Mediastinal paragangliomas: association with mutations in the succinate dehydrogenase genes and aggressive behavior
ABSTRACT Extra-adrenal pheochromocytomas, otherwise known as paragangliomas (PGLs), account for about 20% of catecholamine-producing tumors. Catecholamine excess and mutations in the genes encoding succinate dehydrogenase subunits (SDHx) are frequently found in patients with PGLs. Only 2% of PGLs are found in the mediastinum, and little is known about genetic alterations in patients with mediastinal PGLs, catecholamine production by these tumors, or their clinical behavior. We hypothesized that most mediastinal PGLs are associated with germ line SDHx mutations, norepinephrine and/or dopamine excess, and aggressive behavior. The objective of this study was to characterize genetic, biochemical, and clinical data in a series of ten patients with mediastinal PGLs. All ten primary mediastinal PGL patients had germ line SDHx mutations, six in SDHB, and four in SDHD genes. Chest or back pain were the most common presenting symptoms (five patients), and catecholamines and/or their metabolites were elevated in seven patients. Additional tumors included head and neck PGLs in four patients, pheochromocytoma in one patient, and bladder PGL in another. Metastatic disease was documented in six patients (60%), and a concurrent abdominal mass was found in one patient. We conclude that mediastinal PGLs are strongly associated with SDHB and SDHD gene mutations, noradrenergic phenotype, and aggressive behavior. The present data suggest that all patients with mediastinal PGLs should be screened for SDHx gene mutations, regardless of age.
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ABSTRACT: Context: Mutations in the genes encoding subunits of the succinate dehydrogenase complex cause hereditary paraganglioma syndromes. While the phenotypes associated with the more commonly mutated genes, SDHB and SDHD, are well described, less is known about SDHC-associated paragangliomas. Objective: To describe functionality, penetrance, number of primary tumors, biological behavior and location of paragangliomas associated with SDHC mutations. Design: Families with an SDHC mutation were identified through a large cancer genetics registry. A retrospective chart review was conducted with a focus on patient and tumor characteristics. In addition clinical reports on SDHC-related paragangliomas were identified in the medical literature to further define the phenotype and compare findings. Setting: A cancer genetics clinic and registry at a tertiary referral center. Patients: Eight index patients with SDHC-related paraganglioma were identified. Results: Three of the eight index patients had mediastinal paraganglioma and 4 of 8 patients had more than one paraganglioma. Interestingly, the index patients were the only affected individuals in all families. When combining these index cases with reported cases in the medical literature, the mediastinum is the second most common location for SDHC-related paraganglioma (10% of all tumors) occurring in up to 13% of patients. Conclusions: Our findings suggest that thoracic paragangliomas are common in patients with SDHC mutations, and imaging of this area should be included in surveillance of mutation carriers. In addition, the absence of paragangliomas among at-risk relatives of SDHC mutation carriers suggests a less penetrant phenotype as compared to SDHB and SDHD mutations.The Journal of Clinical Endocrinology and Metabolism 04/2014; 99(8):jc20133853. DOI:10.1210/jc.2013-3853 · 6.31 Impact Factor
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ABSTRACT: Objective: Medullary thyroid carcinoma (MTC) and pheochromocytoma/paraganglioma (PHEO/PGL) are rare neuroendocrine tumors. Because of the increased metastatic rates in certain genetic backgrounds, early diagnosis and treatment are essential to improved patient outcomes. Our objective was to summarize recent findings related to the genetics, diagnosis, and management of MTC and PHEO/PGL.Methods: A literature review was performed.Results: MTC is primarily associated with mutations in the rearranged during transfection (RET) proto-oncogene. Determining the specific genetic mutation can guide patient management and screening. Early detection and appropriate surgical management of MTC is critical to prevent or limit metastatic spread, since treatment options for patients with metastatic disease are limited. PHEO/PGL also have a strong genetic component, with approximately 50% linked to germline and somatic mutations in 15 genes. Although most PHEO/PGLs are benign, factors such as genetic background, size, tumor location, and high methoxytyramine levels are associated with higher rates of metastatic disease. The state-of-the-art diagnosis and localization of PHEO/PGL is based on measurement of plasma metanephrines and methoxytyramine and functional imaging studies. For both PHEO/PGL and MTC, surgery is the only curative treatment. Treatment options for patients with metastatic disease are limited.Conclusions: As genetic testing becomes more widely available, the diagnosis of MTC and PHEO/PGL will be made earlier due to routine screening of at-risk patients. In addition, continued advances in basic science, diagnostic methods, and imaging techniques will improve understanding of the pathogenesis of these diseases and facilitate the introduction of novel treatment strategies for patients with metastatic disease.Endocrine Practice 01/2014; 20(2):1-34. DOI:10.4158/EP13268.RA · 2.59 Impact Factor
Current problems in cancer 01/2014; 38(1):7-41. DOI:10.1016/j.currproblcancer.2014.01.001 · 1.00 Impact Factor