Carcinoid Tumors

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, or 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
Gastrointestinal tumors – classified by tumor location
- Foregut – pancreas, duodenum, bronchus, thymus, stomach
- Midgut – jejunum, ileum, ascending colon, appendix
- Hindgut – transverse and descending 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, cardiac murmurs, jugular venous distension
    - Predominantly involves the right-side heart valves (tricuspid, pulmonic)
      - 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 <1 cm rarely metastasize

Indications for Testing

Carcinoid syndrome (symptoms of flushing and diarrhea); right-sided congestive heart failure

Laboratory Testing

Urinary 5-hydroxyindoleacetic acid (5-HIAA) – metabolic product of serotonin
- Sensitivity 70-75%; specificity >90%
- Recommend two sequential 24-hour urine samples
Chromogranin A – sensitivity 75-85%; specificity <80%
Serotonin – whole blood preferred to serum; highly specific for carcinoid identification
- Not frequently used

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”)
Gastrin – fasting concentrations; prognostic marker in gastric tumors
ACTH/cortisol – useful in thymic and bronchial tumors
Immunohistochemistry – chromogranin A and synaptophysin are most valuable; others include neuron specific enolase polyclonal (NSE P), CAM5.2, PGP9.5, Ki-67 (MIB-1), and gastrin

Imaging Studies

CT/MRI
- If CT/MRI negative, consider somatostatin receptor scintigraphy
  - Indium-111 labeled octreotide
  - Superior to metaiodobenzylguanidine (MIBG) scanning
Echocardiography – expect to see valvular thickening and leaflet damage in carcinoid heart disease
Other imaging as indicated – Octreoscan^™, endoscopic ultrasound; colonoscopy, esophagogastroduodenoscopy, bronchoscopy

Prognosis

Hypergastrinemia – favorable prognosis
Normal gastrin – aggressive disease

Differential Diagnosis

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

Post-resection surveillance based on tumor type and location
- Small bowel/colon, appendix, rectal, thymus
  - 3-12 months
    - Testing – consider 5-hydroxyindoleacetic acid (HIAA), chromogranin A
    - Imaging – CT or MRI
  - >1 year and annually thereafter
    - Testing – consider 5-HIAA, chromogranin A
    - Imaging – as clinically indicated
- Gastric
  - Hypergastrinemic
    - Testing – marker levels and esophagogastroduodenoscopy (EGD) 1 to 2 times/year during years 1-3; annually thereafter
    - Imaging – as clinically indicated
  - Normal gastrin
    - 3-12 months
      - Testing – consider chromogranin A
      - Imaging – CT/MRI
    - >1 year and annually thereafter
      - Testing – consider chromogranin A
      - Imaging – as clinically indicated
- Bronchial – see recommendations for non-small cell lung cancer (NSCLC)
  - Chest x-ray, CBC and chemistries every 3-6 months for first 2 years
    - National Comprehensive Cancer Network (NCCN) recommends CT every 6 months in NSCLC

Tests generally appear in the order most useful for common clinical situations

Test name: 5-Hydroxyindoleacetic Acid (HIAA), Urine

ARUP #: 0080420

Methodology: Quantitative High Performance Liquid Chromatography

Use:

Diagnose carcinoid tumors

Monitor disease

Limitations:

Influenced by foods rich in serotonin (avocado, bananas, eggplant, kiwi, pineapple, plums, tomatoes, walnuts) and medications that may affect metabolism

Serotonin must be avoided 72 hours before and during collection of urine specimen

Follow-up:

Confirm results by repeating 24 hour urine test

CT/MRI to identify tumor location

Test name: Chromogranin A

ARUP #: 0080469

Methodology: Quantitative Enzyme Immunoassay

Use:

Monitor carcinoid tumors

Limitations:

Nonspecific tumor marker in diagnosis

May be elevated due to proton pump inhibitor therapy or impaired renal function

Results obtained with different assay methods or kits cannot be used interchangeably

Test name: Gastrin

ARUP #: 0070075

Methodology: Quanititative Chemiluminescent Immunoassay

Use:

Differentiate gastric tumors

Prognostic marker to determine aggressiveness of disease

Limitations:

12-hour fasting recommended

Test name: Serotonin, Whole Blood

ARUP #: 0080395

Methodology: Quantitative High Performance Liquid Chromatography

Use:

Diagnose carcinoid tumors

Preferred test because most of the blood serotonin resides in the platelets

Limitations:

Certain medications may affect serotonin

Foods containing serotonin do not significantly interfere

Slight increases may be seen in acute intestinal obstruction, acute myocardial infarction, cystic fibrosis, dumping syndromes and nontropical sprue

Test name: Cytokeratin 8,18 Low Molecular Weight (CAM 5.2) by Immunohistochemistry

ARUP #: 2003493