Case Report: Genetic Alterations Associated with the Progression of Carotid Paraganglioma

Paragangliomas (PGLs) are rare neuroendocrine tumors that can develop from any paraganglion across the body. The carotid body is the most often location of PGLs in the head and neck region. Carotid PGLs (CPGLs) are characterized by predominantly non-aggressive behavior; however, all tumors have the potential to metastasize. To date, molecular mechanisms of paraganglioma progression remain elusive. We report a case of a 38-year-old woman with metastatic CPGL manifesting as a recurrent tumor with lymph node metastasis. The tumor was fast-growing and had a high Ki-67 proliferation index. Immunohistochemical (IHC) examination and whole-exome sequencing were performed for both recurrent tumor and metastasis. A germline pathogenic splice acceptor variant in the SDHB gene was found in the patient. Immunoreactivity of the SDHB subunit was weak diffuse in both samples, indicating deficiency of the succinate dehydrogenase. Moreover, the recurrent tumor exhibited loss of heterozygosity (LOH) at the SDHB locus, that is according to Knudson’s "two-hit" hypothesis of cancer causation. We also identified a rare somatic promotor mutation in the TERT gene associated with the tumor progression. Obtained results confirmed the indicative role of the germline SDHB mutation for metastatic CPGLs, as well as the potential prognostic value of the TERT promoter mutation.

SDHB Associated Paraganglioma Syndrome in Africa – A Need for Greater Genetic Testing

A germline mutation is identified in almost 40% of Pheochromocytoma-Paraganglioma (PPGL) Syndromes. Genetic testing and counselling are essential for the management of index cases as well as pre-symptomatic identification and pre-emptive management of affected family members. Mutations in the genes encoding the mitochondrial enzyme succinate dehydrogenase (SDH) are well described in patients with hereditary PPGL. Amongst patients of African ancestry the prevalence, phenotype, germline mutation spectrum and penetrance of SDH mutations is poorly characterized. We describe a multifocal paraganglioma in a young African male with an underlying mis-sense SDHB mutation, with a history of three first-degree relatives who demised at young ages from suspected cardiovascular causes. The same SDHB mutation, Class V variant c.724C>A p.(Arg242Ser), was detected in one of his asymptomatic siblings. As there is limited data describing hereditary PPGL syndromes in Africa this report of an SDHB associated PPGL is a notable contribution to the literature in this growing field. Due to the noteworthy clinical implications of PPGL mutations, it highlights the existing need for broader genetic screening amongst African patients with PPGL despite the limited healthcare resources available in this region.

Mutation Profile of Aggressive Pheochromocytoma and Paraganglioma with Comparison of TCGA Data

In pheochromocytoma and paraganglioma (PPGL), germline or somatic mutations in one of the known susceptibility genes are identified in up to 60% patients. However, the peculiar genetic events that drive the aggressive behavior including metastasis in PPGL are poorly understood. We performed targeted next-generation sequencing analysis to characterize the mutation profile in fifteen aggressive PPGL patients and compared accessible data of aggressive PPGLs from The Cancer Genome Atlas (TCGA) with findings of our cohort. A total of 115 germline and 34 somatic variants were identified with a median 0.58 per megabase tumor mutation burden in our cohort. The most frequent mutation was SDHB germline mutation (27%) and the second frequent mutations were somatic mutations for SETD2, NF1, and HRAS (13%, respectively). Patients were subtyped into three categories based on the kind of mutated genes: pseudohypoxia (n = 5), kinase (n = 5), and unknown (n = 5) group. In copy number variation analysis, deletion of chromosome arm 1p harboring SDHB gene was the most frequently observed. In our cohort, SDHB mutation and pseudohypoxia subtype were significantly associated with poor overall survival. In conclusion, subtyping of mutation profile can be helpful in aggressive PPGL patients with heterogeneous prognosis to make relevant follow-up plan and achieve proper treatment.

A Multifocal Paraganglioma in an African Male Due to an Underlying SDHB Mutation

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors arising from adrenal and extra-adrenal paraganglia. Up to forty percent are due to an underlying germline mutation. Mutations in the subunit B gene of the SDH complex (SDHB) are associated with PGL syndrome four. A 34-yr-old African man from Southern Africa presented with a two-year history of sustained hypertension associated with the classic triad of sweating, headaches and palpitations. Family history was contributory towards early unexpected deaths of his father (age 42) and two younger brothers (ages 13 and 14 respectively). On examination his blood pressure was persistently elevated measuring 146/87mmHg. In view of the classic presenting symptoms and hypertension onset at a young age, a PPGL was suspected. Biochemical investigations were positive with an elevated 24-hour urine normetanephrine level of 35807 (480-2424nmol/24hours), normal metanephrine level of 689 (264-1729nmol/24hours), an elevated normetanephrine:creatinine ratio of 3270 (28-158nmol/mmol creatinine) and an elevated methoxytyramine level 4941.69nmol/24 hours (<800nmol/24 hours). Computed tomography of the abdomen and neck revealed a homogenous soft tissue mass measuring 5.9cm x 3.6cm x 6.6cm anterior to the right kidney and separate from the right adrenal gland and a carotid body tumor measuring 3.6cm x 2.9cm x 4.1cm. Both were radio-avid on a [68Gallium]-DOTATATE-Positron Emission Tomography (PET)-CT. There were no features to suggest metastatic disease. Genetic testing is not available in South Africa; therefore, testing was done at an international laboratory. This revealed a pathological SDHB mutation variant, c.724C>A p.(Arg242Ser) and hence PGL4 syndrome. The patient underwent staged surgery with successful removal of the intra-abdominal tumor. Unfortunately, due to peri-operative complications associated with the second surgery, the patient demised. Histopathological examination of both tumors was consistent with a paraganglioma. Genetic counselling and testing were offered to all living first-degree relatives. His sister tested positive for the same pathological variant. His 6-week-old son will be offered counselling and testing at a later stage. To the best of our knowledge, we are the first to describe the missense SDHB mutation (pathogenic variant c.724C>A p.[Arg242Ser]) and the occurrence of an SDHB associated PGL in a family of African ethnicity. This case highlights the importance of genetic counselling and testing in patients with a confirmed PPGL. Due to resource limitation the African population remains under represented in genetic studies which limits the utility of precision medicine in this group. As such, our case is an important addition to the body of knowledge in this growing field and highlights the need for cost effective genetic screening tools in low resourced settings.

Presyncope in a Woman With Incidental Bladder Mass: A Case of De Novo SDHB Mutation Bladder Paraganglioma

Background: Paragangliomas (PGLs) are catecholamine secreting neuroendocrine tumors originating from extra-adrenal neural crest cells. Urinary bladder paragangliomas (UBPGLs) are extremely rare, accounting for only 0.06% of all bladder tumors. Sporadic UBPGLs associated with Succinate Dehydrogenase B (SDHB) mutation have a higher malignant potential versus patients with a positive family history due to a lack of screening. We present a case of sporadic UBPGL detected early due to follow-up of an incidental bladder mass. Clinical Case: A 31 year-old female presented to the ER with presyncope and lower abdominal pain while running. On arrival she was mildly hypertensive with BP 140/88 mmHg, HR was 98 beats/min, other vital signs were stable. Denied headaches, diaphoresis, or weight loss. No known personal or family history of any endocrine disorders or cancer. CT abdomen pelvis performed for the evaluation of her abdominal pain revealed a large fibroid along with an unexpected finding of a 3 cm enhancing lesion in the right bladder wall, suggestive of a PGL. 24 hr urine total catecholamines and plasma total metanephrines were elevated at 284 mcg (normal range 26-121 mcg/24h), and 386 pg/mL (normal <205 pg/ml) respectively, confirming the diagnosis of UBPGL. Chromogranin A was within the normal range. Metastasis was ruled out with metaiodobenzylguanidine (MIBG) whole-body scan and octreotide scan which showed isolated uptake in the bladder. Pan CT scan was negative for other SBHB mutation associated tumors such as RCC (14% incidence), GIST, and thyroid carcinoma. Genetic testing with PGLNest revealed a heterozygous SDHB mutation (5’-3’ UTR_5’-3’ UTR deletion). Her parents were found to be negative for the mutation. During follow up she developed episodic palpitations. She was treated with alpha followed by beta blocker and underwent successful resection of the tumor with partial cystectomy, and of the fibroid with myomectomy on the same day (TAH was avoided to minimize manipulation of the uterus hence decreasing the risk of intra-abdominal HTN crisis). She has been tumor-free in the three years of follow up post-surgery with imaging and biochemical surveillance. Conclusion: This case illustrates the importance of following up on incidental radiographic findings and adds to the limited literature on sporadic UBPGLs, an uncommon, yet potentially life-threatening tumor. The diagnosis of these tumors is especially challenging when patients present with non-specific symptoms. Fortunately, in our case, the imaging study clued us into the possibility of a PGL. SDHB mutation associated PGLs, in particular, are notorious for their late presentation with metastasis and associated tumors. Hence, timely detection with close follow-up of these patients will likely have an impact on their mortality.

Mutational Profile of Metastatic Pheochromocytoma and Paraganglioma

Background: In pheochromocytoma and paraganglioma (PPGL), germline and somatic mutations in one of the known susceptibility genes are present in about 60% of tumors. However, the genetic events that drive the malignant progression of the disease are yet poorly understood. We aimed to evaluate the mutational profiles of metastatic PPGLs by targeted next-generation sequencing (NGS) to characterize the genetic events in metastatic PPGLs. Methods: Among the previously reported metastatic PPGL series from Asan Medical Center (AMC), Seoul, Korea, fifteen patients with available formalin-fixed, paraffin embedded (FFPE) archival samples for targeted exome sequencing were enrolled in this study. We also analyzed accessible data of aggressive PPGLs from The Cancer Genome Atlas (TCGA) and compared with findings of AMC samples. Results: A total of 115 germline and 34 somatic variants were identified in AMC cohort. Tumors of AMC cohort had median 0.58 per megabase tumor mutation burden. Most frequently mutated mutations were SDHB germline mutation (27%), and SETD2, NF1, HRAS somatic mutations (13%). Genes are subtyped into pseudohypoxia group (n=5), kinase group (n=5) and unknown (n=5) group. In unknown subgroup, two samples showed ATRX mutations and one accompanied SETD2 mutation. In copy number variation analysis, the most frequently observed pattern was deletion of 1p arm where SDHB is present. In survival analysis, SDHB mutation and pseudohypoxia subtype was significantly associated with poor prognosis. Conclusion: The analysis of NGS from patients with metastatic PPGLs demonstrated rare genetic events as well as well-known mutations. The pseudohypoxia subtype presented poor prognosis than kinase or unknown subtypes. Subjects who had no deletion in 1p arm showed favorable treatment response. Further studies to discover driver events and markers of metastasis are warranted.

Transaminitis Evaluation Leads to the Incidental Diagnosis of Familial Paraganglioma Due to SDHB Mutation

Background: Paragangliomas are rare neuroendocrine tumors. Patients with succinate dehydrogenase subunit B (SDHB) gene mutations are predisposed to developing paraganglioma/pheochromocytoma. We are presenting the case of an incidental finding of a paraganglioma during an evaluation for transaminitis. Clinical Case: A 23-year-old male with a medical history of right hydrocele repair as a teenager was evaluated with an ultrasound of the abdomen for elevated liver enzymes and right upper quadrant discomfort. The ultrasound revealed a large lobular solid vascular 13.8 x 8.1 x 11.3 cm mass in the mid abdomen. He underwent a CT of the chest, abdomen and pelvis which demonstrated a large retroperitoneal mass measuring 16 x 10 x 13.7 cm within the right mid abdomen. The mass was described as a large centrally necrotic peripherally enhancing right retroperitoneal mass displacing the IVC anteriorly. The patient subsequently underwent an image-guided biopsy of the mass and the pathology revealed it was a paraganglioma. The patient denied any history of hypertension, orthostasis, headaches or palpitations. Biochemical workup for plasma catecholamines, plasma metanephrines, 24-hour urine catecholamines and metanephrines and cortisol were unremarkable. His transaminitis also resolved. He underwent a retroperitoneal paraganglioma excision and the final pathology was consistent with paraganglioma and negative for capsular invasion. He was referred to a genetic counsellor for testing since paragangliomas can be inherited. He also mentioned a family history of breast cancer in his mother and HTN and prostate cancer in his father. His test revealed that he had a c.289A>T mutation in his SDHB gene. He was encouraged to share the information with his family to help them understand the implications of his genetic test result. He underwent a surveillance PET scan which showed multiple osseous lesions in his temporal calvarium, sphenoid, spine and sacrum suggestive of metastasis. Repeat imaging with a DOTATATE PET scan showed stable disease. His transaminitis was transient, and we did not find a correlation to his paraganglioma. His imaging tests showed no liver metastasis. A CT of the head showed no evidence of intracranial metastasis. The current plan is to continue surveillance. His older brother underwent a genetic testing. He tested positive for the same SDHB mutation and underwent biochemical and imaging tests which were unremarkable. He too will continue surveillance. Conclusions: Patients with a succinate dehydrogenase subunit B (SDHB) gene mutations are predisposed to developing paraganglioma/pheochromocytoma. The tumors produce catecholamines, but can be biochemically silent as in our patient. They are inherited in an autosomal dominant manner. Our case highlights the importance for genetic counseling which increases the chances of early screening and surveillance in affected family members for optimal multidisciplinary management of patients.