Neuroendocrine Tumor (Carcinoid Syndrome)



  • Cluster of symptoms mediated by the release of humoral factors secreted by carcinoid tumors:
    • Cutaneous flushing
    • Diarrhea
    • Bronchospasms
  • The term carcinoid has fallen out of favor due to lack of specificity; neuroendocrine tumor (NET) is favored (e.g., small intestine NET).
  • NETs arise from enterochromaffin (neuroendocrine) cells.
    • Carcinoid tumors: well-differentiated NETs
    • Neuroendocrine carcinomas: high-grade or poorly differentiated NETs
  • NETs represent a diverse range of neoplasms and present with multiple clinical characteristics depending on the site of origin, hormone production, and level of differentiation.
  • NET present in three main ways:
    • Carcinoid syndrome (20–30%)
    • Symptoms secondary to tumor bulk
    • Incidental findings on imaging/endoscopy
  • Most NETs arise in the GI tract (67%) and bronchi (25%); tumors can also arise elsewhere.
  • Classic carcinoid syndrome:
    • Arises from midgut (jejunum, ileum, and cecum) tumors
    • Seen with hepatic metastasis
  • Metastases relates to tumor size: Incidence of metastases is <15% with tumor <1 cm but rises to 95% with tumors >2 cm.
  • >90 % of patients with the carcinoid syndrome have metastatic disease, typically liver.



  • Incidence rates for gastroenteropancreatic (GEP) NETs are roughly 2.5 to 5.0 cases per 100,000.
  • GEP-NET is the second most common digestive cancer.
  • About 0.5% of all malignant diseases are neuroendocrine (carcinoid) tumors originating in the GI or bronchopulmonary systems.
  • Incidence and prevalence have increased substantially over several decades, perhaps due to advances in imaging.
  • Carcinoid syndrome is more common in midgut intestinal tumors (up to 50%); less common with bronchial carcinoids


  • True prevalence is difficult to determine because they are often asymptomatic.
  • Estimated at 35/100,000 persons

Etiology and Pathophysiology

  • Tumors arise from neuroendocrine cells of the aerodigestive tract.
  • 20% of well-differentiated NETs will have carcinoid symptoms.
  • Due to nonspecific presentation, the average time to diagnosis is 9 years.
  • Most commonly misdiagnosed as irritable bowel syndrome (IBS)
  • Common symptoms are linked to bioactive products secreted by tumors.
    • Serotonin, kallikrein, prostaglandins, and histamine are common examples.
  • >40 known tumor products include biogenic amines, peptides (e.g., substance P, vasoactive intestinal polypeptide [VIP], atrial wide natriuretic peptide), tachykinins (e.g., kallikrein, neuropeptide K), and prostaglandins.
  • The liver inactivates bioactive tumor products, but hepatic metastases can release amines, peptides, and prostaglandins into hepatic veins where they enter the systemic circulation.
  • Serotonin contributes to diarrhea (stimulating motility and inhibiting GI absorption), flushing, and bronchospasm and right-sided cardiac findings (tricuspid valve or pulmonary valve dysfunction secondary to valvular endothelial fibrosis).
  • Cardiac findings are typically right-sided because the lungs inactivate mediators in the pulmonary circulation.
  • Kallikrein contributes to flushing by generating bradykinin (a vasodilator).
  • Histamine can cause flushing, pruritus, and possibly peptic ulcers.
  • Prostaglandins cause bronchospasm and alter GI motility.

Multiple genes may be associated: point mutations, deletions, methylation, and chromosomal loss and gain.

Risk Factors

  • African Americans have a higher incidence.
  • Age >50 years

Commonly Associated Conditions

  • Multiple endocrine neoplasia type 1 (MEN1)
  • von Hippel-Lindau syndrome
  • Tuberous sclerosis
  • Neurofibromatosis type 1

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