Immunohistochemical and molecular studies on the pathogenesis of pheochromocytomas and paragangliomas

Abstract In the last decades major progress has been made in discovering genes implicated in the syndromic occurrence of pheochromocytomas (PCC) and paragangliomas (PGL). It’s now well established that about 35% of all PCC/PGL are due to germline mutations in one of the genes: RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, PHD2, HIF2A, KIF1B, and FH. In addition, somatic mutations in RET, VHL, NF1, and HIF2A can also be detected in a subset of sporadic PCC/PGL. However, the pathogenesis of sporadic PCC and PGL is currently poorly understood. This issue has been investigated in the first part of this thesis (Chapters 2 and 3) by a candidate gene approach. SDHB and SDHA immunohistochemistry (IHC) is a valuable tool to identify PCC/PGL patients with mutations in one of the succinate dehydrogenase (SDH) genes. In the second part of this thesis we validated the reproducibility of this assessment method. Moreover, we determined if SDHA IHC could be a valuable tool to guide genetic testing in another tumor type from the SDH-associated tumor spectrum: gastrointestinal stromal tumors. In addition, we searched for new tools to validate SDH mutations. A major problem in PCC management remains the lack of predictive markers for malignancy and the lack of curative treatment options for progressive disease. In the last part of this thesis we focused on activation of intracellular pathways that could be targets for therapy and on validation of a prognostic tool for the distinction between benign and malignant PCC

The Role of Immunohistochemistry and Molecular Analysis of Succinate Dehydrogenase in the Diagnosis of Endocrine and Non-Endocrine Tumors and Related Syndromes

Succinate dehydrogenase (SDH) is an enzyme complex, composed of four protein subunits, that plays a role in both the citric acid cycle and the electron transport chain. The genes for SDHA, SDHB, SDHC, and SDHD are located in the nuclear DNA, and mutations in these genes have initially been described in paragangliomas (PGL) and pheochromocytomas (PCC), which are relatively rare tumors derived from the autonomic nervous system and the adrenal medulla, respectively. Patients with SDH mutations, that are almost exclusively in the germline, are frequently affected by multiple PGL and/or PCC. In addition, other tumors have been associated with SDH mutations as well, including gastrointestinal stromal tumors, SDH-deficient renal cell carcinoma, and pituitary adenomas. Immunohistochemistry for SDHB and SDHA has been shown to be a valuable additional tool in the histopathological analysis of these tumors, and can be considered as a surrogate marker for molecular analysis. In addition, SDHB immunohistochemistry is relevant in the decision-making whether a genetic sequence variant represents a pathogenic mutation or not. In this review, we highlight the current knowledge of the physiologic and pathologic role of the SDH enzyme complex and its involvement in endocrine and non-endocrine tumors, with an emphasis on the applicability of immunohistochemistry