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Somatostatin-secreting tumors or somatostatinomas represent about 4% of gastrointestinal neuroendocrine neoplasms and their estimated incidence is about 1 in 40 million individuals per year. The spectrum of the somatostatinoma syndrome consists of diabetes mellitus, diarrhea/steatorrhea, cholelithiasis, hypochlorhydria, and weight loss. Hereditary pancreatic somatostatinomas can be found as part of multiple neuroendocrine neoplasia type 1 (MEN1) and von-Hippel Lindau (VHL) syndrome, whereas duodenal (peri-ampullary somatostatinomas can be found in patients with neurofibromatosis type 1 (NF1). The polycythemia-paraganglioma-somatostatinoma syndrome is a rare syndrome including multiple paragangliomas, duodenal somatostatinomas (exclusively found at the ampulla of Vater) associated with high erythropoietin (polycythemia) underlying paraganglioma/pheochromocytoma. The diagnosis of a somatostatinoma requires measuring fasting plasma somatostatin hormone concentration. A 3-phase CT, MRI, positron emission tomography (PET)-CT with gallium-labelled somatostatin analogs, or endoscopic ultrasonography should be performed for the precise localization of somatostatinomas in the pancreas or duodenum. A biopsy or surgical resection is required for grading (Ki67 index) and immunohistochemistry for somatostatin expression on tumor samples. Management of somatostatinomas includes medical treatment of the excess somatostatin production, surgical and/or radiological interventions, peptide receptor radiotherapy, and targeted or cytotoxic therapies

Vasoactive intestinal peptide (VIP) is a neurotransmitter which is present in the neurons in the central nervous system, the lung, intestine, adrenals, pancreas, and liver and in neuroendocrine cells in the pancreas. In the gastrointestinal tract, VIP stimulates contraction of enteric smooth muscle cells, secretion from the exocrine pancreas, gastrointestinal blood flow, and inhibition of gastric acid secretion. A VIPoma is a neuroendocrine neoplasm secreting VIP, causing severe watery diarrhea, which can result in hypokalemia and metabolic acidosis. Larger tumors (with highly elevated plasma VIP levels) can cause up to 6-8L of watery stools per day. Other symptoms include hypochlorhydria, stimulation of glycogenolysis, facial flushing, and hypercalcemia. By definition, plasma VIP levels are elevated in all patients with the VIPoma syndrome. VIPomas are usually located in the pancreas (75%) or along the sympathetic chain as seen in ganglioneuromas, ganglioneuroblastomas, or neuroblastomas. The first step in the treatment of a patient with a VIPoma is to correct the fluid and electrolyte deficits. Administration of a somatostatin analog (SSA) can decrease diarrhea, further aiding in the restoration of fluid and electrolyte imbalances. In patients with a metastatic or unresectable VIPoma, SSAs likely prolong progression-free survival. Other treatment options include peptide receptor radionuclide therapy (PRRT) with radiolabeled SSAs (177Lu-DOTATATE), everolimus, sunitinib, cytotoxic chemotherapy, or liver-directed therapies.

The glucagonoma syndrome is caused by a glucagon-secreting pancreatic neuroendocrine neoplasm (glucagonoma). The syndrome includes: a characteristic rash termed necrolytic migratory erythema, painful glossitis, cheilitis & stomatitis, weight loss, anemia, new-onset or worsening diabetes mellitus, hypoaminoacidemia, low zinc levels, deep vein thrombosis, and depression. At diagnosis, a glucagonoma is usually 4-5 cm in size and accompanied by distant metastases, particularly to the liver. The incidence of glucagonoma syndrome is 1-2% of all pancreatic neuroendocrine tumors. Approximately 10% of glucagonomas are associated with multiple endocrine neoplasia type-1 (MEN-1). Glucagonomas highly express somatostatin receptor subtypes (97%) and therefore somatostatin receptor positron emission tomography (PET) with DOTA-labelled somatostatin analogs (DOTATATE, DOTANOC, and DOTATOC) can be used in the localization of glucagonomas. The somatostatin receptor subtypes can also be utilized for the treatment of metastatic glucagonomas with somatostatin analogs or 177Lu-DOTATATE. Other treatment options include sunitinib, everolimus, systemic cytotoxic chemotherapy, and liver-directed therapies

Insulinomas are rare pancreatic neuroendocrine neoplasms (panNENs - incidence of 1-3 cases per million per year). Most are solitary and do not show signs of malignant spread. Multiple synchronous or metachronous panNENs / insulinomas may occur in multiple endocrine neoplasia type 1 (MEN-1). The diagnosis of an insulinoma requires demonstration of inappropriately high insulin, proinsulin, or C-peptide levels for the prevailing hypoglycemia in a 72h fast. Localization of the tumor and exclusion or confirmation of metastatic disease by computed tomography is the preferred initial option followed by endoscopic ultrasonography (EUS) or MRI. Glucagon-like peptide receptor 1 (GLP-1R) receptor positron emission tomography (PET) CT is a most promising new localization technique, but regretfully not widely available yet. For single solitary tumors surgical excision is the treatment of choice. In malignant cases, debulking of the panNENs, including locoregional lymph nodes can be considered. If hyperinsulinemia and hypoglycemia persist, diazoxide with a thiazide diuretic relieves hypoglycemia. Liver metastases can be resected or treated by bland embolization, radioembolization (SIRT), radiofrequency ablation (RFA), microwave and cryoablation, high-intensity focused ultrasound (HIFU), laser, brachytherapy and irreversible electroporation (IRE) depending on local availability. In patients with unresectable low-grade metastatic malignant insulinomas, the long-acting somatostatin analog Lanreotide Autogel is the approved first-line therapy for control of tumor growth and sometimes control of hypoglycemia is achieved with this drug. If indicated, peptide receptor radiotherapy (PRRT) with radiolabeled somatostatin analogs, or Everolimus can be used for tumor, symptom and biochemical control. Malignant NENs can also be treated with cytotoxic chemotherapy regimens, particularly those with a high tumor grade

Ghrelin is a 28 amino acid, acylated peptide mainly produced in the P/D1 neuroendocrine cells of the stomach wall. The peptide stimulates growth hormone release by acting on both the pituitary and hypothalamus, but also stimulates ACTH and prolactin as well as gastric acid secretion and intestinal motility. Ghrelin also increases appetite and food intake. Expression of ghrelin protein and mRNA has been identified in high percentages of gastric neuroendocrine tumors (NETs) but also intestinal and pancreatic NETs. Theoretically, a ghrelinoma could cause acromegaly, diabetes mellitus, diarrhea and gastric acid hypersecretion. Small numbers of cases with elevated plasma ghrelin have been reported. However, patients often have non-specific symptoms, that do not resemble the theoretical syndrome of a ghrelinoma. This suggests a low biological activity of these elevated ghrelin levels, which could by related to the ratio of acylated ghrelin and unacylated ghrelin. At this time the clinical relevance of hyperghrelinemia for NETs remains limited.