MEN2-related pheochromocytoma: current state of knowledge, specific characteristics in MEN2B, and perspectives

Multiple endocrine neoplasia type 2 (MEN2) is a rare hereditary syndrome due to mutations of the proto-oncogene REarranged during Transfection (RET), defined by the association of medullary thyroid carcinoma (MTC) in almost 100% cases, and pheochromocytoma in roughly 50% (primary hyperparathyroidism can be seen in 10-20% of patients with MEN2A). Early thyroidectomy and the efficacy of novel tyrosine kinase inhibitors modified the natural history of MTC, with possibilities of cure or long-term control. The second main compound, pheochromocytoma, is reported with a variable penetrance, from 10 to 80% cases, depending on the mutation of RET. Pheochromocytoma constitutes the main disease to screen in patients with RET mutations. Pheochromocytoma clinical and biochemical diagnosis, as well as the way to treat it are thus crucial. This review will thus focus on the epidemiological specificities of MEN2-related pheochromocytoma, the genotype/phenotype relationship, the modern imaging modalities necessary to confirm the diagnosis in this hereditary context, as well as the optimal management and the possibilities of adrenal sparing surgery. Additional information will include the natural history of MEN2B-pheochromocytoma, the rare cases of malignant pheochromocytoma, and the factors that could modify the penetrance between individuals carrying the same mutation, especially in the same family.