Aetiology
About 85% of phaeochromocytomas 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 phaeochromocytomas are sporadic; however, studies suggest that up to 40% are hereditary in adults and it is likely up to 80% are hereditary in children.[18][20] Conditions associated with hereditary phaeochromocytomas include multiple endocrine neoplasia type 2 (MEN2), Von Hippel-Lindau syndrome, and neurofibromatosis type 1.[19] 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.[21] 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.[22] Other genes with mutations include fumarate hydratase (FH), malate dehydrogenase 2 (MDH2), transmembrane protein 127 (TMEM 127), MYC-associated factor X (MAX), and hypoxia-inducible factor 2-alpha (HIF2A, also known as endothelial PAS domain-containing protein 1, EPAS1).[20] 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.[23]
Phaeochromocytoma and paraganglioma (together known as PPGL) tumours with mutations are broadly categorised into three clinically useful molecular clusters:[20]
pseudohypoxic PPGLs: SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, IDH1/2, MHD2, EGLN1/2, andHIF2/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.[20]
Pathophysiology
Phaeochromocytomas are tumours of the chromaffin cells that arise within the adrenal medulla, whereas paragangliomas are neural crest-derived neuroendocrine tumours that can originate at any level of extra-adrenal sympathetic paraganglia.[24]
Phaeochromocytomas and paragangliomas (PPGLs) synthesise and secrete catecholamines: namely, adrenaline, 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.[24] An adrenergic phenotype (phaeochromocytoma) is characterised by purely elevated adrenaline/metanephrine or both adrenaline/metanephrine and noradrenaline/normetanephrines.[24] A noradrenergic phenotype (paraganglioma) is commonly located outside the adrenals and has increased levels of noradrenaline/normetanephrines, but not adrenaline/metanephrine, as they do not process the enzymatic machinery to convert noradrenaline/normetanephrines to adrenaline/metanephrines.[24] The variation in clinical symptoms associated with PPGLs are related to differences in secretion of adrenaline and noradrenaline and their individual effect on alpha and beta-adrenergic receptors.[25]
Familial phaeochromocytomas tend to be small tumours with low levels of catecholamine release; in contrast, sporadic tumours tend to be larger with high levels of catecholamine release.
Malignant phaeochromocytomas are histologically and biochemically similar to benign tumours. All PPGLs are believed to harbour malignant potential and about 10% to 15% phaeochromocytomas will become metastatic.[26] Results of studies to provide a histopathological criteria that can be applied to predict risk of developing metastatic disease have been controversial.[27] Characteristics that make metastatic disease more likely are large tumour size (>5 cm for phaeochromocytomas, >4 cm for paragangliomas), gross large vessel invasion, extra-adrenal location, and germline predisposition with an SDHB pathogenic variant.[27] 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.[27]
Classification
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