What Have We Learned from Molecular Biology of Paragangliomas and Pheochromocytomas?

Abstract

Recent advances in molecular genetics and genomics have led to increased understanding of the aetiopathogenesis of pheochromocytomas and paragangliomas (PPGLs). Thus, pangenomic studies now provide a comprehensive integrated genomic analysis of PPGLs into distinct molecularly defined subtypes concordant with tumour genotypes. In addition, new embryological discoveries have refined the concept of how normal paraganglia develop, potentially establishing a developmental basis for genotype-phenotype correlations for PPGLs.The challenge for modern pathology is to translate these scientific discoveries into routine practice, which will be based largely on histopathology for the foreseeable future. Here, we review recent progress concerning the cell of origin and molecular pathogenesis of PPGLs, including pathogenetic mechanisms, genetic susceptibility and molecular classification. The current roles and tools of pathologists are considered from a histopathological perspective, including differential diagnoses, genotype-phenotype correlations and the use of immunohistochemistry in identifying hereditary predisposition and validating genetic variants of unknown significance. Current and potential molecular prognosticators are also presented with the hope that predictive molecular biomarkers will be integrated into risk stratification scoring systems to assess the metastatic potential of these intriguing neoplasms and identify potential drug targets.

Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas

“…More recent studies and meta-analysis report the need of periodical image evaluation, the recommended frequency varying generally between 2 and 3 years [ 47 , 128 – 132 ]. Currently, translational research stratification scores have been developed to estimate the risk of new PPGL events and the frequency of metastatic disease [ 133 ]; however, evidence from longitudinal studies is still needed, and guidelines for follow-up continue to evolve. National and international registries are fundamental to collect information necessary to deliver updates that permit the elaboration of clinical guidelines.…”

Challenges in Paragangliomas and Pheochromocytomas: from Histology to Molecular Immunohistochemistry

“…In PPGLs (right), activating EPAS1 (encoding HIF-2α) mutations (green star), inactivating VHL, PHD1/EGLN2 and PHD2/EGLN1 mutations (red stars) as well as aberrant TCA cycle regulation leading to inhibition of PHDs are main genetic events activating the HIF signaling cascade-even at normal oxygen levels events. Even so, immunohistochemistry is still considered an efficient, cheap, and reproducible method to pinpoint cases in need of intensified molecular studies, as well as to evaluate the functional consequences of some genetic variants of uncertain significance detected through clinical genetics workup [93]. In terms of prognostication and clinical significance, SDHB immunohistochemistry is probably the most well-established marker to date.…”

“…The advent of modern next-generation analyses have revolutionized the ability to classify PPGLs, not only in terms of transcriptome clustering but also as a way to detect germline alterations in patients in need of genetic counselling and to pinpoint high-risk mutations in TCA cycle/pseudo-hypoxia-related PPGLs indicating higher risk of metastatic events. Even so, immunohistochemistry is still considered an efficient, cheap, and reproducible method to pinpoint cases in need of intensified molecular studies, as well as to evaluate the functional consequences of some genetic variants of uncertain significance detected through clinical genetics workup [ 93 ]. In terms of prognostication and clinical significance, SDHB immunohistochemistry is probably the most well-established marker to date.…”

Inherited/Genetically-Associated Pheochromocytoma/ Paraganglioma Syndromes and COVID-19

“…Inherited/genetically associated PPG syndromes, particularly those caused by mutations in the succinate dehydrogenase (SDH) B or D genes or the von Hippel-Lindau (VHL) gene, are associated with the stabilization/activation of the hypoxia-inducible factor 1 alpha (HIF1α). This factor is implicated in promoting angiogenesis and tumour growth [3,4].…”