Introduction to Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are a group of diverse neoplasms arising from cells of a neuroendocrine origin. Newer classification and staging systems have been adapted and guidelines published to help establish a more standardized approach. The estimated incidence rate of 1.09/100,000 in 1973 increased to 5.25/100,000 NETs in 2004 and reached 6.98/100,000 NETs in 2012. Although NETs may occur at any age, they are more common after the age of 50 and peak between the ages of 50 and 70. The incidence in patients 65 years or older is 25.3 per 100,000 persons, and, in those aged 50–64 years, it is 14.3 per 100,000 persons; those younger than 50 years had an incidence of 1.75/100,000 in 2012 according to the Surveillance, Epidemiology, and End Results (SEER) database. NETs may be associated with familial genetic neuroendocrine tumor syndromes such as multiple endocrine neoplasia (MEN) syndromes (MEN-1 and MEN-2), neurofibromatosis type 1, Von Hippel–Lindau (VHL) disease, tuberous sclerosis, and Carney complex. NETs are usually slow-growing tumors. They can arise from many organs but commonly from the gastrointestinal (GI) tract and pancreas, lungs, thymus, and other endocrine organs. NETs may synthesize and secrete peptides and/or amines. About 67% of NETs are located in the GI system, and these NETs are sometimes also called carcinoids or GI NETs. Carcinoids secrete numerous peptides, including serotonin (5-hydroxytryptamine (5-HT)) and tachykinins. About 10% of GI NETs metastasize to the liver and release 5-HT into the blood, resulting in carcinoid syndrome characterized by cutaneous flushing, diarrhea, and abdominal pain. Pancreatic NETs (PNETs) comprise the second common group of NETs. These tumors may be either functional (~40%) or nonfunctional (~60%). Functional pancreatic NETs are usually defined by the predominant, clinically relevant hormone secretion of neuroendocrine biomarkers such as insulin, gastrin, glucagon, and vasoactive intestinal peptide (VIP). NETs are graded based on mitotic count and the Ki-67 index. Grading should be combined with the organ-specific tumor, node, and metastasis (TNM) staging system. NETs usually express somatostatin receptors; therefore, somatostatin expression can be used both diagnostically and therapeutically (Klimstra et al., Pancreas 39:707–712, 2010). Somatostatin receptor imaging with 68Ga-DOTATATE is preferably used for initial staging, follow-up, and selecting patients for peptide receptor radionuclide therapy (PRRT). Surgery is the only potentially curative treatment modality for low- and intermediate-grade tumors. Surgery should be considered for patients with early-stage disease, for those with locoregional and resectable metastatic disease, and for some selected symptomatic patients. Somatostatin analogues, everolimus, sunitinib, interferon (IFN), systemic combination chemotherapy, and 177Lu-DOTATATE therapy are the essential systemic treatment options for neuroendocrine carcinoma or advanced, inoperable, metastatic disease.