Neuroendocrine Tumor (Carcinoid Syndrome)
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- Cluster of symptoms mediated by the release of humoral factors secreted by carcinoid tumors:
- Cutaneous flushing
- 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.
- 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