Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) & Carcinoid Tumors

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

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

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

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

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%