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.