Update of Pheochromocytoma Syndromes: Genetics, Biochemical Evaluation, and Imaging

Abstract

Pheochromocytomas and paragangliomas (PCCs/PGLs) are rare commonly benign neuroendocrine tumors that share pathology features and clinical behavior in many cases. While PCCs are chromaffin-derived tumors that arise within the adrenal medulla, PGLs are neural-crest-derived tumors that originate at the extraadrenal paraganglia. Pheochromocytoma-paraganglioma (PPGL) syndromes are rapidly evolving entities in endocrinology and oncology. Discoveries over the last decade have significantly improved our understanding of the disease. These include the finding of new hereditary forms of PPGL and their associated susceptibility genes. Additionally, the availability of new functional imaging tools and advances in targeted radionuclide therapy have improved diagnostic accuracy and provided us with new therapeutic options. In this review article, we present the most recent advances in this field and provide an update of the biochemical classification that further reflects our understanding of the disease.

Keywords: DOTATATE; PRRT; biochemical classification; genetics; paraganglioma; pheochromocytoma.

Figure 1

Genetics and molecular pathways for PPGLs Pathways for the New Genes; Placing the New into Perspective. Mutations of the highlighted genes have been discovered to play a role in the pathogenesis of PPGL. These genes can be classified in cluster 1, 2, or 3. Cluster 1 would be implemented with FH, MDH2, PHD1 (EGLN2), EPAS1/HIF2A and the most recently discovered IRP1 that controls cellular iron metabolism and negatively regulates HIF2α mRNA translation. Cluster 2 would include H-RAS and ATRX, which belongs to the SWI/SNF family of chromatin remodeling proteins, as their upregulation will activate the RAS/RAF/ERK signaling pathway resulting in tumor formation. Finally, cluster 3 would be implemented with both CSDE1 and UBFT fusion at MAML3. Alterations of any of this genes will result in increase of target genes involved in Wnt receptor and Hedgehog signaling pathways.

Figure 2

Proposed Algorithm for Evaluation and Management of PPGL Patient. *Depending on clinical status, growth acceleration, symptoms, and genetic status, the options include: observation, systemic therapy, chemotherapy, PRRT, ¹³¹I-MIBG, or referral to clinical trials. R0, microscopically margin-negative resection; R1, microscopically margin-positive resection; R2, macroscopically margin-positive resection; stage IV, metastatic disease (1).

Figure 3

Schematic algorithm for identifying a possible driver mutation of the newly identified genes mutation. *Often family history is absent; **Unknown; ***Not described yet.