Pheochromocytoma: from the bench to the surgery

Pheochromocytoma (PHEO) is a rare catecholamine-producing tumor of neuroendocrine origin with a variable prevalence of 0.1 to 0.6% in hypertensive subjects. Generally pheochromocytoma arises from chromaffin cells of the adrenal medulla and in 10% of the cases from the sympathetic ganglia, and is named paraganglioma (PGL). Thirty percent of PHEO/PGL are caused by germline mutations. In the last few years, 10 genes (RET, NF1, VHL, subunits of the succinate dehydro- genase [SDH] complex: SDHB, SDHC, SDHD and SDHA, SDHAF2, MAX, and TMEM127) have been found to be associated with predisposition to these tumours. Multiple endocrine neoplasias syndromes have been classified type 1 and 2; multiple endocrine neoplasias type 1 (MEN1) is usually associated with pituitary, parathyroid and paraneoplastic neuroendocrine tumours. Three clinical subtypes MEN2A, MEN2B, and familial MTC (FMTC) have been defined based on the risk of PHEO, hyperparathyroidism, and the presence of characteristic physical features. MEN2 occurs as a result of germline activating missense mutations of the RET proto-oncogene. Recently, Pellegata et al. have reported that germline mutations in CD- KN1B (p27 Kip1) can predispose to the development of multiple endocrine tumours in both rats and humans. Phenotypically, in the rat an overlap of features of both MEN1 and MEN2 is observed. Two patients with no detectable mutation in the MEN1 gene, have been described as showing a mutation in the CDKN1B gene. These findings support an association between germline mutations of CD- KN1B and a MEN1 syndrome condition and suggest the need to search for new genes implicated in neuroendocrine tumor syndromes involving PHEO.