Carcinoid Tumors

Clinical Background

Carcinoid tumors are rare, slow-growing neuroendocrine tumors (NETs).

Epidemiology

• Incidence
  • 2-4/100,000 in U.S. (SEER database, 2003)
  • Most common gastrointestinal NET
• Age – bimodal peaks
  • 15-25 years
  • 65-75 years
• Sex – distribution inverts at 50 years
  • <50 years, M<F, 1:2
  • ≥50 years, M>F, 2:1
• Occurrence – most frequently sporadic
• Ethnicity – somewhat higher incidence in African Americans

Risk Factors

• Multiple Endocrine Neoplasia type 1 (MEN1)
  • Neoplasia of the parathyroid, pancreas, anterior pituitary with 10% incidence of NETs of the lung, thymus and stomach
• Von Hippel-Lindau syndrome
  • Pancreatic neoplasia of neuroendocrine origin occurs in 15% of cases
• Neurofibromatosis type 1 (von Recklinghausen disease)
  • Infrequent carcinoids of the duodenum (somatostatinomas)

Pathophysiology

• Tumor derived from enterochromaffin cells (Kulchitsky cells)
• Symptoms due to secretion of neuroendocrine substances such as serotonin and kallikreins
• Classified by tumor location
  • Foregut – pancreas, duodenum, bronchus, thymus, stomach
  • Midgut – jejunum, ileum, ascending colon
  • Hindgut – ascending colon, rectum

Clinical Presentation

• Relatively slow growing tumor with nonspecific presentation
  • May be found coincidentally during surgery for appendicitis or bowel obstruction
• Symptoms of typical carcinoid syndrome (occur in ~10% of patients)
  • Usually occur with liver metastases; rarely occur with lung tumor
    • May also produce adrenocorticotropic hormone (ACTH)
  • Symptoms include
    • Flushing, wheezing, diarrhea
    • Carcinoid heart disease
      • Typical symptoms include congestive heart failure (CHF), cardiac murmurs, jugular venous distension
      • Predominantly involves the right-side heart valves
        • Causes fibrosis, thickening
      • Develops in 45-60% of patients with metastatic disease
        • Late complication of metastatic disease
    • May be precipitated by certain foods or drinks high in tyramine (eg, blue cheese, chocolate, red wine)
• Gastrointestinal manifestations
  • Diarrhea
  • Fibrosis and abdominal pain
  • Gastric carcinoids
    • Type 1 associated with chronic atrophic gastritis and pernicious anemia (75%)
    • Type 2 associated with Zollinger-Ellison syndrome and MEN1 (5%)
    • Type 3 sporadic, not associated with disease (20%)
• Locating primary tumor may be difficult
  • Gastrointestinal tract – 65%
  • Bronchopulmonary tract – 35%
• Metastatic disease – tumors less than 1 cm rarely metastasize

Diagnosis

Indications for Testing

• Carcinoid syndrome (symptoms of flushing and diarrhea); right-sided CHF

Laboratory Testing

• Urinary 5-hydroxyindoleacetic acid (5-HIAA) – metabolic product of serotonin
  • Sensitivity 70-75%; specificity >95%
• Serotonin – whole blood preferred to serum; highly specific for carcinoid identification
• Chromogranin A – sensitivity 75-85%; specificity <80%

Histology

• Nested or trabecular arrangement of small- to medium-sized cells
  • Finely granular eosinophilic cytoplasm
  • Central round to oval nuclei
  • Stippled chromatin (“salt and pepper”)
• Immunohistochemistry – chromogranin and synaptophysin are most valuable; others include NSE, Cam5.2 (LMW), PGP9.5, and Ki-67

Imaging Studies

• CT/MRI
• If CT/MRI negative, consider somatostatin receptor scintigraphy
  • Indium-111 labelled octreotide
  • Superior to metaiodobenzylguanidine (MIBG) scanning

Differential Diagnosis

• Flushing
  • Pheochromocytoma
  • Menopause
  • Medullary carcinoma of the thyroid
  • Mastocytosis
  • Alcohol
  • Renal cell carcinoma
  • VIPoma (vasoactive intestinal peptide tumors)
• Wheezing
  • Asthma
  • Anaphylaxis
  • Foreign body obstruction
  • Pulmonary edema
• Diarrhea
  • Infections
  • Inflammatory bowel disease
  • Laxative abuse
• Heart valve disease
  • Rheumatic heart diseases
  • Endocarditis
  • Cardiomyopathy
  • Pulmonary hypertension

Monitoring

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Neuron Specific Enolase 0098198 Method: Enzyme-Linked Immunosorbent Assay	Not recommended; not useful in diagnosis or monitoring of carcinoid tumors