Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 26-26: Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) & Carcinoid Tumors + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ GEP-NETs are neuroendocrine tumors that originate in the gastrointestinal tract About 60% GEP-NETs are nonsecretory or secretory without clinical manifestations; they may be detected incidentally or may present with weight loss, abdominal pain, or jaundice Carcinoid tumors arise from the intestines or lung, secrete serotonin, and may metastasize +++ General Considerations ++ Pancreatic neuroendocrine tumors (pNETs) are of several types A cells (20%) secrete glucagon B cells (70%) secrete insulin D cells (5%) secrete somatostatin or gastrin F cells secrete pancreatic polypeptide GEP-NETs Once regarded as rare Incidence has increased to about 37 per million yearly in the United States, due to the incidental detection of small tumors on abdominal scans About 40% are functional, producing hormones that are tumor markers Up to 25% of GEP-NETs are associated with one of four different inherited disorders MEN-1 von Hippel-Lindau disease (VHL) Neurofibromatosis 1 (NF-1) Tuberous sclerosis complex (TSC) Insulinomas secrete excessive amounts of insulin (as well as proinsulin and C-peptide) Usually benign (90% of cases) Solitary in 95% of sporadic cases, but multiple in about 90% of cases arising in multiple endocrine neoplasia type 1 (MEN 1) Gastrinomas secrete excessive gastrin About 50% are malignant and metastasize to liver Typically found in duodenum (49%), pancreas (24%), or lymph nodes (11%) Usually 5-year delay from symptom onset to diagnosis. Occur as part of MEN 1 in ~22% Glucagonomas are usually malignant and usually co-secrete other hormones, eg, gastrin Somatostatinomas and VIPomas (tumors secreting excessive somatostatin or vasoactive intestinal polypeptide) are very rare CCKomas are rare tumors of the endocrine pancreas that secrete cholecystokinin Carcinoid tumors Can arise from the small bowel (53%, particularly terminal ileum), colon (12%), esophagus through duodenum (6%), or lung (bronchial carcinoid [5%]) Although usually indolent, metastases are common, particularly to liver, lymph nodes, and peritoneum Nonfunctional pNETs Produce no significant hormones Usually grow to large size prior to detection May secrete chromogranin A (CgA) or pancreatic polypeptide, which can be used as tumor markers + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Nonfunctioning tumors typically present with mass effect and metastases, such as Pancreatitis Jaundice Abdominal pain Weight loss Insulinoma Secrete insulin Fasting hypoglycemic symptoms Gastrinoma Abdominal pain (75%) Heartburn (44%) Bleeding (25%) Weight loss (17%) Glucagonoma Weight loss, diarrhea, nausea, peptic ulcer, hypoaminoacidemia Necrolytic migratory erythema Diabetes mellitus develops in 35% Somatostatinomas Classic triad of symptoms Diabetes mellitus because of its inhibition of insulin and glucagon secretion Cholelithiasis because of its inhibition of gallbladder motility Steatorrhea because of its inhibition of pancreatic exocrine function Diarrhea, hypochlorhydria, and anemia VIPoma (so called "WDHA" [or Verner-Morrison syndrome]) Watery Diarrhea (profuse) Hypokalemia Acidosis CCKomas May present with liver metastases and symptoms of diarrhea, peptic ulcer disease, and weight loss Patients have elevated serum levels of cholecystokinin and chromogranin A Carcinoid tumors Can produce "carcinoid syndrome" Episodes of abdominal pain, diarrhea, bronchospasm, and weight loss Skin flushing typically affects the upper body, neck, and face and lasts from 30 seconds to 30 minutes, although flushing with bronchial carcinoids can persist for days Other manifestations include carcinoid heart disease Bronchial carcinoids Secrete serotonin Can produce carcinoid syndrome even without hepatic metastases Foregut carcinoids Secrete serotonin that is metabolized by the liver Carcinoid syndrome only results when they have metastasized to the liver Hindgut carcinoids Rarely produce serotonin Do not cause carcinoid syndrome +++ Differential Diagnosis ++ Insulinoma Other cause of hypoglycemia Surreptitious or excess use of insulin or sulfonylurea or other hypoglycemic agents Liver failure Acute alcohol intoxication Sepsis Postprandial hypoglycemia (postgastrectomy, occult diabetes mellitus, idiopathic) Drugs (pentamidine, sulfamethoxazole, quinine) Gastrinoma Peptic ulcer disease due to other cause Nonsteroidal anti-inflammatory drugs Helicobacter pylori infection Gastroesophageal reflux disease Diarrhea due to other cause Hypergastrinemia due to other cause (atrophic gastritis, gastric outlet obstruction, pernicious anemia, chronic kidney disease) Glucagonoma or somatostatinoma Other cause of weight loss, diarrhea, or diabetes mellitus + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ Insulinoma: serum glucose low with nonsuppressed insulin; elevated proinsulin level (see Hypoglycemic Disorders) Gastrinoma: serum gastrin elevated in normocalcemic patient not taking a proton pump inhibitor Somatostatinoma: hypochlorhydria Carcinoid tumors High serum levels of chromogranin A and serotonin Elevated urinary excretion of 5-HIAAA, a renally excreted product of serotonin metabolism +++ Imaging Studies ++ Localization of GEP-NETs and their metastases is best done with PET scanning using 68Ga-DOTATATE, a radiolabeled somatostatin analog For hepatic metastases, MRI scanning is more sensitive than CT Preoperative localization for insulinomas are less successful, with low sensitivities Ultrasonography, 25% CT, 25% Endoscopic ultrasonography, 27% Transhepatic portal vein sampling, 40% Arteriography, 45% Intraoperative palpation, 55% Intraoperative pancreatic ultrasound, 75% Combination of intraoperative palpation, ultrasound and 68Ga-DOTATATE-PET can successfully locate nearly all insulinomas at surgery +++ Diagnostic Procedures ++ Gastrinoma: endoscopy usually (94%) demonstrates prominent gastric folds + Treatment Download Section PDF Listen +++ +++ Medications ++ Proton pump inhibitors at quadruple the usual doses used for gastrinoma (see Zollinger-Ellison Syndrome) Octreotide LAR Subcutaneous injections of 20–30 mg are required every 4 weeks Improves the symptoms of functioning tumors and appears to improve progression-free survival in patients with functioning or nonfunctioning GEP-NETs Enlarging hepatic metastases may be embolized with 90Y-labeled resin or glass microspheres +++ Surgery ++ Initial treatment for all types of GEP-NETs Reasonable option even for patients with stage IV disease The aggressiveness of the surgery may vary from conservative debulking to radical resection and even liver transplantation + Outcome Download Section PDF Listen +++ +++ Complications ++ The surgical complication rate for GEP-NETs is about 40%, with patients commonly developing fistulas and infections Extensive pancreatic resection may cause diabetes mellitus +++ Prognosis ++ Overall 5-year survival higher with functional (77%) than nonfunctional (55%) tumors and higher with benign (91%) than malignant (55%) tumors The prognosis is decidedly worse for patients with metastatic GEP-NETs that express thymidylate synthase Gastrinomas in MEN 1 5-year survival rate, 94% 10-year survival rate, 75% 20-year survival rate, 58% Gastrinomas in sporadic Zollinger-Ellison syndrome 5-year survival rate, 62% 10-year survival rate, 50% 20-year survival rate, 31% + References Download Section PDF Listen +++ + +Cives M et al. Gastroenteropancreatic neuroendocrine tumors. CA Cancer J Clin. 2018 Nov;68(6):471–87. [PubMed: 30295930] + +Dasari A et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017 Oct 1;3(10):1335–42. [PubMed: 28448665] + +Howe JR et al. The surgical management of small bowel neuroendocrine tumors: consensus guidelines of the North American Neuroendocrine Tumor Society. Pancreas. 2017 Jul;46(6):715–31. [PubMed: 28609357] + +Scott AT et al. Evaluation and management of neuroendocrine tumors of the pancreas. Surg Clin North Am. 2019 Aug;99(4):793–814. [PubMed: 31255207] + +Strosberg JR et al. North American Neuroendocrine Tumor Society consensus guidelines for surveillance and medical management of midgut neuroendocrine tumors. Pancreas. 2017 Jul;46(6):707–14. [PubMed: 28609356]