Etiology
About 85% of pheochromocytomas arise in the adrenal medullary catecholamine-producing chromaffin cells; the remainder are extra-adrenal in origin.[3] They may be sporadic or familial in nature.
Most pheochromocytomas are sporadic; however, studies suggest that up to 40% are hereditary in adults and it is likely up to 80% are hereditary in children.[20][21] Conditions associated with hereditary pheochromocytomas include multiple endocrine neoplasia type 2 (MEN2), Von Hippel-Lindau syndrome, and neurofibromatosis type 1.[5] Genes underlying these familial syndromes are the RET proto-oncogene in MEN2, the VHL gene in Von Hippel-Lindau syndrome, and the NF1 gene in neurofibromatosis type 1.
Germline and/or somatic mutations have been identified in more than 20 genes.[22] More than half of the germline mutations occur in one of the succinate dehydrogenase (SDH) genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), which encode the different subunits and assembly protein of a mitochondrial enzyme, succinate dehydrogenase.[23] Other genes with mutations include FH, MDH2, TMEM127, MAX, and EPAS1 (also known as HIF2A).[21] Somatic driver mutations exist in some of the same genes (RET, VHL, NF1, EPAS1) as well as in additional genes including HRAS, CSDE1, ATRX, TERT, and MAML3.[24]
Pheochromocytoma and paraganglioma tumors with mutations are broadly categorized into three clinically useful molecular clusters:[21]
Pseudohypoxic PPGLs: SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, IDH1/2, MHD2, EGLN1/2, and HIF2/EPAS
Kinase signaling PPGLs: RET, NF1, TMEM127, MAX and HRAS
Wnt signaling PPGLs: CSDE1 and MAML3
Underlying mutations can help elucidate the clinical presentation, overall prognosis, and surveillance follow-up.[21]
Pathophysiology
Pheochromocytomas are tumors of the chromaffin cells that arise within the adrenal medulla, whereas paragangliomas are neural crest-derived neuroendocrine tumors that can originate at any level of extra-adrenal sympathetic paraganglia.[25]
Pheochromocytomas and paragangliomas (together known as PPGL) synthesize and secrete catecholamines: namely, epinephrine (adrenaline), norepinephrine (noradrenaline), and, rarely, dopamine. The secretion of catecholamines from a PPGL is episodic; however, once these catecholamines are converted by catechol-O-methyltransferase into metanephrines and normetanephrines, they are constantly released into circulation.[3] Differences in the biochemical phenotype can help guide assessment.[25] An adrenergic phenotype (pheochromocytoma) is characterized by purely elevated epinephrine/metanephrine or both epinephrine/metanephrine and norepinephrine/normetanephrine.[25] A noradrenergic phenotype (paraganglioma) is commonly located outside the adrenals and has increased levels of norepinephrine/normetanephrine, but not epinephrine/metanephrine, as they do not process the enzymatic machinery to convert norepinephrine/normetanephrine to epinephrine/metanephrine.[25] The variation in clinical symptoms associated with PPGLs are related to differences in secretion of epinephrine and norepinephrine and their individual effect on alpha and beta-adrenergic receptors.[26]
Familial pheochromocytomas tend to be small tumors with low levels of catecholamine release; in contrast, sporadic tumors tend to be larger with high levels of catecholamine release.
Malignant pheochromocytomas are histologically and biochemically similar to benign tumors. All PPGLs are believed to harbor malignant potential and about 10% to 15% pheochromocytomas will become metastatic.[27] Results of studies to provide a histopathologic criteria that can be applied to predict risk of developing metastatic disease have been controversial.[28] Characteristics that make metastatic disease more likely are large tumor size (>5 cm for pheochromocytomas, >4 cm for paragangliomas), gross large vessel invasion, extra-adrenal location, and germline predisposition with with an SDHB pathogenic variant.[28] Only three sites can definitively qualify as metastatic as they have no paraganglionic tissue: bone, brain, and lymph node; however, metastatic disease can involve any organ.[28]
Classification
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