Neuroendocrine Neoplasms with Peculiar Biology and Features. MEN1, MEN2A, MEN2B, MEN4, VHL, NF1

A relevant number of neuroendocrine neoplasms (NENs) show a hereditary background being associated with a genetic endocrine neoplastic syndrome. Multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2 (MEN2), variants MEN2A and MEN2B, and multiple endocrine neoplasia type 4 (MEN4) present NENs as main and typical manifestations, while Von Hippel–Lindau disease (VHL) and neurofibromatosis type 1 (NF1) are mainly characterized by neoplasms of non-neuroendocrine origin. Among NENs, pancreatic and thyroid tumors are most frequently associated with hereditary syndromes, the former being found in MEN1, MEN4, VHL, NF1, and the latter in MEN2A and B. Rare NEN sites are lung, thymus, and stomach, while pituitary and parathyroid adenomas are common in MEN1 and MEN4, as well as pheochromocytoma and paragangliomas in MEN2, VHL, NF1. The diagnosis of hereditary NENs is anticipated of approximately two to three decades as compared to the sporadic counterpart. At histology the neuroendocrine tumors associated with genetic syndromes associated with hereditary syndromes are generally well differentiated, low proliferating, multiple, and multifocal. They are also frequently functioning, thus resulting in different types of endocrine syndromes, such as hyperinsulinemic hypoglycemia, Zollinger–Ellison, hyperprolactinemia, hyperparathyroidism, hypersecretion of catecholamines, and other rarer syndromes. Neuroendocrine carcinomas are extremely rare.