Pheochromocytoma and Paraganglioma

Abstract

Pheochromocytoma (PCC) and paraganglioma (PGL) are neuroendocrine tumors that originate in the neural crest. While PCCs develop from chromaffin cells in the adrenal medulla, PGLs develop either from paraganglia in the sympathetic nervous system (and are distributed symmetrically along the entire paravertebral axis from the neck to the pelvis, giving rise to thoracic and abdominal/retroperitoneal PGL) or more rarely from parasympathetic paraganglia (giving rise to head and neck PGL and rarely thoracic PGL). PCCs/PGLs have the highest heritability of all human neoplasms being a good example of diseases with underlying genetic heterogeneity. In this regard, at least 40% of PCC/PGL patients carry a germline mutation in 1 of the 19 genes described so far as related to the disease. In addition to the complexity of the genetics of PCC/PGL, we need to consider the role of somatic mutations, which to date have been identified up to 30–35% of tumors. The latter have been observed to occur not only in the same genes involved in heritable susceptibility but also in the new ones, which have thus recently emerged as key players in the sporadic presentation of these diseases. Despite the increasing proportion of patients already explained by germline or somatic genetic defects, there are still patients with clinical indicators of hereditary disease (i.e., family history, multiple tumors, and/or young age of onset) without a molecular diagnosis, which are being actively investigated.