Description

• 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.

Epidemiology

Incidence

• 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

Prevalence

• 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.

Genetics
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