Pheochromocytoma and paraganglioma: genotype versus anatomic location as determinants of tumor phenotype

To date, germline or somatic genetic events can be detected for at least 60% of paragangliomas. Strong genotype–phenotype associations have been recognized and become increasingly refined. Characteristics closely linked with genotype include syndromic presentation, age of onset, risk of metastatic disease and predominant anatomic site. In contrast, profiles of catecholamine secretion appear to be largely determined by anatomic location or cell type of origin. This review summarizes current knowledge of genotype–phenotype correlations for paragangliomas in different locations and scrutinizes previous publications on the respective tissues of origin to find potential explanations for site-related differences. We hypothesize that differential sensitivities of distinct chromaffin cell populations to hypoxia are major determinants of these differences, with increased sensitivity to hypoxia likely exacerbating vulnerability to mutation-derived disruption of hypoxic signaling pathways. Potential involvement of endothelin-1, tumor necrosis factor type 1 receptor-associated protein and the hypoxia-inducible miR-210 in the development of abdomino-thoracic or head and neck paragangliomas are discussed. Recognition of factors that predispose to chromosomal losses, or amplify sub-threshold molecular alterations towards tumorigenic events in different (chromaffin) cell types, may facilitate the leap from developing targeted therapies towards establishment of tumor preventative measures.