Succinate Dehydrogenase Subunit B Gene Research Articles

EP-630 Pheochromocytoma Associated with SDHB Mutation: A case report

Abstract Introduction Pheochromocytomas and paragangliomas are rare neuroendocrine tumors arising from the chromaffin cells of the adrenal medulla or extra-adrenal tissues. 10% to 20% of tumors are detected before age 18 years. Approximately 10%–15% of pheochromocytoma and 20%–50% of paraganglioma are malignant. Up to 24% of the cases are familial where they may be associated with genetic syndromes like MEN 2, succinate dehydrogenase subunit B (SDHB) gene mutations and VHL syndrome. Germline mutations in SDHB gene increase the risk of PGLs/ PHEOs and RCC with 38%-83% risk of malignancy. We represent a rare case of pheochromocytoma associated with SDHB mutation in a child. Case presentation A 17-year old patient presented with repeated vomiting and hypertension. BMI was 14.4 kg/m2, BP was 140/112 mmgh, PR was127 peats/min. The rest of the clinical examination was unremarkable. Plasma and 24-hour urinary metanephrines levels were highly elevated together with Chromogranin A level. Abdominal CT and MRI scans revealed an enlarged right adrenal gland measuring approximately 45 mm, indenting but not invading the posterior aspect of the IVC. Management Treatment was initiated with α-blockers; (Doxazosin then phenoxybenzamine); followed by β-blockers. The patient underwent laparoscopic right adrenalectomy. The tumor was 50×30×30 mm and weighting 58g. The tumor was positive with chromogranin, and S100. The PASS score was 2. Genetic mutation was detected at SDGB (c.72+1G>A). Conclusion We recommend genetic testing for all suspecting cases of PHEO/PGLs to establish the appropriate follow-up plan.

Pheochromocytoma Associated With SDHB Mutation: A rare Clinical Presentation

Introduction: Pheochromocytomas and paragangliomas are rare neuroendocrine tumors arising from the chromaffin cells of the adrenal medulla or extra-adrenal para-ganglionic tissues. 10% to 20% of tumors are detected before the age of 18 years. Approximately 20%–50% of these tumors are malignant. Up to 24% of the cases may be associated with genetic syndromes like MEN 2, succinate dehydrogenase subunit B (SDHB) gene mutations and VHL syndrome. SDHB is one of the four subunits of the SDH complex. Germline mutations in SDHB gene increase the risk of PGLs/PHEOs and RCC with 38%-83% risk of malignancy.

Familial SDHB gene mutation in disseminated non-hypoxia-related malignant paraganglioma treated with [90Y]Y/[177Lu]Lu- DOTATATE.

Familial paraganglioma may be related to mutations in succinate dehydrogenase (SDH) enzyme complex genes. Among patients with hereditary paraganglioma, SDH subunit B (SDHB) gene mutations are associated with the highest morbidity and mortality related to a higher malignancy rate. We report a family with the c.689G>A (p.Arg230His) mutation in the SDHB gene identified in two family members, a father and his daughter. While the 14-year-old daughter had no evidence of clinical disease, recurrent and later disseminated [131I]metaiodobenzylguanidine uptake-negative head and neck paraganglioma with multiple bone metastases developed in the father who underwent peptide receptor radionuclide therapy with [90Y]Y/[177Lu]Lu-dodecane tetraacetic acid octreotate (DOTATATE) at the time of the genetic diagnosis. This treatment was repeated 6 years later due to disease progression and the patient, who is currently 49 years old, remains alive and in good overall clinical condition at 8 years of follow-up after the original presentation at our unit. The growing armamentarium of imaging methods available for such patients may inform decision making regarding choice of the optimal treatment approach, potentially contributing to improved outcomes.

SDHB Suppresses the Tumorigenesis and Development of ccRCC by Inhibiting Glycolysis.

Metabolic reprogramming is the prominent feature of clear cell renal cell carcinoma (ccRCC). Succinate dehydrogenase subunit B (SDHB) is one of subunits of mitochondrial respiratory chain complex II. The loss of SDHB function is closely related with metabolic changes in kidney cancer cells. However, the role and molecular mechanism of SDHB in ccRCC occurrence and progression are still unclear. In this study, the results of bioinformatics analyses on GEO, TCGA and oncomine databases and immunohistochemistry showed that the expression level of SDHB was downregulated in ccRCC tissues. SDHB level was gradually downregulated as ccRCC stage and grade progressed. The low level of SDHB was associated with poor prognosis of ccRCC patients, especially for advanced ccRCC patients. Increased methylation levels in SDHB gene promoter led to the downregulation of SDHB level in ccRCC tissues. SDHB was correlated with many metabolism related genes and its interacting proteins were enriched in metabolic pathways. SDHB overexpression suppressed the proliferation, colony formation and migration of ccRCC cells by inhibiting aerobic glycolysis. SDHB may be a potential prognostic marker and therapeutic target for ccRCC.

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.

Urinary bladder paraganglioma metastatic to the lung in a patient with SDHB gene mutation: A case report

Introduction: Paragangliomas are tumors originating from the neural crest. Most of them are benign and arise from various locations in the body. Extra-adrenal paragangliomas arise as sporadic cases in most settings or as part of heredofamilial syndromes in about one-quarter of cases. Succinate dehydrogenase subunit B (SDHB) gene mutations are associated with an aggressive clinical disease course of pheochromocytoma/paraganglioma.Methods: We present a 41-year-old male former smoker with a history of a growing right upper lung nodule on chest imaging. He had no cough or respiratory symptoms. Twenty-seven months prior, the patient underwent a cystoprostatectomy due to paraganglioma of the bladder. Genetic testing identified a pathogenic mutation in SDHB gene, c.166_170delCCTCA (p.Pro56Tyrfs*5). He underwent a wedge resection of the lung nodule.Results: Sectioning of the lung wedge revealed a well-circumscribed, firm tan nodule. Microscopically there were nests of large neoplastic cells with round nuclei and eosinophilic granular cytoplasm. Tumor cells were positive for synaptophysin and chromogranin and negative for pan-cytokeratin. S-100 protein highlighted sustentacular cells. Morphologically, the pulmonary neoplasm was similar to the primary tumor of the bladder. These features are consistent with a bladder paraganglioma metastatic to the lung, in a background of a hereditary paraganglioma syndrome.Conclusion: Extra-adrenal paraganglioma occurring in a setting of hereditary paraganglioma syndrome has a high risk of metastasis. Lifelong surveillance even after prompt resection of the primary tumor with negative margins is required to ensure early detection of metastasis and prevent complications associated with it.

Paraganglioma of the Urinary Bladder Metastatic to the Lung in a Patient with SDHB Gene Mutation: A Case Report

Abstract Introduction/Objective Paragangliomas are tumors originating from the neural crest. Most tumors are benign and arise from various locations in the body. Extra-adrenal paragangliomas arise as sporadic cases in most settings or as part of heredofamilial syndromes in about one-quarter of cases. Succinate dehydrogenase subunit B (SDHB) gene mutations are associated with an aggressive clinical disease course of pheochromocytoma/paraganglioma. Methods We present a 41-year-old male former smoker with a history of a growing right upper lung nodule on chest imaging. He had no cough or respiratory symptoms. Twenty-seven months prior the patient underwent a cystoprostatectomy due to paraganglioma of the bladder. Genetic testing identified a pathogenic mutation in SDHB gene, c.166_170delCCTCA (p.Pro56Tyrfs*5). He underwent a wedge resection of the lung nodule. Results Sectioning of the lung wedge revealed a well circumscribed, firm tan nodule. Microscopically there were nests of large neoplastic cells with round nuclei and eosinophilic granular cytoplasm. Tumor cells were positive for synaptophysin and chromogranin and negative for pan-cytokeratin. S100 highlighted sustentacular cells. The pulmonary neoplasm was morphologically similar to the prior tumor of the bladder. These features are consistent with a metastatic urothelial paraganglioma to the lung, in a background of a hereditary paraganglioma syndrome. Conclusion Extra-adrenal paraganglioma occurring in a setting of hereditary paraganglioma syndrome has a higher risk of metastasis. Lifelong surveillance even after prompt resection of primary tumor with negative margins is required to ensure early detection of metastasis and prevention of complications associated with it.

SAT-LB313 A Unicorn With Double Horns - Metastatic Paraganglioma in a Patient With Beckwith-Wiedemann Syndrome and Hereditary Paraganglioma Syndrome Iv

Introduction: Beckwith-Wiedemann syndrome (BWS), a multisystem genomic imprinting disorder in chromosome 11p15.5 region, is an overgrowth syndrome often presenting with macroglossia, abdominal wall defects, hemihyperplasia, enlarged abdominal organs and an increased risk of tumors including neuroblastoma, rhabdomyosarcoma, unilateral Wilm’s tumor, hepatoblastoma, adrenal cortical carcinoma and pheochromocytoma. Six cases of benign bilateral pheochromocytomas and one case of pheochromocytoma with lymph node metastasis in BWS have been described in the literature. We describe the first case of BWS with distant metastatic paraganglioma harboring an SDHB (succinate dehydrogenase subunit B) mutation. Presentation: A 28-year-old male with BWS whose history included an omphalocele and diaphragmatic hernia in infancy, neuroblastoma resected at age 2, and left carotid paraganglioma (PGL) resected at age 22 presented with abdominal pain. CT A/P with contrast revealed a 3.3 x 4.4 cm hypervascular mass and multiple bone metastases. Workup revealed normal plasma/urine metanephrines, elevated plasma dopamine of 178 pg/ml (normal <20) and elevated chromogranin A of 190 ng/ml (normal <90). 68Ga-dotatate PET CT showed hypermetabolic 4.4 cm mass (SUV 83), right hypopharynx mass (SUV 49), and many dota avid areas throughout the skeleton. The abdominal mass was resected and pathology was consistent with PGL. Due to unusual presentation, patient underwent hereditary cancer genetic testing (67 gene panel) and pathogenic mutation (c.713delT) in the SDHB gene was identified, consistent with hereditary PGL syndrome IV. Conclusion: While pheochromocytomas and other tumors are commonly found in association with BWS, PGLs are not. This is the first documented case of a patient with BWS having distant metastatic PGL. Malignant transformation of hereditary and sporadic pheochromocytomas and paraganglioma (PPGLs) is more common in SDHx associated PPGLs (>40% of metastatic PPGLs are related to an SDHB mutation). Hereditary PGL syndromes should be suspected in the case of PGLs that are recurrent, early onset (<45 years), extra-adrenal and/or metastatic. With additional genetic testing, our patient with an already rare growth disorder was found to have hereditary PGL syndrome IV caused by a pathogenic mutation in the SDHB gene. This unique case highlights the rationale and importance of systematic genetic cancer screening in the diagnostic evaluation of PPGLs.

Outcomes of annual surveillance imaging in an adult and paediatric cohort of succinate dehydrogenase B mutation carriers.

For 'asymptomatic carriers' of the succinate dehydrogenase subunit B (SDHB) gene mutations, there is currently no consensus as to the appropriate modality or frequency of surveillance imaging. We present the results of a surveillance programme of SDHB mutation carriers. Review of clinical outcomes of a surveillance regimen in patients identified to have an SDHB gene mutation, based on annual MRI, in a single UK tertiary referral centre. A total of 92 patients were identified with an SDHB gene mutation. a total of 27 index patients presented with symptoms, and 65 patients were identified as asymptomatic carriers. Annual MRI of the abdomen, with alternate year MRI of the neck, thorax and pelvis. Presence of an SDHB-related tumour included paraganglioma (PGL), phaeochromocytoma (PCC), renal cell carcinoma (RCC) and gastrointestinal stromal tumour (GIST). A total of 43 PGLs, eight PCCs and one RCC occurred in the 27 index patients (23 solitary, four synchronous, five metachronous). A further 15 SDHB-related tumours (11 PGLs, three RCCs, one GIST) were identified in the asymptomatic carriers on surveillance screening (25% of screened carriers): 10 on the first surveillance imaging and five on subsequent imaging 2-6 years later. A total of 11 patients had malignant disease. SDHB-related tumours are picked up as early as 2 years after initial negative surveillance scan. We believe the high malignancy rate and early identification rate of tumours justifies the use of 1-2 yearly imaging protocols and MRI-based imaging could form the mainstay of surveillance in this patient group thereby minimizing radiation exposure.

Unusual case of Cowden‐like syndrome, neck paraganglioma, and pituitary adenoma

Pituitary tumors, paragangliomas, and Cowden syndrome do not usually occur together. The synchronous presentation of papillary thyroid carcinoma and neck paraganglioma was revealed in a 43-year-old woman who had been diagnosed with a microprolactinoma one decade before and now presented with a constellation of characteristics that are components of Cowden syndrome, specifically macrocephaly, multiple skin papules, fibrocystic mammary disease, and uterine leiomyofibroma. Germline mutation analysis of phosphatase and tensin homolog (PTEN), succinate dehydrogenase subunit B (SDHB), succinate dehydrogenase subunit C (SDHC), and succinate dehydrogenase subunit D (SDHD) was performed with revelation of 3 polymorphic sites in introns 1, 4, and 8 of the PTEN gene and 1 polymorphic site in exon 1 of the SDHB gene, but absence of known pathogenic mutations. The coexistence of Cowden-like syndrome, neck paraganglioma, and pituitary adenoma is described for the first time, and could represent a novel genetic syndrome with an as yet unidentified common genetic basis.

Malignant paragangliomas with succinate dehydrogenase subunit B mutation in a 13-year old child treated successfully with surgery and 131-I-MIBG

Paragangliomas and phaeochromocytomas are exceptional rare tumours in children arising from the neural crest origin. A number of susceptibility genes have been identified to be associated with familial cases of paragangliomas and phaeochromocytomas. Malignancy frequency has been found to be high especially in patients with succinate dehydrogenase subunit B (SDHB) mutations. We report a case of a 13-year old Chinese girl with right adrenal phaeochromocytoma, paraganglioma in the subhepatic region with invasion into the inferior vena cava, and metastases to the right scapula and vertex. She underwent surgery for excision of the abdominal tumours, and also therapeutic I-131-meta-iodobenzylguanidine (131-I-MIBG) therapy for the metastatic lesions. She required a left adrenalectomy 2 years later due to the occurrence of a left phaeochromocytoma. She remained asymptomatic for 8 years after the initial presentation and is currently alive. Although she does not have any family history of neuroendocrine tumours, susceptibility genes were screened in view of the young age at presentation and multifocal malignant tumours. She was found to carry a known mutation c.572G>A (p.Cys191Tyr) in the SDHB gene. This case illustrates the need for screening of susceptibility genes for familial paragangliomas/phaeochromocytomas in apparently sporadic cases, and the therapeutic benefit of using 131-I-MIBG as an adjuvant treatment for metastatic lesions.

Immunohistochemical Loss of Succinate Dehydrogenase Subunit A (SDHA) in Gastrointestinal Stromal Tumors (GISTs) Signals SDHA Germline Mutation

A subset (7% to 10%) of gastric gastrointestinal stromal tumors (GISTs) is notable for the immunohistochemical loss of succinate dehydrogenase (SDH) subunit B (SDHB), which signals the loss of function of the SDH complex consisting of mitochondrial inner membrane proteins. These SDH-deficient GISTs are known to be KIT/PDGFRA wild type, and most patients affected by this subset of GISTs are young. Some of these patients have germline mutations of SDH subunit genes SDHB, SDHC, or SDHD, known as Carney-Stratakis syndrome when combined with paraganglioma. More recently, germline mutations in SDH subunit A gene (SDHA) have also been reported in few patients with KIT/PDGFRA wild-type GISTs. In this study we immunohistochemically examined 127 SDHB-negative and 556 SDHB-positive gastric GISTs and 261 SDHB-positive intestinal GISTs for SDHA expression using a mouse monoclonal antibody 2E3 (Abcam). Cases with available DNA were tested for SDHA, SDHB, SDHC, and SDHD gene mutations using a hybridization-based custom capture next-generation sequencing assay. A total of 36 SDHA-negative GISTs (28%) were found among 127 SDHB-negative gastric GISTs. No SDHB-positive GIST was SDHA negative. Among 7 SDHA-negative tumors analyzed, there were 7 SDHA mutants, most germline. A second hit indicating biallelic inactivation of SDHA was present in 6 of those cases. These patients had no other SDH subunit gene mutations. Among the 25 SDHA-positive, SDHB-negative GISTs analyzed, we identified 3 SDHA mutations (1 germline), and 11 SDHB, SDHC, or SDHD mutations (mostly germline), and 11 patients with no SDH mutations. Compared with patients with SDHA-positive GISTs, those with SDHA-negative GISTs had an older median age (34 vs. 21 y), lower female to male ratio (1.8 vs. 3.1) but similar mitotic counts and median tumor sizes, with a slow course of disease in most cases, despite a slightly higher rate of liver metastases. SDHA-negative GISTs comprise approximately 30% of SDHB-negative/SDH-deficient GISTs, and SDHA loss generally correlates with SDHA mutations.

Missense mutations in the human SDHB gene increase protein degradation without altering intrinsic enzymatic function

Mutations of succinate dehydrogenase subunit B (SDHB) play a crucial role in the pathogenesis of the most aggressive and metastatic pheochromocytomas (PHEOs) and paragangliomas (PGLs). Although a variety of missense mutations in the coding sequence of the SDHB gene have been found in PHEOs and PGLs, it has been unclear whether these mutations impair mRNA expression, protein stability, subcellular localization, or intrinsic protein function. RT-PCR and Western blot analysis of SDHB mRNA and protein expression from SDHB-related PHEOs and PGLs demonstrated intact mRNA expression but significantly reduced protein expression compared to non-SDHB PHEOs and PGLs. A pulse-chase assay of common SDHB missense mutations in transfected HeLa cell lines demonstrated that the loss of SDHB function was due to a reduction in mutant protein half-life, whereas colocalization of SDHB with mitochondria and immunoprecipitation with SDHA demonstrated intact subcellular localization and complex formation. The half-life of the SDHB protein increased after treatment with histone deacetylase inhibitors (HDACis), implicating the protein quality control machinery in the degradation of mutant SDHB protein. These findings provide the first direct mechanism of functional loss resulting from SDHB mutations and suggest that reducing protein degradation with HDACis may serve as a novel therapeutic paradigm for preventing the development of SDHB-related tumors.

A SDHB malignant paraganglioma with dramatic response to temozolomide–capecitabine

Ten percent of paragangliomas are malignant and one-third occurs in a genetic background. We report a case of succinate dehydrogenase subunit B (SDHB)-related malignant paraganglioma with dramatic response to temozolomide and capecitabine regimen (decrease in tumor size of 70% with RECIST criteria). Tumor cells harbored a new mutation in SDHB gene and showed aberrant hypermethylation of O6-methylguanine-DNA-methyltransferase promoter. Our report suggests the importance of molecular predictive factors of response for the selection of chemotherapeutic as well as targeted agents. This observation points to a possible genotype response to treatment relationships, which could help to design tailor-made treatments in the future.

Diagnostic performance of 18F-dihydroxyphenylalanine positron emission tomography in patients with paraganglioma: a meta-analysis

The aim of this study was to systematically review and conduct a meta-analysis of published data about the diagnostic performance of (18)F-dihydroxyphenylalanine (DOPA) positron emission tomography (PET) in patients with paraganglioma (PG). A comprehensive computer literature search of studies published through 30 June 2011 regarding (18)F-DOPA PET or PET/computed tomography (PET/CT) in patients with PG was performed in PubMed/MEDLINE, Embase and Scopus databases. Pooled sensitivity and specificity of (18)F-DOPA PET or PET/CT in patients with PG on a per patient- and on a per lesion-based analysis were calculated. The area under the receiver-operating characteristic (ROC) curve was calculated to measure the accuracy of (18)F-DOPA PET or PET/CT in patients with PG. Furthermore, a sub-analysis taking into account the different genetic mutations in PG patients was also performed. Eleven studies comprising 275 patients with suspected PG were included in this meta-analysis. The pooled sensitivity of (18)F-DOPA PET and PET/CT in detecting PG was 91% [95% confidence interval (CI) 87-94%] on a per patient-based analysis and 79% (95% CI 76-81%) on a per lesion-based analysis. The pooled specificity of (18)F-DOPA PET and PET/CT in detecting PG was 95% (95% CI 86-99%) on a per patient-based analysis and 95% (95% CI 84-99%) on a per lesion-based analysis. The area under the ROC curve was 0.95 on a per patient- and 0.94 on a per lesion-based analysis. Heterogeneity between the studies about sensitivity of (18)F-DOPA PET or PET/CT was found. A significant increase in sensitivity of (18)F-DOPA PET or PET/CT was observed when a sub-analysis excluding patients with succinate dehydrogenase subunit B (SDHB) gene mutations was performed. In patients with suspected PG (18)F-DOPA PET or PET/CT demonstrated high sensitivity and specificity. (18)F-DOPA PET or PET/CT are accurate methods in this setting. Nevertheless, possible sources of false-negative results should be kept in mind. Furthermore, SDHB gene mutations could influence (18)F-DOPA PET or PET/CT diagnostic performance.

Successful chemotherapy of hepatic metastases in a case of succinate dehydrogenase subunit B-related paraganglioma

Compared to other familial pheochromocytoma/paragangliomas (PHEO/PGLs), the succinate dehydrogenase subunit B (SDHB)-related PHEO/PGLs often present with aggressive and rapidly growing metastatic lesions. Currently, there is no proven effective treatment for malignant PHEO/PGLs. Here, we present a 35-year-old white man with primary malignant abdominal extra-adrenal 11 cm paraganglioma underwent surgical successful resection. But 6 months later, he developed extensive bone, liver, and lymph nodes metastasis, which were demonstrated by computed tomography scan and the (18)F-fluorodeoxyglucose positron emission tomography. However, his (123)I-metaiodobenzylguanidine scintigraphy was negative; therefore, the cyclophosphamide, vincristine, and dacarbazine (CVD) combination chemotherapy was initiated. The combination chemotherapy was very effective showing 80% overall reduction in the liver lesions and 75% overall reduction in the retroperitoneal mass and adenopathy, and normalization of plasma catecholamine and metanephrine levels. However, plasma levels of dopamine (DA) and methoxytyramine (MTY) were only partially affected and remained consistently elevated throughout the remaining period of follow-up evaluation. Genetic testing revealed an SDHB gene mutation. Here, we present an SDHB-related PHEO/PGL patient with extensive tumor burden, numerous organ lesions, and rapidly growing tumors, which responded extremely well to CVD therapy. We conclude patients with SDHB-related PHEO/PGLs can be particularly sensitive to CVD chemotherapy and may have an excellent outcome if this therapy is used and continued on periodic basis. The data in this patient also illustrate the importance of measuring plasma levels of DA and MTY to provide a more complete and accurate assessment of the biochemical response to therapy than provided by measurements restricted to other catecholamines and O-methylated metabolites.

High Frequency ofSDHBGermline Mutations in Patients with Malignant Catecholamine-Producing Paragangliomas: Implications for Genetic Testing

Adrenal and extraadrenal paragangliomas are tumors of chromaffin cells that are usually benign but that may also develop into malignant disease. Mutations of the gene for succinate dehydrogenase subunit B (SDHB) are associated with a high risk of malignancy, but establishing the precise contribution requires relatively large numbers of patients with well-defined malignancy. We assessed the prevalence of SDHB mutations in a series of patients with malignant paraganglioma. SDHB mutation testing was carried out in 44 consecutive patients with malignant paraganglioma. Clinical characteristics of patients with malignant disease due to SDHB mutations were compared with those without mutations. Pathogenic SDHB mutations were found in 13 of the 44 patients (30%). Close to one third of patients had metastases originating from an adrenal primary tumor, compared with a little over two thirds from an extraadrenal tumor. Among the latter patients, the frequency of SDHB mutations was 48%. This study establishes that missense, nonsense, frameshift, and splice site mutations of the SDHB gene are associated with about half of all malignancies originating from extraadrenal paragangliomas. The high frequency of SDHB germline mutations among patients with malignant disease, particularly when originating from an extraadrenal paraganglioma, may justify a high priority for SDHB germline mutation testing in these patients.

The Occurrence of SDHB Gene Mutations in Pheochromocytoma

Pheochromocytomas (PCCs) are rare tumors arising from neural crest-derived chromaffin cells. The majority of these tumors are located in the adrenals and gives rise to catecholamine overproduction. In at least 10% of the cases the tumors are located outside the adrenal gland, in extra-adrenal sites like the bladder and the organ of Zuckerkandl. Recent investigations have found mutations in succinate dehydrogenase subunit B (SDHB), the gene coding for subunit B of the respiratory chain complex II. Mutations in the SDHB gene, with additional loss of the wild-type allele, result in loss of function of respiratory complex II and appear to correlate with extra-adrenal location of PCCs. Also, a link has been established between malignant behavior and inactivating mutations of SDHB. In this article we review the published SDHB gene mutations, as well as the location and behavior of the resulting PCCs.