MEN1 is an autosomal dominant hereditary multiple endocrine neoplasia syndrome with a complete penetrance by the age of 50. The main clinical manifestations of the MEN1 syndrome are multiple adenomas of the parathyroid glands, GEP-NETs, and tumors of the anterior pituitary. Primary hyperparathyroidism (PHPT) is the most common clinical sign, affecting more than 95% of MEN1 patients, with age of onset between 20 and 25 years. PHPT remains benign and may be asymptomatic throughout the patient’s life. GEP-NETs are the second most common tumors in MEN1, mainly occurring in the pancreatic islets and duodenum, usually as multiple tumors. Pituitary tumors are the third most common clinical manifestation of MEN1, including prolactinoma, somatotropinoma, and ACTHomas and non-functioning adenomas. Also thymic, bronchial and gastric carcinoids often develop in MEN1 patients, rarely secreting amine or peptide hormones. Typical multiple cutaneous lesions, facial angiofibromas and collagenomas, have been reported in over 85% and 70% of MEN1 patients, respectively (Fig. 3.1) [8]. The estimated prevalence of MEN1 is about 1 in 30,000 births. Gender distribution appears to be equal.

Clinical characteristics of MEN1-associated abdominal NETs depend on the specific site of tumor development and on the secreted hormone. GEP-NETs in MEN1 patients can be non-functioning or functioning tumors (Table 3.2). The most common GEP-NETs in MEN1 are P-NETs. When endoscopic ultrasonography (EUS) is utilized, P-NETs are found in approximately 40–54% of asymptomatic MEN1 patients [9, 10]; about 50% of 16–25-year-old MEN1 patients harbor P-NETs [10]. With time, almost all MEN1 patients develop multiple nonfunctioning P-NETs, which are a common hallmark of the syndrome. MEN1 predisposes to multiple P-NETs: the majority of them are microadenomas (less than 5 mm in diameter). Lesions over 5 mm in diameter (macroadenomas) are a minority but they are potentially malignant.

Non-functioning tumors are the most frequent P-NETs in MEN1, usually characterized by a later onset. They are usually asymptomatic and discovered incidentally either by imaging examinations or by assessing the increase of pancreatic polypeptide (PP), which is secreted by approximately half of them.

Insulinoma is the most frequent functioning P-NET. It is a prerogative of the MEN1 syndrome, affecting about 15% of MEN1 patients harboring a MEN1 mutation, and generally develops at a young age (Fig. 3.2b). In some patients, neuroglycopenic symptoms, due to the over-secretion of insulin, may be the first manifestation of MEN1 syndrome. The presence of multiple insulinomas and the association with other non-functioning P-NETs or with duodenal gastrinomas characterize the MEN1 organic hyperinsulinism.

The majority of gastrinomas develop in the deep part of the duodenal mucosa (Fig. 3.2a) and are usually multiple.

Glucagonomas, somatostatinomas, vasoactive intestinal polypeptide (VIP)-secreting tumors (VIPomas) and growth hormone-releasing factor tumors (GRFomas) manifest more rarely in MEN1 patients. Glucagonomas are accompanied by the typical necrolytic syndrome. Conversely, somatostatinomas are usually asymptomatic.

The MEN1 gene (OMIM *613733, cytogenetic location 11q13.1) encodes a 610 amino acid nuclear protein, called menin, which is ubiquitously expressed in endocrine and non-endocrine tissues. Menin is directly and indirectly involved in gene transcription regulation, is responsible for positive control of genome stability and apoptosis and for negative regulation of cell growth [13].

Studies on MEN1 pancreatic and duodenal NET tissues evidenced that the inactivation of a single MEN1 allele is associated with endocrine cell hyperplasia, but not neoplasia [14, 15]. Conversely, the adjunctive loss of the second MEN1 wild type copy, at somatic level, results in endocrine cell dysplasia and development of micro and/or macro abdominal NETs [14, 15]. The complete loss of wild type menin, results in a severe reduction of p27^kip1 and pl8^INK4c expression, and it is responsible for increase of cell proliferation due to the lost inhibition of S-phase cell cycle progression. The observation of distinct somatic patterns of loss of the second copy of MEN1 gene suggests that, in multifocal abdominal NETs, each tumor presumably arises separately from a single cell [15].

Somatic mutations of the MEN1 gene have been described also in 27–39% of sporadic P-NETs, and loss of heterozygosity (LOH) at the MEN1 locus (11q13.1) have been reported in 5–93% of sporadic P-NETs [16], confirming the importance of wild type menin in preventing neuroendocrine tumorigenesis of the pancreas, and presumably of other GEP-NETs.

Gastric acid hypersecretion in gastrinomas and Zollinger-Ellison syndrome is well controlled by proton pump inhibitors (PPI). Somatostatin analogues (SSAs) are synthetic molecules (octreotide and lanreotide) that retain the binding affinity for somatostatin receptors (SSTRs), at least with high affinity for SSTR2 and moderate affinity for SSTR5. SSAs are successfully employed for controlling clinical symptoms, inhibiting both pancreatic and gastrointestinal hormone secretion (i.e., insulin, glucagon, gastrin, secretin and VIP). SSAs are effective only in few patients with insulinomas because of the low expression of SSTR2 in tumor cells [17].

Preliminary data on peptide receptor radionuclide therapy (PRRT) suggest a potential therapeutic role of this therapy in the treatment of advanced P-NETs in MEN1 patients [18]. PRRT with radio labeled SSAs takes advantage of the SSA specificity for somatostatin receptors to deliver cytotoxic doses of a radioactive isotope (i.e., yttrium-90 or lutetium-177) selectively to GEP-NETs cells.