of a non-heritable condition. In the 26-year history of this patient's disease, genetic tools have become increasingly cost-effective, sensitive, and precise. A lack of available tests at initial presentation motivated a diagnosis of XLH (a germline genetic condition) based on clinical evidence alone. The similar clinical presentations of many phosphate wasting disorders, the uniqueness of their genetic identifiers like FN1-FGFR1 or PHEX, and the illumination of known, curative therapies through such tests all support the expanded use of gene paneling and tumor sequencing alongside clinical reasoning around phosphate wasting disorders. This fact is further evidenced by the requirement of genetic diagnosis for enrollment in most clinical trials targeting phosphate wasting disorders. Additionally, the advancements in the field over the past 3 decades may warrant the re-evaluation of poorly managed, long-term diagnoses through the lens of a gene panel or specific genetic marker.
4 Conclusion
Tumor-induced osteomalacia (TIO) is a paraneoplastic disease driven by hypersecretion of Fibroblast Growth Factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). In this case report, we present a patient with what we believe to be the longest history of a delayed TIO diagnosis reported in the literature, outlined current diagnostic strategies, and demonstrated the increasing utility of genetic testing in the diagnosis of phosphate wasting disorders.
We highlight the importance of the personal and family histories, as well as potential pitfalls of using exclusively clinical criteria in diagnosing phosphate wasting disorders, as our patient had several clinical findings suggestive of XLH yet had a negative family history of phosphate wasting disorders. Further, we stress the utility of full body imaging, especially a 68Ga-DOTATATE PET/CT scan, in probing cases of high clinical suspicion for TIO, and we applied novel genetic screening methods (i.e. gene paneling and tumor RNA sequencing) to confirm our diagnosis. When possible, performing these tests provides powerful support for a TIO diagnosis. Finally, while our patient has enjoyed a marked recovery 3 months post-surgical resection, we discuss Burosumab, an emerging therapeutic antibody against FGF23 that may be an attractive treatment for undetectable or unresectable tumors in TIO.
The following are the supplementary data related to this article.Video 1
Pre-operative functionality of patient
Video 1 Video 2
Post-operative functionality of patient
Video 2
Transparency document
Transparency document.
Image 1
Acknowledgments
Two of the authors (JMC, JAD) are supported by NIGMS of the National Institutes of Health under award number T32GM007347. The content in this report is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The Transparency document associated with this article can be found, in online version. | Not recovered | ReactionOutcome | CC BY-NC-ND | 33490314 | 18,819,395 | 2021-06 |
What was the outcome of reaction 'Fibroblast growth factor 23 increased'? | Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia.
Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A 68Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases.
1 Introduction
Osteomalacia is the progressive softening of bones due to decreased mineralization of calcium and phosphates at sites of bone remodeling and growth, commonly resulting in bone pain and muscle weakness (Michigami, 2019). Fibroblast Growth Factor 23 (FGF23) is a protein secreted by osteocytes mainly in response to calcitriol and phosphate (Martin et al., 2012). FGF23 regulates plasma phosphate concentration predominately by reducing serum calcitriol which mediates intestinal phosphate absorption and by reducing NPT2-mediated phosphate reabsorption in the kidney. Tumor-Induced Osteomalacia (TIO) is a rare paraneoplastic disease in which a phosphaturic mesenchymal tumor (PMT) secretes significant amounts of FGF23 into the bloodstream, leading to downstream osteomalacia through renal phosphate wasting and defective Vitamin D metabolism (Yin et al., 2018). While less than 500 cases of TIO have been reported worldwide, and formal epidemiological studies of the disease have not been performed, surgical resection offers a potentially curative treatment in contrast to similarly presenting disorders (Folpe, 2019).
X-linked hypophosphatemia (XLH) is a phosphate wasting disorder caused by mutations in the PHEX gene which expresses the enzyme phosphate-regulating neutral endopeptidase (PHEX). Studies suggest that the PHEX enzyme may be involved in the regulation of FGF23 (Beck-Nielsen et al., 2019; Liu et al., 2003). Importantly, diagnosing phosphate wasting disorders based purely on clinical criteria is confounded by the similarity of clinical and radiological presentations of this family of disorders. Knowing the distinct genetic basis for a patient's phosphate wasting disorder often allows clinicians to tailor their treatment/management strategy accordingly, potentially saving years of hardship for affected patients. As such, recent emphasis has been placed on using gene panels to accelerate clinicians' diagnosis of these disorders.
In particular, a potential for misdiagnosis of TIO as XLH exists because FGF23 levels are increased in both, PMT tumors are notoriously difficult to find due to their small size and variable location, and (albeit still rare) the incidence of XLH far exceeds that of TIO (Yin et al., 2018; Carpenter, 1997). Here, we present a 41-year-old female in whom a 26-year delayed TIO diagnosis and concurrent misdiagnosis of XLH was identified via a negative hypophosphatemia gene panel and corrected to TIO through identification of a PMT of her 9th right rib. Surgical resection resulted in biochemical and clinical symptom improvement. Histological analysis was positive for FGF23 (CISH) and the FN1-FGFR1 transcriptional marker. Finally, we highlight recent key advances in diagnosing phosphate wasting disorders, molecular characterization of PMTs, and TIO treatment and management.
2 Case presentation
A 41-year-old woman with a prior clinical diagnosis of hypophosphatemic rickets presented to our institution with a 26-year history of low phosphorus, bone pain, proximal muscle weakness, gait abnormalities, and multiple traumatic and insufficiency fractures of the hip, humerus, and spine (Fig. 1, Fig. 7). She had no history of hearing loss. She had lost all her secondary teeth (edentulous). The patient reported no family history of hypophosphatemia, including her 8-year-old male child and 17-year-old female child, neither of whom showed clinical or laboratory indications of musculoskeletal conditions or phosphate wasting disorders. Her maximum height was 5′2″ but she presented to us at 4′8″ due to progressive spine deformities.
Despite intermittent treatment with conventional therapy with phosphorus supplements and calcitriol during her teens and 20s, she developed progressive gait abnormalities and decreased hip strength and ultimately sustained bilateral hip fractures (Fig. 1A) and small fractures throughout her spine (Fig. 1B-C).Fig. 1 Patient musculoskeletal radiology. X-ray AP Pelvis (A) shows evidence of prior bilateral obturator ring fractures with bilateral femoral head/neck angular deformities. X-ray Spine Total AP/Lateral (B-C) shows normal trabecular bone with vertebral body alignments and interspacing intact, but there is mild flattening of the mid vertebral body at multiple levels. There is evidence of previous insufficiency fractures.
Fig. 1
Despite treatment, the patient's symptoms deteriorated further in her 20s, when she had stability rods and screws placed bilaterally in her femurs and hips, respectively (Fig. 1A). Ten years later, the patient presented with a traumatic left humerus fracture, for which she underwent surgery (Figure 7). Post-operatively, the patient was placed on the osteoporosis medication teriparatide.
Teriparatide therapy failed to prevent more spinal fractures (Fig. 1B-C), bone pain, and muscle weakness over the next year, and the patient was eventually confined to a wheelchair. Orthopedic physicians reevaluated her history, officially diagnosed her with X-linked Hypophosphatemia (XLH) (although patient claims having an “unofficial” XLH diagnosis years prior by previous physicians), and started her on Burosumab (60 mg subcutaneous injection every 28 days) - the monoclonal antibody targeted against FGF23. Unfortunately, laboratory values relevant to phosphate wasting (e.g. TmP/GFR, FGF23) were not reported prior to initiation of Burosumab therapy or referral to our institution for further evaluation and treatment.
The patient remained on Burosumab for 3 months. While on Burosumab, the patient reported mild symptomatic improvement with no reported adverse effects, but still had severe limitations in mobility (difficulty from sit to stand, Video 1), fatigue, and pain. On therapy, FGF23 levels were 33,900 RU/mL (normal <180RU/mL) and 36,900 RU/mL two months later as measured by ELISA (Quidel Corporation). Other notable preoperative laboratory values include a normal serum phosphorus, normal calcium, normal total vitamin D, elevated 1,25 dihydroxyvitamin D (333 pg/mL; normal 19.9–79.3 pg/mL), high alkaline phosphatase (168 U/mL; normal 40–150 U/mL), and high PTH (189 pg/mL, normal 16–77 pg/mL) (Table 2). These findings are abnormal for a patient with TIO, but they should be viewed in the context of Burosumab therapy. After discontinuation, her total FGF23 declined to 1532 RU/mL after discontinuing Burosumab but before excision of her PMT which was still considerably elevated above reference range.
At our clinic, areal bone density of the lumbar spine and left forearm (bone density of the femurs could not be performed due to bilateral hip prostheses) were assessed by dual-energy X-ray absorptiometry (DXA) using a GE Lunar Prodigy Advanced densitometer. Densitometry revealed normal bone density in the spine and significantly lower than expected density in the forearm (Fig. 2A-B). A renal ultrasound showed a 4-mm non-obstructing calculus in the lower pole of the right kidney, indicating nephrolithiasis, a well-documented complication of long-term phosphorus and calcitriol therapy (Jan de Beur, 2005).Fig. 2 Pre-operative DXA scans measuring bone mineral density (BMD). (A) Pre-operative bone density of the lumbar spine, (L1-L4): 1.202 g per square cm, T-score (SD of peak BMD): 0.1 Z-score (SD of age-matched BMD): 0.1. (B) Pre-operative bone density of the left forearm (radius 33%) is: 0.694 g per square cm T-score (SD of peak BMD): −2.1 Z-score (SD of age-matched BMD): −2.1. Bone density of the femurs could not be performed due to bilateral hip prostheses.
Fig. 2
Additionally, a 13-gene Invitae hypophosphatemia panel (https://www.invitae.com/en/hypophosphatemia) (Table 1) was performed to adjudicate her clinical diagnosis of XLH. No pathogenic variants were detected prompting our team to suspect TIO and re-evaluate her previous XLH diagnosis.Table 1 Genes tested on the Invitae hypophosphatemia next-generation sequencing panel (https://www.invitae.com/en/hypophosphatemia), with associated localization, diseases, and pathological mutations (Lloyd et al., 1996; Priante et al., 2017; Root, 2018). Panel is sensitive to deletions, insertions, duplications and copy number variants, and single-nucleotide polymorphisms (SNPs). AD = autosomal dominant, AR = autosomal recessive, VDDR = Vitamin D-dependent rickets.
Table 1Gene Primary location(s) of expression Type of mutation precipitating disease Associated hypophosphatemic/osteomalacic disease
ALPL Osteoblasts Loss of function Hypophosphatasia
CLCN5 Proximal renal tubule Loss of function X-linked recessive hypophosphatemic rickets
CYP27B1 Many cell types Loss of function AR VDDR type 1A
CYP2R1 Hepatocytes Loss of function AR VDDR type 1B
DMP1 Osteoblasts, osteocytes Loss of function AR hypophosphatemic rickets
ENPP1 Chondrocytes, osteocytes, plasma cells Loss of function AR hypophosphatemic rickets
FAH Hepatocytes Loss of function AR tyrosinemia type 1
FAM20C Osteoblasts, osteocytes Loss of function AR osteosclerotic bone dysplasia (Raine syndrome)
FGF23 Osteoblasts, osteocytes Gain of function AD hypophosphatemic rickets
FGFR1 Many cell types Gain of function AD type 1 Pfeiffer syndrome and osteoglophonic dysplasia; synthesis upregulated in many TIO-associated tumors
PHEX Osteoblasts Loss of function, X-linked XLH, increased FGF23 secretion
SLC34A3 Proximal renal tubule Loss of function AR hypophosphatemic rickets with hypercalciuria
VDR Loss of function Calcitriol resistance, VDDR type 2A
Due to suspected TIO, a combined 68Ga-DOTATATE PET/CT scan was performed. The CT Scan (Fig. 3A) revealed an unusual lesion in her 9th lateral right rib; PET scan (Fig. 3B) showed that this lesion had high activity; and a 68Ga-DOTATATE scan (an indirect measure of somatostatin receptors which are highly expressed in most TIO-causing tumors) demonstrated activity in the same region (Fig. 3C-D).Fig. 3 Diagnostic radiologic characterization of the right rib mass. (A) CT (white arrows = mass). (B) PET (white arrows = activity). (C) 68 Ga-DOTATE Scan Axial (red arrows = activity). (D) 68 Ga-DOTATE Scan Coronal (A/P) (red arrows = activity).
Fig. 3
Some TIO patients with unresectable or unidentifiable PMTs have benefited greatly from Burosumab therapy (Jan De Beur et al., 2019). However, the accessibility of our patient's tumor prompted us to refer her to Thoracic Surgery for complete resection of the tumor and rib. Further, Burosumab therapy was discontinued prior to measuring baseline laboratory values due to potential confounding, especially with the FGF23 level.
Intra-operatively, surgeons identified a more concerning lesion on the patient's 10th right rib (Fig. 4A) that had no imaging correlate. This lesion was removed, and the surgeons deferred removal of the 9th right rib to ensure the 10th right rib lesion was not the culprit of her TIO symptoms or other pathology warranting alternative intervention. The patient's hypophosphatemia persisted post-operatively. 4-months after surgery, notable lab values included low serum phosphorus (1.4 mg/dL; normal 2.3–4.7 mg/dL), low 1,25 dihydroxyvitamin D (15 pg/mL; 19.9–79.3 pg/mL), normal total vitamin D (38 ng/mL; 25–80 ng/mL), and elevated total FGF23 (1532 RU/mL; <180 RU/mL). Histopathology of the 10th right rib mass showed only non-specific reactive changes, possibly representing an old fracture site.Fig. 4 Gross appearance of surgical specimens. (A) Intra-operative image of 10th right rib mass (no imaging correlate) removed during the first, unsuccessful surgery. White star (*) denotes the large abnormality that prompted surgeons to remove the 10th rib mass. (B-C) Post-operative images of 9th right rib removed during the second, successful surgery. (B) White stars (*) denote the two areas of abnormality, red arrow denotes the primary lesion of concern for PMT shown in Fig. 5, Fig. 6. (C) Significant thickening observed in the 9th right rib.
Fig. 4
These findings further implicated the active 9th rib lesion in her pathology (Figure 3), prompting Thoracic Surgery to remove the 9th right rib (Fig. 4B-C) 5 months after the first unsuccessful surgery. Gross appearance of the 9th right rib showed two areas of abnormality with one denoting the PMT lesion (Fig. 4B) and significant rib thickening along the lateral surface (Fig. 4C). Histological sections of the 9th right rib showed a morphologically classical phosphaturic mesenchymal tumor, consisting of bland spindled cells in a highly vascular background, with unusually hyalinized to occasionally calcified matrix (Fig. 5). Chromogenic in situ hybridization (CISH) of the tumor and RNA-sequencing for the presence of rearrangements in 138 target genes were pursued using methods previously published (Martinez et al., 2019; Carter et al., 2015). FGF23 CISH was strongly positive (Fig. 6). Sequencing was positive for the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1). Taken together, these results are characteristic of a typical PMT.Fig. 5 Histological appearance of 9th right rib phosphaturic mesenchymal tumor (PMT). A) Lower magnification showing infiltration of rib bone (pink, paucicellular) by the PMT. B) Higher magnification (black box of A) of the PMT specifically showing proliferation of uniform short spindle to ovoid cells with a rich vascular background and cystic changes. C) Low magnification of the PMT from a different depth of sectioning.
Fig. 5Fig. 6 FGF23 chromogenic in situ hybridization (CISH) of 9th right rib phosphaturic mesenchymal tumor (PMT).
Fig. 6Fig. 7 Post-operative portable chest X-ray after rib removal (second successful surgery). A left humeral rod and right chest tube are observed. No pneumothorax is seen. The lungs appear clear except for volume loss related to the overlying thoracic deformity. Extensive bone deformities identified, and multiple performed ribs are seen bilaterally but both appear similar to pre-operative radiographs.
Fig. 7Table 2 Longitudinal patient laboratory values. Op 1 denotes the first unsuccessful 10th rib removal operation. Op 2 denotes the second successful 9th rib removal operation. PTH = parathyroid hormone. Note = Pre-Op 1 labs were taken while the patient was on Burosumab, all other labs were taken while the patient was off Burosumab, and Post-Op 2 labs were taken 3 months after resection.
Table 2Laboratory value Normal range Pre-Op 1 (on Burosumab) Post-Op 1, Pre-Op 2 Post-Op 2 (3 months after 9th right rib resection)
Serum phosphorus 2.3–4.7 mg/dL 2.5 1.4 3.7
Calcium 8.4–10.5 mg/dL 9.7 9.3 10.4
Total vitamin D 25–80 ng/mL 40 38 35
1,25 dihydroxyvitamin D 19.9–79.3 pg/mL 333 15 327
Alkaline phosphatase 40–150 U/L 168 111 130
Chloride 96–106 mmol/L 108 109 105
PTH 16–77 pg/mL 189 Not collected 194
FGF23 <180 RU/mL 36,900 1532 245
3 months post-resection, chest x-rays showed no pneumothorax and no significant changes compared to prior radiographs (Fig. 7). FGF23 levels decreased again but remained slightly elevated (245 RU/mL), serum phosphorus normalized (3.7 mg/dL), alkaline phosphatase normalized (130 U/mL), and total vitamin D was 35 ng/mL. Parathyroid hormone remained elevated (194 pg/mL) (Table 2). Clinical assessments of mobility markedly improved (Video 1, Video 2), and the patient has stated she is in less pain and is more active and feels stronger than ever. She will continue to follow up longitudinally in our Endocrinology clinic.
3 Discussion
TIO is a paraneoplastic disease resulting in elevated FGF23, renal phosphate wasting, defective Vitamin D metabolism, and subsequent osteomalacia. Clinically, patients with TIO present with progressive bone pain, muscle weakness, fatigue, and sporadic insufficiency fractures (Yin et al., 2018). TIO can be suggested by serum hypophosphatemia, hyperphosphaturia, and low or inappropriately normal calcitriol levels, but the identification of a phosphaturic mesenchymal tumor (PMT) in the soft tissue or bone is necessary for definitive diagnosis (Feng et al., 2017). Here, we presented a 41-year-old woman suffering from TIO with a 26-year delay in diagnosis with a concurrent misdiagnosis of XLH.
Diagnosing TIO is often complicated by small tumor size and similar initial clinical presentation to more common phosphate wasting disorders such as XLH. A retrospective study of 144 TIO cases found that TIO was misdiagnosed in over 95% (137/144) of cases, with intervertebral disc herniation, spondyloarthritis, and osteoporosis being the most common misdiagnoses (Feng et al., 2017). In this case, our patient was misdiagnosed for 26 years with little symptomatic improvement with either conventional therapy or Burosumab, and subsequent gene paneling at our institution revealed no genetic evidence of her XLH diagnosis.
Patients who present with bone pain, muscle weakness, and multiple fractures should be evaluated for hypophosphatemia, and TMP/GFR should be performed for hypophosphatemic patients. While diagnostically burdensome, a low TMP/GFR is a powerful indicator of renal phosphate wasting in the absence of secondary hyperthyroidism (Jagtap et al., 2012). Though less sensitive than TMP/GFR, calculating a percent tubular reabsorption of phosphate (TRP) is a more easily collected alternative (Takeda et al., 2015). Additionally, 24-h urine phosphorus and calcium can differentiate between malabsorption and phosphate wasting disorders (Payne, 1998).
Patient FGF23 levels and family/personal histories are also important tools for differentiating between phosphate wasting disorders (Table 3). As discussed in our previous report, TIO distinguishes itself from other FGF23-high phosphate wasting disorders in that it often presents with rapid symptom onset later in life, often with a negative family history. On the other hand, XLH is usually inherited as an X-linked dominant inherited disorder that typically presents in early childhood (MD, 2012). As such, genetic testing and associated costs can often be avoided if a clear X-linked pattern is identified by pedigree. That said, XLH can still occur due to de novo mutations, so absence of a family history should not entirely rule out XLH (Durmaz et al., 2013).Table 3 Phosphate wasting disorder differential diagnosis. A differential diagnosis table (not extensive) for phosphate wasting disorders, including TIO, distinguished by serum FGF23 level, reproduced from Colazo et al. (n.d.), Imel and Econs (2012), and Zoller et al. (2017).
Table 3Phosphate wasting disorders with low FGF23 Phosphate wasting disorders with high or “inappropriately normal” FGF23
Fanconi syndrome X-linked hypophosphatemia (XLH)
Hyperparathyroidism Tumor-induced osteomalacia (TIO)
Diuretics (e.g. acetazolamide) Autosomal dominant/autosomal recessive rickets
Myeloma McCune Albright syndrome
Copper disorders (Menkes) Cutaneous-skeletal hypophosphatemia syndrome (CSHS) (e.g., epidermal nevus syndromes)
Alcohol consumption Iron use (iron polymaltose infusions)
Genetic disorders (e.g. Npt2a mutations)
Finally, in the absence of genetic data, indication of several bone and calcification disorders can help distinguish XLH from TIO, though these criteria are highly variable. Enthesopathy (calcification of the joint capsule, tendon insertions, and ligaments) is a common feature of XLH but not of TIO and results in increased apparent BMD (Beck-Nielsen et al., 2019). By contrast, typical TIO patients have remarkably low BMD, often being labelled osteoporotic. Dentition is another clinical differentiator, in that patients with XLH can have recurrent abscesses and dental loss, while dentition in TIO is usually normal (Lee et al., 2017). However, the patient presented here was edentulous, demonstrating that TIO should not be ruled out based on these features.
Suspected TIO should prompt an investigation for active PMTs in the hands, feet, ribs, nasal cavities, and brain (Colazo et al., n.d). In recent literature, a full body 68Ga-DOTATATE scan has been shown to be a specific imaging test for identifying culprit tumors in osteomalacia (Zhang et al., 2015). The 68Ga-DOTATATE scan works by utilizing 68Gallium (68Ga) conjugated to somatostatin peptide analogues, which allows for somatostatin receptor imaging by PET scan. DOTATATE scans are most often used for diagnosing somatostatin-receptor positive neuroendocrine tumors, but PMTs preferentially express somatostatin type 2 receptors (Houang et al., 2013). Hence, this technique allows for targeted imaging of TIO-causing lesions. That said, false positivity can still occur in hypersplenism, fractures, sarcoidosis, or vertebral hemangiomas (Hofman et al., 2015). If very small and/or multiple tumors of unknown significance are present, selective FGF23 venous sampling has shown promise in deciphering the FGF23-producing tumor (Colazo et al., n.d.; Schober et al., 2017). In this case, since two suspicious lesions were encountered, FGF23 venous sampling could have been utilized, but the anatomical location and proximity of both lesions to each other would have made the process difficult to perform and most likely futile.
Misdiagnosis can also occur after tumor identification, especially in cases in which non-PMT tumors morphologically mimic PMTs in the context of hypophosphatemia (Lee et al., 2016). Recent studies have identified novel gene fusions FN1-FGF1 and FN1-FGFR1 that are transcribed and synthesized by the majority of PMTs. The fusion of FN1 and FGFR1 leads to constitutive overexpression of the 3′ portion of FGFR1 through constitutive activation of the FN1 promoter, and the fusion protein products have suspected roles in autocrine signaling (Lee et al., 2016). These fusion products can be detected by RNA sequencing or FISH of the tumor, and several emerging FGF/R inhibitors have been shown to be therapeutically beneficial in relapsing TIO (Hartley et al., 2020).
While diagnosis of TIO depends solely on postoperative biochemical resolution of laboratory abnormalities, the classification of the resected tumor can be helpful. Our patient's tumor tested positive for FN1-FGFR1 by RNAseq and for FGF23 by chromogenic in situ hybridization (CISH), further suggesting PMT (Martinez et al., 2019; Carter et al., 2015). These results support the use of FN1-FGF1/R1 gene fusions and FGF23 CISH as an additional diagnostic tool for TIO and can be used for comparison between the original and a recurrent tumor.
To date, surgical PMT resection is the only curative therapy for TIO. To mitigate risk of recurrence or metastasis, resection should be performed with wide margins where possible, and patients should be monitored longitudinally post-operatively (Hautmann et al., 2015). Here, our patient had dramatic improvements 3 months post-resection in symptoms and mobility (Video 1, Video 2), as well as in serum FGF23, phosphate, and Vitamin D levels (Table 2). Patients with unresectable or undetectable tumors have historically been placed on supplemental phosphate and calcitriol; however, Burosumab is a novel human anti-FGF23 monoclonal antibody initially approved by the FDA to treat XLH that has been recently approved for treatment of such complex TIO presentations (Carpenter et al., 2016; Day et al., 2020). In particular, Kyowa Kirin and Ultragenyx's Crysvita (burosumab-twza) has been approved for the treatment of TIO associated with PMTs that cannot be curatively resected or localized in adult and pediatric patients 2 years of age and older. Burosumab has been shown to improve serum phosphate levels and histomorphology of bone biopsies in patients with TIO, but mild side effects have been reported, including reactive overproduction of FGF23 and consequent Vitamin D deficiency (Day et al., 2020). For these reasons, monitoring FGF23 levels is not a reliable way to monitor patients on Burosumab; clinicians should focus on serum phosphorous, Alkaline phosphatase, renal phosphate wasting, 1,25 Dihydroxyvitamin D, and clinical signs/symptoms.
Indeed, in the 3 months prior to tumor identification, our patient was placed on Burosumab therapy and enjoyed mild symptomatic improvement and stable lab values (notably a normal serum phosphorus, see Table 2). While no labs were taken pre-induction, her condition deteriorated while off Burosumab between her two rib resections, indicating a positive impact of Burosumab on her condition. Her marked post-operative improvement supports the use of PMT resection when possible.
In this report, we have demonstrated the utility of two powerful genetic tools – gene paneling and RNA sequencing – at guiding clinicians to a challenging diagnosis of a non-heritable condition. In the 26-year history of this patient's disease, genetic tools have become increasingly cost-effective, sensitive, and precise. A lack of available tests at initial presentation motivated a diagnosis of XLH (a germline genetic condition) based on clinical evidence alone. The similar clinical presentations of many phosphate wasting disorders, the uniqueness of their genetic identifiers like FN1-FGFR1 or PHEX, and the illumination of known, curative therapies through such tests all support the expanded use of gene paneling and tumor sequencing alongside clinical reasoning around phosphate wasting disorders. This fact is further evidenced by the requirement of genetic diagnosis for enrollment in most clinical trials targeting phosphate wasting disorders. Additionally, the advancements in the field over the past 3 decades may warrant the re-evaluation of poorly managed, long-term diagnoses through the lens of a gene panel or specific genetic marker.
4 Conclusion
Tumor-induced osteomalacia (TIO) is a paraneoplastic disease driven by hypersecretion of Fibroblast Growth Factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). In this case report, we present a patient with what we believe to be the longest history of a delayed TIO diagnosis reported in the literature, outlined current diagnostic strategies, and demonstrated the increasing utility of genetic testing in the diagnosis of phosphate wasting disorders.
We highlight the importance of the personal and family histories, as well as potential pitfalls of using exclusively clinical criteria in diagnosing phosphate wasting disorders, as our patient had several clinical findings suggestive of XLH yet had a negative family history of phosphate wasting disorders. Further, we stress the utility of full body imaging, especially a 68Ga-DOTATATE PET/CT scan, in probing cases of high clinical suspicion for TIO, and we applied novel genetic screening methods (i.e. gene paneling and tumor RNA sequencing) to confirm our diagnosis. When possible, performing these tests provides powerful support for a TIO diagnosis. Finally, while our patient has enjoyed a marked recovery 3 months post-surgical resection, we discuss Burosumab, an emerging therapeutic antibody against FGF23 that may be an attractive treatment for undetectable or unresectable tumors in TIO.
The following are the supplementary data related to this article.Video 1
Pre-operative functionality of patient
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Post-operative functionality of patient
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Acknowledgments
Two of the authors (JMC, JAD) are supported by NIGMS of the National Institutes of Health under award number T32GM007347. The content in this report is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The Transparency document associated with this article can be found, in online version. | Recovering | ReactionOutcome | CC BY-NC-ND | 33490314 | 18,819,395 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | CARBOPLATIN, ETOPOSIDE | DrugsGivenReaction | CC BY-NC-ND | 33490353 | 18,795,232 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Escherichia infection'. | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | CARBOPLATIN, ETOPOSIDE | DrugsGivenReaction | CC BY-NC-ND | 33490353 | 18,810,098 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Febrile neutropenia'. | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | CARBOPLATIN, ETOPOSIDE | DrugsGivenReaction | CC BY-NC-ND | 33490353 | 18,810,098 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperkalaemia'. | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | CARBOPLATIN, ETOPOSIDE | DrugsGivenReaction | CC BY-NC-ND | 33490353 | 18,795,232 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Necrosis'. | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | CARBOPLATIN, ETOPOSIDE | DrugsGivenReaction | CC BY-NC-ND | 33490353 | 18,810,098 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | CARBOPLATIN, ETOPOSIDE | DrugsGivenReaction | CC BY-NC-ND | 33490353 | 18,795,232 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal failure'. | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | CARBOPLATIN, ETOPOSIDE | DrugsGivenReaction | CC BY-NC-ND | 33490353 | 18,810,098 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Reproductive tract disorder'. | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | CARBOPLATIN, ETOPOSIDE | DrugsGivenReaction | CC BY-NC-ND | 33490353 | 18,810,098 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sepsis'. | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | CARBOPLATIN, ETOPOSIDE | DrugsGivenReaction | CC BY-NC-ND | 33490353 | 18,810,098 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tumour lysis syndrome'. | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | CARBOPLATIN, ETOPOSIDE | DrugsGivenReaction | CC BY-NC-ND | 33490353 | 18,810,098 | 2021-02 |
What is the weight of the patient? | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | 48 kg. | Weight | CC BY-NC-ND | 33490353 | 18,795,232 | 2021-02 |
What was the outcome of reaction 'Acute kidney injury'? | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33490353 | 18,795,232 | 2021-02 |
What was the outcome of reaction 'Escherichia infection'? | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33490353 | 18,810,098 | 2021-02 |
What was the outcome of reaction 'Febrile neutropenia'? | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33490353 | 18,810,098 | 2021-02 |
What was the outcome of reaction 'Hyperkalaemia'? | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33490353 | 18,795,232 | 2021-02 |
What was the outcome of reaction 'Necrosis'? | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33490353 | 18,810,098 | 2021-02 |
What was the outcome of reaction 'Renal failure'? | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33490353 | 18,810,098 | 2021-02 |
What was the outcome of reaction 'Reproductive tract disorder'? | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33490353 | 18,810,098 | 2021-02 |
What was the outcome of reaction 'Sepsis'? | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33490353 | 18,810,098 | 2021-02 |
What was the outcome of reaction 'Tumour lysis syndrome'? | Metastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report.
The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.
1 Introduction
Disorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.
1.1 Case study
This patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.
On laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.
An ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).
Diagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.
Intraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.
On histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.
Our further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.
2 Discussion
Genital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.
In ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).
Mixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.
Our patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.
Patients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.
Careful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.
3 Conclusion
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.
Ethical clearance: Since it is a case report so no ethical clearance is required.
Financial support: Nil.
The manuscript has not been published previously and is not under consideration elsewhere.
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Declaration of Competing Interest
The authors declare that there is no conflict of interest. | Recovering | ReactionOutcome | CC BY-NC-ND | 33490353 | 18,810,098 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Paraneoplastic cerebellar degeneration associated with anti-Yo antibodies in an ovarian cancer case: A case report.
Paraneoplastic neurologic syndromes (PNS) are a rare heterogeneous group of disorders associated with malignancy that can result in significant functional impairment. One syndrome in particular, paraneoplastic cerebellar degeneration (PCD), may be severely disabling. PCD is a rare neurological syndrome, associated with active or subclinical cancer, characterized by acute or subacute onset cerebellar ataxia due to tumor-induced autoimmunity against cerebellar antigens. Treatment of paraneoplastic syndromes is generally unsatisfactory, but early diagnosis and treatment of PCD, which includes neurological treatment, immunotherapy and oncological treatment of associated malignancy, may improve the neurological prognosis. We reported the case of a 59-year-old woman who presented PCD as the first sign of ovarian cancer. Laboratory investigations showed the presence of anti-Yo antibodies in the serum. The brain MRI revealed specific modifications for PCD. After oncological treatment, intravenous immunoglobulin therapy and corticosteroid therapy, the oncological response was satisfactory, but no improvement of the neurologic symptoms was achieved.
1 Introduction
Paraneoplastic neurologic syndromes (PNS) are a group of neurologic conditions that affect 0.5–1% of all cancer patients. Paraneoplastic cerebellar degeneration (PCD) is a rare and severely debilitating immune-mediated neurological syndrome that occurs in less than 1% of all cancer patients. PCD can be associated with any cancer, but the most commonly associated are gynecological and breast cancer, small cell lung cancer and Hodgkin lymphoma (Vogrig et al., 2019, Kannoth, 2012). To reach PCD diagnosis there is need to undergo clinical, laboratory and imagistic evaluations. Clinically, PCD is characterized by acute or subacute development of severe pancerebellar dysfunction. It is typically beginning with dizziness, nausea and gait unsteadiness progressing to ataxia, diplopia, often dysarthria, dysphagia and nystagmus (Dalmau and Rosenfeld, 2008, Vedeler et al., 2006, Mitoma et al., 2016). Serologically, multiple antibodies are highly specific for PCD, of which the most common are Anti-Yo antibodies [Table1]. Anti-Yo–mediated PCD tends to occur predominantly in women around the age of 60 and is mostly associated with gynecologic malignancy (ovary, uterus and breast). The anti-Yo antibody is the most common serological marker in PCD associated with ovarian cancer, although only 50% of these patients have positive serological findings (Kannoth, 2012, Shams'ili et al., 2003).Table1 Main autoantibodies reported in paraneoplastic cerebellar degeneration (Dalmau and Rosenfeld, 2008, Yshii et al., 2020).
Autoantibodies Incidence in PCD Main associated tumors
Anti-Yo(anti-PCA1) 38–50% Ovarian tumor
Breast cancer
Other gynecological cancers
Other adenocarcinomas
Anti-Hu 18–21% SCLC
Neuroendocrine tumors
Anti-CV2/CRMP5 13–27% SCLC 5
Thymoma
Colon cancer
Breast cancer
Anti-Ma2 5% Testicular germ cell tumors
NSCLC
NHL
Cervical cancer
Anti-Tr 14% Hodgkin disease
Anti-amphiphysin 17% Breast cancer
SCLC
Anti-Ri 12–32% Breast cancer
Gynecological cancer
SCLC
Anti-GABAbR unknown SCLC
Neuroendocrine tumor
Anti-Recoverin unknown SCLC
Breast cancer
AGNA/Anti-SOX1 43–50% Lung cancer
Anti-PCA2 unknown SCLC
Anti-GluR1 unknown SCLC
Anti-Zic4 12–29% SCLC
Anti-Titin 80% Thymoma
Early diagnosis and treatment of PCD are essential because any delay can result in progression and irreversible neurological damage (Kannoth, 2012). The PCD treatment includes immunoglobulins, corticosteroids, and chemotherapy in association with supportive therapy.
2 Case report
A 59-year-old, Caucasian, menopausal woman consulted a neurologist complaining of vertigo, dizziness, postural balance disorders, gait instability with a tendency to fall, bilateral plantar paresthesia and intermittent postural tremor of the cephalic extremity with intentional character and accentuated by emotions. Also, the patient was complaining of sad mood, insomnia, frontal-occipital headache with intermittent tension character, generalized pain in the spine and in the right abdominal flank, plus a significant weight loss of 7 kg in 2 months. Clinical onset was 4 months before presentation, accentuated in the last 2 months.
The patient’s medical history, family and social history were insignificant for oncological pathology. Regarding the physiological history, the patient had menarche at the age of 14, G7P2 and menopause at the age of 45.
During the first hospitalization in the neurology department, several investigations were performed. Biological examinations showed mild hepatic cytolysis syndrome 2xULN.
The ECG, chest X-ray and native CT brain revealed no pathological changes. Carotid Doppler US revealed mild carotid atheromatosis and the EEG indicated diffuse irritant path. An abdominal US was performed, showing several round masses of 1.7–2 cm, hypoechoic, located paraaortic, in the hepatic hilum and between the stomach and the pancreas.
The patient was directed to a gastroenterology service where several investigations were carried out, as presented below.
Abdominal CECT scan revealed multiple lymphadenopathies located peritoneal, retroperitoneal and both on the lesser and greater curvatures of the stomach (max. of 2.5 cm in size). Also, there were discovered lymphadenopathies with tendence towards confluence in the splenic and superior polar spine and one supradiaphragmatic lymphadenopathy of 2.5 cm located in the left cardiophrenic angle. An upper digestive EUS with FNA was performed, showing one subepithelial lesion covered by the normal mucosa on the posterior antral wall, hypoechoic, homogeneous, hypervascularized of 1.7 cm. There were also identified multiple lymphadenopathies hypervascularized, located in the hepatic hilum, peripancreatic and perigastric of 2–3 cm in size. Gynecological examination with transvaginal US found out a mass of 43/32 mm, with vascular signal and intermediate echogenicity, located in the left ovary. The histopathological result of the biopsy was a high-grade ovarian serous carcinoma.
The patient consulted our oncology service with the result of the histopathological examination to establish the therapeutic strategy. Considering the neurological symptoms and the fact that the patient's condition worsened, we redirected the patient to the neurology service for a thorough investigation of the neurological syndrome in the context of oncological pathology.
The patient returned to the ER due to ongoing symptoms. In addition, she had severe headache with motor impairment to the upper and lower limbs, orthostatic and impossible gait, bilateral upper arm paresthesia, intolerance to light and noise, hearing loss of the right ear, severe dysarthria, diplopia and vomiting related to head mobilization. The patient was admitted to neurology department with suspected PNS based on clinical and imaging findings. The head CT result was without brain mass lesions or signs of stroke. Laboratory serum tests showed mild hepatic cytolysis syndrome (2xULN) and elevated IgG (1.3xULN). The CSF analysis results indicated pleocytosis, elevated level of glucose and proteins. The electromyogram and electroneurography revealed acute polyneuropathic asymmetric demyelination distal and proximal with secondary axonal damage. Serum antibody panel testing was positive for anti-Yo antibodies and negative for anti-Ri, anti-Hu, anti-Rcoverin, SOX1, Titin, Amphiphysin, CV2 and PNMA2.
Based on the subacute presentation of severe pancerebellar syndrome, clinical symptomatology and the paraclinical results, with ongoing ovarian carcinoma, the diagnosis of PCD with acute polyradiculoneuritis was established and the treatment with intravenous immunoglobulins (IV IgG) was decided. The therapeutic strategy was based on corticosteroid therapy and 5 days of intravenous immunoglobulins as a continuous infusion according to the next regimen: 2 g/kg of body weight with total dose calculated to 65 kg equal with 130 g administered in 5 days (day 1 total dose was 27.5 g with 25 ml/h, days 2–4 dose 25 g with 50 ml/h and day 5, 27.5 g with 100 ml/h).
After obtaining a slight improvement of the neurological symptomatology, the patient was directed to the oncology service to establish the oncological therapeutic strategy. Laboratory blood tests showed grade I normocytic normochromic anemia, minimal hepatic cytolysis syndrome (1.3xULN), CA125 tumor marker elevated (CA125 = 13,025 U/mL), and Anti-Yo antibodies detected positive.
Brain CEMRI revealed: Mild atrophy of the cerebellar hemispheres and vermis [Fig. 1a]. Signal changes (hyposignal in T2) were identified in the medial portions of the cerebellar hemispheres, slightly more pronounced in the right, suggestive for iron deposits [Fig. 1b]. Large fourth ventricle. A few scattered nonenhancing increased in T2 signal abnormalities in frontal lobes [Fig. 1c]. No acute vascular lesions or intracerebral lesions were detected.Fig. 1 Brain MRI with contrast. (a) Axial FLAIR - cerebellar atrophy. (b) Axial SWI - susceptibility artifact related to iron deposition in the median parts of the cerebellar hemispheres. (c) Sag T1-weighted + C - without cerebellar or dural enhancement.
BRCA1 and 2 germline mutations tests were performed showing BRCA1 germline mutation positive.
Considering the histopathological result correlated with the results of imaging examinations, with the presence of multiple centimetric peritoneal and retroperitoneal lymphadenopathies, we interpreted the case as being a high grade ovarian serous carcinoma stage IV FIGO. We decided to administer chemotherapy Taxol-Carboplatin(TC) protocol, weekly, after the informed consent signed by the patient was obtained.
After administration of chemotherapy 3 cycles TC Q1W regimen, Paclitaxel 80 mg/mp total dose 110 mg and Carboplatin 2 AUC total dose 200 mg, serum lab testing for CA125 was 4209 U/mL vs. 13,025 U/mL and Anti-Yo antibodies detected negative. After a good tolerance at weekly chemotherapy regimen, TC Q3W regimen was decided. After administration of 3 cycles TCQ3W Paclitaxel 175 mg/mp total dose 250 mg and Carboplatin 5 AUC total dose 500 mg, tumor marker CA125 value decreased significantly(CA125 = 247.8 U/mL), and a slightly improvement of symptomatology was achieved (disappearance of diplopia and vomiting), but neurological impairment worsened, causing the patient’s death [Fig. 2].Fig. 2 CA125 Tumor’s marker evolution.
3 Discussion
In cancer patients, the neurologic manifestations are mostly the consequence of direct tumor invasion of the nervous system or metastases. Other common causes of neurologic symptoms include infections, vascular or metabolic disorders and neurotoxicity from chemotherapy. In between 0.5 and 1% of cancer patients, an autoimmune response is developed that targets normal neuronal tissues, called PNS (Vogrig et al., 2019, Kannoth, 2012, Vedeler et al., 2006). The associated tumors express modified ectopic neuronal protein, called onconeural antigens, which may trigger the immune response against constitutional proteins at the neuronal level with the presence of highly specific antineuronal antibodies in the serum and cerebrospinal fluid (CSF). The absence of such antibodies cannot rule out the diagnosis of PCD (Dalmau and Rosenfeld, 2008). At least 12 onconeural antibodies are highly specific for PCD, including anti-Yo (PCA-1), anti-PCA2, anti-Hu, anti-Tr, anti-Ri, anti- mGluR1, anti-Zic4, anti-Ma, anti-CV2/CRMP5, anti-VGCC and anti-ANNA3 (Dalmau and Rosenfeld, 2008, Kannoth, 2012, Shams'ili et al., 2003) [Table1]. Our patient presented intense positive anti-Yo antibodies, but negative anti: -amphiphysin, -CV2, -PNMA2, -Ri, -Hu, -Recoverin, -SOX1, and -Titin serum antibodies.
From the clinical point of view, in the case of our patient, PCD has evolved over several months. In the literature, clinically, PCD is characterized by development of severe pancerebellar dysfunction. Onset is usually gradually (weeks/months), although acute forms have been rarely described (Vogrig et al., 2019).
Certain signs of degenerative neurological disease can also be identified by modern imaging techniques. Brain MRI findings appear normal early in the course of PCD but can show cerebellar atrophy in advanced cases (Vedeler et al., 2006). In our case, CT brain imaging did not found pathological points, instead the brain MRI showed cerebellar atrophy, large fourth ventricle and signal abnormalities in frontal lobes.
Given the small number of published cases worldwide of PCD associated with onconeural antibodies in solid tumors (<300 cases), an exact treatment protocol for PCD has not been established yet (Shams'ili et al., 2003, Russo et al., 2013, McKeon et al., 2011). It is known that in a small number of cases, the neurological symptoms of PCD have partially responded to administration of intravenous immunoglobulin therapy and the treatment of primary tumor, in combination with supportive therapy. There are no evidence-based recommendations available regarding the immunosuppressive therapy but it includes steroids, IV IgG, plasmapheresis, cyclophosphamide, azathioprine and rituximab (Kannoth, 2012). In the case we presented, after intravenous immunoglobulin administration in combination with corticosteroid therapy, supportive therapy and chemotherapy protocol TC, the anti-tumor therapeutic response was very good, proven by the decrease of the tumor marker. Although the presence of oncological positive response, the neurological benefit was still small, only managing to obtain a slightly neurological improvement, without stabilizing the progression of neurological degenerative disease.
Although several case reports of PCD are published, we consider the case presented by us to be interesting because a young woman who developed subacute cerebellar degeneration, a disease that requires rapid diagnosis and urgent treatment, has been shown to have the main cause an ovarian cancer. The diagnosis of PCD was supported by the presence of anti-Yo antibodies and the presence of brain MRI changes. The response to chemotherapy was favorable, which leads us to think that if the gynecological tumor had been diagnosed earlier, the neurological prognosis would have been better and the survival time longer.”
4 Conclusion
PCD, a rare pathology, should be suspected in cancer patients with degenerative neurological symptoms, especially in cases of women with gynecological cancers.
In the case we presented, PCD was the first clinical manifestation of the underlying cancer and the diagnosis was established by clinical manifestation of cerebellar ataxia, anti-Yo antibodies raised in the serum and the brain imaging with cerebellar atrophy.
Even if the diagnosis was delayed, after the clinical picture of cerebellar ataxia was quite advanced, treatment with immunoglobulins, corticosteroids and chemotherapy in association with supportive therapy brought an anti-tumor response, with slight improvement of the symptoms but with progression of degenerative neurological disease.
Informed Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
CRediT authorship contribution statement
Sandra Deac: Writing - original draft, Writing - review & editing. Mihaela Marioara Stana: Writing - review & editing. Andrei Dan Havasi: Writing - review & editing. Cainap Calin: Writing - review & editing. Anca-Raluca Popita: . Ana Maria Bordeianu: Writing - review & editing. Simona Cainap: Writing - review & editing. Madalina Bota: Writing - review & editing. Ovidiu Vasile Bochis: Supervision, Writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A Supplementary material
The following are the Supplementary data to this article:Supplementary data 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.gore.2020.100695. | CARBOPLATIN, PACLITAXEL | DrugsGivenReaction | CC BY-NC-ND | 33490355 | 19,016,875 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective for unapproved indication'. | Paraneoplastic cerebellar degeneration associated with anti-Yo antibodies in an ovarian cancer case: A case report.
Paraneoplastic neurologic syndromes (PNS) are a rare heterogeneous group of disorders associated with malignancy that can result in significant functional impairment. One syndrome in particular, paraneoplastic cerebellar degeneration (PCD), may be severely disabling. PCD is a rare neurological syndrome, associated with active or subclinical cancer, characterized by acute or subacute onset cerebellar ataxia due to tumor-induced autoimmunity against cerebellar antigens. Treatment of paraneoplastic syndromes is generally unsatisfactory, but early diagnosis and treatment of PCD, which includes neurological treatment, immunotherapy and oncological treatment of associated malignancy, may improve the neurological prognosis. We reported the case of a 59-year-old woman who presented PCD as the first sign of ovarian cancer. Laboratory investigations showed the presence of anti-Yo antibodies in the serum. The brain MRI revealed specific modifications for PCD. After oncological treatment, intravenous immunoglobulin therapy and corticosteroid therapy, the oncological response was satisfactory, but no improvement of the neurologic symptoms was achieved.
1 Introduction
Paraneoplastic neurologic syndromes (PNS) are a group of neurologic conditions that affect 0.5–1% of all cancer patients. Paraneoplastic cerebellar degeneration (PCD) is a rare and severely debilitating immune-mediated neurological syndrome that occurs in less than 1% of all cancer patients. PCD can be associated with any cancer, but the most commonly associated are gynecological and breast cancer, small cell lung cancer and Hodgkin lymphoma (Vogrig et al., 2019, Kannoth, 2012). To reach PCD diagnosis there is need to undergo clinical, laboratory and imagistic evaluations. Clinically, PCD is characterized by acute or subacute development of severe pancerebellar dysfunction. It is typically beginning with dizziness, nausea and gait unsteadiness progressing to ataxia, diplopia, often dysarthria, dysphagia and nystagmus (Dalmau and Rosenfeld, 2008, Vedeler et al., 2006, Mitoma et al., 2016). Serologically, multiple antibodies are highly specific for PCD, of which the most common are Anti-Yo antibodies [Table1]. Anti-Yo–mediated PCD tends to occur predominantly in women around the age of 60 and is mostly associated with gynecologic malignancy (ovary, uterus and breast). The anti-Yo antibody is the most common serological marker in PCD associated with ovarian cancer, although only 50% of these patients have positive serological findings (Kannoth, 2012, Shams'ili et al., 2003).Table1 Main autoantibodies reported in paraneoplastic cerebellar degeneration (Dalmau and Rosenfeld, 2008, Yshii et al., 2020).
Autoantibodies Incidence in PCD Main associated tumors
Anti-Yo(anti-PCA1) 38–50% Ovarian tumor
Breast cancer
Other gynecological cancers
Other adenocarcinomas
Anti-Hu 18–21% SCLC
Neuroendocrine tumors
Anti-CV2/CRMP5 13–27% SCLC 5
Thymoma
Colon cancer
Breast cancer
Anti-Ma2 5% Testicular germ cell tumors
NSCLC
NHL
Cervical cancer
Anti-Tr 14% Hodgkin disease
Anti-amphiphysin 17% Breast cancer
SCLC
Anti-Ri 12–32% Breast cancer
Gynecological cancer
SCLC
Anti-GABAbR unknown SCLC
Neuroendocrine tumor
Anti-Recoverin unknown SCLC
Breast cancer
AGNA/Anti-SOX1 43–50% Lung cancer
Anti-PCA2 unknown SCLC
Anti-GluR1 unknown SCLC
Anti-Zic4 12–29% SCLC
Anti-Titin 80% Thymoma
Early diagnosis and treatment of PCD are essential because any delay can result in progression and irreversible neurological damage (Kannoth, 2012). The PCD treatment includes immunoglobulins, corticosteroids, and chemotherapy in association with supportive therapy.
2 Case report
A 59-year-old, Caucasian, menopausal woman consulted a neurologist complaining of vertigo, dizziness, postural balance disorders, gait instability with a tendency to fall, bilateral plantar paresthesia and intermittent postural tremor of the cephalic extremity with intentional character and accentuated by emotions. Also, the patient was complaining of sad mood, insomnia, frontal-occipital headache with intermittent tension character, generalized pain in the spine and in the right abdominal flank, plus a significant weight loss of 7 kg in 2 months. Clinical onset was 4 months before presentation, accentuated in the last 2 months.
The patient’s medical history, family and social history were insignificant for oncological pathology. Regarding the physiological history, the patient had menarche at the age of 14, G7P2 and menopause at the age of 45.
During the first hospitalization in the neurology department, several investigations were performed. Biological examinations showed mild hepatic cytolysis syndrome 2xULN.
The ECG, chest X-ray and native CT brain revealed no pathological changes. Carotid Doppler US revealed mild carotid atheromatosis and the EEG indicated diffuse irritant path. An abdominal US was performed, showing several round masses of 1.7–2 cm, hypoechoic, located paraaortic, in the hepatic hilum and between the stomach and the pancreas.
The patient was directed to a gastroenterology service where several investigations were carried out, as presented below.
Abdominal CECT scan revealed multiple lymphadenopathies located peritoneal, retroperitoneal and both on the lesser and greater curvatures of the stomach (max. of 2.5 cm in size). Also, there were discovered lymphadenopathies with tendence towards confluence in the splenic and superior polar spine and one supradiaphragmatic lymphadenopathy of 2.5 cm located in the left cardiophrenic angle. An upper digestive EUS with FNA was performed, showing one subepithelial lesion covered by the normal mucosa on the posterior antral wall, hypoechoic, homogeneous, hypervascularized of 1.7 cm. There were also identified multiple lymphadenopathies hypervascularized, located in the hepatic hilum, peripancreatic and perigastric of 2–3 cm in size. Gynecological examination with transvaginal US found out a mass of 43/32 mm, with vascular signal and intermediate echogenicity, located in the left ovary. The histopathological result of the biopsy was a high-grade ovarian serous carcinoma.
The patient consulted our oncology service with the result of the histopathological examination to establish the therapeutic strategy. Considering the neurological symptoms and the fact that the patient's condition worsened, we redirected the patient to the neurology service for a thorough investigation of the neurological syndrome in the context of oncological pathology.
The patient returned to the ER due to ongoing symptoms. In addition, she had severe headache with motor impairment to the upper and lower limbs, orthostatic and impossible gait, bilateral upper arm paresthesia, intolerance to light and noise, hearing loss of the right ear, severe dysarthria, diplopia and vomiting related to head mobilization. The patient was admitted to neurology department with suspected PNS based on clinical and imaging findings. The head CT result was without brain mass lesions or signs of stroke. Laboratory serum tests showed mild hepatic cytolysis syndrome (2xULN) and elevated IgG (1.3xULN). The CSF analysis results indicated pleocytosis, elevated level of glucose and proteins. The electromyogram and electroneurography revealed acute polyneuropathic asymmetric demyelination distal and proximal with secondary axonal damage. Serum antibody panel testing was positive for anti-Yo antibodies and negative for anti-Ri, anti-Hu, anti-Rcoverin, SOX1, Titin, Amphiphysin, CV2 and PNMA2.
Based on the subacute presentation of severe pancerebellar syndrome, clinical symptomatology and the paraclinical results, with ongoing ovarian carcinoma, the diagnosis of PCD with acute polyradiculoneuritis was established and the treatment with intravenous immunoglobulins (IV IgG) was decided. The therapeutic strategy was based on corticosteroid therapy and 5 days of intravenous immunoglobulins as a continuous infusion according to the next regimen: 2 g/kg of body weight with total dose calculated to 65 kg equal with 130 g administered in 5 days (day 1 total dose was 27.5 g with 25 ml/h, days 2–4 dose 25 g with 50 ml/h and day 5, 27.5 g with 100 ml/h).
After obtaining a slight improvement of the neurological symptomatology, the patient was directed to the oncology service to establish the oncological therapeutic strategy. Laboratory blood tests showed grade I normocytic normochromic anemia, minimal hepatic cytolysis syndrome (1.3xULN), CA125 tumor marker elevated (CA125 = 13,025 U/mL), and Anti-Yo antibodies detected positive.
Brain CEMRI revealed: Mild atrophy of the cerebellar hemispheres and vermis [Fig. 1a]. Signal changes (hyposignal in T2) were identified in the medial portions of the cerebellar hemispheres, slightly more pronounced in the right, suggestive for iron deposits [Fig. 1b]. Large fourth ventricle. A few scattered nonenhancing increased in T2 signal abnormalities in frontal lobes [Fig. 1c]. No acute vascular lesions or intracerebral lesions were detected.Fig. 1 Brain MRI with contrast. (a) Axial FLAIR - cerebellar atrophy. (b) Axial SWI - susceptibility artifact related to iron deposition in the median parts of the cerebellar hemispheres. (c) Sag T1-weighted + C - without cerebellar or dural enhancement.
BRCA1 and 2 germline mutations tests were performed showing BRCA1 germline mutation positive.
Considering the histopathological result correlated with the results of imaging examinations, with the presence of multiple centimetric peritoneal and retroperitoneal lymphadenopathies, we interpreted the case as being a high grade ovarian serous carcinoma stage IV FIGO. We decided to administer chemotherapy Taxol-Carboplatin(TC) protocol, weekly, after the informed consent signed by the patient was obtained.
After administration of chemotherapy 3 cycles TC Q1W regimen, Paclitaxel 80 mg/mp total dose 110 mg and Carboplatin 2 AUC total dose 200 mg, serum lab testing for CA125 was 4209 U/mL vs. 13,025 U/mL and Anti-Yo antibodies detected negative. After a good tolerance at weekly chemotherapy regimen, TC Q3W regimen was decided. After administration of 3 cycles TCQ3W Paclitaxel 175 mg/mp total dose 250 mg and Carboplatin 5 AUC total dose 500 mg, tumor marker CA125 value decreased significantly(CA125 = 247.8 U/mL), and a slightly improvement of symptomatology was achieved (disappearance of diplopia and vomiting), but neurological impairment worsened, causing the patient’s death [Fig. 2].Fig. 2 CA125 Tumor’s marker evolution.
3 Discussion
In cancer patients, the neurologic manifestations are mostly the consequence of direct tumor invasion of the nervous system or metastases. Other common causes of neurologic symptoms include infections, vascular or metabolic disorders and neurotoxicity from chemotherapy. In between 0.5 and 1% of cancer patients, an autoimmune response is developed that targets normal neuronal tissues, called PNS (Vogrig et al., 2019, Kannoth, 2012, Vedeler et al., 2006). The associated tumors express modified ectopic neuronal protein, called onconeural antigens, which may trigger the immune response against constitutional proteins at the neuronal level with the presence of highly specific antineuronal antibodies in the serum and cerebrospinal fluid (CSF). The absence of such antibodies cannot rule out the diagnosis of PCD (Dalmau and Rosenfeld, 2008). At least 12 onconeural antibodies are highly specific for PCD, including anti-Yo (PCA-1), anti-PCA2, anti-Hu, anti-Tr, anti-Ri, anti- mGluR1, anti-Zic4, anti-Ma, anti-CV2/CRMP5, anti-VGCC and anti-ANNA3 (Dalmau and Rosenfeld, 2008, Kannoth, 2012, Shams'ili et al., 2003) [Table1]. Our patient presented intense positive anti-Yo antibodies, but negative anti: -amphiphysin, -CV2, -PNMA2, -Ri, -Hu, -Recoverin, -SOX1, and -Titin serum antibodies.
From the clinical point of view, in the case of our patient, PCD has evolved over several months. In the literature, clinically, PCD is characterized by development of severe pancerebellar dysfunction. Onset is usually gradually (weeks/months), although acute forms have been rarely described (Vogrig et al., 2019).
Certain signs of degenerative neurological disease can also be identified by modern imaging techniques. Brain MRI findings appear normal early in the course of PCD but can show cerebellar atrophy in advanced cases (Vedeler et al., 2006). In our case, CT brain imaging did not found pathological points, instead the brain MRI showed cerebellar atrophy, large fourth ventricle and signal abnormalities in frontal lobes.
Given the small number of published cases worldwide of PCD associated with onconeural antibodies in solid tumors (<300 cases), an exact treatment protocol for PCD has not been established yet (Shams'ili et al., 2003, Russo et al., 2013, McKeon et al., 2011). It is known that in a small number of cases, the neurological symptoms of PCD have partially responded to administration of intravenous immunoglobulin therapy and the treatment of primary tumor, in combination with supportive therapy. There are no evidence-based recommendations available regarding the immunosuppressive therapy but it includes steroids, IV IgG, plasmapheresis, cyclophosphamide, azathioprine and rituximab (Kannoth, 2012). In the case we presented, after intravenous immunoglobulin administration in combination with corticosteroid therapy, supportive therapy and chemotherapy protocol TC, the anti-tumor therapeutic response was very good, proven by the decrease of the tumor marker. Although the presence of oncological positive response, the neurological benefit was still small, only managing to obtain a slightly neurological improvement, without stabilizing the progression of neurological degenerative disease.
Although several case reports of PCD are published, we consider the case presented by us to be interesting because a young woman who developed subacute cerebellar degeneration, a disease that requires rapid diagnosis and urgent treatment, has been shown to have the main cause an ovarian cancer. The diagnosis of PCD was supported by the presence of anti-Yo antibodies and the presence of brain MRI changes. The response to chemotherapy was favorable, which leads us to think that if the gynecological tumor had been diagnosed earlier, the neurological prognosis would have been better and the survival time longer.”
4 Conclusion
PCD, a rare pathology, should be suspected in cancer patients with degenerative neurological symptoms, especially in cases of women with gynecological cancers.
In the case we presented, PCD was the first clinical manifestation of the underlying cancer and the diagnosis was established by clinical manifestation of cerebellar ataxia, anti-Yo antibodies raised in the serum and the brain imaging with cerebellar atrophy.
Even if the diagnosis was delayed, after the clinical picture of cerebellar ataxia was quite advanced, treatment with immunoglobulins, corticosteroids and chemotherapy in association with supportive therapy brought an anti-tumor response, with slight improvement of the symptoms but with progression of degenerative neurological disease.
Informed Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
CRediT authorship contribution statement
Sandra Deac: Writing - original draft, Writing - review & editing. Mihaela Marioara Stana: Writing - review & editing. Andrei Dan Havasi: Writing - review & editing. Cainap Calin: Writing - review & editing. Anca-Raluca Popita: . Ana Maria Bordeianu: Writing - review & editing. Simona Cainap: Writing - review & editing. Madalina Bota: Writing - review & editing. Ovidiu Vasile Bochis: Supervision, Writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A Supplementary material
The following are the Supplementary data to this article:Supplementary data 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.gore.2020.100695. | CARBOPLATIN, HUMAN IMMUNOGLOBULIN G, PACLITAXEL | DrugsGivenReaction | CC BY-NC-ND | 33490355 | 18,819,734 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'No adverse event'. | Paraneoplastic cerebellar degeneration associated with anti-Yo antibodies in an ovarian cancer case: A case report.
Paraneoplastic neurologic syndromes (PNS) are a rare heterogeneous group of disorders associated with malignancy that can result in significant functional impairment. One syndrome in particular, paraneoplastic cerebellar degeneration (PCD), may be severely disabling. PCD is a rare neurological syndrome, associated with active or subclinical cancer, characterized by acute or subacute onset cerebellar ataxia due to tumor-induced autoimmunity against cerebellar antigens. Treatment of paraneoplastic syndromes is generally unsatisfactory, but early diagnosis and treatment of PCD, which includes neurological treatment, immunotherapy and oncological treatment of associated malignancy, may improve the neurological prognosis. We reported the case of a 59-year-old woman who presented PCD as the first sign of ovarian cancer. Laboratory investigations showed the presence of anti-Yo antibodies in the serum. The brain MRI revealed specific modifications for PCD. After oncological treatment, intravenous immunoglobulin therapy and corticosteroid therapy, the oncological response was satisfactory, but no improvement of the neurologic symptoms was achieved.
1 Introduction
Paraneoplastic neurologic syndromes (PNS) are a group of neurologic conditions that affect 0.5–1% of all cancer patients. Paraneoplastic cerebellar degeneration (PCD) is a rare and severely debilitating immune-mediated neurological syndrome that occurs in less than 1% of all cancer patients. PCD can be associated with any cancer, but the most commonly associated are gynecological and breast cancer, small cell lung cancer and Hodgkin lymphoma (Vogrig et al., 2019, Kannoth, 2012). To reach PCD diagnosis there is need to undergo clinical, laboratory and imagistic evaluations. Clinically, PCD is characterized by acute or subacute development of severe pancerebellar dysfunction. It is typically beginning with dizziness, nausea and gait unsteadiness progressing to ataxia, diplopia, often dysarthria, dysphagia and nystagmus (Dalmau and Rosenfeld, 2008, Vedeler et al., 2006, Mitoma et al., 2016). Serologically, multiple antibodies are highly specific for PCD, of which the most common are Anti-Yo antibodies [Table1]. Anti-Yo–mediated PCD tends to occur predominantly in women around the age of 60 and is mostly associated with gynecologic malignancy (ovary, uterus and breast). The anti-Yo antibody is the most common serological marker in PCD associated with ovarian cancer, although only 50% of these patients have positive serological findings (Kannoth, 2012, Shams'ili et al., 2003).Table1 Main autoantibodies reported in paraneoplastic cerebellar degeneration (Dalmau and Rosenfeld, 2008, Yshii et al., 2020).
Autoantibodies Incidence in PCD Main associated tumors
Anti-Yo(anti-PCA1) 38–50% Ovarian tumor
Breast cancer
Other gynecological cancers
Other adenocarcinomas
Anti-Hu 18–21% SCLC
Neuroendocrine tumors
Anti-CV2/CRMP5 13–27% SCLC 5
Thymoma
Colon cancer
Breast cancer
Anti-Ma2 5% Testicular germ cell tumors
NSCLC
NHL
Cervical cancer
Anti-Tr 14% Hodgkin disease
Anti-amphiphysin 17% Breast cancer
SCLC
Anti-Ri 12–32% Breast cancer
Gynecological cancer
SCLC
Anti-GABAbR unknown SCLC
Neuroendocrine tumor
Anti-Recoverin unknown SCLC
Breast cancer
AGNA/Anti-SOX1 43–50% Lung cancer
Anti-PCA2 unknown SCLC
Anti-GluR1 unknown SCLC
Anti-Zic4 12–29% SCLC
Anti-Titin 80% Thymoma
Early diagnosis and treatment of PCD are essential because any delay can result in progression and irreversible neurological damage (Kannoth, 2012). The PCD treatment includes immunoglobulins, corticosteroids, and chemotherapy in association with supportive therapy.
2 Case report
A 59-year-old, Caucasian, menopausal woman consulted a neurologist complaining of vertigo, dizziness, postural balance disorders, gait instability with a tendency to fall, bilateral plantar paresthesia and intermittent postural tremor of the cephalic extremity with intentional character and accentuated by emotions. Also, the patient was complaining of sad mood, insomnia, frontal-occipital headache with intermittent tension character, generalized pain in the spine and in the right abdominal flank, plus a significant weight loss of 7 kg in 2 months. Clinical onset was 4 months before presentation, accentuated in the last 2 months.
The patient’s medical history, family and social history were insignificant for oncological pathology. Regarding the physiological history, the patient had menarche at the age of 14, G7P2 and menopause at the age of 45.
During the first hospitalization in the neurology department, several investigations were performed. Biological examinations showed mild hepatic cytolysis syndrome 2xULN.
The ECG, chest X-ray and native CT brain revealed no pathological changes. Carotid Doppler US revealed mild carotid atheromatosis and the EEG indicated diffuse irritant path. An abdominal US was performed, showing several round masses of 1.7–2 cm, hypoechoic, located paraaortic, in the hepatic hilum and between the stomach and the pancreas.
The patient was directed to a gastroenterology service where several investigations were carried out, as presented below.
Abdominal CECT scan revealed multiple lymphadenopathies located peritoneal, retroperitoneal and both on the lesser and greater curvatures of the stomach (max. of 2.5 cm in size). Also, there were discovered lymphadenopathies with tendence towards confluence in the splenic and superior polar spine and one supradiaphragmatic lymphadenopathy of 2.5 cm located in the left cardiophrenic angle. An upper digestive EUS with FNA was performed, showing one subepithelial lesion covered by the normal mucosa on the posterior antral wall, hypoechoic, homogeneous, hypervascularized of 1.7 cm. There were also identified multiple lymphadenopathies hypervascularized, located in the hepatic hilum, peripancreatic and perigastric of 2–3 cm in size. Gynecological examination with transvaginal US found out a mass of 43/32 mm, with vascular signal and intermediate echogenicity, located in the left ovary. The histopathological result of the biopsy was a high-grade ovarian serous carcinoma.
The patient consulted our oncology service with the result of the histopathological examination to establish the therapeutic strategy. Considering the neurological symptoms and the fact that the patient's condition worsened, we redirected the patient to the neurology service for a thorough investigation of the neurological syndrome in the context of oncological pathology.
The patient returned to the ER due to ongoing symptoms. In addition, she had severe headache with motor impairment to the upper and lower limbs, orthostatic and impossible gait, bilateral upper arm paresthesia, intolerance to light and noise, hearing loss of the right ear, severe dysarthria, diplopia and vomiting related to head mobilization. The patient was admitted to neurology department with suspected PNS based on clinical and imaging findings. The head CT result was without brain mass lesions or signs of stroke. Laboratory serum tests showed mild hepatic cytolysis syndrome (2xULN) and elevated IgG (1.3xULN). The CSF analysis results indicated pleocytosis, elevated level of glucose and proteins. The electromyogram and electroneurography revealed acute polyneuropathic asymmetric demyelination distal and proximal with secondary axonal damage. Serum antibody panel testing was positive for anti-Yo antibodies and negative for anti-Ri, anti-Hu, anti-Rcoverin, SOX1, Titin, Amphiphysin, CV2 and PNMA2.
Based on the subacute presentation of severe pancerebellar syndrome, clinical symptomatology and the paraclinical results, with ongoing ovarian carcinoma, the diagnosis of PCD with acute polyradiculoneuritis was established and the treatment with intravenous immunoglobulins (IV IgG) was decided. The therapeutic strategy was based on corticosteroid therapy and 5 days of intravenous immunoglobulins as a continuous infusion according to the next regimen: 2 g/kg of body weight with total dose calculated to 65 kg equal with 130 g administered in 5 days (day 1 total dose was 27.5 g with 25 ml/h, days 2–4 dose 25 g with 50 ml/h and day 5, 27.5 g with 100 ml/h).
After obtaining a slight improvement of the neurological symptomatology, the patient was directed to the oncology service to establish the oncological therapeutic strategy. Laboratory blood tests showed grade I normocytic normochromic anemia, minimal hepatic cytolysis syndrome (1.3xULN), CA125 tumor marker elevated (CA125 = 13,025 U/mL), and Anti-Yo antibodies detected positive.
Brain CEMRI revealed: Mild atrophy of the cerebellar hemispheres and vermis [Fig. 1a]. Signal changes (hyposignal in T2) were identified in the medial portions of the cerebellar hemispheres, slightly more pronounced in the right, suggestive for iron deposits [Fig. 1b]. Large fourth ventricle. A few scattered nonenhancing increased in T2 signal abnormalities in frontal lobes [Fig. 1c]. No acute vascular lesions or intracerebral lesions were detected.Fig. 1 Brain MRI with contrast. (a) Axial FLAIR - cerebellar atrophy. (b) Axial SWI - susceptibility artifact related to iron deposition in the median parts of the cerebellar hemispheres. (c) Sag T1-weighted + C - without cerebellar or dural enhancement.
BRCA1 and 2 germline mutations tests were performed showing BRCA1 germline mutation positive.
Considering the histopathological result correlated with the results of imaging examinations, with the presence of multiple centimetric peritoneal and retroperitoneal lymphadenopathies, we interpreted the case as being a high grade ovarian serous carcinoma stage IV FIGO. We decided to administer chemotherapy Taxol-Carboplatin(TC) protocol, weekly, after the informed consent signed by the patient was obtained.
After administration of chemotherapy 3 cycles TC Q1W regimen, Paclitaxel 80 mg/mp total dose 110 mg and Carboplatin 2 AUC total dose 200 mg, serum lab testing for CA125 was 4209 U/mL vs. 13,025 U/mL and Anti-Yo antibodies detected negative. After a good tolerance at weekly chemotherapy regimen, TC Q3W regimen was decided. After administration of 3 cycles TCQ3W Paclitaxel 175 mg/mp total dose 250 mg and Carboplatin 5 AUC total dose 500 mg, tumor marker CA125 value decreased significantly(CA125 = 247.8 U/mL), and a slightly improvement of symptomatology was achieved (disappearance of diplopia and vomiting), but neurological impairment worsened, causing the patient’s death [Fig. 2].Fig. 2 CA125 Tumor’s marker evolution.
3 Discussion
In cancer patients, the neurologic manifestations are mostly the consequence of direct tumor invasion of the nervous system or metastases. Other common causes of neurologic symptoms include infections, vascular or metabolic disorders and neurotoxicity from chemotherapy. In between 0.5 and 1% of cancer patients, an autoimmune response is developed that targets normal neuronal tissues, called PNS (Vogrig et al., 2019, Kannoth, 2012, Vedeler et al., 2006). The associated tumors express modified ectopic neuronal protein, called onconeural antigens, which may trigger the immune response against constitutional proteins at the neuronal level with the presence of highly specific antineuronal antibodies in the serum and cerebrospinal fluid (CSF). The absence of such antibodies cannot rule out the diagnosis of PCD (Dalmau and Rosenfeld, 2008). At least 12 onconeural antibodies are highly specific for PCD, including anti-Yo (PCA-1), anti-PCA2, anti-Hu, anti-Tr, anti-Ri, anti- mGluR1, anti-Zic4, anti-Ma, anti-CV2/CRMP5, anti-VGCC and anti-ANNA3 (Dalmau and Rosenfeld, 2008, Kannoth, 2012, Shams'ili et al., 2003) [Table1]. Our patient presented intense positive anti-Yo antibodies, but negative anti: -amphiphysin, -CV2, -PNMA2, -Ri, -Hu, -Recoverin, -SOX1, and -Titin serum antibodies.
From the clinical point of view, in the case of our patient, PCD has evolved over several months. In the literature, clinically, PCD is characterized by development of severe pancerebellar dysfunction. Onset is usually gradually (weeks/months), although acute forms have been rarely described (Vogrig et al., 2019).
Certain signs of degenerative neurological disease can also be identified by modern imaging techniques. Brain MRI findings appear normal early in the course of PCD but can show cerebellar atrophy in advanced cases (Vedeler et al., 2006). In our case, CT brain imaging did not found pathological points, instead the brain MRI showed cerebellar atrophy, large fourth ventricle and signal abnormalities in frontal lobes.
Given the small number of published cases worldwide of PCD associated with onconeural antibodies in solid tumors (<300 cases), an exact treatment protocol for PCD has not been established yet (Shams'ili et al., 2003, Russo et al., 2013, McKeon et al., 2011). It is known that in a small number of cases, the neurological symptoms of PCD have partially responded to administration of intravenous immunoglobulin therapy and the treatment of primary tumor, in combination with supportive therapy. There are no evidence-based recommendations available regarding the immunosuppressive therapy but it includes steroids, IV IgG, plasmapheresis, cyclophosphamide, azathioprine and rituximab (Kannoth, 2012). In the case we presented, after intravenous immunoglobulin administration in combination with corticosteroid therapy, supportive therapy and chemotherapy protocol TC, the anti-tumor therapeutic response was very good, proven by the decrease of the tumor marker. Although the presence of oncological positive response, the neurological benefit was still small, only managing to obtain a slightly neurological improvement, without stabilizing the progression of neurological degenerative disease.
Although several case reports of PCD are published, we consider the case presented by us to be interesting because a young woman who developed subacute cerebellar degeneration, a disease that requires rapid diagnosis and urgent treatment, has been shown to have the main cause an ovarian cancer. The diagnosis of PCD was supported by the presence of anti-Yo antibodies and the presence of brain MRI changes. The response to chemotherapy was favorable, which leads us to think that if the gynecological tumor had been diagnosed earlier, the neurological prognosis would have been better and the survival time longer.”
4 Conclusion
PCD, a rare pathology, should be suspected in cancer patients with degenerative neurological symptoms, especially in cases of women with gynecological cancers.
In the case we presented, PCD was the first clinical manifestation of the underlying cancer and the diagnosis was established by clinical manifestation of cerebellar ataxia, anti-Yo antibodies raised in the serum and the brain imaging with cerebellar atrophy.
Even if the diagnosis was delayed, after the clinical picture of cerebellar ataxia was quite advanced, treatment with immunoglobulins, corticosteroids and chemotherapy in association with supportive therapy brought an anti-tumor response, with slight improvement of the symptoms but with progression of degenerative neurological disease.
Informed Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
CRediT authorship contribution statement
Sandra Deac: Writing - original draft, Writing - review & editing. Mihaela Marioara Stana: Writing - review & editing. Andrei Dan Havasi: Writing - review & editing. Cainap Calin: Writing - review & editing. Anca-Raluca Popita: . Ana Maria Bordeianu: Writing - review & editing. Simona Cainap: Writing - review & editing. Madalina Bota: Writing - review & editing. Ovidiu Vasile Bochis: Supervision, Writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A Supplementary material
The following are the Supplementary data to this article:Supplementary data 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.gore.2020.100695. | CARBOPLATIN, HUMAN IMMUNOGLOBULIN G, PACLITAXEL | DrugsGivenReaction | CC BY-NC-ND | 33490355 | 18,942,075 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Paraneoplastic cerebellar degeneration associated with anti-Yo antibodies in an ovarian cancer case: A case report.
Paraneoplastic neurologic syndromes (PNS) are a rare heterogeneous group of disorders associated with malignancy that can result in significant functional impairment. One syndrome in particular, paraneoplastic cerebellar degeneration (PCD), may be severely disabling. PCD is a rare neurological syndrome, associated with active or subclinical cancer, characterized by acute or subacute onset cerebellar ataxia due to tumor-induced autoimmunity against cerebellar antigens. Treatment of paraneoplastic syndromes is generally unsatisfactory, but early diagnosis and treatment of PCD, which includes neurological treatment, immunotherapy and oncological treatment of associated malignancy, may improve the neurological prognosis. We reported the case of a 59-year-old woman who presented PCD as the first sign of ovarian cancer. Laboratory investigations showed the presence of anti-Yo antibodies in the serum. The brain MRI revealed specific modifications for PCD. After oncological treatment, intravenous immunoglobulin therapy and corticosteroid therapy, the oncological response was satisfactory, but no improvement of the neurologic symptoms was achieved.
1 Introduction
Paraneoplastic neurologic syndromes (PNS) are a group of neurologic conditions that affect 0.5–1% of all cancer patients. Paraneoplastic cerebellar degeneration (PCD) is a rare and severely debilitating immune-mediated neurological syndrome that occurs in less than 1% of all cancer patients. PCD can be associated with any cancer, but the most commonly associated are gynecological and breast cancer, small cell lung cancer and Hodgkin lymphoma (Vogrig et al., 2019, Kannoth, 2012). To reach PCD diagnosis there is need to undergo clinical, laboratory and imagistic evaluations. Clinically, PCD is characterized by acute or subacute development of severe pancerebellar dysfunction. It is typically beginning with dizziness, nausea and gait unsteadiness progressing to ataxia, diplopia, often dysarthria, dysphagia and nystagmus (Dalmau and Rosenfeld, 2008, Vedeler et al., 2006, Mitoma et al., 2016). Serologically, multiple antibodies are highly specific for PCD, of which the most common are Anti-Yo antibodies [Table1]. Anti-Yo–mediated PCD tends to occur predominantly in women around the age of 60 and is mostly associated with gynecologic malignancy (ovary, uterus and breast). The anti-Yo antibody is the most common serological marker in PCD associated with ovarian cancer, although only 50% of these patients have positive serological findings (Kannoth, 2012, Shams'ili et al., 2003).Table1 Main autoantibodies reported in paraneoplastic cerebellar degeneration (Dalmau and Rosenfeld, 2008, Yshii et al., 2020).
Autoantibodies Incidence in PCD Main associated tumors
Anti-Yo(anti-PCA1) 38–50% Ovarian tumor
Breast cancer
Other gynecological cancers
Other adenocarcinomas
Anti-Hu 18–21% SCLC
Neuroendocrine tumors
Anti-CV2/CRMP5 13–27% SCLC 5
Thymoma
Colon cancer
Breast cancer
Anti-Ma2 5% Testicular germ cell tumors
NSCLC
NHL
Cervical cancer
Anti-Tr 14% Hodgkin disease
Anti-amphiphysin 17% Breast cancer
SCLC
Anti-Ri 12–32% Breast cancer
Gynecological cancer
SCLC
Anti-GABAbR unknown SCLC
Neuroendocrine tumor
Anti-Recoverin unknown SCLC
Breast cancer
AGNA/Anti-SOX1 43–50% Lung cancer
Anti-PCA2 unknown SCLC
Anti-GluR1 unknown SCLC
Anti-Zic4 12–29% SCLC
Anti-Titin 80% Thymoma
Early diagnosis and treatment of PCD are essential because any delay can result in progression and irreversible neurological damage (Kannoth, 2012). The PCD treatment includes immunoglobulins, corticosteroids, and chemotherapy in association with supportive therapy.
2 Case report
A 59-year-old, Caucasian, menopausal woman consulted a neurologist complaining of vertigo, dizziness, postural balance disorders, gait instability with a tendency to fall, bilateral plantar paresthesia and intermittent postural tremor of the cephalic extremity with intentional character and accentuated by emotions. Also, the patient was complaining of sad mood, insomnia, frontal-occipital headache with intermittent tension character, generalized pain in the spine and in the right abdominal flank, plus a significant weight loss of 7 kg in 2 months. Clinical onset was 4 months before presentation, accentuated in the last 2 months.
The patient’s medical history, family and social history were insignificant for oncological pathology. Regarding the physiological history, the patient had menarche at the age of 14, G7P2 and menopause at the age of 45.
During the first hospitalization in the neurology department, several investigations were performed. Biological examinations showed mild hepatic cytolysis syndrome 2xULN.
The ECG, chest X-ray and native CT brain revealed no pathological changes. Carotid Doppler US revealed mild carotid atheromatosis and the EEG indicated diffuse irritant path. An abdominal US was performed, showing several round masses of 1.7–2 cm, hypoechoic, located paraaortic, in the hepatic hilum and between the stomach and the pancreas.
The patient was directed to a gastroenterology service where several investigations were carried out, as presented below.
Abdominal CECT scan revealed multiple lymphadenopathies located peritoneal, retroperitoneal and both on the lesser and greater curvatures of the stomach (max. of 2.5 cm in size). Also, there were discovered lymphadenopathies with tendence towards confluence in the splenic and superior polar spine and one supradiaphragmatic lymphadenopathy of 2.5 cm located in the left cardiophrenic angle. An upper digestive EUS with FNA was performed, showing one subepithelial lesion covered by the normal mucosa on the posterior antral wall, hypoechoic, homogeneous, hypervascularized of 1.7 cm. There were also identified multiple lymphadenopathies hypervascularized, located in the hepatic hilum, peripancreatic and perigastric of 2–3 cm in size. Gynecological examination with transvaginal US found out a mass of 43/32 mm, with vascular signal and intermediate echogenicity, located in the left ovary. The histopathological result of the biopsy was a high-grade ovarian serous carcinoma.
The patient consulted our oncology service with the result of the histopathological examination to establish the therapeutic strategy. Considering the neurological symptoms and the fact that the patient's condition worsened, we redirected the patient to the neurology service for a thorough investigation of the neurological syndrome in the context of oncological pathology.
The patient returned to the ER due to ongoing symptoms. In addition, she had severe headache with motor impairment to the upper and lower limbs, orthostatic and impossible gait, bilateral upper arm paresthesia, intolerance to light and noise, hearing loss of the right ear, severe dysarthria, diplopia and vomiting related to head mobilization. The patient was admitted to neurology department with suspected PNS based on clinical and imaging findings. The head CT result was without brain mass lesions or signs of stroke. Laboratory serum tests showed mild hepatic cytolysis syndrome (2xULN) and elevated IgG (1.3xULN). The CSF analysis results indicated pleocytosis, elevated level of glucose and proteins. The electromyogram and electroneurography revealed acute polyneuropathic asymmetric demyelination distal and proximal with secondary axonal damage. Serum antibody panel testing was positive for anti-Yo antibodies and negative for anti-Ri, anti-Hu, anti-Rcoverin, SOX1, Titin, Amphiphysin, CV2 and PNMA2.
Based on the subacute presentation of severe pancerebellar syndrome, clinical symptomatology and the paraclinical results, with ongoing ovarian carcinoma, the diagnosis of PCD with acute polyradiculoneuritis was established and the treatment with intravenous immunoglobulins (IV IgG) was decided. The therapeutic strategy was based on corticosteroid therapy and 5 days of intravenous immunoglobulins as a continuous infusion according to the next regimen: 2 g/kg of body weight with total dose calculated to 65 kg equal with 130 g administered in 5 days (day 1 total dose was 27.5 g with 25 ml/h, days 2–4 dose 25 g with 50 ml/h and day 5, 27.5 g with 100 ml/h).
After obtaining a slight improvement of the neurological symptomatology, the patient was directed to the oncology service to establish the oncological therapeutic strategy. Laboratory blood tests showed grade I normocytic normochromic anemia, minimal hepatic cytolysis syndrome (1.3xULN), CA125 tumor marker elevated (CA125 = 13,025 U/mL), and Anti-Yo antibodies detected positive.
Brain CEMRI revealed: Mild atrophy of the cerebellar hemispheres and vermis [Fig. 1a]. Signal changes (hyposignal in T2) were identified in the medial portions of the cerebellar hemispheres, slightly more pronounced in the right, suggestive for iron deposits [Fig. 1b]. Large fourth ventricle. A few scattered nonenhancing increased in T2 signal abnormalities in frontal lobes [Fig. 1c]. No acute vascular lesions or intracerebral lesions were detected.Fig. 1 Brain MRI with contrast. (a) Axial FLAIR - cerebellar atrophy. (b) Axial SWI - susceptibility artifact related to iron deposition in the median parts of the cerebellar hemispheres. (c) Sag T1-weighted + C - without cerebellar or dural enhancement.
BRCA1 and 2 germline mutations tests were performed showing BRCA1 germline mutation positive.
Considering the histopathological result correlated with the results of imaging examinations, with the presence of multiple centimetric peritoneal and retroperitoneal lymphadenopathies, we interpreted the case as being a high grade ovarian serous carcinoma stage IV FIGO. We decided to administer chemotherapy Taxol-Carboplatin(TC) protocol, weekly, after the informed consent signed by the patient was obtained.
After administration of chemotherapy 3 cycles TC Q1W regimen, Paclitaxel 80 mg/mp total dose 110 mg and Carboplatin 2 AUC total dose 200 mg, serum lab testing for CA125 was 4209 U/mL vs. 13,025 U/mL and Anti-Yo antibodies detected negative. After a good tolerance at weekly chemotherapy regimen, TC Q3W regimen was decided. After administration of 3 cycles TCQ3W Paclitaxel 175 mg/mp total dose 250 mg and Carboplatin 5 AUC total dose 500 mg, tumor marker CA125 value decreased significantly(CA125 = 247.8 U/mL), and a slightly improvement of symptomatology was achieved (disappearance of diplopia and vomiting), but neurological impairment worsened, causing the patient’s death [Fig. 2].Fig. 2 CA125 Tumor’s marker evolution.
3 Discussion
In cancer patients, the neurologic manifestations are mostly the consequence of direct tumor invasion of the nervous system or metastases. Other common causes of neurologic symptoms include infections, vascular or metabolic disorders and neurotoxicity from chemotherapy. In between 0.5 and 1% of cancer patients, an autoimmune response is developed that targets normal neuronal tissues, called PNS (Vogrig et al., 2019, Kannoth, 2012, Vedeler et al., 2006). The associated tumors express modified ectopic neuronal protein, called onconeural antigens, which may trigger the immune response against constitutional proteins at the neuronal level with the presence of highly specific antineuronal antibodies in the serum and cerebrospinal fluid (CSF). The absence of such antibodies cannot rule out the diagnosis of PCD (Dalmau and Rosenfeld, 2008). At least 12 onconeural antibodies are highly specific for PCD, including anti-Yo (PCA-1), anti-PCA2, anti-Hu, anti-Tr, anti-Ri, anti- mGluR1, anti-Zic4, anti-Ma, anti-CV2/CRMP5, anti-VGCC and anti-ANNA3 (Dalmau and Rosenfeld, 2008, Kannoth, 2012, Shams'ili et al., 2003) [Table1]. Our patient presented intense positive anti-Yo antibodies, but negative anti: -amphiphysin, -CV2, -PNMA2, -Ri, -Hu, -Recoverin, -SOX1, and -Titin serum antibodies.
From the clinical point of view, in the case of our patient, PCD has evolved over several months. In the literature, clinically, PCD is characterized by development of severe pancerebellar dysfunction. Onset is usually gradually (weeks/months), although acute forms have been rarely described (Vogrig et al., 2019).
Certain signs of degenerative neurological disease can also be identified by modern imaging techniques. Brain MRI findings appear normal early in the course of PCD but can show cerebellar atrophy in advanced cases (Vedeler et al., 2006). In our case, CT brain imaging did not found pathological points, instead the brain MRI showed cerebellar atrophy, large fourth ventricle and signal abnormalities in frontal lobes.
Given the small number of published cases worldwide of PCD associated with onconeural antibodies in solid tumors (<300 cases), an exact treatment protocol for PCD has not been established yet (Shams'ili et al., 2003, Russo et al., 2013, McKeon et al., 2011). It is known that in a small number of cases, the neurological symptoms of PCD have partially responded to administration of intravenous immunoglobulin therapy and the treatment of primary tumor, in combination with supportive therapy. There are no evidence-based recommendations available regarding the immunosuppressive therapy but it includes steroids, IV IgG, plasmapheresis, cyclophosphamide, azathioprine and rituximab (Kannoth, 2012). In the case we presented, after intravenous immunoglobulin administration in combination with corticosteroid therapy, supportive therapy and chemotherapy protocol TC, the anti-tumor therapeutic response was very good, proven by the decrease of the tumor marker. Although the presence of oncological positive response, the neurological benefit was still small, only managing to obtain a slightly neurological improvement, without stabilizing the progression of neurological degenerative disease.
Although several case reports of PCD are published, we consider the case presented by us to be interesting because a young woman who developed subacute cerebellar degeneration, a disease that requires rapid diagnosis and urgent treatment, has been shown to have the main cause an ovarian cancer. The diagnosis of PCD was supported by the presence of anti-Yo antibodies and the presence of brain MRI changes. The response to chemotherapy was favorable, which leads us to think that if the gynecological tumor had been diagnosed earlier, the neurological prognosis would have been better and the survival time longer.”
4 Conclusion
PCD, a rare pathology, should be suspected in cancer patients with degenerative neurological symptoms, especially in cases of women with gynecological cancers.
In the case we presented, PCD was the first clinical manifestation of the underlying cancer and the diagnosis was established by clinical manifestation of cerebellar ataxia, anti-Yo antibodies raised in the serum and the brain imaging with cerebellar atrophy.
Even if the diagnosis was delayed, after the clinical picture of cerebellar ataxia was quite advanced, treatment with immunoglobulins, corticosteroids and chemotherapy in association with supportive therapy brought an anti-tumor response, with slight improvement of the symptoms but with progression of degenerative neurological disease.
Informed Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
CRediT authorship contribution statement
Sandra Deac: Writing - original draft, Writing - review & editing. Mihaela Marioara Stana: Writing - review & editing. Andrei Dan Havasi: Writing - review & editing. Cainap Calin: Writing - review & editing. Anca-Raluca Popita: . Ana Maria Bordeianu: Writing - review & editing. Simona Cainap: Writing - review & editing. Madalina Bota: Writing - review & editing. Ovidiu Vasile Bochis: Supervision, Writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A Supplementary material
The following are the Supplementary data to this article:Supplementary data 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.gore.2020.100695. | CARBOPLATIN, HUMAN IMMUNOGLOBULIN G, PACLITAXEL | DrugsGivenReaction | CC BY-NC-ND | 33490355 | 18,819,734 | 2021-02 |
What was the administration route of drug 'HUMAN IMMUNOGLOBULIN G'? | Paraneoplastic cerebellar degeneration associated with anti-Yo antibodies in an ovarian cancer case: A case report.
Paraneoplastic neurologic syndromes (PNS) are a rare heterogeneous group of disorders associated with malignancy that can result in significant functional impairment. One syndrome in particular, paraneoplastic cerebellar degeneration (PCD), may be severely disabling. PCD is a rare neurological syndrome, associated with active or subclinical cancer, characterized by acute or subacute onset cerebellar ataxia due to tumor-induced autoimmunity against cerebellar antigens. Treatment of paraneoplastic syndromes is generally unsatisfactory, but early diagnosis and treatment of PCD, which includes neurological treatment, immunotherapy and oncological treatment of associated malignancy, may improve the neurological prognosis. We reported the case of a 59-year-old woman who presented PCD as the first sign of ovarian cancer. Laboratory investigations showed the presence of anti-Yo antibodies in the serum. The brain MRI revealed specific modifications for PCD. After oncological treatment, intravenous immunoglobulin therapy and corticosteroid therapy, the oncological response was satisfactory, but no improvement of the neurologic symptoms was achieved.
1 Introduction
Paraneoplastic neurologic syndromes (PNS) are a group of neurologic conditions that affect 0.5–1% of all cancer patients. Paraneoplastic cerebellar degeneration (PCD) is a rare and severely debilitating immune-mediated neurological syndrome that occurs in less than 1% of all cancer patients. PCD can be associated with any cancer, but the most commonly associated are gynecological and breast cancer, small cell lung cancer and Hodgkin lymphoma (Vogrig et al., 2019, Kannoth, 2012). To reach PCD diagnosis there is need to undergo clinical, laboratory and imagistic evaluations. Clinically, PCD is characterized by acute or subacute development of severe pancerebellar dysfunction. It is typically beginning with dizziness, nausea and gait unsteadiness progressing to ataxia, diplopia, often dysarthria, dysphagia and nystagmus (Dalmau and Rosenfeld, 2008, Vedeler et al., 2006, Mitoma et al., 2016). Serologically, multiple antibodies are highly specific for PCD, of which the most common are Anti-Yo antibodies [Table1]. Anti-Yo–mediated PCD tends to occur predominantly in women around the age of 60 and is mostly associated with gynecologic malignancy (ovary, uterus and breast). The anti-Yo antibody is the most common serological marker in PCD associated with ovarian cancer, although only 50% of these patients have positive serological findings (Kannoth, 2012, Shams'ili et al., 2003).Table1 Main autoantibodies reported in paraneoplastic cerebellar degeneration (Dalmau and Rosenfeld, 2008, Yshii et al., 2020).
Autoantibodies Incidence in PCD Main associated tumors
Anti-Yo(anti-PCA1) 38–50% Ovarian tumor
Breast cancer
Other gynecological cancers
Other adenocarcinomas
Anti-Hu 18–21% SCLC
Neuroendocrine tumors
Anti-CV2/CRMP5 13–27% SCLC 5
Thymoma
Colon cancer
Breast cancer
Anti-Ma2 5% Testicular germ cell tumors
NSCLC
NHL
Cervical cancer
Anti-Tr 14% Hodgkin disease
Anti-amphiphysin 17% Breast cancer
SCLC
Anti-Ri 12–32% Breast cancer
Gynecological cancer
SCLC
Anti-GABAbR unknown SCLC
Neuroendocrine tumor
Anti-Recoverin unknown SCLC
Breast cancer
AGNA/Anti-SOX1 43–50% Lung cancer
Anti-PCA2 unknown SCLC
Anti-GluR1 unknown SCLC
Anti-Zic4 12–29% SCLC
Anti-Titin 80% Thymoma
Early diagnosis and treatment of PCD are essential because any delay can result in progression and irreversible neurological damage (Kannoth, 2012). The PCD treatment includes immunoglobulins, corticosteroids, and chemotherapy in association with supportive therapy.
2 Case report
A 59-year-old, Caucasian, menopausal woman consulted a neurologist complaining of vertigo, dizziness, postural balance disorders, gait instability with a tendency to fall, bilateral plantar paresthesia and intermittent postural tremor of the cephalic extremity with intentional character and accentuated by emotions. Also, the patient was complaining of sad mood, insomnia, frontal-occipital headache with intermittent tension character, generalized pain in the spine and in the right abdominal flank, plus a significant weight loss of 7 kg in 2 months. Clinical onset was 4 months before presentation, accentuated in the last 2 months.
The patient’s medical history, family and social history were insignificant for oncological pathology. Regarding the physiological history, the patient had menarche at the age of 14, G7P2 and menopause at the age of 45.
During the first hospitalization in the neurology department, several investigations were performed. Biological examinations showed mild hepatic cytolysis syndrome 2xULN.
The ECG, chest X-ray and native CT brain revealed no pathological changes. Carotid Doppler US revealed mild carotid atheromatosis and the EEG indicated diffuse irritant path. An abdominal US was performed, showing several round masses of 1.7–2 cm, hypoechoic, located paraaortic, in the hepatic hilum and between the stomach and the pancreas.
The patient was directed to a gastroenterology service where several investigations were carried out, as presented below.
Abdominal CECT scan revealed multiple lymphadenopathies located peritoneal, retroperitoneal and both on the lesser and greater curvatures of the stomach (max. of 2.5 cm in size). Also, there were discovered lymphadenopathies with tendence towards confluence in the splenic and superior polar spine and one supradiaphragmatic lymphadenopathy of 2.5 cm located in the left cardiophrenic angle. An upper digestive EUS with FNA was performed, showing one subepithelial lesion covered by the normal mucosa on the posterior antral wall, hypoechoic, homogeneous, hypervascularized of 1.7 cm. There were also identified multiple lymphadenopathies hypervascularized, located in the hepatic hilum, peripancreatic and perigastric of 2–3 cm in size. Gynecological examination with transvaginal US found out a mass of 43/32 mm, with vascular signal and intermediate echogenicity, located in the left ovary. The histopathological result of the biopsy was a high-grade ovarian serous carcinoma.
The patient consulted our oncology service with the result of the histopathological examination to establish the therapeutic strategy. Considering the neurological symptoms and the fact that the patient's condition worsened, we redirected the patient to the neurology service for a thorough investigation of the neurological syndrome in the context of oncological pathology.
The patient returned to the ER due to ongoing symptoms. In addition, she had severe headache with motor impairment to the upper and lower limbs, orthostatic and impossible gait, bilateral upper arm paresthesia, intolerance to light and noise, hearing loss of the right ear, severe dysarthria, diplopia and vomiting related to head mobilization. The patient was admitted to neurology department with suspected PNS based on clinical and imaging findings. The head CT result was without brain mass lesions or signs of stroke. Laboratory serum tests showed mild hepatic cytolysis syndrome (2xULN) and elevated IgG (1.3xULN). The CSF analysis results indicated pleocytosis, elevated level of glucose and proteins. The electromyogram and electroneurography revealed acute polyneuropathic asymmetric demyelination distal and proximal with secondary axonal damage. Serum antibody panel testing was positive for anti-Yo antibodies and negative for anti-Ri, anti-Hu, anti-Rcoverin, SOX1, Titin, Amphiphysin, CV2 and PNMA2.
Based on the subacute presentation of severe pancerebellar syndrome, clinical symptomatology and the paraclinical results, with ongoing ovarian carcinoma, the diagnosis of PCD with acute polyradiculoneuritis was established and the treatment with intravenous immunoglobulins (IV IgG) was decided. The therapeutic strategy was based on corticosteroid therapy and 5 days of intravenous immunoglobulins as a continuous infusion according to the next regimen: 2 g/kg of body weight with total dose calculated to 65 kg equal with 130 g administered in 5 days (day 1 total dose was 27.5 g with 25 ml/h, days 2–4 dose 25 g with 50 ml/h and day 5, 27.5 g with 100 ml/h).
After obtaining a slight improvement of the neurological symptomatology, the patient was directed to the oncology service to establish the oncological therapeutic strategy. Laboratory blood tests showed grade I normocytic normochromic anemia, minimal hepatic cytolysis syndrome (1.3xULN), CA125 tumor marker elevated (CA125 = 13,025 U/mL), and Anti-Yo antibodies detected positive.
Brain CEMRI revealed: Mild atrophy of the cerebellar hemispheres and vermis [Fig. 1a]. Signal changes (hyposignal in T2) were identified in the medial portions of the cerebellar hemispheres, slightly more pronounced in the right, suggestive for iron deposits [Fig. 1b]. Large fourth ventricle. A few scattered nonenhancing increased in T2 signal abnormalities in frontal lobes [Fig. 1c]. No acute vascular lesions or intracerebral lesions were detected.Fig. 1 Brain MRI with contrast. (a) Axial FLAIR - cerebellar atrophy. (b) Axial SWI - susceptibility artifact related to iron deposition in the median parts of the cerebellar hemispheres. (c) Sag T1-weighted + C - without cerebellar or dural enhancement.
BRCA1 and 2 germline mutations tests were performed showing BRCA1 germline mutation positive.
Considering the histopathological result correlated with the results of imaging examinations, with the presence of multiple centimetric peritoneal and retroperitoneal lymphadenopathies, we interpreted the case as being a high grade ovarian serous carcinoma stage IV FIGO. We decided to administer chemotherapy Taxol-Carboplatin(TC) protocol, weekly, after the informed consent signed by the patient was obtained.
After administration of chemotherapy 3 cycles TC Q1W regimen, Paclitaxel 80 mg/mp total dose 110 mg and Carboplatin 2 AUC total dose 200 mg, serum lab testing for CA125 was 4209 U/mL vs. 13,025 U/mL and Anti-Yo antibodies detected negative. After a good tolerance at weekly chemotherapy regimen, TC Q3W regimen was decided. After administration of 3 cycles TCQ3W Paclitaxel 175 mg/mp total dose 250 mg and Carboplatin 5 AUC total dose 500 mg, tumor marker CA125 value decreased significantly(CA125 = 247.8 U/mL), and a slightly improvement of symptomatology was achieved (disappearance of diplopia and vomiting), but neurological impairment worsened, causing the patient’s death [Fig. 2].Fig. 2 CA125 Tumor’s marker evolution.
3 Discussion
In cancer patients, the neurologic manifestations are mostly the consequence of direct tumor invasion of the nervous system or metastases. Other common causes of neurologic symptoms include infections, vascular or metabolic disorders and neurotoxicity from chemotherapy. In between 0.5 and 1% of cancer patients, an autoimmune response is developed that targets normal neuronal tissues, called PNS (Vogrig et al., 2019, Kannoth, 2012, Vedeler et al., 2006). The associated tumors express modified ectopic neuronal protein, called onconeural antigens, which may trigger the immune response against constitutional proteins at the neuronal level with the presence of highly specific antineuronal antibodies in the serum and cerebrospinal fluid (CSF). The absence of such antibodies cannot rule out the diagnosis of PCD (Dalmau and Rosenfeld, 2008). At least 12 onconeural antibodies are highly specific for PCD, including anti-Yo (PCA-1), anti-PCA2, anti-Hu, anti-Tr, anti-Ri, anti- mGluR1, anti-Zic4, anti-Ma, anti-CV2/CRMP5, anti-VGCC and anti-ANNA3 (Dalmau and Rosenfeld, 2008, Kannoth, 2012, Shams'ili et al., 2003) [Table1]. Our patient presented intense positive anti-Yo antibodies, but negative anti: -amphiphysin, -CV2, -PNMA2, -Ri, -Hu, -Recoverin, -SOX1, and -Titin serum antibodies.
From the clinical point of view, in the case of our patient, PCD has evolved over several months. In the literature, clinically, PCD is characterized by development of severe pancerebellar dysfunction. Onset is usually gradually (weeks/months), although acute forms have been rarely described (Vogrig et al., 2019).
Certain signs of degenerative neurological disease can also be identified by modern imaging techniques. Brain MRI findings appear normal early in the course of PCD but can show cerebellar atrophy in advanced cases (Vedeler et al., 2006). In our case, CT brain imaging did not found pathological points, instead the brain MRI showed cerebellar atrophy, large fourth ventricle and signal abnormalities in frontal lobes.
Given the small number of published cases worldwide of PCD associated with onconeural antibodies in solid tumors (<300 cases), an exact treatment protocol for PCD has not been established yet (Shams'ili et al., 2003, Russo et al., 2013, McKeon et al., 2011). It is known that in a small number of cases, the neurological symptoms of PCD have partially responded to administration of intravenous immunoglobulin therapy and the treatment of primary tumor, in combination with supportive therapy. There are no evidence-based recommendations available regarding the immunosuppressive therapy but it includes steroids, IV IgG, plasmapheresis, cyclophosphamide, azathioprine and rituximab (Kannoth, 2012). In the case we presented, after intravenous immunoglobulin administration in combination with corticosteroid therapy, supportive therapy and chemotherapy protocol TC, the anti-tumor therapeutic response was very good, proven by the decrease of the tumor marker. Although the presence of oncological positive response, the neurological benefit was still small, only managing to obtain a slightly neurological improvement, without stabilizing the progression of neurological degenerative disease.
Although several case reports of PCD are published, we consider the case presented by us to be interesting because a young woman who developed subacute cerebellar degeneration, a disease that requires rapid diagnosis and urgent treatment, has been shown to have the main cause an ovarian cancer. The diagnosis of PCD was supported by the presence of anti-Yo antibodies and the presence of brain MRI changes. The response to chemotherapy was favorable, which leads us to think that if the gynecological tumor had been diagnosed earlier, the neurological prognosis would have been better and the survival time longer.”
4 Conclusion
PCD, a rare pathology, should be suspected in cancer patients with degenerative neurological symptoms, especially in cases of women with gynecological cancers.
In the case we presented, PCD was the first clinical manifestation of the underlying cancer and the diagnosis was established by clinical manifestation of cerebellar ataxia, anti-Yo antibodies raised in the serum and the brain imaging with cerebellar atrophy.
Even if the diagnosis was delayed, after the clinical picture of cerebellar ataxia was quite advanced, treatment with immunoglobulins, corticosteroids and chemotherapy in association with supportive therapy brought an anti-tumor response, with slight improvement of the symptoms but with progression of degenerative neurological disease.
Informed Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
CRediT authorship contribution statement
Sandra Deac: Writing - original draft, Writing - review & editing. Mihaela Marioara Stana: Writing - review & editing. Andrei Dan Havasi: Writing - review & editing. Cainap Calin: Writing - review & editing. Anca-Raluca Popita: . Ana Maria Bordeianu: Writing - review & editing. Simona Cainap: Writing - review & editing. Madalina Bota: Writing - review & editing. Ovidiu Vasile Bochis: Supervision, Writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A Supplementary material
The following are the Supplementary data to this article:Supplementary data 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.gore.2020.100695. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33490355 | 18,819,734 | 2021-02 |
What was the outcome of reaction 'Condition aggravated'? | Paraneoplastic cerebellar degeneration associated with anti-Yo antibodies in an ovarian cancer case: A case report.
Paraneoplastic neurologic syndromes (PNS) are a rare heterogeneous group of disorders associated with malignancy that can result in significant functional impairment. One syndrome in particular, paraneoplastic cerebellar degeneration (PCD), may be severely disabling. PCD is a rare neurological syndrome, associated with active or subclinical cancer, characterized by acute or subacute onset cerebellar ataxia due to tumor-induced autoimmunity against cerebellar antigens. Treatment of paraneoplastic syndromes is generally unsatisfactory, but early diagnosis and treatment of PCD, which includes neurological treatment, immunotherapy and oncological treatment of associated malignancy, may improve the neurological prognosis. We reported the case of a 59-year-old woman who presented PCD as the first sign of ovarian cancer. Laboratory investigations showed the presence of anti-Yo antibodies in the serum. The brain MRI revealed specific modifications for PCD. After oncological treatment, intravenous immunoglobulin therapy and corticosteroid therapy, the oncological response was satisfactory, but no improvement of the neurologic symptoms was achieved.
1 Introduction
Paraneoplastic neurologic syndromes (PNS) are a group of neurologic conditions that affect 0.5–1% of all cancer patients. Paraneoplastic cerebellar degeneration (PCD) is a rare and severely debilitating immune-mediated neurological syndrome that occurs in less than 1% of all cancer patients. PCD can be associated with any cancer, but the most commonly associated are gynecological and breast cancer, small cell lung cancer and Hodgkin lymphoma (Vogrig et al., 2019, Kannoth, 2012). To reach PCD diagnosis there is need to undergo clinical, laboratory and imagistic evaluations. Clinically, PCD is characterized by acute or subacute development of severe pancerebellar dysfunction. It is typically beginning with dizziness, nausea and gait unsteadiness progressing to ataxia, diplopia, often dysarthria, dysphagia and nystagmus (Dalmau and Rosenfeld, 2008, Vedeler et al., 2006, Mitoma et al., 2016). Serologically, multiple antibodies are highly specific for PCD, of which the most common are Anti-Yo antibodies [Table1]. Anti-Yo–mediated PCD tends to occur predominantly in women around the age of 60 and is mostly associated with gynecologic malignancy (ovary, uterus and breast). The anti-Yo antibody is the most common serological marker in PCD associated with ovarian cancer, although only 50% of these patients have positive serological findings (Kannoth, 2012, Shams'ili et al., 2003).Table1 Main autoantibodies reported in paraneoplastic cerebellar degeneration (Dalmau and Rosenfeld, 2008, Yshii et al., 2020).
Autoantibodies Incidence in PCD Main associated tumors
Anti-Yo(anti-PCA1) 38–50% Ovarian tumor
Breast cancer
Other gynecological cancers
Other adenocarcinomas
Anti-Hu 18–21% SCLC
Neuroendocrine tumors
Anti-CV2/CRMP5 13–27% SCLC 5
Thymoma
Colon cancer
Breast cancer
Anti-Ma2 5% Testicular germ cell tumors
NSCLC
NHL
Cervical cancer
Anti-Tr 14% Hodgkin disease
Anti-amphiphysin 17% Breast cancer
SCLC
Anti-Ri 12–32% Breast cancer
Gynecological cancer
SCLC
Anti-GABAbR unknown SCLC
Neuroendocrine tumor
Anti-Recoverin unknown SCLC
Breast cancer
AGNA/Anti-SOX1 43–50% Lung cancer
Anti-PCA2 unknown SCLC
Anti-GluR1 unknown SCLC
Anti-Zic4 12–29% SCLC
Anti-Titin 80% Thymoma
Early diagnosis and treatment of PCD are essential because any delay can result in progression and irreversible neurological damage (Kannoth, 2012). The PCD treatment includes immunoglobulins, corticosteroids, and chemotherapy in association with supportive therapy.
2 Case report
A 59-year-old, Caucasian, menopausal woman consulted a neurologist complaining of vertigo, dizziness, postural balance disorders, gait instability with a tendency to fall, bilateral plantar paresthesia and intermittent postural tremor of the cephalic extremity with intentional character and accentuated by emotions. Also, the patient was complaining of sad mood, insomnia, frontal-occipital headache with intermittent tension character, generalized pain in the spine and in the right abdominal flank, plus a significant weight loss of 7 kg in 2 months. Clinical onset was 4 months before presentation, accentuated in the last 2 months.
The patient’s medical history, family and social history were insignificant for oncological pathology. Regarding the physiological history, the patient had menarche at the age of 14, G7P2 and menopause at the age of 45.
During the first hospitalization in the neurology department, several investigations were performed. Biological examinations showed mild hepatic cytolysis syndrome 2xULN.
The ECG, chest X-ray and native CT brain revealed no pathological changes. Carotid Doppler US revealed mild carotid atheromatosis and the EEG indicated diffuse irritant path. An abdominal US was performed, showing several round masses of 1.7–2 cm, hypoechoic, located paraaortic, in the hepatic hilum and between the stomach and the pancreas.
The patient was directed to a gastroenterology service where several investigations were carried out, as presented below.
Abdominal CECT scan revealed multiple lymphadenopathies located peritoneal, retroperitoneal and both on the lesser and greater curvatures of the stomach (max. of 2.5 cm in size). Also, there were discovered lymphadenopathies with tendence towards confluence in the splenic and superior polar spine and one supradiaphragmatic lymphadenopathy of 2.5 cm located in the left cardiophrenic angle. An upper digestive EUS with FNA was performed, showing one subepithelial lesion covered by the normal mucosa on the posterior antral wall, hypoechoic, homogeneous, hypervascularized of 1.7 cm. There were also identified multiple lymphadenopathies hypervascularized, located in the hepatic hilum, peripancreatic and perigastric of 2–3 cm in size. Gynecological examination with transvaginal US found out a mass of 43/32 mm, with vascular signal and intermediate echogenicity, located in the left ovary. The histopathological result of the biopsy was a high-grade ovarian serous carcinoma.
The patient consulted our oncology service with the result of the histopathological examination to establish the therapeutic strategy. Considering the neurological symptoms and the fact that the patient's condition worsened, we redirected the patient to the neurology service for a thorough investigation of the neurological syndrome in the context of oncological pathology.
The patient returned to the ER due to ongoing symptoms. In addition, she had severe headache with motor impairment to the upper and lower limbs, orthostatic and impossible gait, bilateral upper arm paresthesia, intolerance to light and noise, hearing loss of the right ear, severe dysarthria, diplopia and vomiting related to head mobilization. The patient was admitted to neurology department with suspected PNS based on clinical and imaging findings. The head CT result was without brain mass lesions or signs of stroke. Laboratory serum tests showed mild hepatic cytolysis syndrome (2xULN) and elevated IgG (1.3xULN). The CSF analysis results indicated pleocytosis, elevated level of glucose and proteins. The electromyogram and electroneurography revealed acute polyneuropathic asymmetric demyelination distal and proximal with secondary axonal damage. Serum antibody panel testing was positive for anti-Yo antibodies and negative for anti-Ri, anti-Hu, anti-Rcoverin, SOX1, Titin, Amphiphysin, CV2 and PNMA2.
Based on the subacute presentation of severe pancerebellar syndrome, clinical symptomatology and the paraclinical results, with ongoing ovarian carcinoma, the diagnosis of PCD with acute polyradiculoneuritis was established and the treatment with intravenous immunoglobulins (IV IgG) was decided. The therapeutic strategy was based on corticosteroid therapy and 5 days of intravenous immunoglobulins as a continuous infusion according to the next regimen: 2 g/kg of body weight with total dose calculated to 65 kg equal with 130 g administered in 5 days (day 1 total dose was 27.5 g with 25 ml/h, days 2–4 dose 25 g with 50 ml/h and day 5, 27.5 g with 100 ml/h).
After obtaining a slight improvement of the neurological symptomatology, the patient was directed to the oncology service to establish the oncological therapeutic strategy. Laboratory blood tests showed grade I normocytic normochromic anemia, minimal hepatic cytolysis syndrome (1.3xULN), CA125 tumor marker elevated (CA125 = 13,025 U/mL), and Anti-Yo antibodies detected positive.
Brain CEMRI revealed: Mild atrophy of the cerebellar hemispheres and vermis [Fig. 1a]. Signal changes (hyposignal in T2) were identified in the medial portions of the cerebellar hemispheres, slightly more pronounced in the right, suggestive for iron deposits [Fig. 1b]. Large fourth ventricle. A few scattered nonenhancing increased in T2 signal abnormalities in frontal lobes [Fig. 1c]. No acute vascular lesions or intracerebral lesions were detected.Fig. 1 Brain MRI with contrast. (a) Axial FLAIR - cerebellar atrophy. (b) Axial SWI - susceptibility artifact related to iron deposition in the median parts of the cerebellar hemispheres. (c) Sag T1-weighted + C - without cerebellar or dural enhancement.
BRCA1 and 2 germline mutations tests were performed showing BRCA1 germline mutation positive.
Considering the histopathological result correlated with the results of imaging examinations, with the presence of multiple centimetric peritoneal and retroperitoneal lymphadenopathies, we interpreted the case as being a high grade ovarian serous carcinoma stage IV FIGO. We decided to administer chemotherapy Taxol-Carboplatin(TC) protocol, weekly, after the informed consent signed by the patient was obtained.
After administration of chemotherapy 3 cycles TC Q1W regimen, Paclitaxel 80 mg/mp total dose 110 mg and Carboplatin 2 AUC total dose 200 mg, serum lab testing for CA125 was 4209 U/mL vs. 13,025 U/mL and Anti-Yo antibodies detected negative. After a good tolerance at weekly chemotherapy regimen, TC Q3W regimen was decided. After administration of 3 cycles TCQ3W Paclitaxel 175 mg/mp total dose 250 mg and Carboplatin 5 AUC total dose 500 mg, tumor marker CA125 value decreased significantly(CA125 = 247.8 U/mL), and a slightly improvement of symptomatology was achieved (disappearance of diplopia and vomiting), but neurological impairment worsened, causing the patient’s death [Fig. 2].Fig. 2 CA125 Tumor’s marker evolution.
3 Discussion
In cancer patients, the neurologic manifestations are mostly the consequence of direct tumor invasion of the nervous system or metastases. Other common causes of neurologic symptoms include infections, vascular or metabolic disorders and neurotoxicity from chemotherapy. In between 0.5 and 1% of cancer patients, an autoimmune response is developed that targets normal neuronal tissues, called PNS (Vogrig et al., 2019, Kannoth, 2012, Vedeler et al., 2006). The associated tumors express modified ectopic neuronal protein, called onconeural antigens, which may trigger the immune response against constitutional proteins at the neuronal level with the presence of highly specific antineuronal antibodies in the serum and cerebrospinal fluid (CSF). The absence of such antibodies cannot rule out the diagnosis of PCD (Dalmau and Rosenfeld, 2008). At least 12 onconeural antibodies are highly specific for PCD, including anti-Yo (PCA-1), anti-PCA2, anti-Hu, anti-Tr, anti-Ri, anti- mGluR1, anti-Zic4, anti-Ma, anti-CV2/CRMP5, anti-VGCC and anti-ANNA3 (Dalmau and Rosenfeld, 2008, Kannoth, 2012, Shams'ili et al., 2003) [Table1]. Our patient presented intense positive anti-Yo antibodies, but negative anti: -amphiphysin, -CV2, -PNMA2, -Ri, -Hu, -Recoverin, -SOX1, and -Titin serum antibodies.
From the clinical point of view, in the case of our patient, PCD has evolved over several months. In the literature, clinically, PCD is characterized by development of severe pancerebellar dysfunction. Onset is usually gradually (weeks/months), although acute forms have been rarely described (Vogrig et al., 2019).
Certain signs of degenerative neurological disease can also be identified by modern imaging techniques. Brain MRI findings appear normal early in the course of PCD but can show cerebellar atrophy in advanced cases (Vedeler et al., 2006). In our case, CT brain imaging did not found pathological points, instead the brain MRI showed cerebellar atrophy, large fourth ventricle and signal abnormalities in frontal lobes.
Given the small number of published cases worldwide of PCD associated with onconeural antibodies in solid tumors (<300 cases), an exact treatment protocol for PCD has not been established yet (Shams'ili et al., 2003, Russo et al., 2013, McKeon et al., 2011). It is known that in a small number of cases, the neurological symptoms of PCD have partially responded to administration of intravenous immunoglobulin therapy and the treatment of primary tumor, in combination with supportive therapy. There are no evidence-based recommendations available regarding the immunosuppressive therapy but it includes steroids, IV IgG, plasmapheresis, cyclophosphamide, azathioprine and rituximab (Kannoth, 2012). In the case we presented, after intravenous immunoglobulin administration in combination with corticosteroid therapy, supportive therapy and chemotherapy protocol TC, the anti-tumor therapeutic response was very good, proven by the decrease of the tumor marker. Although the presence of oncological positive response, the neurological benefit was still small, only managing to obtain a slightly neurological improvement, without stabilizing the progression of neurological degenerative disease.
Although several case reports of PCD are published, we consider the case presented by us to be interesting because a young woman who developed subacute cerebellar degeneration, a disease that requires rapid diagnosis and urgent treatment, has been shown to have the main cause an ovarian cancer. The diagnosis of PCD was supported by the presence of anti-Yo antibodies and the presence of brain MRI changes. The response to chemotherapy was favorable, which leads us to think that if the gynecological tumor had been diagnosed earlier, the neurological prognosis would have been better and the survival time longer.”
4 Conclusion
PCD, a rare pathology, should be suspected in cancer patients with degenerative neurological symptoms, especially in cases of women with gynecological cancers.
In the case we presented, PCD was the first clinical manifestation of the underlying cancer and the diagnosis was established by clinical manifestation of cerebellar ataxia, anti-Yo antibodies raised in the serum and the brain imaging with cerebellar atrophy.
Even if the diagnosis was delayed, after the clinical picture of cerebellar ataxia was quite advanced, treatment with immunoglobulins, corticosteroids and chemotherapy in association with supportive therapy brought an anti-tumor response, with slight improvement of the symptoms but with progression of degenerative neurological disease.
Informed Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
CRediT authorship contribution statement
Sandra Deac: Writing - original draft, Writing - review & editing. Mihaela Marioara Stana: Writing - review & editing. Andrei Dan Havasi: Writing - review & editing. Cainap Calin: Writing - review & editing. Anca-Raluca Popita: . Ana Maria Bordeianu: Writing - review & editing. Simona Cainap: Writing - review & editing. Madalina Bota: Writing - review & editing. Ovidiu Vasile Bochis: Supervision, Writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A Supplementary material
The following are the Supplementary data to this article:Supplementary data 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.gore.2020.100695. | Fatal | ReactionOutcome | CC BY-NC-ND | 33490355 | 19,016,875 | 2021-02 |
What was the outcome of reaction 'Drug ineffective for unapproved indication'? | Paraneoplastic cerebellar degeneration associated with anti-Yo antibodies in an ovarian cancer case: A case report.
Paraneoplastic neurologic syndromes (PNS) are a rare heterogeneous group of disorders associated with malignancy that can result in significant functional impairment. One syndrome in particular, paraneoplastic cerebellar degeneration (PCD), may be severely disabling. PCD is a rare neurological syndrome, associated with active or subclinical cancer, characterized by acute or subacute onset cerebellar ataxia due to tumor-induced autoimmunity against cerebellar antigens. Treatment of paraneoplastic syndromes is generally unsatisfactory, but early diagnosis and treatment of PCD, which includes neurological treatment, immunotherapy and oncological treatment of associated malignancy, may improve the neurological prognosis. We reported the case of a 59-year-old woman who presented PCD as the first sign of ovarian cancer. Laboratory investigations showed the presence of anti-Yo antibodies in the serum. The brain MRI revealed specific modifications for PCD. After oncological treatment, intravenous immunoglobulin therapy and corticosteroid therapy, the oncological response was satisfactory, but no improvement of the neurologic symptoms was achieved.
1 Introduction
Paraneoplastic neurologic syndromes (PNS) are a group of neurologic conditions that affect 0.5–1% of all cancer patients. Paraneoplastic cerebellar degeneration (PCD) is a rare and severely debilitating immune-mediated neurological syndrome that occurs in less than 1% of all cancer patients. PCD can be associated with any cancer, but the most commonly associated are gynecological and breast cancer, small cell lung cancer and Hodgkin lymphoma (Vogrig et al., 2019, Kannoth, 2012). To reach PCD diagnosis there is need to undergo clinical, laboratory and imagistic evaluations. Clinically, PCD is characterized by acute or subacute development of severe pancerebellar dysfunction. It is typically beginning with dizziness, nausea and gait unsteadiness progressing to ataxia, diplopia, often dysarthria, dysphagia and nystagmus (Dalmau and Rosenfeld, 2008, Vedeler et al., 2006, Mitoma et al., 2016). Serologically, multiple antibodies are highly specific for PCD, of which the most common are Anti-Yo antibodies [Table1]. Anti-Yo–mediated PCD tends to occur predominantly in women around the age of 60 and is mostly associated with gynecologic malignancy (ovary, uterus and breast). The anti-Yo antibody is the most common serological marker in PCD associated with ovarian cancer, although only 50% of these patients have positive serological findings (Kannoth, 2012, Shams'ili et al., 2003).Table1 Main autoantibodies reported in paraneoplastic cerebellar degeneration (Dalmau and Rosenfeld, 2008, Yshii et al., 2020).
Autoantibodies Incidence in PCD Main associated tumors
Anti-Yo(anti-PCA1) 38–50% Ovarian tumor
Breast cancer
Other gynecological cancers
Other adenocarcinomas
Anti-Hu 18–21% SCLC
Neuroendocrine tumors
Anti-CV2/CRMP5 13–27% SCLC 5
Thymoma
Colon cancer
Breast cancer
Anti-Ma2 5% Testicular germ cell tumors
NSCLC
NHL
Cervical cancer
Anti-Tr 14% Hodgkin disease
Anti-amphiphysin 17% Breast cancer
SCLC
Anti-Ri 12–32% Breast cancer
Gynecological cancer
SCLC
Anti-GABAbR unknown SCLC
Neuroendocrine tumor
Anti-Recoverin unknown SCLC
Breast cancer
AGNA/Anti-SOX1 43–50% Lung cancer
Anti-PCA2 unknown SCLC
Anti-GluR1 unknown SCLC
Anti-Zic4 12–29% SCLC
Anti-Titin 80% Thymoma
Early diagnosis and treatment of PCD are essential because any delay can result in progression and irreversible neurological damage (Kannoth, 2012). The PCD treatment includes immunoglobulins, corticosteroids, and chemotherapy in association with supportive therapy.
2 Case report
A 59-year-old, Caucasian, menopausal woman consulted a neurologist complaining of vertigo, dizziness, postural balance disorders, gait instability with a tendency to fall, bilateral plantar paresthesia and intermittent postural tremor of the cephalic extremity with intentional character and accentuated by emotions. Also, the patient was complaining of sad mood, insomnia, frontal-occipital headache with intermittent tension character, generalized pain in the spine and in the right abdominal flank, plus a significant weight loss of 7 kg in 2 months. Clinical onset was 4 months before presentation, accentuated in the last 2 months.
The patient’s medical history, family and social history were insignificant for oncological pathology. Regarding the physiological history, the patient had menarche at the age of 14, G7P2 and menopause at the age of 45.
During the first hospitalization in the neurology department, several investigations were performed. Biological examinations showed mild hepatic cytolysis syndrome 2xULN.
The ECG, chest X-ray and native CT brain revealed no pathological changes. Carotid Doppler US revealed mild carotid atheromatosis and the EEG indicated diffuse irritant path. An abdominal US was performed, showing several round masses of 1.7–2 cm, hypoechoic, located paraaortic, in the hepatic hilum and between the stomach and the pancreas.
The patient was directed to a gastroenterology service where several investigations were carried out, as presented below.
Abdominal CECT scan revealed multiple lymphadenopathies located peritoneal, retroperitoneal and both on the lesser and greater curvatures of the stomach (max. of 2.5 cm in size). Also, there were discovered lymphadenopathies with tendence towards confluence in the splenic and superior polar spine and one supradiaphragmatic lymphadenopathy of 2.5 cm located in the left cardiophrenic angle. An upper digestive EUS with FNA was performed, showing one subepithelial lesion covered by the normal mucosa on the posterior antral wall, hypoechoic, homogeneous, hypervascularized of 1.7 cm. There were also identified multiple lymphadenopathies hypervascularized, located in the hepatic hilum, peripancreatic and perigastric of 2–3 cm in size. Gynecological examination with transvaginal US found out a mass of 43/32 mm, with vascular signal and intermediate echogenicity, located in the left ovary. The histopathological result of the biopsy was a high-grade ovarian serous carcinoma.
The patient consulted our oncology service with the result of the histopathological examination to establish the therapeutic strategy. Considering the neurological symptoms and the fact that the patient's condition worsened, we redirected the patient to the neurology service for a thorough investigation of the neurological syndrome in the context of oncological pathology.
The patient returned to the ER due to ongoing symptoms. In addition, she had severe headache with motor impairment to the upper and lower limbs, orthostatic and impossible gait, bilateral upper arm paresthesia, intolerance to light and noise, hearing loss of the right ear, severe dysarthria, diplopia and vomiting related to head mobilization. The patient was admitted to neurology department with suspected PNS based on clinical and imaging findings. The head CT result was without brain mass lesions or signs of stroke. Laboratory serum tests showed mild hepatic cytolysis syndrome (2xULN) and elevated IgG (1.3xULN). The CSF analysis results indicated pleocytosis, elevated level of glucose and proteins. The electromyogram and electroneurography revealed acute polyneuropathic asymmetric demyelination distal and proximal with secondary axonal damage. Serum antibody panel testing was positive for anti-Yo antibodies and negative for anti-Ri, anti-Hu, anti-Rcoverin, SOX1, Titin, Amphiphysin, CV2 and PNMA2.
Based on the subacute presentation of severe pancerebellar syndrome, clinical symptomatology and the paraclinical results, with ongoing ovarian carcinoma, the diagnosis of PCD with acute polyradiculoneuritis was established and the treatment with intravenous immunoglobulins (IV IgG) was decided. The therapeutic strategy was based on corticosteroid therapy and 5 days of intravenous immunoglobulins as a continuous infusion according to the next regimen: 2 g/kg of body weight with total dose calculated to 65 kg equal with 130 g administered in 5 days (day 1 total dose was 27.5 g with 25 ml/h, days 2–4 dose 25 g with 50 ml/h and day 5, 27.5 g with 100 ml/h).
After obtaining a slight improvement of the neurological symptomatology, the patient was directed to the oncology service to establish the oncological therapeutic strategy. Laboratory blood tests showed grade I normocytic normochromic anemia, minimal hepatic cytolysis syndrome (1.3xULN), CA125 tumor marker elevated (CA125 = 13,025 U/mL), and Anti-Yo antibodies detected positive.
Brain CEMRI revealed: Mild atrophy of the cerebellar hemispheres and vermis [Fig. 1a]. Signal changes (hyposignal in T2) were identified in the medial portions of the cerebellar hemispheres, slightly more pronounced in the right, suggestive for iron deposits [Fig. 1b]. Large fourth ventricle. A few scattered nonenhancing increased in T2 signal abnormalities in frontal lobes [Fig. 1c]. No acute vascular lesions or intracerebral lesions were detected.Fig. 1 Brain MRI with contrast. (a) Axial FLAIR - cerebellar atrophy. (b) Axial SWI - susceptibility artifact related to iron deposition in the median parts of the cerebellar hemispheres. (c) Sag T1-weighted + C - without cerebellar or dural enhancement.
BRCA1 and 2 germline mutations tests were performed showing BRCA1 germline mutation positive.
Considering the histopathological result correlated with the results of imaging examinations, with the presence of multiple centimetric peritoneal and retroperitoneal lymphadenopathies, we interpreted the case as being a high grade ovarian serous carcinoma stage IV FIGO. We decided to administer chemotherapy Taxol-Carboplatin(TC) protocol, weekly, after the informed consent signed by the patient was obtained.
After administration of chemotherapy 3 cycles TC Q1W regimen, Paclitaxel 80 mg/mp total dose 110 mg and Carboplatin 2 AUC total dose 200 mg, serum lab testing for CA125 was 4209 U/mL vs. 13,025 U/mL and Anti-Yo antibodies detected negative. After a good tolerance at weekly chemotherapy regimen, TC Q3W regimen was decided. After administration of 3 cycles TCQ3W Paclitaxel 175 mg/mp total dose 250 mg and Carboplatin 5 AUC total dose 500 mg, tumor marker CA125 value decreased significantly(CA125 = 247.8 U/mL), and a slightly improvement of symptomatology was achieved (disappearance of diplopia and vomiting), but neurological impairment worsened, causing the patient’s death [Fig. 2].Fig. 2 CA125 Tumor’s marker evolution.
3 Discussion
In cancer patients, the neurologic manifestations are mostly the consequence of direct tumor invasion of the nervous system or metastases. Other common causes of neurologic symptoms include infections, vascular or metabolic disorders and neurotoxicity from chemotherapy. In between 0.5 and 1% of cancer patients, an autoimmune response is developed that targets normal neuronal tissues, called PNS (Vogrig et al., 2019, Kannoth, 2012, Vedeler et al., 2006). The associated tumors express modified ectopic neuronal protein, called onconeural antigens, which may trigger the immune response against constitutional proteins at the neuronal level with the presence of highly specific antineuronal antibodies in the serum and cerebrospinal fluid (CSF). The absence of such antibodies cannot rule out the diagnosis of PCD (Dalmau and Rosenfeld, 2008). At least 12 onconeural antibodies are highly specific for PCD, including anti-Yo (PCA-1), anti-PCA2, anti-Hu, anti-Tr, anti-Ri, anti- mGluR1, anti-Zic4, anti-Ma, anti-CV2/CRMP5, anti-VGCC and anti-ANNA3 (Dalmau and Rosenfeld, 2008, Kannoth, 2012, Shams'ili et al., 2003) [Table1]. Our patient presented intense positive anti-Yo antibodies, but negative anti: -amphiphysin, -CV2, -PNMA2, -Ri, -Hu, -Recoverin, -SOX1, and -Titin serum antibodies.
From the clinical point of view, in the case of our patient, PCD has evolved over several months. In the literature, clinically, PCD is characterized by development of severe pancerebellar dysfunction. Onset is usually gradually (weeks/months), although acute forms have been rarely described (Vogrig et al., 2019).
Certain signs of degenerative neurological disease can also be identified by modern imaging techniques. Brain MRI findings appear normal early in the course of PCD but can show cerebellar atrophy in advanced cases (Vedeler et al., 2006). In our case, CT brain imaging did not found pathological points, instead the brain MRI showed cerebellar atrophy, large fourth ventricle and signal abnormalities in frontal lobes.
Given the small number of published cases worldwide of PCD associated with onconeural antibodies in solid tumors (<300 cases), an exact treatment protocol for PCD has not been established yet (Shams'ili et al., 2003, Russo et al., 2013, McKeon et al., 2011). It is known that in a small number of cases, the neurological symptoms of PCD have partially responded to administration of intravenous immunoglobulin therapy and the treatment of primary tumor, in combination with supportive therapy. There are no evidence-based recommendations available regarding the immunosuppressive therapy but it includes steroids, IV IgG, plasmapheresis, cyclophosphamide, azathioprine and rituximab (Kannoth, 2012). In the case we presented, after intravenous immunoglobulin administration in combination with corticosteroid therapy, supportive therapy and chemotherapy protocol TC, the anti-tumor therapeutic response was very good, proven by the decrease of the tumor marker. Although the presence of oncological positive response, the neurological benefit was still small, only managing to obtain a slightly neurological improvement, without stabilizing the progression of neurological degenerative disease.
Although several case reports of PCD are published, we consider the case presented by us to be interesting because a young woman who developed subacute cerebellar degeneration, a disease that requires rapid diagnosis and urgent treatment, has been shown to have the main cause an ovarian cancer. The diagnosis of PCD was supported by the presence of anti-Yo antibodies and the presence of brain MRI changes. The response to chemotherapy was favorable, which leads us to think that if the gynecological tumor had been diagnosed earlier, the neurological prognosis would have been better and the survival time longer.”
4 Conclusion
PCD, a rare pathology, should be suspected in cancer patients with degenerative neurological symptoms, especially in cases of women with gynecological cancers.
In the case we presented, PCD was the first clinical manifestation of the underlying cancer and the diagnosis was established by clinical manifestation of cerebellar ataxia, anti-Yo antibodies raised in the serum and the brain imaging with cerebellar atrophy.
Even if the diagnosis was delayed, after the clinical picture of cerebellar ataxia was quite advanced, treatment with immunoglobulins, corticosteroids and chemotherapy in association with supportive therapy brought an anti-tumor response, with slight improvement of the symptoms but with progression of degenerative neurological disease.
Informed Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
CRediT authorship contribution statement
Sandra Deac: Writing - original draft, Writing - review & editing. Mihaela Marioara Stana: Writing - review & editing. Andrei Dan Havasi: Writing - review & editing. Cainap Calin: Writing - review & editing. Anca-Raluca Popita: . Ana Maria Bordeianu: Writing - review & editing. Simona Cainap: Writing - review & editing. Madalina Bota: Writing - review & editing. Ovidiu Vasile Bochis: Supervision, Writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A Supplementary material
The following are the Supplementary data to this article:Supplementary data 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.gore.2020.100695. | Fatal | ReactionOutcome | CC BY-NC-ND | 33490355 | 18,819,734 | 2021-02 |
What was the outcome of reaction 'Off label use'? | Paraneoplastic cerebellar degeneration associated with anti-Yo antibodies in an ovarian cancer case: A case report.
Paraneoplastic neurologic syndromes (PNS) are a rare heterogeneous group of disorders associated with malignancy that can result in significant functional impairment. One syndrome in particular, paraneoplastic cerebellar degeneration (PCD), may be severely disabling. PCD is a rare neurological syndrome, associated with active or subclinical cancer, characterized by acute or subacute onset cerebellar ataxia due to tumor-induced autoimmunity against cerebellar antigens. Treatment of paraneoplastic syndromes is generally unsatisfactory, but early diagnosis and treatment of PCD, which includes neurological treatment, immunotherapy and oncological treatment of associated malignancy, may improve the neurological prognosis. We reported the case of a 59-year-old woman who presented PCD as the first sign of ovarian cancer. Laboratory investigations showed the presence of anti-Yo antibodies in the serum. The brain MRI revealed specific modifications for PCD. After oncological treatment, intravenous immunoglobulin therapy and corticosteroid therapy, the oncological response was satisfactory, but no improvement of the neurologic symptoms was achieved.
1 Introduction
Paraneoplastic neurologic syndromes (PNS) are a group of neurologic conditions that affect 0.5–1% of all cancer patients. Paraneoplastic cerebellar degeneration (PCD) is a rare and severely debilitating immune-mediated neurological syndrome that occurs in less than 1% of all cancer patients. PCD can be associated with any cancer, but the most commonly associated are gynecological and breast cancer, small cell lung cancer and Hodgkin lymphoma (Vogrig et al., 2019, Kannoth, 2012). To reach PCD diagnosis there is need to undergo clinical, laboratory and imagistic evaluations. Clinically, PCD is characterized by acute or subacute development of severe pancerebellar dysfunction. It is typically beginning with dizziness, nausea and gait unsteadiness progressing to ataxia, diplopia, often dysarthria, dysphagia and nystagmus (Dalmau and Rosenfeld, 2008, Vedeler et al., 2006, Mitoma et al., 2016). Serologically, multiple antibodies are highly specific for PCD, of which the most common are Anti-Yo antibodies [Table1]. Anti-Yo–mediated PCD tends to occur predominantly in women around the age of 60 and is mostly associated with gynecologic malignancy (ovary, uterus and breast). The anti-Yo antibody is the most common serological marker in PCD associated with ovarian cancer, although only 50% of these patients have positive serological findings (Kannoth, 2012, Shams'ili et al., 2003).Table1 Main autoantibodies reported in paraneoplastic cerebellar degeneration (Dalmau and Rosenfeld, 2008, Yshii et al., 2020).
Autoantibodies Incidence in PCD Main associated tumors
Anti-Yo(anti-PCA1) 38–50% Ovarian tumor
Breast cancer
Other gynecological cancers
Other adenocarcinomas
Anti-Hu 18–21% SCLC
Neuroendocrine tumors
Anti-CV2/CRMP5 13–27% SCLC 5
Thymoma
Colon cancer
Breast cancer
Anti-Ma2 5% Testicular germ cell tumors
NSCLC
NHL
Cervical cancer
Anti-Tr 14% Hodgkin disease
Anti-amphiphysin 17% Breast cancer
SCLC
Anti-Ri 12–32% Breast cancer
Gynecological cancer
SCLC
Anti-GABAbR unknown SCLC
Neuroendocrine tumor
Anti-Recoverin unknown SCLC
Breast cancer
AGNA/Anti-SOX1 43–50% Lung cancer
Anti-PCA2 unknown SCLC
Anti-GluR1 unknown SCLC
Anti-Zic4 12–29% SCLC
Anti-Titin 80% Thymoma
Early diagnosis and treatment of PCD are essential because any delay can result in progression and irreversible neurological damage (Kannoth, 2012). The PCD treatment includes immunoglobulins, corticosteroids, and chemotherapy in association with supportive therapy.
2 Case report
A 59-year-old, Caucasian, menopausal woman consulted a neurologist complaining of vertigo, dizziness, postural balance disorders, gait instability with a tendency to fall, bilateral plantar paresthesia and intermittent postural tremor of the cephalic extremity with intentional character and accentuated by emotions. Also, the patient was complaining of sad mood, insomnia, frontal-occipital headache with intermittent tension character, generalized pain in the spine and in the right abdominal flank, plus a significant weight loss of 7 kg in 2 months. Clinical onset was 4 months before presentation, accentuated in the last 2 months.
The patient’s medical history, family and social history were insignificant for oncological pathology. Regarding the physiological history, the patient had menarche at the age of 14, G7P2 and menopause at the age of 45.
During the first hospitalization in the neurology department, several investigations were performed. Biological examinations showed mild hepatic cytolysis syndrome 2xULN.
The ECG, chest X-ray and native CT brain revealed no pathological changes. Carotid Doppler US revealed mild carotid atheromatosis and the EEG indicated diffuse irritant path. An abdominal US was performed, showing several round masses of 1.7–2 cm, hypoechoic, located paraaortic, in the hepatic hilum and between the stomach and the pancreas.
The patient was directed to a gastroenterology service where several investigations were carried out, as presented below.
Abdominal CECT scan revealed multiple lymphadenopathies located peritoneal, retroperitoneal and both on the lesser and greater curvatures of the stomach (max. of 2.5 cm in size). Also, there were discovered lymphadenopathies with tendence towards confluence in the splenic and superior polar spine and one supradiaphragmatic lymphadenopathy of 2.5 cm located in the left cardiophrenic angle. An upper digestive EUS with FNA was performed, showing one subepithelial lesion covered by the normal mucosa on the posterior antral wall, hypoechoic, homogeneous, hypervascularized of 1.7 cm. There were also identified multiple lymphadenopathies hypervascularized, located in the hepatic hilum, peripancreatic and perigastric of 2–3 cm in size. Gynecological examination with transvaginal US found out a mass of 43/32 mm, with vascular signal and intermediate echogenicity, located in the left ovary. The histopathological result of the biopsy was a high-grade ovarian serous carcinoma.
The patient consulted our oncology service with the result of the histopathological examination to establish the therapeutic strategy. Considering the neurological symptoms and the fact that the patient's condition worsened, we redirected the patient to the neurology service for a thorough investigation of the neurological syndrome in the context of oncological pathology.
The patient returned to the ER due to ongoing symptoms. In addition, she had severe headache with motor impairment to the upper and lower limbs, orthostatic and impossible gait, bilateral upper arm paresthesia, intolerance to light and noise, hearing loss of the right ear, severe dysarthria, diplopia and vomiting related to head mobilization. The patient was admitted to neurology department with suspected PNS based on clinical and imaging findings. The head CT result was without brain mass lesions or signs of stroke. Laboratory serum tests showed mild hepatic cytolysis syndrome (2xULN) and elevated IgG (1.3xULN). The CSF analysis results indicated pleocytosis, elevated level of glucose and proteins. The electromyogram and electroneurography revealed acute polyneuropathic asymmetric demyelination distal and proximal with secondary axonal damage. Serum antibody panel testing was positive for anti-Yo antibodies and negative for anti-Ri, anti-Hu, anti-Rcoverin, SOX1, Titin, Amphiphysin, CV2 and PNMA2.
Based on the subacute presentation of severe pancerebellar syndrome, clinical symptomatology and the paraclinical results, with ongoing ovarian carcinoma, the diagnosis of PCD with acute polyradiculoneuritis was established and the treatment with intravenous immunoglobulins (IV IgG) was decided. The therapeutic strategy was based on corticosteroid therapy and 5 days of intravenous immunoglobulins as a continuous infusion according to the next regimen: 2 g/kg of body weight with total dose calculated to 65 kg equal with 130 g administered in 5 days (day 1 total dose was 27.5 g with 25 ml/h, days 2–4 dose 25 g with 50 ml/h and day 5, 27.5 g with 100 ml/h).
After obtaining a slight improvement of the neurological symptomatology, the patient was directed to the oncology service to establish the oncological therapeutic strategy. Laboratory blood tests showed grade I normocytic normochromic anemia, minimal hepatic cytolysis syndrome (1.3xULN), CA125 tumor marker elevated (CA125 = 13,025 U/mL), and Anti-Yo antibodies detected positive.
Brain CEMRI revealed: Mild atrophy of the cerebellar hemispheres and vermis [Fig. 1a]. Signal changes (hyposignal in T2) were identified in the medial portions of the cerebellar hemispheres, slightly more pronounced in the right, suggestive for iron deposits [Fig. 1b]. Large fourth ventricle. A few scattered nonenhancing increased in T2 signal abnormalities in frontal lobes [Fig. 1c]. No acute vascular lesions or intracerebral lesions were detected.Fig. 1 Brain MRI with contrast. (a) Axial FLAIR - cerebellar atrophy. (b) Axial SWI - susceptibility artifact related to iron deposition in the median parts of the cerebellar hemispheres. (c) Sag T1-weighted + C - without cerebellar or dural enhancement.
BRCA1 and 2 germline mutations tests were performed showing BRCA1 germline mutation positive.
Considering the histopathological result correlated with the results of imaging examinations, with the presence of multiple centimetric peritoneal and retroperitoneal lymphadenopathies, we interpreted the case as being a high grade ovarian serous carcinoma stage IV FIGO. We decided to administer chemotherapy Taxol-Carboplatin(TC) protocol, weekly, after the informed consent signed by the patient was obtained.
After administration of chemotherapy 3 cycles TC Q1W regimen, Paclitaxel 80 mg/mp total dose 110 mg and Carboplatin 2 AUC total dose 200 mg, serum lab testing for CA125 was 4209 U/mL vs. 13,025 U/mL and Anti-Yo antibodies detected negative. After a good tolerance at weekly chemotherapy regimen, TC Q3W regimen was decided. After administration of 3 cycles TCQ3W Paclitaxel 175 mg/mp total dose 250 mg and Carboplatin 5 AUC total dose 500 mg, tumor marker CA125 value decreased significantly(CA125 = 247.8 U/mL), and a slightly improvement of symptomatology was achieved (disappearance of diplopia and vomiting), but neurological impairment worsened, causing the patient’s death [Fig. 2].Fig. 2 CA125 Tumor’s marker evolution.
3 Discussion
In cancer patients, the neurologic manifestations are mostly the consequence of direct tumor invasion of the nervous system or metastases. Other common causes of neurologic symptoms include infections, vascular or metabolic disorders and neurotoxicity from chemotherapy. In between 0.5 and 1% of cancer patients, an autoimmune response is developed that targets normal neuronal tissues, called PNS (Vogrig et al., 2019, Kannoth, 2012, Vedeler et al., 2006). The associated tumors express modified ectopic neuronal protein, called onconeural antigens, which may trigger the immune response against constitutional proteins at the neuronal level with the presence of highly specific antineuronal antibodies in the serum and cerebrospinal fluid (CSF). The absence of such antibodies cannot rule out the diagnosis of PCD (Dalmau and Rosenfeld, 2008). At least 12 onconeural antibodies are highly specific for PCD, including anti-Yo (PCA-1), anti-PCA2, anti-Hu, anti-Tr, anti-Ri, anti- mGluR1, anti-Zic4, anti-Ma, anti-CV2/CRMP5, anti-VGCC and anti-ANNA3 (Dalmau and Rosenfeld, 2008, Kannoth, 2012, Shams'ili et al., 2003) [Table1]. Our patient presented intense positive anti-Yo antibodies, but negative anti: -amphiphysin, -CV2, -PNMA2, -Ri, -Hu, -Recoverin, -SOX1, and -Titin serum antibodies.
From the clinical point of view, in the case of our patient, PCD has evolved over several months. In the literature, clinically, PCD is characterized by development of severe pancerebellar dysfunction. Onset is usually gradually (weeks/months), although acute forms have been rarely described (Vogrig et al., 2019).
Certain signs of degenerative neurological disease can also be identified by modern imaging techniques. Brain MRI findings appear normal early in the course of PCD but can show cerebellar atrophy in advanced cases (Vedeler et al., 2006). In our case, CT brain imaging did not found pathological points, instead the brain MRI showed cerebellar atrophy, large fourth ventricle and signal abnormalities in frontal lobes.
Given the small number of published cases worldwide of PCD associated with onconeural antibodies in solid tumors (<300 cases), an exact treatment protocol for PCD has not been established yet (Shams'ili et al., 2003, Russo et al., 2013, McKeon et al., 2011). It is known that in a small number of cases, the neurological symptoms of PCD have partially responded to administration of intravenous immunoglobulin therapy and the treatment of primary tumor, in combination with supportive therapy. There are no evidence-based recommendations available regarding the immunosuppressive therapy but it includes steroids, IV IgG, plasmapheresis, cyclophosphamide, azathioprine and rituximab (Kannoth, 2012). In the case we presented, after intravenous immunoglobulin administration in combination with corticosteroid therapy, supportive therapy and chemotherapy protocol TC, the anti-tumor therapeutic response was very good, proven by the decrease of the tumor marker. Although the presence of oncological positive response, the neurological benefit was still small, only managing to obtain a slightly neurological improvement, without stabilizing the progression of neurological degenerative disease.
Although several case reports of PCD are published, we consider the case presented by us to be interesting because a young woman who developed subacute cerebellar degeneration, a disease that requires rapid diagnosis and urgent treatment, has been shown to have the main cause an ovarian cancer. The diagnosis of PCD was supported by the presence of anti-Yo antibodies and the presence of brain MRI changes. The response to chemotherapy was favorable, which leads us to think that if the gynecological tumor had been diagnosed earlier, the neurological prognosis would have been better and the survival time longer.”
4 Conclusion
PCD, a rare pathology, should be suspected in cancer patients with degenerative neurological symptoms, especially in cases of women with gynecological cancers.
In the case we presented, PCD was the first clinical manifestation of the underlying cancer and the diagnosis was established by clinical manifestation of cerebellar ataxia, anti-Yo antibodies raised in the serum and the brain imaging with cerebellar atrophy.
Even if the diagnosis was delayed, after the clinical picture of cerebellar ataxia was quite advanced, treatment with immunoglobulins, corticosteroids and chemotherapy in association with supportive therapy brought an anti-tumor response, with slight improvement of the symptoms but with progression of degenerative neurological disease.
Informed Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
CRediT authorship contribution statement
Sandra Deac: Writing - original draft, Writing - review & editing. Mihaela Marioara Stana: Writing - review & editing. Andrei Dan Havasi: Writing - review & editing. Cainap Calin: Writing - review & editing. Anca-Raluca Popita: . Ana Maria Bordeianu: Writing - review & editing. Simona Cainap: Writing - review & editing. Madalina Bota: Writing - review & editing. Ovidiu Vasile Bochis: Supervision, Writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A Supplementary material
The following are the Supplementary data to this article:Supplementary data 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.gore.2020.100695. | Fatal | ReactionOutcome | CC BY-NC-ND | 33490355 | 18,819,734 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cytomegalovirus infection'. | A case of urgent colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient receiving heparin for COVID-19 coagulopathy.
COVID-19 rarely causes lower gastrointestinal bleeding even though its RNA has been detected in patient's stool. Urgent colonoscopy in a COVID-19 patient with massive bloody stool requires various procedural and equipment considerations. Here, we present a case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID-19 coagulopathy. We also share various management methods for the prevention of COVID-19 contamination. A 71-year-old man was diagnosed with COVID-19 pneumonia and subsequently underwent hemodiafiltration. Heparin was initiated for COVID-19 coagulopathy. At day 42, the patient experienced 2000 mL of bloody stool. An operator performed urgent colonoscopy with three assistants in a negative-pressure room with full personal protective equipment. A hemorrhagic ulceration was detected at the cecum, and endoscopic hemostasis was performed. Immunohistochemistry was positive for cytomegalovirus. Postprocedure, the endoscopic systems were thoroughly cleaned, and specific measures for endoscope reprocessing and disinfection were performed to prevent contamination with COVID-19.
Introduction
A novel coronavirus, severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), was first identified in Wuhan, China, and subsequently named COVID‐19 by the World Health Organization.
1
,
2
,
3
The common symptoms of COVID‐19 at the onset of illness are fever, cough, fatigue, myalgia, and dyspnea. SARS‐CoV‐2 enters cells via the angiotensin converting enzyme 2 (ACE2) receptor. ACE2 was highly expressed not only in type II alveolar cells of the lung but also in esophageal epithelial cells and the absorptive enterocytes of ileum and colon, suggesting gastrointestinal (GI) symptoms and possible fecal transmission.
1
,
3
A review of the GI symptoms caused by COVID‐19 showed that the incidence ranged from 3% (1/41) to 79% (159/201).
4
The rate of each symptom reported was as follows: anorexia 39.9% (55/138) to 50.2% (101/201), diarrhea 2% (2/99) to 49.5% (146/295), vomiting 3.6% (5/138) to 66.7% (4/6), nausea 1% (1/99) to 29.4% (59/201), abdominal pain 2.2% (3/138) to 6.0% (12/201), and GI bleeding 4% (2/52) to 13.7% (10/73). GI bleeding may require urgent endoscopy intervention. In addition, recent reports showed many cases of COVID‐19 coagulopathy, which are managed with heparin.
5
This, in turn, will likely increase the rate of GI bleeding.
SARS‐CoV‐2 is highly contagious as the virus can remain viable and infectious in aerosols for 3 h and on plastic and stainless steel surfaces for up to 3 days.
2
In addition, given that SARS‐CoV‐2 RNA has been detected in patient's stool, it is possible that SARS‐CoV‐2 could also be transmitted via the fecal–oral route.
6
Interestingly, even among patients without GI symptoms, SARS‐CoV‐2 RNA was detected in feces (39.1%, 9/23) compared to patients with GI symptoms (52.4%, 22/42). Thus, in reference to these facts, various considerations are required to prevent COVID‐19 infections spreading to medical staff and virus contamination of endoscopic equipment when performing a colonoscopy. Several papers demonstrated the management methods used in endoscopy centers to prevent the spread of the virus.
7
,
8
,
9
However, these guidelines are sometimes inadequate as each country or institution may encounter a new unaddressed situation. To our knowledge, there has been no previous case report on urgent colonoscopy for a COVID‐19 case with massive hemorrhage. Here, we present an urgent case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID‐19 coagulopathy, as well as the various management methods for preventing contamination by COVID‐19.
Case report
A 71‐year‐old man complained of fever, with computed tomography showing bilateral pneumonia. The patient had underlying autoimmune pancreatitis and diabetes mellitus and was on steroids (oral prednisolone: 15 mg/day). The nasopharyngeal swab sample confirmed the presence of SARS‐CoV‐2. The patient was admitted to our hospital and subsequently required artificial respiration. Intravenous prednisolone was prescribed (20 mg/day) instead of oral prednisolone. The patient's condition did not improve even on treatment with favipiravir initially and then on hydroxychloroquine. Hemodiafiltration was started at day 18, and heparin was prescribed for both hemodialysis and coagulopathy secondary to coronavirus. At day 42, the patient suddenly complained of a large volume of bloody stool (approximately 2000 mL). Despite receiving 1400 mL of red blood cell transfusion, the bloody stool continued, resulting in hypovolemic shock. Computed tomography showed diffuse wall thickening of the ascending colon and cecum. Stool cultures were negative, including for Clostridium difficile. Heparin was stopped, and we performed an urgent colonoscopy in a specific negative‐pressure room with full personal protect equipment (PPE) to prevent cross‐infection (Fig. 1a,b). The endoscopic system was covered with a sheet of vinyl chloride to prevent contamination. The patient's hip was also covered with a special vinyl chloride sheet to prevent the spread of hemorrhagic feces. The colonoscopy showed ulceration at the cecum and ascending colon (Fig. 1c). An exposed vessel under the clot was detected at the cecal ulceration and treated with endoscopic clips for hemostasis. In addition, heparin was changed to nafamostat mesilate with subsequent cessation of the bloody stool. A blood test and immunohistochemical examination of the biopsy specimen were positive for cytomegalovirus (CMV). The patient was then started on ganciclovir. However, respiratory function and general condition worsened, and unfortunately, the patient died 2 weeks after endoscopic hemostasis. This case report was approved by our institutional ethical board (ERB‐C‐1600).
Figure 1 Endoscopic system and personal protective equipment (PPE) for a case of COVID‐19 cecal hemorrhagic ulcer. (a) The endoscopic system was covered by a vinyl chloride sheet prior to being moved to a negative‐pressure room. PPE used when the patient is positive for COVID‐19 or at high risk of it; covering all of exposed skin utilizing an N95 mask, two pairs of gloves, shoe covers, disposable hairnet, disposable face shield, and waterproof disposable gowns. (b) A special blue vinyl chloride sheet with a hole for colonoscope (red arrow and red box) was used to prevent the spread of hemorrhagic feces. The procedure was performed in a negative‐pressure room with an operator, one assistant for the endoscopic procedure, and two assistants observing the respiratory system and patient's status. (c) Cecal ulceration on urgent colonoscopy in a patient with COVID‐19. The exposed vessel was detected under a clot (white arrow) on the ulcer.
Discussion
There are three main issues regarding an urgent colonoscopy for a patient with COVID‐19, as follows: 1. PPE for medical staff due to infectious risk
2
; case‐by‐case management for endoscopic procedures; and.
3
reprocessing and cleaning of endoscopic systems, various equipment, and rooms.
In treating COVID‐19‐positive patients, PPE is recommended as follows: two pairs of gloves, hairnet, protective face shield, long‐sleeved waterproof gowns, shoe covers, and high‐filter respiratory masks (N95, FFP2, or FFP3).
7
,
8
,
9
We utilized all of the above, with a special hairnet covering the operator's neck. An assistant should help the operator to put on the PPE, and pretraining should be implemented using e‐learning.
7
,
8
,
9
A marketed endoscopic lens cleaner (Cleash, Fujifilm, Tokyo) was applied on the face shield to prevent fogging. The minimum number of endoscopists and assistants should be in the red zone to prevent further infection. We paid attention to possibilities of periendoscopic infections from aerosol particles as the patient had a tracheostomy. Further dispersion might occur by colonoscopic insufflation. Therefore, we wore N95 mask and utilized a special waterproof (vinyl chloride) sheet covering the patient's hip, with a small hole for insertion of the endoscope.
Statements from European Society for Gastrointestinal Endoscopy (ESGE) and European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) showed four categories for endoscopic indications, such as (i) perform always, (ii and iii) case‐by‐case management with high or low priority, and (iv) postpone always.
7
However, for patients with the coronavirus under artificial respiration, acute lower GI bleeding with hemodynamic instability is the only indication for urgent endoscopy, which is categorized as “perform always” as in our case. In a lower gastrointestinal hemorrhagic case, a paper on COVID‐19 and inflammatory bowel disease (IBD) showed that 3% of patients had CMV colitis in a total of 76 IBD patients.
10
In our case, steroids prescribed for the patient's autoimmune pancreatitis weakened his immune system, similar to IBD patients. Endoscopists should always consider CMV when a patient on steroid develops lower GI hemorrhage.
In our case, we used single‐use endoscopic accessories, and all were disposed as recommended by several papers.
7
,
8
,
9
Postprocedure, the endoscopic system was wiped in the red zone and moved to the gray zone, and the vinyl chloride sheet was removed. Then, it was moved back to our endoscopic room and wiped clean again. Regarding the endoscope, it was placed in a special box to prevent infections in the gray zone and brought to the washing area of our endoscopic room. It was thoroughly washed by an assistant, who wore gloves, disposable face shield, waterproof disposable gown, and an N95 mask. During flushing of the channel before putting the endoscope in an endoscopic machine wash, we used an N95 mask as, theoretically, aerosolization could occur. Afterward, a standard reprocessing procedure similar to regular disinfection of endoscopy was performed.
7
,
8
,
9
Due to flushing, the floor can be contaminated by droplets and particles. Thus, we disinfected the floor with 1:50 dilution of a household chlorine‐based bleach (final concentration 0.1%, 1000 ppm). The room where the endoscopy was performed was also disinfected with this solution.
Here, we present a case of an urgent colonoscopic hemostasis for a patient with COVID‐19, our tips, and the various management methods used to prevent contamination by COVID‐19.
Acknowledgments
We thank all members of the Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, for helping with this study. We also thank Kaito Sakuragi, Yuta Yamaguchi, Toshimasa Takahashi, Kouken Matsuo, Naomi Yoshizawa, Kiyomi Matsuda, and other members in our endoscopic center for the special effort required in this urgent endoscopy. | FAVIPIRAVIR, HEPARIN SODIUM, HYDROXYCHLOROQUINE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33490630 | 18,538,037 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypovolaemic shock'. | A case of urgent colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient receiving heparin for COVID-19 coagulopathy.
COVID-19 rarely causes lower gastrointestinal bleeding even though its RNA has been detected in patient's stool. Urgent colonoscopy in a COVID-19 patient with massive bloody stool requires various procedural and equipment considerations. Here, we present a case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID-19 coagulopathy. We also share various management methods for the prevention of COVID-19 contamination. A 71-year-old man was diagnosed with COVID-19 pneumonia and subsequently underwent hemodiafiltration. Heparin was initiated for COVID-19 coagulopathy. At day 42, the patient experienced 2000 mL of bloody stool. An operator performed urgent colonoscopy with three assistants in a negative-pressure room with full personal protective equipment. A hemorrhagic ulceration was detected at the cecum, and endoscopic hemostasis was performed. Immunohistochemistry was positive for cytomegalovirus. Postprocedure, the endoscopic systems were thoroughly cleaned, and specific measures for endoscope reprocessing and disinfection were performed to prevent contamination with COVID-19.
Introduction
A novel coronavirus, severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), was first identified in Wuhan, China, and subsequently named COVID‐19 by the World Health Organization.
1
,
2
,
3
The common symptoms of COVID‐19 at the onset of illness are fever, cough, fatigue, myalgia, and dyspnea. SARS‐CoV‐2 enters cells via the angiotensin converting enzyme 2 (ACE2) receptor. ACE2 was highly expressed not only in type II alveolar cells of the lung but also in esophageal epithelial cells and the absorptive enterocytes of ileum and colon, suggesting gastrointestinal (GI) symptoms and possible fecal transmission.
1
,
3
A review of the GI symptoms caused by COVID‐19 showed that the incidence ranged from 3% (1/41) to 79% (159/201).
4
The rate of each symptom reported was as follows: anorexia 39.9% (55/138) to 50.2% (101/201), diarrhea 2% (2/99) to 49.5% (146/295), vomiting 3.6% (5/138) to 66.7% (4/6), nausea 1% (1/99) to 29.4% (59/201), abdominal pain 2.2% (3/138) to 6.0% (12/201), and GI bleeding 4% (2/52) to 13.7% (10/73). GI bleeding may require urgent endoscopy intervention. In addition, recent reports showed many cases of COVID‐19 coagulopathy, which are managed with heparin.
5
This, in turn, will likely increase the rate of GI bleeding.
SARS‐CoV‐2 is highly contagious as the virus can remain viable and infectious in aerosols for 3 h and on plastic and stainless steel surfaces for up to 3 days.
2
In addition, given that SARS‐CoV‐2 RNA has been detected in patient's stool, it is possible that SARS‐CoV‐2 could also be transmitted via the fecal–oral route.
6
Interestingly, even among patients without GI symptoms, SARS‐CoV‐2 RNA was detected in feces (39.1%, 9/23) compared to patients with GI symptoms (52.4%, 22/42). Thus, in reference to these facts, various considerations are required to prevent COVID‐19 infections spreading to medical staff and virus contamination of endoscopic equipment when performing a colonoscopy. Several papers demonstrated the management methods used in endoscopy centers to prevent the spread of the virus.
7
,
8
,
9
However, these guidelines are sometimes inadequate as each country or institution may encounter a new unaddressed situation. To our knowledge, there has been no previous case report on urgent colonoscopy for a COVID‐19 case with massive hemorrhage. Here, we present an urgent case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID‐19 coagulopathy, as well as the various management methods for preventing contamination by COVID‐19.
Case report
A 71‐year‐old man complained of fever, with computed tomography showing bilateral pneumonia. The patient had underlying autoimmune pancreatitis and diabetes mellitus and was on steroids (oral prednisolone: 15 mg/day). The nasopharyngeal swab sample confirmed the presence of SARS‐CoV‐2. The patient was admitted to our hospital and subsequently required artificial respiration. Intravenous prednisolone was prescribed (20 mg/day) instead of oral prednisolone. The patient's condition did not improve even on treatment with favipiravir initially and then on hydroxychloroquine. Hemodiafiltration was started at day 18, and heparin was prescribed for both hemodialysis and coagulopathy secondary to coronavirus. At day 42, the patient suddenly complained of a large volume of bloody stool (approximately 2000 mL). Despite receiving 1400 mL of red blood cell transfusion, the bloody stool continued, resulting in hypovolemic shock. Computed tomography showed diffuse wall thickening of the ascending colon and cecum. Stool cultures were negative, including for Clostridium difficile. Heparin was stopped, and we performed an urgent colonoscopy in a specific negative‐pressure room with full personal protect equipment (PPE) to prevent cross‐infection (Fig. 1a,b). The endoscopic system was covered with a sheet of vinyl chloride to prevent contamination. The patient's hip was also covered with a special vinyl chloride sheet to prevent the spread of hemorrhagic feces. The colonoscopy showed ulceration at the cecum and ascending colon (Fig. 1c). An exposed vessel under the clot was detected at the cecal ulceration and treated with endoscopic clips for hemostasis. In addition, heparin was changed to nafamostat mesilate with subsequent cessation of the bloody stool. A blood test and immunohistochemical examination of the biopsy specimen were positive for cytomegalovirus (CMV). The patient was then started on ganciclovir. However, respiratory function and general condition worsened, and unfortunately, the patient died 2 weeks after endoscopic hemostasis. This case report was approved by our institutional ethical board (ERB‐C‐1600).
Figure 1 Endoscopic system and personal protective equipment (PPE) for a case of COVID‐19 cecal hemorrhagic ulcer. (a) The endoscopic system was covered by a vinyl chloride sheet prior to being moved to a negative‐pressure room. PPE used when the patient is positive for COVID‐19 or at high risk of it; covering all of exposed skin utilizing an N95 mask, two pairs of gloves, shoe covers, disposable hairnet, disposable face shield, and waterproof disposable gowns. (b) A special blue vinyl chloride sheet with a hole for colonoscope (red arrow and red box) was used to prevent the spread of hemorrhagic feces. The procedure was performed in a negative‐pressure room with an operator, one assistant for the endoscopic procedure, and two assistants observing the respiratory system and patient's status. (c) Cecal ulceration on urgent colonoscopy in a patient with COVID‐19. The exposed vessel was detected under a clot (white arrow) on the ulcer.
Discussion
There are three main issues regarding an urgent colonoscopy for a patient with COVID‐19, as follows: 1. PPE for medical staff due to infectious risk
2
; case‐by‐case management for endoscopic procedures; and.
3
reprocessing and cleaning of endoscopic systems, various equipment, and rooms.
In treating COVID‐19‐positive patients, PPE is recommended as follows: two pairs of gloves, hairnet, protective face shield, long‐sleeved waterproof gowns, shoe covers, and high‐filter respiratory masks (N95, FFP2, or FFP3).
7
,
8
,
9
We utilized all of the above, with a special hairnet covering the operator's neck. An assistant should help the operator to put on the PPE, and pretraining should be implemented using e‐learning.
7
,
8
,
9
A marketed endoscopic lens cleaner (Cleash, Fujifilm, Tokyo) was applied on the face shield to prevent fogging. The minimum number of endoscopists and assistants should be in the red zone to prevent further infection. We paid attention to possibilities of periendoscopic infections from aerosol particles as the patient had a tracheostomy. Further dispersion might occur by colonoscopic insufflation. Therefore, we wore N95 mask and utilized a special waterproof (vinyl chloride) sheet covering the patient's hip, with a small hole for insertion of the endoscope.
Statements from European Society for Gastrointestinal Endoscopy (ESGE) and European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) showed four categories for endoscopic indications, such as (i) perform always, (ii and iii) case‐by‐case management with high or low priority, and (iv) postpone always.
7
However, for patients with the coronavirus under artificial respiration, acute lower GI bleeding with hemodynamic instability is the only indication for urgent endoscopy, which is categorized as “perform always” as in our case. In a lower gastrointestinal hemorrhagic case, a paper on COVID‐19 and inflammatory bowel disease (IBD) showed that 3% of patients had CMV colitis in a total of 76 IBD patients.
10
In our case, steroids prescribed for the patient's autoimmune pancreatitis weakened his immune system, similar to IBD patients. Endoscopists should always consider CMV when a patient on steroid develops lower GI hemorrhage.
In our case, we used single‐use endoscopic accessories, and all were disposed as recommended by several papers.
7
,
8
,
9
Postprocedure, the endoscopic system was wiped in the red zone and moved to the gray zone, and the vinyl chloride sheet was removed. Then, it was moved back to our endoscopic room and wiped clean again. Regarding the endoscope, it was placed in a special box to prevent infections in the gray zone and brought to the washing area of our endoscopic room. It was thoroughly washed by an assistant, who wore gloves, disposable face shield, waterproof disposable gown, and an N95 mask. During flushing of the channel before putting the endoscope in an endoscopic machine wash, we used an N95 mask as, theoretically, aerosolization could occur. Afterward, a standard reprocessing procedure similar to regular disinfection of endoscopy was performed.
7
,
8
,
9
Due to flushing, the floor can be contaminated by droplets and particles. Thus, we disinfected the floor with 1:50 dilution of a household chlorine‐based bleach (final concentration 0.1%, 1000 ppm). The room where the endoscopy was performed was also disinfected with this solution.
Here, we present a case of an urgent colonoscopic hemostasis for a patient with COVID‐19, our tips, and the various management methods used to prevent contamination by COVID‐19.
Acknowledgments
We thank all members of the Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, for helping with this study. We also thank Kaito Sakuragi, Yuta Yamaguchi, Toshimasa Takahashi, Kouken Matsuo, Naomi Yoshizawa, Kiyomi Matsuda, and other members in our endoscopic center for the special effort required in this urgent endoscopy. | FAVIPIRAVIR, HEPARIN SODIUM, HYDROXYCHLOROQUINE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33490630 | 18,538,037 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Large intestinal haemorrhage'. | A case of urgent colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient receiving heparin for COVID-19 coagulopathy.
COVID-19 rarely causes lower gastrointestinal bleeding even though its RNA has been detected in patient's stool. Urgent colonoscopy in a COVID-19 patient with massive bloody stool requires various procedural and equipment considerations. Here, we present a case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID-19 coagulopathy. We also share various management methods for the prevention of COVID-19 contamination. A 71-year-old man was diagnosed with COVID-19 pneumonia and subsequently underwent hemodiafiltration. Heparin was initiated for COVID-19 coagulopathy. At day 42, the patient experienced 2000 mL of bloody stool. An operator performed urgent colonoscopy with three assistants in a negative-pressure room with full personal protective equipment. A hemorrhagic ulceration was detected at the cecum, and endoscopic hemostasis was performed. Immunohistochemistry was positive for cytomegalovirus. Postprocedure, the endoscopic systems were thoroughly cleaned, and specific measures for endoscope reprocessing and disinfection were performed to prevent contamination with COVID-19.
Introduction
A novel coronavirus, severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), was first identified in Wuhan, China, and subsequently named COVID‐19 by the World Health Organization.
1
,
2
,
3
The common symptoms of COVID‐19 at the onset of illness are fever, cough, fatigue, myalgia, and dyspnea. SARS‐CoV‐2 enters cells via the angiotensin converting enzyme 2 (ACE2) receptor. ACE2 was highly expressed not only in type II alveolar cells of the lung but also in esophageal epithelial cells and the absorptive enterocytes of ileum and colon, suggesting gastrointestinal (GI) symptoms and possible fecal transmission.
1
,
3
A review of the GI symptoms caused by COVID‐19 showed that the incidence ranged from 3% (1/41) to 79% (159/201).
4
The rate of each symptom reported was as follows: anorexia 39.9% (55/138) to 50.2% (101/201), diarrhea 2% (2/99) to 49.5% (146/295), vomiting 3.6% (5/138) to 66.7% (4/6), nausea 1% (1/99) to 29.4% (59/201), abdominal pain 2.2% (3/138) to 6.0% (12/201), and GI bleeding 4% (2/52) to 13.7% (10/73). GI bleeding may require urgent endoscopy intervention. In addition, recent reports showed many cases of COVID‐19 coagulopathy, which are managed with heparin.
5
This, in turn, will likely increase the rate of GI bleeding.
SARS‐CoV‐2 is highly contagious as the virus can remain viable and infectious in aerosols for 3 h and on plastic and stainless steel surfaces for up to 3 days.
2
In addition, given that SARS‐CoV‐2 RNA has been detected in patient's stool, it is possible that SARS‐CoV‐2 could also be transmitted via the fecal–oral route.
6
Interestingly, even among patients without GI symptoms, SARS‐CoV‐2 RNA was detected in feces (39.1%, 9/23) compared to patients with GI symptoms (52.4%, 22/42). Thus, in reference to these facts, various considerations are required to prevent COVID‐19 infections spreading to medical staff and virus contamination of endoscopic equipment when performing a colonoscopy. Several papers demonstrated the management methods used in endoscopy centers to prevent the spread of the virus.
7
,
8
,
9
However, these guidelines are sometimes inadequate as each country or institution may encounter a new unaddressed situation. To our knowledge, there has been no previous case report on urgent colonoscopy for a COVID‐19 case with massive hemorrhage. Here, we present an urgent case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID‐19 coagulopathy, as well as the various management methods for preventing contamination by COVID‐19.
Case report
A 71‐year‐old man complained of fever, with computed tomography showing bilateral pneumonia. The patient had underlying autoimmune pancreatitis and diabetes mellitus and was on steroids (oral prednisolone: 15 mg/day). The nasopharyngeal swab sample confirmed the presence of SARS‐CoV‐2. The patient was admitted to our hospital and subsequently required artificial respiration. Intravenous prednisolone was prescribed (20 mg/day) instead of oral prednisolone. The patient's condition did not improve even on treatment with favipiravir initially and then on hydroxychloroquine. Hemodiafiltration was started at day 18, and heparin was prescribed for both hemodialysis and coagulopathy secondary to coronavirus. At day 42, the patient suddenly complained of a large volume of bloody stool (approximately 2000 mL). Despite receiving 1400 mL of red blood cell transfusion, the bloody stool continued, resulting in hypovolemic shock. Computed tomography showed diffuse wall thickening of the ascending colon and cecum. Stool cultures were negative, including for Clostridium difficile. Heparin was stopped, and we performed an urgent colonoscopy in a specific negative‐pressure room with full personal protect equipment (PPE) to prevent cross‐infection (Fig. 1a,b). The endoscopic system was covered with a sheet of vinyl chloride to prevent contamination. The patient's hip was also covered with a special vinyl chloride sheet to prevent the spread of hemorrhagic feces. The colonoscopy showed ulceration at the cecum and ascending colon (Fig. 1c). An exposed vessel under the clot was detected at the cecal ulceration and treated with endoscopic clips for hemostasis. In addition, heparin was changed to nafamostat mesilate with subsequent cessation of the bloody stool. A blood test and immunohistochemical examination of the biopsy specimen were positive for cytomegalovirus (CMV). The patient was then started on ganciclovir. However, respiratory function and general condition worsened, and unfortunately, the patient died 2 weeks after endoscopic hemostasis. This case report was approved by our institutional ethical board (ERB‐C‐1600).
Figure 1 Endoscopic system and personal protective equipment (PPE) for a case of COVID‐19 cecal hemorrhagic ulcer. (a) The endoscopic system was covered by a vinyl chloride sheet prior to being moved to a negative‐pressure room. PPE used when the patient is positive for COVID‐19 or at high risk of it; covering all of exposed skin utilizing an N95 mask, two pairs of gloves, shoe covers, disposable hairnet, disposable face shield, and waterproof disposable gowns. (b) A special blue vinyl chloride sheet with a hole for colonoscope (red arrow and red box) was used to prevent the spread of hemorrhagic feces. The procedure was performed in a negative‐pressure room with an operator, one assistant for the endoscopic procedure, and two assistants observing the respiratory system and patient's status. (c) Cecal ulceration on urgent colonoscopy in a patient with COVID‐19. The exposed vessel was detected under a clot (white arrow) on the ulcer.
Discussion
There are three main issues regarding an urgent colonoscopy for a patient with COVID‐19, as follows: 1. PPE for medical staff due to infectious risk
2
; case‐by‐case management for endoscopic procedures; and.
3
reprocessing and cleaning of endoscopic systems, various equipment, and rooms.
In treating COVID‐19‐positive patients, PPE is recommended as follows: two pairs of gloves, hairnet, protective face shield, long‐sleeved waterproof gowns, shoe covers, and high‐filter respiratory masks (N95, FFP2, or FFP3).
7
,
8
,
9
We utilized all of the above, with a special hairnet covering the operator's neck. An assistant should help the operator to put on the PPE, and pretraining should be implemented using e‐learning.
7
,
8
,
9
A marketed endoscopic lens cleaner (Cleash, Fujifilm, Tokyo) was applied on the face shield to prevent fogging. The minimum number of endoscopists and assistants should be in the red zone to prevent further infection. We paid attention to possibilities of periendoscopic infections from aerosol particles as the patient had a tracheostomy. Further dispersion might occur by colonoscopic insufflation. Therefore, we wore N95 mask and utilized a special waterproof (vinyl chloride) sheet covering the patient's hip, with a small hole for insertion of the endoscope.
Statements from European Society for Gastrointestinal Endoscopy (ESGE) and European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) showed four categories for endoscopic indications, such as (i) perform always, (ii and iii) case‐by‐case management with high or low priority, and (iv) postpone always.
7
However, for patients with the coronavirus under artificial respiration, acute lower GI bleeding with hemodynamic instability is the only indication for urgent endoscopy, which is categorized as “perform always” as in our case. In a lower gastrointestinal hemorrhagic case, a paper on COVID‐19 and inflammatory bowel disease (IBD) showed that 3% of patients had CMV colitis in a total of 76 IBD patients.
10
In our case, steroids prescribed for the patient's autoimmune pancreatitis weakened his immune system, similar to IBD patients. Endoscopists should always consider CMV when a patient on steroid develops lower GI hemorrhage.
In our case, we used single‐use endoscopic accessories, and all were disposed as recommended by several papers.
7
,
8
,
9
Postprocedure, the endoscopic system was wiped in the red zone and moved to the gray zone, and the vinyl chloride sheet was removed. Then, it was moved back to our endoscopic room and wiped clean again. Regarding the endoscope, it was placed in a special box to prevent infections in the gray zone and brought to the washing area of our endoscopic room. It was thoroughly washed by an assistant, who wore gloves, disposable face shield, waterproof disposable gown, and an N95 mask. During flushing of the channel before putting the endoscope in an endoscopic machine wash, we used an N95 mask as, theoretically, aerosolization could occur. Afterward, a standard reprocessing procedure similar to regular disinfection of endoscopy was performed.
7
,
8
,
9
Due to flushing, the floor can be contaminated by droplets and particles. Thus, we disinfected the floor with 1:50 dilution of a household chlorine‐based bleach (final concentration 0.1%, 1000 ppm). The room where the endoscopy was performed was also disinfected with this solution.
Here, we present a case of an urgent colonoscopic hemostasis for a patient with COVID‐19, our tips, and the various management methods used to prevent contamination by COVID‐19.
Acknowledgments
We thank all members of the Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, for helping with this study. We also thank Kaito Sakuragi, Yuta Yamaguchi, Toshimasa Takahashi, Kouken Matsuo, Naomi Yoshizawa, Kiyomi Matsuda, and other members in our endoscopic center for the special effort required in this urgent endoscopy. | FAVIPIRAVIR, HEPARIN SODIUM, HYDROXYCHLOROQUINE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33490630 | 18,538,037 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Large intestinal ulcer'. | A case of urgent colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient receiving heparin for COVID-19 coagulopathy.
COVID-19 rarely causes lower gastrointestinal bleeding even though its RNA has been detected in patient's stool. Urgent colonoscopy in a COVID-19 patient with massive bloody stool requires various procedural and equipment considerations. Here, we present a case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID-19 coagulopathy. We also share various management methods for the prevention of COVID-19 contamination. A 71-year-old man was diagnosed with COVID-19 pneumonia and subsequently underwent hemodiafiltration. Heparin was initiated for COVID-19 coagulopathy. At day 42, the patient experienced 2000 mL of bloody stool. An operator performed urgent colonoscopy with three assistants in a negative-pressure room with full personal protective equipment. A hemorrhagic ulceration was detected at the cecum, and endoscopic hemostasis was performed. Immunohistochemistry was positive for cytomegalovirus. Postprocedure, the endoscopic systems were thoroughly cleaned, and specific measures for endoscope reprocessing and disinfection were performed to prevent contamination with COVID-19.
Introduction
A novel coronavirus, severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), was first identified in Wuhan, China, and subsequently named COVID‐19 by the World Health Organization.
1
,
2
,
3
The common symptoms of COVID‐19 at the onset of illness are fever, cough, fatigue, myalgia, and dyspnea. SARS‐CoV‐2 enters cells via the angiotensin converting enzyme 2 (ACE2) receptor. ACE2 was highly expressed not only in type II alveolar cells of the lung but also in esophageal epithelial cells and the absorptive enterocytes of ileum and colon, suggesting gastrointestinal (GI) symptoms and possible fecal transmission.
1
,
3
A review of the GI symptoms caused by COVID‐19 showed that the incidence ranged from 3% (1/41) to 79% (159/201).
4
The rate of each symptom reported was as follows: anorexia 39.9% (55/138) to 50.2% (101/201), diarrhea 2% (2/99) to 49.5% (146/295), vomiting 3.6% (5/138) to 66.7% (4/6), nausea 1% (1/99) to 29.4% (59/201), abdominal pain 2.2% (3/138) to 6.0% (12/201), and GI bleeding 4% (2/52) to 13.7% (10/73). GI bleeding may require urgent endoscopy intervention. In addition, recent reports showed many cases of COVID‐19 coagulopathy, which are managed with heparin.
5
This, in turn, will likely increase the rate of GI bleeding.
SARS‐CoV‐2 is highly contagious as the virus can remain viable and infectious in aerosols for 3 h and on plastic and stainless steel surfaces for up to 3 days.
2
In addition, given that SARS‐CoV‐2 RNA has been detected in patient's stool, it is possible that SARS‐CoV‐2 could also be transmitted via the fecal–oral route.
6
Interestingly, even among patients without GI symptoms, SARS‐CoV‐2 RNA was detected in feces (39.1%, 9/23) compared to patients with GI symptoms (52.4%, 22/42). Thus, in reference to these facts, various considerations are required to prevent COVID‐19 infections spreading to medical staff and virus contamination of endoscopic equipment when performing a colonoscopy. Several papers demonstrated the management methods used in endoscopy centers to prevent the spread of the virus.
7
,
8
,
9
However, these guidelines are sometimes inadequate as each country or institution may encounter a new unaddressed situation. To our knowledge, there has been no previous case report on urgent colonoscopy for a COVID‐19 case with massive hemorrhage. Here, we present an urgent case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID‐19 coagulopathy, as well as the various management methods for preventing contamination by COVID‐19.
Case report
A 71‐year‐old man complained of fever, with computed tomography showing bilateral pneumonia. The patient had underlying autoimmune pancreatitis and diabetes mellitus and was on steroids (oral prednisolone: 15 mg/day). The nasopharyngeal swab sample confirmed the presence of SARS‐CoV‐2. The patient was admitted to our hospital and subsequently required artificial respiration. Intravenous prednisolone was prescribed (20 mg/day) instead of oral prednisolone. The patient's condition did not improve even on treatment with favipiravir initially and then on hydroxychloroquine. Hemodiafiltration was started at day 18, and heparin was prescribed for both hemodialysis and coagulopathy secondary to coronavirus. At day 42, the patient suddenly complained of a large volume of bloody stool (approximately 2000 mL). Despite receiving 1400 mL of red blood cell transfusion, the bloody stool continued, resulting in hypovolemic shock. Computed tomography showed diffuse wall thickening of the ascending colon and cecum. Stool cultures were negative, including for Clostridium difficile. Heparin was stopped, and we performed an urgent colonoscopy in a specific negative‐pressure room with full personal protect equipment (PPE) to prevent cross‐infection (Fig. 1a,b). The endoscopic system was covered with a sheet of vinyl chloride to prevent contamination. The patient's hip was also covered with a special vinyl chloride sheet to prevent the spread of hemorrhagic feces. The colonoscopy showed ulceration at the cecum and ascending colon (Fig. 1c). An exposed vessel under the clot was detected at the cecal ulceration and treated with endoscopic clips for hemostasis. In addition, heparin was changed to nafamostat mesilate with subsequent cessation of the bloody stool. A blood test and immunohistochemical examination of the biopsy specimen were positive for cytomegalovirus (CMV). The patient was then started on ganciclovir. However, respiratory function and general condition worsened, and unfortunately, the patient died 2 weeks after endoscopic hemostasis. This case report was approved by our institutional ethical board (ERB‐C‐1600).
Figure 1 Endoscopic system and personal protective equipment (PPE) for a case of COVID‐19 cecal hemorrhagic ulcer. (a) The endoscopic system was covered by a vinyl chloride sheet prior to being moved to a negative‐pressure room. PPE used when the patient is positive for COVID‐19 or at high risk of it; covering all of exposed skin utilizing an N95 mask, two pairs of gloves, shoe covers, disposable hairnet, disposable face shield, and waterproof disposable gowns. (b) A special blue vinyl chloride sheet with a hole for colonoscope (red arrow and red box) was used to prevent the spread of hemorrhagic feces. The procedure was performed in a negative‐pressure room with an operator, one assistant for the endoscopic procedure, and two assistants observing the respiratory system and patient's status. (c) Cecal ulceration on urgent colonoscopy in a patient with COVID‐19. The exposed vessel was detected under a clot (white arrow) on the ulcer.
Discussion
There are three main issues regarding an urgent colonoscopy for a patient with COVID‐19, as follows: 1. PPE for medical staff due to infectious risk
2
; case‐by‐case management for endoscopic procedures; and.
3
reprocessing and cleaning of endoscopic systems, various equipment, and rooms.
In treating COVID‐19‐positive patients, PPE is recommended as follows: two pairs of gloves, hairnet, protective face shield, long‐sleeved waterproof gowns, shoe covers, and high‐filter respiratory masks (N95, FFP2, or FFP3).
7
,
8
,
9
We utilized all of the above, with a special hairnet covering the operator's neck. An assistant should help the operator to put on the PPE, and pretraining should be implemented using e‐learning.
7
,
8
,
9
A marketed endoscopic lens cleaner (Cleash, Fujifilm, Tokyo) was applied on the face shield to prevent fogging. The minimum number of endoscopists and assistants should be in the red zone to prevent further infection. We paid attention to possibilities of periendoscopic infections from aerosol particles as the patient had a tracheostomy. Further dispersion might occur by colonoscopic insufflation. Therefore, we wore N95 mask and utilized a special waterproof (vinyl chloride) sheet covering the patient's hip, with a small hole for insertion of the endoscope.
Statements from European Society for Gastrointestinal Endoscopy (ESGE) and European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) showed four categories for endoscopic indications, such as (i) perform always, (ii and iii) case‐by‐case management with high or low priority, and (iv) postpone always.
7
However, for patients with the coronavirus under artificial respiration, acute lower GI bleeding with hemodynamic instability is the only indication for urgent endoscopy, which is categorized as “perform always” as in our case. In a lower gastrointestinal hemorrhagic case, a paper on COVID‐19 and inflammatory bowel disease (IBD) showed that 3% of patients had CMV colitis in a total of 76 IBD patients.
10
In our case, steroids prescribed for the patient's autoimmune pancreatitis weakened his immune system, similar to IBD patients. Endoscopists should always consider CMV when a patient on steroid develops lower GI hemorrhage.
In our case, we used single‐use endoscopic accessories, and all were disposed as recommended by several papers.
7
,
8
,
9
Postprocedure, the endoscopic system was wiped in the red zone and moved to the gray zone, and the vinyl chloride sheet was removed. Then, it was moved back to our endoscopic room and wiped clean again. Regarding the endoscope, it was placed in a special box to prevent infections in the gray zone and brought to the washing area of our endoscopic room. It was thoroughly washed by an assistant, who wore gloves, disposable face shield, waterproof disposable gown, and an N95 mask. During flushing of the channel before putting the endoscope in an endoscopic machine wash, we used an N95 mask as, theoretically, aerosolization could occur. Afterward, a standard reprocessing procedure similar to regular disinfection of endoscopy was performed.
7
,
8
,
9
Due to flushing, the floor can be contaminated by droplets and particles. Thus, we disinfected the floor with 1:50 dilution of a household chlorine‐based bleach (final concentration 0.1%, 1000 ppm). The room where the endoscopy was performed was also disinfected with this solution.
Here, we present a case of an urgent colonoscopic hemostasis for a patient with COVID‐19, our tips, and the various management methods used to prevent contamination by COVID‐19.
Acknowledgments
We thank all members of the Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, for helping with this study. We also thank Kaito Sakuragi, Yuta Yamaguchi, Toshimasa Takahashi, Kouken Matsuo, Naomi Yoshizawa, Kiyomi Matsuda, and other members in our endoscopic center for the special effort required in this urgent endoscopy. | FAVIPIRAVIR, HEPARIN SODIUM, HYDROXYCHLOROQUINE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33490630 | 18,538,037 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | A case of urgent colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient receiving heparin for COVID-19 coagulopathy.
COVID-19 rarely causes lower gastrointestinal bleeding even though its RNA has been detected in patient's stool. Urgent colonoscopy in a COVID-19 patient with massive bloody stool requires various procedural and equipment considerations. Here, we present a case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID-19 coagulopathy. We also share various management methods for the prevention of COVID-19 contamination. A 71-year-old man was diagnosed with COVID-19 pneumonia and subsequently underwent hemodiafiltration. Heparin was initiated for COVID-19 coagulopathy. At day 42, the patient experienced 2000 mL of bloody stool. An operator performed urgent colonoscopy with three assistants in a negative-pressure room with full personal protective equipment. A hemorrhagic ulceration was detected at the cecum, and endoscopic hemostasis was performed. Immunohistochemistry was positive for cytomegalovirus. Postprocedure, the endoscopic systems were thoroughly cleaned, and specific measures for endoscope reprocessing and disinfection were performed to prevent contamination with COVID-19.
Introduction
A novel coronavirus, severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), was first identified in Wuhan, China, and subsequently named COVID‐19 by the World Health Organization.
1
,
2
,
3
The common symptoms of COVID‐19 at the onset of illness are fever, cough, fatigue, myalgia, and dyspnea. SARS‐CoV‐2 enters cells via the angiotensin converting enzyme 2 (ACE2) receptor. ACE2 was highly expressed not only in type II alveolar cells of the lung but also in esophageal epithelial cells and the absorptive enterocytes of ileum and colon, suggesting gastrointestinal (GI) symptoms and possible fecal transmission.
1
,
3
A review of the GI symptoms caused by COVID‐19 showed that the incidence ranged from 3% (1/41) to 79% (159/201).
4
The rate of each symptom reported was as follows: anorexia 39.9% (55/138) to 50.2% (101/201), diarrhea 2% (2/99) to 49.5% (146/295), vomiting 3.6% (5/138) to 66.7% (4/6), nausea 1% (1/99) to 29.4% (59/201), abdominal pain 2.2% (3/138) to 6.0% (12/201), and GI bleeding 4% (2/52) to 13.7% (10/73). GI bleeding may require urgent endoscopy intervention. In addition, recent reports showed many cases of COVID‐19 coagulopathy, which are managed with heparin.
5
This, in turn, will likely increase the rate of GI bleeding.
SARS‐CoV‐2 is highly contagious as the virus can remain viable and infectious in aerosols for 3 h and on plastic and stainless steel surfaces for up to 3 days.
2
In addition, given that SARS‐CoV‐2 RNA has been detected in patient's stool, it is possible that SARS‐CoV‐2 could also be transmitted via the fecal–oral route.
6
Interestingly, even among patients without GI symptoms, SARS‐CoV‐2 RNA was detected in feces (39.1%, 9/23) compared to patients with GI symptoms (52.4%, 22/42). Thus, in reference to these facts, various considerations are required to prevent COVID‐19 infections spreading to medical staff and virus contamination of endoscopic equipment when performing a colonoscopy. Several papers demonstrated the management methods used in endoscopy centers to prevent the spread of the virus.
7
,
8
,
9
However, these guidelines are sometimes inadequate as each country or institution may encounter a new unaddressed situation. To our knowledge, there has been no previous case report on urgent colonoscopy for a COVID‐19 case with massive hemorrhage. Here, we present an urgent case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID‐19 coagulopathy, as well as the various management methods for preventing contamination by COVID‐19.
Case report
A 71‐year‐old man complained of fever, with computed tomography showing bilateral pneumonia. The patient had underlying autoimmune pancreatitis and diabetes mellitus and was on steroids (oral prednisolone: 15 mg/day). The nasopharyngeal swab sample confirmed the presence of SARS‐CoV‐2. The patient was admitted to our hospital and subsequently required artificial respiration. Intravenous prednisolone was prescribed (20 mg/day) instead of oral prednisolone. The patient's condition did not improve even on treatment with favipiravir initially and then on hydroxychloroquine. Hemodiafiltration was started at day 18, and heparin was prescribed for both hemodialysis and coagulopathy secondary to coronavirus. At day 42, the patient suddenly complained of a large volume of bloody stool (approximately 2000 mL). Despite receiving 1400 mL of red blood cell transfusion, the bloody stool continued, resulting in hypovolemic shock. Computed tomography showed diffuse wall thickening of the ascending colon and cecum. Stool cultures were negative, including for Clostridium difficile. Heparin was stopped, and we performed an urgent colonoscopy in a specific negative‐pressure room with full personal protect equipment (PPE) to prevent cross‐infection (Fig. 1a,b). The endoscopic system was covered with a sheet of vinyl chloride to prevent contamination. The patient's hip was also covered with a special vinyl chloride sheet to prevent the spread of hemorrhagic feces. The colonoscopy showed ulceration at the cecum and ascending colon (Fig. 1c). An exposed vessel under the clot was detected at the cecal ulceration and treated with endoscopic clips for hemostasis. In addition, heparin was changed to nafamostat mesilate with subsequent cessation of the bloody stool. A blood test and immunohistochemical examination of the biopsy specimen were positive for cytomegalovirus (CMV). The patient was then started on ganciclovir. However, respiratory function and general condition worsened, and unfortunately, the patient died 2 weeks after endoscopic hemostasis. This case report was approved by our institutional ethical board (ERB‐C‐1600).
Figure 1 Endoscopic system and personal protective equipment (PPE) for a case of COVID‐19 cecal hemorrhagic ulcer. (a) The endoscopic system was covered by a vinyl chloride sheet prior to being moved to a negative‐pressure room. PPE used when the patient is positive for COVID‐19 or at high risk of it; covering all of exposed skin utilizing an N95 mask, two pairs of gloves, shoe covers, disposable hairnet, disposable face shield, and waterproof disposable gowns. (b) A special blue vinyl chloride sheet with a hole for colonoscope (red arrow and red box) was used to prevent the spread of hemorrhagic feces. The procedure was performed in a negative‐pressure room with an operator, one assistant for the endoscopic procedure, and two assistants observing the respiratory system and patient's status. (c) Cecal ulceration on urgent colonoscopy in a patient with COVID‐19. The exposed vessel was detected under a clot (white arrow) on the ulcer.
Discussion
There are three main issues regarding an urgent colonoscopy for a patient with COVID‐19, as follows: 1. PPE for medical staff due to infectious risk
2
; case‐by‐case management for endoscopic procedures; and.
3
reprocessing and cleaning of endoscopic systems, various equipment, and rooms.
In treating COVID‐19‐positive patients, PPE is recommended as follows: two pairs of gloves, hairnet, protective face shield, long‐sleeved waterproof gowns, shoe covers, and high‐filter respiratory masks (N95, FFP2, or FFP3).
7
,
8
,
9
We utilized all of the above, with a special hairnet covering the operator's neck. An assistant should help the operator to put on the PPE, and pretraining should be implemented using e‐learning.
7
,
8
,
9
A marketed endoscopic lens cleaner (Cleash, Fujifilm, Tokyo) was applied on the face shield to prevent fogging. The minimum number of endoscopists and assistants should be in the red zone to prevent further infection. We paid attention to possibilities of periendoscopic infections from aerosol particles as the patient had a tracheostomy. Further dispersion might occur by colonoscopic insufflation. Therefore, we wore N95 mask and utilized a special waterproof (vinyl chloride) sheet covering the patient's hip, with a small hole for insertion of the endoscope.
Statements from European Society for Gastrointestinal Endoscopy (ESGE) and European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) showed four categories for endoscopic indications, such as (i) perform always, (ii and iii) case‐by‐case management with high or low priority, and (iv) postpone always.
7
However, for patients with the coronavirus under artificial respiration, acute lower GI bleeding with hemodynamic instability is the only indication for urgent endoscopy, which is categorized as “perform always” as in our case. In a lower gastrointestinal hemorrhagic case, a paper on COVID‐19 and inflammatory bowel disease (IBD) showed that 3% of patients had CMV colitis in a total of 76 IBD patients.
10
In our case, steroids prescribed for the patient's autoimmune pancreatitis weakened his immune system, similar to IBD patients. Endoscopists should always consider CMV when a patient on steroid develops lower GI hemorrhage.
In our case, we used single‐use endoscopic accessories, and all were disposed as recommended by several papers.
7
,
8
,
9
Postprocedure, the endoscopic system was wiped in the red zone and moved to the gray zone, and the vinyl chloride sheet was removed. Then, it was moved back to our endoscopic room and wiped clean again. Regarding the endoscope, it was placed in a special box to prevent infections in the gray zone and brought to the washing area of our endoscopic room. It was thoroughly washed by an assistant, who wore gloves, disposable face shield, waterproof disposable gown, and an N95 mask. During flushing of the channel before putting the endoscope in an endoscopic machine wash, we used an N95 mask as, theoretically, aerosolization could occur. Afterward, a standard reprocessing procedure similar to regular disinfection of endoscopy was performed.
7
,
8
,
9
Due to flushing, the floor can be contaminated by droplets and particles. Thus, we disinfected the floor with 1:50 dilution of a household chlorine‐based bleach (final concentration 0.1%, 1000 ppm). The room where the endoscopy was performed was also disinfected with this solution.
Here, we present a case of an urgent colonoscopic hemostasis for a patient with COVID‐19, our tips, and the various management methods used to prevent contamination by COVID‐19.
Acknowledgments
We thank all members of the Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, for helping with this study. We also thank Kaito Sakuragi, Yuta Yamaguchi, Toshimasa Takahashi, Kouken Matsuo, Naomi Yoshizawa, Kiyomi Matsuda, and other members in our endoscopic center for the special effort required in this urgent endoscopy. | FAVIPIRAVIR, HEPARIN SODIUM, HYDROXYCHLOROQUINE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33490630 | 18,538,037 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | A case of urgent colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient receiving heparin for COVID-19 coagulopathy.
COVID-19 rarely causes lower gastrointestinal bleeding even though its RNA has been detected in patient's stool. Urgent colonoscopy in a COVID-19 patient with massive bloody stool requires various procedural and equipment considerations. Here, we present a case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID-19 coagulopathy. We also share various management methods for the prevention of COVID-19 contamination. A 71-year-old man was diagnosed with COVID-19 pneumonia and subsequently underwent hemodiafiltration. Heparin was initiated for COVID-19 coagulopathy. At day 42, the patient experienced 2000 mL of bloody stool. An operator performed urgent colonoscopy with three assistants in a negative-pressure room with full personal protective equipment. A hemorrhagic ulceration was detected at the cecum, and endoscopic hemostasis was performed. Immunohistochemistry was positive for cytomegalovirus. Postprocedure, the endoscopic systems were thoroughly cleaned, and specific measures for endoscope reprocessing and disinfection were performed to prevent contamination with COVID-19.
Introduction
A novel coronavirus, severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), was first identified in Wuhan, China, and subsequently named COVID‐19 by the World Health Organization.
1
,
2
,
3
The common symptoms of COVID‐19 at the onset of illness are fever, cough, fatigue, myalgia, and dyspnea. SARS‐CoV‐2 enters cells via the angiotensin converting enzyme 2 (ACE2) receptor. ACE2 was highly expressed not only in type II alveolar cells of the lung but also in esophageal epithelial cells and the absorptive enterocytes of ileum and colon, suggesting gastrointestinal (GI) symptoms and possible fecal transmission.
1
,
3
A review of the GI symptoms caused by COVID‐19 showed that the incidence ranged from 3% (1/41) to 79% (159/201).
4
The rate of each symptom reported was as follows: anorexia 39.9% (55/138) to 50.2% (101/201), diarrhea 2% (2/99) to 49.5% (146/295), vomiting 3.6% (5/138) to 66.7% (4/6), nausea 1% (1/99) to 29.4% (59/201), abdominal pain 2.2% (3/138) to 6.0% (12/201), and GI bleeding 4% (2/52) to 13.7% (10/73). GI bleeding may require urgent endoscopy intervention. In addition, recent reports showed many cases of COVID‐19 coagulopathy, which are managed with heparin.
5
This, in turn, will likely increase the rate of GI bleeding.
SARS‐CoV‐2 is highly contagious as the virus can remain viable and infectious in aerosols for 3 h and on plastic and stainless steel surfaces for up to 3 days.
2
In addition, given that SARS‐CoV‐2 RNA has been detected in patient's stool, it is possible that SARS‐CoV‐2 could also be transmitted via the fecal–oral route.
6
Interestingly, even among patients without GI symptoms, SARS‐CoV‐2 RNA was detected in feces (39.1%, 9/23) compared to patients with GI symptoms (52.4%, 22/42). Thus, in reference to these facts, various considerations are required to prevent COVID‐19 infections spreading to medical staff and virus contamination of endoscopic equipment when performing a colonoscopy. Several papers demonstrated the management methods used in endoscopy centers to prevent the spread of the virus.
7
,
8
,
9
However, these guidelines are sometimes inadequate as each country or institution may encounter a new unaddressed situation. To our knowledge, there has been no previous case report on urgent colonoscopy for a COVID‐19 case with massive hemorrhage. Here, we present an urgent case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID‐19 coagulopathy, as well as the various management methods for preventing contamination by COVID‐19.
Case report
A 71‐year‐old man complained of fever, with computed tomography showing bilateral pneumonia. The patient had underlying autoimmune pancreatitis and diabetes mellitus and was on steroids (oral prednisolone: 15 mg/day). The nasopharyngeal swab sample confirmed the presence of SARS‐CoV‐2. The patient was admitted to our hospital and subsequently required artificial respiration. Intravenous prednisolone was prescribed (20 mg/day) instead of oral prednisolone. The patient's condition did not improve even on treatment with favipiravir initially and then on hydroxychloroquine. Hemodiafiltration was started at day 18, and heparin was prescribed for both hemodialysis and coagulopathy secondary to coronavirus. At day 42, the patient suddenly complained of a large volume of bloody stool (approximately 2000 mL). Despite receiving 1400 mL of red blood cell transfusion, the bloody stool continued, resulting in hypovolemic shock. Computed tomography showed diffuse wall thickening of the ascending colon and cecum. Stool cultures were negative, including for Clostridium difficile. Heparin was stopped, and we performed an urgent colonoscopy in a specific negative‐pressure room with full personal protect equipment (PPE) to prevent cross‐infection (Fig. 1a,b). The endoscopic system was covered with a sheet of vinyl chloride to prevent contamination. The patient's hip was also covered with a special vinyl chloride sheet to prevent the spread of hemorrhagic feces. The colonoscopy showed ulceration at the cecum and ascending colon (Fig. 1c). An exposed vessel under the clot was detected at the cecal ulceration and treated with endoscopic clips for hemostasis. In addition, heparin was changed to nafamostat mesilate with subsequent cessation of the bloody stool. A blood test and immunohistochemical examination of the biopsy specimen were positive for cytomegalovirus (CMV). The patient was then started on ganciclovir. However, respiratory function and general condition worsened, and unfortunately, the patient died 2 weeks after endoscopic hemostasis. This case report was approved by our institutional ethical board (ERB‐C‐1600).
Figure 1 Endoscopic system and personal protective equipment (PPE) for a case of COVID‐19 cecal hemorrhagic ulcer. (a) The endoscopic system was covered by a vinyl chloride sheet prior to being moved to a negative‐pressure room. PPE used when the patient is positive for COVID‐19 or at high risk of it; covering all of exposed skin utilizing an N95 mask, two pairs of gloves, shoe covers, disposable hairnet, disposable face shield, and waterproof disposable gowns. (b) A special blue vinyl chloride sheet with a hole for colonoscope (red arrow and red box) was used to prevent the spread of hemorrhagic feces. The procedure was performed in a negative‐pressure room with an operator, one assistant for the endoscopic procedure, and two assistants observing the respiratory system and patient's status. (c) Cecal ulceration on urgent colonoscopy in a patient with COVID‐19. The exposed vessel was detected under a clot (white arrow) on the ulcer.
Discussion
There are three main issues regarding an urgent colonoscopy for a patient with COVID‐19, as follows: 1. PPE for medical staff due to infectious risk
2
; case‐by‐case management for endoscopic procedures; and.
3
reprocessing and cleaning of endoscopic systems, various equipment, and rooms.
In treating COVID‐19‐positive patients, PPE is recommended as follows: two pairs of gloves, hairnet, protective face shield, long‐sleeved waterproof gowns, shoe covers, and high‐filter respiratory masks (N95, FFP2, or FFP3).
7
,
8
,
9
We utilized all of the above, with a special hairnet covering the operator's neck. An assistant should help the operator to put on the PPE, and pretraining should be implemented using e‐learning.
7
,
8
,
9
A marketed endoscopic lens cleaner (Cleash, Fujifilm, Tokyo) was applied on the face shield to prevent fogging. The minimum number of endoscopists and assistants should be in the red zone to prevent further infection. We paid attention to possibilities of periendoscopic infections from aerosol particles as the patient had a tracheostomy. Further dispersion might occur by colonoscopic insufflation. Therefore, we wore N95 mask and utilized a special waterproof (vinyl chloride) sheet covering the patient's hip, with a small hole for insertion of the endoscope.
Statements from European Society for Gastrointestinal Endoscopy (ESGE) and European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) showed four categories for endoscopic indications, such as (i) perform always, (ii and iii) case‐by‐case management with high or low priority, and (iv) postpone always.
7
However, for patients with the coronavirus under artificial respiration, acute lower GI bleeding with hemodynamic instability is the only indication for urgent endoscopy, which is categorized as “perform always” as in our case. In a lower gastrointestinal hemorrhagic case, a paper on COVID‐19 and inflammatory bowel disease (IBD) showed that 3% of patients had CMV colitis in a total of 76 IBD patients.
10
In our case, steroids prescribed for the patient's autoimmune pancreatitis weakened his immune system, similar to IBD patients. Endoscopists should always consider CMV when a patient on steroid develops lower GI hemorrhage.
In our case, we used single‐use endoscopic accessories, and all were disposed as recommended by several papers.
7
,
8
,
9
Postprocedure, the endoscopic system was wiped in the red zone and moved to the gray zone, and the vinyl chloride sheet was removed. Then, it was moved back to our endoscopic room and wiped clean again. Regarding the endoscope, it was placed in a special box to prevent infections in the gray zone and brought to the washing area of our endoscopic room. It was thoroughly washed by an assistant, who wore gloves, disposable face shield, waterproof disposable gown, and an N95 mask. During flushing of the channel before putting the endoscope in an endoscopic machine wash, we used an N95 mask as, theoretically, aerosolization could occur. Afterward, a standard reprocessing procedure similar to regular disinfection of endoscopy was performed.
7
,
8
,
9
Due to flushing, the floor can be contaminated by droplets and particles. Thus, we disinfected the floor with 1:50 dilution of a household chlorine‐based bleach (final concentration 0.1%, 1000 ppm). The room where the endoscopy was performed was also disinfected with this solution.
Here, we present a case of an urgent colonoscopic hemostasis for a patient with COVID‐19, our tips, and the various management methods used to prevent contamination by COVID‐19.
Acknowledgments
We thank all members of the Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, for helping with this study. We also thank Kaito Sakuragi, Yuta Yamaguchi, Toshimasa Takahashi, Kouken Matsuo, Naomi Yoshizawa, Kiyomi Matsuda, and other members in our endoscopic center for the special effort required in this urgent endoscopy. | FAVIPIRAVIR, HEPARIN SODIUM, HYDROXYCHLOROQUINE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33490630 | 18,538,037 | 2021-01 |
What was the outcome of reaction 'Hypovolaemic shock'? | A case of urgent colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient receiving heparin for COVID-19 coagulopathy.
COVID-19 rarely causes lower gastrointestinal bleeding even though its RNA has been detected in patient's stool. Urgent colonoscopy in a COVID-19 patient with massive bloody stool requires various procedural and equipment considerations. Here, we present a case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID-19 coagulopathy. We also share various management methods for the prevention of COVID-19 contamination. A 71-year-old man was diagnosed with COVID-19 pneumonia and subsequently underwent hemodiafiltration. Heparin was initiated for COVID-19 coagulopathy. At day 42, the patient experienced 2000 mL of bloody stool. An operator performed urgent colonoscopy with three assistants in a negative-pressure room with full personal protective equipment. A hemorrhagic ulceration was detected at the cecum, and endoscopic hemostasis was performed. Immunohistochemistry was positive for cytomegalovirus. Postprocedure, the endoscopic systems were thoroughly cleaned, and specific measures for endoscope reprocessing and disinfection were performed to prevent contamination with COVID-19.
Introduction
A novel coronavirus, severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), was first identified in Wuhan, China, and subsequently named COVID‐19 by the World Health Organization.
1
,
2
,
3
The common symptoms of COVID‐19 at the onset of illness are fever, cough, fatigue, myalgia, and dyspnea. SARS‐CoV‐2 enters cells via the angiotensin converting enzyme 2 (ACE2) receptor. ACE2 was highly expressed not only in type II alveolar cells of the lung but also in esophageal epithelial cells and the absorptive enterocytes of ileum and colon, suggesting gastrointestinal (GI) symptoms and possible fecal transmission.
1
,
3
A review of the GI symptoms caused by COVID‐19 showed that the incidence ranged from 3% (1/41) to 79% (159/201).
4
The rate of each symptom reported was as follows: anorexia 39.9% (55/138) to 50.2% (101/201), diarrhea 2% (2/99) to 49.5% (146/295), vomiting 3.6% (5/138) to 66.7% (4/6), nausea 1% (1/99) to 29.4% (59/201), abdominal pain 2.2% (3/138) to 6.0% (12/201), and GI bleeding 4% (2/52) to 13.7% (10/73). GI bleeding may require urgent endoscopy intervention. In addition, recent reports showed many cases of COVID‐19 coagulopathy, which are managed with heparin.
5
This, in turn, will likely increase the rate of GI bleeding.
SARS‐CoV‐2 is highly contagious as the virus can remain viable and infectious in aerosols for 3 h and on plastic and stainless steel surfaces for up to 3 days.
2
In addition, given that SARS‐CoV‐2 RNA has been detected in patient's stool, it is possible that SARS‐CoV‐2 could also be transmitted via the fecal–oral route.
6
Interestingly, even among patients without GI symptoms, SARS‐CoV‐2 RNA was detected in feces (39.1%, 9/23) compared to patients with GI symptoms (52.4%, 22/42). Thus, in reference to these facts, various considerations are required to prevent COVID‐19 infections spreading to medical staff and virus contamination of endoscopic equipment when performing a colonoscopy. Several papers demonstrated the management methods used in endoscopy centers to prevent the spread of the virus.
7
,
8
,
9
However, these guidelines are sometimes inadequate as each country or institution may encounter a new unaddressed situation. To our knowledge, there has been no previous case report on urgent colonoscopy for a COVID‐19 case with massive hemorrhage. Here, we present an urgent case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID‐19 coagulopathy, as well as the various management methods for preventing contamination by COVID‐19.
Case report
A 71‐year‐old man complained of fever, with computed tomography showing bilateral pneumonia. The patient had underlying autoimmune pancreatitis and diabetes mellitus and was on steroids (oral prednisolone: 15 mg/day). The nasopharyngeal swab sample confirmed the presence of SARS‐CoV‐2. The patient was admitted to our hospital and subsequently required artificial respiration. Intravenous prednisolone was prescribed (20 mg/day) instead of oral prednisolone. The patient's condition did not improve even on treatment with favipiravir initially and then on hydroxychloroquine. Hemodiafiltration was started at day 18, and heparin was prescribed for both hemodialysis and coagulopathy secondary to coronavirus. At day 42, the patient suddenly complained of a large volume of bloody stool (approximately 2000 mL). Despite receiving 1400 mL of red blood cell transfusion, the bloody stool continued, resulting in hypovolemic shock. Computed tomography showed diffuse wall thickening of the ascending colon and cecum. Stool cultures were negative, including for Clostridium difficile. Heparin was stopped, and we performed an urgent colonoscopy in a specific negative‐pressure room with full personal protect equipment (PPE) to prevent cross‐infection (Fig. 1a,b). The endoscopic system was covered with a sheet of vinyl chloride to prevent contamination. The patient's hip was also covered with a special vinyl chloride sheet to prevent the spread of hemorrhagic feces. The colonoscopy showed ulceration at the cecum and ascending colon (Fig. 1c). An exposed vessel under the clot was detected at the cecal ulceration and treated with endoscopic clips for hemostasis. In addition, heparin was changed to nafamostat mesilate with subsequent cessation of the bloody stool. A blood test and immunohistochemical examination of the biopsy specimen were positive for cytomegalovirus (CMV). The patient was then started on ganciclovir. However, respiratory function and general condition worsened, and unfortunately, the patient died 2 weeks after endoscopic hemostasis. This case report was approved by our institutional ethical board (ERB‐C‐1600).
Figure 1 Endoscopic system and personal protective equipment (PPE) for a case of COVID‐19 cecal hemorrhagic ulcer. (a) The endoscopic system was covered by a vinyl chloride sheet prior to being moved to a negative‐pressure room. PPE used when the patient is positive for COVID‐19 or at high risk of it; covering all of exposed skin utilizing an N95 mask, two pairs of gloves, shoe covers, disposable hairnet, disposable face shield, and waterproof disposable gowns. (b) A special blue vinyl chloride sheet with a hole for colonoscope (red arrow and red box) was used to prevent the spread of hemorrhagic feces. The procedure was performed in a negative‐pressure room with an operator, one assistant for the endoscopic procedure, and two assistants observing the respiratory system and patient's status. (c) Cecal ulceration on urgent colonoscopy in a patient with COVID‐19. The exposed vessel was detected under a clot (white arrow) on the ulcer.
Discussion
There are three main issues regarding an urgent colonoscopy for a patient with COVID‐19, as follows: 1. PPE for medical staff due to infectious risk
2
; case‐by‐case management for endoscopic procedures; and.
3
reprocessing and cleaning of endoscopic systems, various equipment, and rooms.
In treating COVID‐19‐positive patients, PPE is recommended as follows: two pairs of gloves, hairnet, protective face shield, long‐sleeved waterproof gowns, shoe covers, and high‐filter respiratory masks (N95, FFP2, or FFP3).
7
,
8
,
9
We utilized all of the above, with a special hairnet covering the operator's neck. An assistant should help the operator to put on the PPE, and pretraining should be implemented using e‐learning.
7
,
8
,
9
A marketed endoscopic lens cleaner (Cleash, Fujifilm, Tokyo) was applied on the face shield to prevent fogging. The minimum number of endoscopists and assistants should be in the red zone to prevent further infection. We paid attention to possibilities of periendoscopic infections from aerosol particles as the patient had a tracheostomy. Further dispersion might occur by colonoscopic insufflation. Therefore, we wore N95 mask and utilized a special waterproof (vinyl chloride) sheet covering the patient's hip, with a small hole for insertion of the endoscope.
Statements from European Society for Gastrointestinal Endoscopy (ESGE) and European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) showed four categories for endoscopic indications, such as (i) perform always, (ii and iii) case‐by‐case management with high or low priority, and (iv) postpone always.
7
However, for patients with the coronavirus under artificial respiration, acute lower GI bleeding with hemodynamic instability is the only indication for urgent endoscopy, which is categorized as “perform always” as in our case. In a lower gastrointestinal hemorrhagic case, a paper on COVID‐19 and inflammatory bowel disease (IBD) showed that 3% of patients had CMV colitis in a total of 76 IBD patients.
10
In our case, steroids prescribed for the patient's autoimmune pancreatitis weakened his immune system, similar to IBD patients. Endoscopists should always consider CMV when a patient on steroid develops lower GI hemorrhage.
In our case, we used single‐use endoscopic accessories, and all were disposed as recommended by several papers.
7
,
8
,
9
Postprocedure, the endoscopic system was wiped in the red zone and moved to the gray zone, and the vinyl chloride sheet was removed. Then, it was moved back to our endoscopic room and wiped clean again. Regarding the endoscope, it was placed in a special box to prevent infections in the gray zone and brought to the washing area of our endoscopic room. It was thoroughly washed by an assistant, who wore gloves, disposable face shield, waterproof disposable gown, and an N95 mask. During flushing of the channel before putting the endoscope in an endoscopic machine wash, we used an N95 mask as, theoretically, aerosolization could occur. Afterward, a standard reprocessing procedure similar to regular disinfection of endoscopy was performed.
7
,
8
,
9
Due to flushing, the floor can be contaminated by droplets and particles. Thus, we disinfected the floor with 1:50 dilution of a household chlorine‐based bleach (final concentration 0.1%, 1000 ppm). The room where the endoscopy was performed was also disinfected with this solution.
Here, we present a case of an urgent colonoscopic hemostasis for a patient with COVID‐19, our tips, and the various management methods used to prevent contamination by COVID‐19.
Acknowledgments
We thank all members of the Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, for helping with this study. We also thank Kaito Sakuragi, Yuta Yamaguchi, Toshimasa Takahashi, Kouken Matsuo, Naomi Yoshizawa, Kiyomi Matsuda, and other members in our endoscopic center for the special effort required in this urgent endoscopy. | Recovered | ReactionOutcome | CC BY | 33490630 | 18,538,037 | 2021-01 |
What was the outcome of reaction 'Large intestinal haemorrhage'? | A case of urgent colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient receiving heparin for COVID-19 coagulopathy.
COVID-19 rarely causes lower gastrointestinal bleeding even though its RNA has been detected in patient's stool. Urgent colonoscopy in a COVID-19 patient with massive bloody stool requires various procedural and equipment considerations. Here, we present a case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID-19 coagulopathy. We also share various management methods for the prevention of COVID-19 contamination. A 71-year-old man was diagnosed with COVID-19 pneumonia and subsequently underwent hemodiafiltration. Heparin was initiated for COVID-19 coagulopathy. At day 42, the patient experienced 2000 mL of bloody stool. An operator performed urgent colonoscopy with three assistants in a negative-pressure room with full personal protective equipment. A hemorrhagic ulceration was detected at the cecum, and endoscopic hemostasis was performed. Immunohistochemistry was positive for cytomegalovirus. Postprocedure, the endoscopic systems were thoroughly cleaned, and specific measures for endoscope reprocessing and disinfection were performed to prevent contamination with COVID-19.
Introduction
A novel coronavirus, severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), was first identified in Wuhan, China, and subsequently named COVID‐19 by the World Health Organization.
1
,
2
,
3
The common symptoms of COVID‐19 at the onset of illness are fever, cough, fatigue, myalgia, and dyspnea. SARS‐CoV‐2 enters cells via the angiotensin converting enzyme 2 (ACE2) receptor. ACE2 was highly expressed not only in type II alveolar cells of the lung but also in esophageal epithelial cells and the absorptive enterocytes of ileum and colon, suggesting gastrointestinal (GI) symptoms and possible fecal transmission.
1
,
3
A review of the GI symptoms caused by COVID‐19 showed that the incidence ranged from 3% (1/41) to 79% (159/201).
4
The rate of each symptom reported was as follows: anorexia 39.9% (55/138) to 50.2% (101/201), diarrhea 2% (2/99) to 49.5% (146/295), vomiting 3.6% (5/138) to 66.7% (4/6), nausea 1% (1/99) to 29.4% (59/201), abdominal pain 2.2% (3/138) to 6.0% (12/201), and GI bleeding 4% (2/52) to 13.7% (10/73). GI bleeding may require urgent endoscopy intervention. In addition, recent reports showed many cases of COVID‐19 coagulopathy, which are managed with heparin.
5
This, in turn, will likely increase the rate of GI bleeding.
SARS‐CoV‐2 is highly contagious as the virus can remain viable and infectious in aerosols for 3 h and on plastic and stainless steel surfaces for up to 3 days.
2
In addition, given that SARS‐CoV‐2 RNA has been detected in patient's stool, it is possible that SARS‐CoV‐2 could also be transmitted via the fecal–oral route.
6
Interestingly, even among patients without GI symptoms, SARS‐CoV‐2 RNA was detected in feces (39.1%, 9/23) compared to patients with GI symptoms (52.4%, 22/42). Thus, in reference to these facts, various considerations are required to prevent COVID‐19 infections spreading to medical staff and virus contamination of endoscopic equipment when performing a colonoscopy. Several papers demonstrated the management methods used in endoscopy centers to prevent the spread of the virus.
7
,
8
,
9
However, these guidelines are sometimes inadequate as each country or institution may encounter a new unaddressed situation. To our knowledge, there has been no previous case report on urgent colonoscopy for a COVID‐19 case with massive hemorrhage. Here, we present an urgent case of colonoscopic hemostasis of a cecal hemorrhagic ulceration in a patient on heparin for COVID‐19 coagulopathy, as well as the various management methods for preventing contamination by COVID‐19.
Case report
A 71‐year‐old man complained of fever, with computed tomography showing bilateral pneumonia. The patient had underlying autoimmune pancreatitis and diabetes mellitus and was on steroids (oral prednisolone: 15 mg/day). The nasopharyngeal swab sample confirmed the presence of SARS‐CoV‐2. The patient was admitted to our hospital and subsequently required artificial respiration. Intravenous prednisolone was prescribed (20 mg/day) instead of oral prednisolone. The patient's condition did not improve even on treatment with favipiravir initially and then on hydroxychloroquine. Hemodiafiltration was started at day 18, and heparin was prescribed for both hemodialysis and coagulopathy secondary to coronavirus. At day 42, the patient suddenly complained of a large volume of bloody stool (approximately 2000 mL). Despite receiving 1400 mL of red blood cell transfusion, the bloody stool continued, resulting in hypovolemic shock. Computed tomography showed diffuse wall thickening of the ascending colon and cecum. Stool cultures were negative, including for Clostridium difficile. Heparin was stopped, and we performed an urgent colonoscopy in a specific negative‐pressure room with full personal protect equipment (PPE) to prevent cross‐infection (Fig. 1a,b). The endoscopic system was covered with a sheet of vinyl chloride to prevent contamination. The patient's hip was also covered with a special vinyl chloride sheet to prevent the spread of hemorrhagic feces. The colonoscopy showed ulceration at the cecum and ascending colon (Fig. 1c). An exposed vessel under the clot was detected at the cecal ulceration and treated with endoscopic clips for hemostasis. In addition, heparin was changed to nafamostat mesilate with subsequent cessation of the bloody stool. A blood test and immunohistochemical examination of the biopsy specimen were positive for cytomegalovirus (CMV). The patient was then started on ganciclovir. However, respiratory function and general condition worsened, and unfortunately, the patient died 2 weeks after endoscopic hemostasis. This case report was approved by our institutional ethical board (ERB‐C‐1600).
Figure 1 Endoscopic system and personal protective equipment (PPE) for a case of COVID‐19 cecal hemorrhagic ulcer. (a) The endoscopic system was covered by a vinyl chloride sheet prior to being moved to a negative‐pressure room. PPE used when the patient is positive for COVID‐19 or at high risk of it; covering all of exposed skin utilizing an N95 mask, two pairs of gloves, shoe covers, disposable hairnet, disposable face shield, and waterproof disposable gowns. (b) A special blue vinyl chloride sheet with a hole for colonoscope (red arrow and red box) was used to prevent the spread of hemorrhagic feces. The procedure was performed in a negative‐pressure room with an operator, one assistant for the endoscopic procedure, and two assistants observing the respiratory system and patient's status. (c) Cecal ulceration on urgent colonoscopy in a patient with COVID‐19. The exposed vessel was detected under a clot (white arrow) on the ulcer.
Discussion
There are three main issues regarding an urgent colonoscopy for a patient with COVID‐19, as follows: 1. PPE for medical staff due to infectious risk
2
; case‐by‐case management for endoscopic procedures; and.
3
reprocessing and cleaning of endoscopic systems, various equipment, and rooms.
In treating COVID‐19‐positive patients, PPE is recommended as follows: two pairs of gloves, hairnet, protective face shield, long‐sleeved waterproof gowns, shoe covers, and high‐filter respiratory masks (N95, FFP2, or FFP3).
7
,
8
,
9
We utilized all of the above, with a special hairnet covering the operator's neck. An assistant should help the operator to put on the PPE, and pretraining should be implemented using e‐learning.
7
,
8
,
9
A marketed endoscopic lens cleaner (Cleash, Fujifilm, Tokyo) was applied on the face shield to prevent fogging. The minimum number of endoscopists and assistants should be in the red zone to prevent further infection. We paid attention to possibilities of periendoscopic infections from aerosol particles as the patient had a tracheostomy. Further dispersion might occur by colonoscopic insufflation. Therefore, we wore N95 mask and utilized a special waterproof (vinyl chloride) sheet covering the patient's hip, with a small hole for insertion of the endoscope.
Statements from European Society for Gastrointestinal Endoscopy (ESGE) and European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) showed four categories for endoscopic indications, such as (i) perform always, (ii and iii) case‐by‐case management with high or low priority, and (iv) postpone always.
7
However, for patients with the coronavirus under artificial respiration, acute lower GI bleeding with hemodynamic instability is the only indication for urgent endoscopy, which is categorized as “perform always” as in our case. In a lower gastrointestinal hemorrhagic case, a paper on COVID‐19 and inflammatory bowel disease (IBD) showed that 3% of patients had CMV colitis in a total of 76 IBD patients.
10
In our case, steroids prescribed for the patient's autoimmune pancreatitis weakened his immune system, similar to IBD patients. Endoscopists should always consider CMV when a patient on steroid develops lower GI hemorrhage.
In our case, we used single‐use endoscopic accessories, and all were disposed as recommended by several papers.
7
,
8
,
9
Postprocedure, the endoscopic system was wiped in the red zone and moved to the gray zone, and the vinyl chloride sheet was removed. Then, it was moved back to our endoscopic room and wiped clean again. Regarding the endoscope, it was placed in a special box to prevent infections in the gray zone and brought to the washing area of our endoscopic room. It was thoroughly washed by an assistant, who wore gloves, disposable face shield, waterproof disposable gown, and an N95 mask. During flushing of the channel before putting the endoscope in an endoscopic machine wash, we used an N95 mask as, theoretically, aerosolization could occur. Afterward, a standard reprocessing procedure similar to regular disinfection of endoscopy was performed.
7
,
8
,
9
Due to flushing, the floor can be contaminated by droplets and particles. Thus, we disinfected the floor with 1:50 dilution of a household chlorine‐based bleach (final concentration 0.1%, 1000 ppm). The room where the endoscopy was performed was also disinfected with this solution.
Here, we present a case of an urgent colonoscopic hemostasis for a patient with COVID‐19, our tips, and the various management methods used to prevent contamination by COVID‐19.
Acknowledgments
We thank all members of the Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, for helping with this study. We also thank Kaito Sakuragi, Yuta Yamaguchi, Toshimasa Takahashi, Kouken Matsuo, Naomi Yoshizawa, Kiyomi Matsuda, and other members in our endoscopic center for the special effort required in this urgent endoscopy. | Recovered | ReactionOutcome | CC BY | 33490630 | 18,538,037 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Large intestine perforation'. | Drain site enterocutaneous fistula after hyperthermic intraperitoneal chemotherapy.
Spontaneous sigmoid colon perforation after cytoreduction surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is a rare complication. It is more commonly seen with mitomycin-based HIPEC. This case study's patient presented with pus discharge at the drain site after 4 weeks of surgery. The symptoms persisted after conservative treatment. High suspicion after the feculent smell of the discharge fluidled to the prompt diagnosis of enterocutaneous fistula. There was limitedperforation with abscess formation, followed by fistula formation. The patient was treated successfully with surgery.
Introduction
A fistula is defined as an abnormal communication between two epithelialized hollow spaces or organs. Enterocutaneous fistula connects the bowel to the skin. It can be classified according to the source, output volume, and etiology. Fistulas from different organs have different types of outputs. Electrolyte and nutritional losses can vary accordingly. The low‐output, moderate‐output, and high‐output fistulas were defined as having drain volumes less than 200 mL/day, between 200 and 500 mL/day, and more than 500 mL/day, respectively. High‐output fistulas do not heal spontaneously, and these patients are at a higher risk of metabolic disturbances, fluid loss, and malnutrition. The prevalence of enterocutaneous fistulas in the general population is not known. However, postoperative prevalence of enterocutaneous fistulas is 1.5% for trauma,
1
3.6% for general surgery,
2
and 15–35% for patients with Crohn's disease .
3
The latter is the most common cause of spontaneous fistulas. These are classically treated with immunosuppressive drugs like thiopurines, biologic agents like tumor necrosis factor inhibitors, and antibiotics like metronidazole to reduce bowel inflammation and diarrhea.
Spontaneous fistula is a known but rare complication of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This will usually result in fecal peritonitis but occasionally results in a fistula as outlined in this report. The occurrence of such complications depends on the extent of the peritoneal disease. Mortality ranges from 36 to 44% in the literature.
4
In 15% of cases, the site of perforation in fecal peritonitis remains unclear.
5
The peritoneal trauma due to the direct toxic effect of HIPEC with extensive cytoreduction surgery, occasionally combined with the severe chemotherapy‐induced neutropenia, may be the reason why.
6
This study aims to report a case of spontaneous limited perforation with abscess formation followed by enterocutaneous fistula formation in an ovarian carcinoma patient after CRS with HIPEC in our tertiary care center.
Case report
A 48‐year‐old female was evaluated outside of our center and diagnosed with left ovarian carcinoma. She underwent total laparoscopic hysterectomy with bilateral salpingo‐ophrectomy and received seven cycles of taxane/platinum (TP regimen)‐based adjuvant chemotherapy. After approximately 18 months of disease‐free interval, she was evaluated and diagnosed with recurrent ovarian carcinoma, stage IIIC. In a multidisciplinary tumor board discussion, she was planned for chemotherapy followed by surgical reassessment. After eight cycles of TP‐based chemotherapy, she was reevaluated with positron emission tomography‐computed tomography (PET‐CT). It showed multiple metabolically avid lesions at the surgical bed, omentum, right paracolic gutter, parietal wall, and suprapubic region, suggestive of partially responsive operable disease. Secondary cytoreduction surgery (total omentectomy and disease‐specific peritonectomy) with bilateral pelvic node dissection was performed. Intraoperatively, large omental caking was observed, 10 × 8 cm in size, with multiple peritoneal deposits in the bilateral paracolic gutter, right subdiaphragmatic region, pelvis, lesser omentum, and over segment 6 of the liver. The peritoneal carcinoma index was 13. Staged HIPEC was performed on postoperative day (POD) 1 because of intraoperative instability during the previous definitive surgery. The drug Cisplatin was used in 2 liters of normal saline perfusate at 41–43°C for 1 h. She recovered uneventfully. Histopathological features included high‐grade serous carcinoma and immunopositivity for WT1 and CK7. All retrieved pelvic nodes were free of malignancy. She developed a surgical site infection at the drain site in the left iliac fossa after 1 month of surgery, which worsened with conservative treatment. Later, she presented with fecal discharging sinus (Fig. 1a). Contrast‐enhanced CT with CT‐fistulogram revealed enterocutaneous fistula (Fig. 1b,c). Exploratory laparotomy with partial sigmoid colectomy and fistulous tract excision, followed by colocolic anastomosis, were performed. Intraoperatively, a fistulous tract from the sigmoid colon to left iliac fossa skin was identified (Fig. 1d). Postoperative recovery was uneventful.
Figure 1 (a) Fistulous tract opening in left iliac fossa (yellow arrow). Computed tomography fistulogram shows thick‐walled communicating tract from the sigmoid colon to exterior (yellow arrow) in sagittal (b) and axial (c) views. (d) The intraoperative demonstration of enterocutaneous fistula (yellow arrow).
Discussion
Although enterocutaneous fistulas are a known complication of major surgery for ovarian cancer,
7
,
8
the delayed emergence of a fistula 4 weeks after surgery and CRS/HIPREC appears to be rare. The physiopathology of this postoperative complication is probably due to intraoperative/postoperative peritoneal bacterial contamination. Chua et al. showed that the morbidity and mortality of CRS/HIPEC were similar to those of other major gastrointestinal operations.
9
These fistulas are significantly associated with the operative time, previous systemic chemotherapy or radiotherapy, the number of anastomoses, and the nutritional status. Kusamura et al. found that the extent of cytoreduction surgery and a dose of CDDP ≥240 mg were independent risk factors for digestive fistulas.
10
Intestinal wall edema after CRS/HIPEC causes loosening of the intercellular tight junctions, and this helps in bacterial translocation.
11
HIPEC aggravates visceral edema. Changes in gut microbiota and impaired immunity due to major surgeries are other probable factors for digestive fistulas. Nevertheless, these hypotheses are not proven, but a possible explanation could be an extensive systemic inflammatory response leading to the suppression of cell‐mediated immunity.
12
In our tertiary care center, complete CRS/HIPEC is a complex and aggressive surgical procedure because of the heavy disease burden in the patients. Cisplatin is the most commonly used chemotherapeutic agent in HIPEC for ovarian malignancies. The duration of HIPEC was 60 min in this case. Staged HIPEC was used in this patient as her vitals during the index surgery (complete CRS) were unstable, preventing the administration of HIPEC in the same sitting. Duration of CRS was approximately 8.5 h. This major surgical trauma followed by HIPEC on postoperative day 1 could have caused the bowel edema and exacerbated the impaired immunity in the patient. In addition, the gut microbiota could be changed due to perioperative interventions of CRS/HIPEC, like preoperative mechanical bowel preparation, perioperative antibiotics administration, and the prolonged postoperative ileus‐decreasing intestinal clearance.
This patient presented with symptoms of surgical site infection at the drain site after 1 month of surgery. We advised medical treatment, but the patient did not respond to it and presented with fecal discharge from the same site. Evaluation with radiological imaging confirmed the diagnosis of enterocutaneous fistula, and the patient was treated curatively with surgical intervention. The principles of surgical management are to eliminate the source of infection, to reduce bacterial contamination with peritoneal lavage, and to prevent persistent or recurrent intraperitoneal infection with intraoperative drain placement.
13
Broad‐spectrum antibiotics are also started for the coverage of the most common pathogens until the bacterial culture/sensitivity reports from intraoperative samples are obtained.
The role of the somatostatin analog octreotide for the treatment of digestive fistula remains controversial. It can significantly decrease the fistula output and hence reduces the time to fistula closure.
14
Total parenteral/enteral nutrition helps in infection control and fistulous tract maturation. Fluid and electrolyte correction with abdominal sepsis control are key factors for normal intestinal function and motility.
The mortality reported in various series from postoperative peritonitis due to digestive fistulas is 10–47%.
13
,
14
However, this figure is reduced to 8% after CRS/HIPEC in our center (unpublished data from prospectively maintained departmental database). The reasons may be prompt surgical treatment delivery offered by the experts with a combined multidisciplinary approach.
In conclusion, postoperative enterocutaneous fistula after CRS/HIPEC is a rare entity, which can occur in patients treated with aggressive surgeries for high peritoneal carcinoma index. It may be due to bacterial translocation as a result of bowel edema after the surgery and intraperitoneal chemotherapy. Treatment principles do not differ from other forms of peritonitis. Resuscitation, control of sepsis, and nutritional support are the initial treatment modalities. Definitive surgery to restore gastrointestinal tract continuity, such as in our case, is warranted if the conservative approaches fail. A prompt multidisciplinary approach decreases morbidity and mortality. | CISPLATIN, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33490634 | 18,980,362 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Oedema'. | Drain site enterocutaneous fistula after hyperthermic intraperitoneal chemotherapy.
Spontaneous sigmoid colon perforation after cytoreduction surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is a rare complication. It is more commonly seen with mitomycin-based HIPEC. This case study's patient presented with pus discharge at the drain site after 4 weeks of surgery. The symptoms persisted after conservative treatment. High suspicion after the feculent smell of the discharge fluidled to the prompt diagnosis of enterocutaneous fistula. There was limitedperforation with abscess formation, followed by fistula formation. The patient was treated successfully with surgery.
Introduction
A fistula is defined as an abnormal communication between two epithelialized hollow spaces or organs. Enterocutaneous fistula connects the bowel to the skin. It can be classified according to the source, output volume, and etiology. Fistulas from different organs have different types of outputs. Electrolyte and nutritional losses can vary accordingly. The low‐output, moderate‐output, and high‐output fistulas were defined as having drain volumes less than 200 mL/day, between 200 and 500 mL/day, and more than 500 mL/day, respectively. High‐output fistulas do not heal spontaneously, and these patients are at a higher risk of metabolic disturbances, fluid loss, and malnutrition. The prevalence of enterocutaneous fistulas in the general population is not known. However, postoperative prevalence of enterocutaneous fistulas is 1.5% for trauma,
1
3.6% for general surgery,
2
and 15–35% for patients with Crohn's disease .
3
The latter is the most common cause of spontaneous fistulas. These are classically treated with immunosuppressive drugs like thiopurines, biologic agents like tumor necrosis factor inhibitors, and antibiotics like metronidazole to reduce bowel inflammation and diarrhea.
Spontaneous fistula is a known but rare complication of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This will usually result in fecal peritonitis but occasionally results in a fistula as outlined in this report. The occurrence of such complications depends on the extent of the peritoneal disease. Mortality ranges from 36 to 44% in the literature.
4
In 15% of cases, the site of perforation in fecal peritonitis remains unclear.
5
The peritoneal trauma due to the direct toxic effect of HIPEC with extensive cytoreduction surgery, occasionally combined with the severe chemotherapy‐induced neutropenia, may be the reason why.
6
This study aims to report a case of spontaneous limited perforation with abscess formation followed by enterocutaneous fistula formation in an ovarian carcinoma patient after CRS with HIPEC in our tertiary care center.
Case report
A 48‐year‐old female was evaluated outside of our center and diagnosed with left ovarian carcinoma. She underwent total laparoscopic hysterectomy with bilateral salpingo‐ophrectomy and received seven cycles of taxane/platinum (TP regimen)‐based adjuvant chemotherapy. After approximately 18 months of disease‐free interval, she was evaluated and diagnosed with recurrent ovarian carcinoma, stage IIIC. In a multidisciplinary tumor board discussion, she was planned for chemotherapy followed by surgical reassessment. After eight cycles of TP‐based chemotherapy, she was reevaluated with positron emission tomography‐computed tomography (PET‐CT). It showed multiple metabolically avid lesions at the surgical bed, omentum, right paracolic gutter, parietal wall, and suprapubic region, suggestive of partially responsive operable disease. Secondary cytoreduction surgery (total omentectomy and disease‐specific peritonectomy) with bilateral pelvic node dissection was performed. Intraoperatively, large omental caking was observed, 10 × 8 cm in size, with multiple peritoneal deposits in the bilateral paracolic gutter, right subdiaphragmatic region, pelvis, lesser omentum, and over segment 6 of the liver. The peritoneal carcinoma index was 13. Staged HIPEC was performed on postoperative day (POD) 1 because of intraoperative instability during the previous definitive surgery. The drug Cisplatin was used in 2 liters of normal saline perfusate at 41–43°C for 1 h. She recovered uneventfully. Histopathological features included high‐grade serous carcinoma and immunopositivity for WT1 and CK7. All retrieved pelvic nodes were free of malignancy. She developed a surgical site infection at the drain site in the left iliac fossa after 1 month of surgery, which worsened with conservative treatment. Later, she presented with fecal discharging sinus (Fig. 1a). Contrast‐enhanced CT with CT‐fistulogram revealed enterocutaneous fistula (Fig. 1b,c). Exploratory laparotomy with partial sigmoid colectomy and fistulous tract excision, followed by colocolic anastomosis, were performed. Intraoperatively, a fistulous tract from the sigmoid colon to left iliac fossa skin was identified (Fig. 1d). Postoperative recovery was uneventful.
Figure 1 (a) Fistulous tract opening in left iliac fossa (yellow arrow). Computed tomography fistulogram shows thick‐walled communicating tract from the sigmoid colon to exterior (yellow arrow) in sagittal (b) and axial (c) views. (d) The intraoperative demonstration of enterocutaneous fistula (yellow arrow).
Discussion
Although enterocutaneous fistulas are a known complication of major surgery for ovarian cancer,
7
,
8
the delayed emergence of a fistula 4 weeks after surgery and CRS/HIPREC appears to be rare. The physiopathology of this postoperative complication is probably due to intraoperative/postoperative peritoneal bacterial contamination. Chua et al. showed that the morbidity and mortality of CRS/HIPEC were similar to those of other major gastrointestinal operations.
9
These fistulas are significantly associated with the operative time, previous systemic chemotherapy or radiotherapy, the number of anastomoses, and the nutritional status. Kusamura et al. found that the extent of cytoreduction surgery and a dose of CDDP ≥240 mg were independent risk factors for digestive fistulas.
10
Intestinal wall edema after CRS/HIPEC causes loosening of the intercellular tight junctions, and this helps in bacterial translocation.
11
HIPEC aggravates visceral edema. Changes in gut microbiota and impaired immunity due to major surgeries are other probable factors for digestive fistulas. Nevertheless, these hypotheses are not proven, but a possible explanation could be an extensive systemic inflammatory response leading to the suppression of cell‐mediated immunity.
12
In our tertiary care center, complete CRS/HIPEC is a complex and aggressive surgical procedure because of the heavy disease burden in the patients. Cisplatin is the most commonly used chemotherapeutic agent in HIPEC for ovarian malignancies. The duration of HIPEC was 60 min in this case. Staged HIPEC was used in this patient as her vitals during the index surgery (complete CRS) were unstable, preventing the administration of HIPEC in the same sitting. Duration of CRS was approximately 8.5 h. This major surgical trauma followed by HIPEC on postoperative day 1 could have caused the bowel edema and exacerbated the impaired immunity in the patient. In addition, the gut microbiota could be changed due to perioperative interventions of CRS/HIPEC, like preoperative mechanical bowel preparation, perioperative antibiotics administration, and the prolonged postoperative ileus‐decreasing intestinal clearance.
This patient presented with symptoms of surgical site infection at the drain site after 1 month of surgery. We advised medical treatment, but the patient did not respond to it and presented with fecal discharge from the same site. Evaluation with radiological imaging confirmed the diagnosis of enterocutaneous fistula, and the patient was treated curatively with surgical intervention. The principles of surgical management are to eliminate the source of infection, to reduce bacterial contamination with peritoneal lavage, and to prevent persistent or recurrent intraperitoneal infection with intraoperative drain placement.
13
Broad‐spectrum antibiotics are also started for the coverage of the most common pathogens until the bacterial culture/sensitivity reports from intraoperative samples are obtained.
The role of the somatostatin analog octreotide for the treatment of digestive fistula remains controversial. It can significantly decrease the fistula output and hence reduces the time to fistula closure.
14
Total parenteral/enteral nutrition helps in infection control and fistulous tract maturation. Fluid and electrolyte correction with abdominal sepsis control are key factors for normal intestinal function and motility.
The mortality reported in various series from postoperative peritonitis due to digestive fistulas is 10–47%.
13
,
14
However, this figure is reduced to 8% after CRS/HIPEC in our center (unpublished data from prospectively maintained departmental database). The reasons may be prompt surgical treatment delivery offered by the experts with a combined multidisciplinary approach.
In conclusion, postoperative enterocutaneous fistula after CRS/HIPEC is a rare entity, which can occur in patients treated with aggressive surgeries for high peritoneal carcinoma index. It may be due to bacterial translocation as a result of bowel edema after the surgery and intraperitoneal chemotherapy. Treatment principles do not differ from other forms of peritonitis. Resuscitation, control of sepsis, and nutritional support are the initial treatment modalities. Definitive surgery to restore gastrointestinal tract continuity, such as in our case, is warranted if the conservative approaches fail. A prompt multidisciplinary approach decreases morbidity and mortality. | CISPLATIN | DrugsGivenReaction | CC BY | 33490634 | 18,873,222 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Postoperative wound infection'. | Drain site enterocutaneous fistula after hyperthermic intraperitoneal chemotherapy.
Spontaneous sigmoid colon perforation after cytoreduction surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is a rare complication. It is more commonly seen with mitomycin-based HIPEC. This case study's patient presented with pus discharge at the drain site after 4 weeks of surgery. The symptoms persisted after conservative treatment. High suspicion after the feculent smell of the discharge fluidled to the prompt diagnosis of enterocutaneous fistula. There was limitedperforation with abscess formation, followed by fistula formation. The patient was treated successfully with surgery.
Introduction
A fistula is defined as an abnormal communication between two epithelialized hollow spaces or organs. Enterocutaneous fistula connects the bowel to the skin. It can be classified according to the source, output volume, and etiology. Fistulas from different organs have different types of outputs. Electrolyte and nutritional losses can vary accordingly. The low‐output, moderate‐output, and high‐output fistulas were defined as having drain volumes less than 200 mL/day, between 200 and 500 mL/day, and more than 500 mL/day, respectively. High‐output fistulas do not heal spontaneously, and these patients are at a higher risk of metabolic disturbances, fluid loss, and malnutrition. The prevalence of enterocutaneous fistulas in the general population is not known. However, postoperative prevalence of enterocutaneous fistulas is 1.5% for trauma,
1
3.6% for general surgery,
2
and 15–35% for patients with Crohn's disease .
3
The latter is the most common cause of spontaneous fistulas. These are classically treated with immunosuppressive drugs like thiopurines, biologic agents like tumor necrosis factor inhibitors, and antibiotics like metronidazole to reduce bowel inflammation and diarrhea.
Spontaneous fistula is a known but rare complication of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This will usually result in fecal peritonitis but occasionally results in a fistula as outlined in this report. The occurrence of such complications depends on the extent of the peritoneal disease. Mortality ranges from 36 to 44% in the literature.
4
In 15% of cases, the site of perforation in fecal peritonitis remains unclear.
5
The peritoneal trauma due to the direct toxic effect of HIPEC with extensive cytoreduction surgery, occasionally combined with the severe chemotherapy‐induced neutropenia, may be the reason why.
6
This study aims to report a case of spontaneous limited perforation with abscess formation followed by enterocutaneous fistula formation in an ovarian carcinoma patient after CRS with HIPEC in our tertiary care center.
Case report
A 48‐year‐old female was evaluated outside of our center and diagnosed with left ovarian carcinoma. She underwent total laparoscopic hysterectomy with bilateral salpingo‐ophrectomy and received seven cycles of taxane/platinum (TP regimen)‐based adjuvant chemotherapy. After approximately 18 months of disease‐free interval, she was evaluated and diagnosed with recurrent ovarian carcinoma, stage IIIC. In a multidisciplinary tumor board discussion, she was planned for chemotherapy followed by surgical reassessment. After eight cycles of TP‐based chemotherapy, she was reevaluated with positron emission tomography‐computed tomography (PET‐CT). It showed multiple metabolically avid lesions at the surgical bed, omentum, right paracolic gutter, parietal wall, and suprapubic region, suggestive of partially responsive operable disease. Secondary cytoreduction surgery (total omentectomy and disease‐specific peritonectomy) with bilateral pelvic node dissection was performed. Intraoperatively, large omental caking was observed, 10 × 8 cm in size, with multiple peritoneal deposits in the bilateral paracolic gutter, right subdiaphragmatic region, pelvis, lesser omentum, and over segment 6 of the liver. The peritoneal carcinoma index was 13. Staged HIPEC was performed on postoperative day (POD) 1 because of intraoperative instability during the previous definitive surgery. The drug Cisplatin was used in 2 liters of normal saline perfusate at 41–43°C for 1 h. She recovered uneventfully. Histopathological features included high‐grade serous carcinoma and immunopositivity for WT1 and CK7. All retrieved pelvic nodes were free of malignancy. She developed a surgical site infection at the drain site in the left iliac fossa after 1 month of surgery, which worsened with conservative treatment. Later, she presented with fecal discharging sinus (Fig. 1a). Contrast‐enhanced CT with CT‐fistulogram revealed enterocutaneous fistula (Fig. 1b,c). Exploratory laparotomy with partial sigmoid colectomy and fistulous tract excision, followed by colocolic anastomosis, were performed. Intraoperatively, a fistulous tract from the sigmoid colon to left iliac fossa skin was identified (Fig. 1d). Postoperative recovery was uneventful.
Figure 1 (a) Fistulous tract opening in left iliac fossa (yellow arrow). Computed tomography fistulogram shows thick‐walled communicating tract from the sigmoid colon to exterior (yellow arrow) in sagittal (b) and axial (c) views. (d) The intraoperative demonstration of enterocutaneous fistula (yellow arrow).
Discussion
Although enterocutaneous fistulas are a known complication of major surgery for ovarian cancer,
7
,
8
the delayed emergence of a fistula 4 weeks after surgery and CRS/HIPREC appears to be rare. The physiopathology of this postoperative complication is probably due to intraoperative/postoperative peritoneal bacterial contamination. Chua et al. showed that the morbidity and mortality of CRS/HIPEC were similar to those of other major gastrointestinal operations.
9
These fistulas are significantly associated with the operative time, previous systemic chemotherapy or radiotherapy, the number of anastomoses, and the nutritional status. Kusamura et al. found that the extent of cytoreduction surgery and a dose of CDDP ≥240 mg were independent risk factors for digestive fistulas.
10
Intestinal wall edema after CRS/HIPEC causes loosening of the intercellular tight junctions, and this helps in bacterial translocation.
11
HIPEC aggravates visceral edema. Changes in gut microbiota and impaired immunity due to major surgeries are other probable factors for digestive fistulas. Nevertheless, these hypotheses are not proven, but a possible explanation could be an extensive systemic inflammatory response leading to the suppression of cell‐mediated immunity.
12
In our tertiary care center, complete CRS/HIPEC is a complex and aggressive surgical procedure because of the heavy disease burden in the patients. Cisplatin is the most commonly used chemotherapeutic agent in HIPEC for ovarian malignancies. The duration of HIPEC was 60 min in this case. Staged HIPEC was used in this patient as her vitals during the index surgery (complete CRS) were unstable, preventing the administration of HIPEC in the same sitting. Duration of CRS was approximately 8.5 h. This major surgical trauma followed by HIPEC on postoperative day 1 could have caused the bowel edema and exacerbated the impaired immunity in the patient. In addition, the gut microbiota could be changed due to perioperative interventions of CRS/HIPEC, like preoperative mechanical bowel preparation, perioperative antibiotics administration, and the prolonged postoperative ileus‐decreasing intestinal clearance.
This patient presented with symptoms of surgical site infection at the drain site after 1 month of surgery. We advised medical treatment, but the patient did not respond to it and presented with fecal discharge from the same site. Evaluation with radiological imaging confirmed the diagnosis of enterocutaneous fistula, and the patient was treated curatively with surgical intervention. The principles of surgical management are to eliminate the source of infection, to reduce bacterial contamination with peritoneal lavage, and to prevent persistent or recurrent intraperitoneal infection with intraoperative drain placement.
13
Broad‐spectrum antibiotics are also started for the coverage of the most common pathogens until the bacterial culture/sensitivity reports from intraoperative samples are obtained.
The role of the somatostatin analog octreotide for the treatment of digestive fistula remains controversial. It can significantly decrease the fistula output and hence reduces the time to fistula closure.
14
Total parenteral/enteral nutrition helps in infection control and fistulous tract maturation. Fluid and electrolyte correction with abdominal sepsis control are key factors for normal intestinal function and motility.
The mortality reported in various series from postoperative peritonitis due to digestive fistulas is 10–47%.
13
,
14
However, this figure is reduced to 8% after CRS/HIPEC in our center (unpublished data from prospectively maintained departmental database). The reasons may be prompt surgical treatment delivery offered by the experts with a combined multidisciplinary approach.
In conclusion, postoperative enterocutaneous fistula after CRS/HIPEC is a rare entity, which can occur in patients treated with aggressive surgeries for high peritoneal carcinoma index. It may be due to bacterial translocation as a result of bowel edema after the surgery and intraperitoneal chemotherapy. Treatment principles do not differ from other forms of peritonitis. Resuscitation, control of sepsis, and nutritional support are the initial treatment modalities. Definitive surgery to restore gastrointestinal tract continuity, such as in our case, is warranted if the conservative approaches fail. A prompt multidisciplinary approach decreases morbidity and mortality. | CISPLATIN | DrugsGivenReaction | CC BY | 33490634 | 18,873,222 | 2021-01 |
What was the administration route of drug 'CISPLATIN'? | Drain site enterocutaneous fistula after hyperthermic intraperitoneal chemotherapy.
Spontaneous sigmoid colon perforation after cytoreduction surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is a rare complication. It is more commonly seen with mitomycin-based HIPEC. This case study's patient presented with pus discharge at the drain site after 4 weeks of surgery. The symptoms persisted after conservative treatment. High suspicion after the feculent smell of the discharge fluidled to the prompt diagnosis of enterocutaneous fistula. There was limitedperforation with abscess formation, followed by fistula formation. The patient was treated successfully with surgery.
Introduction
A fistula is defined as an abnormal communication between two epithelialized hollow spaces or organs. Enterocutaneous fistula connects the bowel to the skin. It can be classified according to the source, output volume, and etiology. Fistulas from different organs have different types of outputs. Electrolyte and nutritional losses can vary accordingly. The low‐output, moderate‐output, and high‐output fistulas were defined as having drain volumes less than 200 mL/day, between 200 and 500 mL/day, and more than 500 mL/day, respectively. High‐output fistulas do not heal spontaneously, and these patients are at a higher risk of metabolic disturbances, fluid loss, and malnutrition. The prevalence of enterocutaneous fistulas in the general population is not known. However, postoperative prevalence of enterocutaneous fistulas is 1.5% for trauma,
1
3.6% for general surgery,
2
and 15–35% for patients with Crohn's disease .
3
The latter is the most common cause of spontaneous fistulas. These are classically treated with immunosuppressive drugs like thiopurines, biologic agents like tumor necrosis factor inhibitors, and antibiotics like metronidazole to reduce bowel inflammation and diarrhea.
Spontaneous fistula is a known but rare complication of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This will usually result in fecal peritonitis but occasionally results in a fistula as outlined in this report. The occurrence of such complications depends on the extent of the peritoneal disease. Mortality ranges from 36 to 44% in the literature.
4
In 15% of cases, the site of perforation in fecal peritonitis remains unclear.
5
The peritoneal trauma due to the direct toxic effect of HIPEC with extensive cytoreduction surgery, occasionally combined with the severe chemotherapy‐induced neutropenia, may be the reason why.
6
This study aims to report a case of spontaneous limited perforation with abscess formation followed by enterocutaneous fistula formation in an ovarian carcinoma patient after CRS with HIPEC in our tertiary care center.
Case report
A 48‐year‐old female was evaluated outside of our center and diagnosed with left ovarian carcinoma. She underwent total laparoscopic hysterectomy with bilateral salpingo‐ophrectomy and received seven cycles of taxane/platinum (TP regimen)‐based adjuvant chemotherapy. After approximately 18 months of disease‐free interval, she was evaluated and diagnosed with recurrent ovarian carcinoma, stage IIIC. In a multidisciplinary tumor board discussion, she was planned for chemotherapy followed by surgical reassessment. After eight cycles of TP‐based chemotherapy, she was reevaluated with positron emission tomography‐computed tomography (PET‐CT). It showed multiple metabolically avid lesions at the surgical bed, omentum, right paracolic gutter, parietal wall, and suprapubic region, suggestive of partially responsive operable disease. Secondary cytoreduction surgery (total omentectomy and disease‐specific peritonectomy) with bilateral pelvic node dissection was performed. Intraoperatively, large omental caking was observed, 10 × 8 cm in size, with multiple peritoneal deposits in the bilateral paracolic gutter, right subdiaphragmatic region, pelvis, lesser omentum, and over segment 6 of the liver. The peritoneal carcinoma index was 13. Staged HIPEC was performed on postoperative day (POD) 1 because of intraoperative instability during the previous definitive surgery. The drug Cisplatin was used in 2 liters of normal saline perfusate at 41–43°C for 1 h. She recovered uneventfully. Histopathological features included high‐grade serous carcinoma and immunopositivity for WT1 and CK7. All retrieved pelvic nodes were free of malignancy. She developed a surgical site infection at the drain site in the left iliac fossa after 1 month of surgery, which worsened with conservative treatment. Later, she presented with fecal discharging sinus (Fig. 1a). Contrast‐enhanced CT with CT‐fistulogram revealed enterocutaneous fistula (Fig. 1b,c). Exploratory laparotomy with partial sigmoid colectomy and fistulous tract excision, followed by colocolic anastomosis, were performed. Intraoperatively, a fistulous tract from the sigmoid colon to left iliac fossa skin was identified (Fig. 1d). Postoperative recovery was uneventful.
Figure 1 (a) Fistulous tract opening in left iliac fossa (yellow arrow). Computed tomography fistulogram shows thick‐walled communicating tract from the sigmoid colon to exterior (yellow arrow) in sagittal (b) and axial (c) views. (d) The intraoperative demonstration of enterocutaneous fistula (yellow arrow).
Discussion
Although enterocutaneous fistulas are a known complication of major surgery for ovarian cancer,
7
,
8
the delayed emergence of a fistula 4 weeks after surgery and CRS/HIPREC appears to be rare. The physiopathology of this postoperative complication is probably due to intraoperative/postoperative peritoneal bacterial contamination. Chua et al. showed that the morbidity and mortality of CRS/HIPEC were similar to those of other major gastrointestinal operations.
9
These fistulas are significantly associated with the operative time, previous systemic chemotherapy or radiotherapy, the number of anastomoses, and the nutritional status. Kusamura et al. found that the extent of cytoreduction surgery and a dose of CDDP ≥240 mg were independent risk factors for digestive fistulas.
10
Intestinal wall edema after CRS/HIPEC causes loosening of the intercellular tight junctions, and this helps in bacterial translocation.
11
HIPEC aggravates visceral edema. Changes in gut microbiota and impaired immunity due to major surgeries are other probable factors for digestive fistulas. Nevertheless, these hypotheses are not proven, but a possible explanation could be an extensive systemic inflammatory response leading to the suppression of cell‐mediated immunity.
12
In our tertiary care center, complete CRS/HIPEC is a complex and aggressive surgical procedure because of the heavy disease burden in the patients. Cisplatin is the most commonly used chemotherapeutic agent in HIPEC for ovarian malignancies. The duration of HIPEC was 60 min in this case. Staged HIPEC was used in this patient as her vitals during the index surgery (complete CRS) were unstable, preventing the administration of HIPEC in the same sitting. Duration of CRS was approximately 8.5 h. This major surgical trauma followed by HIPEC on postoperative day 1 could have caused the bowel edema and exacerbated the impaired immunity in the patient. In addition, the gut microbiota could be changed due to perioperative interventions of CRS/HIPEC, like preoperative mechanical bowel preparation, perioperative antibiotics administration, and the prolonged postoperative ileus‐decreasing intestinal clearance.
This patient presented with symptoms of surgical site infection at the drain site after 1 month of surgery. We advised medical treatment, but the patient did not respond to it and presented with fecal discharge from the same site. Evaluation with radiological imaging confirmed the diagnosis of enterocutaneous fistula, and the patient was treated curatively with surgical intervention. The principles of surgical management are to eliminate the source of infection, to reduce bacterial contamination with peritoneal lavage, and to prevent persistent or recurrent intraperitoneal infection with intraoperative drain placement.
13
Broad‐spectrum antibiotics are also started for the coverage of the most common pathogens until the bacterial culture/sensitivity reports from intraoperative samples are obtained.
The role of the somatostatin analog octreotide for the treatment of digestive fistula remains controversial. It can significantly decrease the fistula output and hence reduces the time to fistula closure.
14
Total parenteral/enteral nutrition helps in infection control and fistulous tract maturation. Fluid and electrolyte correction with abdominal sepsis control are key factors for normal intestinal function and motility.
The mortality reported in various series from postoperative peritonitis due to digestive fistulas is 10–47%.
13
,
14
However, this figure is reduced to 8% after CRS/HIPEC in our center (unpublished data from prospectively maintained departmental database). The reasons may be prompt surgical treatment delivery offered by the experts with a combined multidisciplinary approach.
In conclusion, postoperative enterocutaneous fistula after CRS/HIPEC is a rare entity, which can occur in patients treated with aggressive surgeries for high peritoneal carcinoma index. It may be due to bacterial translocation as a result of bowel edema after the surgery and intraperitoneal chemotherapy. Treatment principles do not differ from other forms of peritonitis. Resuscitation, control of sepsis, and nutritional support are the initial treatment modalities. Definitive surgery to restore gastrointestinal tract continuity, such as in our case, is warranted if the conservative approaches fail. A prompt multidisciplinary approach decreases morbidity and mortality. | Intraperitoneal | DrugAdministrationRoute | CC BY | 33490634 | 18,980,362 | 2021-01 |
What was the administration route of drug 'SODIUM CHLORIDE'? | Drain site enterocutaneous fistula after hyperthermic intraperitoneal chemotherapy.
Spontaneous sigmoid colon perforation after cytoreduction surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is a rare complication. It is more commonly seen with mitomycin-based HIPEC. This case study's patient presented with pus discharge at the drain site after 4 weeks of surgery. The symptoms persisted after conservative treatment. High suspicion after the feculent smell of the discharge fluidled to the prompt diagnosis of enterocutaneous fistula. There was limitedperforation with abscess formation, followed by fistula formation. The patient was treated successfully with surgery.
Introduction
A fistula is defined as an abnormal communication between two epithelialized hollow spaces or organs. Enterocutaneous fistula connects the bowel to the skin. It can be classified according to the source, output volume, and etiology. Fistulas from different organs have different types of outputs. Electrolyte and nutritional losses can vary accordingly. The low‐output, moderate‐output, and high‐output fistulas were defined as having drain volumes less than 200 mL/day, between 200 and 500 mL/day, and more than 500 mL/day, respectively. High‐output fistulas do not heal spontaneously, and these patients are at a higher risk of metabolic disturbances, fluid loss, and malnutrition. The prevalence of enterocutaneous fistulas in the general population is not known. However, postoperative prevalence of enterocutaneous fistulas is 1.5% for trauma,
1
3.6% for general surgery,
2
and 15–35% for patients with Crohn's disease .
3
The latter is the most common cause of spontaneous fistulas. These are classically treated with immunosuppressive drugs like thiopurines, biologic agents like tumor necrosis factor inhibitors, and antibiotics like metronidazole to reduce bowel inflammation and diarrhea.
Spontaneous fistula is a known but rare complication of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This will usually result in fecal peritonitis but occasionally results in a fistula as outlined in this report. The occurrence of such complications depends on the extent of the peritoneal disease. Mortality ranges from 36 to 44% in the literature.
4
In 15% of cases, the site of perforation in fecal peritonitis remains unclear.
5
The peritoneal trauma due to the direct toxic effect of HIPEC with extensive cytoreduction surgery, occasionally combined with the severe chemotherapy‐induced neutropenia, may be the reason why.
6
This study aims to report a case of spontaneous limited perforation with abscess formation followed by enterocutaneous fistula formation in an ovarian carcinoma patient after CRS with HIPEC in our tertiary care center.
Case report
A 48‐year‐old female was evaluated outside of our center and diagnosed with left ovarian carcinoma. She underwent total laparoscopic hysterectomy with bilateral salpingo‐ophrectomy and received seven cycles of taxane/platinum (TP regimen)‐based adjuvant chemotherapy. After approximately 18 months of disease‐free interval, she was evaluated and diagnosed with recurrent ovarian carcinoma, stage IIIC. In a multidisciplinary tumor board discussion, she was planned for chemotherapy followed by surgical reassessment. After eight cycles of TP‐based chemotherapy, she was reevaluated with positron emission tomography‐computed tomography (PET‐CT). It showed multiple metabolically avid lesions at the surgical bed, omentum, right paracolic gutter, parietal wall, and suprapubic region, suggestive of partially responsive operable disease. Secondary cytoreduction surgery (total omentectomy and disease‐specific peritonectomy) with bilateral pelvic node dissection was performed. Intraoperatively, large omental caking was observed, 10 × 8 cm in size, with multiple peritoneal deposits in the bilateral paracolic gutter, right subdiaphragmatic region, pelvis, lesser omentum, and over segment 6 of the liver. The peritoneal carcinoma index was 13. Staged HIPEC was performed on postoperative day (POD) 1 because of intraoperative instability during the previous definitive surgery. The drug Cisplatin was used in 2 liters of normal saline perfusate at 41–43°C for 1 h. She recovered uneventfully. Histopathological features included high‐grade serous carcinoma and immunopositivity for WT1 and CK7. All retrieved pelvic nodes were free of malignancy. She developed a surgical site infection at the drain site in the left iliac fossa after 1 month of surgery, which worsened with conservative treatment. Later, she presented with fecal discharging sinus (Fig. 1a). Contrast‐enhanced CT with CT‐fistulogram revealed enterocutaneous fistula (Fig. 1b,c). Exploratory laparotomy with partial sigmoid colectomy and fistulous tract excision, followed by colocolic anastomosis, were performed. Intraoperatively, a fistulous tract from the sigmoid colon to left iliac fossa skin was identified (Fig. 1d). Postoperative recovery was uneventful.
Figure 1 (a) Fistulous tract opening in left iliac fossa (yellow arrow). Computed tomography fistulogram shows thick‐walled communicating tract from the sigmoid colon to exterior (yellow arrow) in sagittal (b) and axial (c) views. (d) The intraoperative demonstration of enterocutaneous fistula (yellow arrow).
Discussion
Although enterocutaneous fistulas are a known complication of major surgery for ovarian cancer,
7
,
8
the delayed emergence of a fistula 4 weeks after surgery and CRS/HIPREC appears to be rare. The physiopathology of this postoperative complication is probably due to intraoperative/postoperative peritoneal bacterial contamination. Chua et al. showed that the morbidity and mortality of CRS/HIPEC were similar to those of other major gastrointestinal operations.
9
These fistulas are significantly associated with the operative time, previous systemic chemotherapy or radiotherapy, the number of anastomoses, and the nutritional status. Kusamura et al. found that the extent of cytoreduction surgery and a dose of CDDP ≥240 mg were independent risk factors for digestive fistulas.
10
Intestinal wall edema after CRS/HIPEC causes loosening of the intercellular tight junctions, and this helps in bacterial translocation.
11
HIPEC aggravates visceral edema. Changes in gut microbiota and impaired immunity due to major surgeries are other probable factors for digestive fistulas. Nevertheless, these hypotheses are not proven, but a possible explanation could be an extensive systemic inflammatory response leading to the suppression of cell‐mediated immunity.
12
In our tertiary care center, complete CRS/HIPEC is a complex and aggressive surgical procedure because of the heavy disease burden in the patients. Cisplatin is the most commonly used chemotherapeutic agent in HIPEC for ovarian malignancies. The duration of HIPEC was 60 min in this case. Staged HIPEC was used in this patient as her vitals during the index surgery (complete CRS) were unstable, preventing the administration of HIPEC in the same sitting. Duration of CRS was approximately 8.5 h. This major surgical trauma followed by HIPEC on postoperative day 1 could have caused the bowel edema and exacerbated the impaired immunity in the patient. In addition, the gut microbiota could be changed due to perioperative interventions of CRS/HIPEC, like preoperative mechanical bowel preparation, perioperative antibiotics administration, and the prolonged postoperative ileus‐decreasing intestinal clearance.
This patient presented with symptoms of surgical site infection at the drain site after 1 month of surgery. We advised medical treatment, but the patient did not respond to it and presented with fecal discharge from the same site. Evaluation with radiological imaging confirmed the diagnosis of enterocutaneous fistula, and the patient was treated curatively with surgical intervention. The principles of surgical management are to eliminate the source of infection, to reduce bacterial contamination with peritoneal lavage, and to prevent persistent or recurrent intraperitoneal infection with intraoperative drain placement.
13
Broad‐spectrum antibiotics are also started for the coverage of the most common pathogens until the bacterial culture/sensitivity reports from intraoperative samples are obtained.
The role of the somatostatin analog octreotide for the treatment of digestive fistula remains controversial. It can significantly decrease the fistula output and hence reduces the time to fistula closure.
14
Total parenteral/enteral nutrition helps in infection control and fistulous tract maturation. Fluid and electrolyte correction with abdominal sepsis control are key factors for normal intestinal function and motility.
The mortality reported in various series from postoperative peritonitis due to digestive fistulas is 10–47%.
13
,
14
However, this figure is reduced to 8% after CRS/HIPEC in our center (unpublished data from prospectively maintained departmental database). The reasons may be prompt surgical treatment delivery offered by the experts with a combined multidisciplinary approach.
In conclusion, postoperative enterocutaneous fistula after CRS/HIPEC is a rare entity, which can occur in patients treated with aggressive surgeries for high peritoneal carcinoma index. It may be due to bacterial translocation as a result of bowel edema after the surgery and intraperitoneal chemotherapy. Treatment principles do not differ from other forms of peritonitis. Resuscitation, control of sepsis, and nutritional support are the initial treatment modalities. Definitive surgery to restore gastrointestinal tract continuity, such as in our case, is warranted if the conservative approaches fail. A prompt multidisciplinary approach decreases morbidity and mortality. | Intraperitoneal | DrugAdministrationRoute | CC BY | 33490634 | 18,980,362 | 2021-01 |
What was the dosage of drug 'SODIUM CHLORIDE'? | Drain site enterocutaneous fistula after hyperthermic intraperitoneal chemotherapy.
Spontaneous sigmoid colon perforation after cytoreduction surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is a rare complication. It is more commonly seen with mitomycin-based HIPEC. This case study's patient presented with pus discharge at the drain site after 4 weeks of surgery. The symptoms persisted after conservative treatment. High suspicion after the feculent smell of the discharge fluidled to the prompt diagnosis of enterocutaneous fistula. There was limitedperforation with abscess formation, followed by fistula formation. The patient was treated successfully with surgery.
Introduction
A fistula is defined as an abnormal communication between two epithelialized hollow spaces or organs. Enterocutaneous fistula connects the bowel to the skin. It can be classified according to the source, output volume, and etiology. Fistulas from different organs have different types of outputs. Electrolyte and nutritional losses can vary accordingly. The low‐output, moderate‐output, and high‐output fistulas were defined as having drain volumes less than 200 mL/day, between 200 and 500 mL/day, and more than 500 mL/day, respectively. High‐output fistulas do not heal spontaneously, and these patients are at a higher risk of metabolic disturbances, fluid loss, and malnutrition. The prevalence of enterocutaneous fistulas in the general population is not known. However, postoperative prevalence of enterocutaneous fistulas is 1.5% for trauma,
1
3.6% for general surgery,
2
and 15–35% for patients with Crohn's disease .
3
The latter is the most common cause of spontaneous fistulas. These are classically treated with immunosuppressive drugs like thiopurines, biologic agents like tumor necrosis factor inhibitors, and antibiotics like metronidazole to reduce bowel inflammation and diarrhea.
Spontaneous fistula is a known but rare complication of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This will usually result in fecal peritonitis but occasionally results in a fistula as outlined in this report. The occurrence of such complications depends on the extent of the peritoneal disease. Mortality ranges from 36 to 44% in the literature.
4
In 15% of cases, the site of perforation in fecal peritonitis remains unclear.
5
The peritoneal trauma due to the direct toxic effect of HIPEC with extensive cytoreduction surgery, occasionally combined with the severe chemotherapy‐induced neutropenia, may be the reason why.
6
This study aims to report a case of spontaneous limited perforation with abscess formation followed by enterocutaneous fistula formation in an ovarian carcinoma patient after CRS with HIPEC in our tertiary care center.
Case report
A 48‐year‐old female was evaluated outside of our center and diagnosed with left ovarian carcinoma. She underwent total laparoscopic hysterectomy with bilateral salpingo‐ophrectomy and received seven cycles of taxane/platinum (TP regimen)‐based adjuvant chemotherapy. After approximately 18 months of disease‐free interval, she was evaluated and diagnosed with recurrent ovarian carcinoma, stage IIIC. In a multidisciplinary tumor board discussion, she was planned for chemotherapy followed by surgical reassessment. After eight cycles of TP‐based chemotherapy, she was reevaluated with positron emission tomography‐computed tomography (PET‐CT). It showed multiple metabolically avid lesions at the surgical bed, omentum, right paracolic gutter, parietal wall, and suprapubic region, suggestive of partially responsive operable disease. Secondary cytoreduction surgery (total omentectomy and disease‐specific peritonectomy) with bilateral pelvic node dissection was performed. Intraoperatively, large omental caking was observed, 10 × 8 cm in size, with multiple peritoneal deposits in the bilateral paracolic gutter, right subdiaphragmatic region, pelvis, lesser omentum, and over segment 6 of the liver. The peritoneal carcinoma index was 13. Staged HIPEC was performed on postoperative day (POD) 1 because of intraoperative instability during the previous definitive surgery. The drug Cisplatin was used in 2 liters of normal saline perfusate at 41–43°C for 1 h. She recovered uneventfully. Histopathological features included high‐grade serous carcinoma and immunopositivity for WT1 and CK7. All retrieved pelvic nodes were free of malignancy. She developed a surgical site infection at the drain site in the left iliac fossa after 1 month of surgery, which worsened with conservative treatment. Later, she presented with fecal discharging sinus (Fig. 1a). Contrast‐enhanced CT with CT‐fistulogram revealed enterocutaneous fistula (Fig. 1b,c). Exploratory laparotomy with partial sigmoid colectomy and fistulous tract excision, followed by colocolic anastomosis, were performed. Intraoperatively, a fistulous tract from the sigmoid colon to left iliac fossa skin was identified (Fig. 1d). Postoperative recovery was uneventful.
Figure 1 (a) Fistulous tract opening in left iliac fossa (yellow arrow). Computed tomography fistulogram shows thick‐walled communicating tract from the sigmoid colon to exterior (yellow arrow) in sagittal (b) and axial (c) views. (d) The intraoperative demonstration of enterocutaneous fistula (yellow arrow).
Discussion
Although enterocutaneous fistulas are a known complication of major surgery for ovarian cancer,
7
,
8
the delayed emergence of a fistula 4 weeks after surgery and CRS/HIPREC appears to be rare. The physiopathology of this postoperative complication is probably due to intraoperative/postoperative peritoneal bacterial contamination. Chua et al. showed that the morbidity and mortality of CRS/HIPEC were similar to those of other major gastrointestinal operations.
9
These fistulas are significantly associated with the operative time, previous systemic chemotherapy or radiotherapy, the number of anastomoses, and the nutritional status. Kusamura et al. found that the extent of cytoreduction surgery and a dose of CDDP ≥240 mg were independent risk factors for digestive fistulas.
10
Intestinal wall edema after CRS/HIPEC causes loosening of the intercellular tight junctions, and this helps in bacterial translocation.
11
HIPEC aggravates visceral edema. Changes in gut microbiota and impaired immunity due to major surgeries are other probable factors for digestive fistulas. Nevertheless, these hypotheses are not proven, but a possible explanation could be an extensive systemic inflammatory response leading to the suppression of cell‐mediated immunity.
12
In our tertiary care center, complete CRS/HIPEC is a complex and aggressive surgical procedure because of the heavy disease burden in the patients. Cisplatin is the most commonly used chemotherapeutic agent in HIPEC for ovarian malignancies. The duration of HIPEC was 60 min in this case. Staged HIPEC was used in this patient as her vitals during the index surgery (complete CRS) were unstable, preventing the administration of HIPEC in the same sitting. Duration of CRS was approximately 8.5 h. This major surgical trauma followed by HIPEC on postoperative day 1 could have caused the bowel edema and exacerbated the impaired immunity in the patient. In addition, the gut microbiota could be changed due to perioperative interventions of CRS/HIPEC, like preoperative mechanical bowel preparation, perioperative antibiotics administration, and the prolonged postoperative ileus‐decreasing intestinal clearance.
This patient presented with symptoms of surgical site infection at the drain site after 1 month of surgery. We advised medical treatment, but the patient did not respond to it and presented with fecal discharge from the same site. Evaluation with radiological imaging confirmed the diagnosis of enterocutaneous fistula, and the patient was treated curatively with surgical intervention. The principles of surgical management are to eliminate the source of infection, to reduce bacterial contamination with peritoneal lavage, and to prevent persistent or recurrent intraperitoneal infection with intraoperative drain placement.
13
Broad‐spectrum antibiotics are also started for the coverage of the most common pathogens until the bacterial culture/sensitivity reports from intraoperative samples are obtained.
The role of the somatostatin analog octreotide for the treatment of digestive fistula remains controversial. It can significantly decrease the fistula output and hence reduces the time to fistula closure.
14
Total parenteral/enteral nutrition helps in infection control and fistulous tract maturation. Fluid and electrolyte correction with abdominal sepsis control are key factors for normal intestinal function and motility.
The mortality reported in various series from postoperative peritonitis due to digestive fistulas is 10–47%.
13
,
14
However, this figure is reduced to 8% after CRS/HIPEC in our center (unpublished data from prospectively maintained departmental database). The reasons may be prompt surgical treatment delivery offered by the experts with a combined multidisciplinary approach.
In conclusion, postoperative enterocutaneous fistula after CRS/HIPEC is a rare entity, which can occur in patients treated with aggressive surgeries for high peritoneal carcinoma index. It may be due to bacterial translocation as a result of bowel edema after the surgery and intraperitoneal chemotherapy. Treatment principles do not differ from other forms of peritonitis. Resuscitation, control of sepsis, and nutritional support are the initial treatment modalities. Definitive surgery to restore gastrointestinal tract continuity, such as in our case, is warranted if the conservative approaches fail. A prompt multidisciplinary approach decreases morbidity and mortality. | CISPLATIN IN 2L OF SODIUM... | DrugDosageText | CC BY | 33490634 | 18,980,362 | 2021-01 |
What was the outcome of reaction 'Large intestine perforation'? | Drain site enterocutaneous fistula after hyperthermic intraperitoneal chemotherapy.
Spontaneous sigmoid colon perforation after cytoreduction surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is a rare complication. It is more commonly seen with mitomycin-based HIPEC. This case study's patient presented with pus discharge at the drain site after 4 weeks of surgery. The symptoms persisted after conservative treatment. High suspicion after the feculent smell of the discharge fluidled to the prompt diagnosis of enterocutaneous fistula. There was limitedperforation with abscess formation, followed by fistula formation. The patient was treated successfully with surgery.
Introduction
A fistula is defined as an abnormal communication between two epithelialized hollow spaces or organs. Enterocutaneous fistula connects the bowel to the skin. It can be classified according to the source, output volume, and etiology. Fistulas from different organs have different types of outputs. Electrolyte and nutritional losses can vary accordingly. The low‐output, moderate‐output, and high‐output fistulas were defined as having drain volumes less than 200 mL/day, between 200 and 500 mL/day, and more than 500 mL/day, respectively. High‐output fistulas do not heal spontaneously, and these patients are at a higher risk of metabolic disturbances, fluid loss, and malnutrition. The prevalence of enterocutaneous fistulas in the general population is not known. However, postoperative prevalence of enterocutaneous fistulas is 1.5% for trauma,
1
3.6% for general surgery,
2
and 15–35% for patients with Crohn's disease .
3
The latter is the most common cause of spontaneous fistulas. These are classically treated with immunosuppressive drugs like thiopurines, biologic agents like tumor necrosis factor inhibitors, and antibiotics like metronidazole to reduce bowel inflammation and diarrhea.
Spontaneous fistula is a known but rare complication of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This will usually result in fecal peritonitis but occasionally results in a fistula as outlined in this report. The occurrence of such complications depends on the extent of the peritoneal disease. Mortality ranges from 36 to 44% in the literature.
4
In 15% of cases, the site of perforation in fecal peritonitis remains unclear.
5
The peritoneal trauma due to the direct toxic effect of HIPEC with extensive cytoreduction surgery, occasionally combined with the severe chemotherapy‐induced neutropenia, may be the reason why.
6
This study aims to report a case of spontaneous limited perforation with abscess formation followed by enterocutaneous fistula formation in an ovarian carcinoma patient after CRS with HIPEC in our tertiary care center.
Case report
A 48‐year‐old female was evaluated outside of our center and diagnosed with left ovarian carcinoma. She underwent total laparoscopic hysterectomy with bilateral salpingo‐ophrectomy and received seven cycles of taxane/platinum (TP regimen)‐based adjuvant chemotherapy. After approximately 18 months of disease‐free interval, she was evaluated and diagnosed with recurrent ovarian carcinoma, stage IIIC. In a multidisciplinary tumor board discussion, she was planned for chemotherapy followed by surgical reassessment. After eight cycles of TP‐based chemotherapy, she was reevaluated with positron emission tomography‐computed tomography (PET‐CT). It showed multiple metabolically avid lesions at the surgical bed, omentum, right paracolic gutter, parietal wall, and suprapubic region, suggestive of partially responsive operable disease. Secondary cytoreduction surgery (total omentectomy and disease‐specific peritonectomy) with bilateral pelvic node dissection was performed. Intraoperatively, large omental caking was observed, 10 × 8 cm in size, with multiple peritoneal deposits in the bilateral paracolic gutter, right subdiaphragmatic region, pelvis, lesser omentum, and over segment 6 of the liver. The peritoneal carcinoma index was 13. Staged HIPEC was performed on postoperative day (POD) 1 because of intraoperative instability during the previous definitive surgery. The drug Cisplatin was used in 2 liters of normal saline perfusate at 41–43°C for 1 h. She recovered uneventfully. Histopathological features included high‐grade serous carcinoma and immunopositivity for WT1 and CK7. All retrieved pelvic nodes were free of malignancy. She developed a surgical site infection at the drain site in the left iliac fossa after 1 month of surgery, which worsened with conservative treatment. Later, she presented with fecal discharging sinus (Fig. 1a). Contrast‐enhanced CT with CT‐fistulogram revealed enterocutaneous fistula (Fig. 1b,c). Exploratory laparotomy with partial sigmoid colectomy and fistulous tract excision, followed by colocolic anastomosis, were performed. Intraoperatively, a fistulous tract from the sigmoid colon to left iliac fossa skin was identified (Fig. 1d). Postoperative recovery was uneventful.
Figure 1 (a) Fistulous tract opening in left iliac fossa (yellow arrow). Computed tomography fistulogram shows thick‐walled communicating tract from the sigmoid colon to exterior (yellow arrow) in sagittal (b) and axial (c) views. (d) The intraoperative demonstration of enterocutaneous fistula (yellow arrow).
Discussion
Although enterocutaneous fistulas are a known complication of major surgery for ovarian cancer,
7
,
8
the delayed emergence of a fistula 4 weeks after surgery and CRS/HIPREC appears to be rare. The physiopathology of this postoperative complication is probably due to intraoperative/postoperative peritoneal bacterial contamination. Chua et al. showed that the morbidity and mortality of CRS/HIPEC were similar to those of other major gastrointestinal operations.
9
These fistulas are significantly associated with the operative time, previous systemic chemotherapy or radiotherapy, the number of anastomoses, and the nutritional status. Kusamura et al. found that the extent of cytoreduction surgery and a dose of CDDP ≥240 mg were independent risk factors for digestive fistulas.
10
Intestinal wall edema after CRS/HIPEC causes loosening of the intercellular tight junctions, and this helps in bacterial translocation.
11
HIPEC aggravates visceral edema. Changes in gut microbiota and impaired immunity due to major surgeries are other probable factors for digestive fistulas. Nevertheless, these hypotheses are not proven, but a possible explanation could be an extensive systemic inflammatory response leading to the suppression of cell‐mediated immunity.
12
In our tertiary care center, complete CRS/HIPEC is a complex and aggressive surgical procedure because of the heavy disease burden in the patients. Cisplatin is the most commonly used chemotherapeutic agent in HIPEC for ovarian malignancies. The duration of HIPEC was 60 min in this case. Staged HIPEC was used in this patient as her vitals during the index surgery (complete CRS) were unstable, preventing the administration of HIPEC in the same sitting. Duration of CRS was approximately 8.5 h. This major surgical trauma followed by HIPEC on postoperative day 1 could have caused the bowel edema and exacerbated the impaired immunity in the patient. In addition, the gut microbiota could be changed due to perioperative interventions of CRS/HIPEC, like preoperative mechanical bowel preparation, perioperative antibiotics administration, and the prolonged postoperative ileus‐decreasing intestinal clearance.
This patient presented with symptoms of surgical site infection at the drain site after 1 month of surgery. We advised medical treatment, but the patient did not respond to it and presented with fecal discharge from the same site. Evaluation with radiological imaging confirmed the diagnosis of enterocutaneous fistula, and the patient was treated curatively with surgical intervention. The principles of surgical management are to eliminate the source of infection, to reduce bacterial contamination with peritoneal lavage, and to prevent persistent or recurrent intraperitoneal infection with intraoperative drain placement.
13
Broad‐spectrum antibiotics are also started for the coverage of the most common pathogens until the bacterial culture/sensitivity reports from intraoperative samples are obtained.
The role of the somatostatin analog octreotide for the treatment of digestive fistula remains controversial. It can significantly decrease the fistula output and hence reduces the time to fistula closure.
14
Total parenteral/enteral nutrition helps in infection control and fistulous tract maturation. Fluid and electrolyte correction with abdominal sepsis control are key factors for normal intestinal function and motility.
The mortality reported in various series from postoperative peritonitis due to digestive fistulas is 10–47%.
13
,
14
However, this figure is reduced to 8% after CRS/HIPEC in our center (unpublished data from prospectively maintained departmental database). The reasons may be prompt surgical treatment delivery offered by the experts with a combined multidisciplinary approach.
In conclusion, postoperative enterocutaneous fistula after CRS/HIPEC is a rare entity, which can occur in patients treated with aggressive surgeries for high peritoneal carcinoma index. It may be due to bacterial translocation as a result of bowel edema after the surgery and intraperitoneal chemotherapy. Treatment principles do not differ from other forms of peritonitis. Resuscitation, control of sepsis, and nutritional support are the initial treatment modalities. Definitive surgery to restore gastrointestinal tract continuity, such as in our case, is warranted if the conservative approaches fail. A prompt multidisciplinary approach decreases morbidity and mortality. | Recovering | ReactionOutcome | CC BY | 33490634 | 18,980,362 | 2021-01 |
What was the outcome of reaction 'Oedema'? | Drain site enterocutaneous fistula after hyperthermic intraperitoneal chemotherapy.
Spontaneous sigmoid colon perforation after cytoreduction surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is a rare complication. It is more commonly seen with mitomycin-based HIPEC. This case study's patient presented with pus discharge at the drain site after 4 weeks of surgery. The symptoms persisted after conservative treatment. High suspicion after the feculent smell of the discharge fluidled to the prompt diagnosis of enterocutaneous fistula. There was limitedperforation with abscess formation, followed by fistula formation. The patient was treated successfully with surgery.
Introduction
A fistula is defined as an abnormal communication between two epithelialized hollow spaces or organs. Enterocutaneous fistula connects the bowel to the skin. It can be classified according to the source, output volume, and etiology. Fistulas from different organs have different types of outputs. Electrolyte and nutritional losses can vary accordingly. The low‐output, moderate‐output, and high‐output fistulas were defined as having drain volumes less than 200 mL/day, between 200 and 500 mL/day, and more than 500 mL/day, respectively. High‐output fistulas do not heal spontaneously, and these patients are at a higher risk of metabolic disturbances, fluid loss, and malnutrition. The prevalence of enterocutaneous fistulas in the general population is not known. However, postoperative prevalence of enterocutaneous fistulas is 1.5% for trauma,
1
3.6% for general surgery,
2
and 15–35% for patients with Crohn's disease .
3
The latter is the most common cause of spontaneous fistulas. These are classically treated with immunosuppressive drugs like thiopurines, biologic agents like tumor necrosis factor inhibitors, and antibiotics like metronidazole to reduce bowel inflammation and diarrhea.
Spontaneous fistula is a known but rare complication of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This will usually result in fecal peritonitis but occasionally results in a fistula as outlined in this report. The occurrence of such complications depends on the extent of the peritoneal disease. Mortality ranges from 36 to 44% in the literature.
4
In 15% of cases, the site of perforation in fecal peritonitis remains unclear.
5
The peritoneal trauma due to the direct toxic effect of HIPEC with extensive cytoreduction surgery, occasionally combined with the severe chemotherapy‐induced neutropenia, may be the reason why.
6
This study aims to report a case of spontaneous limited perforation with abscess formation followed by enterocutaneous fistula formation in an ovarian carcinoma patient after CRS with HIPEC in our tertiary care center.
Case report
A 48‐year‐old female was evaluated outside of our center and diagnosed with left ovarian carcinoma. She underwent total laparoscopic hysterectomy with bilateral salpingo‐ophrectomy and received seven cycles of taxane/platinum (TP regimen)‐based adjuvant chemotherapy. After approximately 18 months of disease‐free interval, she was evaluated and diagnosed with recurrent ovarian carcinoma, stage IIIC. In a multidisciplinary tumor board discussion, she was planned for chemotherapy followed by surgical reassessment. After eight cycles of TP‐based chemotherapy, she was reevaluated with positron emission tomography‐computed tomography (PET‐CT). It showed multiple metabolically avid lesions at the surgical bed, omentum, right paracolic gutter, parietal wall, and suprapubic region, suggestive of partially responsive operable disease. Secondary cytoreduction surgery (total omentectomy and disease‐specific peritonectomy) with bilateral pelvic node dissection was performed. Intraoperatively, large omental caking was observed, 10 × 8 cm in size, with multiple peritoneal deposits in the bilateral paracolic gutter, right subdiaphragmatic region, pelvis, lesser omentum, and over segment 6 of the liver. The peritoneal carcinoma index was 13. Staged HIPEC was performed on postoperative day (POD) 1 because of intraoperative instability during the previous definitive surgery. The drug Cisplatin was used in 2 liters of normal saline perfusate at 41–43°C for 1 h. She recovered uneventfully. Histopathological features included high‐grade serous carcinoma and immunopositivity for WT1 and CK7. All retrieved pelvic nodes were free of malignancy. She developed a surgical site infection at the drain site in the left iliac fossa after 1 month of surgery, which worsened with conservative treatment. Later, she presented with fecal discharging sinus (Fig. 1a). Contrast‐enhanced CT with CT‐fistulogram revealed enterocutaneous fistula (Fig. 1b,c). Exploratory laparotomy with partial sigmoid colectomy and fistulous tract excision, followed by colocolic anastomosis, were performed. Intraoperatively, a fistulous tract from the sigmoid colon to left iliac fossa skin was identified (Fig. 1d). Postoperative recovery was uneventful.
Figure 1 (a) Fistulous tract opening in left iliac fossa (yellow arrow). Computed tomography fistulogram shows thick‐walled communicating tract from the sigmoid colon to exterior (yellow arrow) in sagittal (b) and axial (c) views. (d) The intraoperative demonstration of enterocutaneous fistula (yellow arrow).
Discussion
Although enterocutaneous fistulas are a known complication of major surgery for ovarian cancer,
7
,
8
the delayed emergence of a fistula 4 weeks after surgery and CRS/HIPREC appears to be rare. The physiopathology of this postoperative complication is probably due to intraoperative/postoperative peritoneal bacterial contamination. Chua et al. showed that the morbidity and mortality of CRS/HIPEC were similar to those of other major gastrointestinal operations.
9
These fistulas are significantly associated with the operative time, previous systemic chemotherapy or radiotherapy, the number of anastomoses, and the nutritional status. Kusamura et al. found that the extent of cytoreduction surgery and a dose of CDDP ≥240 mg were independent risk factors for digestive fistulas.
10
Intestinal wall edema after CRS/HIPEC causes loosening of the intercellular tight junctions, and this helps in bacterial translocation.
11
HIPEC aggravates visceral edema. Changes in gut microbiota and impaired immunity due to major surgeries are other probable factors for digestive fistulas. Nevertheless, these hypotheses are not proven, but a possible explanation could be an extensive systemic inflammatory response leading to the suppression of cell‐mediated immunity.
12
In our tertiary care center, complete CRS/HIPEC is a complex and aggressive surgical procedure because of the heavy disease burden in the patients. Cisplatin is the most commonly used chemotherapeutic agent in HIPEC for ovarian malignancies. The duration of HIPEC was 60 min in this case. Staged HIPEC was used in this patient as her vitals during the index surgery (complete CRS) were unstable, preventing the administration of HIPEC in the same sitting. Duration of CRS was approximately 8.5 h. This major surgical trauma followed by HIPEC on postoperative day 1 could have caused the bowel edema and exacerbated the impaired immunity in the patient. In addition, the gut microbiota could be changed due to perioperative interventions of CRS/HIPEC, like preoperative mechanical bowel preparation, perioperative antibiotics administration, and the prolonged postoperative ileus‐decreasing intestinal clearance.
This patient presented with symptoms of surgical site infection at the drain site after 1 month of surgery. We advised medical treatment, but the patient did not respond to it and presented with fecal discharge from the same site. Evaluation with radiological imaging confirmed the diagnosis of enterocutaneous fistula, and the patient was treated curatively with surgical intervention. The principles of surgical management are to eliminate the source of infection, to reduce bacterial contamination with peritoneal lavage, and to prevent persistent or recurrent intraperitoneal infection with intraoperative drain placement.
13
Broad‐spectrum antibiotics are also started for the coverage of the most common pathogens until the bacterial culture/sensitivity reports from intraoperative samples are obtained.
The role of the somatostatin analog octreotide for the treatment of digestive fistula remains controversial. It can significantly decrease the fistula output and hence reduces the time to fistula closure.
14
Total parenteral/enteral nutrition helps in infection control and fistulous tract maturation. Fluid and electrolyte correction with abdominal sepsis control are key factors for normal intestinal function and motility.
The mortality reported in various series from postoperative peritonitis due to digestive fistulas is 10–47%.
13
,
14
However, this figure is reduced to 8% after CRS/HIPEC in our center (unpublished data from prospectively maintained departmental database). The reasons may be prompt surgical treatment delivery offered by the experts with a combined multidisciplinary approach.
In conclusion, postoperative enterocutaneous fistula after CRS/HIPEC is a rare entity, which can occur in patients treated with aggressive surgeries for high peritoneal carcinoma index. It may be due to bacterial translocation as a result of bowel edema after the surgery and intraperitoneal chemotherapy. Treatment principles do not differ from other forms of peritonitis. Resuscitation, control of sepsis, and nutritional support are the initial treatment modalities. Definitive surgery to restore gastrointestinal tract continuity, such as in our case, is warranted if the conservative approaches fail. A prompt multidisciplinary approach decreases morbidity and mortality. | Recovered | ReactionOutcome | CC BY | 33490634 | 18,873,222 | 2021-01 |
What was the outcome of reaction 'Postoperative wound infection'? | Drain site enterocutaneous fistula after hyperthermic intraperitoneal chemotherapy.
Spontaneous sigmoid colon perforation after cytoreduction surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is a rare complication. It is more commonly seen with mitomycin-based HIPEC. This case study's patient presented with pus discharge at the drain site after 4 weeks of surgery. The symptoms persisted after conservative treatment. High suspicion after the feculent smell of the discharge fluidled to the prompt diagnosis of enterocutaneous fistula. There was limitedperforation with abscess formation, followed by fistula formation. The patient was treated successfully with surgery.
Introduction
A fistula is defined as an abnormal communication between two epithelialized hollow spaces or organs. Enterocutaneous fistula connects the bowel to the skin. It can be classified according to the source, output volume, and etiology. Fistulas from different organs have different types of outputs. Electrolyte and nutritional losses can vary accordingly. The low‐output, moderate‐output, and high‐output fistulas were defined as having drain volumes less than 200 mL/day, between 200 and 500 mL/day, and more than 500 mL/day, respectively. High‐output fistulas do not heal spontaneously, and these patients are at a higher risk of metabolic disturbances, fluid loss, and malnutrition. The prevalence of enterocutaneous fistulas in the general population is not known. However, postoperative prevalence of enterocutaneous fistulas is 1.5% for trauma,
1
3.6% for general surgery,
2
and 15–35% for patients with Crohn's disease .
3
The latter is the most common cause of spontaneous fistulas. These are classically treated with immunosuppressive drugs like thiopurines, biologic agents like tumor necrosis factor inhibitors, and antibiotics like metronidazole to reduce bowel inflammation and diarrhea.
Spontaneous fistula is a known but rare complication of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This will usually result in fecal peritonitis but occasionally results in a fistula as outlined in this report. The occurrence of such complications depends on the extent of the peritoneal disease. Mortality ranges from 36 to 44% in the literature.
4
In 15% of cases, the site of perforation in fecal peritonitis remains unclear.
5
The peritoneal trauma due to the direct toxic effect of HIPEC with extensive cytoreduction surgery, occasionally combined with the severe chemotherapy‐induced neutropenia, may be the reason why.
6
This study aims to report a case of spontaneous limited perforation with abscess formation followed by enterocutaneous fistula formation in an ovarian carcinoma patient after CRS with HIPEC in our tertiary care center.
Case report
A 48‐year‐old female was evaluated outside of our center and diagnosed with left ovarian carcinoma. She underwent total laparoscopic hysterectomy with bilateral salpingo‐ophrectomy and received seven cycles of taxane/platinum (TP regimen)‐based adjuvant chemotherapy. After approximately 18 months of disease‐free interval, she was evaluated and diagnosed with recurrent ovarian carcinoma, stage IIIC. In a multidisciplinary tumor board discussion, she was planned for chemotherapy followed by surgical reassessment. After eight cycles of TP‐based chemotherapy, she was reevaluated with positron emission tomography‐computed tomography (PET‐CT). It showed multiple metabolically avid lesions at the surgical bed, omentum, right paracolic gutter, parietal wall, and suprapubic region, suggestive of partially responsive operable disease. Secondary cytoreduction surgery (total omentectomy and disease‐specific peritonectomy) with bilateral pelvic node dissection was performed. Intraoperatively, large omental caking was observed, 10 × 8 cm in size, with multiple peritoneal deposits in the bilateral paracolic gutter, right subdiaphragmatic region, pelvis, lesser omentum, and over segment 6 of the liver. The peritoneal carcinoma index was 13. Staged HIPEC was performed on postoperative day (POD) 1 because of intraoperative instability during the previous definitive surgery. The drug Cisplatin was used in 2 liters of normal saline perfusate at 41–43°C for 1 h. She recovered uneventfully. Histopathological features included high‐grade serous carcinoma and immunopositivity for WT1 and CK7. All retrieved pelvic nodes were free of malignancy. She developed a surgical site infection at the drain site in the left iliac fossa after 1 month of surgery, which worsened with conservative treatment. Later, she presented with fecal discharging sinus (Fig. 1a). Contrast‐enhanced CT with CT‐fistulogram revealed enterocutaneous fistula (Fig. 1b,c). Exploratory laparotomy with partial sigmoid colectomy and fistulous tract excision, followed by colocolic anastomosis, were performed. Intraoperatively, a fistulous tract from the sigmoid colon to left iliac fossa skin was identified (Fig. 1d). Postoperative recovery was uneventful.
Figure 1 (a) Fistulous tract opening in left iliac fossa (yellow arrow). Computed tomography fistulogram shows thick‐walled communicating tract from the sigmoid colon to exterior (yellow arrow) in sagittal (b) and axial (c) views. (d) The intraoperative demonstration of enterocutaneous fistula (yellow arrow).
Discussion
Although enterocutaneous fistulas are a known complication of major surgery for ovarian cancer,
7
,
8
the delayed emergence of a fistula 4 weeks after surgery and CRS/HIPREC appears to be rare. The physiopathology of this postoperative complication is probably due to intraoperative/postoperative peritoneal bacterial contamination. Chua et al. showed that the morbidity and mortality of CRS/HIPEC were similar to those of other major gastrointestinal operations.
9
These fistulas are significantly associated with the operative time, previous systemic chemotherapy or radiotherapy, the number of anastomoses, and the nutritional status. Kusamura et al. found that the extent of cytoreduction surgery and a dose of CDDP ≥240 mg were independent risk factors for digestive fistulas.
10
Intestinal wall edema after CRS/HIPEC causes loosening of the intercellular tight junctions, and this helps in bacterial translocation.
11
HIPEC aggravates visceral edema. Changes in gut microbiota and impaired immunity due to major surgeries are other probable factors for digestive fistulas. Nevertheless, these hypotheses are not proven, but a possible explanation could be an extensive systemic inflammatory response leading to the suppression of cell‐mediated immunity.
12
In our tertiary care center, complete CRS/HIPEC is a complex and aggressive surgical procedure because of the heavy disease burden in the patients. Cisplatin is the most commonly used chemotherapeutic agent in HIPEC for ovarian malignancies. The duration of HIPEC was 60 min in this case. Staged HIPEC was used in this patient as her vitals during the index surgery (complete CRS) were unstable, preventing the administration of HIPEC in the same sitting. Duration of CRS was approximately 8.5 h. This major surgical trauma followed by HIPEC on postoperative day 1 could have caused the bowel edema and exacerbated the impaired immunity in the patient. In addition, the gut microbiota could be changed due to perioperative interventions of CRS/HIPEC, like preoperative mechanical bowel preparation, perioperative antibiotics administration, and the prolonged postoperative ileus‐decreasing intestinal clearance.
This patient presented with symptoms of surgical site infection at the drain site after 1 month of surgery. We advised medical treatment, but the patient did not respond to it and presented with fecal discharge from the same site. Evaluation with radiological imaging confirmed the diagnosis of enterocutaneous fistula, and the patient was treated curatively with surgical intervention. The principles of surgical management are to eliminate the source of infection, to reduce bacterial contamination with peritoneal lavage, and to prevent persistent or recurrent intraperitoneal infection with intraoperative drain placement.
13
Broad‐spectrum antibiotics are also started for the coverage of the most common pathogens until the bacterial culture/sensitivity reports from intraoperative samples are obtained.
The role of the somatostatin analog octreotide for the treatment of digestive fistula remains controversial. It can significantly decrease the fistula output and hence reduces the time to fistula closure.
14
Total parenteral/enteral nutrition helps in infection control and fistulous tract maturation. Fluid and electrolyte correction with abdominal sepsis control are key factors for normal intestinal function and motility.
The mortality reported in various series from postoperative peritonitis due to digestive fistulas is 10–47%.
13
,
14
However, this figure is reduced to 8% after CRS/HIPEC in our center (unpublished data from prospectively maintained departmental database). The reasons may be prompt surgical treatment delivery offered by the experts with a combined multidisciplinary approach.
In conclusion, postoperative enterocutaneous fistula after CRS/HIPEC is a rare entity, which can occur in patients treated with aggressive surgeries for high peritoneal carcinoma index. It may be due to bacterial translocation as a result of bowel edema after the surgery and intraperitoneal chemotherapy. Treatment principles do not differ from other forms of peritonitis. Resuscitation, control of sepsis, and nutritional support are the initial treatment modalities. Definitive surgery to restore gastrointestinal tract continuity, such as in our case, is warranted if the conservative approaches fail. A prompt multidisciplinary approach decreases morbidity and mortality. | Recovered | ReactionOutcome | CC BY | 33490634 | 18,873,222 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cerebral haemorrhage'. | Posterior reversible encephalopathy syndrome and COVID-19: A series of 6 cases from Lombardy, Italy.
Posterior reversible encephalopathy cases are increasingly being reported in patients affected by COVID-19, but the largest series so far only includes 4 patients. We present a series of 6 patients diagnosed with PRES during COVID-19 hospitalized in 5 Centers in Lombardia, Italy. 5 out of the 6 patients required intensive care assistence and seizures developed at weaning from assisted ventilation. 3 out of 6 patients underwent cerebrospinal fluid analysis which was normal in all cases, with negative PCR for Sars-CoV-2 genome search. PRES occurrence may be less rare than supposed in COVID-19 patients and a high suspicion index is warranted for prompt diagnosis and treatment.
1 Introduction
Since Hinchey's classical first description of 15 PRES cases [1], numerous other reports have been reported in the literature, but only few papers have been published so far concerning PRES patients in the course of Covid-19 infection, with the largest series including only 4 patients [2] and still few reports [3] concerning neuroradiological peculiarities of brain imaging in this context are published
We report a series of 6 COVID-19 patients developing PRES, from the same geographical region. Moreover, in the present paper we take advantage of the description of these clinical cases to formulate etiopathogenetic considerations and we also propose the use of a prophylactic therapy with an anti-epileptic treatment in what we identified as a delicate transition from forced ventilation to restoration of normal breathing.
All patients reported in this publication were diagnosed by neurological departments located in different hospitals in the Lombardy Region, the most densely populated (approximately 10.000.000 inhabitants) in Italy and one of the most productive and most developed areas of the entire European Union, but also unfortunately the Region in which the covid-19 pandemic was more dramatic with a very significant number of deaths.
The clinical symptomatology of PRES is known, the most significant symptoms in our 6 cases (summarized together with treatment and outcome in Table 1) include alterations in consciousness up to coma, arterial hypertension or significant blood pressure (BP) fluctuations, either focal or generalized epileptic seizures until status epilepticus which continues to represent a potential risk factor for death, visual disturbances ranging from homonymous hemianopsia and to other visual field deficits, up to cortical blindness.Table 1 Summary of the main findings in patients 1–6.
Table 1 1 2 3 4 5 6
Sex/age M/54 F/63 M/64 F/64 M/68 F/57
Assisted ventilation Yes Yes Yes Yes Yes No
ICU Yes Yes Yes Yes Yes No
Antibiotics Ceftriaxone
Azithromycin Piperacillin
Tazobactam Ceftriaxone
Azithromycin Ceftriaxone No Levofloxacin
Hydroxychloroquine No Yes No Yes Yes Yes
Antiretroviral Lopinavir/ritonavir Lopinavir/ritonavir Ritonavir/Darunavir Darunavir/Cobicistat Lopinavir/Ritonavir No
Seizures Yes
Partial onset+generalization Yes
Partial onset+generalization Yes
Partial onset+generalization No No Yes
Partial onset+generalization
Visual field defect Yes Yes Yes Yes Yes Yes
Reduced responsiveness No Yes Yes Yes Yes No
Headache No No Yes No Yes No
Poorly controlled blood pressure Yes Yes No Yes Yes Yes
Outcome at dismissal Right homonymous hemianopsia Full recovery Full recovery Full recovery Partial recovery Full recovery
2 Case 1
A 54-year-old male patient presented in the Emergency Room (ER) for fever and dyspnea started 10 days before. A chest X-ray showed bilateral ground glass opacification (GGO), and the SARS-CoV-2 swab resulted positive. He was first ventilated with CPAP, then transferred to the ICU and treated with invasive ventilation, together with lopinavir/ritonavir, azithromycin and ceftriaxone. The course was complicated by acute renal failure following dialysis treatment, and by episodes of atrial fibrillation treated with pharmacological cardioversion. Following clinical improvement, he was transferred to the medical ward, where he developed a secondarily generalized seizure and subsequent poorly controlled blood pressure values.
Brain CT scan revealed areas of subcortical hypodensity in both occipital regions, with greater expression on the left. The EEG presented slow dominant theta-delta band activity with bilateral diffusion, however without abnormalities with paroxysmal significance. Brain MRI was consistent with a diagnosis of PRES (Fig. 1a).Fig. 1 FLAIR sequences of brain MRI.
Fig. 1
At dismissal, the patient was alert, cooperative, with right homonymous hemianopsia and a slight hypotonic tetraparesis compatible with a critical illness polyneuropathy (CIP).
3 Case 2
A 63-year-old female patient presented in ER after a week of fever, cough and myalgias unresponsive to symptomatic therapies. Chest X-ray showed bilateral GGO with consolidation at bases and the pharyngeal swab was positive for SARS-Cov2. Despite treatment with antiviral therapy (lopinavir/ritonavir), hydroxychloroquine, antibiotic therapy (piperacillin/tazobactam) and antithrombotic prophylaxis with low-molecular weight heparin (LMWH), her condition worsened and she was admitted to ICU for invasive ventilation. She also needed hemodynamic support and she underwent immunomodulatory therapy with interleukin-1 antagonist with benefit. She was extubated, but two days later she presented a partial motor seizure with clonic movements of her left side of the face and then in the left hemisome, followed by generalized seizures and epileptic status confirmed by EEG. She was treated with phenytoin, diazepam and levetiracetam, with clinical response and EEG normalization. A first brain CT scan and a subsequent brain MRI (Fig. 1 b) revealed a picture consistent with PRES. Search for SARS-Cov-2 on CSF was negative. The brain MRI performed three weeks later showed a marked improvement, confirming the diagnosis of PRES. The patient is now asymptomatic and had no more epileptic seizures.
4 Case 3
A 64-year-old male was hospitalized after a week of fever unresponsive to antipyretic drugs. The chest X-ray showed GGO. The SARS-CoV-2 swab resulted positive. He was treated with antibiotics and antiretroviral therapy. He first required CPAP treatment, then he needed mechanical ventilation for twenty-three days. After withdrawal of sedation, the patient presented a focal seizure with head and eyes turned to the right, then he became unresponsive and he presented a tetraparesis with normal deep tendon reflexes and absence of other pathological reflexes. EEG confirmed a non-convulsive epileptic status. CSF test for SAR-CoV-2 was negative. Brain MRI showed diffuse white matter hypodense alterations in both hemispheres with symmetrical distribution, mainly affecting the occipital lobes; these lesions did not present contrast-enhancement; few hemosiderin spots suggestive for small hemorrhages were also present. Follow-up MRI was normal, further supporting PRES diagnosis, and clinical recovery was complete.
5 Case 4
A 64-year-old female patient, hospitalized after 10 days of fever and breathing difficulties, was treated at home with antibiotics. At hospital admission she had fever (39 °C) and dyspnea, and neurological examination was normal. Chest x-ray showed GGO in the right basal region, and the nasopharyngeal swab was positive for SARS-CoV-2. Antiviral therapy associated with hydroxychloroquine was started. Due to hypoxia which occurred 24 h later, she was transferred to the ICU, sedated and subjected to mechanical ventilation. After 23 days of ICU admission, the bronchial aspirate for SARS-CoV-2 turned negative. Two days later, after sedation withdrawal she was drowsy with an altered mental status and she complained of blurred vision. Brain CT and MRI (Fig. 1c) were consistent with PRES, with a subsequent haemorrhagic component and improvement at follow-up. The patient became alert again, oriented with normalization of the visual function. This case report was reported in a previous publication [4].
6 Case 5
A 68-year-old male was admitted to the infectious disease department of the Hospital of Gravedona, after eight days of dyspnea and fever, and he had a positive swab for SARS-CoV-2. Oxygen-therapy with CPAP was immediately initiated due to breathing difficulties but worsening of respiratory conditions necessitated a transfer of the patient to ICU and a treatment with invasive ventilation; the patient was treated with hydorxychloroquine and lopinavir/ritonavir. Upon awakening there was a good recovery of alertness and cognitive functions, however the patient complained of visual disturbances in the right visual field and difficulty in walking due to the marked reduction of muscle tone. MRI (Fig. 1d) was consistent with PRES. There was subsequently a progressive improvement of the visual disturbances.
7 Case 6
A 57 years-old female was hospitalized for fever and mild dyspnea and a positive swab test for SARS-CoV-2. Chest x-ray showed no active lesions. In the following days, low-flow oxygen therapy was needed and a treatment with levofloxacin and hydroxychloroquine started. On day-9, the patient suddenly had an aversive seizure with head and eyes turned to the right associated with aphasia. A generalized seizure followed shortly, and it was treated with diazepam iv.
Brain MRI was consistent with PRES (Fig. 1e). In the following days a global aphasia, and frontal neurological symptoms and signs with fatuity and disinhibition appeared; she recovered from aphasia, but she started to complain of visual disturbances in the left hemifield, as well as of rare visual hallucinations. CSF examination showed a slight increase of protein and normal cells, and a negative search for SARS-CoV-2. In the following weeks, she did a full recovery both clinically and in brain imaging.
8 Discussion
Our case series of 6 patients has been collected through reporting by 5 neurology/ICU units in Lombardy with cases occurring during the peak of the epidemic in our region; thus, the number of PRES cases is overall low; the lack of sound epidemiological data on PRES incidence in a pre-COVID era makes it impossible to conclude for an increased risk of developing this syndrome in the context of COVID-19 infection.
CSF data of our three patients who underwent the spinal tap (cases 2, 3 and 6) were substantially normal; of note, PCR search for Sars-Cov-2 genome was negative in all cases; this highlights that PRES in these cases is likely not related to direct viral invasion in the CNS and CSF.
Blood pressure fluctuations are the most relevant factor in PRES pathogenesis; a number of other conditions/treatments have also been reported in association with this syndrome, including hyodroxychloroquine treatment [5]; this drug was administered in 4 of our 6 patients.
In COVID-19 patients, PRES lesions may in some cases present with haemorrhagic features [3,6]; endothelial dysfunction may be relevant in this context [7].
Of note, the distinction between cases of haemorrhagic PRES and recently described patterns of diffuse leukoencephalopathy with microbleeds in COVID-19 patients with persistent confusion and lethargy [8] is not straightforward and might reflect a continuum of alterations involving both the endothelium and the white matter.
It is still not known whether PRES incidence has been substantially increasing in the pandemic; an anecdotal report by Kishfy, Casasola and others at Mount Aubum Hospital in Cambridge, MA, USA [9] described 2 cases in a week as compared with a previous mean of 1.4 cases/yr.
In 4 of our patients, the most critical time for the occurrence of seizures for the patient was represented by the transition from oxygen therapy to the return to a normal breathing. Most of the patients first presented a partial motor seizure, followed by one or more generalized seizures, in cases 2 and 4 then ending up in a status epilepticus. It is possible that the restoration of normal cerebral oxygenation has led to an epileptogenic irritative activity on the cortex not differently from what happens deliberately with hyperpnea during EEG recording. However, case 6 was not subjected to assisted ventilation.
Credit author statement
I declare that all the co-authors have provided relevant contribution for the writing of this article and that thay agree with the submission. | CEFTRIAXONE, COBICISTAT\DARUNAVIR ETHANOLATE, HYDROXYCHLOROQUINE | DrugsGivenReaction | CC BY-NC-ND | 33490654 | 18,970,763 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Posterior reversible encephalopathy syndrome and COVID-19: A series of 6 cases from Lombardy, Italy.
Posterior reversible encephalopathy cases are increasingly being reported in patients affected by COVID-19, but the largest series so far only includes 4 patients. We present a series of 6 patients diagnosed with PRES during COVID-19 hospitalized in 5 Centers in Lombardia, Italy. 5 out of the 6 patients required intensive care assistence and seizures developed at weaning from assisted ventilation. 3 out of 6 patients underwent cerebrospinal fluid analysis which was normal in all cases, with negative PCR for Sars-CoV-2 genome search. PRES occurrence may be less rare than supposed in COVID-19 patients and a high suspicion index is warranted for prompt diagnosis and treatment.
1 Introduction
Since Hinchey's classical first description of 15 PRES cases [1], numerous other reports have been reported in the literature, but only few papers have been published so far concerning PRES patients in the course of Covid-19 infection, with the largest series including only 4 patients [2] and still few reports [3] concerning neuroradiological peculiarities of brain imaging in this context are published
We report a series of 6 COVID-19 patients developing PRES, from the same geographical region. Moreover, in the present paper we take advantage of the description of these clinical cases to formulate etiopathogenetic considerations and we also propose the use of a prophylactic therapy with an anti-epileptic treatment in what we identified as a delicate transition from forced ventilation to restoration of normal breathing.
All patients reported in this publication were diagnosed by neurological departments located in different hospitals in the Lombardy Region, the most densely populated (approximately 10.000.000 inhabitants) in Italy and one of the most productive and most developed areas of the entire European Union, but also unfortunately the Region in which the covid-19 pandemic was more dramatic with a very significant number of deaths.
The clinical symptomatology of PRES is known, the most significant symptoms in our 6 cases (summarized together with treatment and outcome in Table 1) include alterations in consciousness up to coma, arterial hypertension or significant blood pressure (BP) fluctuations, either focal or generalized epileptic seizures until status epilepticus which continues to represent a potential risk factor for death, visual disturbances ranging from homonymous hemianopsia and to other visual field deficits, up to cortical blindness.Table 1 Summary of the main findings in patients 1–6.
Table 1 1 2 3 4 5 6
Sex/age M/54 F/63 M/64 F/64 M/68 F/57
Assisted ventilation Yes Yes Yes Yes Yes No
ICU Yes Yes Yes Yes Yes No
Antibiotics Ceftriaxone
Azithromycin Piperacillin
Tazobactam Ceftriaxone
Azithromycin Ceftriaxone No Levofloxacin
Hydroxychloroquine No Yes No Yes Yes Yes
Antiretroviral Lopinavir/ritonavir Lopinavir/ritonavir Ritonavir/Darunavir Darunavir/Cobicistat Lopinavir/Ritonavir No
Seizures Yes
Partial onset+generalization Yes
Partial onset+generalization Yes
Partial onset+generalization No No Yes
Partial onset+generalization
Visual field defect Yes Yes Yes Yes Yes Yes
Reduced responsiveness No Yes Yes Yes Yes No
Headache No No Yes No Yes No
Poorly controlled blood pressure Yes Yes No Yes Yes Yes
Outcome at dismissal Right homonymous hemianopsia Full recovery Full recovery Full recovery Partial recovery Full recovery
2 Case 1
A 54-year-old male patient presented in the Emergency Room (ER) for fever and dyspnea started 10 days before. A chest X-ray showed bilateral ground glass opacification (GGO), and the SARS-CoV-2 swab resulted positive. He was first ventilated with CPAP, then transferred to the ICU and treated with invasive ventilation, together with lopinavir/ritonavir, azithromycin and ceftriaxone. The course was complicated by acute renal failure following dialysis treatment, and by episodes of atrial fibrillation treated with pharmacological cardioversion. Following clinical improvement, he was transferred to the medical ward, where he developed a secondarily generalized seizure and subsequent poorly controlled blood pressure values.
Brain CT scan revealed areas of subcortical hypodensity in both occipital regions, with greater expression on the left. The EEG presented slow dominant theta-delta band activity with bilateral diffusion, however without abnormalities with paroxysmal significance. Brain MRI was consistent with a diagnosis of PRES (Fig. 1a).Fig. 1 FLAIR sequences of brain MRI.
Fig. 1
At dismissal, the patient was alert, cooperative, with right homonymous hemianopsia and a slight hypotonic tetraparesis compatible with a critical illness polyneuropathy (CIP).
3 Case 2
A 63-year-old female patient presented in ER after a week of fever, cough and myalgias unresponsive to symptomatic therapies. Chest X-ray showed bilateral GGO with consolidation at bases and the pharyngeal swab was positive for SARS-Cov2. Despite treatment with antiviral therapy (lopinavir/ritonavir), hydroxychloroquine, antibiotic therapy (piperacillin/tazobactam) and antithrombotic prophylaxis with low-molecular weight heparin (LMWH), her condition worsened and she was admitted to ICU for invasive ventilation. She also needed hemodynamic support and she underwent immunomodulatory therapy with interleukin-1 antagonist with benefit. She was extubated, but two days later she presented a partial motor seizure with clonic movements of her left side of the face and then in the left hemisome, followed by generalized seizures and epileptic status confirmed by EEG. She was treated with phenytoin, diazepam and levetiracetam, with clinical response and EEG normalization. A first brain CT scan and a subsequent brain MRI (Fig. 1 b) revealed a picture consistent with PRES. Search for SARS-Cov-2 on CSF was negative. The brain MRI performed three weeks later showed a marked improvement, confirming the diagnosis of PRES. The patient is now asymptomatic and had no more epileptic seizures.
4 Case 3
A 64-year-old male was hospitalized after a week of fever unresponsive to antipyretic drugs. The chest X-ray showed GGO. The SARS-CoV-2 swab resulted positive. He was treated with antibiotics and antiretroviral therapy. He first required CPAP treatment, then he needed mechanical ventilation for twenty-three days. After withdrawal of sedation, the patient presented a focal seizure with head and eyes turned to the right, then he became unresponsive and he presented a tetraparesis with normal deep tendon reflexes and absence of other pathological reflexes. EEG confirmed a non-convulsive epileptic status. CSF test for SAR-CoV-2 was negative. Brain MRI showed diffuse white matter hypodense alterations in both hemispheres with symmetrical distribution, mainly affecting the occipital lobes; these lesions did not present contrast-enhancement; few hemosiderin spots suggestive for small hemorrhages were also present. Follow-up MRI was normal, further supporting PRES diagnosis, and clinical recovery was complete.
5 Case 4
A 64-year-old female patient, hospitalized after 10 days of fever and breathing difficulties, was treated at home with antibiotics. At hospital admission she had fever (39 °C) and dyspnea, and neurological examination was normal. Chest x-ray showed GGO in the right basal region, and the nasopharyngeal swab was positive for SARS-CoV-2. Antiviral therapy associated with hydroxychloroquine was started. Due to hypoxia which occurred 24 h later, she was transferred to the ICU, sedated and subjected to mechanical ventilation. After 23 days of ICU admission, the bronchial aspirate for SARS-CoV-2 turned negative. Two days later, after sedation withdrawal she was drowsy with an altered mental status and she complained of blurred vision. Brain CT and MRI (Fig. 1c) were consistent with PRES, with a subsequent haemorrhagic component and improvement at follow-up. The patient became alert again, oriented with normalization of the visual function. This case report was reported in a previous publication [4].
6 Case 5
A 68-year-old male was admitted to the infectious disease department of the Hospital of Gravedona, after eight days of dyspnea and fever, and he had a positive swab for SARS-CoV-2. Oxygen-therapy with CPAP was immediately initiated due to breathing difficulties but worsening of respiratory conditions necessitated a transfer of the patient to ICU and a treatment with invasive ventilation; the patient was treated with hydorxychloroquine and lopinavir/ritonavir. Upon awakening there was a good recovery of alertness and cognitive functions, however the patient complained of visual disturbances in the right visual field and difficulty in walking due to the marked reduction of muscle tone. MRI (Fig. 1d) was consistent with PRES. There was subsequently a progressive improvement of the visual disturbances.
7 Case 6
A 57 years-old female was hospitalized for fever and mild dyspnea and a positive swab test for SARS-CoV-2. Chest x-ray showed no active lesions. In the following days, low-flow oxygen therapy was needed and a treatment with levofloxacin and hydroxychloroquine started. On day-9, the patient suddenly had an aversive seizure with head and eyes turned to the right associated with aphasia. A generalized seizure followed shortly, and it was treated with diazepam iv.
Brain MRI was consistent with PRES (Fig. 1e). In the following days a global aphasia, and frontal neurological symptoms and signs with fatuity and disinhibition appeared; she recovered from aphasia, but she started to complain of visual disturbances in the left hemifield, as well as of rare visual hallucinations. CSF examination showed a slight increase of protein and normal cells, and a negative search for SARS-CoV-2. In the following weeks, she did a full recovery both clinically and in brain imaging.
8 Discussion
Our case series of 6 patients has been collected through reporting by 5 neurology/ICU units in Lombardy with cases occurring during the peak of the epidemic in our region; thus, the number of PRES cases is overall low; the lack of sound epidemiological data on PRES incidence in a pre-COVID era makes it impossible to conclude for an increased risk of developing this syndrome in the context of COVID-19 infection.
CSF data of our three patients who underwent the spinal tap (cases 2, 3 and 6) were substantially normal; of note, PCR search for Sars-Cov-2 genome was negative in all cases; this highlights that PRES in these cases is likely not related to direct viral invasion in the CNS and CSF.
Blood pressure fluctuations are the most relevant factor in PRES pathogenesis; a number of other conditions/treatments have also been reported in association with this syndrome, including hyodroxychloroquine treatment [5]; this drug was administered in 4 of our 6 patients.
In COVID-19 patients, PRES lesions may in some cases present with haemorrhagic features [3,6]; endothelial dysfunction may be relevant in this context [7].
Of note, the distinction between cases of haemorrhagic PRES and recently described patterns of diffuse leukoencephalopathy with microbleeds in COVID-19 patients with persistent confusion and lethargy [8] is not straightforward and might reflect a continuum of alterations involving both the endothelium and the white matter.
It is still not known whether PRES incidence has been substantially increasing in the pandemic; an anecdotal report by Kishfy, Casasola and others at Mount Aubum Hospital in Cambridge, MA, USA [9] described 2 cases in a week as compared with a previous mean of 1.4 cases/yr.
In 4 of our patients, the most critical time for the occurrence of seizures for the patient was represented by the transition from oxygen therapy to the return to a normal breathing. Most of the patients first presented a partial motor seizure, followed by one or more generalized seizures, in cases 2 and 4 then ending up in a status epilepticus. It is possible that the restoration of normal cerebral oxygenation has led to an epileptogenic irritative activity on the cortex not differently from what happens deliberately with hyperpnea during EEG recording. However, case 6 was not subjected to assisted ventilation.
Credit author statement
I declare that all the co-authors have provided relevant contribution for the writing of this article and that thay agree with the submission. | HEPARIN SODIUM, HYDROXYCHLOROQUINE, LOPINAVIR\RITONAVIR, PIPERACILLIN SODIUM, TAZOBACTAM | DrugsGivenReaction | CC BY-NC-ND | 33490654 | 18,883,942 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Posterior reversible encephalopathy syndrome and COVID-19: A series of 6 cases from Lombardy, Italy.
Posterior reversible encephalopathy cases are increasingly being reported in patients affected by COVID-19, but the largest series so far only includes 4 patients. We present a series of 6 patients diagnosed with PRES during COVID-19 hospitalized in 5 Centers in Lombardia, Italy. 5 out of the 6 patients required intensive care assistence and seizures developed at weaning from assisted ventilation. 3 out of 6 patients underwent cerebrospinal fluid analysis which was normal in all cases, with negative PCR for Sars-CoV-2 genome search. PRES occurrence may be less rare than supposed in COVID-19 patients and a high suspicion index is warranted for prompt diagnosis and treatment.
1 Introduction
Since Hinchey's classical first description of 15 PRES cases [1], numerous other reports have been reported in the literature, but only few papers have been published so far concerning PRES patients in the course of Covid-19 infection, with the largest series including only 4 patients [2] and still few reports [3] concerning neuroradiological peculiarities of brain imaging in this context are published
We report a series of 6 COVID-19 patients developing PRES, from the same geographical region. Moreover, in the present paper we take advantage of the description of these clinical cases to formulate etiopathogenetic considerations and we also propose the use of a prophylactic therapy with an anti-epileptic treatment in what we identified as a delicate transition from forced ventilation to restoration of normal breathing.
All patients reported in this publication were diagnosed by neurological departments located in different hospitals in the Lombardy Region, the most densely populated (approximately 10.000.000 inhabitants) in Italy and one of the most productive and most developed areas of the entire European Union, but also unfortunately the Region in which the covid-19 pandemic was more dramatic with a very significant number of deaths.
The clinical symptomatology of PRES is known, the most significant symptoms in our 6 cases (summarized together with treatment and outcome in Table 1) include alterations in consciousness up to coma, arterial hypertension or significant blood pressure (BP) fluctuations, either focal or generalized epileptic seizures until status epilepticus which continues to represent a potential risk factor for death, visual disturbances ranging from homonymous hemianopsia and to other visual field deficits, up to cortical blindness.Table 1 Summary of the main findings in patients 1–6.
Table 1 1 2 3 4 5 6
Sex/age M/54 F/63 M/64 F/64 M/68 F/57
Assisted ventilation Yes Yes Yes Yes Yes No
ICU Yes Yes Yes Yes Yes No
Antibiotics Ceftriaxone
Azithromycin Piperacillin
Tazobactam Ceftriaxone
Azithromycin Ceftriaxone No Levofloxacin
Hydroxychloroquine No Yes No Yes Yes Yes
Antiretroviral Lopinavir/ritonavir Lopinavir/ritonavir Ritonavir/Darunavir Darunavir/Cobicistat Lopinavir/Ritonavir No
Seizures Yes
Partial onset+generalization Yes
Partial onset+generalization Yes
Partial onset+generalization No No Yes
Partial onset+generalization
Visual field defect Yes Yes Yes Yes Yes Yes
Reduced responsiveness No Yes Yes Yes Yes No
Headache No No Yes No Yes No
Poorly controlled blood pressure Yes Yes No Yes Yes Yes
Outcome at dismissal Right homonymous hemianopsia Full recovery Full recovery Full recovery Partial recovery Full recovery
2 Case 1
A 54-year-old male patient presented in the Emergency Room (ER) for fever and dyspnea started 10 days before. A chest X-ray showed bilateral ground glass opacification (GGO), and the SARS-CoV-2 swab resulted positive. He was first ventilated with CPAP, then transferred to the ICU and treated with invasive ventilation, together with lopinavir/ritonavir, azithromycin and ceftriaxone. The course was complicated by acute renal failure following dialysis treatment, and by episodes of atrial fibrillation treated with pharmacological cardioversion. Following clinical improvement, he was transferred to the medical ward, where he developed a secondarily generalized seizure and subsequent poorly controlled blood pressure values.
Brain CT scan revealed areas of subcortical hypodensity in both occipital regions, with greater expression on the left. The EEG presented slow dominant theta-delta band activity with bilateral diffusion, however without abnormalities with paroxysmal significance. Brain MRI was consistent with a diagnosis of PRES (Fig. 1a).Fig. 1 FLAIR sequences of brain MRI.
Fig. 1
At dismissal, the patient was alert, cooperative, with right homonymous hemianopsia and a slight hypotonic tetraparesis compatible with a critical illness polyneuropathy (CIP).
3 Case 2
A 63-year-old female patient presented in ER after a week of fever, cough and myalgias unresponsive to symptomatic therapies. Chest X-ray showed bilateral GGO with consolidation at bases and the pharyngeal swab was positive for SARS-Cov2. Despite treatment with antiviral therapy (lopinavir/ritonavir), hydroxychloroquine, antibiotic therapy (piperacillin/tazobactam) and antithrombotic prophylaxis with low-molecular weight heparin (LMWH), her condition worsened and she was admitted to ICU for invasive ventilation. She also needed hemodynamic support and she underwent immunomodulatory therapy with interleukin-1 antagonist with benefit. She was extubated, but two days later she presented a partial motor seizure with clonic movements of her left side of the face and then in the left hemisome, followed by generalized seizures and epileptic status confirmed by EEG. She was treated with phenytoin, diazepam and levetiracetam, with clinical response and EEG normalization. A first brain CT scan and a subsequent brain MRI (Fig. 1 b) revealed a picture consistent with PRES. Search for SARS-Cov-2 on CSF was negative. The brain MRI performed three weeks later showed a marked improvement, confirming the diagnosis of PRES. The patient is now asymptomatic and had no more epileptic seizures.
4 Case 3
A 64-year-old male was hospitalized after a week of fever unresponsive to antipyretic drugs. The chest X-ray showed GGO. The SARS-CoV-2 swab resulted positive. He was treated with antibiotics and antiretroviral therapy. He first required CPAP treatment, then he needed mechanical ventilation for twenty-three days. After withdrawal of sedation, the patient presented a focal seizure with head and eyes turned to the right, then he became unresponsive and he presented a tetraparesis with normal deep tendon reflexes and absence of other pathological reflexes. EEG confirmed a non-convulsive epileptic status. CSF test for SAR-CoV-2 was negative. Brain MRI showed diffuse white matter hypodense alterations in both hemispheres with symmetrical distribution, mainly affecting the occipital lobes; these lesions did not present contrast-enhancement; few hemosiderin spots suggestive for small hemorrhages were also present. Follow-up MRI was normal, further supporting PRES diagnosis, and clinical recovery was complete.
5 Case 4
A 64-year-old female patient, hospitalized after 10 days of fever and breathing difficulties, was treated at home with antibiotics. At hospital admission she had fever (39 °C) and dyspnea, and neurological examination was normal. Chest x-ray showed GGO in the right basal region, and the nasopharyngeal swab was positive for SARS-CoV-2. Antiviral therapy associated with hydroxychloroquine was started. Due to hypoxia which occurred 24 h later, she was transferred to the ICU, sedated and subjected to mechanical ventilation. After 23 days of ICU admission, the bronchial aspirate for SARS-CoV-2 turned negative. Two days later, after sedation withdrawal she was drowsy with an altered mental status and she complained of blurred vision. Brain CT and MRI (Fig. 1c) were consistent with PRES, with a subsequent haemorrhagic component and improvement at follow-up. The patient became alert again, oriented with normalization of the visual function. This case report was reported in a previous publication [4].
6 Case 5
A 68-year-old male was admitted to the infectious disease department of the Hospital of Gravedona, after eight days of dyspnea and fever, and he had a positive swab for SARS-CoV-2. Oxygen-therapy with CPAP was immediately initiated due to breathing difficulties but worsening of respiratory conditions necessitated a transfer of the patient to ICU and a treatment with invasive ventilation; the patient was treated with hydorxychloroquine and lopinavir/ritonavir. Upon awakening there was a good recovery of alertness and cognitive functions, however the patient complained of visual disturbances in the right visual field and difficulty in walking due to the marked reduction of muscle tone. MRI (Fig. 1d) was consistent with PRES. There was subsequently a progressive improvement of the visual disturbances.
7 Case 6
A 57 years-old female was hospitalized for fever and mild dyspnea and a positive swab test for SARS-CoV-2. Chest x-ray showed no active lesions. In the following days, low-flow oxygen therapy was needed and a treatment with levofloxacin and hydroxychloroquine started. On day-9, the patient suddenly had an aversive seizure with head and eyes turned to the right associated with aphasia. A generalized seizure followed shortly, and it was treated with diazepam iv.
Brain MRI was consistent with PRES (Fig. 1e). In the following days a global aphasia, and frontal neurological symptoms and signs with fatuity and disinhibition appeared; she recovered from aphasia, but she started to complain of visual disturbances in the left hemifield, as well as of rare visual hallucinations. CSF examination showed a slight increase of protein and normal cells, and a negative search for SARS-CoV-2. In the following weeks, she did a full recovery both clinically and in brain imaging.
8 Discussion
Our case series of 6 patients has been collected through reporting by 5 neurology/ICU units in Lombardy with cases occurring during the peak of the epidemic in our region; thus, the number of PRES cases is overall low; the lack of sound epidemiological data on PRES incidence in a pre-COVID era makes it impossible to conclude for an increased risk of developing this syndrome in the context of COVID-19 infection.
CSF data of our three patients who underwent the spinal tap (cases 2, 3 and 6) were substantially normal; of note, PCR search for Sars-Cov-2 genome was negative in all cases; this highlights that PRES in these cases is likely not related to direct viral invasion in the CNS and CSF.
Blood pressure fluctuations are the most relevant factor in PRES pathogenesis; a number of other conditions/treatments have also been reported in association with this syndrome, including hyodroxychloroquine treatment [5]; this drug was administered in 4 of our 6 patients.
In COVID-19 patients, PRES lesions may in some cases present with haemorrhagic features [3,6]; endothelial dysfunction may be relevant in this context [7].
Of note, the distinction between cases of haemorrhagic PRES and recently described patterns of diffuse leukoencephalopathy with microbleeds in COVID-19 patients with persistent confusion and lethargy [8] is not straightforward and might reflect a continuum of alterations involving both the endothelium and the white matter.
It is still not known whether PRES incidence has been substantially increasing in the pandemic; an anecdotal report by Kishfy, Casasola and others at Mount Aubum Hospital in Cambridge, MA, USA [9] described 2 cases in a week as compared with a previous mean of 1.4 cases/yr.
In 4 of our patients, the most critical time for the occurrence of seizures for the patient was represented by the transition from oxygen therapy to the return to a normal breathing. Most of the patients first presented a partial motor seizure, followed by one or more generalized seizures, in cases 2 and 4 then ending up in a status epilepticus. It is possible that the restoration of normal cerebral oxygenation has led to an epileptogenic irritative activity on the cortex not differently from what happens deliberately with hyperpnea during EEG recording. However, case 6 was not subjected to assisted ventilation.
Credit author statement
I declare that all the co-authors have provided relevant contribution for the writing of this article and that thay agree with the submission. | HEPARIN SODIUM, HYDROXYCHLOROQUINE, LOPINAVIR\RITONAVIR, PIPERACILLIN SODIUM, TAZOBACTAM | DrugsGivenReaction | CC BY-NC-ND | 33490654 | 18,883,942 | 2021-03 |
What was the administration route of drug 'LOPINAVIR\RITONAVIR'? | Posterior reversible encephalopathy syndrome and COVID-19: A series of 6 cases from Lombardy, Italy.
Posterior reversible encephalopathy cases are increasingly being reported in patients affected by COVID-19, but the largest series so far only includes 4 patients. We present a series of 6 patients diagnosed with PRES during COVID-19 hospitalized in 5 Centers in Lombardia, Italy. 5 out of the 6 patients required intensive care assistence and seizures developed at weaning from assisted ventilation. 3 out of 6 patients underwent cerebrospinal fluid analysis which was normal in all cases, with negative PCR for Sars-CoV-2 genome search. PRES occurrence may be less rare than supposed in COVID-19 patients and a high suspicion index is warranted for prompt diagnosis and treatment.
1 Introduction
Since Hinchey's classical first description of 15 PRES cases [1], numerous other reports have been reported in the literature, but only few papers have been published so far concerning PRES patients in the course of Covid-19 infection, with the largest series including only 4 patients [2] and still few reports [3] concerning neuroradiological peculiarities of brain imaging in this context are published
We report a series of 6 COVID-19 patients developing PRES, from the same geographical region. Moreover, in the present paper we take advantage of the description of these clinical cases to formulate etiopathogenetic considerations and we also propose the use of a prophylactic therapy with an anti-epileptic treatment in what we identified as a delicate transition from forced ventilation to restoration of normal breathing.
All patients reported in this publication were diagnosed by neurological departments located in different hospitals in the Lombardy Region, the most densely populated (approximately 10.000.000 inhabitants) in Italy and one of the most productive and most developed areas of the entire European Union, but also unfortunately the Region in which the covid-19 pandemic was more dramatic with a very significant number of deaths.
The clinical symptomatology of PRES is known, the most significant symptoms in our 6 cases (summarized together with treatment and outcome in Table 1) include alterations in consciousness up to coma, arterial hypertension or significant blood pressure (BP) fluctuations, either focal or generalized epileptic seizures until status epilepticus which continues to represent a potential risk factor for death, visual disturbances ranging from homonymous hemianopsia and to other visual field deficits, up to cortical blindness.Table 1 Summary of the main findings in patients 1–6.
Table 1 1 2 3 4 5 6
Sex/age M/54 F/63 M/64 F/64 M/68 F/57
Assisted ventilation Yes Yes Yes Yes Yes No
ICU Yes Yes Yes Yes Yes No
Antibiotics Ceftriaxone
Azithromycin Piperacillin
Tazobactam Ceftriaxone
Azithromycin Ceftriaxone No Levofloxacin
Hydroxychloroquine No Yes No Yes Yes Yes
Antiretroviral Lopinavir/ritonavir Lopinavir/ritonavir Ritonavir/Darunavir Darunavir/Cobicistat Lopinavir/Ritonavir No
Seizures Yes
Partial onset+generalization Yes
Partial onset+generalization Yes
Partial onset+generalization No No Yes
Partial onset+generalization
Visual field defect Yes Yes Yes Yes Yes Yes
Reduced responsiveness No Yes Yes Yes Yes No
Headache No No Yes No Yes No
Poorly controlled blood pressure Yes Yes No Yes Yes Yes
Outcome at dismissal Right homonymous hemianopsia Full recovery Full recovery Full recovery Partial recovery Full recovery
2 Case 1
A 54-year-old male patient presented in the Emergency Room (ER) for fever and dyspnea started 10 days before. A chest X-ray showed bilateral ground glass opacification (GGO), and the SARS-CoV-2 swab resulted positive. He was first ventilated with CPAP, then transferred to the ICU and treated with invasive ventilation, together with lopinavir/ritonavir, azithromycin and ceftriaxone. The course was complicated by acute renal failure following dialysis treatment, and by episodes of atrial fibrillation treated with pharmacological cardioversion. Following clinical improvement, he was transferred to the medical ward, where he developed a secondarily generalized seizure and subsequent poorly controlled blood pressure values.
Brain CT scan revealed areas of subcortical hypodensity in both occipital regions, with greater expression on the left. The EEG presented slow dominant theta-delta band activity with bilateral diffusion, however without abnormalities with paroxysmal significance. Brain MRI was consistent with a diagnosis of PRES (Fig. 1a).Fig. 1 FLAIR sequences of brain MRI.
Fig. 1
At dismissal, the patient was alert, cooperative, with right homonymous hemianopsia and a slight hypotonic tetraparesis compatible with a critical illness polyneuropathy (CIP).
3 Case 2
A 63-year-old female patient presented in ER after a week of fever, cough and myalgias unresponsive to symptomatic therapies. Chest X-ray showed bilateral GGO with consolidation at bases and the pharyngeal swab was positive for SARS-Cov2. Despite treatment with antiviral therapy (lopinavir/ritonavir), hydroxychloroquine, antibiotic therapy (piperacillin/tazobactam) and antithrombotic prophylaxis with low-molecular weight heparin (LMWH), her condition worsened and she was admitted to ICU for invasive ventilation. She also needed hemodynamic support and she underwent immunomodulatory therapy with interleukin-1 antagonist with benefit. She was extubated, but two days later she presented a partial motor seizure with clonic movements of her left side of the face and then in the left hemisome, followed by generalized seizures and epileptic status confirmed by EEG. She was treated with phenytoin, diazepam and levetiracetam, with clinical response and EEG normalization. A first brain CT scan and a subsequent brain MRI (Fig. 1 b) revealed a picture consistent with PRES. Search for SARS-Cov-2 on CSF was negative. The brain MRI performed three weeks later showed a marked improvement, confirming the diagnosis of PRES. The patient is now asymptomatic and had no more epileptic seizures.
4 Case 3
A 64-year-old male was hospitalized after a week of fever unresponsive to antipyretic drugs. The chest X-ray showed GGO. The SARS-CoV-2 swab resulted positive. He was treated with antibiotics and antiretroviral therapy. He first required CPAP treatment, then he needed mechanical ventilation for twenty-three days. After withdrawal of sedation, the patient presented a focal seizure with head and eyes turned to the right, then he became unresponsive and he presented a tetraparesis with normal deep tendon reflexes and absence of other pathological reflexes. EEG confirmed a non-convulsive epileptic status. CSF test for SAR-CoV-2 was negative. Brain MRI showed diffuse white matter hypodense alterations in both hemispheres with symmetrical distribution, mainly affecting the occipital lobes; these lesions did not present contrast-enhancement; few hemosiderin spots suggestive for small hemorrhages were also present. Follow-up MRI was normal, further supporting PRES diagnosis, and clinical recovery was complete.
5 Case 4
A 64-year-old female patient, hospitalized after 10 days of fever and breathing difficulties, was treated at home with antibiotics. At hospital admission she had fever (39 °C) and dyspnea, and neurological examination was normal. Chest x-ray showed GGO in the right basal region, and the nasopharyngeal swab was positive for SARS-CoV-2. Antiviral therapy associated with hydroxychloroquine was started. Due to hypoxia which occurred 24 h later, she was transferred to the ICU, sedated and subjected to mechanical ventilation. After 23 days of ICU admission, the bronchial aspirate for SARS-CoV-2 turned negative. Two days later, after sedation withdrawal she was drowsy with an altered mental status and she complained of blurred vision. Brain CT and MRI (Fig. 1c) were consistent with PRES, with a subsequent haemorrhagic component and improvement at follow-up. The patient became alert again, oriented with normalization of the visual function. This case report was reported in a previous publication [4].
6 Case 5
A 68-year-old male was admitted to the infectious disease department of the Hospital of Gravedona, after eight days of dyspnea and fever, and he had a positive swab for SARS-CoV-2. Oxygen-therapy with CPAP was immediately initiated due to breathing difficulties but worsening of respiratory conditions necessitated a transfer of the patient to ICU and a treatment with invasive ventilation; the patient was treated with hydorxychloroquine and lopinavir/ritonavir. Upon awakening there was a good recovery of alertness and cognitive functions, however the patient complained of visual disturbances in the right visual field and difficulty in walking due to the marked reduction of muscle tone. MRI (Fig. 1d) was consistent with PRES. There was subsequently a progressive improvement of the visual disturbances.
7 Case 6
A 57 years-old female was hospitalized for fever and mild dyspnea and a positive swab test for SARS-CoV-2. Chest x-ray showed no active lesions. In the following days, low-flow oxygen therapy was needed and a treatment with levofloxacin and hydroxychloroquine started. On day-9, the patient suddenly had an aversive seizure with head and eyes turned to the right associated with aphasia. A generalized seizure followed shortly, and it was treated with diazepam iv.
Brain MRI was consistent with PRES (Fig. 1e). In the following days a global aphasia, and frontal neurological symptoms and signs with fatuity and disinhibition appeared; she recovered from aphasia, but she started to complain of visual disturbances in the left hemifield, as well as of rare visual hallucinations. CSF examination showed a slight increase of protein and normal cells, and a negative search for SARS-CoV-2. In the following weeks, she did a full recovery both clinically and in brain imaging.
8 Discussion
Our case series of 6 patients has been collected through reporting by 5 neurology/ICU units in Lombardy with cases occurring during the peak of the epidemic in our region; thus, the number of PRES cases is overall low; the lack of sound epidemiological data on PRES incidence in a pre-COVID era makes it impossible to conclude for an increased risk of developing this syndrome in the context of COVID-19 infection.
CSF data of our three patients who underwent the spinal tap (cases 2, 3 and 6) were substantially normal; of note, PCR search for Sars-Cov-2 genome was negative in all cases; this highlights that PRES in these cases is likely not related to direct viral invasion in the CNS and CSF.
Blood pressure fluctuations are the most relevant factor in PRES pathogenesis; a number of other conditions/treatments have also been reported in association with this syndrome, including hyodroxychloroquine treatment [5]; this drug was administered in 4 of our 6 patients.
In COVID-19 patients, PRES lesions may in some cases present with haemorrhagic features [3,6]; endothelial dysfunction may be relevant in this context [7].
Of note, the distinction between cases of haemorrhagic PRES and recently described patterns of diffuse leukoencephalopathy with microbleeds in COVID-19 patients with persistent confusion and lethargy [8] is not straightforward and might reflect a continuum of alterations involving both the endothelium and the white matter.
It is still not known whether PRES incidence has been substantially increasing in the pandemic; an anecdotal report by Kishfy, Casasola and others at Mount Aubum Hospital in Cambridge, MA, USA [9] described 2 cases in a week as compared with a previous mean of 1.4 cases/yr.
In 4 of our patients, the most critical time for the occurrence of seizures for the patient was represented by the transition from oxygen therapy to the return to a normal breathing. Most of the patients first presented a partial motor seizure, followed by one or more generalized seizures, in cases 2 and 4 then ending up in a status epilepticus. It is possible that the restoration of normal cerebral oxygenation has led to an epileptogenic irritative activity on the cortex not differently from what happens deliberately with hyperpnea during EEG recording. However, case 6 was not subjected to assisted ventilation.
Credit author statement
I declare that all the co-authors have provided relevant contribution for the writing of this article and that thay agree with the submission. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33490654 | 18,883,942 | 2021-03 |
What was the outcome of reaction 'Cerebral haemorrhage'? | Posterior reversible encephalopathy syndrome and COVID-19: A series of 6 cases from Lombardy, Italy.
Posterior reversible encephalopathy cases are increasingly being reported in patients affected by COVID-19, but the largest series so far only includes 4 patients. We present a series of 6 patients diagnosed with PRES during COVID-19 hospitalized in 5 Centers in Lombardia, Italy. 5 out of the 6 patients required intensive care assistence and seizures developed at weaning from assisted ventilation. 3 out of 6 patients underwent cerebrospinal fluid analysis which was normal in all cases, with negative PCR for Sars-CoV-2 genome search. PRES occurrence may be less rare than supposed in COVID-19 patients and a high suspicion index is warranted for prompt diagnosis and treatment.
1 Introduction
Since Hinchey's classical first description of 15 PRES cases [1], numerous other reports have been reported in the literature, but only few papers have been published so far concerning PRES patients in the course of Covid-19 infection, with the largest series including only 4 patients [2] and still few reports [3] concerning neuroradiological peculiarities of brain imaging in this context are published
We report a series of 6 COVID-19 patients developing PRES, from the same geographical region. Moreover, in the present paper we take advantage of the description of these clinical cases to formulate etiopathogenetic considerations and we also propose the use of a prophylactic therapy with an anti-epileptic treatment in what we identified as a delicate transition from forced ventilation to restoration of normal breathing.
All patients reported in this publication were diagnosed by neurological departments located in different hospitals in the Lombardy Region, the most densely populated (approximately 10.000.000 inhabitants) in Italy and one of the most productive and most developed areas of the entire European Union, but also unfortunately the Region in which the covid-19 pandemic was more dramatic with a very significant number of deaths.
The clinical symptomatology of PRES is known, the most significant symptoms in our 6 cases (summarized together with treatment and outcome in Table 1) include alterations in consciousness up to coma, arterial hypertension or significant blood pressure (BP) fluctuations, either focal or generalized epileptic seizures until status epilepticus which continues to represent a potential risk factor for death, visual disturbances ranging from homonymous hemianopsia and to other visual field deficits, up to cortical blindness.Table 1 Summary of the main findings in patients 1–6.
Table 1 1 2 3 4 5 6
Sex/age M/54 F/63 M/64 F/64 M/68 F/57
Assisted ventilation Yes Yes Yes Yes Yes No
ICU Yes Yes Yes Yes Yes No
Antibiotics Ceftriaxone
Azithromycin Piperacillin
Tazobactam Ceftriaxone
Azithromycin Ceftriaxone No Levofloxacin
Hydroxychloroquine No Yes No Yes Yes Yes
Antiretroviral Lopinavir/ritonavir Lopinavir/ritonavir Ritonavir/Darunavir Darunavir/Cobicistat Lopinavir/Ritonavir No
Seizures Yes
Partial onset+generalization Yes
Partial onset+generalization Yes
Partial onset+generalization No No Yes
Partial onset+generalization
Visual field defect Yes Yes Yes Yes Yes Yes
Reduced responsiveness No Yes Yes Yes Yes No
Headache No No Yes No Yes No
Poorly controlled blood pressure Yes Yes No Yes Yes Yes
Outcome at dismissal Right homonymous hemianopsia Full recovery Full recovery Full recovery Partial recovery Full recovery
2 Case 1
A 54-year-old male patient presented in the Emergency Room (ER) for fever and dyspnea started 10 days before. A chest X-ray showed bilateral ground glass opacification (GGO), and the SARS-CoV-2 swab resulted positive. He was first ventilated with CPAP, then transferred to the ICU and treated with invasive ventilation, together with lopinavir/ritonavir, azithromycin and ceftriaxone. The course was complicated by acute renal failure following dialysis treatment, and by episodes of atrial fibrillation treated with pharmacological cardioversion. Following clinical improvement, he was transferred to the medical ward, where he developed a secondarily generalized seizure and subsequent poorly controlled blood pressure values.
Brain CT scan revealed areas of subcortical hypodensity in both occipital regions, with greater expression on the left. The EEG presented slow dominant theta-delta band activity with bilateral diffusion, however without abnormalities with paroxysmal significance. Brain MRI was consistent with a diagnosis of PRES (Fig. 1a).Fig. 1 FLAIR sequences of brain MRI.
Fig. 1
At dismissal, the patient was alert, cooperative, with right homonymous hemianopsia and a slight hypotonic tetraparesis compatible with a critical illness polyneuropathy (CIP).
3 Case 2
A 63-year-old female patient presented in ER after a week of fever, cough and myalgias unresponsive to symptomatic therapies. Chest X-ray showed bilateral GGO with consolidation at bases and the pharyngeal swab was positive for SARS-Cov2. Despite treatment with antiviral therapy (lopinavir/ritonavir), hydroxychloroquine, antibiotic therapy (piperacillin/tazobactam) and antithrombotic prophylaxis with low-molecular weight heparin (LMWH), her condition worsened and she was admitted to ICU for invasive ventilation. She also needed hemodynamic support and she underwent immunomodulatory therapy with interleukin-1 antagonist with benefit. She was extubated, but two days later she presented a partial motor seizure with clonic movements of her left side of the face and then in the left hemisome, followed by generalized seizures and epileptic status confirmed by EEG. She was treated with phenytoin, diazepam and levetiracetam, with clinical response and EEG normalization. A first brain CT scan and a subsequent brain MRI (Fig. 1 b) revealed a picture consistent with PRES. Search for SARS-Cov-2 on CSF was negative. The brain MRI performed three weeks later showed a marked improvement, confirming the diagnosis of PRES. The patient is now asymptomatic and had no more epileptic seizures.
4 Case 3
A 64-year-old male was hospitalized after a week of fever unresponsive to antipyretic drugs. The chest X-ray showed GGO. The SARS-CoV-2 swab resulted positive. He was treated with antibiotics and antiretroviral therapy. He first required CPAP treatment, then he needed mechanical ventilation for twenty-three days. After withdrawal of sedation, the patient presented a focal seizure with head and eyes turned to the right, then he became unresponsive and he presented a tetraparesis with normal deep tendon reflexes and absence of other pathological reflexes. EEG confirmed a non-convulsive epileptic status. CSF test for SAR-CoV-2 was negative. Brain MRI showed diffuse white matter hypodense alterations in both hemispheres with symmetrical distribution, mainly affecting the occipital lobes; these lesions did not present contrast-enhancement; few hemosiderin spots suggestive for small hemorrhages were also present. Follow-up MRI was normal, further supporting PRES diagnosis, and clinical recovery was complete.
5 Case 4
A 64-year-old female patient, hospitalized after 10 days of fever and breathing difficulties, was treated at home with antibiotics. At hospital admission she had fever (39 °C) and dyspnea, and neurological examination was normal. Chest x-ray showed GGO in the right basal region, and the nasopharyngeal swab was positive for SARS-CoV-2. Antiviral therapy associated with hydroxychloroquine was started. Due to hypoxia which occurred 24 h later, she was transferred to the ICU, sedated and subjected to mechanical ventilation. After 23 days of ICU admission, the bronchial aspirate for SARS-CoV-2 turned negative. Two days later, after sedation withdrawal she was drowsy with an altered mental status and she complained of blurred vision. Brain CT and MRI (Fig. 1c) were consistent with PRES, with a subsequent haemorrhagic component and improvement at follow-up. The patient became alert again, oriented with normalization of the visual function. This case report was reported in a previous publication [4].
6 Case 5
A 68-year-old male was admitted to the infectious disease department of the Hospital of Gravedona, after eight days of dyspnea and fever, and he had a positive swab for SARS-CoV-2. Oxygen-therapy with CPAP was immediately initiated due to breathing difficulties but worsening of respiratory conditions necessitated a transfer of the patient to ICU and a treatment with invasive ventilation; the patient was treated with hydorxychloroquine and lopinavir/ritonavir. Upon awakening there was a good recovery of alertness and cognitive functions, however the patient complained of visual disturbances in the right visual field and difficulty in walking due to the marked reduction of muscle tone. MRI (Fig. 1d) was consistent with PRES. There was subsequently a progressive improvement of the visual disturbances.
7 Case 6
A 57 years-old female was hospitalized for fever and mild dyspnea and a positive swab test for SARS-CoV-2. Chest x-ray showed no active lesions. In the following days, low-flow oxygen therapy was needed and a treatment with levofloxacin and hydroxychloroquine started. On day-9, the patient suddenly had an aversive seizure with head and eyes turned to the right associated with aphasia. A generalized seizure followed shortly, and it was treated with diazepam iv.
Brain MRI was consistent with PRES (Fig. 1e). In the following days a global aphasia, and frontal neurological symptoms and signs with fatuity and disinhibition appeared; she recovered from aphasia, but she started to complain of visual disturbances in the left hemifield, as well as of rare visual hallucinations. CSF examination showed a slight increase of protein and normal cells, and a negative search for SARS-CoV-2. In the following weeks, she did a full recovery both clinically and in brain imaging.
8 Discussion
Our case series of 6 patients has been collected through reporting by 5 neurology/ICU units in Lombardy with cases occurring during the peak of the epidemic in our region; thus, the number of PRES cases is overall low; the lack of sound epidemiological data on PRES incidence in a pre-COVID era makes it impossible to conclude for an increased risk of developing this syndrome in the context of COVID-19 infection.
CSF data of our three patients who underwent the spinal tap (cases 2, 3 and 6) were substantially normal; of note, PCR search for Sars-Cov-2 genome was negative in all cases; this highlights that PRES in these cases is likely not related to direct viral invasion in the CNS and CSF.
Blood pressure fluctuations are the most relevant factor in PRES pathogenesis; a number of other conditions/treatments have also been reported in association with this syndrome, including hyodroxychloroquine treatment [5]; this drug was administered in 4 of our 6 patients.
In COVID-19 patients, PRES lesions may in some cases present with haemorrhagic features [3,6]; endothelial dysfunction may be relevant in this context [7].
Of note, the distinction between cases of haemorrhagic PRES and recently described patterns of diffuse leukoencephalopathy with microbleeds in COVID-19 patients with persistent confusion and lethargy [8] is not straightforward and might reflect a continuum of alterations involving both the endothelium and the white matter.
It is still not known whether PRES incidence has been substantially increasing in the pandemic; an anecdotal report by Kishfy, Casasola and others at Mount Aubum Hospital in Cambridge, MA, USA [9] described 2 cases in a week as compared with a previous mean of 1.4 cases/yr.
In 4 of our patients, the most critical time for the occurrence of seizures for the patient was represented by the transition from oxygen therapy to the return to a normal breathing. Most of the patients first presented a partial motor seizure, followed by one or more generalized seizures, in cases 2 and 4 then ending up in a status epilepticus. It is possible that the restoration of normal cerebral oxygenation has led to an epileptogenic irritative activity on the cortex not differently from what happens deliberately with hyperpnea during EEG recording. However, case 6 was not subjected to assisted ventilation.
Credit author statement
I declare that all the co-authors have provided relevant contribution for the writing of this article and that thay agree with the submission. | Recovered | ReactionOutcome | CC BY-NC-ND | 33490654 | 18,970,763 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Enterocutaneous fistula'. | Reirradiation for Rectal Cancer Using Pencil Beam Scanning Proton Therapy: A Single Institutional Experience.
Reirradiation for rectal cancer (RC) after prior pelvic radiation therapy (RT) has been shown to be safe and effective. However, limited data exist for proton therapy (PT), including pencil beam scanning proton therapy (PBS-PT). We hypothesize that PT is safe and feasible for re-treatment and may allow for decreased toxicity and treatment escalation.
A single-institution, retrospective, institutional review board-approved analysis of all patients with RC and prior pelvic RT receiving PBS-PT reirradiation was performed. Data on patient and treatment characteristics and outcomes were collected. Local progression, progression-free survival, overall survival, and late grade >3 toxicity were estimated using the Kaplan-Meier method.
Twenty-eight patients (median follow-up: 28.6 months) received PBS-PT reirradiation between 2016 and 2019, including 18 patients with recurrent RC (median prior dose: 54.0 Gy) and 10 patients with de novo RC and variable prior RT. The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 twice daily), and 24 of 28 patients received concurrent chemotherapy. Six underwent surgical resection. Three (10.7%) experienced grade 3 acute toxicities, and 1 did not complete RT owing to toxicity. Four (14.2%) had late grade <3 toxicity, including 1 grade 5 toxicity in a patient with a prior RT-related injury. The 1-year local progression, progression-free survival, and overall survival rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively.
This is the largest series using PT for reirradiation for RC and the first study using PBS-PT. Low acute toxicity rates and acceptable late toxicity support PBS-PT as an option for this high-risk patient population, with a need for continued follow-up.
Introduction
Rectal cancer (RC) is a common malignancy, with approximately 40,000 new cases per year in the United States and 800,000 worldwide. Therapy for locally advanced disease often consists of neoadjuvant concurrent chemotherapy and radiation, followed by surgical resection with total mesorectal excision—a paradigm that has improved local control, survival, and treatment-related toxicities.1, 2, 3 In the modern era, local relapse affects approximately 7% of patients in the long term and is associated with pain, obstruction, bleeding, discharge, and change in stool habits.4
Reirradiation for RC may be implemented in the treatment of locally recurrent RCs and de novo RC with prior radiation for other pelvic malignancy. It may be administered either as part of a curative or palliative regimen, with patients eligible for and receiving curative resection having the most favorable survival outcomes.5,6 However, it presents risk of late complications given the radiation sensitivity of nearby organs and tissues of the abdomen and pelvis—in particular, the bladder, bowel, bone marrow, and lumbosacral plexus. This affects the approach of reirradiation in multiple ways, including treatment volumes, prescribed dose, fractionation scheme, and technique of delivery.
Numerous experiences have described disease and toxicity outcomes of reirradiation for RC, using these aforementioned modifications in treatment delivery to achieve safe and effective therapy.7 A landmark prospective study by Valentini et al demonstrated the safety and efficacy of hyperfractionated reirradiation with concurrent chemotherapy, often given neoadjuvantly.8 This study has served as a reference for both disease outcomes and treatment toxicities. Multiple retrospective studies have corroborated these findings.9, 10, 11, 12 However, to our knowledge, nearly all published studies have evaluated reirradiation using either 3-dimensional conformal radiation therapy (RT) or intensity modulated RT techniques.13,14 Literature evaluating rectal reirradiation with proton therapy (PT) is emerging and has demonstrated a significantly reduced low dose to the bowel and bone marrow, as well as clinical feasibility, safety, and efficacy—thus far with passive-scatter techniques.15,16 PBS-PT provides true intensity modulated PT; thus, we hypothesize that its use may result in improved short- and long-term toxicity profiles in the setting of reirradiation for RC. We report the disease and toxicity outcomes from a retrospective, single-institution experience using PBS-PT for reirradiation for RC.
Methods and materials
Patient selection and treatment
An institutional review board–approved retrospective chart review was completed of all patients treated with reirradiation using PBS-PT at a single institution between 2016 and 2019 for either recurrent RC or de novo RC with prior pelvic RT for another malignancy. Patient demographic information, disease characteristics, and treatment characteristics were collected. Prior RT plan reports were accessed when possible, and all PBS-PT plans underwent peer review per departmental protocol. All patients were presented at a multidisciplinary tumor board. Concurrent chemotherapy and curative-intent surgical resection were planned whenever feasible and appropriate.
Proton beam reirradiation
Patients underwent computed tomography (CT) simulation in the supine or prone position with a comfortably full bladder and vac-lok immobilization. Contouring of the target and organ-at-risk volumes was performed. Gross tumor volume (GTV) was delineated using physical examination, CT simulation, and diagnostic imaging data (positron emission tomography and/or magnetic resonance imaging). A clinical target volume (CTV) was generated by expanding the GTV by 1.5 to 3.0 cm craniocaudally, extending to the pelvic sidewall laterally, and including the presacral space posteriorly. When a boost was planned, a second smaller isotropic expansion of 0.5 to 1.5 cm was used, or simply the gross tumor without expansion. The choice of CTV expansion is based on the method outlined by Valentini et al,8 with smaller expansions on the GTV used in cases of inoperable recurrences involving the bone. Planning target volumes were generated by dosimetry, accounting for setup and proton beam range uncertainty. Earlier cases used a uniform 5 mm expansion, later transitioning to nonuniform expansions (3.5-5 mm) based on translational uncertainty, and eventually generation of a planning target volume using robust optimization algorithms. Dosing was guided by the method by Valentini et al.8 Hyperfractionation was employed when feasible for the patient.
Plan optimization was performed using Eclipse (Varian Medical Systems, Palo Alto, CA) and Raystation (RaySearch Laboratories, Stockholm, Sweden). All patients were treated with PBS-PT, typically with 2 lateral fields with single-field optimization technique, with some cases using a third field and/or multiple-field optimization. Opposed lateral fields, rather than posterior oblique fields, were used in many cases due to relative biological effectiveness (RBE) uncertainty at the end range, because this configuration limits overlap of end-ranging segments of the beams into previously irradiated bladder as well as bowel anterior to the CTV. Furthermore, using PBS-PT, the anterior edge of the field can be shaped and modulated off of bladder and bowel with opposed lateral fields, in contrast to the same arrangement using photon-based 3-dimensional conformal RT, where this is not possible.
When using a multiple field optimization technique, air in the bowel was accounted for using a density override algorithm. Quality assurance CT images were obtained during the course of therapy, with frequency depending on the particular case and clinical discretion. Dose constraints for the bladder and bowel entailed keeping maximum doses of approximately 90% of the prescription dose, which itself depended on prior radiation dose and time interval. In all cases, these constraints on the bladder and bowel structures were prioritized over full prescription isodose coverage of the anterior target volume. A representative plan is shown in Figure 1.Figure 1 Example pencil beam scanning proton therapy plan with axial, coronal, and sagittal views with corresponding dose–volume histogram. The patient was simulated prone, dose was prescribed via a simultaneous integrated boost with clinical target volume 1 (blue; gross target volume with 2-2.5 cm craniocaudal expansion, laterally to pelvic sidewalls and posteriorly to sacrum) receiving 4000 cGy in 100 cGy/fraction and clinical target volume 2 (red; gross target volume + 1.0 cm isotropic expansion) receiving 4800 cGy in 120 cGy/fraction. Proton planning target volumes were generated based on setup and range uncertainty. Two lateral beams using a multiple-field optimization technique were used. Bladder (yellow), large bowel (brown), small bowel (green), right femoral head (turquoise), and left femoral head (fuschia). (A color version of this figure is available at https://doi.org/10.1016/j.adro.2020.10.008.)
Statistics
Efficacy outcomes included local progression (LP), progression-free survival (PFS), and overall survival (OS). LP was calculated from completion of reirradiation to time of local failure by pathologic or radiologic confirmation. Patients who did not experience LP were censored at the time of the last follow-up visit. PFS was calculated from completion of reirradiation to the date of any progression or death, irrespective of the cause. OS was calculated from completion of reirradiation to the date of death, irrespective of the cause. The vital status of patients was checked using medical record/obituary documentation, and OS was censored on the date of the last documentation confirming living status in patients still alive on that date.
Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 5.0. Acute toxicity was assessed using provider documentation from weekly on-treatment visits. Late toxicity was defined as symptoms attributable to RT persisting or occurring >3 months after completion of reirradiation. All clinical outcomes were estimated using the Kaplan-Meier method. A univariable Cox proportional hazards model was used to model the relationship between GTV and outcome. A P value of <.05 was considered statistically significant. All analyses were completed using SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY).
Patient, disease, and treatment characteristics
Patient, disease, and treatment characteristics are summarized in Table 1. Twenty-eight patients (median follow-up 28.6 months; range, 25.3-31.9 months) received PBS-PT reirradiation from 2016 to 2019. Of these, 18 patients (64.3%) had recurrent RC (median prior dose: 54.0 Gy; range, 43.2-63.0 Gy) and 10 patients had de novo RC and variable prior RT (8 received full-dose external beam RT or brachytherapy for prostate cancer; 1 patient received external beam RT and brachytherapy boost for endometrial cancer; 1 patient received whole abdominal RT for ovarian cancer with a pelvic boost). The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 patients twice daily), and 24 of 28 patients (85.7%) received concurrent chemotherapy, with 18 of 28 (64.3%) receiving twice-daily oral capecitabine on days with reirradiation. Overall, 25 of 28 patients (89.3%) completed the planned course of reirradiation.Table 1 Patient and treatment characteristics (n = 28)
Characteristics n (%)
Sex
Male 19 (67.9%)
Female 9 (32.1%)
Age, y, median (range) 68 (41-87)
Follow-up, mo, median (range) 28.6 (25.3-31.9)
Recurrent rectal cancer 18 (64.3)
Prior RT dose, Gy, median (range) 54.0 (43.2-63.0)
Anatomic location of recurrence
Rectal 6 (33.3)
Presacral 11 (61.1)
Pelvic bone 1 (5.6)
Treatment for initial rectal cancer (n = 18)
Neoadjuvant conformal RT 8 (44.4)
Adjuvant conformal RT 2 (11.2)
Other 8 (44.4)
de novo rectal cancer (n = 10) 10 (35.7)
Prior pelvic RT Definitive for prostate cancer (equivalent total dose in 2 Gy fractions >70 Gy)8
Definitive for ovarian cancer1
Definitive for endometrial cancer1
Treatment before reirradiation for recurrence
Upfront surgery, n 2
Systemic therapy, n 8
Reirradiation dose, Gy, median (range) 48.0 (16.0-60.0)
Reirradiation interval, mo, median (range) 48.5 (12.7-494.8)
Concurrent chemotherapy with reirradiation 24 (85.7)
Hyperfractionated reirradiation 21 (75.0)
Completed reirradiation course 25 (89.3)
Underwent resection after reirradiation 6 (21.4)
R0 6
Gross tumor volume, cm3, median (range) 86.4 (13.6-821.8)
Abbreviation: RT = radiation therapy.
Table 2 Acute toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Grade 2, n (%) 3, n (%) 4, n (%) 5, n (%)
Gastrointestinal 4 (14.2) 2 (7.1) 0 (0.0) 0 (0.0)
Skin 4 (14.2) 1 (3.6) 0 (0.0) 0 (0.0)
Urologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Hematologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Total 8 (28.6) 3 (10.7) 0 (0.0) 0 (0.0)
Disease outcomes and toxicity
The 1-year LP, PFS, and OS rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively. The median times to LP, PFS, and OS were 23.4 months (range, 1.6-39.8 months; 95% CI, 12.9-33.9 months), 11.6 months (range, 0.6-39.8 months; 95% CI, 8.6-14.5 months), and 29.2 months (range, 1.6-45.9 months; 95% CI, 19.7-38.8 months), respectively (Fig 2A-C). In a univariable Cox proportional hazards model with GTV (cm3) included as a continuous variable, increasing GTV was highly statistically significantly associated with LP (hazard ratio [HR]: 1.005; 95% CI, 1.002-1.008; P = .003) and PFS (HR: 1.004; 95% CI, 1.002-1.006; P = .001), but not with OS (HR: 1.002; 95% CI, 1.000-1.005; P = .102). The 1-year LP rate for recurrent versus de novo RC was significantly different at 52.3% (95% CI, 23.9%-80.1%) and 0% (P = .002), respectively. The 1-year OS rate for recurrent versus de novo RC was 72.2% (95% CI, 51.4%-93.0%) and 100% (P = .058), respectively.Figure 2 Kaplan-Meier curves for (A) local progression, (B) progression-free survival, (C) overall survival, and (D) late grade >3 toxicities for all patients (n = 28).
Six patients (21.4%) underwent surgical resection after reirradiation, with further breakdown by de novo RC and recurrent RC patients being 3 of 10 (30%) and 3 of 18 (16.7%), respectively. All resections resulted in R0 resection. Of these patients, 4 eventually experienced LP (3 with recurrent RC), with a 1-year LP rate of resected patients of 16.7% versus 40% for those who did not receive resection (P = .786). The 1-year OS rate for patients undergoing and not undergoing resection was 100% and 76.8%, respectively; this difference was statistically significant (P = .027).
Acute toxicities are listed in Table 2. The 1-year rate of late grade >3 toxicities (G3+ Tox) was 13.3% in the Kaplan-Meier analysis (Fig 2D). Six late G3+ Tox occurred in 4 separate patients, with no evidence of tumor recurrence at toxicity onset (summarized by patient in Table 3). Patient 1 ultimately developed grade 5 toxicity and had a history of significant late toxicity from prior whole abdominal and pelvic boost radiation for ovarian cancer in the 1970s, including baseline and longstanding radiation colitis, loss of a kidney, and cystitis. This patient developed rectal bleeding at 3 months, a rectovaginal fistula at 9 months, and ultimately a bleeding stage IV decubitus ulcer and died of presacral hemorrhage at 26 months without evidence of tumor recurrence. Patient 2 developed an enterocutaneous fistula passing through the presacral region, as well as pyelonephritis resolving with parenteral antibiotics, approximately 1 year from completion of reirradiation. The treatment course was entirely in a medical ward without stay in either intermediate or intensive care. Of note, this patient was receiving bevacizumab systemic therapy at the time of the fistula diagnosis. This patient also experienced multiple delays and breaks in the planned treatment course related to social and logistic factors. This was the only patient who experienced G3+ Tox in both the acute and late term.Table 3 Grade ≥3 late toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Patient no. Grade Toxicity Time to toxicity, mo
1 3 Rectovaginal fistula 8.5
1 5 Presacral hemorrhage 25.6
2 3 Enterocutaneous fistula 11
2 3 Pyelonephritis (resolved) 11
3 3 Presacral abscess/rectovaginal fistula 31
4 3 Colovaginal fistula (improved) 12
Six grade 3+ events were observed in 4 patients.
Patient 3 developed a presacral abscess and rectovaginal fistula approximately 2.5 years from completion of reirradiation. The site of local recurrence, which was treated with reirradiation, involved the vaginal fornices. Patient 4 had a long history of presacral abscess and transvaginal drainage procedures before reirradiation and developed increased vaginal discharge approximately 1 year from completion of reirradiation. The patient received a diagnosis of colovaginal fistula, which improved with percutaneous drainage.
Discussion
This is the largest report with the longest median follow-up to date of reirradiation for RC using PT. Additionally, all patients in our cohort received PBS-PT, making this the first such report. In contrast with prior studies, this study also included patients receiving prior pelvic RT for other malignancies.
Focusing on disease outcomes and restricting the analysis to recurrent RC only, we noted 1-year LP and OS rates of 52.3% and 71.4% in the present study versus 1-year local control and OS of 76.3% and 87.5% in the historical study by Valentini et al.8 Considerable heterogeneity in this retrospective cohort, particularly with respect to prior therapies (namely surgical resection) may account for the differences in these outcomes. Of the 10 patients who experienced local failure, 2 had multiply recurrent disease before reirradiation, 1 did not receive surgical resection after initial conformal RT, and 3 had received systemic therapy for local recurrence before being referred for reirradiation. All of these circumstances are mutually exclusive. As such, these patients had disease and treatment factors putting them at a high baseline risk and would also not have been eligible for a prospective study such as that by Valentini et al.8 Patients with de novo RC with previously irradiated pelvis show 2 failures as of the present, with 1 of these occurring in a patient who did not receive resection, and appear comparable with what would be expected without a history of pelvic RT. Nevertheless, the majority of patients in this study received hyperfractionated reirradiation with concurrent chemotherapy, reflecting an overall general consistency with reirradiation delivery technique.
Rates of acute grade 3 toxicity were low at 10.7%, and all but 3 patients completed the planned course of reirradiation (only 1 case was toxicity-mediated). These are comparable to the rate reported by Valentini et al (5.1%),8 who only accounted for gastrointestinal toxicity. Furthermore, relative to the study by Valentini et al,8 the median reirradiation dose in the present series was higher (48 vs 40.8 Gy). In addition, all patients in the trial by Valentini et al8 were treated with hyperfractionated RT compared with 75% of patients in our cohort. This supports tolerability of hyperfractionated reirradiation and concurrent chemotherapy with PBS-PT and is corroborated by the existing literature on PT for reirradiation for RC.
Four patients experienced late G3+ Tox, including 1 grade 5 toxicity. Overall, the rate of G3+ Tox at 1 year estimated with the Kaplan-Meier method was low at 13.3% (95% CI, 0.0%-27.7%). Of note, in 2 of these affected patients, a dose of 48 Gy in 1.2 Gy fractions was delivered, and in another patient 54 Gy in 1.5 Gy fractions was used, which represented the upper limit of the total dose in those patients who received a hyperfractionated course in this cohort. Additionally, as noted in the results section, 1 patient who experienced a grade 3 fistula had been undergoing bevacizumab therapy, another had a long history of presacral abscess and transvaginal procedures, and the patient with grade 5 toxicity had a history of significant toxicity with prior RT.
Comparing these late G3+ Tox with those reported by Valentini et al is difficult because late toxicities were not graded (although 1 was noted to require surgical intervention, and no treatment-related death was reported). However, the late G3+ Tox rates in the present report are comparable with prior published experiences of passive scatter PT reirradiation, although with a longer median follow-up of 28.6 months (range, 25.3-31.9 months). In the first known report using PT for reirradiation, 7 patients were treated using a double-scatter proton technique, and the median dose was 6120 cGy (RBE; 4500-6480 cGy) in conventional fractionation, with 6 patients receiving concurrent chemotherapy.15 With a median follow-up of 14 months, there were 3 acute grade 3 toxicities (abdominal pain, diarrhea) probably related to reirradiation, and 3 late grade 4 toxicities (2 bowel obstruction, 1 entero-vaginal fistula) possibly related to reirradiation.
Another experience evaluated 15 patients, also treated with passive-scatter technique, but with a 1.5 Gy accelerated fractionated course to a total dose of 39 to 45 Gy (RBE), and with all patients receiving concurrent chemotherapy.16 With a median follow-up of 14 months, 1 acute grade 3 toxicity (lymphopenia) and 2 late grade 3 toxicities (dysuria, rectal bleeding) were noted. Given the sample sizes of these and the present experiences and differing methods of treatment delivery, it is difficult to elucidate a dose-response relationship with respect to acute or late toxicity. Furthermore, our study solely implemented PBS-PT, thus making it more difficult to directly compare existing data largely gathered using passive-scatter techniques.
Six patients (21.4%) in our series received surgical resection after reirradiation, a lower proportion than in prior experiences (50.8% in the study by Valentini et al8), reflecting the high-risk patient cohort in our report. However, all 6 resulted in an R0 resection. Although the sample sizes are small for comparison, there was a strong trend toward superior OS in patients receiving resection (P = .107). This is consistent with prior reirradiation studies and likely multifactorial.
Other limitations to our study are primarily related to its retrospective nature. First and perhaps most important, there is selection bias inherent with any retrospective report and variable prior treatments. In this cohort, different RT regimens were used, inclusive of both conventionally fractionated and hyperfractionated courses. Second, the assessment of late toxicities was dependent on assessments that were not standardized, with imaging ranging from pelvic magnetic resonance to positron emission tomography/CT to CT.
Maturation and expansion of these data will better establish disease and toxicity outcomes in these patients. Longer follow-up and further accrual may help establish a dose–response relationship with respect to disease outcomes as well as the development of late toxicity. Moreover, such a relationship may be highly dependent on whether disease is recurrent or de novo.
Conclusions
The low acute toxicity rates, rare treatment interruption, and acceptable late toxicity reported here thus far support PBS-PT as an option for this high-risk patient population. Further follow-up and prospective studies, as those completed in the 3-dimensional conformal RT era, evaluating the use of PT for reirradiation for RC will help further clarify disease outcomes and toxicity profiles.
Sources of support: This work had no specific funding.
Disclosures: Dr Kaiser reports personal fees from Varian Medical Systems outside of the submitted work. | BEVACIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33490730 | 18,926,203 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Female genital tract fistula'. | Reirradiation for Rectal Cancer Using Pencil Beam Scanning Proton Therapy: A Single Institutional Experience.
Reirradiation for rectal cancer (RC) after prior pelvic radiation therapy (RT) has been shown to be safe and effective. However, limited data exist for proton therapy (PT), including pencil beam scanning proton therapy (PBS-PT). We hypothesize that PT is safe and feasible for re-treatment and may allow for decreased toxicity and treatment escalation.
A single-institution, retrospective, institutional review board-approved analysis of all patients with RC and prior pelvic RT receiving PBS-PT reirradiation was performed. Data on patient and treatment characteristics and outcomes were collected. Local progression, progression-free survival, overall survival, and late grade >3 toxicity were estimated using the Kaplan-Meier method.
Twenty-eight patients (median follow-up: 28.6 months) received PBS-PT reirradiation between 2016 and 2019, including 18 patients with recurrent RC (median prior dose: 54.0 Gy) and 10 patients with de novo RC and variable prior RT. The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 twice daily), and 24 of 28 patients received concurrent chemotherapy. Six underwent surgical resection. Three (10.7%) experienced grade 3 acute toxicities, and 1 did not complete RT owing to toxicity. Four (14.2%) had late grade <3 toxicity, including 1 grade 5 toxicity in a patient with a prior RT-related injury. The 1-year local progression, progression-free survival, and overall survival rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively.
This is the largest series using PT for reirradiation for RC and the first study using PBS-PT. Low acute toxicity rates and acceptable late toxicity support PBS-PT as an option for this high-risk patient population, with a need for continued follow-up.
Introduction
Rectal cancer (RC) is a common malignancy, with approximately 40,000 new cases per year in the United States and 800,000 worldwide. Therapy for locally advanced disease often consists of neoadjuvant concurrent chemotherapy and radiation, followed by surgical resection with total mesorectal excision—a paradigm that has improved local control, survival, and treatment-related toxicities.1, 2, 3 In the modern era, local relapse affects approximately 7% of patients in the long term and is associated with pain, obstruction, bleeding, discharge, and change in stool habits.4
Reirradiation for RC may be implemented in the treatment of locally recurrent RCs and de novo RC with prior radiation for other pelvic malignancy. It may be administered either as part of a curative or palliative regimen, with patients eligible for and receiving curative resection having the most favorable survival outcomes.5,6 However, it presents risk of late complications given the radiation sensitivity of nearby organs and tissues of the abdomen and pelvis—in particular, the bladder, bowel, bone marrow, and lumbosacral plexus. This affects the approach of reirradiation in multiple ways, including treatment volumes, prescribed dose, fractionation scheme, and technique of delivery.
Numerous experiences have described disease and toxicity outcomes of reirradiation for RC, using these aforementioned modifications in treatment delivery to achieve safe and effective therapy.7 A landmark prospective study by Valentini et al demonstrated the safety and efficacy of hyperfractionated reirradiation with concurrent chemotherapy, often given neoadjuvantly.8 This study has served as a reference for both disease outcomes and treatment toxicities. Multiple retrospective studies have corroborated these findings.9, 10, 11, 12 However, to our knowledge, nearly all published studies have evaluated reirradiation using either 3-dimensional conformal radiation therapy (RT) or intensity modulated RT techniques.13,14 Literature evaluating rectal reirradiation with proton therapy (PT) is emerging and has demonstrated a significantly reduced low dose to the bowel and bone marrow, as well as clinical feasibility, safety, and efficacy—thus far with passive-scatter techniques.15,16 PBS-PT provides true intensity modulated PT; thus, we hypothesize that its use may result in improved short- and long-term toxicity profiles in the setting of reirradiation for RC. We report the disease and toxicity outcomes from a retrospective, single-institution experience using PBS-PT for reirradiation for RC.
Methods and materials
Patient selection and treatment
An institutional review board–approved retrospective chart review was completed of all patients treated with reirradiation using PBS-PT at a single institution between 2016 and 2019 for either recurrent RC or de novo RC with prior pelvic RT for another malignancy. Patient demographic information, disease characteristics, and treatment characteristics were collected. Prior RT plan reports were accessed when possible, and all PBS-PT plans underwent peer review per departmental protocol. All patients were presented at a multidisciplinary tumor board. Concurrent chemotherapy and curative-intent surgical resection were planned whenever feasible and appropriate.
Proton beam reirradiation
Patients underwent computed tomography (CT) simulation in the supine or prone position with a comfortably full bladder and vac-lok immobilization. Contouring of the target and organ-at-risk volumes was performed. Gross tumor volume (GTV) was delineated using physical examination, CT simulation, and diagnostic imaging data (positron emission tomography and/or magnetic resonance imaging). A clinical target volume (CTV) was generated by expanding the GTV by 1.5 to 3.0 cm craniocaudally, extending to the pelvic sidewall laterally, and including the presacral space posteriorly. When a boost was planned, a second smaller isotropic expansion of 0.5 to 1.5 cm was used, or simply the gross tumor without expansion. The choice of CTV expansion is based on the method outlined by Valentini et al,8 with smaller expansions on the GTV used in cases of inoperable recurrences involving the bone. Planning target volumes were generated by dosimetry, accounting for setup and proton beam range uncertainty. Earlier cases used a uniform 5 mm expansion, later transitioning to nonuniform expansions (3.5-5 mm) based on translational uncertainty, and eventually generation of a planning target volume using robust optimization algorithms. Dosing was guided by the method by Valentini et al.8 Hyperfractionation was employed when feasible for the patient.
Plan optimization was performed using Eclipse (Varian Medical Systems, Palo Alto, CA) and Raystation (RaySearch Laboratories, Stockholm, Sweden). All patients were treated with PBS-PT, typically with 2 lateral fields with single-field optimization technique, with some cases using a third field and/or multiple-field optimization. Opposed lateral fields, rather than posterior oblique fields, were used in many cases due to relative biological effectiveness (RBE) uncertainty at the end range, because this configuration limits overlap of end-ranging segments of the beams into previously irradiated bladder as well as bowel anterior to the CTV. Furthermore, using PBS-PT, the anterior edge of the field can be shaped and modulated off of bladder and bowel with opposed lateral fields, in contrast to the same arrangement using photon-based 3-dimensional conformal RT, where this is not possible.
When using a multiple field optimization technique, air in the bowel was accounted for using a density override algorithm. Quality assurance CT images were obtained during the course of therapy, with frequency depending on the particular case and clinical discretion. Dose constraints for the bladder and bowel entailed keeping maximum doses of approximately 90% of the prescription dose, which itself depended on prior radiation dose and time interval. In all cases, these constraints on the bladder and bowel structures were prioritized over full prescription isodose coverage of the anterior target volume. A representative plan is shown in Figure 1.Figure 1 Example pencil beam scanning proton therapy plan with axial, coronal, and sagittal views with corresponding dose–volume histogram. The patient was simulated prone, dose was prescribed via a simultaneous integrated boost with clinical target volume 1 (blue; gross target volume with 2-2.5 cm craniocaudal expansion, laterally to pelvic sidewalls and posteriorly to sacrum) receiving 4000 cGy in 100 cGy/fraction and clinical target volume 2 (red; gross target volume + 1.0 cm isotropic expansion) receiving 4800 cGy in 120 cGy/fraction. Proton planning target volumes were generated based on setup and range uncertainty. Two lateral beams using a multiple-field optimization technique were used. Bladder (yellow), large bowel (brown), small bowel (green), right femoral head (turquoise), and left femoral head (fuschia). (A color version of this figure is available at https://doi.org/10.1016/j.adro.2020.10.008.)
Statistics
Efficacy outcomes included local progression (LP), progression-free survival (PFS), and overall survival (OS). LP was calculated from completion of reirradiation to time of local failure by pathologic or radiologic confirmation. Patients who did not experience LP were censored at the time of the last follow-up visit. PFS was calculated from completion of reirradiation to the date of any progression or death, irrespective of the cause. OS was calculated from completion of reirradiation to the date of death, irrespective of the cause. The vital status of patients was checked using medical record/obituary documentation, and OS was censored on the date of the last documentation confirming living status in patients still alive on that date.
Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 5.0. Acute toxicity was assessed using provider documentation from weekly on-treatment visits. Late toxicity was defined as symptoms attributable to RT persisting or occurring >3 months after completion of reirradiation. All clinical outcomes were estimated using the Kaplan-Meier method. A univariable Cox proportional hazards model was used to model the relationship between GTV and outcome. A P value of <.05 was considered statistically significant. All analyses were completed using SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY).
Patient, disease, and treatment characteristics
Patient, disease, and treatment characteristics are summarized in Table 1. Twenty-eight patients (median follow-up 28.6 months; range, 25.3-31.9 months) received PBS-PT reirradiation from 2016 to 2019. Of these, 18 patients (64.3%) had recurrent RC (median prior dose: 54.0 Gy; range, 43.2-63.0 Gy) and 10 patients had de novo RC and variable prior RT (8 received full-dose external beam RT or brachytherapy for prostate cancer; 1 patient received external beam RT and brachytherapy boost for endometrial cancer; 1 patient received whole abdominal RT for ovarian cancer with a pelvic boost). The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 patients twice daily), and 24 of 28 patients (85.7%) received concurrent chemotherapy, with 18 of 28 (64.3%) receiving twice-daily oral capecitabine on days with reirradiation. Overall, 25 of 28 patients (89.3%) completed the planned course of reirradiation.Table 1 Patient and treatment characteristics (n = 28)
Characteristics n (%)
Sex
Male 19 (67.9%)
Female 9 (32.1%)
Age, y, median (range) 68 (41-87)
Follow-up, mo, median (range) 28.6 (25.3-31.9)
Recurrent rectal cancer 18 (64.3)
Prior RT dose, Gy, median (range) 54.0 (43.2-63.0)
Anatomic location of recurrence
Rectal 6 (33.3)
Presacral 11 (61.1)
Pelvic bone 1 (5.6)
Treatment for initial rectal cancer (n = 18)
Neoadjuvant conformal RT 8 (44.4)
Adjuvant conformal RT 2 (11.2)
Other 8 (44.4)
de novo rectal cancer (n = 10) 10 (35.7)
Prior pelvic RT Definitive for prostate cancer (equivalent total dose in 2 Gy fractions >70 Gy)8
Definitive for ovarian cancer1
Definitive for endometrial cancer1
Treatment before reirradiation for recurrence
Upfront surgery, n 2
Systemic therapy, n 8
Reirradiation dose, Gy, median (range) 48.0 (16.0-60.0)
Reirradiation interval, mo, median (range) 48.5 (12.7-494.8)
Concurrent chemotherapy with reirradiation 24 (85.7)
Hyperfractionated reirradiation 21 (75.0)
Completed reirradiation course 25 (89.3)
Underwent resection after reirradiation 6 (21.4)
R0 6
Gross tumor volume, cm3, median (range) 86.4 (13.6-821.8)
Abbreviation: RT = radiation therapy.
Table 2 Acute toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Grade 2, n (%) 3, n (%) 4, n (%) 5, n (%)
Gastrointestinal 4 (14.2) 2 (7.1) 0 (0.0) 0 (0.0)
Skin 4 (14.2) 1 (3.6) 0 (0.0) 0 (0.0)
Urologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Hematologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Total 8 (28.6) 3 (10.7) 0 (0.0) 0 (0.0)
Disease outcomes and toxicity
The 1-year LP, PFS, and OS rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively. The median times to LP, PFS, and OS were 23.4 months (range, 1.6-39.8 months; 95% CI, 12.9-33.9 months), 11.6 months (range, 0.6-39.8 months; 95% CI, 8.6-14.5 months), and 29.2 months (range, 1.6-45.9 months; 95% CI, 19.7-38.8 months), respectively (Fig 2A-C). In a univariable Cox proportional hazards model with GTV (cm3) included as a continuous variable, increasing GTV was highly statistically significantly associated with LP (hazard ratio [HR]: 1.005; 95% CI, 1.002-1.008; P = .003) and PFS (HR: 1.004; 95% CI, 1.002-1.006; P = .001), but not with OS (HR: 1.002; 95% CI, 1.000-1.005; P = .102). The 1-year LP rate for recurrent versus de novo RC was significantly different at 52.3% (95% CI, 23.9%-80.1%) and 0% (P = .002), respectively. The 1-year OS rate for recurrent versus de novo RC was 72.2% (95% CI, 51.4%-93.0%) and 100% (P = .058), respectively.Figure 2 Kaplan-Meier curves for (A) local progression, (B) progression-free survival, (C) overall survival, and (D) late grade >3 toxicities for all patients (n = 28).
Six patients (21.4%) underwent surgical resection after reirradiation, with further breakdown by de novo RC and recurrent RC patients being 3 of 10 (30%) and 3 of 18 (16.7%), respectively. All resections resulted in R0 resection. Of these patients, 4 eventually experienced LP (3 with recurrent RC), with a 1-year LP rate of resected patients of 16.7% versus 40% for those who did not receive resection (P = .786). The 1-year OS rate for patients undergoing and not undergoing resection was 100% and 76.8%, respectively; this difference was statistically significant (P = .027).
Acute toxicities are listed in Table 2. The 1-year rate of late grade >3 toxicities (G3+ Tox) was 13.3% in the Kaplan-Meier analysis (Fig 2D). Six late G3+ Tox occurred in 4 separate patients, with no evidence of tumor recurrence at toxicity onset (summarized by patient in Table 3). Patient 1 ultimately developed grade 5 toxicity and had a history of significant late toxicity from prior whole abdominal and pelvic boost radiation for ovarian cancer in the 1970s, including baseline and longstanding radiation colitis, loss of a kidney, and cystitis. This patient developed rectal bleeding at 3 months, a rectovaginal fistula at 9 months, and ultimately a bleeding stage IV decubitus ulcer and died of presacral hemorrhage at 26 months without evidence of tumor recurrence. Patient 2 developed an enterocutaneous fistula passing through the presacral region, as well as pyelonephritis resolving with parenteral antibiotics, approximately 1 year from completion of reirradiation. The treatment course was entirely in a medical ward without stay in either intermediate or intensive care. Of note, this patient was receiving bevacizumab systemic therapy at the time of the fistula diagnosis. This patient also experienced multiple delays and breaks in the planned treatment course related to social and logistic factors. This was the only patient who experienced G3+ Tox in both the acute and late term.Table 3 Grade ≥3 late toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Patient no. Grade Toxicity Time to toxicity, mo
1 3 Rectovaginal fistula 8.5
1 5 Presacral hemorrhage 25.6
2 3 Enterocutaneous fistula 11
2 3 Pyelonephritis (resolved) 11
3 3 Presacral abscess/rectovaginal fistula 31
4 3 Colovaginal fistula (improved) 12
Six grade 3+ events were observed in 4 patients.
Patient 3 developed a presacral abscess and rectovaginal fistula approximately 2.5 years from completion of reirradiation. The site of local recurrence, which was treated with reirradiation, involved the vaginal fornices. Patient 4 had a long history of presacral abscess and transvaginal drainage procedures before reirradiation and developed increased vaginal discharge approximately 1 year from completion of reirradiation. The patient received a diagnosis of colovaginal fistula, which improved with percutaneous drainage.
Discussion
This is the largest report with the longest median follow-up to date of reirradiation for RC using PT. Additionally, all patients in our cohort received PBS-PT, making this the first such report. In contrast with prior studies, this study also included patients receiving prior pelvic RT for other malignancies.
Focusing on disease outcomes and restricting the analysis to recurrent RC only, we noted 1-year LP and OS rates of 52.3% and 71.4% in the present study versus 1-year local control and OS of 76.3% and 87.5% in the historical study by Valentini et al.8 Considerable heterogeneity in this retrospective cohort, particularly with respect to prior therapies (namely surgical resection) may account for the differences in these outcomes. Of the 10 patients who experienced local failure, 2 had multiply recurrent disease before reirradiation, 1 did not receive surgical resection after initial conformal RT, and 3 had received systemic therapy for local recurrence before being referred for reirradiation. All of these circumstances are mutually exclusive. As such, these patients had disease and treatment factors putting them at a high baseline risk and would also not have been eligible for a prospective study such as that by Valentini et al.8 Patients with de novo RC with previously irradiated pelvis show 2 failures as of the present, with 1 of these occurring in a patient who did not receive resection, and appear comparable with what would be expected without a history of pelvic RT. Nevertheless, the majority of patients in this study received hyperfractionated reirradiation with concurrent chemotherapy, reflecting an overall general consistency with reirradiation delivery technique.
Rates of acute grade 3 toxicity were low at 10.7%, and all but 3 patients completed the planned course of reirradiation (only 1 case was toxicity-mediated). These are comparable to the rate reported by Valentini et al (5.1%),8 who only accounted for gastrointestinal toxicity. Furthermore, relative to the study by Valentini et al,8 the median reirradiation dose in the present series was higher (48 vs 40.8 Gy). In addition, all patients in the trial by Valentini et al8 were treated with hyperfractionated RT compared with 75% of patients in our cohort. This supports tolerability of hyperfractionated reirradiation and concurrent chemotherapy with PBS-PT and is corroborated by the existing literature on PT for reirradiation for RC.
Four patients experienced late G3+ Tox, including 1 grade 5 toxicity. Overall, the rate of G3+ Tox at 1 year estimated with the Kaplan-Meier method was low at 13.3% (95% CI, 0.0%-27.7%). Of note, in 2 of these affected patients, a dose of 48 Gy in 1.2 Gy fractions was delivered, and in another patient 54 Gy in 1.5 Gy fractions was used, which represented the upper limit of the total dose in those patients who received a hyperfractionated course in this cohort. Additionally, as noted in the results section, 1 patient who experienced a grade 3 fistula had been undergoing bevacizumab therapy, another had a long history of presacral abscess and transvaginal procedures, and the patient with grade 5 toxicity had a history of significant toxicity with prior RT.
Comparing these late G3+ Tox with those reported by Valentini et al is difficult because late toxicities were not graded (although 1 was noted to require surgical intervention, and no treatment-related death was reported). However, the late G3+ Tox rates in the present report are comparable with prior published experiences of passive scatter PT reirradiation, although with a longer median follow-up of 28.6 months (range, 25.3-31.9 months). In the first known report using PT for reirradiation, 7 patients were treated using a double-scatter proton technique, and the median dose was 6120 cGy (RBE; 4500-6480 cGy) in conventional fractionation, with 6 patients receiving concurrent chemotherapy.15 With a median follow-up of 14 months, there were 3 acute grade 3 toxicities (abdominal pain, diarrhea) probably related to reirradiation, and 3 late grade 4 toxicities (2 bowel obstruction, 1 entero-vaginal fistula) possibly related to reirradiation.
Another experience evaluated 15 patients, also treated with passive-scatter technique, but with a 1.5 Gy accelerated fractionated course to a total dose of 39 to 45 Gy (RBE), and with all patients receiving concurrent chemotherapy.16 With a median follow-up of 14 months, 1 acute grade 3 toxicity (lymphopenia) and 2 late grade 3 toxicities (dysuria, rectal bleeding) were noted. Given the sample sizes of these and the present experiences and differing methods of treatment delivery, it is difficult to elucidate a dose-response relationship with respect to acute or late toxicity. Furthermore, our study solely implemented PBS-PT, thus making it more difficult to directly compare existing data largely gathered using passive-scatter techniques.
Six patients (21.4%) in our series received surgical resection after reirradiation, a lower proportion than in prior experiences (50.8% in the study by Valentini et al8), reflecting the high-risk patient cohort in our report. However, all 6 resulted in an R0 resection. Although the sample sizes are small for comparison, there was a strong trend toward superior OS in patients receiving resection (P = .107). This is consistent with prior reirradiation studies and likely multifactorial.
Other limitations to our study are primarily related to its retrospective nature. First and perhaps most important, there is selection bias inherent with any retrospective report and variable prior treatments. In this cohort, different RT regimens were used, inclusive of both conventionally fractionated and hyperfractionated courses. Second, the assessment of late toxicities was dependent on assessments that were not standardized, with imaging ranging from pelvic magnetic resonance to positron emission tomography/CT to CT.
Maturation and expansion of these data will better establish disease and toxicity outcomes in these patients. Longer follow-up and further accrual may help establish a dose–response relationship with respect to disease outcomes as well as the development of late toxicity. Moreover, such a relationship may be highly dependent on whether disease is recurrent or de novo.
Conclusions
The low acute toxicity rates, rare treatment interruption, and acceptable late toxicity reported here thus far support PBS-PT as an option for this high-risk patient population. Further follow-up and prospective studies, as those completed in the 3-dimensional conformal RT era, evaluating the use of PT for reirradiation for RC will help further clarify disease outcomes and toxicity profiles.
Sources of support: This work had no specific funding.
Disclosures: Dr Kaiser reports personal fees from Varian Medical Systems outside of the submitted work. | CAPECITABINE | DrugsGivenReaction | CC BY-NC-ND | 33490730 | 18,926,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pelvic abscess'. | Reirradiation for Rectal Cancer Using Pencil Beam Scanning Proton Therapy: A Single Institutional Experience.
Reirradiation for rectal cancer (RC) after prior pelvic radiation therapy (RT) has been shown to be safe and effective. However, limited data exist for proton therapy (PT), including pencil beam scanning proton therapy (PBS-PT). We hypothesize that PT is safe and feasible for re-treatment and may allow for decreased toxicity and treatment escalation.
A single-institution, retrospective, institutional review board-approved analysis of all patients with RC and prior pelvic RT receiving PBS-PT reirradiation was performed. Data on patient and treatment characteristics and outcomes were collected. Local progression, progression-free survival, overall survival, and late grade >3 toxicity were estimated using the Kaplan-Meier method.
Twenty-eight patients (median follow-up: 28.6 months) received PBS-PT reirradiation between 2016 and 2019, including 18 patients with recurrent RC (median prior dose: 54.0 Gy) and 10 patients with de novo RC and variable prior RT. The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 twice daily), and 24 of 28 patients received concurrent chemotherapy. Six underwent surgical resection. Three (10.7%) experienced grade 3 acute toxicities, and 1 did not complete RT owing to toxicity. Four (14.2%) had late grade <3 toxicity, including 1 grade 5 toxicity in a patient with a prior RT-related injury. The 1-year local progression, progression-free survival, and overall survival rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively.
This is the largest series using PT for reirradiation for RC and the first study using PBS-PT. Low acute toxicity rates and acceptable late toxicity support PBS-PT as an option for this high-risk patient population, with a need for continued follow-up.
Introduction
Rectal cancer (RC) is a common malignancy, with approximately 40,000 new cases per year in the United States and 800,000 worldwide. Therapy for locally advanced disease often consists of neoadjuvant concurrent chemotherapy and radiation, followed by surgical resection with total mesorectal excision—a paradigm that has improved local control, survival, and treatment-related toxicities.1, 2, 3 In the modern era, local relapse affects approximately 7% of patients in the long term and is associated with pain, obstruction, bleeding, discharge, and change in stool habits.4
Reirradiation for RC may be implemented in the treatment of locally recurrent RCs and de novo RC with prior radiation for other pelvic malignancy. It may be administered either as part of a curative or palliative regimen, with patients eligible for and receiving curative resection having the most favorable survival outcomes.5,6 However, it presents risk of late complications given the radiation sensitivity of nearby organs and tissues of the abdomen and pelvis—in particular, the bladder, bowel, bone marrow, and lumbosacral plexus. This affects the approach of reirradiation in multiple ways, including treatment volumes, prescribed dose, fractionation scheme, and technique of delivery.
Numerous experiences have described disease and toxicity outcomes of reirradiation for RC, using these aforementioned modifications in treatment delivery to achieve safe and effective therapy.7 A landmark prospective study by Valentini et al demonstrated the safety and efficacy of hyperfractionated reirradiation with concurrent chemotherapy, often given neoadjuvantly.8 This study has served as a reference for both disease outcomes and treatment toxicities. Multiple retrospective studies have corroborated these findings.9, 10, 11, 12 However, to our knowledge, nearly all published studies have evaluated reirradiation using either 3-dimensional conformal radiation therapy (RT) or intensity modulated RT techniques.13,14 Literature evaluating rectal reirradiation with proton therapy (PT) is emerging and has demonstrated a significantly reduced low dose to the bowel and bone marrow, as well as clinical feasibility, safety, and efficacy—thus far with passive-scatter techniques.15,16 PBS-PT provides true intensity modulated PT; thus, we hypothesize that its use may result in improved short- and long-term toxicity profiles in the setting of reirradiation for RC. We report the disease and toxicity outcomes from a retrospective, single-institution experience using PBS-PT for reirradiation for RC.
Methods and materials
Patient selection and treatment
An institutional review board–approved retrospective chart review was completed of all patients treated with reirradiation using PBS-PT at a single institution between 2016 and 2019 for either recurrent RC or de novo RC with prior pelvic RT for another malignancy. Patient demographic information, disease characteristics, and treatment characteristics were collected. Prior RT plan reports were accessed when possible, and all PBS-PT plans underwent peer review per departmental protocol. All patients were presented at a multidisciplinary tumor board. Concurrent chemotherapy and curative-intent surgical resection were planned whenever feasible and appropriate.
Proton beam reirradiation
Patients underwent computed tomography (CT) simulation in the supine or prone position with a comfortably full bladder and vac-lok immobilization. Contouring of the target and organ-at-risk volumes was performed. Gross tumor volume (GTV) was delineated using physical examination, CT simulation, and diagnostic imaging data (positron emission tomography and/or magnetic resonance imaging). A clinical target volume (CTV) was generated by expanding the GTV by 1.5 to 3.0 cm craniocaudally, extending to the pelvic sidewall laterally, and including the presacral space posteriorly. When a boost was planned, a second smaller isotropic expansion of 0.5 to 1.5 cm was used, or simply the gross tumor without expansion. The choice of CTV expansion is based on the method outlined by Valentini et al,8 with smaller expansions on the GTV used in cases of inoperable recurrences involving the bone. Planning target volumes were generated by dosimetry, accounting for setup and proton beam range uncertainty. Earlier cases used a uniform 5 mm expansion, later transitioning to nonuniform expansions (3.5-5 mm) based on translational uncertainty, and eventually generation of a planning target volume using robust optimization algorithms. Dosing was guided by the method by Valentini et al.8 Hyperfractionation was employed when feasible for the patient.
Plan optimization was performed using Eclipse (Varian Medical Systems, Palo Alto, CA) and Raystation (RaySearch Laboratories, Stockholm, Sweden). All patients were treated with PBS-PT, typically with 2 lateral fields with single-field optimization technique, with some cases using a third field and/or multiple-field optimization. Opposed lateral fields, rather than posterior oblique fields, were used in many cases due to relative biological effectiveness (RBE) uncertainty at the end range, because this configuration limits overlap of end-ranging segments of the beams into previously irradiated bladder as well as bowel anterior to the CTV. Furthermore, using PBS-PT, the anterior edge of the field can be shaped and modulated off of bladder and bowel with opposed lateral fields, in contrast to the same arrangement using photon-based 3-dimensional conformal RT, where this is not possible.
When using a multiple field optimization technique, air in the bowel was accounted for using a density override algorithm. Quality assurance CT images were obtained during the course of therapy, with frequency depending on the particular case and clinical discretion. Dose constraints for the bladder and bowel entailed keeping maximum doses of approximately 90% of the prescription dose, which itself depended on prior radiation dose and time interval. In all cases, these constraints on the bladder and bowel structures were prioritized over full prescription isodose coverage of the anterior target volume. A representative plan is shown in Figure 1.Figure 1 Example pencil beam scanning proton therapy plan with axial, coronal, and sagittal views with corresponding dose–volume histogram. The patient was simulated prone, dose was prescribed via a simultaneous integrated boost with clinical target volume 1 (blue; gross target volume with 2-2.5 cm craniocaudal expansion, laterally to pelvic sidewalls and posteriorly to sacrum) receiving 4000 cGy in 100 cGy/fraction and clinical target volume 2 (red; gross target volume + 1.0 cm isotropic expansion) receiving 4800 cGy in 120 cGy/fraction. Proton planning target volumes were generated based on setup and range uncertainty. Two lateral beams using a multiple-field optimization technique were used. Bladder (yellow), large bowel (brown), small bowel (green), right femoral head (turquoise), and left femoral head (fuschia). (A color version of this figure is available at https://doi.org/10.1016/j.adro.2020.10.008.)
Statistics
Efficacy outcomes included local progression (LP), progression-free survival (PFS), and overall survival (OS). LP was calculated from completion of reirradiation to time of local failure by pathologic or radiologic confirmation. Patients who did not experience LP were censored at the time of the last follow-up visit. PFS was calculated from completion of reirradiation to the date of any progression or death, irrespective of the cause. OS was calculated from completion of reirradiation to the date of death, irrespective of the cause. The vital status of patients was checked using medical record/obituary documentation, and OS was censored on the date of the last documentation confirming living status in patients still alive on that date.
Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 5.0. Acute toxicity was assessed using provider documentation from weekly on-treatment visits. Late toxicity was defined as symptoms attributable to RT persisting or occurring >3 months after completion of reirradiation. All clinical outcomes were estimated using the Kaplan-Meier method. A univariable Cox proportional hazards model was used to model the relationship between GTV and outcome. A P value of <.05 was considered statistically significant. All analyses were completed using SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY).
Patient, disease, and treatment characteristics
Patient, disease, and treatment characteristics are summarized in Table 1. Twenty-eight patients (median follow-up 28.6 months; range, 25.3-31.9 months) received PBS-PT reirradiation from 2016 to 2019. Of these, 18 patients (64.3%) had recurrent RC (median prior dose: 54.0 Gy; range, 43.2-63.0 Gy) and 10 patients had de novo RC and variable prior RT (8 received full-dose external beam RT or brachytherapy for prostate cancer; 1 patient received external beam RT and brachytherapy boost for endometrial cancer; 1 patient received whole abdominal RT for ovarian cancer with a pelvic boost). The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 patients twice daily), and 24 of 28 patients (85.7%) received concurrent chemotherapy, with 18 of 28 (64.3%) receiving twice-daily oral capecitabine on days with reirradiation. Overall, 25 of 28 patients (89.3%) completed the planned course of reirradiation.Table 1 Patient and treatment characteristics (n = 28)
Characteristics n (%)
Sex
Male 19 (67.9%)
Female 9 (32.1%)
Age, y, median (range) 68 (41-87)
Follow-up, mo, median (range) 28.6 (25.3-31.9)
Recurrent rectal cancer 18 (64.3)
Prior RT dose, Gy, median (range) 54.0 (43.2-63.0)
Anatomic location of recurrence
Rectal 6 (33.3)
Presacral 11 (61.1)
Pelvic bone 1 (5.6)
Treatment for initial rectal cancer (n = 18)
Neoadjuvant conformal RT 8 (44.4)
Adjuvant conformal RT 2 (11.2)
Other 8 (44.4)
de novo rectal cancer (n = 10) 10 (35.7)
Prior pelvic RT Definitive for prostate cancer (equivalent total dose in 2 Gy fractions >70 Gy)8
Definitive for ovarian cancer1
Definitive for endometrial cancer1
Treatment before reirradiation for recurrence
Upfront surgery, n 2
Systemic therapy, n 8
Reirradiation dose, Gy, median (range) 48.0 (16.0-60.0)
Reirradiation interval, mo, median (range) 48.5 (12.7-494.8)
Concurrent chemotherapy with reirradiation 24 (85.7)
Hyperfractionated reirradiation 21 (75.0)
Completed reirradiation course 25 (89.3)
Underwent resection after reirradiation 6 (21.4)
R0 6
Gross tumor volume, cm3, median (range) 86.4 (13.6-821.8)
Abbreviation: RT = radiation therapy.
Table 2 Acute toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Grade 2, n (%) 3, n (%) 4, n (%) 5, n (%)
Gastrointestinal 4 (14.2) 2 (7.1) 0 (0.0) 0 (0.0)
Skin 4 (14.2) 1 (3.6) 0 (0.0) 0 (0.0)
Urologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Hematologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Total 8 (28.6) 3 (10.7) 0 (0.0) 0 (0.0)
Disease outcomes and toxicity
The 1-year LP, PFS, and OS rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively. The median times to LP, PFS, and OS were 23.4 months (range, 1.6-39.8 months; 95% CI, 12.9-33.9 months), 11.6 months (range, 0.6-39.8 months; 95% CI, 8.6-14.5 months), and 29.2 months (range, 1.6-45.9 months; 95% CI, 19.7-38.8 months), respectively (Fig 2A-C). In a univariable Cox proportional hazards model with GTV (cm3) included as a continuous variable, increasing GTV was highly statistically significantly associated with LP (hazard ratio [HR]: 1.005; 95% CI, 1.002-1.008; P = .003) and PFS (HR: 1.004; 95% CI, 1.002-1.006; P = .001), but not with OS (HR: 1.002; 95% CI, 1.000-1.005; P = .102). The 1-year LP rate for recurrent versus de novo RC was significantly different at 52.3% (95% CI, 23.9%-80.1%) and 0% (P = .002), respectively. The 1-year OS rate for recurrent versus de novo RC was 72.2% (95% CI, 51.4%-93.0%) and 100% (P = .058), respectively.Figure 2 Kaplan-Meier curves for (A) local progression, (B) progression-free survival, (C) overall survival, and (D) late grade >3 toxicities for all patients (n = 28).
Six patients (21.4%) underwent surgical resection after reirradiation, with further breakdown by de novo RC and recurrent RC patients being 3 of 10 (30%) and 3 of 18 (16.7%), respectively. All resections resulted in R0 resection. Of these patients, 4 eventually experienced LP (3 with recurrent RC), with a 1-year LP rate of resected patients of 16.7% versus 40% for those who did not receive resection (P = .786). The 1-year OS rate for patients undergoing and not undergoing resection was 100% and 76.8%, respectively; this difference was statistically significant (P = .027).
Acute toxicities are listed in Table 2. The 1-year rate of late grade >3 toxicities (G3+ Tox) was 13.3% in the Kaplan-Meier analysis (Fig 2D). Six late G3+ Tox occurred in 4 separate patients, with no evidence of tumor recurrence at toxicity onset (summarized by patient in Table 3). Patient 1 ultimately developed grade 5 toxicity and had a history of significant late toxicity from prior whole abdominal and pelvic boost radiation for ovarian cancer in the 1970s, including baseline and longstanding radiation colitis, loss of a kidney, and cystitis. This patient developed rectal bleeding at 3 months, a rectovaginal fistula at 9 months, and ultimately a bleeding stage IV decubitus ulcer and died of presacral hemorrhage at 26 months without evidence of tumor recurrence. Patient 2 developed an enterocutaneous fistula passing through the presacral region, as well as pyelonephritis resolving with parenteral antibiotics, approximately 1 year from completion of reirradiation. The treatment course was entirely in a medical ward without stay in either intermediate or intensive care. Of note, this patient was receiving bevacizumab systemic therapy at the time of the fistula diagnosis. This patient also experienced multiple delays and breaks in the planned treatment course related to social and logistic factors. This was the only patient who experienced G3+ Tox in both the acute and late term.Table 3 Grade ≥3 late toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Patient no. Grade Toxicity Time to toxicity, mo
1 3 Rectovaginal fistula 8.5
1 5 Presacral hemorrhage 25.6
2 3 Enterocutaneous fistula 11
2 3 Pyelonephritis (resolved) 11
3 3 Presacral abscess/rectovaginal fistula 31
4 3 Colovaginal fistula (improved) 12
Six grade 3+ events were observed in 4 patients.
Patient 3 developed a presacral abscess and rectovaginal fistula approximately 2.5 years from completion of reirradiation. The site of local recurrence, which was treated with reirradiation, involved the vaginal fornices. Patient 4 had a long history of presacral abscess and transvaginal drainage procedures before reirradiation and developed increased vaginal discharge approximately 1 year from completion of reirradiation. The patient received a diagnosis of colovaginal fistula, which improved with percutaneous drainage.
Discussion
This is the largest report with the longest median follow-up to date of reirradiation for RC using PT. Additionally, all patients in our cohort received PBS-PT, making this the first such report. In contrast with prior studies, this study also included patients receiving prior pelvic RT for other malignancies.
Focusing on disease outcomes and restricting the analysis to recurrent RC only, we noted 1-year LP and OS rates of 52.3% and 71.4% in the present study versus 1-year local control and OS of 76.3% and 87.5% in the historical study by Valentini et al.8 Considerable heterogeneity in this retrospective cohort, particularly with respect to prior therapies (namely surgical resection) may account for the differences in these outcomes. Of the 10 patients who experienced local failure, 2 had multiply recurrent disease before reirradiation, 1 did not receive surgical resection after initial conformal RT, and 3 had received systemic therapy for local recurrence before being referred for reirradiation. All of these circumstances are mutually exclusive. As such, these patients had disease and treatment factors putting them at a high baseline risk and would also not have been eligible for a prospective study such as that by Valentini et al.8 Patients with de novo RC with previously irradiated pelvis show 2 failures as of the present, with 1 of these occurring in a patient who did not receive resection, and appear comparable with what would be expected without a history of pelvic RT. Nevertheless, the majority of patients in this study received hyperfractionated reirradiation with concurrent chemotherapy, reflecting an overall general consistency with reirradiation delivery technique.
Rates of acute grade 3 toxicity were low at 10.7%, and all but 3 patients completed the planned course of reirradiation (only 1 case was toxicity-mediated). These are comparable to the rate reported by Valentini et al (5.1%),8 who only accounted for gastrointestinal toxicity. Furthermore, relative to the study by Valentini et al,8 the median reirradiation dose in the present series was higher (48 vs 40.8 Gy). In addition, all patients in the trial by Valentini et al8 were treated with hyperfractionated RT compared with 75% of patients in our cohort. This supports tolerability of hyperfractionated reirradiation and concurrent chemotherapy with PBS-PT and is corroborated by the existing literature on PT for reirradiation for RC.
Four patients experienced late G3+ Tox, including 1 grade 5 toxicity. Overall, the rate of G3+ Tox at 1 year estimated with the Kaplan-Meier method was low at 13.3% (95% CI, 0.0%-27.7%). Of note, in 2 of these affected patients, a dose of 48 Gy in 1.2 Gy fractions was delivered, and in another patient 54 Gy in 1.5 Gy fractions was used, which represented the upper limit of the total dose in those patients who received a hyperfractionated course in this cohort. Additionally, as noted in the results section, 1 patient who experienced a grade 3 fistula had been undergoing bevacizumab therapy, another had a long history of presacral abscess and transvaginal procedures, and the patient with grade 5 toxicity had a history of significant toxicity with prior RT.
Comparing these late G3+ Tox with those reported by Valentini et al is difficult because late toxicities were not graded (although 1 was noted to require surgical intervention, and no treatment-related death was reported). However, the late G3+ Tox rates in the present report are comparable with prior published experiences of passive scatter PT reirradiation, although with a longer median follow-up of 28.6 months (range, 25.3-31.9 months). In the first known report using PT for reirradiation, 7 patients were treated using a double-scatter proton technique, and the median dose was 6120 cGy (RBE; 4500-6480 cGy) in conventional fractionation, with 6 patients receiving concurrent chemotherapy.15 With a median follow-up of 14 months, there were 3 acute grade 3 toxicities (abdominal pain, diarrhea) probably related to reirradiation, and 3 late grade 4 toxicities (2 bowel obstruction, 1 entero-vaginal fistula) possibly related to reirradiation.
Another experience evaluated 15 patients, also treated with passive-scatter technique, but with a 1.5 Gy accelerated fractionated course to a total dose of 39 to 45 Gy (RBE), and with all patients receiving concurrent chemotherapy.16 With a median follow-up of 14 months, 1 acute grade 3 toxicity (lymphopenia) and 2 late grade 3 toxicities (dysuria, rectal bleeding) were noted. Given the sample sizes of these and the present experiences and differing methods of treatment delivery, it is difficult to elucidate a dose-response relationship with respect to acute or late toxicity. Furthermore, our study solely implemented PBS-PT, thus making it more difficult to directly compare existing data largely gathered using passive-scatter techniques.
Six patients (21.4%) in our series received surgical resection after reirradiation, a lower proportion than in prior experiences (50.8% in the study by Valentini et al8), reflecting the high-risk patient cohort in our report. However, all 6 resulted in an R0 resection. Although the sample sizes are small for comparison, there was a strong trend toward superior OS in patients receiving resection (P = .107). This is consistent with prior reirradiation studies and likely multifactorial.
Other limitations to our study are primarily related to its retrospective nature. First and perhaps most important, there is selection bias inherent with any retrospective report and variable prior treatments. In this cohort, different RT regimens were used, inclusive of both conventionally fractionated and hyperfractionated courses. Second, the assessment of late toxicities was dependent on assessments that were not standardized, with imaging ranging from pelvic magnetic resonance to positron emission tomography/CT to CT.
Maturation and expansion of these data will better establish disease and toxicity outcomes in these patients. Longer follow-up and further accrual may help establish a dose–response relationship with respect to disease outcomes as well as the development of late toxicity. Moreover, such a relationship may be highly dependent on whether disease is recurrent or de novo.
Conclusions
The low acute toxicity rates, rare treatment interruption, and acceptable late toxicity reported here thus far support PBS-PT as an option for this high-risk patient population. Further follow-up and prospective studies, as those completed in the 3-dimensional conformal RT era, evaluating the use of PT for reirradiation for RC will help further clarify disease outcomes and toxicity profiles.
Sources of support: This work had no specific funding.
Disclosures: Dr Kaiser reports personal fees from Varian Medical Systems outside of the submitted work. | CAPECITABINE | DrugsGivenReaction | CC BY-NC-ND | 33490730 | 18,926,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pelvic haemorrhage'. | Reirradiation for Rectal Cancer Using Pencil Beam Scanning Proton Therapy: A Single Institutional Experience.
Reirradiation for rectal cancer (RC) after prior pelvic radiation therapy (RT) has been shown to be safe and effective. However, limited data exist for proton therapy (PT), including pencil beam scanning proton therapy (PBS-PT). We hypothesize that PT is safe and feasible for re-treatment and may allow for decreased toxicity and treatment escalation.
A single-institution, retrospective, institutional review board-approved analysis of all patients with RC and prior pelvic RT receiving PBS-PT reirradiation was performed. Data on patient and treatment characteristics and outcomes were collected. Local progression, progression-free survival, overall survival, and late grade >3 toxicity were estimated using the Kaplan-Meier method.
Twenty-eight patients (median follow-up: 28.6 months) received PBS-PT reirradiation between 2016 and 2019, including 18 patients with recurrent RC (median prior dose: 54.0 Gy) and 10 patients with de novo RC and variable prior RT. The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 twice daily), and 24 of 28 patients received concurrent chemotherapy. Six underwent surgical resection. Three (10.7%) experienced grade 3 acute toxicities, and 1 did not complete RT owing to toxicity. Four (14.2%) had late grade <3 toxicity, including 1 grade 5 toxicity in a patient with a prior RT-related injury. The 1-year local progression, progression-free survival, and overall survival rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively.
This is the largest series using PT for reirradiation for RC and the first study using PBS-PT. Low acute toxicity rates and acceptable late toxicity support PBS-PT as an option for this high-risk patient population, with a need for continued follow-up.
Introduction
Rectal cancer (RC) is a common malignancy, with approximately 40,000 new cases per year in the United States and 800,000 worldwide. Therapy for locally advanced disease often consists of neoadjuvant concurrent chemotherapy and radiation, followed by surgical resection with total mesorectal excision—a paradigm that has improved local control, survival, and treatment-related toxicities.1, 2, 3 In the modern era, local relapse affects approximately 7% of patients in the long term and is associated with pain, obstruction, bleeding, discharge, and change in stool habits.4
Reirradiation for RC may be implemented in the treatment of locally recurrent RCs and de novo RC with prior radiation for other pelvic malignancy. It may be administered either as part of a curative or palliative regimen, with patients eligible for and receiving curative resection having the most favorable survival outcomes.5,6 However, it presents risk of late complications given the radiation sensitivity of nearby organs and tissues of the abdomen and pelvis—in particular, the bladder, bowel, bone marrow, and lumbosacral plexus. This affects the approach of reirradiation in multiple ways, including treatment volumes, prescribed dose, fractionation scheme, and technique of delivery.
Numerous experiences have described disease and toxicity outcomes of reirradiation for RC, using these aforementioned modifications in treatment delivery to achieve safe and effective therapy.7 A landmark prospective study by Valentini et al demonstrated the safety and efficacy of hyperfractionated reirradiation with concurrent chemotherapy, often given neoadjuvantly.8 This study has served as a reference for both disease outcomes and treatment toxicities. Multiple retrospective studies have corroborated these findings.9, 10, 11, 12 However, to our knowledge, nearly all published studies have evaluated reirradiation using either 3-dimensional conformal radiation therapy (RT) or intensity modulated RT techniques.13,14 Literature evaluating rectal reirradiation with proton therapy (PT) is emerging and has demonstrated a significantly reduced low dose to the bowel and bone marrow, as well as clinical feasibility, safety, and efficacy—thus far with passive-scatter techniques.15,16 PBS-PT provides true intensity modulated PT; thus, we hypothesize that its use may result in improved short- and long-term toxicity profiles in the setting of reirradiation for RC. We report the disease and toxicity outcomes from a retrospective, single-institution experience using PBS-PT for reirradiation for RC.
Methods and materials
Patient selection and treatment
An institutional review board–approved retrospective chart review was completed of all patients treated with reirradiation using PBS-PT at a single institution between 2016 and 2019 for either recurrent RC or de novo RC with prior pelvic RT for another malignancy. Patient demographic information, disease characteristics, and treatment characteristics were collected. Prior RT plan reports were accessed when possible, and all PBS-PT plans underwent peer review per departmental protocol. All patients were presented at a multidisciplinary tumor board. Concurrent chemotherapy and curative-intent surgical resection were planned whenever feasible and appropriate.
Proton beam reirradiation
Patients underwent computed tomography (CT) simulation in the supine or prone position with a comfortably full bladder and vac-lok immobilization. Contouring of the target and organ-at-risk volumes was performed. Gross tumor volume (GTV) was delineated using physical examination, CT simulation, and diagnostic imaging data (positron emission tomography and/or magnetic resonance imaging). A clinical target volume (CTV) was generated by expanding the GTV by 1.5 to 3.0 cm craniocaudally, extending to the pelvic sidewall laterally, and including the presacral space posteriorly. When a boost was planned, a second smaller isotropic expansion of 0.5 to 1.5 cm was used, or simply the gross tumor without expansion. The choice of CTV expansion is based on the method outlined by Valentini et al,8 with smaller expansions on the GTV used in cases of inoperable recurrences involving the bone. Planning target volumes were generated by dosimetry, accounting for setup and proton beam range uncertainty. Earlier cases used a uniform 5 mm expansion, later transitioning to nonuniform expansions (3.5-5 mm) based on translational uncertainty, and eventually generation of a planning target volume using robust optimization algorithms. Dosing was guided by the method by Valentini et al.8 Hyperfractionation was employed when feasible for the patient.
Plan optimization was performed using Eclipse (Varian Medical Systems, Palo Alto, CA) and Raystation (RaySearch Laboratories, Stockholm, Sweden). All patients were treated with PBS-PT, typically with 2 lateral fields with single-field optimization technique, with some cases using a third field and/or multiple-field optimization. Opposed lateral fields, rather than posterior oblique fields, were used in many cases due to relative biological effectiveness (RBE) uncertainty at the end range, because this configuration limits overlap of end-ranging segments of the beams into previously irradiated bladder as well as bowel anterior to the CTV. Furthermore, using PBS-PT, the anterior edge of the field can be shaped and modulated off of bladder and bowel with opposed lateral fields, in contrast to the same arrangement using photon-based 3-dimensional conformal RT, where this is not possible.
When using a multiple field optimization technique, air in the bowel was accounted for using a density override algorithm. Quality assurance CT images were obtained during the course of therapy, with frequency depending on the particular case and clinical discretion. Dose constraints for the bladder and bowel entailed keeping maximum doses of approximately 90% of the prescription dose, which itself depended on prior radiation dose and time interval. In all cases, these constraints on the bladder and bowel structures were prioritized over full prescription isodose coverage of the anterior target volume. A representative plan is shown in Figure 1.Figure 1 Example pencil beam scanning proton therapy plan with axial, coronal, and sagittal views with corresponding dose–volume histogram. The patient was simulated prone, dose was prescribed via a simultaneous integrated boost with clinical target volume 1 (blue; gross target volume with 2-2.5 cm craniocaudal expansion, laterally to pelvic sidewalls and posteriorly to sacrum) receiving 4000 cGy in 100 cGy/fraction and clinical target volume 2 (red; gross target volume + 1.0 cm isotropic expansion) receiving 4800 cGy in 120 cGy/fraction. Proton planning target volumes were generated based on setup and range uncertainty. Two lateral beams using a multiple-field optimization technique were used. Bladder (yellow), large bowel (brown), small bowel (green), right femoral head (turquoise), and left femoral head (fuschia). (A color version of this figure is available at https://doi.org/10.1016/j.adro.2020.10.008.)
Statistics
Efficacy outcomes included local progression (LP), progression-free survival (PFS), and overall survival (OS). LP was calculated from completion of reirradiation to time of local failure by pathologic or radiologic confirmation. Patients who did not experience LP were censored at the time of the last follow-up visit. PFS was calculated from completion of reirradiation to the date of any progression or death, irrespective of the cause. OS was calculated from completion of reirradiation to the date of death, irrespective of the cause. The vital status of patients was checked using medical record/obituary documentation, and OS was censored on the date of the last documentation confirming living status in patients still alive on that date.
Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 5.0. Acute toxicity was assessed using provider documentation from weekly on-treatment visits. Late toxicity was defined as symptoms attributable to RT persisting or occurring >3 months after completion of reirradiation. All clinical outcomes were estimated using the Kaplan-Meier method. A univariable Cox proportional hazards model was used to model the relationship between GTV and outcome. A P value of <.05 was considered statistically significant. All analyses were completed using SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY).
Patient, disease, and treatment characteristics
Patient, disease, and treatment characteristics are summarized in Table 1. Twenty-eight patients (median follow-up 28.6 months; range, 25.3-31.9 months) received PBS-PT reirradiation from 2016 to 2019. Of these, 18 patients (64.3%) had recurrent RC (median prior dose: 54.0 Gy; range, 43.2-63.0 Gy) and 10 patients had de novo RC and variable prior RT (8 received full-dose external beam RT or brachytherapy for prostate cancer; 1 patient received external beam RT and brachytherapy boost for endometrial cancer; 1 patient received whole abdominal RT for ovarian cancer with a pelvic boost). The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 patients twice daily), and 24 of 28 patients (85.7%) received concurrent chemotherapy, with 18 of 28 (64.3%) receiving twice-daily oral capecitabine on days with reirradiation. Overall, 25 of 28 patients (89.3%) completed the planned course of reirradiation.Table 1 Patient and treatment characteristics (n = 28)
Characteristics n (%)
Sex
Male 19 (67.9%)
Female 9 (32.1%)
Age, y, median (range) 68 (41-87)
Follow-up, mo, median (range) 28.6 (25.3-31.9)
Recurrent rectal cancer 18 (64.3)
Prior RT dose, Gy, median (range) 54.0 (43.2-63.0)
Anatomic location of recurrence
Rectal 6 (33.3)
Presacral 11 (61.1)
Pelvic bone 1 (5.6)
Treatment for initial rectal cancer (n = 18)
Neoadjuvant conformal RT 8 (44.4)
Adjuvant conformal RT 2 (11.2)
Other 8 (44.4)
de novo rectal cancer (n = 10) 10 (35.7)
Prior pelvic RT Definitive for prostate cancer (equivalent total dose in 2 Gy fractions >70 Gy)8
Definitive for ovarian cancer1
Definitive for endometrial cancer1
Treatment before reirradiation for recurrence
Upfront surgery, n 2
Systemic therapy, n 8
Reirradiation dose, Gy, median (range) 48.0 (16.0-60.0)
Reirradiation interval, mo, median (range) 48.5 (12.7-494.8)
Concurrent chemotherapy with reirradiation 24 (85.7)
Hyperfractionated reirradiation 21 (75.0)
Completed reirradiation course 25 (89.3)
Underwent resection after reirradiation 6 (21.4)
R0 6
Gross tumor volume, cm3, median (range) 86.4 (13.6-821.8)
Abbreviation: RT = radiation therapy.
Table 2 Acute toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Grade 2, n (%) 3, n (%) 4, n (%) 5, n (%)
Gastrointestinal 4 (14.2) 2 (7.1) 0 (0.0) 0 (0.0)
Skin 4 (14.2) 1 (3.6) 0 (0.0) 0 (0.0)
Urologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Hematologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Total 8 (28.6) 3 (10.7) 0 (0.0) 0 (0.0)
Disease outcomes and toxicity
The 1-year LP, PFS, and OS rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively. The median times to LP, PFS, and OS were 23.4 months (range, 1.6-39.8 months; 95% CI, 12.9-33.9 months), 11.6 months (range, 0.6-39.8 months; 95% CI, 8.6-14.5 months), and 29.2 months (range, 1.6-45.9 months; 95% CI, 19.7-38.8 months), respectively (Fig 2A-C). In a univariable Cox proportional hazards model with GTV (cm3) included as a continuous variable, increasing GTV was highly statistically significantly associated with LP (hazard ratio [HR]: 1.005; 95% CI, 1.002-1.008; P = .003) and PFS (HR: 1.004; 95% CI, 1.002-1.006; P = .001), but not with OS (HR: 1.002; 95% CI, 1.000-1.005; P = .102). The 1-year LP rate for recurrent versus de novo RC was significantly different at 52.3% (95% CI, 23.9%-80.1%) and 0% (P = .002), respectively. The 1-year OS rate for recurrent versus de novo RC was 72.2% (95% CI, 51.4%-93.0%) and 100% (P = .058), respectively.Figure 2 Kaplan-Meier curves for (A) local progression, (B) progression-free survival, (C) overall survival, and (D) late grade >3 toxicities for all patients (n = 28).
Six patients (21.4%) underwent surgical resection after reirradiation, with further breakdown by de novo RC and recurrent RC patients being 3 of 10 (30%) and 3 of 18 (16.7%), respectively. All resections resulted in R0 resection. Of these patients, 4 eventually experienced LP (3 with recurrent RC), with a 1-year LP rate of resected patients of 16.7% versus 40% for those who did not receive resection (P = .786). The 1-year OS rate for patients undergoing and not undergoing resection was 100% and 76.8%, respectively; this difference was statistically significant (P = .027).
Acute toxicities are listed in Table 2. The 1-year rate of late grade >3 toxicities (G3+ Tox) was 13.3% in the Kaplan-Meier analysis (Fig 2D). Six late G3+ Tox occurred in 4 separate patients, with no evidence of tumor recurrence at toxicity onset (summarized by patient in Table 3). Patient 1 ultimately developed grade 5 toxicity and had a history of significant late toxicity from prior whole abdominal and pelvic boost radiation for ovarian cancer in the 1970s, including baseline and longstanding radiation colitis, loss of a kidney, and cystitis. This patient developed rectal bleeding at 3 months, a rectovaginal fistula at 9 months, and ultimately a bleeding stage IV decubitus ulcer and died of presacral hemorrhage at 26 months without evidence of tumor recurrence. Patient 2 developed an enterocutaneous fistula passing through the presacral region, as well as pyelonephritis resolving with parenteral antibiotics, approximately 1 year from completion of reirradiation. The treatment course was entirely in a medical ward without stay in either intermediate or intensive care. Of note, this patient was receiving bevacizumab systemic therapy at the time of the fistula diagnosis. This patient also experienced multiple delays and breaks in the planned treatment course related to social and logistic factors. This was the only patient who experienced G3+ Tox in both the acute and late term.Table 3 Grade ≥3 late toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Patient no. Grade Toxicity Time to toxicity, mo
1 3 Rectovaginal fistula 8.5
1 5 Presacral hemorrhage 25.6
2 3 Enterocutaneous fistula 11
2 3 Pyelonephritis (resolved) 11
3 3 Presacral abscess/rectovaginal fistula 31
4 3 Colovaginal fistula (improved) 12
Six grade 3+ events were observed in 4 patients.
Patient 3 developed a presacral abscess and rectovaginal fistula approximately 2.5 years from completion of reirradiation. The site of local recurrence, which was treated with reirradiation, involved the vaginal fornices. Patient 4 had a long history of presacral abscess and transvaginal drainage procedures before reirradiation and developed increased vaginal discharge approximately 1 year from completion of reirradiation. The patient received a diagnosis of colovaginal fistula, which improved with percutaneous drainage.
Discussion
This is the largest report with the longest median follow-up to date of reirradiation for RC using PT. Additionally, all patients in our cohort received PBS-PT, making this the first such report. In contrast with prior studies, this study also included patients receiving prior pelvic RT for other malignancies.
Focusing on disease outcomes and restricting the analysis to recurrent RC only, we noted 1-year LP and OS rates of 52.3% and 71.4% in the present study versus 1-year local control and OS of 76.3% and 87.5% in the historical study by Valentini et al.8 Considerable heterogeneity in this retrospective cohort, particularly with respect to prior therapies (namely surgical resection) may account for the differences in these outcomes. Of the 10 patients who experienced local failure, 2 had multiply recurrent disease before reirradiation, 1 did not receive surgical resection after initial conformal RT, and 3 had received systemic therapy for local recurrence before being referred for reirradiation. All of these circumstances are mutually exclusive. As such, these patients had disease and treatment factors putting them at a high baseline risk and would also not have been eligible for a prospective study such as that by Valentini et al.8 Patients with de novo RC with previously irradiated pelvis show 2 failures as of the present, with 1 of these occurring in a patient who did not receive resection, and appear comparable with what would be expected without a history of pelvic RT. Nevertheless, the majority of patients in this study received hyperfractionated reirradiation with concurrent chemotherapy, reflecting an overall general consistency with reirradiation delivery technique.
Rates of acute grade 3 toxicity were low at 10.7%, and all but 3 patients completed the planned course of reirradiation (only 1 case was toxicity-mediated). These are comparable to the rate reported by Valentini et al (5.1%),8 who only accounted for gastrointestinal toxicity. Furthermore, relative to the study by Valentini et al,8 the median reirradiation dose in the present series was higher (48 vs 40.8 Gy). In addition, all patients in the trial by Valentini et al8 were treated with hyperfractionated RT compared with 75% of patients in our cohort. This supports tolerability of hyperfractionated reirradiation and concurrent chemotherapy with PBS-PT and is corroborated by the existing literature on PT for reirradiation for RC.
Four patients experienced late G3+ Tox, including 1 grade 5 toxicity. Overall, the rate of G3+ Tox at 1 year estimated with the Kaplan-Meier method was low at 13.3% (95% CI, 0.0%-27.7%). Of note, in 2 of these affected patients, a dose of 48 Gy in 1.2 Gy fractions was delivered, and in another patient 54 Gy in 1.5 Gy fractions was used, which represented the upper limit of the total dose in those patients who received a hyperfractionated course in this cohort. Additionally, as noted in the results section, 1 patient who experienced a grade 3 fistula had been undergoing bevacizumab therapy, another had a long history of presacral abscess and transvaginal procedures, and the patient with grade 5 toxicity had a history of significant toxicity with prior RT.
Comparing these late G3+ Tox with those reported by Valentini et al is difficult because late toxicities were not graded (although 1 was noted to require surgical intervention, and no treatment-related death was reported). However, the late G3+ Tox rates in the present report are comparable with prior published experiences of passive scatter PT reirradiation, although with a longer median follow-up of 28.6 months (range, 25.3-31.9 months). In the first known report using PT for reirradiation, 7 patients were treated using a double-scatter proton technique, and the median dose was 6120 cGy (RBE; 4500-6480 cGy) in conventional fractionation, with 6 patients receiving concurrent chemotherapy.15 With a median follow-up of 14 months, there were 3 acute grade 3 toxicities (abdominal pain, diarrhea) probably related to reirradiation, and 3 late grade 4 toxicities (2 bowel obstruction, 1 entero-vaginal fistula) possibly related to reirradiation.
Another experience evaluated 15 patients, also treated with passive-scatter technique, but with a 1.5 Gy accelerated fractionated course to a total dose of 39 to 45 Gy (RBE), and with all patients receiving concurrent chemotherapy.16 With a median follow-up of 14 months, 1 acute grade 3 toxicity (lymphopenia) and 2 late grade 3 toxicities (dysuria, rectal bleeding) were noted. Given the sample sizes of these and the present experiences and differing methods of treatment delivery, it is difficult to elucidate a dose-response relationship with respect to acute or late toxicity. Furthermore, our study solely implemented PBS-PT, thus making it more difficult to directly compare existing data largely gathered using passive-scatter techniques.
Six patients (21.4%) in our series received surgical resection after reirradiation, a lower proportion than in prior experiences (50.8% in the study by Valentini et al8), reflecting the high-risk patient cohort in our report. However, all 6 resulted in an R0 resection. Although the sample sizes are small for comparison, there was a strong trend toward superior OS in patients receiving resection (P = .107). This is consistent with prior reirradiation studies and likely multifactorial.
Other limitations to our study are primarily related to its retrospective nature. First and perhaps most important, there is selection bias inherent with any retrospective report and variable prior treatments. In this cohort, different RT regimens were used, inclusive of both conventionally fractionated and hyperfractionated courses. Second, the assessment of late toxicities was dependent on assessments that were not standardized, with imaging ranging from pelvic magnetic resonance to positron emission tomography/CT to CT.
Maturation and expansion of these data will better establish disease and toxicity outcomes in these patients. Longer follow-up and further accrual may help establish a dose–response relationship with respect to disease outcomes as well as the development of late toxicity. Moreover, such a relationship may be highly dependent on whether disease is recurrent or de novo.
Conclusions
The low acute toxicity rates, rare treatment interruption, and acceptable late toxicity reported here thus far support PBS-PT as an option for this high-risk patient population. Further follow-up and prospective studies, as those completed in the 3-dimensional conformal RT era, evaluating the use of PT for reirradiation for RC will help further clarify disease outcomes and toxicity profiles.
Sources of support: This work had no specific funding.
Disclosures: Dr Kaiser reports personal fees from Varian Medical Systems outside of the submitted work. | CAPECITABINE | DrugsGivenReaction | CC BY-NC-ND | 33490730 | 18,926,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyelonephritis'. | Reirradiation for Rectal Cancer Using Pencil Beam Scanning Proton Therapy: A Single Institutional Experience.
Reirradiation for rectal cancer (RC) after prior pelvic radiation therapy (RT) has been shown to be safe and effective. However, limited data exist for proton therapy (PT), including pencil beam scanning proton therapy (PBS-PT). We hypothesize that PT is safe and feasible for re-treatment and may allow for decreased toxicity and treatment escalation.
A single-institution, retrospective, institutional review board-approved analysis of all patients with RC and prior pelvic RT receiving PBS-PT reirradiation was performed. Data on patient and treatment characteristics and outcomes were collected. Local progression, progression-free survival, overall survival, and late grade >3 toxicity were estimated using the Kaplan-Meier method.
Twenty-eight patients (median follow-up: 28.6 months) received PBS-PT reirradiation between 2016 and 2019, including 18 patients with recurrent RC (median prior dose: 54.0 Gy) and 10 patients with de novo RC and variable prior RT. The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 twice daily), and 24 of 28 patients received concurrent chemotherapy. Six underwent surgical resection. Three (10.7%) experienced grade 3 acute toxicities, and 1 did not complete RT owing to toxicity. Four (14.2%) had late grade <3 toxicity, including 1 grade 5 toxicity in a patient with a prior RT-related injury. The 1-year local progression, progression-free survival, and overall survival rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively.
This is the largest series using PT for reirradiation for RC and the first study using PBS-PT. Low acute toxicity rates and acceptable late toxicity support PBS-PT as an option for this high-risk patient population, with a need for continued follow-up.
Introduction
Rectal cancer (RC) is a common malignancy, with approximately 40,000 new cases per year in the United States and 800,000 worldwide. Therapy for locally advanced disease often consists of neoadjuvant concurrent chemotherapy and radiation, followed by surgical resection with total mesorectal excision—a paradigm that has improved local control, survival, and treatment-related toxicities.1, 2, 3 In the modern era, local relapse affects approximately 7% of patients in the long term and is associated with pain, obstruction, bleeding, discharge, and change in stool habits.4
Reirradiation for RC may be implemented in the treatment of locally recurrent RCs and de novo RC with prior radiation for other pelvic malignancy. It may be administered either as part of a curative or palliative regimen, with patients eligible for and receiving curative resection having the most favorable survival outcomes.5,6 However, it presents risk of late complications given the radiation sensitivity of nearby organs and tissues of the abdomen and pelvis—in particular, the bladder, bowel, bone marrow, and lumbosacral plexus. This affects the approach of reirradiation in multiple ways, including treatment volumes, prescribed dose, fractionation scheme, and technique of delivery.
Numerous experiences have described disease and toxicity outcomes of reirradiation for RC, using these aforementioned modifications in treatment delivery to achieve safe and effective therapy.7 A landmark prospective study by Valentini et al demonstrated the safety and efficacy of hyperfractionated reirradiation with concurrent chemotherapy, often given neoadjuvantly.8 This study has served as a reference for both disease outcomes and treatment toxicities. Multiple retrospective studies have corroborated these findings.9, 10, 11, 12 However, to our knowledge, nearly all published studies have evaluated reirradiation using either 3-dimensional conformal radiation therapy (RT) or intensity modulated RT techniques.13,14 Literature evaluating rectal reirradiation with proton therapy (PT) is emerging and has demonstrated a significantly reduced low dose to the bowel and bone marrow, as well as clinical feasibility, safety, and efficacy—thus far with passive-scatter techniques.15,16 PBS-PT provides true intensity modulated PT; thus, we hypothesize that its use may result in improved short- and long-term toxicity profiles in the setting of reirradiation for RC. We report the disease and toxicity outcomes from a retrospective, single-institution experience using PBS-PT for reirradiation for RC.
Methods and materials
Patient selection and treatment
An institutional review board–approved retrospective chart review was completed of all patients treated with reirradiation using PBS-PT at a single institution between 2016 and 2019 for either recurrent RC or de novo RC with prior pelvic RT for another malignancy. Patient demographic information, disease characteristics, and treatment characteristics were collected. Prior RT plan reports were accessed when possible, and all PBS-PT plans underwent peer review per departmental protocol. All patients were presented at a multidisciplinary tumor board. Concurrent chemotherapy and curative-intent surgical resection were planned whenever feasible and appropriate.
Proton beam reirradiation
Patients underwent computed tomography (CT) simulation in the supine or prone position with a comfortably full bladder and vac-lok immobilization. Contouring of the target and organ-at-risk volumes was performed. Gross tumor volume (GTV) was delineated using physical examination, CT simulation, and diagnostic imaging data (positron emission tomography and/or magnetic resonance imaging). A clinical target volume (CTV) was generated by expanding the GTV by 1.5 to 3.0 cm craniocaudally, extending to the pelvic sidewall laterally, and including the presacral space posteriorly. When a boost was planned, a second smaller isotropic expansion of 0.5 to 1.5 cm was used, or simply the gross tumor without expansion. The choice of CTV expansion is based on the method outlined by Valentini et al,8 with smaller expansions on the GTV used in cases of inoperable recurrences involving the bone. Planning target volumes were generated by dosimetry, accounting for setup and proton beam range uncertainty. Earlier cases used a uniform 5 mm expansion, later transitioning to nonuniform expansions (3.5-5 mm) based on translational uncertainty, and eventually generation of a planning target volume using robust optimization algorithms. Dosing was guided by the method by Valentini et al.8 Hyperfractionation was employed when feasible for the patient.
Plan optimization was performed using Eclipse (Varian Medical Systems, Palo Alto, CA) and Raystation (RaySearch Laboratories, Stockholm, Sweden). All patients were treated with PBS-PT, typically with 2 lateral fields with single-field optimization technique, with some cases using a third field and/or multiple-field optimization. Opposed lateral fields, rather than posterior oblique fields, were used in many cases due to relative biological effectiveness (RBE) uncertainty at the end range, because this configuration limits overlap of end-ranging segments of the beams into previously irradiated bladder as well as bowel anterior to the CTV. Furthermore, using PBS-PT, the anterior edge of the field can be shaped and modulated off of bladder and bowel with opposed lateral fields, in contrast to the same arrangement using photon-based 3-dimensional conformal RT, where this is not possible.
When using a multiple field optimization technique, air in the bowel was accounted for using a density override algorithm. Quality assurance CT images were obtained during the course of therapy, with frequency depending on the particular case and clinical discretion. Dose constraints for the bladder and bowel entailed keeping maximum doses of approximately 90% of the prescription dose, which itself depended on prior radiation dose and time interval. In all cases, these constraints on the bladder and bowel structures were prioritized over full prescription isodose coverage of the anterior target volume. A representative plan is shown in Figure 1.Figure 1 Example pencil beam scanning proton therapy plan with axial, coronal, and sagittal views with corresponding dose–volume histogram. The patient was simulated prone, dose was prescribed via a simultaneous integrated boost with clinical target volume 1 (blue; gross target volume with 2-2.5 cm craniocaudal expansion, laterally to pelvic sidewalls and posteriorly to sacrum) receiving 4000 cGy in 100 cGy/fraction and clinical target volume 2 (red; gross target volume + 1.0 cm isotropic expansion) receiving 4800 cGy in 120 cGy/fraction. Proton planning target volumes were generated based on setup and range uncertainty. Two lateral beams using a multiple-field optimization technique were used. Bladder (yellow), large bowel (brown), small bowel (green), right femoral head (turquoise), and left femoral head (fuschia). (A color version of this figure is available at https://doi.org/10.1016/j.adro.2020.10.008.)
Statistics
Efficacy outcomes included local progression (LP), progression-free survival (PFS), and overall survival (OS). LP was calculated from completion of reirradiation to time of local failure by pathologic or radiologic confirmation. Patients who did not experience LP were censored at the time of the last follow-up visit. PFS was calculated from completion of reirradiation to the date of any progression or death, irrespective of the cause. OS was calculated from completion of reirradiation to the date of death, irrespective of the cause. The vital status of patients was checked using medical record/obituary documentation, and OS was censored on the date of the last documentation confirming living status in patients still alive on that date.
Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 5.0. Acute toxicity was assessed using provider documentation from weekly on-treatment visits. Late toxicity was defined as symptoms attributable to RT persisting or occurring >3 months after completion of reirradiation. All clinical outcomes were estimated using the Kaplan-Meier method. A univariable Cox proportional hazards model was used to model the relationship between GTV and outcome. A P value of <.05 was considered statistically significant. All analyses were completed using SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY).
Patient, disease, and treatment characteristics
Patient, disease, and treatment characteristics are summarized in Table 1. Twenty-eight patients (median follow-up 28.6 months; range, 25.3-31.9 months) received PBS-PT reirradiation from 2016 to 2019. Of these, 18 patients (64.3%) had recurrent RC (median prior dose: 54.0 Gy; range, 43.2-63.0 Gy) and 10 patients had de novo RC and variable prior RT (8 received full-dose external beam RT or brachytherapy for prostate cancer; 1 patient received external beam RT and brachytherapy boost for endometrial cancer; 1 patient received whole abdominal RT for ovarian cancer with a pelvic boost). The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 patients twice daily), and 24 of 28 patients (85.7%) received concurrent chemotherapy, with 18 of 28 (64.3%) receiving twice-daily oral capecitabine on days with reirradiation. Overall, 25 of 28 patients (89.3%) completed the planned course of reirradiation.Table 1 Patient and treatment characteristics (n = 28)
Characteristics n (%)
Sex
Male 19 (67.9%)
Female 9 (32.1%)
Age, y, median (range) 68 (41-87)
Follow-up, mo, median (range) 28.6 (25.3-31.9)
Recurrent rectal cancer 18 (64.3)
Prior RT dose, Gy, median (range) 54.0 (43.2-63.0)
Anatomic location of recurrence
Rectal 6 (33.3)
Presacral 11 (61.1)
Pelvic bone 1 (5.6)
Treatment for initial rectal cancer (n = 18)
Neoadjuvant conformal RT 8 (44.4)
Adjuvant conformal RT 2 (11.2)
Other 8 (44.4)
de novo rectal cancer (n = 10) 10 (35.7)
Prior pelvic RT Definitive for prostate cancer (equivalent total dose in 2 Gy fractions >70 Gy)8
Definitive for ovarian cancer1
Definitive for endometrial cancer1
Treatment before reirradiation for recurrence
Upfront surgery, n 2
Systemic therapy, n 8
Reirradiation dose, Gy, median (range) 48.0 (16.0-60.0)
Reirradiation interval, mo, median (range) 48.5 (12.7-494.8)
Concurrent chemotherapy with reirradiation 24 (85.7)
Hyperfractionated reirradiation 21 (75.0)
Completed reirradiation course 25 (89.3)
Underwent resection after reirradiation 6 (21.4)
R0 6
Gross tumor volume, cm3, median (range) 86.4 (13.6-821.8)
Abbreviation: RT = radiation therapy.
Table 2 Acute toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Grade 2, n (%) 3, n (%) 4, n (%) 5, n (%)
Gastrointestinal 4 (14.2) 2 (7.1) 0 (0.0) 0 (0.0)
Skin 4 (14.2) 1 (3.6) 0 (0.0) 0 (0.0)
Urologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Hematologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Total 8 (28.6) 3 (10.7) 0 (0.0) 0 (0.0)
Disease outcomes and toxicity
The 1-year LP, PFS, and OS rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively. The median times to LP, PFS, and OS were 23.4 months (range, 1.6-39.8 months; 95% CI, 12.9-33.9 months), 11.6 months (range, 0.6-39.8 months; 95% CI, 8.6-14.5 months), and 29.2 months (range, 1.6-45.9 months; 95% CI, 19.7-38.8 months), respectively (Fig 2A-C). In a univariable Cox proportional hazards model with GTV (cm3) included as a continuous variable, increasing GTV was highly statistically significantly associated with LP (hazard ratio [HR]: 1.005; 95% CI, 1.002-1.008; P = .003) and PFS (HR: 1.004; 95% CI, 1.002-1.006; P = .001), but not with OS (HR: 1.002; 95% CI, 1.000-1.005; P = .102). The 1-year LP rate for recurrent versus de novo RC was significantly different at 52.3% (95% CI, 23.9%-80.1%) and 0% (P = .002), respectively. The 1-year OS rate for recurrent versus de novo RC was 72.2% (95% CI, 51.4%-93.0%) and 100% (P = .058), respectively.Figure 2 Kaplan-Meier curves for (A) local progression, (B) progression-free survival, (C) overall survival, and (D) late grade >3 toxicities for all patients (n = 28).
Six patients (21.4%) underwent surgical resection after reirradiation, with further breakdown by de novo RC and recurrent RC patients being 3 of 10 (30%) and 3 of 18 (16.7%), respectively. All resections resulted in R0 resection. Of these patients, 4 eventually experienced LP (3 with recurrent RC), with a 1-year LP rate of resected patients of 16.7% versus 40% for those who did not receive resection (P = .786). The 1-year OS rate for patients undergoing and not undergoing resection was 100% and 76.8%, respectively; this difference was statistically significant (P = .027).
Acute toxicities are listed in Table 2. The 1-year rate of late grade >3 toxicities (G3+ Tox) was 13.3% in the Kaplan-Meier analysis (Fig 2D). Six late G3+ Tox occurred in 4 separate patients, with no evidence of tumor recurrence at toxicity onset (summarized by patient in Table 3). Patient 1 ultimately developed grade 5 toxicity and had a history of significant late toxicity from prior whole abdominal and pelvic boost radiation for ovarian cancer in the 1970s, including baseline and longstanding radiation colitis, loss of a kidney, and cystitis. This patient developed rectal bleeding at 3 months, a rectovaginal fistula at 9 months, and ultimately a bleeding stage IV decubitus ulcer and died of presacral hemorrhage at 26 months without evidence of tumor recurrence. Patient 2 developed an enterocutaneous fistula passing through the presacral region, as well as pyelonephritis resolving with parenteral antibiotics, approximately 1 year from completion of reirradiation. The treatment course was entirely in a medical ward without stay in either intermediate or intensive care. Of note, this patient was receiving bevacizumab systemic therapy at the time of the fistula diagnosis. This patient also experienced multiple delays and breaks in the planned treatment course related to social and logistic factors. This was the only patient who experienced G3+ Tox in both the acute and late term.Table 3 Grade ≥3 late toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Patient no. Grade Toxicity Time to toxicity, mo
1 3 Rectovaginal fistula 8.5
1 5 Presacral hemorrhage 25.6
2 3 Enterocutaneous fistula 11
2 3 Pyelonephritis (resolved) 11
3 3 Presacral abscess/rectovaginal fistula 31
4 3 Colovaginal fistula (improved) 12
Six grade 3+ events were observed in 4 patients.
Patient 3 developed a presacral abscess and rectovaginal fistula approximately 2.5 years from completion of reirradiation. The site of local recurrence, which was treated with reirradiation, involved the vaginal fornices. Patient 4 had a long history of presacral abscess and transvaginal drainage procedures before reirradiation and developed increased vaginal discharge approximately 1 year from completion of reirradiation. The patient received a diagnosis of colovaginal fistula, which improved with percutaneous drainage.
Discussion
This is the largest report with the longest median follow-up to date of reirradiation for RC using PT. Additionally, all patients in our cohort received PBS-PT, making this the first such report. In contrast with prior studies, this study also included patients receiving prior pelvic RT for other malignancies.
Focusing on disease outcomes and restricting the analysis to recurrent RC only, we noted 1-year LP and OS rates of 52.3% and 71.4% in the present study versus 1-year local control and OS of 76.3% and 87.5% in the historical study by Valentini et al.8 Considerable heterogeneity in this retrospective cohort, particularly with respect to prior therapies (namely surgical resection) may account for the differences in these outcomes. Of the 10 patients who experienced local failure, 2 had multiply recurrent disease before reirradiation, 1 did not receive surgical resection after initial conformal RT, and 3 had received systemic therapy for local recurrence before being referred for reirradiation. All of these circumstances are mutually exclusive. As such, these patients had disease and treatment factors putting them at a high baseline risk and would also not have been eligible for a prospective study such as that by Valentini et al.8 Patients with de novo RC with previously irradiated pelvis show 2 failures as of the present, with 1 of these occurring in a patient who did not receive resection, and appear comparable with what would be expected without a history of pelvic RT. Nevertheless, the majority of patients in this study received hyperfractionated reirradiation with concurrent chemotherapy, reflecting an overall general consistency with reirradiation delivery technique.
Rates of acute grade 3 toxicity were low at 10.7%, and all but 3 patients completed the planned course of reirradiation (only 1 case was toxicity-mediated). These are comparable to the rate reported by Valentini et al (5.1%),8 who only accounted for gastrointestinal toxicity. Furthermore, relative to the study by Valentini et al,8 the median reirradiation dose in the present series was higher (48 vs 40.8 Gy). In addition, all patients in the trial by Valentini et al8 were treated with hyperfractionated RT compared with 75% of patients in our cohort. This supports tolerability of hyperfractionated reirradiation and concurrent chemotherapy with PBS-PT and is corroborated by the existing literature on PT for reirradiation for RC.
Four patients experienced late G3+ Tox, including 1 grade 5 toxicity. Overall, the rate of G3+ Tox at 1 year estimated with the Kaplan-Meier method was low at 13.3% (95% CI, 0.0%-27.7%). Of note, in 2 of these affected patients, a dose of 48 Gy in 1.2 Gy fractions was delivered, and in another patient 54 Gy in 1.5 Gy fractions was used, which represented the upper limit of the total dose in those patients who received a hyperfractionated course in this cohort. Additionally, as noted in the results section, 1 patient who experienced a grade 3 fistula had been undergoing bevacizumab therapy, another had a long history of presacral abscess and transvaginal procedures, and the patient with grade 5 toxicity had a history of significant toxicity with prior RT.
Comparing these late G3+ Tox with those reported by Valentini et al is difficult because late toxicities were not graded (although 1 was noted to require surgical intervention, and no treatment-related death was reported). However, the late G3+ Tox rates in the present report are comparable with prior published experiences of passive scatter PT reirradiation, although with a longer median follow-up of 28.6 months (range, 25.3-31.9 months). In the first known report using PT for reirradiation, 7 patients were treated using a double-scatter proton technique, and the median dose was 6120 cGy (RBE; 4500-6480 cGy) in conventional fractionation, with 6 patients receiving concurrent chemotherapy.15 With a median follow-up of 14 months, there were 3 acute grade 3 toxicities (abdominal pain, diarrhea) probably related to reirradiation, and 3 late grade 4 toxicities (2 bowel obstruction, 1 entero-vaginal fistula) possibly related to reirradiation.
Another experience evaluated 15 patients, also treated with passive-scatter technique, but with a 1.5 Gy accelerated fractionated course to a total dose of 39 to 45 Gy (RBE), and with all patients receiving concurrent chemotherapy.16 With a median follow-up of 14 months, 1 acute grade 3 toxicity (lymphopenia) and 2 late grade 3 toxicities (dysuria, rectal bleeding) were noted. Given the sample sizes of these and the present experiences and differing methods of treatment delivery, it is difficult to elucidate a dose-response relationship with respect to acute or late toxicity. Furthermore, our study solely implemented PBS-PT, thus making it more difficult to directly compare existing data largely gathered using passive-scatter techniques.
Six patients (21.4%) in our series received surgical resection after reirradiation, a lower proportion than in prior experiences (50.8% in the study by Valentini et al8), reflecting the high-risk patient cohort in our report. However, all 6 resulted in an R0 resection. Although the sample sizes are small for comparison, there was a strong trend toward superior OS in patients receiving resection (P = .107). This is consistent with prior reirradiation studies and likely multifactorial.
Other limitations to our study are primarily related to its retrospective nature. First and perhaps most important, there is selection bias inherent with any retrospective report and variable prior treatments. In this cohort, different RT regimens were used, inclusive of both conventionally fractionated and hyperfractionated courses. Second, the assessment of late toxicities was dependent on assessments that were not standardized, with imaging ranging from pelvic magnetic resonance to positron emission tomography/CT to CT.
Maturation and expansion of these data will better establish disease and toxicity outcomes in these patients. Longer follow-up and further accrual may help establish a dose–response relationship with respect to disease outcomes as well as the development of late toxicity. Moreover, such a relationship may be highly dependent on whether disease is recurrent or de novo.
Conclusions
The low acute toxicity rates, rare treatment interruption, and acceptable late toxicity reported here thus far support PBS-PT as an option for this high-risk patient population. Further follow-up and prospective studies, as those completed in the 3-dimensional conformal RT era, evaluating the use of PT for reirradiation for RC will help further clarify disease outcomes and toxicity profiles.
Sources of support: This work had no specific funding.
Disclosures: Dr Kaiser reports personal fees from Varian Medical Systems outside of the submitted work. | BEVACIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33490730 | 18,926,203 | 2021 |
What was the administration route of drug 'CAPECITABINE'? | Reirradiation for Rectal Cancer Using Pencil Beam Scanning Proton Therapy: A Single Institutional Experience.
Reirradiation for rectal cancer (RC) after prior pelvic radiation therapy (RT) has been shown to be safe and effective. However, limited data exist for proton therapy (PT), including pencil beam scanning proton therapy (PBS-PT). We hypothesize that PT is safe and feasible for re-treatment and may allow for decreased toxicity and treatment escalation.
A single-institution, retrospective, institutional review board-approved analysis of all patients with RC and prior pelvic RT receiving PBS-PT reirradiation was performed. Data on patient and treatment characteristics and outcomes were collected. Local progression, progression-free survival, overall survival, and late grade >3 toxicity were estimated using the Kaplan-Meier method.
Twenty-eight patients (median follow-up: 28.6 months) received PBS-PT reirradiation between 2016 and 2019, including 18 patients with recurrent RC (median prior dose: 54.0 Gy) and 10 patients with de novo RC and variable prior RT. The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 twice daily), and 24 of 28 patients received concurrent chemotherapy. Six underwent surgical resection. Three (10.7%) experienced grade 3 acute toxicities, and 1 did not complete RT owing to toxicity. Four (14.2%) had late grade <3 toxicity, including 1 grade 5 toxicity in a patient with a prior RT-related injury. The 1-year local progression, progression-free survival, and overall survival rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively.
This is the largest series using PT for reirradiation for RC and the first study using PBS-PT. Low acute toxicity rates and acceptable late toxicity support PBS-PT as an option for this high-risk patient population, with a need for continued follow-up.
Introduction
Rectal cancer (RC) is a common malignancy, with approximately 40,000 new cases per year in the United States and 800,000 worldwide. Therapy for locally advanced disease often consists of neoadjuvant concurrent chemotherapy and radiation, followed by surgical resection with total mesorectal excision—a paradigm that has improved local control, survival, and treatment-related toxicities.1, 2, 3 In the modern era, local relapse affects approximately 7% of patients in the long term and is associated with pain, obstruction, bleeding, discharge, and change in stool habits.4
Reirradiation for RC may be implemented in the treatment of locally recurrent RCs and de novo RC with prior radiation for other pelvic malignancy. It may be administered either as part of a curative or palliative regimen, with patients eligible for and receiving curative resection having the most favorable survival outcomes.5,6 However, it presents risk of late complications given the radiation sensitivity of nearby organs and tissues of the abdomen and pelvis—in particular, the bladder, bowel, bone marrow, and lumbosacral plexus. This affects the approach of reirradiation in multiple ways, including treatment volumes, prescribed dose, fractionation scheme, and technique of delivery.
Numerous experiences have described disease and toxicity outcomes of reirradiation for RC, using these aforementioned modifications in treatment delivery to achieve safe and effective therapy.7 A landmark prospective study by Valentini et al demonstrated the safety and efficacy of hyperfractionated reirradiation with concurrent chemotherapy, often given neoadjuvantly.8 This study has served as a reference for both disease outcomes and treatment toxicities. Multiple retrospective studies have corroborated these findings.9, 10, 11, 12 However, to our knowledge, nearly all published studies have evaluated reirradiation using either 3-dimensional conformal radiation therapy (RT) or intensity modulated RT techniques.13,14 Literature evaluating rectal reirradiation with proton therapy (PT) is emerging and has demonstrated a significantly reduced low dose to the bowel and bone marrow, as well as clinical feasibility, safety, and efficacy—thus far with passive-scatter techniques.15,16 PBS-PT provides true intensity modulated PT; thus, we hypothesize that its use may result in improved short- and long-term toxicity profiles in the setting of reirradiation for RC. We report the disease and toxicity outcomes from a retrospective, single-institution experience using PBS-PT for reirradiation for RC.
Methods and materials
Patient selection and treatment
An institutional review board–approved retrospective chart review was completed of all patients treated with reirradiation using PBS-PT at a single institution between 2016 and 2019 for either recurrent RC or de novo RC with prior pelvic RT for another malignancy. Patient demographic information, disease characteristics, and treatment characteristics were collected. Prior RT plan reports were accessed when possible, and all PBS-PT plans underwent peer review per departmental protocol. All patients were presented at a multidisciplinary tumor board. Concurrent chemotherapy and curative-intent surgical resection were planned whenever feasible and appropriate.
Proton beam reirradiation
Patients underwent computed tomography (CT) simulation in the supine or prone position with a comfortably full bladder and vac-lok immobilization. Contouring of the target and organ-at-risk volumes was performed. Gross tumor volume (GTV) was delineated using physical examination, CT simulation, and diagnostic imaging data (positron emission tomography and/or magnetic resonance imaging). A clinical target volume (CTV) was generated by expanding the GTV by 1.5 to 3.0 cm craniocaudally, extending to the pelvic sidewall laterally, and including the presacral space posteriorly. When a boost was planned, a second smaller isotropic expansion of 0.5 to 1.5 cm was used, or simply the gross tumor without expansion. The choice of CTV expansion is based on the method outlined by Valentini et al,8 with smaller expansions on the GTV used in cases of inoperable recurrences involving the bone. Planning target volumes were generated by dosimetry, accounting for setup and proton beam range uncertainty. Earlier cases used a uniform 5 mm expansion, later transitioning to nonuniform expansions (3.5-5 mm) based on translational uncertainty, and eventually generation of a planning target volume using robust optimization algorithms. Dosing was guided by the method by Valentini et al.8 Hyperfractionation was employed when feasible for the patient.
Plan optimization was performed using Eclipse (Varian Medical Systems, Palo Alto, CA) and Raystation (RaySearch Laboratories, Stockholm, Sweden). All patients were treated with PBS-PT, typically with 2 lateral fields with single-field optimization technique, with some cases using a third field and/or multiple-field optimization. Opposed lateral fields, rather than posterior oblique fields, were used in many cases due to relative biological effectiveness (RBE) uncertainty at the end range, because this configuration limits overlap of end-ranging segments of the beams into previously irradiated bladder as well as bowel anterior to the CTV. Furthermore, using PBS-PT, the anterior edge of the field can be shaped and modulated off of bladder and bowel with opposed lateral fields, in contrast to the same arrangement using photon-based 3-dimensional conformal RT, where this is not possible.
When using a multiple field optimization technique, air in the bowel was accounted for using a density override algorithm. Quality assurance CT images were obtained during the course of therapy, with frequency depending on the particular case and clinical discretion. Dose constraints for the bladder and bowel entailed keeping maximum doses of approximately 90% of the prescription dose, which itself depended on prior radiation dose and time interval. In all cases, these constraints on the bladder and bowel structures were prioritized over full prescription isodose coverage of the anterior target volume. A representative plan is shown in Figure 1.Figure 1 Example pencil beam scanning proton therapy plan with axial, coronal, and sagittal views with corresponding dose–volume histogram. The patient was simulated prone, dose was prescribed via a simultaneous integrated boost with clinical target volume 1 (blue; gross target volume with 2-2.5 cm craniocaudal expansion, laterally to pelvic sidewalls and posteriorly to sacrum) receiving 4000 cGy in 100 cGy/fraction and clinical target volume 2 (red; gross target volume + 1.0 cm isotropic expansion) receiving 4800 cGy in 120 cGy/fraction. Proton planning target volumes were generated based on setup and range uncertainty. Two lateral beams using a multiple-field optimization technique were used. Bladder (yellow), large bowel (brown), small bowel (green), right femoral head (turquoise), and left femoral head (fuschia). (A color version of this figure is available at https://doi.org/10.1016/j.adro.2020.10.008.)
Statistics
Efficacy outcomes included local progression (LP), progression-free survival (PFS), and overall survival (OS). LP was calculated from completion of reirradiation to time of local failure by pathologic or radiologic confirmation. Patients who did not experience LP were censored at the time of the last follow-up visit. PFS was calculated from completion of reirradiation to the date of any progression or death, irrespective of the cause. OS was calculated from completion of reirradiation to the date of death, irrespective of the cause. The vital status of patients was checked using medical record/obituary documentation, and OS was censored on the date of the last documentation confirming living status in patients still alive on that date.
Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 5.0. Acute toxicity was assessed using provider documentation from weekly on-treatment visits. Late toxicity was defined as symptoms attributable to RT persisting or occurring >3 months after completion of reirradiation. All clinical outcomes were estimated using the Kaplan-Meier method. A univariable Cox proportional hazards model was used to model the relationship between GTV and outcome. A P value of <.05 was considered statistically significant. All analyses were completed using SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY).
Patient, disease, and treatment characteristics
Patient, disease, and treatment characteristics are summarized in Table 1. Twenty-eight patients (median follow-up 28.6 months; range, 25.3-31.9 months) received PBS-PT reirradiation from 2016 to 2019. Of these, 18 patients (64.3%) had recurrent RC (median prior dose: 54.0 Gy; range, 43.2-63.0 Gy) and 10 patients had de novo RC and variable prior RT (8 received full-dose external beam RT or brachytherapy for prostate cancer; 1 patient received external beam RT and brachytherapy boost for endometrial cancer; 1 patient received whole abdominal RT for ovarian cancer with a pelvic boost). The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 patients twice daily), and 24 of 28 patients (85.7%) received concurrent chemotherapy, with 18 of 28 (64.3%) receiving twice-daily oral capecitabine on days with reirradiation. Overall, 25 of 28 patients (89.3%) completed the planned course of reirradiation.Table 1 Patient and treatment characteristics (n = 28)
Characteristics n (%)
Sex
Male 19 (67.9%)
Female 9 (32.1%)
Age, y, median (range) 68 (41-87)
Follow-up, mo, median (range) 28.6 (25.3-31.9)
Recurrent rectal cancer 18 (64.3)
Prior RT dose, Gy, median (range) 54.0 (43.2-63.0)
Anatomic location of recurrence
Rectal 6 (33.3)
Presacral 11 (61.1)
Pelvic bone 1 (5.6)
Treatment for initial rectal cancer (n = 18)
Neoadjuvant conformal RT 8 (44.4)
Adjuvant conformal RT 2 (11.2)
Other 8 (44.4)
de novo rectal cancer (n = 10) 10 (35.7)
Prior pelvic RT Definitive for prostate cancer (equivalent total dose in 2 Gy fractions >70 Gy)8
Definitive for ovarian cancer1
Definitive for endometrial cancer1
Treatment before reirradiation for recurrence
Upfront surgery, n 2
Systemic therapy, n 8
Reirradiation dose, Gy, median (range) 48.0 (16.0-60.0)
Reirradiation interval, mo, median (range) 48.5 (12.7-494.8)
Concurrent chemotherapy with reirradiation 24 (85.7)
Hyperfractionated reirradiation 21 (75.0)
Completed reirradiation course 25 (89.3)
Underwent resection after reirradiation 6 (21.4)
R0 6
Gross tumor volume, cm3, median (range) 86.4 (13.6-821.8)
Abbreviation: RT = radiation therapy.
Table 2 Acute toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Grade 2, n (%) 3, n (%) 4, n (%) 5, n (%)
Gastrointestinal 4 (14.2) 2 (7.1) 0 (0.0) 0 (0.0)
Skin 4 (14.2) 1 (3.6) 0 (0.0) 0 (0.0)
Urologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Hematologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Total 8 (28.6) 3 (10.7) 0 (0.0) 0 (0.0)
Disease outcomes and toxicity
The 1-year LP, PFS, and OS rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively. The median times to LP, PFS, and OS were 23.4 months (range, 1.6-39.8 months; 95% CI, 12.9-33.9 months), 11.6 months (range, 0.6-39.8 months; 95% CI, 8.6-14.5 months), and 29.2 months (range, 1.6-45.9 months; 95% CI, 19.7-38.8 months), respectively (Fig 2A-C). In a univariable Cox proportional hazards model with GTV (cm3) included as a continuous variable, increasing GTV was highly statistically significantly associated with LP (hazard ratio [HR]: 1.005; 95% CI, 1.002-1.008; P = .003) and PFS (HR: 1.004; 95% CI, 1.002-1.006; P = .001), but not with OS (HR: 1.002; 95% CI, 1.000-1.005; P = .102). The 1-year LP rate for recurrent versus de novo RC was significantly different at 52.3% (95% CI, 23.9%-80.1%) and 0% (P = .002), respectively. The 1-year OS rate for recurrent versus de novo RC was 72.2% (95% CI, 51.4%-93.0%) and 100% (P = .058), respectively.Figure 2 Kaplan-Meier curves for (A) local progression, (B) progression-free survival, (C) overall survival, and (D) late grade >3 toxicities for all patients (n = 28).
Six patients (21.4%) underwent surgical resection after reirradiation, with further breakdown by de novo RC and recurrent RC patients being 3 of 10 (30%) and 3 of 18 (16.7%), respectively. All resections resulted in R0 resection. Of these patients, 4 eventually experienced LP (3 with recurrent RC), with a 1-year LP rate of resected patients of 16.7% versus 40% for those who did not receive resection (P = .786). The 1-year OS rate for patients undergoing and not undergoing resection was 100% and 76.8%, respectively; this difference was statistically significant (P = .027).
Acute toxicities are listed in Table 2. The 1-year rate of late grade >3 toxicities (G3+ Tox) was 13.3% in the Kaplan-Meier analysis (Fig 2D). Six late G3+ Tox occurred in 4 separate patients, with no evidence of tumor recurrence at toxicity onset (summarized by patient in Table 3). Patient 1 ultimately developed grade 5 toxicity and had a history of significant late toxicity from prior whole abdominal and pelvic boost radiation for ovarian cancer in the 1970s, including baseline and longstanding radiation colitis, loss of a kidney, and cystitis. This patient developed rectal bleeding at 3 months, a rectovaginal fistula at 9 months, and ultimately a bleeding stage IV decubitus ulcer and died of presacral hemorrhage at 26 months without evidence of tumor recurrence. Patient 2 developed an enterocutaneous fistula passing through the presacral region, as well as pyelonephritis resolving with parenteral antibiotics, approximately 1 year from completion of reirradiation. The treatment course was entirely in a medical ward without stay in either intermediate or intensive care. Of note, this patient was receiving bevacizumab systemic therapy at the time of the fistula diagnosis. This patient also experienced multiple delays and breaks in the planned treatment course related to social and logistic factors. This was the only patient who experienced G3+ Tox in both the acute and late term.Table 3 Grade ≥3 late toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Patient no. Grade Toxicity Time to toxicity, mo
1 3 Rectovaginal fistula 8.5
1 5 Presacral hemorrhage 25.6
2 3 Enterocutaneous fistula 11
2 3 Pyelonephritis (resolved) 11
3 3 Presacral abscess/rectovaginal fistula 31
4 3 Colovaginal fistula (improved) 12
Six grade 3+ events were observed in 4 patients.
Patient 3 developed a presacral abscess and rectovaginal fistula approximately 2.5 years from completion of reirradiation. The site of local recurrence, which was treated with reirradiation, involved the vaginal fornices. Patient 4 had a long history of presacral abscess and transvaginal drainage procedures before reirradiation and developed increased vaginal discharge approximately 1 year from completion of reirradiation. The patient received a diagnosis of colovaginal fistula, which improved with percutaneous drainage.
Discussion
This is the largest report with the longest median follow-up to date of reirradiation for RC using PT. Additionally, all patients in our cohort received PBS-PT, making this the first such report. In contrast with prior studies, this study also included patients receiving prior pelvic RT for other malignancies.
Focusing on disease outcomes and restricting the analysis to recurrent RC only, we noted 1-year LP and OS rates of 52.3% and 71.4% in the present study versus 1-year local control and OS of 76.3% and 87.5% in the historical study by Valentini et al.8 Considerable heterogeneity in this retrospective cohort, particularly with respect to prior therapies (namely surgical resection) may account for the differences in these outcomes. Of the 10 patients who experienced local failure, 2 had multiply recurrent disease before reirradiation, 1 did not receive surgical resection after initial conformal RT, and 3 had received systemic therapy for local recurrence before being referred for reirradiation. All of these circumstances are mutually exclusive. As such, these patients had disease and treatment factors putting them at a high baseline risk and would also not have been eligible for a prospective study such as that by Valentini et al.8 Patients with de novo RC with previously irradiated pelvis show 2 failures as of the present, with 1 of these occurring in a patient who did not receive resection, and appear comparable with what would be expected without a history of pelvic RT. Nevertheless, the majority of patients in this study received hyperfractionated reirradiation with concurrent chemotherapy, reflecting an overall general consistency with reirradiation delivery technique.
Rates of acute grade 3 toxicity were low at 10.7%, and all but 3 patients completed the planned course of reirradiation (only 1 case was toxicity-mediated). These are comparable to the rate reported by Valentini et al (5.1%),8 who only accounted for gastrointestinal toxicity. Furthermore, relative to the study by Valentini et al,8 the median reirradiation dose in the present series was higher (48 vs 40.8 Gy). In addition, all patients in the trial by Valentini et al8 were treated with hyperfractionated RT compared with 75% of patients in our cohort. This supports tolerability of hyperfractionated reirradiation and concurrent chemotherapy with PBS-PT and is corroborated by the existing literature on PT for reirradiation for RC.
Four patients experienced late G3+ Tox, including 1 grade 5 toxicity. Overall, the rate of G3+ Tox at 1 year estimated with the Kaplan-Meier method was low at 13.3% (95% CI, 0.0%-27.7%). Of note, in 2 of these affected patients, a dose of 48 Gy in 1.2 Gy fractions was delivered, and in another patient 54 Gy in 1.5 Gy fractions was used, which represented the upper limit of the total dose in those patients who received a hyperfractionated course in this cohort. Additionally, as noted in the results section, 1 patient who experienced a grade 3 fistula had been undergoing bevacizumab therapy, another had a long history of presacral abscess and transvaginal procedures, and the patient with grade 5 toxicity had a history of significant toxicity with prior RT.
Comparing these late G3+ Tox with those reported by Valentini et al is difficult because late toxicities were not graded (although 1 was noted to require surgical intervention, and no treatment-related death was reported). However, the late G3+ Tox rates in the present report are comparable with prior published experiences of passive scatter PT reirradiation, although with a longer median follow-up of 28.6 months (range, 25.3-31.9 months). In the first known report using PT for reirradiation, 7 patients were treated using a double-scatter proton technique, and the median dose was 6120 cGy (RBE; 4500-6480 cGy) in conventional fractionation, with 6 patients receiving concurrent chemotherapy.15 With a median follow-up of 14 months, there were 3 acute grade 3 toxicities (abdominal pain, diarrhea) probably related to reirradiation, and 3 late grade 4 toxicities (2 bowel obstruction, 1 entero-vaginal fistula) possibly related to reirradiation.
Another experience evaluated 15 patients, also treated with passive-scatter technique, but with a 1.5 Gy accelerated fractionated course to a total dose of 39 to 45 Gy (RBE), and with all patients receiving concurrent chemotherapy.16 With a median follow-up of 14 months, 1 acute grade 3 toxicity (lymphopenia) and 2 late grade 3 toxicities (dysuria, rectal bleeding) were noted. Given the sample sizes of these and the present experiences and differing methods of treatment delivery, it is difficult to elucidate a dose-response relationship with respect to acute or late toxicity. Furthermore, our study solely implemented PBS-PT, thus making it more difficult to directly compare existing data largely gathered using passive-scatter techniques.
Six patients (21.4%) in our series received surgical resection after reirradiation, a lower proportion than in prior experiences (50.8% in the study by Valentini et al8), reflecting the high-risk patient cohort in our report. However, all 6 resulted in an R0 resection. Although the sample sizes are small for comparison, there was a strong trend toward superior OS in patients receiving resection (P = .107). This is consistent with prior reirradiation studies and likely multifactorial.
Other limitations to our study are primarily related to its retrospective nature. First and perhaps most important, there is selection bias inherent with any retrospective report and variable prior treatments. In this cohort, different RT regimens were used, inclusive of both conventionally fractionated and hyperfractionated courses. Second, the assessment of late toxicities was dependent on assessments that were not standardized, with imaging ranging from pelvic magnetic resonance to positron emission tomography/CT to CT.
Maturation and expansion of these data will better establish disease and toxicity outcomes in these patients. Longer follow-up and further accrual may help establish a dose–response relationship with respect to disease outcomes as well as the development of late toxicity. Moreover, such a relationship may be highly dependent on whether disease is recurrent or de novo.
Conclusions
The low acute toxicity rates, rare treatment interruption, and acceptable late toxicity reported here thus far support PBS-PT as an option for this high-risk patient population. Further follow-up and prospective studies, as those completed in the 3-dimensional conformal RT era, evaluating the use of PT for reirradiation for RC will help further clarify disease outcomes and toxicity profiles.
Sources of support: This work had no specific funding.
Disclosures: Dr Kaiser reports personal fees from Varian Medical Systems outside of the submitted work. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33490730 | 18,926,433 | 2021 |
What was the outcome of reaction 'Female genital tract fistula'? | Reirradiation for Rectal Cancer Using Pencil Beam Scanning Proton Therapy: A Single Institutional Experience.
Reirradiation for rectal cancer (RC) after prior pelvic radiation therapy (RT) has been shown to be safe and effective. However, limited data exist for proton therapy (PT), including pencil beam scanning proton therapy (PBS-PT). We hypothesize that PT is safe and feasible for re-treatment and may allow for decreased toxicity and treatment escalation.
A single-institution, retrospective, institutional review board-approved analysis of all patients with RC and prior pelvic RT receiving PBS-PT reirradiation was performed. Data on patient and treatment characteristics and outcomes were collected. Local progression, progression-free survival, overall survival, and late grade >3 toxicity were estimated using the Kaplan-Meier method.
Twenty-eight patients (median follow-up: 28.6 months) received PBS-PT reirradiation between 2016 and 2019, including 18 patients with recurrent RC (median prior dose: 54.0 Gy) and 10 patients with de novo RC and variable prior RT. The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 twice daily), and 24 of 28 patients received concurrent chemotherapy. Six underwent surgical resection. Three (10.7%) experienced grade 3 acute toxicities, and 1 did not complete RT owing to toxicity. Four (14.2%) had late grade <3 toxicity, including 1 grade 5 toxicity in a patient with a prior RT-related injury. The 1-year local progression, progression-free survival, and overall survival rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively.
This is the largest series using PT for reirradiation for RC and the first study using PBS-PT. Low acute toxicity rates and acceptable late toxicity support PBS-PT as an option for this high-risk patient population, with a need for continued follow-up.
Introduction
Rectal cancer (RC) is a common malignancy, with approximately 40,000 new cases per year in the United States and 800,000 worldwide. Therapy for locally advanced disease often consists of neoadjuvant concurrent chemotherapy and radiation, followed by surgical resection with total mesorectal excision—a paradigm that has improved local control, survival, and treatment-related toxicities.1, 2, 3 In the modern era, local relapse affects approximately 7% of patients in the long term and is associated with pain, obstruction, bleeding, discharge, and change in stool habits.4
Reirradiation for RC may be implemented in the treatment of locally recurrent RCs and de novo RC with prior radiation for other pelvic malignancy. It may be administered either as part of a curative or palliative regimen, with patients eligible for and receiving curative resection having the most favorable survival outcomes.5,6 However, it presents risk of late complications given the radiation sensitivity of nearby organs and tissues of the abdomen and pelvis—in particular, the bladder, bowel, bone marrow, and lumbosacral plexus. This affects the approach of reirradiation in multiple ways, including treatment volumes, prescribed dose, fractionation scheme, and technique of delivery.
Numerous experiences have described disease and toxicity outcomes of reirradiation for RC, using these aforementioned modifications in treatment delivery to achieve safe and effective therapy.7 A landmark prospective study by Valentini et al demonstrated the safety and efficacy of hyperfractionated reirradiation with concurrent chemotherapy, often given neoadjuvantly.8 This study has served as a reference for both disease outcomes and treatment toxicities. Multiple retrospective studies have corroborated these findings.9, 10, 11, 12 However, to our knowledge, nearly all published studies have evaluated reirradiation using either 3-dimensional conformal radiation therapy (RT) or intensity modulated RT techniques.13,14 Literature evaluating rectal reirradiation with proton therapy (PT) is emerging and has demonstrated a significantly reduced low dose to the bowel and bone marrow, as well as clinical feasibility, safety, and efficacy—thus far with passive-scatter techniques.15,16 PBS-PT provides true intensity modulated PT; thus, we hypothesize that its use may result in improved short- and long-term toxicity profiles in the setting of reirradiation for RC. We report the disease and toxicity outcomes from a retrospective, single-institution experience using PBS-PT for reirradiation for RC.
Methods and materials
Patient selection and treatment
An institutional review board–approved retrospective chart review was completed of all patients treated with reirradiation using PBS-PT at a single institution between 2016 and 2019 for either recurrent RC or de novo RC with prior pelvic RT for another malignancy. Patient demographic information, disease characteristics, and treatment characteristics were collected. Prior RT plan reports were accessed when possible, and all PBS-PT plans underwent peer review per departmental protocol. All patients were presented at a multidisciplinary tumor board. Concurrent chemotherapy and curative-intent surgical resection were planned whenever feasible and appropriate.
Proton beam reirradiation
Patients underwent computed tomography (CT) simulation in the supine or prone position with a comfortably full bladder and vac-lok immobilization. Contouring of the target and organ-at-risk volumes was performed. Gross tumor volume (GTV) was delineated using physical examination, CT simulation, and diagnostic imaging data (positron emission tomography and/or magnetic resonance imaging). A clinical target volume (CTV) was generated by expanding the GTV by 1.5 to 3.0 cm craniocaudally, extending to the pelvic sidewall laterally, and including the presacral space posteriorly. When a boost was planned, a second smaller isotropic expansion of 0.5 to 1.5 cm was used, or simply the gross tumor without expansion. The choice of CTV expansion is based on the method outlined by Valentini et al,8 with smaller expansions on the GTV used in cases of inoperable recurrences involving the bone. Planning target volumes were generated by dosimetry, accounting for setup and proton beam range uncertainty. Earlier cases used a uniform 5 mm expansion, later transitioning to nonuniform expansions (3.5-5 mm) based on translational uncertainty, and eventually generation of a planning target volume using robust optimization algorithms. Dosing was guided by the method by Valentini et al.8 Hyperfractionation was employed when feasible for the patient.
Plan optimization was performed using Eclipse (Varian Medical Systems, Palo Alto, CA) and Raystation (RaySearch Laboratories, Stockholm, Sweden). All patients were treated with PBS-PT, typically with 2 lateral fields with single-field optimization technique, with some cases using a third field and/or multiple-field optimization. Opposed lateral fields, rather than posterior oblique fields, were used in many cases due to relative biological effectiveness (RBE) uncertainty at the end range, because this configuration limits overlap of end-ranging segments of the beams into previously irradiated bladder as well as bowel anterior to the CTV. Furthermore, using PBS-PT, the anterior edge of the field can be shaped and modulated off of bladder and bowel with opposed lateral fields, in contrast to the same arrangement using photon-based 3-dimensional conformal RT, where this is not possible.
When using a multiple field optimization technique, air in the bowel was accounted for using a density override algorithm. Quality assurance CT images were obtained during the course of therapy, with frequency depending on the particular case and clinical discretion. Dose constraints for the bladder and bowel entailed keeping maximum doses of approximately 90% of the prescription dose, which itself depended on prior radiation dose and time interval. In all cases, these constraints on the bladder and bowel structures were prioritized over full prescription isodose coverage of the anterior target volume. A representative plan is shown in Figure 1.Figure 1 Example pencil beam scanning proton therapy plan with axial, coronal, and sagittal views with corresponding dose–volume histogram. The patient was simulated prone, dose was prescribed via a simultaneous integrated boost with clinical target volume 1 (blue; gross target volume with 2-2.5 cm craniocaudal expansion, laterally to pelvic sidewalls and posteriorly to sacrum) receiving 4000 cGy in 100 cGy/fraction and clinical target volume 2 (red; gross target volume + 1.0 cm isotropic expansion) receiving 4800 cGy in 120 cGy/fraction. Proton planning target volumes were generated based on setup and range uncertainty. Two lateral beams using a multiple-field optimization technique were used. Bladder (yellow), large bowel (brown), small bowel (green), right femoral head (turquoise), and left femoral head (fuschia). (A color version of this figure is available at https://doi.org/10.1016/j.adro.2020.10.008.)
Statistics
Efficacy outcomes included local progression (LP), progression-free survival (PFS), and overall survival (OS). LP was calculated from completion of reirradiation to time of local failure by pathologic or radiologic confirmation. Patients who did not experience LP were censored at the time of the last follow-up visit. PFS was calculated from completion of reirradiation to the date of any progression or death, irrespective of the cause. OS was calculated from completion of reirradiation to the date of death, irrespective of the cause. The vital status of patients was checked using medical record/obituary documentation, and OS was censored on the date of the last documentation confirming living status in patients still alive on that date.
Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 5.0. Acute toxicity was assessed using provider documentation from weekly on-treatment visits. Late toxicity was defined as symptoms attributable to RT persisting or occurring >3 months after completion of reirradiation. All clinical outcomes were estimated using the Kaplan-Meier method. A univariable Cox proportional hazards model was used to model the relationship between GTV and outcome. A P value of <.05 was considered statistically significant. All analyses were completed using SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY).
Patient, disease, and treatment characteristics
Patient, disease, and treatment characteristics are summarized in Table 1. Twenty-eight patients (median follow-up 28.6 months; range, 25.3-31.9 months) received PBS-PT reirradiation from 2016 to 2019. Of these, 18 patients (64.3%) had recurrent RC (median prior dose: 54.0 Gy; range, 43.2-63.0 Gy) and 10 patients had de novo RC and variable prior RT (8 received full-dose external beam RT or brachytherapy for prostate cancer; 1 patient received external beam RT and brachytherapy boost for endometrial cancer; 1 patient received whole abdominal RT for ovarian cancer with a pelvic boost). The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 patients twice daily), and 24 of 28 patients (85.7%) received concurrent chemotherapy, with 18 of 28 (64.3%) receiving twice-daily oral capecitabine on days with reirradiation. Overall, 25 of 28 patients (89.3%) completed the planned course of reirradiation.Table 1 Patient and treatment characteristics (n = 28)
Characteristics n (%)
Sex
Male 19 (67.9%)
Female 9 (32.1%)
Age, y, median (range) 68 (41-87)
Follow-up, mo, median (range) 28.6 (25.3-31.9)
Recurrent rectal cancer 18 (64.3)
Prior RT dose, Gy, median (range) 54.0 (43.2-63.0)
Anatomic location of recurrence
Rectal 6 (33.3)
Presacral 11 (61.1)
Pelvic bone 1 (5.6)
Treatment for initial rectal cancer (n = 18)
Neoadjuvant conformal RT 8 (44.4)
Adjuvant conformal RT 2 (11.2)
Other 8 (44.4)
de novo rectal cancer (n = 10) 10 (35.7)
Prior pelvic RT Definitive for prostate cancer (equivalent total dose in 2 Gy fractions >70 Gy)8
Definitive for ovarian cancer1
Definitive for endometrial cancer1
Treatment before reirradiation for recurrence
Upfront surgery, n 2
Systemic therapy, n 8
Reirradiation dose, Gy, median (range) 48.0 (16.0-60.0)
Reirradiation interval, mo, median (range) 48.5 (12.7-494.8)
Concurrent chemotherapy with reirradiation 24 (85.7)
Hyperfractionated reirradiation 21 (75.0)
Completed reirradiation course 25 (89.3)
Underwent resection after reirradiation 6 (21.4)
R0 6
Gross tumor volume, cm3, median (range) 86.4 (13.6-821.8)
Abbreviation: RT = radiation therapy.
Table 2 Acute toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Grade 2, n (%) 3, n (%) 4, n (%) 5, n (%)
Gastrointestinal 4 (14.2) 2 (7.1) 0 (0.0) 0 (0.0)
Skin 4 (14.2) 1 (3.6) 0 (0.0) 0 (0.0)
Urologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Hematologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Total 8 (28.6) 3 (10.7) 0 (0.0) 0 (0.0)
Disease outcomes and toxicity
The 1-year LP, PFS, and OS rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively. The median times to LP, PFS, and OS were 23.4 months (range, 1.6-39.8 months; 95% CI, 12.9-33.9 months), 11.6 months (range, 0.6-39.8 months; 95% CI, 8.6-14.5 months), and 29.2 months (range, 1.6-45.9 months; 95% CI, 19.7-38.8 months), respectively (Fig 2A-C). In a univariable Cox proportional hazards model with GTV (cm3) included as a continuous variable, increasing GTV was highly statistically significantly associated with LP (hazard ratio [HR]: 1.005; 95% CI, 1.002-1.008; P = .003) and PFS (HR: 1.004; 95% CI, 1.002-1.006; P = .001), but not with OS (HR: 1.002; 95% CI, 1.000-1.005; P = .102). The 1-year LP rate for recurrent versus de novo RC was significantly different at 52.3% (95% CI, 23.9%-80.1%) and 0% (P = .002), respectively. The 1-year OS rate for recurrent versus de novo RC was 72.2% (95% CI, 51.4%-93.0%) and 100% (P = .058), respectively.Figure 2 Kaplan-Meier curves for (A) local progression, (B) progression-free survival, (C) overall survival, and (D) late grade >3 toxicities for all patients (n = 28).
Six patients (21.4%) underwent surgical resection after reirradiation, with further breakdown by de novo RC and recurrent RC patients being 3 of 10 (30%) and 3 of 18 (16.7%), respectively. All resections resulted in R0 resection. Of these patients, 4 eventually experienced LP (3 with recurrent RC), with a 1-year LP rate of resected patients of 16.7% versus 40% for those who did not receive resection (P = .786). The 1-year OS rate for patients undergoing and not undergoing resection was 100% and 76.8%, respectively; this difference was statistically significant (P = .027).
Acute toxicities are listed in Table 2. The 1-year rate of late grade >3 toxicities (G3+ Tox) was 13.3% in the Kaplan-Meier analysis (Fig 2D). Six late G3+ Tox occurred in 4 separate patients, with no evidence of tumor recurrence at toxicity onset (summarized by patient in Table 3). Patient 1 ultimately developed grade 5 toxicity and had a history of significant late toxicity from prior whole abdominal and pelvic boost radiation for ovarian cancer in the 1970s, including baseline and longstanding radiation colitis, loss of a kidney, and cystitis. This patient developed rectal bleeding at 3 months, a rectovaginal fistula at 9 months, and ultimately a bleeding stage IV decubitus ulcer and died of presacral hemorrhage at 26 months without evidence of tumor recurrence. Patient 2 developed an enterocutaneous fistula passing through the presacral region, as well as pyelonephritis resolving with parenteral antibiotics, approximately 1 year from completion of reirradiation. The treatment course was entirely in a medical ward without stay in either intermediate or intensive care. Of note, this patient was receiving bevacizumab systemic therapy at the time of the fistula diagnosis. This patient also experienced multiple delays and breaks in the planned treatment course related to social and logistic factors. This was the only patient who experienced G3+ Tox in both the acute and late term.Table 3 Grade ≥3 late toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Patient no. Grade Toxicity Time to toxicity, mo
1 3 Rectovaginal fistula 8.5
1 5 Presacral hemorrhage 25.6
2 3 Enterocutaneous fistula 11
2 3 Pyelonephritis (resolved) 11
3 3 Presacral abscess/rectovaginal fistula 31
4 3 Colovaginal fistula (improved) 12
Six grade 3+ events were observed in 4 patients.
Patient 3 developed a presacral abscess and rectovaginal fistula approximately 2.5 years from completion of reirradiation. The site of local recurrence, which was treated with reirradiation, involved the vaginal fornices. Patient 4 had a long history of presacral abscess and transvaginal drainage procedures before reirradiation and developed increased vaginal discharge approximately 1 year from completion of reirradiation. The patient received a diagnosis of colovaginal fistula, which improved with percutaneous drainage.
Discussion
This is the largest report with the longest median follow-up to date of reirradiation for RC using PT. Additionally, all patients in our cohort received PBS-PT, making this the first such report. In contrast with prior studies, this study also included patients receiving prior pelvic RT for other malignancies.
Focusing on disease outcomes and restricting the analysis to recurrent RC only, we noted 1-year LP and OS rates of 52.3% and 71.4% in the present study versus 1-year local control and OS of 76.3% and 87.5% in the historical study by Valentini et al.8 Considerable heterogeneity in this retrospective cohort, particularly with respect to prior therapies (namely surgical resection) may account for the differences in these outcomes. Of the 10 patients who experienced local failure, 2 had multiply recurrent disease before reirradiation, 1 did not receive surgical resection after initial conformal RT, and 3 had received systemic therapy for local recurrence before being referred for reirradiation. All of these circumstances are mutually exclusive. As such, these patients had disease and treatment factors putting them at a high baseline risk and would also not have been eligible for a prospective study such as that by Valentini et al.8 Patients with de novo RC with previously irradiated pelvis show 2 failures as of the present, with 1 of these occurring in a patient who did not receive resection, and appear comparable with what would be expected without a history of pelvic RT. Nevertheless, the majority of patients in this study received hyperfractionated reirradiation with concurrent chemotherapy, reflecting an overall general consistency with reirradiation delivery technique.
Rates of acute grade 3 toxicity were low at 10.7%, and all but 3 patients completed the planned course of reirradiation (only 1 case was toxicity-mediated). These are comparable to the rate reported by Valentini et al (5.1%),8 who only accounted for gastrointestinal toxicity. Furthermore, relative to the study by Valentini et al,8 the median reirradiation dose in the present series was higher (48 vs 40.8 Gy). In addition, all patients in the trial by Valentini et al8 were treated with hyperfractionated RT compared with 75% of patients in our cohort. This supports tolerability of hyperfractionated reirradiation and concurrent chemotherapy with PBS-PT and is corroborated by the existing literature on PT for reirradiation for RC.
Four patients experienced late G3+ Tox, including 1 grade 5 toxicity. Overall, the rate of G3+ Tox at 1 year estimated with the Kaplan-Meier method was low at 13.3% (95% CI, 0.0%-27.7%). Of note, in 2 of these affected patients, a dose of 48 Gy in 1.2 Gy fractions was delivered, and in another patient 54 Gy in 1.5 Gy fractions was used, which represented the upper limit of the total dose in those patients who received a hyperfractionated course in this cohort. Additionally, as noted in the results section, 1 patient who experienced a grade 3 fistula had been undergoing bevacizumab therapy, another had a long history of presacral abscess and transvaginal procedures, and the patient with grade 5 toxicity had a history of significant toxicity with prior RT.
Comparing these late G3+ Tox with those reported by Valentini et al is difficult because late toxicities were not graded (although 1 was noted to require surgical intervention, and no treatment-related death was reported). However, the late G3+ Tox rates in the present report are comparable with prior published experiences of passive scatter PT reirradiation, although with a longer median follow-up of 28.6 months (range, 25.3-31.9 months). In the first known report using PT for reirradiation, 7 patients were treated using a double-scatter proton technique, and the median dose was 6120 cGy (RBE; 4500-6480 cGy) in conventional fractionation, with 6 patients receiving concurrent chemotherapy.15 With a median follow-up of 14 months, there were 3 acute grade 3 toxicities (abdominal pain, diarrhea) probably related to reirradiation, and 3 late grade 4 toxicities (2 bowel obstruction, 1 entero-vaginal fistula) possibly related to reirradiation.
Another experience evaluated 15 patients, also treated with passive-scatter technique, but with a 1.5 Gy accelerated fractionated course to a total dose of 39 to 45 Gy (RBE), and with all patients receiving concurrent chemotherapy.16 With a median follow-up of 14 months, 1 acute grade 3 toxicity (lymphopenia) and 2 late grade 3 toxicities (dysuria, rectal bleeding) were noted. Given the sample sizes of these and the present experiences and differing methods of treatment delivery, it is difficult to elucidate a dose-response relationship with respect to acute or late toxicity. Furthermore, our study solely implemented PBS-PT, thus making it more difficult to directly compare existing data largely gathered using passive-scatter techniques.
Six patients (21.4%) in our series received surgical resection after reirradiation, a lower proportion than in prior experiences (50.8% in the study by Valentini et al8), reflecting the high-risk patient cohort in our report. However, all 6 resulted in an R0 resection. Although the sample sizes are small for comparison, there was a strong trend toward superior OS in patients receiving resection (P = .107). This is consistent with prior reirradiation studies and likely multifactorial.
Other limitations to our study are primarily related to its retrospective nature. First and perhaps most important, there is selection bias inherent with any retrospective report and variable prior treatments. In this cohort, different RT regimens were used, inclusive of both conventionally fractionated and hyperfractionated courses. Second, the assessment of late toxicities was dependent on assessments that were not standardized, with imaging ranging from pelvic magnetic resonance to positron emission tomography/CT to CT.
Maturation and expansion of these data will better establish disease and toxicity outcomes in these patients. Longer follow-up and further accrual may help establish a dose–response relationship with respect to disease outcomes as well as the development of late toxicity. Moreover, such a relationship may be highly dependent on whether disease is recurrent or de novo.
Conclusions
The low acute toxicity rates, rare treatment interruption, and acceptable late toxicity reported here thus far support PBS-PT as an option for this high-risk patient population. Further follow-up and prospective studies, as those completed in the 3-dimensional conformal RT era, evaluating the use of PT for reirradiation for RC will help further clarify disease outcomes and toxicity profiles.
Sources of support: This work had no specific funding.
Disclosures: Dr Kaiser reports personal fees from Varian Medical Systems outside of the submitted work. | Recovering | ReactionOutcome | CC BY-NC-ND | 33490730 | 18,926,433 | 2021 |
What was the outcome of reaction 'Pelvic haemorrhage'? | Reirradiation for Rectal Cancer Using Pencil Beam Scanning Proton Therapy: A Single Institutional Experience.
Reirradiation for rectal cancer (RC) after prior pelvic radiation therapy (RT) has been shown to be safe and effective. However, limited data exist for proton therapy (PT), including pencil beam scanning proton therapy (PBS-PT). We hypothesize that PT is safe and feasible for re-treatment and may allow for decreased toxicity and treatment escalation.
A single-institution, retrospective, institutional review board-approved analysis of all patients with RC and prior pelvic RT receiving PBS-PT reirradiation was performed. Data on patient and treatment characteristics and outcomes were collected. Local progression, progression-free survival, overall survival, and late grade >3 toxicity were estimated using the Kaplan-Meier method.
Twenty-eight patients (median follow-up: 28.6 months) received PBS-PT reirradiation between 2016 and 2019, including 18 patients with recurrent RC (median prior dose: 54.0 Gy) and 10 patients with de novo RC and variable prior RT. The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 twice daily), and 24 of 28 patients received concurrent chemotherapy. Six underwent surgical resection. Three (10.7%) experienced grade 3 acute toxicities, and 1 did not complete RT owing to toxicity. Four (14.2%) had late grade <3 toxicity, including 1 grade 5 toxicity in a patient with a prior RT-related injury. The 1-year local progression, progression-free survival, and overall survival rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively.
This is the largest series using PT for reirradiation for RC and the first study using PBS-PT. Low acute toxicity rates and acceptable late toxicity support PBS-PT as an option for this high-risk patient population, with a need for continued follow-up.
Introduction
Rectal cancer (RC) is a common malignancy, with approximately 40,000 new cases per year in the United States and 800,000 worldwide. Therapy for locally advanced disease often consists of neoadjuvant concurrent chemotherapy and radiation, followed by surgical resection with total mesorectal excision—a paradigm that has improved local control, survival, and treatment-related toxicities.1, 2, 3 In the modern era, local relapse affects approximately 7% of patients in the long term and is associated with pain, obstruction, bleeding, discharge, and change in stool habits.4
Reirradiation for RC may be implemented in the treatment of locally recurrent RCs and de novo RC with prior radiation for other pelvic malignancy. It may be administered either as part of a curative or palliative regimen, with patients eligible for and receiving curative resection having the most favorable survival outcomes.5,6 However, it presents risk of late complications given the radiation sensitivity of nearby organs and tissues of the abdomen and pelvis—in particular, the bladder, bowel, bone marrow, and lumbosacral plexus. This affects the approach of reirradiation in multiple ways, including treatment volumes, prescribed dose, fractionation scheme, and technique of delivery.
Numerous experiences have described disease and toxicity outcomes of reirradiation for RC, using these aforementioned modifications in treatment delivery to achieve safe and effective therapy.7 A landmark prospective study by Valentini et al demonstrated the safety and efficacy of hyperfractionated reirradiation with concurrent chemotherapy, often given neoadjuvantly.8 This study has served as a reference for both disease outcomes and treatment toxicities. Multiple retrospective studies have corroborated these findings.9, 10, 11, 12 However, to our knowledge, nearly all published studies have evaluated reirradiation using either 3-dimensional conformal radiation therapy (RT) or intensity modulated RT techniques.13,14 Literature evaluating rectal reirradiation with proton therapy (PT) is emerging and has demonstrated a significantly reduced low dose to the bowel and bone marrow, as well as clinical feasibility, safety, and efficacy—thus far with passive-scatter techniques.15,16 PBS-PT provides true intensity modulated PT; thus, we hypothesize that its use may result in improved short- and long-term toxicity profiles in the setting of reirradiation for RC. We report the disease and toxicity outcomes from a retrospective, single-institution experience using PBS-PT for reirradiation for RC.
Methods and materials
Patient selection and treatment
An institutional review board–approved retrospective chart review was completed of all patients treated with reirradiation using PBS-PT at a single institution between 2016 and 2019 for either recurrent RC or de novo RC with prior pelvic RT for another malignancy. Patient demographic information, disease characteristics, and treatment characteristics were collected. Prior RT plan reports were accessed when possible, and all PBS-PT plans underwent peer review per departmental protocol. All patients were presented at a multidisciplinary tumor board. Concurrent chemotherapy and curative-intent surgical resection were planned whenever feasible and appropriate.
Proton beam reirradiation
Patients underwent computed tomography (CT) simulation in the supine or prone position with a comfortably full bladder and vac-lok immobilization. Contouring of the target and organ-at-risk volumes was performed. Gross tumor volume (GTV) was delineated using physical examination, CT simulation, and diagnostic imaging data (positron emission tomography and/or magnetic resonance imaging). A clinical target volume (CTV) was generated by expanding the GTV by 1.5 to 3.0 cm craniocaudally, extending to the pelvic sidewall laterally, and including the presacral space posteriorly. When a boost was planned, a second smaller isotropic expansion of 0.5 to 1.5 cm was used, or simply the gross tumor without expansion. The choice of CTV expansion is based on the method outlined by Valentini et al,8 with smaller expansions on the GTV used in cases of inoperable recurrences involving the bone. Planning target volumes were generated by dosimetry, accounting for setup and proton beam range uncertainty. Earlier cases used a uniform 5 mm expansion, later transitioning to nonuniform expansions (3.5-5 mm) based on translational uncertainty, and eventually generation of a planning target volume using robust optimization algorithms. Dosing was guided by the method by Valentini et al.8 Hyperfractionation was employed when feasible for the patient.
Plan optimization was performed using Eclipse (Varian Medical Systems, Palo Alto, CA) and Raystation (RaySearch Laboratories, Stockholm, Sweden). All patients were treated with PBS-PT, typically with 2 lateral fields with single-field optimization technique, with some cases using a third field and/or multiple-field optimization. Opposed lateral fields, rather than posterior oblique fields, were used in many cases due to relative biological effectiveness (RBE) uncertainty at the end range, because this configuration limits overlap of end-ranging segments of the beams into previously irradiated bladder as well as bowel anterior to the CTV. Furthermore, using PBS-PT, the anterior edge of the field can be shaped and modulated off of bladder and bowel with opposed lateral fields, in contrast to the same arrangement using photon-based 3-dimensional conformal RT, where this is not possible.
When using a multiple field optimization technique, air in the bowel was accounted for using a density override algorithm. Quality assurance CT images were obtained during the course of therapy, with frequency depending on the particular case and clinical discretion. Dose constraints for the bladder and bowel entailed keeping maximum doses of approximately 90% of the prescription dose, which itself depended on prior radiation dose and time interval. In all cases, these constraints on the bladder and bowel structures were prioritized over full prescription isodose coverage of the anterior target volume. A representative plan is shown in Figure 1.Figure 1 Example pencil beam scanning proton therapy plan with axial, coronal, and sagittal views with corresponding dose–volume histogram. The patient was simulated prone, dose was prescribed via a simultaneous integrated boost with clinical target volume 1 (blue; gross target volume with 2-2.5 cm craniocaudal expansion, laterally to pelvic sidewalls and posteriorly to sacrum) receiving 4000 cGy in 100 cGy/fraction and clinical target volume 2 (red; gross target volume + 1.0 cm isotropic expansion) receiving 4800 cGy in 120 cGy/fraction. Proton planning target volumes were generated based on setup and range uncertainty. Two lateral beams using a multiple-field optimization technique were used. Bladder (yellow), large bowel (brown), small bowel (green), right femoral head (turquoise), and left femoral head (fuschia). (A color version of this figure is available at https://doi.org/10.1016/j.adro.2020.10.008.)
Statistics
Efficacy outcomes included local progression (LP), progression-free survival (PFS), and overall survival (OS). LP was calculated from completion of reirradiation to time of local failure by pathologic or radiologic confirmation. Patients who did not experience LP were censored at the time of the last follow-up visit. PFS was calculated from completion of reirradiation to the date of any progression or death, irrespective of the cause. OS was calculated from completion of reirradiation to the date of death, irrespective of the cause. The vital status of patients was checked using medical record/obituary documentation, and OS was censored on the date of the last documentation confirming living status in patients still alive on that date.
Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 5.0. Acute toxicity was assessed using provider documentation from weekly on-treatment visits. Late toxicity was defined as symptoms attributable to RT persisting or occurring >3 months after completion of reirradiation. All clinical outcomes were estimated using the Kaplan-Meier method. A univariable Cox proportional hazards model was used to model the relationship between GTV and outcome. A P value of <.05 was considered statistically significant. All analyses were completed using SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY).
Patient, disease, and treatment characteristics
Patient, disease, and treatment characteristics are summarized in Table 1. Twenty-eight patients (median follow-up 28.6 months; range, 25.3-31.9 months) received PBS-PT reirradiation from 2016 to 2019. Of these, 18 patients (64.3%) had recurrent RC (median prior dose: 54.0 Gy; range, 43.2-63.0 Gy) and 10 patients had de novo RC and variable prior RT (8 received full-dose external beam RT or brachytherapy for prostate cancer; 1 patient received external beam RT and brachytherapy boost for endometrial cancer; 1 patient received whole abdominal RT for ovarian cancer with a pelvic boost). The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 patients twice daily), and 24 of 28 patients (85.7%) received concurrent chemotherapy, with 18 of 28 (64.3%) receiving twice-daily oral capecitabine on days with reirradiation. Overall, 25 of 28 patients (89.3%) completed the planned course of reirradiation.Table 1 Patient and treatment characteristics (n = 28)
Characteristics n (%)
Sex
Male 19 (67.9%)
Female 9 (32.1%)
Age, y, median (range) 68 (41-87)
Follow-up, mo, median (range) 28.6 (25.3-31.9)
Recurrent rectal cancer 18 (64.3)
Prior RT dose, Gy, median (range) 54.0 (43.2-63.0)
Anatomic location of recurrence
Rectal 6 (33.3)
Presacral 11 (61.1)
Pelvic bone 1 (5.6)
Treatment for initial rectal cancer (n = 18)
Neoadjuvant conformal RT 8 (44.4)
Adjuvant conformal RT 2 (11.2)
Other 8 (44.4)
de novo rectal cancer (n = 10) 10 (35.7)
Prior pelvic RT Definitive for prostate cancer (equivalent total dose in 2 Gy fractions >70 Gy)8
Definitive for ovarian cancer1
Definitive for endometrial cancer1
Treatment before reirradiation for recurrence
Upfront surgery, n 2
Systemic therapy, n 8
Reirradiation dose, Gy, median (range) 48.0 (16.0-60.0)
Reirradiation interval, mo, median (range) 48.5 (12.7-494.8)
Concurrent chemotherapy with reirradiation 24 (85.7)
Hyperfractionated reirradiation 21 (75.0)
Completed reirradiation course 25 (89.3)
Underwent resection after reirradiation 6 (21.4)
R0 6
Gross tumor volume, cm3, median (range) 86.4 (13.6-821.8)
Abbreviation: RT = radiation therapy.
Table 2 Acute toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Grade 2, n (%) 3, n (%) 4, n (%) 5, n (%)
Gastrointestinal 4 (14.2) 2 (7.1) 0 (0.0) 0 (0.0)
Skin 4 (14.2) 1 (3.6) 0 (0.0) 0 (0.0)
Urologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Hematologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Total 8 (28.6) 3 (10.7) 0 (0.0) 0 (0.0)
Disease outcomes and toxicity
The 1-year LP, PFS, and OS rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively. The median times to LP, PFS, and OS were 23.4 months (range, 1.6-39.8 months; 95% CI, 12.9-33.9 months), 11.6 months (range, 0.6-39.8 months; 95% CI, 8.6-14.5 months), and 29.2 months (range, 1.6-45.9 months; 95% CI, 19.7-38.8 months), respectively (Fig 2A-C). In a univariable Cox proportional hazards model with GTV (cm3) included as a continuous variable, increasing GTV was highly statistically significantly associated with LP (hazard ratio [HR]: 1.005; 95% CI, 1.002-1.008; P = .003) and PFS (HR: 1.004; 95% CI, 1.002-1.006; P = .001), but not with OS (HR: 1.002; 95% CI, 1.000-1.005; P = .102). The 1-year LP rate for recurrent versus de novo RC was significantly different at 52.3% (95% CI, 23.9%-80.1%) and 0% (P = .002), respectively. The 1-year OS rate for recurrent versus de novo RC was 72.2% (95% CI, 51.4%-93.0%) and 100% (P = .058), respectively.Figure 2 Kaplan-Meier curves for (A) local progression, (B) progression-free survival, (C) overall survival, and (D) late grade >3 toxicities for all patients (n = 28).
Six patients (21.4%) underwent surgical resection after reirradiation, with further breakdown by de novo RC and recurrent RC patients being 3 of 10 (30%) and 3 of 18 (16.7%), respectively. All resections resulted in R0 resection. Of these patients, 4 eventually experienced LP (3 with recurrent RC), with a 1-year LP rate of resected patients of 16.7% versus 40% for those who did not receive resection (P = .786). The 1-year OS rate for patients undergoing and not undergoing resection was 100% and 76.8%, respectively; this difference was statistically significant (P = .027).
Acute toxicities are listed in Table 2. The 1-year rate of late grade >3 toxicities (G3+ Tox) was 13.3% in the Kaplan-Meier analysis (Fig 2D). Six late G3+ Tox occurred in 4 separate patients, with no evidence of tumor recurrence at toxicity onset (summarized by patient in Table 3). Patient 1 ultimately developed grade 5 toxicity and had a history of significant late toxicity from prior whole abdominal and pelvic boost radiation for ovarian cancer in the 1970s, including baseline and longstanding radiation colitis, loss of a kidney, and cystitis. This patient developed rectal bleeding at 3 months, a rectovaginal fistula at 9 months, and ultimately a bleeding stage IV decubitus ulcer and died of presacral hemorrhage at 26 months without evidence of tumor recurrence. Patient 2 developed an enterocutaneous fistula passing through the presacral region, as well as pyelonephritis resolving with parenteral antibiotics, approximately 1 year from completion of reirradiation. The treatment course was entirely in a medical ward without stay in either intermediate or intensive care. Of note, this patient was receiving bevacizumab systemic therapy at the time of the fistula diagnosis. This patient also experienced multiple delays and breaks in the planned treatment course related to social and logistic factors. This was the only patient who experienced G3+ Tox in both the acute and late term.Table 3 Grade ≥3 late toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Patient no. Grade Toxicity Time to toxicity, mo
1 3 Rectovaginal fistula 8.5
1 5 Presacral hemorrhage 25.6
2 3 Enterocutaneous fistula 11
2 3 Pyelonephritis (resolved) 11
3 3 Presacral abscess/rectovaginal fistula 31
4 3 Colovaginal fistula (improved) 12
Six grade 3+ events were observed in 4 patients.
Patient 3 developed a presacral abscess and rectovaginal fistula approximately 2.5 years from completion of reirradiation. The site of local recurrence, which was treated with reirradiation, involved the vaginal fornices. Patient 4 had a long history of presacral abscess and transvaginal drainage procedures before reirradiation and developed increased vaginal discharge approximately 1 year from completion of reirradiation. The patient received a diagnosis of colovaginal fistula, which improved with percutaneous drainage.
Discussion
This is the largest report with the longest median follow-up to date of reirradiation for RC using PT. Additionally, all patients in our cohort received PBS-PT, making this the first such report. In contrast with prior studies, this study also included patients receiving prior pelvic RT for other malignancies.
Focusing on disease outcomes and restricting the analysis to recurrent RC only, we noted 1-year LP and OS rates of 52.3% and 71.4% in the present study versus 1-year local control and OS of 76.3% and 87.5% in the historical study by Valentini et al.8 Considerable heterogeneity in this retrospective cohort, particularly with respect to prior therapies (namely surgical resection) may account for the differences in these outcomes. Of the 10 patients who experienced local failure, 2 had multiply recurrent disease before reirradiation, 1 did not receive surgical resection after initial conformal RT, and 3 had received systemic therapy for local recurrence before being referred for reirradiation. All of these circumstances are mutually exclusive. As such, these patients had disease and treatment factors putting them at a high baseline risk and would also not have been eligible for a prospective study such as that by Valentini et al.8 Patients with de novo RC with previously irradiated pelvis show 2 failures as of the present, with 1 of these occurring in a patient who did not receive resection, and appear comparable with what would be expected without a history of pelvic RT. Nevertheless, the majority of patients in this study received hyperfractionated reirradiation with concurrent chemotherapy, reflecting an overall general consistency with reirradiation delivery technique.
Rates of acute grade 3 toxicity were low at 10.7%, and all but 3 patients completed the planned course of reirradiation (only 1 case was toxicity-mediated). These are comparable to the rate reported by Valentini et al (5.1%),8 who only accounted for gastrointestinal toxicity. Furthermore, relative to the study by Valentini et al,8 the median reirradiation dose in the present series was higher (48 vs 40.8 Gy). In addition, all patients in the trial by Valentini et al8 were treated with hyperfractionated RT compared with 75% of patients in our cohort. This supports tolerability of hyperfractionated reirradiation and concurrent chemotherapy with PBS-PT and is corroborated by the existing literature on PT for reirradiation for RC.
Four patients experienced late G3+ Tox, including 1 grade 5 toxicity. Overall, the rate of G3+ Tox at 1 year estimated with the Kaplan-Meier method was low at 13.3% (95% CI, 0.0%-27.7%). Of note, in 2 of these affected patients, a dose of 48 Gy in 1.2 Gy fractions was delivered, and in another patient 54 Gy in 1.5 Gy fractions was used, which represented the upper limit of the total dose in those patients who received a hyperfractionated course in this cohort. Additionally, as noted in the results section, 1 patient who experienced a grade 3 fistula had been undergoing bevacizumab therapy, another had a long history of presacral abscess and transvaginal procedures, and the patient with grade 5 toxicity had a history of significant toxicity with prior RT.
Comparing these late G3+ Tox with those reported by Valentini et al is difficult because late toxicities were not graded (although 1 was noted to require surgical intervention, and no treatment-related death was reported). However, the late G3+ Tox rates in the present report are comparable with prior published experiences of passive scatter PT reirradiation, although with a longer median follow-up of 28.6 months (range, 25.3-31.9 months). In the first known report using PT for reirradiation, 7 patients were treated using a double-scatter proton technique, and the median dose was 6120 cGy (RBE; 4500-6480 cGy) in conventional fractionation, with 6 patients receiving concurrent chemotherapy.15 With a median follow-up of 14 months, there were 3 acute grade 3 toxicities (abdominal pain, diarrhea) probably related to reirradiation, and 3 late grade 4 toxicities (2 bowel obstruction, 1 entero-vaginal fistula) possibly related to reirradiation.
Another experience evaluated 15 patients, also treated with passive-scatter technique, but with a 1.5 Gy accelerated fractionated course to a total dose of 39 to 45 Gy (RBE), and with all patients receiving concurrent chemotherapy.16 With a median follow-up of 14 months, 1 acute grade 3 toxicity (lymphopenia) and 2 late grade 3 toxicities (dysuria, rectal bleeding) were noted. Given the sample sizes of these and the present experiences and differing methods of treatment delivery, it is difficult to elucidate a dose-response relationship with respect to acute or late toxicity. Furthermore, our study solely implemented PBS-PT, thus making it more difficult to directly compare existing data largely gathered using passive-scatter techniques.
Six patients (21.4%) in our series received surgical resection after reirradiation, a lower proportion than in prior experiences (50.8% in the study by Valentini et al8), reflecting the high-risk patient cohort in our report. However, all 6 resulted in an R0 resection. Although the sample sizes are small for comparison, there was a strong trend toward superior OS in patients receiving resection (P = .107). This is consistent with prior reirradiation studies and likely multifactorial.
Other limitations to our study are primarily related to its retrospective nature. First and perhaps most important, there is selection bias inherent with any retrospective report and variable prior treatments. In this cohort, different RT regimens were used, inclusive of both conventionally fractionated and hyperfractionated courses. Second, the assessment of late toxicities was dependent on assessments that were not standardized, with imaging ranging from pelvic magnetic resonance to positron emission tomography/CT to CT.
Maturation and expansion of these data will better establish disease and toxicity outcomes in these patients. Longer follow-up and further accrual may help establish a dose–response relationship with respect to disease outcomes as well as the development of late toxicity. Moreover, such a relationship may be highly dependent on whether disease is recurrent or de novo.
Conclusions
The low acute toxicity rates, rare treatment interruption, and acceptable late toxicity reported here thus far support PBS-PT as an option for this high-risk patient population. Further follow-up and prospective studies, as those completed in the 3-dimensional conformal RT era, evaluating the use of PT for reirradiation for RC will help further clarify disease outcomes and toxicity profiles.
Sources of support: This work had no specific funding.
Disclosures: Dr Kaiser reports personal fees from Varian Medical Systems outside of the submitted work. | Fatal | ReactionOutcome | CC BY-NC-ND | 33490730 | 18,926,433 | 2021 |
What was the outcome of reaction 'Pyelonephritis'? | Reirradiation for Rectal Cancer Using Pencil Beam Scanning Proton Therapy: A Single Institutional Experience.
Reirradiation for rectal cancer (RC) after prior pelvic radiation therapy (RT) has been shown to be safe and effective. However, limited data exist for proton therapy (PT), including pencil beam scanning proton therapy (PBS-PT). We hypothesize that PT is safe and feasible for re-treatment and may allow for decreased toxicity and treatment escalation.
A single-institution, retrospective, institutional review board-approved analysis of all patients with RC and prior pelvic RT receiving PBS-PT reirradiation was performed. Data on patient and treatment characteristics and outcomes were collected. Local progression, progression-free survival, overall survival, and late grade >3 toxicity were estimated using the Kaplan-Meier method.
Twenty-eight patients (median follow-up: 28.6 months) received PBS-PT reirradiation between 2016 and 2019, including 18 patients with recurrent RC (median prior dose: 54.0 Gy) and 10 patients with de novo RC and variable prior RT. The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 twice daily), and 24 of 28 patients received concurrent chemotherapy. Six underwent surgical resection. Three (10.7%) experienced grade 3 acute toxicities, and 1 did not complete RT owing to toxicity. Four (14.2%) had late grade <3 toxicity, including 1 grade 5 toxicity in a patient with a prior RT-related injury. The 1-year local progression, progression-free survival, and overall survival rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively.
This is the largest series using PT for reirradiation for RC and the first study using PBS-PT. Low acute toxicity rates and acceptable late toxicity support PBS-PT as an option for this high-risk patient population, with a need for continued follow-up.
Introduction
Rectal cancer (RC) is a common malignancy, with approximately 40,000 new cases per year in the United States and 800,000 worldwide. Therapy for locally advanced disease often consists of neoadjuvant concurrent chemotherapy and radiation, followed by surgical resection with total mesorectal excision—a paradigm that has improved local control, survival, and treatment-related toxicities.1, 2, 3 In the modern era, local relapse affects approximately 7% of patients in the long term and is associated with pain, obstruction, bleeding, discharge, and change in stool habits.4
Reirradiation for RC may be implemented in the treatment of locally recurrent RCs and de novo RC with prior radiation for other pelvic malignancy. It may be administered either as part of a curative or palliative regimen, with patients eligible for and receiving curative resection having the most favorable survival outcomes.5,6 However, it presents risk of late complications given the radiation sensitivity of nearby organs and tissues of the abdomen and pelvis—in particular, the bladder, bowel, bone marrow, and lumbosacral plexus. This affects the approach of reirradiation in multiple ways, including treatment volumes, prescribed dose, fractionation scheme, and technique of delivery.
Numerous experiences have described disease and toxicity outcomes of reirradiation for RC, using these aforementioned modifications in treatment delivery to achieve safe and effective therapy.7 A landmark prospective study by Valentini et al demonstrated the safety and efficacy of hyperfractionated reirradiation with concurrent chemotherapy, often given neoadjuvantly.8 This study has served as a reference for both disease outcomes and treatment toxicities. Multiple retrospective studies have corroborated these findings.9, 10, 11, 12 However, to our knowledge, nearly all published studies have evaluated reirradiation using either 3-dimensional conformal radiation therapy (RT) or intensity modulated RT techniques.13,14 Literature evaluating rectal reirradiation with proton therapy (PT) is emerging and has demonstrated a significantly reduced low dose to the bowel and bone marrow, as well as clinical feasibility, safety, and efficacy—thus far with passive-scatter techniques.15,16 PBS-PT provides true intensity modulated PT; thus, we hypothesize that its use may result in improved short- and long-term toxicity profiles in the setting of reirradiation for RC. We report the disease and toxicity outcomes from a retrospective, single-institution experience using PBS-PT for reirradiation for RC.
Methods and materials
Patient selection and treatment
An institutional review board–approved retrospective chart review was completed of all patients treated with reirradiation using PBS-PT at a single institution between 2016 and 2019 for either recurrent RC or de novo RC with prior pelvic RT for another malignancy. Patient demographic information, disease characteristics, and treatment characteristics were collected. Prior RT plan reports were accessed when possible, and all PBS-PT plans underwent peer review per departmental protocol. All patients were presented at a multidisciplinary tumor board. Concurrent chemotherapy and curative-intent surgical resection were planned whenever feasible and appropriate.
Proton beam reirradiation
Patients underwent computed tomography (CT) simulation in the supine or prone position with a comfortably full bladder and vac-lok immobilization. Contouring of the target and organ-at-risk volumes was performed. Gross tumor volume (GTV) was delineated using physical examination, CT simulation, and diagnostic imaging data (positron emission tomography and/or magnetic resonance imaging). A clinical target volume (CTV) was generated by expanding the GTV by 1.5 to 3.0 cm craniocaudally, extending to the pelvic sidewall laterally, and including the presacral space posteriorly. When a boost was planned, a second smaller isotropic expansion of 0.5 to 1.5 cm was used, or simply the gross tumor without expansion. The choice of CTV expansion is based on the method outlined by Valentini et al,8 with smaller expansions on the GTV used in cases of inoperable recurrences involving the bone. Planning target volumes were generated by dosimetry, accounting for setup and proton beam range uncertainty. Earlier cases used a uniform 5 mm expansion, later transitioning to nonuniform expansions (3.5-5 mm) based on translational uncertainty, and eventually generation of a planning target volume using robust optimization algorithms. Dosing was guided by the method by Valentini et al.8 Hyperfractionation was employed when feasible for the patient.
Plan optimization was performed using Eclipse (Varian Medical Systems, Palo Alto, CA) and Raystation (RaySearch Laboratories, Stockholm, Sweden). All patients were treated with PBS-PT, typically with 2 lateral fields with single-field optimization technique, with some cases using a third field and/or multiple-field optimization. Opposed lateral fields, rather than posterior oblique fields, were used in many cases due to relative biological effectiveness (RBE) uncertainty at the end range, because this configuration limits overlap of end-ranging segments of the beams into previously irradiated bladder as well as bowel anterior to the CTV. Furthermore, using PBS-PT, the anterior edge of the field can be shaped and modulated off of bladder and bowel with opposed lateral fields, in contrast to the same arrangement using photon-based 3-dimensional conformal RT, where this is not possible.
When using a multiple field optimization technique, air in the bowel was accounted for using a density override algorithm. Quality assurance CT images were obtained during the course of therapy, with frequency depending on the particular case and clinical discretion. Dose constraints for the bladder and bowel entailed keeping maximum doses of approximately 90% of the prescription dose, which itself depended on prior radiation dose and time interval. In all cases, these constraints on the bladder and bowel structures were prioritized over full prescription isodose coverage of the anterior target volume. A representative plan is shown in Figure 1.Figure 1 Example pencil beam scanning proton therapy plan with axial, coronal, and sagittal views with corresponding dose–volume histogram. The patient was simulated prone, dose was prescribed via a simultaneous integrated boost with clinical target volume 1 (blue; gross target volume with 2-2.5 cm craniocaudal expansion, laterally to pelvic sidewalls and posteriorly to sacrum) receiving 4000 cGy in 100 cGy/fraction and clinical target volume 2 (red; gross target volume + 1.0 cm isotropic expansion) receiving 4800 cGy in 120 cGy/fraction. Proton planning target volumes were generated based on setup and range uncertainty. Two lateral beams using a multiple-field optimization technique were used. Bladder (yellow), large bowel (brown), small bowel (green), right femoral head (turquoise), and left femoral head (fuschia). (A color version of this figure is available at https://doi.org/10.1016/j.adro.2020.10.008.)
Statistics
Efficacy outcomes included local progression (LP), progression-free survival (PFS), and overall survival (OS). LP was calculated from completion of reirradiation to time of local failure by pathologic or radiologic confirmation. Patients who did not experience LP were censored at the time of the last follow-up visit. PFS was calculated from completion of reirradiation to the date of any progression or death, irrespective of the cause. OS was calculated from completion of reirradiation to the date of death, irrespective of the cause. The vital status of patients was checked using medical record/obituary documentation, and OS was censored on the date of the last documentation confirming living status in patients still alive on that date.
Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 5.0. Acute toxicity was assessed using provider documentation from weekly on-treatment visits. Late toxicity was defined as symptoms attributable to RT persisting or occurring >3 months after completion of reirradiation. All clinical outcomes were estimated using the Kaplan-Meier method. A univariable Cox proportional hazards model was used to model the relationship between GTV and outcome. A P value of <.05 was considered statistically significant. All analyses were completed using SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY).
Patient, disease, and treatment characteristics
Patient, disease, and treatment characteristics are summarized in Table 1. Twenty-eight patients (median follow-up 28.6 months; range, 25.3-31.9 months) received PBS-PT reirradiation from 2016 to 2019. Of these, 18 patients (64.3%) had recurrent RC (median prior dose: 54.0 Gy; range, 43.2-63.0 Gy) and 10 patients had de novo RC and variable prior RT (8 received full-dose external beam RT or brachytherapy for prostate cancer; 1 patient received external beam RT and brachytherapy boost for endometrial cancer; 1 patient received whole abdominal RT for ovarian cancer with a pelvic boost). The median reirradiation dose was 44.4 Gy (range, 16.0-60.0 Gy; 21 of 28 patients twice daily), and 24 of 28 patients (85.7%) received concurrent chemotherapy, with 18 of 28 (64.3%) receiving twice-daily oral capecitabine on days with reirradiation. Overall, 25 of 28 patients (89.3%) completed the planned course of reirradiation.Table 1 Patient and treatment characteristics (n = 28)
Characteristics n (%)
Sex
Male 19 (67.9%)
Female 9 (32.1%)
Age, y, median (range) 68 (41-87)
Follow-up, mo, median (range) 28.6 (25.3-31.9)
Recurrent rectal cancer 18 (64.3)
Prior RT dose, Gy, median (range) 54.0 (43.2-63.0)
Anatomic location of recurrence
Rectal 6 (33.3)
Presacral 11 (61.1)
Pelvic bone 1 (5.6)
Treatment for initial rectal cancer (n = 18)
Neoadjuvant conformal RT 8 (44.4)
Adjuvant conformal RT 2 (11.2)
Other 8 (44.4)
de novo rectal cancer (n = 10) 10 (35.7)
Prior pelvic RT Definitive for prostate cancer (equivalent total dose in 2 Gy fractions >70 Gy)8
Definitive for ovarian cancer1
Definitive for endometrial cancer1
Treatment before reirradiation for recurrence
Upfront surgery, n 2
Systemic therapy, n 8
Reirradiation dose, Gy, median (range) 48.0 (16.0-60.0)
Reirradiation interval, mo, median (range) 48.5 (12.7-494.8)
Concurrent chemotherapy with reirradiation 24 (85.7)
Hyperfractionated reirradiation 21 (75.0)
Completed reirradiation course 25 (89.3)
Underwent resection after reirradiation 6 (21.4)
R0 6
Gross tumor volume, cm3, median (range) 86.4 (13.6-821.8)
Abbreviation: RT = radiation therapy.
Table 2 Acute toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Grade 2, n (%) 3, n (%) 4, n (%) 5, n (%)
Gastrointestinal 4 (14.2) 2 (7.1) 0 (0.0) 0 (0.0)
Skin 4 (14.2) 1 (3.6) 0 (0.0) 0 (0.0)
Urologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Hematologic 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Total 8 (28.6) 3 (10.7) 0 (0.0) 0 (0.0)
Disease outcomes and toxicity
The 1-year LP, PFS, and OS rates were 33.7% (95% confidence interval [CI], 14.5%-52.9%), 45.0% (95% CI, 26.2%-63.8%), and 81.8% (95% CI, 67.3%-96.3%), respectively. The median times to LP, PFS, and OS were 23.4 months (range, 1.6-39.8 months; 95% CI, 12.9-33.9 months), 11.6 months (range, 0.6-39.8 months; 95% CI, 8.6-14.5 months), and 29.2 months (range, 1.6-45.9 months; 95% CI, 19.7-38.8 months), respectively (Fig 2A-C). In a univariable Cox proportional hazards model with GTV (cm3) included as a continuous variable, increasing GTV was highly statistically significantly associated with LP (hazard ratio [HR]: 1.005; 95% CI, 1.002-1.008; P = .003) and PFS (HR: 1.004; 95% CI, 1.002-1.006; P = .001), but not with OS (HR: 1.002; 95% CI, 1.000-1.005; P = .102). The 1-year LP rate for recurrent versus de novo RC was significantly different at 52.3% (95% CI, 23.9%-80.1%) and 0% (P = .002), respectively. The 1-year OS rate for recurrent versus de novo RC was 72.2% (95% CI, 51.4%-93.0%) and 100% (P = .058), respectively.Figure 2 Kaplan-Meier curves for (A) local progression, (B) progression-free survival, (C) overall survival, and (D) late grade >3 toxicities for all patients (n = 28).
Six patients (21.4%) underwent surgical resection after reirradiation, with further breakdown by de novo RC and recurrent RC patients being 3 of 10 (30%) and 3 of 18 (16.7%), respectively. All resections resulted in R0 resection. Of these patients, 4 eventually experienced LP (3 with recurrent RC), with a 1-year LP rate of resected patients of 16.7% versus 40% for those who did not receive resection (P = .786). The 1-year OS rate for patients undergoing and not undergoing resection was 100% and 76.8%, respectively; this difference was statistically significant (P = .027).
Acute toxicities are listed in Table 2. The 1-year rate of late grade >3 toxicities (G3+ Tox) was 13.3% in the Kaplan-Meier analysis (Fig 2D). Six late G3+ Tox occurred in 4 separate patients, with no evidence of tumor recurrence at toxicity onset (summarized by patient in Table 3). Patient 1 ultimately developed grade 5 toxicity and had a history of significant late toxicity from prior whole abdominal and pelvic boost radiation for ovarian cancer in the 1970s, including baseline and longstanding radiation colitis, loss of a kidney, and cystitis. This patient developed rectal bleeding at 3 months, a rectovaginal fistula at 9 months, and ultimately a bleeding stage IV decubitus ulcer and died of presacral hemorrhage at 26 months without evidence of tumor recurrence. Patient 2 developed an enterocutaneous fistula passing through the presacral region, as well as pyelonephritis resolving with parenteral antibiotics, approximately 1 year from completion of reirradiation. The treatment course was entirely in a medical ward without stay in either intermediate or intensive care. Of note, this patient was receiving bevacizumab systemic therapy at the time of the fistula diagnosis. This patient also experienced multiple delays and breaks in the planned treatment course related to social and logistic factors. This was the only patient who experienced G3+ Tox in both the acute and late term.Table 3 Grade ≥3 late toxicities graded by Common Terminology Criteria for Adverse Events, version 5.0
Patient no. Grade Toxicity Time to toxicity, mo
1 3 Rectovaginal fistula 8.5
1 5 Presacral hemorrhage 25.6
2 3 Enterocutaneous fistula 11
2 3 Pyelonephritis (resolved) 11
3 3 Presacral abscess/rectovaginal fistula 31
4 3 Colovaginal fistula (improved) 12
Six grade 3+ events were observed in 4 patients.
Patient 3 developed a presacral abscess and rectovaginal fistula approximately 2.5 years from completion of reirradiation. The site of local recurrence, which was treated with reirradiation, involved the vaginal fornices. Patient 4 had a long history of presacral abscess and transvaginal drainage procedures before reirradiation and developed increased vaginal discharge approximately 1 year from completion of reirradiation. The patient received a diagnosis of colovaginal fistula, which improved with percutaneous drainage.
Discussion
This is the largest report with the longest median follow-up to date of reirradiation for RC using PT. Additionally, all patients in our cohort received PBS-PT, making this the first such report. In contrast with prior studies, this study also included patients receiving prior pelvic RT for other malignancies.
Focusing on disease outcomes and restricting the analysis to recurrent RC only, we noted 1-year LP and OS rates of 52.3% and 71.4% in the present study versus 1-year local control and OS of 76.3% and 87.5% in the historical study by Valentini et al.8 Considerable heterogeneity in this retrospective cohort, particularly with respect to prior therapies (namely surgical resection) may account for the differences in these outcomes. Of the 10 patients who experienced local failure, 2 had multiply recurrent disease before reirradiation, 1 did not receive surgical resection after initial conformal RT, and 3 had received systemic therapy for local recurrence before being referred for reirradiation. All of these circumstances are mutually exclusive. As such, these patients had disease and treatment factors putting them at a high baseline risk and would also not have been eligible for a prospective study such as that by Valentini et al.8 Patients with de novo RC with previously irradiated pelvis show 2 failures as of the present, with 1 of these occurring in a patient who did not receive resection, and appear comparable with what would be expected without a history of pelvic RT. Nevertheless, the majority of patients in this study received hyperfractionated reirradiation with concurrent chemotherapy, reflecting an overall general consistency with reirradiation delivery technique.
Rates of acute grade 3 toxicity were low at 10.7%, and all but 3 patients completed the planned course of reirradiation (only 1 case was toxicity-mediated). These are comparable to the rate reported by Valentini et al (5.1%),8 who only accounted for gastrointestinal toxicity. Furthermore, relative to the study by Valentini et al,8 the median reirradiation dose in the present series was higher (48 vs 40.8 Gy). In addition, all patients in the trial by Valentini et al8 were treated with hyperfractionated RT compared with 75% of patients in our cohort. This supports tolerability of hyperfractionated reirradiation and concurrent chemotherapy with PBS-PT and is corroborated by the existing literature on PT for reirradiation for RC.
Four patients experienced late G3+ Tox, including 1 grade 5 toxicity. Overall, the rate of G3+ Tox at 1 year estimated with the Kaplan-Meier method was low at 13.3% (95% CI, 0.0%-27.7%). Of note, in 2 of these affected patients, a dose of 48 Gy in 1.2 Gy fractions was delivered, and in another patient 54 Gy in 1.5 Gy fractions was used, which represented the upper limit of the total dose in those patients who received a hyperfractionated course in this cohort. Additionally, as noted in the results section, 1 patient who experienced a grade 3 fistula had been undergoing bevacizumab therapy, another had a long history of presacral abscess and transvaginal procedures, and the patient with grade 5 toxicity had a history of significant toxicity with prior RT.
Comparing these late G3+ Tox with those reported by Valentini et al is difficult because late toxicities were not graded (although 1 was noted to require surgical intervention, and no treatment-related death was reported). However, the late G3+ Tox rates in the present report are comparable with prior published experiences of passive scatter PT reirradiation, although with a longer median follow-up of 28.6 months (range, 25.3-31.9 months). In the first known report using PT for reirradiation, 7 patients were treated using a double-scatter proton technique, and the median dose was 6120 cGy (RBE; 4500-6480 cGy) in conventional fractionation, with 6 patients receiving concurrent chemotherapy.15 With a median follow-up of 14 months, there were 3 acute grade 3 toxicities (abdominal pain, diarrhea) probably related to reirradiation, and 3 late grade 4 toxicities (2 bowel obstruction, 1 entero-vaginal fistula) possibly related to reirradiation.
Another experience evaluated 15 patients, also treated with passive-scatter technique, but with a 1.5 Gy accelerated fractionated course to a total dose of 39 to 45 Gy (RBE), and with all patients receiving concurrent chemotherapy.16 With a median follow-up of 14 months, 1 acute grade 3 toxicity (lymphopenia) and 2 late grade 3 toxicities (dysuria, rectal bleeding) were noted. Given the sample sizes of these and the present experiences and differing methods of treatment delivery, it is difficult to elucidate a dose-response relationship with respect to acute or late toxicity. Furthermore, our study solely implemented PBS-PT, thus making it more difficult to directly compare existing data largely gathered using passive-scatter techniques.
Six patients (21.4%) in our series received surgical resection after reirradiation, a lower proportion than in prior experiences (50.8% in the study by Valentini et al8), reflecting the high-risk patient cohort in our report. However, all 6 resulted in an R0 resection. Although the sample sizes are small for comparison, there was a strong trend toward superior OS in patients receiving resection (P = .107). This is consistent with prior reirradiation studies and likely multifactorial.
Other limitations to our study are primarily related to its retrospective nature. First and perhaps most important, there is selection bias inherent with any retrospective report and variable prior treatments. In this cohort, different RT regimens were used, inclusive of both conventionally fractionated and hyperfractionated courses. Second, the assessment of late toxicities was dependent on assessments that were not standardized, with imaging ranging from pelvic magnetic resonance to positron emission tomography/CT to CT.
Maturation and expansion of these data will better establish disease and toxicity outcomes in these patients. Longer follow-up and further accrual may help establish a dose–response relationship with respect to disease outcomes as well as the development of late toxicity. Moreover, such a relationship may be highly dependent on whether disease is recurrent or de novo.
Conclusions
The low acute toxicity rates, rare treatment interruption, and acceptable late toxicity reported here thus far support PBS-PT as an option for this high-risk patient population. Further follow-up and prospective studies, as those completed in the 3-dimensional conformal RT era, evaluating the use of PT for reirradiation for RC will help further clarify disease outcomes and toxicity profiles.
Sources of support: This work had no specific funding.
Disclosures: Dr Kaiser reports personal fees from Varian Medical Systems outside of the submitted work. | Recovered | ReactionOutcome | CC BY-NC-ND | 33490730 | 18,926,203 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Lutetium Lu-177 Dotatate Flare Reaction.
Lutetium Lu-177 dotatate is the first peptide receptor radionuclide therapy approved by the US Food and Drug Administration. Well-designed studies in Europe have shown dramatic effectiveness in improving progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors, which are progressive and generally metastatic. This therapy is a molecular targeted therapy linking a beta-emitting radioisotope to dotatate, which binds tightly to somatostatin receptors on neuroendocrine tumors cells. Various adverse effects of this therapy have been reported in the literature, including potential toxicity to renal, hepatic, and hematologic tissues and risk of second malignancy. Our study sought to explore acute adverse effects in this patient population.
We tracked adverse effects and patient experience in our first year of therapy experience with this new agent.
In our first 12 patients who received Lutetium Lu-177 dotatate, tumor flare reactions occurred in 5 patients due to worsening symptoms of bone or soft tissue metastasis. This flare reaction can be mitigated with short course of corticosteroid therapy or other strategies.
Flare reaction is common in patients with progressive metastatic gastroenteropancreatic neuroendocrine tumors and can be managed successfully with several strategies.
Introduction
The advent of peptide receptor radionuclide therapy (PRRT) has provided clinicians with new therapeutic strategies to treat patients with neoplasms for which treatment is less effective and where fewer options remain.1 These therapies offer a molecularly targeted means of delivering precise radiation therapy to the tumors, which are frequently metastatic and resistant to other conventional therapies. Gastroenteropancreatic neuroendocrine tumors (GEP NETs) exemplify a group of tumors that are challenging due to a high likelihood of recurrence and metastasis, and relatively few active therapies that can cause meaningful progression free survival.2 The first of these therapies approved by the US Food and Drug Administration is Lutetium Lu-177 Dotatate (TM Lutathera), an agent that includes a dotatate moiety, which binds tightly to somatostatin receptors on NET cells, and the beta-emitting radionuclide Lutetium-177, with a half-life of 6.7 days and a maximum beta range of 2 mm in tissue. This agent has been used in Europe for many years, and landmark studies have demonstrated substantial improvements in response rates and progression free survival in the GEP NET patient population.3,4 There have also been demonstrable improvements in quality of life.5 Several adverse reactions to this therapy have been reported, including renal, hepatic, and hematologic injury, and increased risk of late organ injury and secondary neoplasms.3,6, 7, 8, 9, 10 In this report, we document a flare reaction in 5 of our initial 12 patients treated and suggest therapeutic strategies to help mitigate this reaction. Although various toxicities including renal, hematologic and gastrointestional have been reported in the literature, flare reaction and suggested mitigation strategies have not been widely reported. Palliative external radiation therapy has been frequently associated with pain flare in patients with bony metastasis.11, 12, 13 The temporary use of corticosteroids has been successfully used to diminish this acute effect.14,15
Methods and Materials
As the flagship teaching hospital of one of the largest hospital systems in our state with a high volume of patients with cancer, we have closely followed the research related to PRRTs. We have also been excited about a potential therapeutic strategy to manage patients with progressive NETs. Upon lutetium Lu-177 dotatate approval by the US Food and Drug Administration, our clinical team expressed interest in initiating a program to serve patients with GEP NETs in our system, and as well as those from other hospitals and oncology programs in the state. Delivery of this agent is complex, due in particular to the need for the infusion of amino acid solution as a renal protectant. This solution is highly emetogenic, requiring pretreatment with a group of antiemetic therapies which include ondansetron, aprepitant, and dexamethasone (12-mg single dose). All patients received their monthly somatostatin analog (SSA) dose after completion of their 7-hour amino acid solution infusion. We initiated this program in 2018 through a collaborative effort of radiation oncology, radiation safety, nuclear medicine, oncology nursing, and pharmacy. We developed standard protocols, procedures, and consent; staff and patient educational materials, and documentation standards for lutetium Lu-177 receipt, administration, and patient release. These include monitoring of hematologic, renal, and hepatic function as well as patient adverse effects. By protocol, a total of 4 doses are delivered at 8-week intervals and each dose is followed by the administration of SSA to avoid competition for tumor binding sites.
Results
As seen in Table 1, we have treated 12 patients between December 2018 and April 2020. Eight were female and 4 are male. The age range at the time of treatment initiation was 45 to 77 years with a median of 66 years. All patients have GEP NETs with the exception of one patient with a NET arising from a dysplastic kidney, for whom we were able to gain authorization for treatment. All patients had documented progression of disease on SSAs. Some patients also had progression on chemotherapy or mTor inhibitors, palliative external beam irradiation, as well as prior therapy with bland, chemotherapy, or radioembolization of hepatic metastases. All patients had hepatic metastases, and most had metastasis to retroperitoneal or mesenteric nodes as well. Several patients also had bony metastases, pulmonary metastases, and other areas of metastatic disease, including subcutaneous metastases. Most patients had some symptoms of carcinoid syndrome. Some had symptoms emanating from areas of metastases, including bone pain, liver pain, small bowel dysfunction, early satiety, and neuropathic pain related to nerve compression. All patients had documentation of avidity on gallium dotatate positron emission tomography scanning before treatment initiation.Table 1 Patient characeeristics and flare reactions
Patient no./age/sex Primary site Prior therapy Flare type (CTCAE score) Mitigation success
1/69/f Sm bowel SSA, temozolomide Cranial nerve dysfunction (2) Fair
2/46/f Sm bowel SSA, pall RT Bone pain (2) Good
3/68/m Pancreas SSA, everolimus, Y90 and chemo emb
4/57/f Sm bowel SSA
5/68/f Sm bowel SSA, bland and Y90 emb Epigastric pain (2) Fair
6/56/m Sm bowel SSA, TACE Small bowel dysfunction (2) Fair
7/47/f Sm bowel SSA pSBO (3) Good
8/65/f Kidney SSA
9/68/m Sm bowel SSA, Y90
10/77/f Sm bowel SSA, TACE, ablation. Liver resection
11/73/f Sm bowel SSA, TACE, everolimus, Y90
12/45/m Pancreas SSA, everolimus
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; emb = embolization; pall = palliative; pSBO = partial small bowel obstruction; RT = radiation therapy; sm = small; SSA = somatostatin analog therapy; TACE = transarterial chemoembolization.
Five patients exhibited flare reactions of symptoms during the first week after lutetium Lu-177 dotatate therapy. Two of these were related to bone metastases. In one patient with base of skull metastases, seventh cranial nerve dysfunction was noted. In another with spine metastasis, increased spine pain occurred. In a patient with extremely bulky left liver metastasis, increased epigastric pain and early satiety occurred. In 2 patients with extensive mesenteric metastases, increased bowel dysfunction and partial small bowel obstruction occurred. All of the flare reactions were quantified by Common Terminology Criteria for Adverse Events grades 2 (4 patients) or 3 (1 patient). Mitigation with a short course of oral corticosteroids was generally successful, as well as use of symptomatic medications. Steroid courses either included a methylprednisolone dose pack or a week of prednisone 40 mg daily. In patients who developed a flare reaction after the first of 4 lutetium Lu-177 dotatate administrations, we recommended a steroid course for subsequent courses, and also elected to arrange a phone or physical visit with their radiation oncologist or medical oncologist within the first week after administration to monitor and appropriately manage flare symptoms.
Discussion
Lutetium Lu-177 dotatate has become an additional effective therapy in the management of patients with GEP NETs.3,4 It is an excellent example of a targeted molecular therapy, as it binds avidly to the somatostatin receptors on NET cells, and delivers a high radiation dose via the beta emitting isotope Lutetium-177. Its use has been associated with a high likelihood of improving progression free survival. It is therefore not unexpected that flare reactions might occur similar to those which occur through the use of external radiation therapy. Flare reactions certainly occur on occasion in patients with symptomatic bony metastases who undergo palliative radiation therapy.11,12 This reaction might be treated with a temporary course of corticosteroids, or analgesics as appropriate.14,15
In our patients with GEP NETs receiving Lutetium Lu-177 dotatate, we have observed flare reactions associated with bony metastasis and soft tissue deposits of disease, in the liver and small bowel mesentery. These flare reactions are presumably mediated by transient local edema or inflammation secondary to initial tumor cell injury. Therefore, one might conjecture that such a process could occur either in bone or soft tissue if the local environment is subject to swelling causing nerve pressure or other organ dysfunction. Given the risk of such side effects recurring with subsequent doses of the Lutetium Lu-177 dotatate, we discovered that either a short prophylactic course of corticosteroids in subsequent courses was useful, or that close monitoring in the first week after therapy was warranted to manage adverse effects as needed. The single dose of 12 mg of dexamethasone administered on the day of treatment as an antiemetic was clearly not enough to prevent the flare reaction in these patients, likely owing to concomitant timing and lack of steroid presence on subsequent days when radiation was still present.
Mitigation of flare related symptoms with steroids or symptomatic medications as judged by patient report and MD assessment was fair to good. It is likely that a patient already focally symptomatic from a GEP-NET lesion, such as in bone or soft tissue, may be at increased risk for experiencing a flare reaction. Radiation oncologists are particularly adept at managing these symptoms owing to the fact that that they may commonly occur during courses of external beam irradiation. One potential benefit of having a radiation oncologist involved in radionuclide therapy for cancer is their expertise in dealing with adverse effects which are in some ways analogous to external radiation therapy.
Conclusions
Tumor flare reactions are common with the use of Lutetium Lu-177 dotatate in the management of GEP NETs. In our series of 12 patients, 2 had flare reactions characterized by bony metastasis causing spine pain and cranial nerve dysfunction due to skull base metastasis. An additional 3 patients had flare reactions due to soft tissue metastasis causing pain due to liver metastasis in one and bowel dysfunction in 2. All flare reactions were manifested in the first of 4 administrations. Management with a short course of corticosteroids and appropriate analgesics was generally successful. Use of such strategy for the 3 subsequent courses was helpful, as was close monitoring of the patient in the week after therapy to determine what interventions might be helpful.
Sources of support: This work had no specific funding.
Disclosures: none.
Data sharing statement: All data generated and analyzed during this study are included in this published article. | AMINO ACIDS, SOURCE UNSPECIFIED, SOMATOSTATIN, TEMOZOLOMIDE | DrugsGivenReaction | CC BY-NC-ND | 33490736 | 18,933,479 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Small intestinal obstruction'. | Lutetium Lu-177 Dotatate Flare Reaction.
Lutetium Lu-177 dotatate is the first peptide receptor radionuclide therapy approved by the US Food and Drug Administration. Well-designed studies in Europe have shown dramatic effectiveness in improving progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors, which are progressive and generally metastatic. This therapy is a molecular targeted therapy linking a beta-emitting radioisotope to dotatate, which binds tightly to somatostatin receptors on neuroendocrine tumors cells. Various adverse effects of this therapy have been reported in the literature, including potential toxicity to renal, hepatic, and hematologic tissues and risk of second malignancy. Our study sought to explore acute adverse effects in this patient population.
We tracked adverse effects and patient experience in our first year of therapy experience with this new agent.
In our first 12 patients who received Lutetium Lu-177 dotatate, tumor flare reactions occurred in 5 patients due to worsening symptoms of bone or soft tissue metastasis. This flare reaction can be mitigated with short course of corticosteroid therapy or other strategies.
Flare reaction is common in patients with progressive metastatic gastroenteropancreatic neuroendocrine tumors and can be managed successfully with several strategies.
Introduction
The advent of peptide receptor radionuclide therapy (PRRT) has provided clinicians with new therapeutic strategies to treat patients with neoplasms for which treatment is less effective and where fewer options remain.1 These therapies offer a molecularly targeted means of delivering precise radiation therapy to the tumors, which are frequently metastatic and resistant to other conventional therapies. Gastroenteropancreatic neuroendocrine tumors (GEP NETs) exemplify a group of tumors that are challenging due to a high likelihood of recurrence and metastasis, and relatively few active therapies that can cause meaningful progression free survival.2 The first of these therapies approved by the US Food and Drug Administration is Lutetium Lu-177 Dotatate (TM Lutathera), an agent that includes a dotatate moiety, which binds tightly to somatostatin receptors on NET cells, and the beta-emitting radionuclide Lutetium-177, with a half-life of 6.7 days and a maximum beta range of 2 mm in tissue. This agent has been used in Europe for many years, and landmark studies have demonstrated substantial improvements in response rates and progression free survival in the GEP NET patient population.3,4 There have also been demonstrable improvements in quality of life.5 Several adverse reactions to this therapy have been reported, including renal, hepatic, and hematologic injury, and increased risk of late organ injury and secondary neoplasms.3,6, 7, 8, 9, 10 In this report, we document a flare reaction in 5 of our initial 12 patients treated and suggest therapeutic strategies to help mitigate this reaction. Although various toxicities including renal, hematologic and gastrointestional have been reported in the literature, flare reaction and suggested mitigation strategies have not been widely reported. Palliative external radiation therapy has been frequently associated with pain flare in patients with bony metastasis.11, 12, 13 The temporary use of corticosteroids has been successfully used to diminish this acute effect.14,15
Methods and Materials
As the flagship teaching hospital of one of the largest hospital systems in our state with a high volume of patients with cancer, we have closely followed the research related to PRRTs. We have also been excited about a potential therapeutic strategy to manage patients with progressive NETs. Upon lutetium Lu-177 dotatate approval by the US Food and Drug Administration, our clinical team expressed interest in initiating a program to serve patients with GEP NETs in our system, and as well as those from other hospitals and oncology programs in the state. Delivery of this agent is complex, due in particular to the need for the infusion of amino acid solution as a renal protectant. This solution is highly emetogenic, requiring pretreatment with a group of antiemetic therapies which include ondansetron, aprepitant, and dexamethasone (12-mg single dose). All patients received their monthly somatostatin analog (SSA) dose after completion of their 7-hour amino acid solution infusion. We initiated this program in 2018 through a collaborative effort of radiation oncology, radiation safety, nuclear medicine, oncology nursing, and pharmacy. We developed standard protocols, procedures, and consent; staff and patient educational materials, and documentation standards for lutetium Lu-177 receipt, administration, and patient release. These include monitoring of hematologic, renal, and hepatic function as well as patient adverse effects. By protocol, a total of 4 doses are delivered at 8-week intervals and each dose is followed by the administration of SSA to avoid competition for tumor binding sites.
Results
As seen in Table 1, we have treated 12 patients between December 2018 and April 2020. Eight were female and 4 are male. The age range at the time of treatment initiation was 45 to 77 years with a median of 66 years. All patients have GEP NETs with the exception of one patient with a NET arising from a dysplastic kidney, for whom we were able to gain authorization for treatment. All patients had documented progression of disease on SSAs. Some patients also had progression on chemotherapy or mTor inhibitors, palliative external beam irradiation, as well as prior therapy with bland, chemotherapy, or radioembolization of hepatic metastases. All patients had hepatic metastases, and most had metastasis to retroperitoneal or mesenteric nodes as well. Several patients also had bony metastases, pulmonary metastases, and other areas of metastatic disease, including subcutaneous metastases. Most patients had some symptoms of carcinoid syndrome. Some had symptoms emanating from areas of metastases, including bone pain, liver pain, small bowel dysfunction, early satiety, and neuropathic pain related to nerve compression. All patients had documentation of avidity on gallium dotatate positron emission tomography scanning before treatment initiation.Table 1 Patient characeeristics and flare reactions
Patient no./age/sex Primary site Prior therapy Flare type (CTCAE score) Mitigation success
1/69/f Sm bowel SSA, temozolomide Cranial nerve dysfunction (2) Fair
2/46/f Sm bowel SSA, pall RT Bone pain (2) Good
3/68/m Pancreas SSA, everolimus, Y90 and chemo emb
4/57/f Sm bowel SSA
5/68/f Sm bowel SSA, bland and Y90 emb Epigastric pain (2) Fair
6/56/m Sm bowel SSA, TACE Small bowel dysfunction (2) Fair
7/47/f Sm bowel SSA pSBO (3) Good
8/65/f Kidney SSA
9/68/m Sm bowel SSA, Y90
10/77/f Sm bowel SSA, TACE, ablation. Liver resection
11/73/f Sm bowel SSA, TACE, everolimus, Y90
12/45/m Pancreas SSA, everolimus
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; emb = embolization; pall = palliative; pSBO = partial small bowel obstruction; RT = radiation therapy; sm = small; SSA = somatostatin analog therapy; TACE = transarterial chemoembolization.
Five patients exhibited flare reactions of symptoms during the first week after lutetium Lu-177 dotatate therapy. Two of these were related to bone metastases. In one patient with base of skull metastases, seventh cranial nerve dysfunction was noted. In another with spine metastasis, increased spine pain occurred. In a patient with extremely bulky left liver metastasis, increased epigastric pain and early satiety occurred. In 2 patients with extensive mesenteric metastases, increased bowel dysfunction and partial small bowel obstruction occurred. All of the flare reactions were quantified by Common Terminology Criteria for Adverse Events grades 2 (4 patients) or 3 (1 patient). Mitigation with a short course of oral corticosteroids was generally successful, as well as use of symptomatic medications. Steroid courses either included a methylprednisolone dose pack or a week of prednisone 40 mg daily. In patients who developed a flare reaction after the first of 4 lutetium Lu-177 dotatate administrations, we recommended a steroid course for subsequent courses, and also elected to arrange a phone or physical visit with their radiation oncologist or medical oncologist within the first week after administration to monitor and appropriately manage flare symptoms.
Discussion
Lutetium Lu-177 dotatate has become an additional effective therapy in the management of patients with GEP NETs.3,4 It is an excellent example of a targeted molecular therapy, as it binds avidly to the somatostatin receptors on NET cells, and delivers a high radiation dose via the beta emitting isotope Lutetium-177. Its use has been associated with a high likelihood of improving progression free survival. It is therefore not unexpected that flare reactions might occur similar to those which occur through the use of external radiation therapy. Flare reactions certainly occur on occasion in patients with symptomatic bony metastases who undergo palliative radiation therapy.11,12 This reaction might be treated with a temporary course of corticosteroids, or analgesics as appropriate.14,15
In our patients with GEP NETs receiving Lutetium Lu-177 dotatate, we have observed flare reactions associated with bony metastasis and soft tissue deposits of disease, in the liver and small bowel mesentery. These flare reactions are presumably mediated by transient local edema or inflammation secondary to initial tumor cell injury. Therefore, one might conjecture that such a process could occur either in bone or soft tissue if the local environment is subject to swelling causing nerve pressure or other organ dysfunction. Given the risk of such side effects recurring with subsequent doses of the Lutetium Lu-177 dotatate, we discovered that either a short prophylactic course of corticosteroids in subsequent courses was useful, or that close monitoring in the first week after therapy was warranted to manage adverse effects as needed. The single dose of 12 mg of dexamethasone administered on the day of treatment as an antiemetic was clearly not enough to prevent the flare reaction in these patients, likely owing to concomitant timing and lack of steroid presence on subsequent days when radiation was still present.
Mitigation of flare related symptoms with steroids or symptomatic medications as judged by patient report and MD assessment was fair to good. It is likely that a patient already focally symptomatic from a GEP-NET lesion, such as in bone or soft tissue, may be at increased risk for experiencing a flare reaction. Radiation oncologists are particularly adept at managing these symptoms owing to the fact that that they may commonly occur during courses of external beam irradiation. One potential benefit of having a radiation oncologist involved in radionuclide therapy for cancer is their expertise in dealing with adverse effects which are in some ways analogous to external radiation therapy.
Conclusions
Tumor flare reactions are common with the use of Lutetium Lu-177 dotatate in the management of GEP NETs. In our series of 12 patients, 2 had flare reactions characterized by bony metastasis causing spine pain and cranial nerve dysfunction due to skull base metastasis. An additional 3 patients had flare reactions due to soft tissue metastasis causing pain due to liver metastasis in one and bowel dysfunction in 2. All flare reactions were manifested in the first of 4 administrations. Management with a short course of corticosteroids and appropriate analgesics was generally successful. Use of such strategy for the 3 subsequent courses was helpful, as was close monitoring of the patient in the week after therapy to determine what interventions might be helpful.
Sources of support: This work had no specific funding.
Disclosures: none.
Data sharing statement: All data generated and analyzed during this study are included in this published article. | APREPITANT, DEXAMETHASONE, LUTETIUM OXODOTREOTIDE LU-177, ONDANSETRON | DrugsGivenReaction | CC BY-NC-ND | 33490736 | 18,922,597 | 2021 |
What was the administration route of drug 'TEMOZOLOMIDE'? | Lutetium Lu-177 Dotatate Flare Reaction.
Lutetium Lu-177 dotatate is the first peptide receptor radionuclide therapy approved by the US Food and Drug Administration. Well-designed studies in Europe have shown dramatic effectiveness in improving progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors, which are progressive and generally metastatic. This therapy is a molecular targeted therapy linking a beta-emitting radioisotope to dotatate, which binds tightly to somatostatin receptors on neuroendocrine tumors cells. Various adverse effects of this therapy have been reported in the literature, including potential toxicity to renal, hepatic, and hematologic tissues and risk of second malignancy. Our study sought to explore acute adverse effects in this patient population.
We tracked adverse effects and patient experience in our first year of therapy experience with this new agent.
In our first 12 patients who received Lutetium Lu-177 dotatate, tumor flare reactions occurred in 5 patients due to worsening symptoms of bone or soft tissue metastasis. This flare reaction can be mitigated with short course of corticosteroid therapy or other strategies.
Flare reaction is common in patients with progressive metastatic gastroenteropancreatic neuroendocrine tumors and can be managed successfully with several strategies.
Introduction
The advent of peptide receptor radionuclide therapy (PRRT) has provided clinicians with new therapeutic strategies to treat patients with neoplasms for which treatment is less effective and where fewer options remain.1 These therapies offer a molecularly targeted means of delivering precise radiation therapy to the tumors, which are frequently metastatic and resistant to other conventional therapies. Gastroenteropancreatic neuroendocrine tumors (GEP NETs) exemplify a group of tumors that are challenging due to a high likelihood of recurrence and metastasis, and relatively few active therapies that can cause meaningful progression free survival.2 The first of these therapies approved by the US Food and Drug Administration is Lutetium Lu-177 Dotatate (TM Lutathera), an agent that includes a dotatate moiety, which binds tightly to somatostatin receptors on NET cells, and the beta-emitting radionuclide Lutetium-177, with a half-life of 6.7 days and a maximum beta range of 2 mm in tissue. This agent has been used in Europe for many years, and landmark studies have demonstrated substantial improvements in response rates and progression free survival in the GEP NET patient population.3,4 There have also been demonstrable improvements in quality of life.5 Several adverse reactions to this therapy have been reported, including renal, hepatic, and hematologic injury, and increased risk of late organ injury and secondary neoplasms.3,6, 7, 8, 9, 10 In this report, we document a flare reaction in 5 of our initial 12 patients treated and suggest therapeutic strategies to help mitigate this reaction. Although various toxicities including renal, hematologic and gastrointestional have been reported in the literature, flare reaction and suggested mitigation strategies have not been widely reported. Palliative external radiation therapy has been frequently associated with pain flare in patients with bony metastasis.11, 12, 13 The temporary use of corticosteroids has been successfully used to diminish this acute effect.14,15
Methods and Materials
As the flagship teaching hospital of one of the largest hospital systems in our state with a high volume of patients with cancer, we have closely followed the research related to PRRTs. We have also been excited about a potential therapeutic strategy to manage patients with progressive NETs. Upon lutetium Lu-177 dotatate approval by the US Food and Drug Administration, our clinical team expressed interest in initiating a program to serve patients with GEP NETs in our system, and as well as those from other hospitals and oncology programs in the state. Delivery of this agent is complex, due in particular to the need for the infusion of amino acid solution as a renal protectant. This solution is highly emetogenic, requiring pretreatment with a group of antiemetic therapies which include ondansetron, aprepitant, and dexamethasone (12-mg single dose). All patients received their monthly somatostatin analog (SSA) dose after completion of their 7-hour amino acid solution infusion. We initiated this program in 2018 through a collaborative effort of radiation oncology, radiation safety, nuclear medicine, oncology nursing, and pharmacy. We developed standard protocols, procedures, and consent; staff and patient educational materials, and documentation standards for lutetium Lu-177 receipt, administration, and patient release. These include monitoring of hematologic, renal, and hepatic function as well as patient adverse effects. By protocol, a total of 4 doses are delivered at 8-week intervals and each dose is followed by the administration of SSA to avoid competition for tumor binding sites.
Results
As seen in Table 1, we have treated 12 patients between December 2018 and April 2020. Eight were female and 4 are male. The age range at the time of treatment initiation was 45 to 77 years with a median of 66 years. All patients have GEP NETs with the exception of one patient with a NET arising from a dysplastic kidney, for whom we were able to gain authorization for treatment. All patients had documented progression of disease on SSAs. Some patients also had progression on chemotherapy or mTor inhibitors, palliative external beam irradiation, as well as prior therapy with bland, chemotherapy, or radioembolization of hepatic metastases. All patients had hepatic metastases, and most had metastasis to retroperitoneal or mesenteric nodes as well. Several patients also had bony metastases, pulmonary metastases, and other areas of metastatic disease, including subcutaneous metastases. Most patients had some symptoms of carcinoid syndrome. Some had symptoms emanating from areas of metastases, including bone pain, liver pain, small bowel dysfunction, early satiety, and neuropathic pain related to nerve compression. All patients had documentation of avidity on gallium dotatate positron emission tomography scanning before treatment initiation.Table 1 Patient characeeristics and flare reactions
Patient no./age/sex Primary site Prior therapy Flare type (CTCAE score) Mitigation success
1/69/f Sm bowel SSA, temozolomide Cranial nerve dysfunction (2) Fair
2/46/f Sm bowel SSA, pall RT Bone pain (2) Good
3/68/m Pancreas SSA, everolimus, Y90 and chemo emb
4/57/f Sm bowel SSA
5/68/f Sm bowel SSA, bland and Y90 emb Epigastric pain (2) Fair
6/56/m Sm bowel SSA, TACE Small bowel dysfunction (2) Fair
7/47/f Sm bowel SSA pSBO (3) Good
8/65/f Kidney SSA
9/68/m Sm bowel SSA, Y90
10/77/f Sm bowel SSA, TACE, ablation. Liver resection
11/73/f Sm bowel SSA, TACE, everolimus, Y90
12/45/m Pancreas SSA, everolimus
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; emb = embolization; pall = palliative; pSBO = partial small bowel obstruction; RT = radiation therapy; sm = small; SSA = somatostatin analog therapy; TACE = transarterial chemoembolization.
Five patients exhibited flare reactions of symptoms during the first week after lutetium Lu-177 dotatate therapy. Two of these were related to bone metastases. In one patient with base of skull metastases, seventh cranial nerve dysfunction was noted. In another with spine metastasis, increased spine pain occurred. In a patient with extremely bulky left liver metastasis, increased epigastric pain and early satiety occurred. In 2 patients with extensive mesenteric metastases, increased bowel dysfunction and partial small bowel obstruction occurred. All of the flare reactions were quantified by Common Terminology Criteria for Adverse Events grades 2 (4 patients) or 3 (1 patient). Mitigation with a short course of oral corticosteroids was generally successful, as well as use of symptomatic medications. Steroid courses either included a methylprednisolone dose pack or a week of prednisone 40 mg daily. In patients who developed a flare reaction after the first of 4 lutetium Lu-177 dotatate administrations, we recommended a steroid course for subsequent courses, and also elected to arrange a phone or physical visit with their radiation oncologist or medical oncologist within the first week after administration to monitor and appropriately manage flare symptoms.
Discussion
Lutetium Lu-177 dotatate has become an additional effective therapy in the management of patients with GEP NETs.3,4 It is an excellent example of a targeted molecular therapy, as it binds avidly to the somatostatin receptors on NET cells, and delivers a high radiation dose via the beta emitting isotope Lutetium-177. Its use has been associated with a high likelihood of improving progression free survival. It is therefore not unexpected that flare reactions might occur similar to those which occur through the use of external radiation therapy. Flare reactions certainly occur on occasion in patients with symptomatic bony metastases who undergo palliative radiation therapy.11,12 This reaction might be treated with a temporary course of corticosteroids, or analgesics as appropriate.14,15
In our patients with GEP NETs receiving Lutetium Lu-177 dotatate, we have observed flare reactions associated with bony metastasis and soft tissue deposits of disease, in the liver and small bowel mesentery. These flare reactions are presumably mediated by transient local edema or inflammation secondary to initial tumor cell injury. Therefore, one might conjecture that such a process could occur either in bone or soft tissue if the local environment is subject to swelling causing nerve pressure or other organ dysfunction. Given the risk of such side effects recurring with subsequent doses of the Lutetium Lu-177 dotatate, we discovered that either a short prophylactic course of corticosteroids in subsequent courses was useful, or that close monitoring in the first week after therapy was warranted to manage adverse effects as needed. The single dose of 12 mg of dexamethasone administered on the day of treatment as an antiemetic was clearly not enough to prevent the flare reaction in these patients, likely owing to concomitant timing and lack of steroid presence on subsequent days when radiation was still present.
Mitigation of flare related symptoms with steroids or symptomatic medications as judged by patient report and MD assessment was fair to good. It is likely that a patient already focally symptomatic from a GEP-NET lesion, such as in bone or soft tissue, may be at increased risk for experiencing a flare reaction. Radiation oncologists are particularly adept at managing these symptoms owing to the fact that that they may commonly occur during courses of external beam irradiation. One potential benefit of having a radiation oncologist involved in radionuclide therapy for cancer is their expertise in dealing with adverse effects which are in some ways analogous to external radiation therapy.
Conclusions
Tumor flare reactions are common with the use of Lutetium Lu-177 dotatate in the management of GEP NETs. In our series of 12 patients, 2 had flare reactions characterized by bony metastasis causing spine pain and cranial nerve dysfunction due to skull base metastasis. An additional 3 patients had flare reactions due to soft tissue metastasis causing pain due to liver metastasis in one and bowel dysfunction in 2. All flare reactions were manifested in the first of 4 administrations. Management with a short course of corticosteroids and appropriate analgesics was generally successful. Use of such strategy for the 3 subsequent courses was helpful, as was close monitoring of the patient in the week after therapy to determine what interventions might be helpful.
Sources of support: This work had no specific funding.
Disclosures: none.
Data sharing statement: All data generated and analyzed during this study are included in this published article. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33490736 | 18,933,479 | 2021 |
What was the dosage of drug 'AMINO ACIDS, SOURCE UNSPECIFIED'? | Lutetium Lu-177 Dotatate Flare Reaction.
Lutetium Lu-177 dotatate is the first peptide receptor radionuclide therapy approved by the US Food and Drug Administration. Well-designed studies in Europe have shown dramatic effectiveness in improving progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors, which are progressive and generally metastatic. This therapy is a molecular targeted therapy linking a beta-emitting radioisotope to dotatate, which binds tightly to somatostatin receptors on neuroendocrine tumors cells. Various adverse effects of this therapy have been reported in the literature, including potential toxicity to renal, hepatic, and hematologic tissues and risk of second malignancy. Our study sought to explore acute adverse effects in this patient population.
We tracked adverse effects and patient experience in our first year of therapy experience with this new agent.
In our first 12 patients who received Lutetium Lu-177 dotatate, tumor flare reactions occurred in 5 patients due to worsening symptoms of bone or soft tissue metastasis. This flare reaction can be mitigated with short course of corticosteroid therapy or other strategies.
Flare reaction is common in patients with progressive metastatic gastroenteropancreatic neuroendocrine tumors and can be managed successfully with several strategies.
Introduction
The advent of peptide receptor radionuclide therapy (PRRT) has provided clinicians with new therapeutic strategies to treat patients with neoplasms for which treatment is less effective and where fewer options remain.1 These therapies offer a molecularly targeted means of delivering precise radiation therapy to the tumors, which are frequently metastatic and resistant to other conventional therapies. Gastroenteropancreatic neuroendocrine tumors (GEP NETs) exemplify a group of tumors that are challenging due to a high likelihood of recurrence and metastasis, and relatively few active therapies that can cause meaningful progression free survival.2 The first of these therapies approved by the US Food and Drug Administration is Lutetium Lu-177 Dotatate (TM Lutathera), an agent that includes a dotatate moiety, which binds tightly to somatostatin receptors on NET cells, and the beta-emitting radionuclide Lutetium-177, with a half-life of 6.7 days and a maximum beta range of 2 mm in tissue. This agent has been used in Europe for many years, and landmark studies have demonstrated substantial improvements in response rates and progression free survival in the GEP NET patient population.3,4 There have also been demonstrable improvements in quality of life.5 Several adverse reactions to this therapy have been reported, including renal, hepatic, and hematologic injury, and increased risk of late organ injury and secondary neoplasms.3,6, 7, 8, 9, 10 In this report, we document a flare reaction in 5 of our initial 12 patients treated and suggest therapeutic strategies to help mitigate this reaction. Although various toxicities including renal, hematologic and gastrointestional have been reported in the literature, flare reaction and suggested mitigation strategies have not been widely reported. Palliative external radiation therapy has been frequently associated with pain flare in patients with bony metastasis.11, 12, 13 The temporary use of corticosteroids has been successfully used to diminish this acute effect.14,15
Methods and Materials
As the flagship teaching hospital of one of the largest hospital systems in our state with a high volume of patients with cancer, we have closely followed the research related to PRRTs. We have also been excited about a potential therapeutic strategy to manage patients with progressive NETs. Upon lutetium Lu-177 dotatate approval by the US Food and Drug Administration, our clinical team expressed interest in initiating a program to serve patients with GEP NETs in our system, and as well as those from other hospitals and oncology programs in the state. Delivery of this agent is complex, due in particular to the need for the infusion of amino acid solution as a renal protectant. This solution is highly emetogenic, requiring pretreatment with a group of antiemetic therapies which include ondansetron, aprepitant, and dexamethasone (12-mg single dose). All patients received their monthly somatostatin analog (SSA) dose after completion of their 7-hour amino acid solution infusion. We initiated this program in 2018 through a collaborative effort of radiation oncology, radiation safety, nuclear medicine, oncology nursing, and pharmacy. We developed standard protocols, procedures, and consent; staff and patient educational materials, and documentation standards for lutetium Lu-177 receipt, administration, and patient release. These include monitoring of hematologic, renal, and hepatic function as well as patient adverse effects. By protocol, a total of 4 doses are delivered at 8-week intervals and each dose is followed by the administration of SSA to avoid competition for tumor binding sites.
Results
As seen in Table 1, we have treated 12 patients between December 2018 and April 2020. Eight were female and 4 are male. The age range at the time of treatment initiation was 45 to 77 years with a median of 66 years. All patients have GEP NETs with the exception of one patient with a NET arising from a dysplastic kidney, for whom we were able to gain authorization for treatment. All patients had documented progression of disease on SSAs. Some patients also had progression on chemotherapy or mTor inhibitors, palliative external beam irradiation, as well as prior therapy with bland, chemotherapy, or radioembolization of hepatic metastases. All patients had hepatic metastases, and most had metastasis to retroperitoneal or mesenteric nodes as well. Several patients also had bony metastases, pulmonary metastases, and other areas of metastatic disease, including subcutaneous metastases. Most patients had some symptoms of carcinoid syndrome. Some had symptoms emanating from areas of metastases, including bone pain, liver pain, small bowel dysfunction, early satiety, and neuropathic pain related to nerve compression. All patients had documentation of avidity on gallium dotatate positron emission tomography scanning before treatment initiation.Table 1 Patient characeeristics and flare reactions
Patient no./age/sex Primary site Prior therapy Flare type (CTCAE score) Mitigation success
1/69/f Sm bowel SSA, temozolomide Cranial nerve dysfunction (2) Fair
2/46/f Sm bowel SSA, pall RT Bone pain (2) Good
3/68/m Pancreas SSA, everolimus, Y90 and chemo emb
4/57/f Sm bowel SSA
5/68/f Sm bowel SSA, bland and Y90 emb Epigastric pain (2) Fair
6/56/m Sm bowel SSA, TACE Small bowel dysfunction (2) Fair
7/47/f Sm bowel SSA pSBO (3) Good
8/65/f Kidney SSA
9/68/m Sm bowel SSA, Y90
10/77/f Sm bowel SSA, TACE, ablation. Liver resection
11/73/f Sm bowel SSA, TACE, everolimus, Y90
12/45/m Pancreas SSA, everolimus
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; emb = embolization; pall = palliative; pSBO = partial small bowel obstruction; RT = radiation therapy; sm = small; SSA = somatostatin analog therapy; TACE = transarterial chemoembolization.
Five patients exhibited flare reactions of symptoms during the first week after lutetium Lu-177 dotatate therapy. Two of these were related to bone metastases. In one patient with base of skull metastases, seventh cranial nerve dysfunction was noted. In another with spine metastasis, increased spine pain occurred. In a patient with extremely bulky left liver metastasis, increased epigastric pain and early satiety occurred. In 2 patients with extensive mesenteric metastases, increased bowel dysfunction and partial small bowel obstruction occurred. All of the flare reactions were quantified by Common Terminology Criteria for Adverse Events grades 2 (4 patients) or 3 (1 patient). Mitigation with a short course of oral corticosteroids was generally successful, as well as use of symptomatic medications. Steroid courses either included a methylprednisolone dose pack or a week of prednisone 40 mg daily. In patients who developed a flare reaction after the first of 4 lutetium Lu-177 dotatate administrations, we recommended a steroid course for subsequent courses, and also elected to arrange a phone or physical visit with their radiation oncologist or medical oncologist within the first week after administration to monitor and appropriately manage flare symptoms.
Discussion
Lutetium Lu-177 dotatate has become an additional effective therapy in the management of patients with GEP NETs.3,4 It is an excellent example of a targeted molecular therapy, as it binds avidly to the somatostatin receptors on NET cells, and delivers a high radiation dose via the beta emitting isotope Lutetium-177. Its use has been associated with a high likelihood of improving progression free survival. It is therefore not unexpected that flare reactions might occur similar to those which occur through the use of external radiation therapy. Flare reactions certainly occur on occasion in patients with symptomatic bony metastases who undergo palliative radiation therapy.11,12 This reaction might be treated with a temporary course of corticosteroids, or analgesics as appropriate.14,15
In our patients with GEP NETs receiving Lutetium Lu-177 dotatate, we have observed flare reactions associated with bony metastasis and soft tissue deposits of disease, in the liver and small bowel mesentery. These flare reactions are presumably mediated by transient local edema or inflammation secondary to initial tumor cell injury. Therefore, one might conjecture that such a process could occur either in bone or soft tissue if the local environment is subject to swelling causing nerve pressure or other organ dysfunction. Given the risk of such side effects recurring with subsequent doses of the Lutetium Lu-177 dotatate, we discovered that either a short prophylactic course of corticosteroids in subsequent courses was useful, or that close monitoring in the first week after therapy was warranted to manage adverse effects as needed. The single dose of 12 mg of dexamethasone administered on the day of treatment as an antiemetic was clearly not enough to prevent the flare reaction in these patients, likely owing to concomitant timing and lack of steroid presence on subsequent days when radiation was still present.
Mitigation of flare related symptoms with steroids or symptomatic medications as judged by patient report and MD assessment was fair to good. It is likely that a patient already focally symptomatic from a GEP-NET lesion, such as in bone or soft tissue, may be at increased risk for experiencing a flare reaction. Radiation oncologists are particularly adept at managing these symptoms owing to the fact that that they may commonly occur during courses of external beam irradiation. One potential benefit of having a radiation oncologist involved in radionuclide therapy for cancer is their expertise in dealing with adverse effects which are in some ways analogous to external radiation therapy.
Conclusions
Tumor flare reactions are common with the use of Lutetium Lu-177 dotatate in the management of GEP NETs. In our series of 12 patients, 2 had flare reactions characterized by bony metastasis causing spine pain and cranial nerve dysfunction due to skull base metastasis. An additional 3 patients had flare reactions due to soft tissue metastasis causing pain due to liver metastasis in one and bowel dysfunction in 2. All flare reactions were manifested in the first of 4 administrations. Management with a short course of corticosteroids and appropriate analgesics was generally successful. Use of such strategy for the 3 subsequent courses was helpful, as was close monitoring of the patient in the week after therapy to determine what interventions might be helpful.
Sources of support: This work had no specific funding.
Disclosures: none.
Data sharing statement: All data generated and analyzed during this study are included in this published article. | 7?HOUR SOLUTION INFUSION | DrugDosageText | CC BY-NC-ND | 33490736 | 18,933,479 | 2021 |
What was the dosage of drug 'LUTETIUM OXODOTREOTIDE LU-177'? | Lutetium Lu-177 Dotatate Flare Reaction.
Lutetium Lu-177 dotatate is the first peptide receptor radionuclide therapy approved by the US Food and Drug Administration. Well-designed studies in Europe have shown dramatic effectiveness in improving progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors, which are progressive and generally metastatic. This therapy is a molecular targeted therapy linking a beta-emitting radioisotope to dotatate, which binds tightly to somatostatin receptors on neuroendocrine tumors cells. Various adverse effects of this therapy have been reported in the literature, including potential toxicity to renal, hepatic, and hematologic tissues and risk of second malignancy. Our study sought to explore acute adverse effects in this patient population.
We tracked adverse effects and patient experience in our first year of therapy experience with this new agent.
In our first 12 patients who received Lutetium Lu-177 dotatate, tumor flare reactions occurred in 5 patients due to worsening symptoms of bone or soft tissue metastasis. This flare reaction can be mitigated with short course of corticosteroid therapy or other strategies.
Flare reaction is common in patients with progressive metastatic gastroenteropancreatic neuroendocrine tumors and can be managed successfully with several strategies.
Introduction
The advent of peptide receptor radionuclide therapy (PRRT) has provided clinicians with new therapeutic strategies to treat patients with neoplasms for which treatment is less effective and where fewer options remain.1 These therapies offer a molecularly targeted means of delivering precise radiation therapy to the tumors, which are frequently metastatic and resistant to other conventional therapies. Gastroenteropancreatic neuroendocrine tumors (GEP NETs) exemplify a group of tumors that are challenging due to a high likelihood of recurrence and metastasis, and relatively few active therapies that can cause meaningful progression free survival.2 The first of these therapies approved by the US Food and Drug Administration is Lutetium Lu-177 Dotatate (TM Lutathera), an agent that includes a dotatate moiety, which binds tightly to somatostatin receptors on NET cells, and the beta-emitting radionuclide Lutetium-177, with a half-life of 6.7 days and a maximum beta range of 2 mm in tissue. This agent has been used in Europe for many years, and landmark studies have demonstrated substantial improvements in response rates and progression free survival in the GEP NET patient population.3,4 There have also been demonstrable improvements in quality of life.5 Several adverse reactions to this therapy have been reported, including renal, hepatic, and hematologic injury, and increased risk of late organ injury and secondary neoplasms.3,6, 7, 8, 9, 10 In this report, we document a flare reaction in 5 of our initial 12 patients treated and suggest therapeutic strategies to help mitigate this reaction. Although various toxicities including renal, hematologic and gastrointestional have been reported in the literature, flare reaction and suggested mitigation strategies have not been widely reported. Palliative external radiation therapy has been frequently associated with pain flare in patients with bony metastasis.11, 12, 13 The temporary use of corticosteroids has been successfully used to diminish this acute effect.14,15
Methods and Materials
As the flagship teaching hospital of one of the largest hospital systems in our state with a high volume of patients with cancer, we have closely followed the research related to PRRTs. We have also been excited about a potential therapeutic strategy to manage patients with progressive NETs. Upon lutetium Lu-177 dotatate approval by the US Food and Drug Administration, our clinical team expressed interest in initiating a program to serve patients with GEP NETs in our system, and as well as those from other hospitals and oncology programs in the state. Delivery of this agent is complex, due in particular to the need for the infusion of amino acid solution as a renal protectant. This solution is highly emetogenic, requiring pretreatment with a group of antiemetic therapies which include ondansetron, aprepitant, and dexamethasone (12-mg single dose). All patients received their monthly somatostatin analog (SSA) dose after completion of their 7-hour amino acid solution infusion. We initiated this program in 2018 through a collaborative effort of radiation oncology, radiation safety, nuclear medicine, oncology nursing, and pharmacy. We developed standard protocols, procedures, and consent; staff and patient educational materials, and documentation standards for lutetium Lu-177 receipt, administration, and patient release. These include monitoring of hematologic, renal, and hepatic function as well as patient adverse effects. By protocol, a total of 4 doses are delivered at 8-week intervals and each dose is followed by the administration of SSA to avoid competition for tumor binding sites.
Results
As seen in Table 1, we have treated 12 patients between December 2018 and April 2020. Eight were female and 4 are male. The age range at the time of treatment initiation was 45 to 77 years with a median of 66 years. All patients have GEP NETs with the exception of one patient with a NET arising from a dysplastic kidney, for whom we were able to gain authorization for treatment. All patients had documented progression of disease on SSAs. Some patients also had progression on chemotherapy or mTor inhibitors, palliative external beam irradiation, as well as prior therapy with bland, chemotherapy, or radioembolization of hepatic metastases. All patients had hepatic metastases, and most had metastasis to retroperitoneal or mesenteric nodes as well. Several patients also had bony metastases, pulmonary metastases, and other areas of metastatic disease, including subcutaneous metastases. Most patients had some symptoms of carcinoid syndrome. Some had symptoms emanating from areas of metastases, including bone pain, liver pain, small bowel dysfunction, early satiety, and neuropathic pain related to nerve compression. All patients had documentation of avidity on gallium dotatate positron emission tomography scanning before treatment initiation.Table 1 Patient characeeristics and flare reactions
Patient no./age/sex Primary site Prior therapy Flare type (CTCAE score) Mitigation success
1/69/f Sm bowel SSA, temozolomide Cranial nerve dysfunction (2) Fair
2/46/f Sm bowel SSA, pall RT Bone pain (2) Good
3/68/m Pancreas SSA, everolimus, Y90 and chemo emb
4/57/f Sm bowel SSA
5/68/f Sm bowel SSA, bland and Y90 emb Epigastric pain (2) Fair
6/56/m Sm bowel SSA, TACE Small bowel dysfunction (2) Fair
7/47/f Sm bowel SSA pSBO (3) Good
8/65/f Kidney SSA
9/68/m Sm bowel SSA, Y90
10/77/f Sm bowel SSA, TACE, ablation. Liver resection
11/73/f Sm bowel SSA, TACE, everolimus, Y90
12/45/m Pancreas SSA, everolimus
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; emb = embolization; pall = palliative; pSBO = partial small bowel obstruction; RT = radiation therapy; sm = small; SSA = somatostatin analog therapy; TACE = transarterial chemoembolization.
Five patients exhibited flare reactions of symptoms during the first week after lutetium Lu-177 dotatate therapy. Two of these were related to bone metastases. In one patient with base of skull metastases, seventh cranial nerve dysfunction was noted. In another with spine metastasis, increased spine pain occurred. In a patient with extremely bulky left liver metastasis, increased epigastric pain and early satiety occurred. In 2 patients with extensive mesenteric metastases, increased bowel dysfunction and partial small bowel obstruction occurred. All of the flare reactions were quantified by Common Terminology Criteria for Adverse Events grades 2 (4 patients) or 3 (1 patient). Mitigation with a short course of oral corticosteroids was generally successful, as well as use of symptomatic medications. Steroid courses either included a methylprednisolone dose pack or a week of prednisone 40 mg daily. In patients who developed a flare reaction after the first of 4 lutetium Lu-177 dotatate administrations, we recommended a steroid course for subsequent courses, and also elected to arrange a phone or physical visit with their radiation oncologist or medical oncologist within the first week after administration to monitor and appropriately manage flare symptoms.
Discussion
Lutetium Lu-177 dotatate has become an additional effective therapy in the management of patients with GEP NETs.3,4 It is an excellent example of a targeted molecular therapy, as it binds avidly to the somatostatin receptors on NET cells, and delivers a high radiation dose via the beta emitting isotope Lutetium-177. Its use has been associated with a high likelihood of improving progression free survival. It is therefore not unexpected that flare reactions might occur similar to those which occur through the use of external radiation therapy. Flare reactions certainly occur on occasion in patients with symptomatic bony metastases who undergo palliative radiation therapy.11,12 This reaction might be treated with a temporary course of corticosteroids, or analgesics as appropriate.14,15
In our patients with GEP NETs receiving Lutetium Lu-177 dotatate, we have observed flare reactions associated with bony metastasis and soft tissue deposits of disease, in the liver and small bowel mesentery. These flare reactions are presumably mediated by transient local edema or inflammation secondary to initial tumor cell injury. Therefore, one might conjecture that such a process could occur either in bone or soft tissue if the local environment is subject to swelling causing nerve pressure or other organ dysfunction. Given the risk of such side effects recurring with subsequent doses of the Lutetium Lu-177 dotatate, we discovered that either a short prophylactic course of corticosteroids in subsequent courses was useful, or that close monitoring in the first week after therapy was warranted to manage adverse effects as needed. The single dose of 12 mg of dexamethasone administered on the day of treatment as an antiemetic was clearly not enough to prevent the flare reaction in these patients, likely owing to concomitant timing and lack of steroid presence on subsequent days when radiation was still present.
Mitigation of flare related symptoms with steroids or symptomatic medications as judged by patient report and MD assessment was fair to good. It is likely that a patient already focally symptomatic from a GEP-NET lesion, such as in bone or soft tissue, may be at increased risk for experiencing a flare reaction. Radiation oncologists are particularly adept at managing these symptoms owing to the fact that that they may commonly occur during courses of external beam irradiation. One potential benefit of having a radiation oncologist involved in radionuclide therapy for cancer is their expertise in dealing with adverse effects which are in some ways analogous to external radiation therapy.
Conclusions
Tumor flare reactions are common with the use of Lutetium Lu-177 dotatate in the management of GEP NETs. In our series of 12 patients, 2 had flare reactions characterized by bony metastasis causing spine pain and cranial nerve dysfunction due to skull base metastasis. An additional 3 patients had flare reactions due to soft tissue metastasis causing pain due to liver metastasis in one and bowel dysfunction in 2. All flare reactions were manifested in the first of 4 administrations. Management with a short course of corticosteroids and appropriate analgesics was generally successful. Use of such strategy for the 3 subsequent courses was helpful, as was close monitoring of the patient in the week after therapy to determine what interventions might be helpful.
Sources of support: This work had no specific funding.
Disclosures: none.
Data sharing statement: All data generated and analyzed during this study are included in this published article. | 4 DF DELIVERED AT 8 WEEK INTERVAL | DrugDosageText | CC BY-NC-ND | 33490736 | 18,922,597 | 2021 |
What was the dosage of drug 'SOMATOSTATIN'? | Lutetium Lu-177 Dotatate Flare Reaction.
Lutetium Lu-177 dotatate is the first peptide receptor radionuclide therapy approved by the US Food and Drug Administration. Well-designed studies in Europe have shown dramatic effectiveness in improving progression-free survival in patients with gastroenteropancreatic neuroendocrine tumors, which are progressive and generally metastatic. This therapy is a molecular targeted therapy linking a beta-emitting radioisotope to dotatate, which binds tightly to somatostatin receptors on neuroendocrine tumors cells. Various adverse effects of this therapy have been reported in the literature, including potential toxicity to renal, hepatic, and hematologic tissues and risk of second malignancy. Our study sought to explore acute adverse effects in this patient population.
We tracked adverse effects and patient experience in our first year of therapy experience with this new agent.
In our first 12 patients who received Lutetium Lu-177 dotatate, tumor flare reactions occurred in 5 patients due to worsening symptoms of bone or soft tissue metastasis. This flare reaction can be mitigated with short course of corticosteroid therapy or other strategies.
Flare reaction is common in patients with progressive metastatic gastroenteropancreatic neuroendocrine tumors and can be managed successfully with several strategies.
Introduction
The advent of peptide receptor radionuclide therapy (PRRT) has provided clinicians with new therapeutic strategies to treat patients with neoplasms for which treatment is less effective and where fewer options remain.1 These therapies offer a molecularly targeted means of delivering precise radiation therapy to the tumors, which are frequently metastatic and resistant to other conventional therapies. Gastroenteropancreatic neuroendocrine tumors (GEP NETs) exemplify a group of tumors that are challenging due to a high likelihood of recurrence and metastasis, and relatively few active therapies that can cause meaningful progression free survival.2 The first of these therapies approved by the US Food and Drug Administration is Lutetium Lu-177 Dotatate (TM Lutathera), an agent that includes a dotatate moiety, which binds tightly to somatostatin receptors on NET cells, and the beta-emitting radionuclide Lutetium-177, with a half-life of 6.7 days and a maximum beta range of 2 mm in tissue. This agent has been used in Europe for many years, and landmark studies have demonstrated substantial improvements in response rates and progression free survival in the GEP NET patient population.3,4 There have also been demonstrable improvements in quality of life.5 Several adverse reactions to this therapy have been reported, including renal, hepatic, and hematologic injury, and increased risk of late organ injury and secondary neoplasms.3,6, 7, 8, 9, 10 In this report, we document a flare reaction in 5 of our initial 12 patients treated and suggest therapeutic strategies to help mitigate this reaction. Although various toxicities including renal, hematologic and gastrointestional have been reported in the literature, flare reaction and suggested mitigation strategies have not been widely reported. Palliative external radiation therapy has been frequently associated with pain flare in patients with bony metastasis.11, 12, 13 The temporary use of corticosteroids has been successfully used to diminish this acute effect.14,15
Methods and Materials
As the flagship teaching hospital of one of the largest hospital systems in our state with a high volume of patients with cancer, we have closely followed the research related to PRRTs. We have also been excited about a potential therapeutic strategy to manage patients with progressive NETs. Upon lutetium Lu-177 dotatate approval by the US Food and Drug Administration, our clinical team expressed interest in initiating a program to serve patients with GEP NETs in our system, and as well as those from other hospitals and oncology programs in the state. Delivery of this agent is complex, due in particular to the need for the infusion of amino acid solution as a renal protectant. This solution is highly emetogenic, requiring pretreatment with a group of antiemetic therapies which include ondansetron, aprepitant, and dexamethasone (12-mg single dose). All patients received their monthly somatostatin analog (SSA) dose after completion of their 7-hour amino acid solution infusion. We initiated this program in 2018 through a collaborative effort of radiation oncology, radiation safety, nuclear medicine, oncology nursing, and pharmacy. We developed standard protocols, procedures, and consent; staff and patient educational materials, and documentation standards for lutetium Lu-177 receipt, administration, and patient release. These include monitoring of hematologic, renal, and hepatic function as well as patient adverse effects. By protocol, a total of 4 doses are delivered at 8-week intervals and each dose is followed by the administration of SSA to avoid competition for tumor binding sites.
Results
As seen in Table 1, we have treated 12 patients between December 2018 and April 2020. Eight were female and 4 are male. The age range at the time of treatment initiation was 45 to 77 years with a median of 66 years. All patients have GEP NETs with the exception of one patient with a NET arising from a dysplastic kidney, for whom we were able to gain authorization for treatment. All patients had documented progression of disease on SSAs. Some patients also had progression on chemotherapy or mTor inhibitors, palliative external beam irradiation, as well as prior therapy with bland, chemotherapy, or radioembolization of hepatic metastases. All patients had hepatic metastases, and most had metastasis to retroperitoneal or mesenteric nodes as well. Several patients also had bony metastases, pulmonary metastases, and other areas of metastatic disease, including subcutaneous metastases. Most patients had some symptoms of carcinoid syndrome. Some had symptoms emanating from areas of metastases, including bone pain, liver pain, small bowel dysfunction, early satiety, and neuropathic pain related to nerve compression. All patients had documentation of avidity on gallium dotatate positron emission tomography scanning before treatment initiation.Table 1 Patient characeeristics and flare reactions
Patient no./age/sex Primary site Prior therapy Flare type (CTCAE score) Mitigation success
1/69/f Sm bowel SSA, temozolomide Cranial nerve dysfunction (2) Fair
2/46/f Sm bowel SSA, pall RT Bone pain (2) Good
3/68/m Pancreas SSA, everolimus, Y90 and chemo emb
4/57/f Sm bowel SSA
5/68/f Sm bowel SSA, bland and Y90 emb Epigastric pain (2) Fair
6/56/m Sm bowel SSA, TACE Small bowel dysfunction (2) Fair
7/47/f Sm bowel SSA pSBO (3) Good
8/65/f Kidney SSA
9/68/m Sm bowel SSA, Y90
10/77/f Sm bowel SSA, TACE, ablation. Liver resection
11/73/f Sm bowel SSA, TACE, everolimus, Y90
12/45/m Pancreas SSA, everolimus
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; emb = embolization; pall = palliative; pSBO = partial small bowel obstruction; RT = radiation therapy; sm = small; SSA = somatostatin analog therapy; TACE = transarterial chemoembolization.
Five patients exhibited flare reactions of symptoms during the first week after lutetium Lu-177 dotatate therapy. Two of these were related to bone metastases. In one patient with base of skull metastases, seventh cranial nerve dysfunction was noted. In another with spine metastasis, increased spine pain occurred. In a patient with extremely bulky left liver metastasis, increased epigastric pain and early satiety occurred. In 2 patients with extensive mesenteric metastases, increased bowel dysfunction and partial small bowel obstruction occurred. All of the flare reactions were quantified by Common Terminology Criteria for Adverse Events grades 2 (4 patients) or 3 (1 patient). Mitigation with a short course of oral corticosteroids was generally successful, as well as use of symptomatic medications. Steroid courses either included a methylprednisolone dose pack or a week of prednisone 40 mg daily. In patients who developed a flare reaction after the first of 4 lutetium Lu-177 dotatate administrations, we recommended a steroid course for subsequent courses, and also elected to arrange a phone or physical visit with their radiation oncologist or medical oncologist within the first week after administration to monitor and appropriately manage flare symptoms.
Discussion
Lutetium Lu-177 dotatate has become an additional effective therapy in the management of patients with GEP NETs.3,4 It is an excellent example of a targeted molecular therapy, as it binds avidly to the somatostatin receptors on NET cells, and delivers a high radiation dose via the beta emitting isotope Lutetium-177. Its use has been associated with a high likelihood of improving progression free survival. It is therefore not unexpected that flare reactions might occur similar to those which occur through the use of external radiation therapy. Flare reactions certainly occur on occasion in patients with symptomatic bony metastases who undergo palliative radiation therapy.11,12 This reaction might be treated with a temporary course of corticosteroids, or analgesics as appropriate.14,15
In our patients with GEP NETs receiving Lutetium Lu-177 dotatate, we have observed flare reactions associated with bony metastasis and soft tissue deposits of disease, in the liver and small bowel mesentery. These flare reactions are presumably mediated by transient local edema or inflammation secondary to initial tumor cell injury. Therefore, one might conjecture that such a process could occur either in bone or soft tissue if the local environment is subject to swelling causing nerve pressure or other organ dysfunction. Given the risk of such side effects recurring with subsequent doses of the Lutetium Lu-177 dotatate, we discovered that either a short prophylactic course of corticosteroids in subsequent courses was useful, or that close monitoring in the first week after therapy was warranted to manage adverse effects as needed. The single dose of 12 mg of dexamethasone administered on the day of treatment as an antiemetic was clearly not enough to prevent the flare reaction in these patients, likely owing to concomitant timing and lack of steroid presence on subsequent days when radiation was still present.
Mitigation of flare related symptoms with steroids or symptomatic medications as judged by patient report and MD assessment was fair to good. It is likely that a patient already focally symptomatic from a GEP-NET lesion, such as in bone or soft tissue, may be at increased risk for experiencing a flare reaction. Radiation oncologists are particularly adept at managing these symptoms owing to the fact that that they may commonly occur during courses of external beam irradiation. One potential benefit of having a radiation oncologist involved in radionuclide therapy for cancer is their expertise in dealing with adverse effects which are in some ways analogous to external radiation therapy.
Conclusions
Tumor flare reactions are common with the use of Lutetium Lu-177 dotatate in the management of GEP NETs. In our series of 12 patients, 2 had flare reactions characterized by bony metastasis causing spine pain and cranial nerve dysfunction due to skull base metastasis. An additional 3 patients had flare reactions due to soft tissue metastasis causing pain due to liver metastasis in one and bowel dysfunction in 2. All flare reactions were manifested in the first of 4 administrations. Management with a short course of corticosteroids and appropriate analgesics was generally successful. Use of such strategy for the 3 subsequent courses was helpful, as was close monitoring of the patient in the week after therapy to determine what interventions might be helpful.
Sources of support: This work had no specific funding.
Disclosures: none.
Data sharing statement: All data generated and analyzed during this study are included in this published article. | UNK, MONTHLY | DrugDosageText | CC BY-NC-ND | 33490736 | 18,933,479 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug abuse'. | Focal bilateral motor seizures precipitated by abrupt cessation of chronic lormetazepam abuse and amitriptyline overdose.
We report the case of an adult psychiatric patient who developed new-onset focal bilateral motor seizures (FBMS) in the context of a severe benzodiazepine withdrawal syndrome. The patient was forced to interrupt chronic lormetazepam abuse and overdosed on amitriptyline (800 mg in an oral solution) before the onset of seizures. Typical signs of amitriptyline intoxication such as sedation and anticholinergic effects were not observed. Video-EEG recordings revealed a stereotypical ictal motor pattern with asymmetric tonic posturing and bilateral clonic movements of the upper limbs, but there were no abnormalities identified by EEG. Seizures recurred multiple times per day but resolved simultaneously when withdrawal symptomatology subsided eight days after onset. Nonepileptic seizures (NES) were considered in the differential diagnosis because of the patient's psychiatric history including preserved awareness during the bilateral convulsions, the absence of postictal confusion, and normal EEG. The present case indicates that FBMS may occur during benzodiazepine withdrawal in patients who overdosed on amitriptyline. The diagnosis may be challenging as FBMS may mimic NES in the absence of abnormal neurophysiologic findings. This may be especially challenging in patients with an underlying psychiatric disease.
1 Introduction
Epileptic seizures (ES) have been frequently reported as clinical manifestations of benzodiazepine withdrawal, an acute disorder precipitated by an abrupt discontinuation of chronic therapies including benzodiazepines. The withdrawal symptomatology may also include insomnia, irritability, muscular pain and stiffness, hand tremor, anxiety, and psychotic episodes [1]. An acute reduction in brain gamma-aminobutyric acid function has been indicated as a pathogenic mechanism of the syndrome [2]. While generalized tonic–clonic seizures are the most common, focal seizures are rarely reported in this condition. Particularly, focal nonconvulsive seizures have been described in patients treated with flumazenil during detoxification from lormetazepam abuse [3].
2 Case report
A 46-year-old woman with a clinical history of schizoaffective and personality disorders presented to our hospital with new-onset convulsive seizures. It was reported that the patient was forced to interrupt chronic lormetazepam abuse (a daily drug consumption of 150–250 mg of an oral solution) the day before the onset of seizures. When she ran out of the medication, she ingested an oral solution containing 800 mg of amitriptyline as a supposed sedative substitute for lormetazepam. Convulsive seizures recurred multiple times per day in the hospital during daytime and night-time hours in a clinical context of insomnia, restlessness, muscular rigidity, and painful spasms affecting the back muscles that implicated a benzodiazepine withdrawal syndrome. There was no evidence of amitriptyline toxicity, as the patient did not show sedation, anticholinergic effects, arterial hypotension, or cardiac arrhythmias. The amitriptyline blood level was not obtained. Seizures presented with a duration of approximately 53 s and a paroxysmal, stereotyped sequence of movements that was documented with video-EEG. The recordings of seizures, using the usual 10–20 system of electrode placement, did not show EEG abnormalities or postictal slowing of the background activity, but the tracings were disturbed by myogenic artifacts throughout the course of the events (Fig. 1, Fig. 2). Awareness was preserved during the episodes. The patient occasionally called for help at seizure onset but remained unresponsive until the cessation of movements. Rapid recovery of speech and an absence of postictal confusion were reported on different occasions. Magnetic resonance imaging of the brain was normal. Three days after the patient's admission, a cluster of convulsive episodes prompted a short intensive treatment with propofol and mechanical ventilation. Seizures were increasingly observed again after extubation, despite oral treatment with clonazepam, levetiracetam, and repeated intravenous administrations of diazepam. Regardless of the inefficacy of the treatment during an eight-day period of intense seizure activity, the patient eventually became seizure-free. The remission of seizures occurred simultaneously with the cessation of insomnia and muscular symptoms related to lormetazepam withdrawal. Clonazepam and levetiracetam were subsequently reduced and discontinued as the patient remained asymptomatic. Despite the absence of ictal EEG abnormalities, a retrospective analysis of the seizure semiology based on video recordings and additional recorded observations of the episodes at bedside suggested the clinical diagnosis of FBMS, presumably arising from the supplementary sensorimotor area (SSMA). This diagnostic conclusion was supported by the evidence of a paroxysmal, stereotyped ictal motor pattern with early abduction of the arm flexed at the elbow and subsequent asymmetric tonic posturing of the upper limb that reproduced the figure four sign [4] at seizure onset. The left arm was extended, and the right arm was flexed (at the elbow), while the head was briefly turned to the left at this point of the seizure. Consequent bilateral clonic movements of the upper limbs showed a typical epileptic pattern with a gradual frequency decline and a progressive amplitude increase of movements [5]. A stereotyped left hemifacial spasm was also noted during the tonic contraction of the upper limbs. The short duration of the episodes, occasional evidence of cyanosis and lack of pupillary reactivity served as additional clues to the ES diagnosis. Although the clinical picture was initially confounded by the patient's preserved awareness during the bilateral convulsions, the absence of postictal confusion, and the normal EEG findings, these features finally appeared consistent with FBMS arising in the SSMA, as previously reported in the literature [[6], [7], [8]]. The patient was discharged with a normal neurologic status nine days after the last convulsive episode. Seizures did not recur even without antiseizure medication during the following month, after which the patient was lost to follow-up.Fig. 1 EEG recording of the initial phase of a focal bilateral motor seizure with a still-frame from the video.
EEG recording of the initial phase of a focal bilateral motor seizure with a still-frame from the video.
The EEG does not reveal evident abnormalities at seizure onset. The tracing is progressively disturbed by myogenic artifacts during the evolution of the seizure motor pattern.
Fig. 1Fig. 2 EEG recording of the final phase of a focal bilateral motor seizure.
Phasic myogenic artifacts mark the tracing during the ending clonic phase of the seizure. The EEG shows the persistence of the background activity in the immediate postictal period.
Fig. 2
3 Discussion
The manifestation of convulsive seizures without EEG abnormalities in the context of benzodiazepine withdrawal syndrome and psychiatric disease requires a differential diagnosis of ES and nonepileptic seizures (NES). In fact, the abrupt interruption of high dosage, chronic benzodiazepine treatment represents a potential precipitating factor for ES, while NES are occasionally observed as imitators of epilepsy in patients with mental health problems [9,10]. In addition to the psychiatric disorders and the normal neurophysiologic findings, the patient's preserved awareness during the bilateral convulsions and the absence of postictal confusion confounded the clinical picture with the potential to misdiagnose FBMS as NES. FBMS are described as motor onset seizures arising in one cerebral hemisphere and rapidly involving bilateral motor networks, often with asymmetric tonic posturing [11]. The SSMA is classically recognized as the anatomical origin of FBMS [11]. Clinical characteristics of focal onset seizures arising in the SSMA include short duration (typically not exceeding 40 s) [6,12]; predominant onset during sleep [6,8]; somatosensory aura [8,13]; preserved awareness [6,8,13]; absence of postictal confusion [8]; vocalization or speech arrest [6,8,13]; unilateral tonic posturing [8,13] or bilateral, asymmetric tonic posturing [4,13,14]; bilateral abduction of the upper extremities [6]; and bilateral thrashing movements [6,8] that usually constitute a paroxysmal, stereotyped motor pattern in the same individual [6]. Particularly, asymmetric tonic posturing has been related to the asynchronous activation of the SSMA [4,14], thus representing a key semiologic feature of seizures involving this cortical area [8,12]. Authors have also referred to asymmetric tonic posturing as the figure four sign that marks focal to bilateral tonic–clonic seizures [4]. The lateralizing value of this sign has been repeatedly reported with the epileptogenic focus usually contralateral to the arm that is extended at the elbow [4,14]. In contrast, NES with convulsive-like manifestations are characterized by long duration (frequently exceeding 2 min); fluctuating course; and asynchronous movements (typically side-to-side head movements and out of phase limb movements) that show unchanged frequency and variable amplitude throughout the event [10].
In our patient, the convulsive disorders shared most of the mentioned clinical characteristics of focal onset seizures arising in the SSMA. In particular, the origin of ictal symptoms in the SSMA was suggested by the early stereotyped contraction of the left arm and consequent asymmetric tonic posturing of limbs, while a left hemifacial spasm appeared consistent with the presumed epileptic focus in the right cerebral hemisphere. The progression of these phenomena to bilateral, tonic extension and clonic movements of the upper extremities characterized the final phase of the motor pattern mimicking focal to bilateral tonic–clonic seizures. However, the absence of awareness impairments, postictal confusion and EEG slowing in the immediate postictal phase discredited the apparent bilateral tonic–clonic evolution of focal seizures, suggesting limited epileptic involvement of the SSMA during the entire course of the events. While the seizure semiology could be referred to FBMS arising from the SSMA, the absence of ictal EEG abnormalities to confirm epileptic seizures is a limiting factor for the diagnosis of frontal lobe seizures. This suggests the potential utility of EEG recordings with additional midline electrodes (placed according to the 10–10 system) and/or ictal SPECT, as a supplementary method to confirm the epileptic nature and the anatomical origin of the seizures. However, it is not uncommon for seizures arising in the mesial and deep structures of the frontal lobe to have absent scalp ictal EEG changes utilizing the 10-20 international system of electrode placement.
Although structural brain abnormalities were not documented in our patient, neurochemical alterations induced by benzodiazepine withdrawal into specific networks may have resulted in a major seizure susceptibility of the SSMA. Interestingly, a major intrinsic epileptogenicity of specific cortical areas has been postulated by Albiero et al. to explain the occurrence of focal seizures in patients who underwent detoxification from chronic lormetazepam abuse [3]. Additional information is needed to ascertain the major occurrence of focal seizures in patients who interrupted chronic lormetazepam abuse. Although amitriptyline may have lowered the seizure threshold, the precise clinical impact of the substitution remains uncertain in our patient, as typical symptoms of amitriptyline intoxication such as sedation, arterial hypotension, cardiac arrhythmias or anticholinergic effects [15] were not observed during the period of recurrent seizures. In contrast, the strict concomitance of seizures with classic benzodiazepine abstinence symptoms such as insomnia, restlessness, rigidity, and muscular pain clearly indicated the primary precipitating role of lormetazepam withdrawal. A previous report remarked that lormetazepam is the benzodiazepine that is most frequently associated with abuse and dependence [16], particularly when it is used in the form of an oral solution [17]. The presence of ethanol in the oral solution of lormetazepam has been specifically suspected to increase the risks for abuse and dependence. Although ethanol quantities may not be relevant in patients treated with accurate doses of lormetazepam (1.5–2.5 mg daily for insomnia), the pathogenic effect of ethanol may be significant in lormetazepam addicted patients. The present case provides additional information about the risks of lormetazepam addiction as a component of psychiatric care. We suggest strict monitoring of patients treated with an oral solution of this medication.
4 Conclusion
FBMS may be observed during the clinical manifestation of lormetazepam withdrawal in patients who overdosed on amitriptyline. FBMS may produce a confusing clinical picture, with the potential to misdiagnose NES, especially when no abnormal neurophysiologic findings are clearly identified and when patients have a known underlying psychiatric disease.
The following is the supplementary data related to this article.Video 1
Focal bilateral motor seizure precipitated by lormetazepam withdrawal and amitriptyline overdose.
The seizure begins with a tonic posture of the left hand and abduction of the left arm flexed at the elbow. The left arm is then elevated and extended anteriorly, while the right arm is initially flexed at the elbow and rotated inward, reproducing the figure four sign. The head is briefly turned to the left during the asymmetric posturing of the upper extremities. Consequently, the right arm is also extended anteriorly. A slight facial cyanosis and a grimace with left hemifacial spasm (consistent with the presumed origin of the seizure in the right cerebral hemisphere) are noted during the extension of the upper limbs. There is no eye blink at the threatening gesture or pupillary response to the light at this point of the seizure. Convulsions cease with a sequence of vibratory and clonic movements of the upper extremities and trunk. The duration of the seizure is approximately 53 s and amitriptyline overdose.
Video 1
Ethical statement
The authors state that the study described in the paper complies with the publishing ethics of the journal.
The patient’s face has been partially obscured in the attached video, as requested by the patient herself at the time of the given consent.
Declaration of competing interest
The authors state that there is no conflict of interest. | AMITRIPTYLINE, CLONAZEPAM, DIAZEPAM, LEVETIRACETAM, LORMETAZEPAM | DrugsGivenReaction | CC BY-NC-ND | 33490945 | 18,821,337 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug withdrawal syndrome'. | Focal bilateral motor seizures precipitated by abrupt cessation of chronic lormetazepam abuse and amitriptyline overdose.
We report the case of an adult psychiatric patient who developed new-onset focal bilateral motor seizures (FBMS) in the context of a severe benzodiazepine withdrawal syndrome. The patient was forced to interrupt chronic lormetazepam abuse and overdosed on amitriptyline (800 mg in an oral solution) before the onset of seizures. Typical signs of amitriptyline intoxication such as sedation and anticholinergic effects were not observed. Video-EEG recordings revealed a stereotypical ictal motor pattern with asymmetric tonic posturing and bilateral clonic movements of the upper limbs, but there were no abnormalities identified by EEG. Seizures recurred multiple times per day but resolved simultaneously when withdrawal symptomatology subsided eight days after onset. Nonepileptic seizures (NES) were considered in the differential diagnosis because of the patient's psychiatric history including preserved awareness during the bilateral convulsions, the absence of postictal confusion, and normal EEG. The present case indicates that FBMS may occur during benzodiazepine withdrawal in patients who overdosed on amitriptyline. The diagnosis may be challenging as FBMS may mimic NES in the absence of abnormal neurophysiologic findings. This may be especially challenging in patients with an underlying psychiatric disease.
1 Introduction
Epileptic seizures (ES) have been frequently reported as clinical manifestations of benzodiazepine withdrawal, an acute disorder precipitated by an abrupt discontinuation of chronic therapies including benzodiazepines. The withdrawal symptomatology may also include insomnia, irritability, muscular pain and stiffness, hand tremor, anxiety, and psychotic episodes [1]. An acute reduction in brain gamma-aminobutyric acid function has been indicated as a pathogenic mechanism of the syndrome [2]. While generalized tonic–clonic seizures are the most common, focal seizures are rarely reported in this condition. Particularly, focal nonconvulsive seizures have been described in patients treated with flumazenil during detoxification from lormetazepam abuse [3].
2 Case report
A 46-year-old woman with a clinical history of schizoaffective and personality disorders presented to our hospital with new-onset convulsive seizures. It was reported that the patient was forced to interrupt chronic lormetazepam abuse (a daily drug consumption of 150–250 mg of an oral solution) the day before the onset of seizures. When she ran out of the medication, she ingested an oral solution containing 800 mg of amitriptyline as a supposed sedative substitute for lormetazepam. Convulsive seizures recurred multiple times per day in the hospital during daytime and night-time hours in a clinical context of insomnia, restlessness, muscular rigidity, and painful spasms affecting the back muscles that implicated a benzodiazepine withdrawal syndrome. There was no evidence of amitriptyline toxicity, as the patient did not show sedation, anticholinergic effects, arterial hypotension, or cardiac arrhythmias. The amitriptyline blood level was not obtained. Seizures presented with a duration of approximately 53 s and a paroxysmal, stereotyped sequence of movements that was documented with video-EEG. The recordings of seizures, using the usual 10–20 system of electrode placement, did not show EEG abnormalities or postictal slowing of the background activity, but the tracings were disturbed by myogenic artifacts throughout the course of the events (Fig. 1, Fig. 2). Awareness was preserved during the episodes. The patient occasionally called for help at seizure onset but remained unresponsive until the cessation of movements. Rapid recovery of speech and an absence of postictal confusion were reported on different occasions. Magnetic resonance imaging of the brain was normal. Three days after the patient's admission, a cluster of convulsive episodes prompted a short intensive treatment with propofol and mechanical ventilation. Seizures were increasingly observed again after extubation, despite oral treatment with clonazepam, levetiracetam, and repeated intravenous administrations of diazepam. Regardless of the inefficacy of the treatment during an eight-day period of intense seizure activity, the patient eventually became seizure-free. The remission of seizures occurred simultaneously with the cessation of insomnia and muscular symptoms related to lormetazepam withdrawal. Clonazepam and levetiracetam were subsequently reduced and discontinued as the patient remained asymptomatic. Despite the absence of ictal EEG abnormalities, a retrospective analysis of the seizure semiology based on video recordings and additional recorded observations of the episodes at bedside suggested the clinical diagnosis of FBMS, presumably arising from the supplementary sensorimotor area (SSMA). This diagnostic conclusion was supported by the evidence of a paroxysmal, stereotyped ictal motor pattern with early abduction of the arm flexed at the elbow and subsequent asymmetric tonic posturing of the upper limb that reproduced the figure four sign [4] at seizure onset. The left arm was extended, and the right arm was flexed (at the elbow), while the head was briefly turned to the left at this point of the seizure. Consequent bilateral clonic movements of the upper limbs showed a typical epileptic pattern with a gradual frequency decline and a progressive amplitude increase of movements [5]. A stereotyped left hemifacial spasm was also noted during the tonic contraction of the upper limbs. The short duration of the episodes, occasional evidence of cyanosis and lack of pupillary reactivity served as additional clues to the ES diagnosis. Although the clinical picture was initially confounded by the patient's preserved awareness during the bilateral convulsions, the absence of postictal confusion, and the normal EEG findings, these features finally appeared consistent with FBMS arising in the SSMA, as previously reported in the literature [[6], [7], [8]]. The patient was discharged with a normal neurologic status nine days after the last convulsive episode. Seizures did not recur even without antiseizure medication during the following month, after which the patient was lost to follow-up.Fig. 1 EEG recording of the initial phase of a focal bilateral motor seizure with a still-frame from the video.
EEG recording of the initial phase of a focal bilateral motor seizure with a still-frame from the video.
The EEG does not reveal evident abnormalities at seizure onset. The tracing is progressively disturbed by myogenic artifacts during the evolution of the seizure motor pattern.
Fig. 1Fig. 2 EEG recording of the final phase of a focal bilateral motor seizure.
Phasic myogenic artifacts mark the tracing during the ending clonic phase of the seizure. The EEG shows the persistence of the background activity in the immediate postictal period.
Fig. 2
3 Discussion
The manifestation of convulsive seizures without EEG abnormalities in the context of benzodiazepine withdrawal syndrome and psychiatric disease requires a differential diagnosis of ES and nonepileptic seizures (NES). In fact, the abrupt interruption of high dosage, chronic benzodiazepine treatment represents a potential precipitating factor for ES, while NES are occasionally observed as imitators of epilepsy in patients with mental health problems [9,10]. In addition to the psychiatric disorders and the normal neurophysiologic findings, the patient's preserved awareness during the bilateral convulsions and the absence of postictal confusion confounded the clinical picture with the potential to misdiagnose FBMS as NES. FBMS are described as motor onset seizures arising in one cerebral hemisphere and rapidly involving bilateral motor networks, often with asymmetric tonic posturing [11]. The SSMA is classically recognized as the anatomical origin of FBMS [11]. Clinical characteristics of focal onset seizures arising in the SSMA include short duration (typically not exceeding 40 s) [6,12]; predominant onset during sleep [6,8]; somatosensory aura [8,13]; preserved awareness [6,8,13]; absence of postictal confusion [8]; vocalization or speech arrest [6,8,13]; unilateral tonic posturing [8,13] or bilateral, asymmetric tonic posturing [4,13,14]; bilateral abduction of the upper extremities [6]; and bilateral thrashing movements [6,8] that usually constitute a paroxysmal, stereotyped motor pattern in the same individual [6]. Particularly, asymmetric tonic posturing has been related to the asynchronous activation of the SSMA [4,14], thus representing a key semiologic feature of seizures involving this cortical area [8,12]. Authors have also referred to asymmetric tonic posturing as the figure four sign that marks focal to bilateral tonic–clonic seizures [4]. The lateralizing value of this sign has been repeatedly reported with the epileptogenic focus usually contralateral to the arm that is extended at the elbow [4,14]. In contrast, NES with convulsive-like manifestations are characterized by long duration (frequently exceeding 2 min); fluctuating course; and asynchronous movements (typically side-to-side head movements and out of phase limb movements) that show unchanged frequency and variable amplitude throughout the event [10].
In our patient, the convulsive disorders shared most of the mentioned clinical characteristics of focal onset seizures arising in the SSMA. In particular, the origin of ictal symptoms in the SSMA was suggested by the early stereotyped contraction of the left arm and consequent asymmetric tonic posturing of limbs, while a left hemifacial spasm appeared consistent with the presumed epileptic focus in the right cerebral hemisphere. The progression of these phenomena to bilateral, tonic extension and clonic movements of the upper extremities characterized the final phase of the motor pattern mimicking focal to bilateral tonic–clonic seizures. However, the absence of awareness impairments, postictal confusion and EEG slowing in the immediate postictal phase discredited the apparent bilateral tonic–clonic evolution of focal seizures, suggesting limited epileptic involvement of the SSMA during the entire course of the events. While the seizure semiology could be referred to FBMS arising from the SSMA, the absence of ictal EEG abnormalities to confirm epileptic seizures is a limiting factor for the diagnosis of frontal lobe seizures. This suggests the potential utility of EEG recordings with additional midline electrodes (placed according to the 10–10 system) and/or ictal SPECT, as a supplementary method to confirm the epileptic nature and the anatomical origin of the seizures. However, it is not uncommon for seizures arising in the mesial and deep structures of the frontal lobe to have absent scalp ictal EEG changes utilizing the 10-20 international system of electrode placement.
Although structural brain abnormalities were not documented in our patient, neurochemical alterations induced by benzodiazepine withdrawal into specific networks may have resulted in a major seizure susceptibility of the SSMA. Interestingly, a major intrinsic epileptogenicity of specific cortical areas has been postulated by Albiero et al. to explain the occurrence of focal seizures in patients who underwent detoxification from chronic lormetazepam abuse [3]. Additional information is needed to ascertain the major occurrence of focal seizures in patients who interrupted chronic lormetazepam abuse. Although amitriptyline may have lowered the seizure threshold, the precise clinical impact of the substitution remains uncertain in our patient, as typical symptoms of amitriptyline intoxication such as sedation, arterial hypotension, cardiac arrhythmias or anticholinergic effects [15] were not observed during the period of recurrent seizures. In contrast, the strict concomitance of seizures with classic benzodiazepine abstinence symptoms such as insomnia, restlessness, rigidity, and muscular pain clearly indicated the primary precipitating role of lormetazepam withdrawal. A previous report remarked that lormetazepam is the benzodiazepine that is most frequently associated with abuse and dependence [16], particularly when it is used in the form of an oral solution [17]. The presence of ethanol in the oral solution of lormetazepam has been specifically suspected to increase the risks for abuse and dependence. Although ethanol quantities may not be relevant in patients treated with accurate doses of lormetazepam (1.5–2.5 mg daily for insomnia), the pathogenic effect of ethanol may be significant in lormetazepam addicted patients. The present case provides additional information about the risks of lormetazepam addiction as a component of psychiatric care. We suggest strict monitoring of patients treated with an oral solution of this medication.
4 Conclusion
FBMS may be observed during the clinical manifestation of lormetazepam withdrawal in patients who overdosed on amitriptyline. FBMS may produce a confusing clinical picture, with the potential to misdiagnose NES, especially when no abnormal neurophysiologic findings are clearly identified and when patients have a known underlying psychiatric disease.
The following is the supplementary data related to this article.Video 1
Focal bilateral motor seizure precipitated by lormetazepam withdrawal and amitriptyline overdose.
The seizure begins with a tonic posture of the left hand and abduction of the left arm flexed at the elbow. The left arm is then elevated and extended anteriorly, while the right arm is initially flexed at the elbow and rotated inward, reproducing the figure four sign. The head is briefly turned to the left during the asymmetric posturing of the upper extremities. Consequently, the right arm is also extended anteriorly. A slight facial cyanosis and a grimace with left hemifacial spasm (consistent with the presumed origin of the seizure in the right cerebral hemisphere) are noted during the extension of the upper limbs. There is no eye blink at the threatening gesture or pupillary response to the light at this point of the seizure. Convulsions cease with a sequence of vibratory and clonic movements of the upper extremities and trunk. The duration of the seizure is approximately 53 s and amitriptyline overdose.
Video 1
Ethical statement
The authors state that the study described in the paper complies with the publishing ethics of the journal.
The patient’s face has been partially obscured in the attached video, as requested by the patient herself at the time of the given consent.
Declaration of competing interest
The authors state that there is no conflict of interest. | AMITRIPTYLINE, CLONAZEPAM, DIAZEPAM, LEVETIRACETAM, LORMETAZEPAM | DrugsGivenReaction | CC BY-NC-ND | 33490945 | 18,821,337 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intentional product misuse'. | Focal bilateral motor seizures precipitated by abrupt cessation of chronic lormetazepam abuse and amitriptyline overdose.
We report the case of an adult psychiatric patient who developed new-onset focal bilateral motor seizures (FBMS) in the context of a severe benzodiazepine withdrawal syndrome. The patient was forced to interrupt chronic lormetazepam abuse and overdosed on amitriptyline (800 mg in an oral solution) before the onset of seizures. Typical signs of amitriptyline intoxication such as sedation and anticholinergic effects were not observed. Video-EEG recordings revealed a stereotypical ictal motor pattern with asymmetric tonic posturing and bilateral clonic movements of the upper limbs, but there were no abnormalities identified by EEG. Seizures recurred multiple times per day but resolved simultaneously when withdrawal symptomatology subsided eight days after onset. Nonepileptic seizures (NES) were considered in the differential diagnosis because of the patient's psychiatric history including preserved awareness during the bilateral convulsions, the absence of postictal confusion, and normal EEG. The present case indicates that FBMS may occur during benzodiazepine withdrawal in patients who overdosed on amitriptyline. The diagnosis may be challenging as FBMS may mimic NES in the absence of abnormal neurophysiologic findings. This may be especially challenging in patients with an underlying psychiatric disease.
1 Introduction
Epileptic seizures (ES) have been frequently reported as clinical manifestations of benzodiazepine withdrawal, an acute disorder precipitated by an abrupt discontinuation of chronic therapies including benzodiazepines. The withdrawal symptomatology may also include insomnia, irritability, muscular pain and stiffness, hand tremor, anxiety, and psychotic episodes [1]. An acute reduction in brain gamma-aminobutyric acid function has been indicated as a pathogenic mechanism of the syndrome [2]. While generalized tonic–clonic seizures are the most common, focal seizures are rarely reported in this condition. Particularly, focal nonconvulsive seizures have been described in patients treated with flumazenil during detoxification from lormetazepam abuse [3].
2 Case report
A 46-year-old woman with a clinical history of schizoaffective and personality disorders presented to our hospital with new-onset convulsive seizures. It was reported that the patient was forced to interrupt chronic lormetazepam abuse (a daily drug consumption of 150–250 mg of an oral solution) the day before the onset of seizures. When she ran out of the medication, she ingested an oral solution containing 800 mg of amitriptyline as a supposed sedative substitute for lormetazepam. Convulsive seizures recurred multiple times per day in the hospital during daytime and night-time hours in a clinical context of insomnia, restlessness, muscular rigidity, and painful spasms affecting the back muscles that implicated a benzodiazepine withdrawal syndrome. There was no evidence of amitriptyline toxicity, as the patient did not show sedation, anticholinergic effects, arterial hypotension, or cardiac arrhythmias. The amitriptyline blood level was not obtained. Seizures presented with a duration of approximately 53 s and a paroxysmal, stereotyped sequence of movements that was documented with video-EEG. The recordings of seizures, using the usual 10–20 system of electrode placement, did not show EEG abnormalities or postictal slowing of the background activity, but the tracings were disturbed by myogenic artifacts throughout the course of the events (Fig. 1, Fig. 2). Awareness was preserved during the episodes. The patient occasionally called for help at seizure onset but remained unresponsive until the cessation of movements. Rapid recovery of speech and an absence of postictal confusion were reported on different occasions. Magnetic resonance imaging of the brain was normal. Three days after the patient's admission, a cluster of convulsive episodes prompted a short intensive treatment with propofol and mechanical ventilation. Seizures were increasingly observed again after extubation, despite oral treatment with clonazepam, levetiracetam, and repeated intravenous administrations of diazepam. Regardless of the inefficacy of the treatment during an eight-day period of intense seizure activity, the patient eventually became seizure-free. The remission of seizures occurred simultaneously with the cessation of insomnia and muscular symptoms related to lormetazepam withdrawal. Clonazepam and levetiracetam were subsequently reduced and discontinued as the patient remained asymptomatic. Despite the absence of ictal EEG abnormalities, a retrospective analysis of the seizure semiology based on video recordings and additional recorded observations of the episodes at bedside suggested the clinical diagnosis of FBMS, presumably arising from the supplementary sensorimotor area (SSMA). This diagnostic conclusion was supported by the evidence of a paroxysmal, stereotyped ictal motor pattern with early abduction of the arm flexed at the elbow and subsequent asymmetric tonic posturing of the upper limb that reproduced the figure four sign [4] at seizure onset. The left arm was extended, and the right arm was flexed (at the elbow), while the head was briefly turned to the left at this point of the seizure. Consequent bilateral clonic movements of the upper limbs showed a typical epileptic pattern with a gradual frequency decline and a progressive amplitude increase of movements [5]. A stereotyped left hemifacial spasm was also noted during the tonic contraction of the upper limbs. The short duration of the episodes, occasional evidence of cyanosis and lack of pupillary reactivity served as additional clues to the ES diagnosis. Although the clinical picture was initially confounded by the patient's preserved awareness during the bilateral convulsions, the absence of postictal confusion, and the normal EEG findings, these features finally appeared consistent with FBMS arising in the SSMA, as previously reported in the literature [[6], [7], [8]]. The patient was discharged with a normal neurologic status nine days after the last convulsive episode. Seizures did not recur even without antiseizure medication during the following month, after which the patient was lost to follow-up.Fig. 1 EEG recording of the initial phase of a focal bilateral motor seizure with a still-frame from the video.
EEG recording of the initial phase of a focal bilateral motor seizure with a still-frame from the video.
The EEG does not reveal evident abnormalities at seizure onset. The tracing is progressively disturbed by myogenic artifacts during the evolution of the seizure motor pattern.
Fig. 1Fig. 2 EEG recording of the final phase of a focal bilateral motor seizure.
Phasic myogenic artifacts mark the tracing during the ending clonic phase of the seizure. The EEG shows the persistence of the background activity in the immediate postictal period.
Fig. 2
3 Discussion
The manifestation of convulsive seizures without EEG abnormalities in the context of benzodiazepine withdrawal syndrome and psychiatric disease requires a differential diagnosis of ES and nonepileptic seizures (NES). In fact, the abrupt interruption of high dosage, chronic benzodiazepine treatment represents a potential precipitating factor for ES, while NES are occasionally observed as imitators of epilepsy in patients with mental health problems [9,10]. In addition to the psychiatric disorders and the normal neurophysiologic findings, the patient's preserved awareness during the bilateral convulsions and the absence of postictal confusion confounded the clinical picture with the potential to misdiagnose FBMS as NES. FBMS are described as motor onset seizures arising in one cerebral hemisphere and rapidly involving bilateral motor networks, often with asymmetric tonic posturing [11]. The SSMA is classically recognized as the anatomical origin of FBMS [11]. Clinical characteristics of focal onset seizures arising in the SSMA include short duration (typically not exceeding 40 s) [6,12]; predominant onset during sleep [6,8]; somatosensory aura [8,13]; preserved awareness [6,8,13]; absence of postictal confusion [8]; vocalization or speech arrest [6,8,13]; unilateral tonic posturing [8,13] or bilateral, asymmetric tonic posturing [4,13,14]; bilateral abduction of the upper extremities [6]; and bilateral thrashing movements [6,8] that usually constitute a paroxysmal, stereotyped motor pattern in the same individual [6]. Particularly, asymmetric tonic posturing has been related to the asynchronous activation of the SSMA [4,14], thus representing a key semiologic feature of seizures involving this cortical area [8,12]. Authors have also referred to asymmetric tonic posturing as the figure four sign that marks focal to bilateral tonic–clonic seizures [4]. The lateralizing value of this sign has been repeatedly reported with the epileptogenic focus usually contralateral to the arm that is extended at the elbow [4,14]. In contrast, NES with convulsive-like manifestations are characterized by long duration (frequently exceeding 2 min); fluctuating course; and asynchronous movements (typically side-to-side head movements and out of phase limb movements) that show unchanged frequency and variable amplitude throughout the event [10].
In our patient, the convulsive disorders shared most of the mentioned clinical characteristics of focal onset seizures arising in the SSMA. In particular, the origin of ictal symptoms in the SSMA was suggested by the early stereotyped contraction of the left arm and consequent asymmetric tonic posturing of limbs, while a left hemifacial spasm appeared consistent with the presumed epileptic focus in the right cerebral hemisphere. The progression of these phenomena to bilateral, tonic extension and clonic movements of the upper extremities characterized the final phase of the motor pattern mimicking focal to bilateral tonic–clonic seizures. However, the absence of awareness impairments, postictal confusion and EEG slowing in the immediate postictal phase discredited the apparent bilateral tonic–clonic evolution of focal seizures, suggesting limited epileptic involvement of the SSMA during the entire course of the events. While the seizure semiology could be referred to FBMS arising from the SSMA, the absence of ictal EEG abnormalities to confirm epileptic seizures is a limiting factor for the diagnosis of frontal lobe seizures. This suggests the potential utility of EEG recordings with additional midline electrodes (placed according to the 10–10 system) and/or ictal SPECT, as a supplementary method to confirm the epileptic nature and the anatomical origin of the seizures. However, it is not uncommon for seizures arising in the mesial and deep structures of the frontal lobe to have absent scalp ictal EEG changes utilizing the 10-20 international system of electrode placement.
Although structural brain abnormalities were not documented in our patient, neurochemical alterations induced by benzodiazepine withdrawal into specific networks may have resulted in a major seizure susceptibility of the SSMA. Interestingly, a major intrinsic epileptogenicity of specific cortical areas has been postulated by Albiero et al. to explain the occurrence of focal seizures in patients who underwent detoxification from chronic lormetazepam abuse [3]. Additional information is needed to ascertain the major occurrence of focal seizures in patients who interrupted chronic lormetazepam abuse. Although amitriptyline may have lowered the seizure threshold, the precise clinical impact of the substitution remains uncertain in our patient, as typical symptoms of amitriptyline intoxication such as sedation, arterial hypotension, cardiac arrhythmias or anticholinergic effects [15] were not observed during the period of recurrent seizures. In contrast, the strict concomitance of seizures with classic benzodiazepine abstinence symptoms such as insomnia, restlessness, rigidity, and muscular pain clearly indicated the primary precipitating role of lormetazepam withdrawal. A previous report remarked that lormetazepam is the benzodiazepine that is most frequently associated with abuse and dependence [16], particularly when it is used in the form of an oral solution [17]. The presence of ethanol in the oral solution of lormetazepam has been specifically suspected to increase the risks for abuse and dependence. Although ethanol quantities may not be relevant in patients treated with accurate doses of lormetazepam (1.5–2.5 mg daily for insomnia), the pathogenic effect of ethanol may be significant in lormetazepam addicted patients. The present case provides additional information about the risks of lormetazepam addiction as a component of psychiatric care. We suggest strict monitoring of patients treated with an oral solution of this medication.
4 Conclusion
FBMS may be observed during the clinical manifestation of lormetazepam withdrawal in patients who overdosed on amitriptyline. FBMS may produce a confusing clinical picture, with the potential to misdiagnose NES, especially when no abnormal neurophysiologic findings are clearly identified and when patients have a known underlying psychiatric disease.
The following is the supplementary data related to this article.Video 1
Focal bilateral motor seizure precipitated by lormetazepam withdrawal and amitriptyline overdose.
The seizure begins with a tonic posture of the left hand and abduction of the left arm flexed at the elbow. The left arm is then elevated and extended anteriorly, while the right arm is initially flexed at the elbow and rotated inward, reproducing the figure four sign. The head is briefly turned to the left during the asymmetric posturing of the upper extremities. Consequently, the right arm is also extended anteriorly. A slight facial cyanosis and a grimace with left hemifacial spasm (consistent with the presumed origin of the seizure in the right cerebral hemisphere) are noted during the extension of the upper limbs. There is no eye blink at the threatening gesture or pupillary response to the light at this point of the seizure. Convulsions cease with a sequence of vibratory and clonic movements of the upper extremities and trunk. The duration of the seizure is approximately 53 s and amitriptyline overdose.
Video 1
Ethical statement
The authors state that the study described in the paper complies with the publishing ethics of the journal.
The patient’s face has been partially obscured in the attached video, as requested by the patient herself at the time of the given consent.
Declaration of competing interest
The authors state that there is no conflict of interest. | AMITRIPTYLINE, CLONAZEPAM, DIAZEPAM, LEVETIRACETAM, LORMETAZEPAM | DrugsGivenReaction | CC BY-NC-ND | 33490945 | 18,821,337 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Overdose'. | Focal bilateral motor seizures precipitated by abrupt cessation of chronic lormetazepam abuse and amitriptyline overdose.
We report the case of an adult psychiatric patient who developed new-onset focal bilateral motor seizures (FBMS) in the context of a severe benzodiazepine withdrawal syndrome. The patient was forced to interrupt chronic lormetazepam abuse and overdosed on amitriptyline (800 mg in an oral solution) before the onset of seizures. Typical signs of amitriptyline intoxication such as sedation and anticholinergic effects were not observed. Video-EEG recordings revealed a stereotypical ictal motor pattern with asymmetric tonic posturing and bilateral clonic movements of the upper limbs, but there were no abnormalities identified by EEG. Seizures recurred multiple times per day but resolved simultaneously when withdrawal symptomatology subsided eight days after onset. Nonepileptic seizures (NES) were considered in the differential diagnosis because of the patient's psychiatric history including preserved awareness during the bilateral convulsions, the absence of postictal confusion, and normal EEG. The present case indicates that FBMS may occur during benzodiazepine withdrawal in patients who overdosed on amitriptyline. The diagnosis may be challenging as FBMS may mimic NES in the absence of abnormal neurophysiologic findings. This may be especially challenging in patients with an underlying psychiatric disease.
1 Introduction
Epileptic seizures (ES) have been frequently reported as clinical manifestations of benzodiazepine withdrawal, an acute disorder precipitated by an abrupt discontinuation of chronic therapies including benzodiazepines. The withdrawal symptomatology may also include insomnia, irritability, muscular pain and stiffness, hand tremor, anxiety, and psychotic episodes [1]. An acute reduction in brain gamma-aminobutyric acid function has been indicated as a pathogenic mechanism of the syndrome [2]. While generalized tonic–clonic seizures are the most common, focal seizures are rarely reported in this condition. Particularly, focal nonconvulsive seizures have been described in patients treated with flumazenil during detoxification from lormetazepam abuse [3].
2 Case report
A 46-year-old woman with a clinical history of schizoaffective and personality disorders presented to our hospital with new-onset convulsive seizures. It was reported that the patient was forced to interrupt chronic lormetazepam abuse (a daily drug consumption of 150–250 mg of an oral solution) the day before the onset of seizures. When she ran out of the medication, she ingested an oral solution containing 800 mg of amitriptyline as a supposed sedative substitute for lormetazepam. Convulsive seizures recurred multiple times per day in the hospital during daytime and night-time hours in a clinical context of insomnia, restlessness, muscular rigidity, and painful spasms affecting the back muscles that implicated a benzodiazepine withdrawal syndrome. There was no evidence of amitriptyline toxicity, as the patient did not show sedation, anticholinergic effects, arterial hypotension, or cardiac arrhythmias. The amitriptyline blood level was not obtained. Seizures presented with a duration of approximately 53 s and a paroxysmal, stereotyped sequence of movements that was documented with video-EEG. The recordings of seizures, using the usual 10–20 system of electrode placement, did not show EEG abnormalities or postictal slowing of the background activity, but the tracings were disturbed by myogenic artifacts throughout the course of the events (Fig. 1, Fig. 2). Awareness was preserved during the episodes. The patient occasionally called for help at seizure onset but remained unresponsive until the cessation of movements. Rapid recovery of speech and an absence of postictal confusion were reported on different occasions. Magnetic resonance imaging of the brain was normal. Three days after the patient's admission, a cluster of convulsive episodes prompted a short intensive treatment with propofol and mechanical ventilation. Seizures were increasingly observed again after extubation, despite oral treatment with clonazepam, levetiracetam, and repeated intravenous administrations of diazepam. Regardless of the inefficacy of the treatment during an eight-day period of intense seizure activity, the patient eventually became seizure-free. The remission of seizures occurred simultaneously with the cessation of insomnia and muscular symptoms related to lormetazepam withdrawal. Clonazepam and levetiracetam were subsequently reduced and discontinued as the patient remained asymptomatic. Despite the absence of ictal EEG abnormalities, a retrospective analysis of the seizure semiology based on video recordings and additional recorded observations of the episodes at bedside suggested the clinical diagnosis of FBMS, presumably arising from the supplementary sensorimotor area (SSMA). This diagnostic conclusion was supported by the evidence of a paroxysmal, stereotyped ictal motor pattern with early abduction of the arm flexed at the elbow and subsequent asymmetric tonic posturing of the upper limb that reproduced the figure four sign [4] at seizure onset. The left arm was extended, and the right arm was flexed (at the elbow), while the head was briefly turned to the left at this point of the seizure. Consequent bilateral clonic movements of the upper limbs showed a typical epileptic pattern with a gradual frequency decline and a progressive amplitude increase of movements [5]. A stereotyped left hemifacial spasm was also noted during the tonic contraction of the upper limbs. The short duration of the episodes, occasional evidence of cyanosis and lack of pupillary reactivity served as additional clues to the ES diagnosis. Although the clinical picture was initially confounded by the patient's preserved awareness during the bilateral convulsions, the absence of postictal confusion, and the normal EEG findings, these features finally appeared consistent with FBMS arising in the SSMA, as previously reported in the literature [[6], [7], [8]]. The patient was discharged with a normal neurologic status nine days after the last convulsive episode. Seizures did not recur even without antiseizure medication during the following month, after which the patient was lost to follow-up.Fig. 1 EEG recording of the initial phase of a focal bilateral motor seizure with a still-frame from the video.
EEG recording of the initial phase of a focal bilateral motor seizure with a still-frame from the video.
The EEG does not reveal evident abnormalities at seizure onset. The tracing is progressively disturbed by myogenic artifacts during the evolution of the seizure motor pattern.
Fig. 1Fig. 2 EEG recording of the final phase of a focal bilateral motor seizure.
Phasic myogenic artifacts mark the tracing during the ending clonic phase of the seizure. The EEG shows the persistence of the background activity in the immediate postictal period.
Fig. 2
3 Discussion
The manifestation of convulsive seizures without EEG abnormalities in the context of benzodiazepine withdrawal syndrome and psychiatric disease requires a differential diagnosis of ES and nonepileptic seizures (NES). In fact, the abrupt interruption of high dosage, chronic benzodiazepine treatment represents a potential precipitating factor for ES, while NES are occasionally observed as imitators of epilepsy in patients with mental health problems [9,10]. In addition to the psychiatric disorders and the normal neurophysiologic findings, the patient's preserved awareness during the bilateral convulsions and the absence of postictal confusion confounded the clinical picture with the potential to misdiagnose FBMS as NES. FBMS are described as motor onset seizures arising in one cerebral hemisphere and rapidly involving bilateral motor networks, often with asymmetric tonic posturing [11]. The SSMA is classically recognized as the anatomical origin of FBMS [11]. Clinical characteristics of focal onset seizures arising in the SSMA include short duration (typically not exceeding 40 s) [6,12]; predominant onset during sleep [6,8]; somatosensory aura [8,13]; preserved awareness [6,8,13]; absence of postictal confusion [8]; vocalization or speech arrest [6,8,13]; unilateral tonic posturing [8,13] or bilateral, asymmetric tonic posturing [4,13,14]; bilateral abduction of the upper extremities [6]; and bilateral thrashing movements [6,8] that usually constitute a paroxysmal, stereotyped motor pattern in the same individual [6]. Particularly, asymmetric tonic posturing has been related to the asynchronous activation of the SSMA [4,14], thus representing a key semiologic feature of seizures involving this cortical area [8,12]. Authors have also referred to asymmetric tonic posturing as the figure four sign that marks focal to bilateral tonic–clonic seizures [4]. The lateralizing value of this sign has been repeatedly reported with the epileptogenic focus usually contralateral to the arm that is extended at the elbow [4,14]. In contrast, NES with convulsive-like manifestations are characterized by long duration (frequently exceeding 2 min); fluctuating course; and asynchronous movements (typically side-to-side head movements and out of phase limb movements) that show unchanged frequency and variable amplitude throughout the event [10].
In our patient, the convulsive disorders shared most of the mentioned clinical characteristics of focal onset seizures arising in the SSMA. In particular, the origin of ictal symptoms in the SSMA was suggested by the early stereotyped contraction of the left arm and consequent asymmetric tonic posturing of limbs, while a left hemifacial spasm appeared consistent with the presumed epileptic focus in the right cerebral hemisphere. The progression of these phenomena to bilateral, tonic extension and clonic movements of the upper extremities characterized the final phase of the motor pattern mimicking focal to bilateral tonic–clonic seizures. However, the absence of awareness impairments, postictal confusion and EEG slowing in the immediate postictal phase discredited the apparent bilateral tonic–clonic evolution of focal seizures, suggesting limited epileptic involvement of the SSMA during the entire course of the events. While the seizure semiology could be referred to FBMS arising from the SSMA, the absence of ictal EEG abnormalities to confirm epileptic seizures is a limiting factor for the diagnosis of frontal lobe seizures. This suggests the potential utility of EEG recordings with additional midline electrodes (placed according to the 10–10 system) and/or ictal SPECT, as a supplementary method to confirm the epileptic nature and the anatomical origin of the seizures. However, it is not uncommon for seizures arising in the mesial and deep structures of the frontal lobe to have absent scalp ictal EEG changes utilizing the 10-20 international system of electrode placement.
Although structural brain abnormalities were not documented in our patient, neurochemical alterations induced by benzodiazepine withdrawal into specific networks may have resulted in a major seizure susceptibility of the SSMA. Interestingly, a major intrinsic epileptogenicity of specific cortical areas has been postulated by Albiero et al. to explain the occurrence of focal seizures in patients who underwent detoxification from chronic lormetazepam abuse [3]. Additional information is needed to ascertain the major occurrence of focal seizures in patients who interrupted chronic lormetazepam abuse. Although amitriptyline may have lowered the seizure threshold, the precise clinical impact of the substitution remains uncertain in our patient, as typical symptoms of amitriptyline intoxication such as sedation, arterial hypotension, cardiac arrhythmias or anticholinergic effects [15] were not observed during the period of recurrent seizures. In contrast, the strict concomitance of seizures with classic benzodiazepine abstinence symptoms such as insomnia, restlessness, rigidity, and muscular pain clearly indicated the primary precipitating role of lormetazepam withdrawal. A previous report remarked that lormetazepam is the benzodiazepine that is most frequently associated with abuse and dependence [16], particularly when it is used in the form of an oral solution [17]. The presence of ethanol in the oral solution of lormetazepam has been specifically suspected to increase the risks for abuse and dependence. Although ethanol quantities may not be relevant in patients treated with accurate doses of lormetazepam (1.5–2.5 mg daily for insomnia), the pathogenic effect of ethanol may be significant in lormetazepam addicted patients. The present case provides additional information about the risks of lormetazepam addiction as a component of psychiatric care. We suggest strict monitoring of patients treated with an oral solution of this medication.
4 Conclusion
FBMS may be observed during the clinical manifestation of lormetazepam withdrawal in patients who overdosed on amitriptyline. FBMS may produce a confusing clinical picture, with the potential to misdiagnose NES, especially when no abnormal neurophysiologic findings are clearly identified and when patients have a known underlying psychiatric disease.
The following is the supplementary data related to this article.Video 1
Focal bilateral motor seizure precipitated by lormetazepam withdrawal and amitriptyline overdose.
The seizure begins with a tonic posture of the left hand and abduction of the left arm flexed at the elbow. The left arm is then elevated and extended anteriorly, while the right arm is initially flexed at the elbow and rotated inward, reproducing the figure four sign. The head is briefly turned to the left during the asymmetric posturing of the upper extremities. Consequently, the right arm is also extended anteriorly. A slight facial cyanosis and a grimace with left hemifacial spasm (consistent with the presumed origin of the seizure in the right cerebral hemisphere) are noted during the extension of the upper limbs. There is no eye blink at the threatening gesture or pupillary response to the light at this point of the seizure. Convulsions cease with a sequence of vibratory and clonic movements of the upper extremities and trunk. The duration of the seizure is approximately 53 s and amitriptyline overdose.
Video 1
Ethical statement
The authors state that the study described in the paper complies with the publishing ethics of the journal.
The patient’s face has been partially obscured in the attached video, as requested by the patient herself at the time of the given consent.
Declaration of competing interest
The authors state that there is no conflict of interest. | AMITRIPTYLINE, CLONAZEPAM, DIAZEPAM, LEVETIRACETAM, LORMETAZEPAM | DrugsGivenReaction | CC BY-NC-ND | 33490945 | 18,821,337 | 2021 |
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