Carcinoid Tumors

Diagnosis

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
    • Recommend two sequential 24-hour urine samples
  • Chromogranin A
  • Serotonin – whole blood preferred to serum
    • Highly specific for carcinoid identification
    • Not frequently used
  • Gastrin – fasting concentrations
    • Prognostic marker in gastric tumors with hypergastrinemia syndrome
  • ACTH/cortisol – useful in thymic and bronchial tumors with Cushing syndrome

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 A and synaptophysin are most valuable; others include neuron specific enolase polyclonal (NSE P), CAM 5.2, PGP 9.5, 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 (EGD), bronchoscopy

Prognosis

  • Hypergastrinemia – favorable prognosis
  • Normal gastrin – aggressive disease

Differential Diagnosis

Monitoring

  • Post-resection surveillance based on tumor type and location
    • Small bowel/colon, appendix, rectal, thymus carcinoids
      • 3-12 months
        • Testing – consider 5-hydroxyindoleacetic acid (5-HIAA), chromogranin A
          • Normal 5-HIAA does not rule out recurrent tumor
        • Imaging – CT or MRI
      • >1 year and annually thereafter
        • Testing – consider 5-HIAA, chromogranin A
        • Imaging – as clinically indicated
    • Gastric carcinoids
      • Hypergastrinemic
        • Testing – marker levels and esophagogastroduodenoscopy (EGD)
          • 1 to 2 times/year during years 1-3; annually thereafter
          • Gastrin levels are usually uninformative in type 1 tumors
        • 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 carcinoids – 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

Clinical Background

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

Epidemiology

  • Incidence
    • 2-4/100,000 in U.S. (NCCN, 2014)
    • Most common gastrointestinal NET
  • Age – bimodal peaks
    • 15-25 years
    • 65-75 years
  • Sex – distribution inverts at age 50
    • <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

Pathophysiology

  • Tumor derived from enterochromaffin cells (Kulchitsky cells)
  • May secrete various hormones, vasoactive substances
    • Bronchial/thymic – ACTH
    • Small intestine/appendix – serotonin, histamine, tachykinins
  • Gastrointestinal (GI) tumors – classified by tumor location
    • Foregut – pancreas, duodenum, bronchus, thymus, stomach
    • Midgut – jejunum, ileum, ascending colon, appendix
    • Hindgut – transverse and descending colon, rectum
  • GI location ~2/3 of the time; bronchopulmonary location ~1/3 of the time

Clinical Presentation

  • Relatively slow growing tumor with nonspecific presentation
    • May be found coincidentally during surgery for appendicitis or bowel obstruction
  • Classic carcinoid syndrome – occurs in ~10% of patients
    • Usually occurs with liver metastases; rarely occurs with lung tumors
      • 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)
          • Fibrosis, thickening of valves
        • Develops in 45-60% of patients with metastatic disease as late complication
      • May be precipitated by certain foods or drinks high in tyramine (eg, blue cheese, chocolate, red wine)
  • Gastrointestinal manifestations
    • Diarrhea
    • Abdominal pain (often secondary to fibrosis)
    • Gastric carcinoids
      • Type 1 associated with chronic atrophic gastritis – absent acid secretion and hypergastrinemia
      • Type 2 associated with Zollinger-Ellison syndrome, hypergastrinemia, and MEN1
      • Type 3 sporadic – normal gastrin levels
  • Metastatic disease – tumors <1 cm rarely metastasize

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
Test Name and Number Recommended Use Limitations Follow Up
5-Hydroxyindoleacetic Acid (HIAA), Urine 0080420
Method: Quantitative High Performance Liquid Chromatography

Diagnose carcinoid tumors

Monitor disease

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

Confirm results by repeating 24 hour urine test

CT/MRI to identify tumor location

Chromogranin A 0080469
Method: Quantitative Enzyme Immunoassay

Monitor carcinoid tumors

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

 
Gastrin 0070075
Method: Quantitative Chemiluminescent Immunoassay
Differentiate gastric carcinoid tumors

12-hour fasting recommended

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

 
Serotonin, Whole Blood 0080395
Method: Quantitative High Performance Liquid Chromatography

Diagnose carcinoid tumors

Preferred serotonin test if using in evaluation since most of the blood serotonin resides in the platelets

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

 
Chromogranin A by Immunohistochemistry 2003830
Method: Immunohistochemistry

Aid in diagnosing carcinoid tumors

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Synaptophysin by Immunohistochemistry 2004139
Method: Immunohistochemistry

Aid in diagnosing carcinoid tumors

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Cytokeratin 8,18 Low Molecular Weight (CAM 5.2) by Immunohistochemistry 2003493
Method: Immunohistochemistry

Aid in diagnosing carcinoid tumors

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Gastrin by Immunohistochemistry 2003896
Method: Immunohistochemistry

Aid in diagnosing carcinoid tumors

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry

Aid in diagnosing carcinoid tumors

Stained and resulted by ARUP

   
Neuron Specific Enolase, Polyclonal (NSE P) by Immunohistochemistry 2004052
Method: Immunohistochemistry

Aid in diagnosing carcinoid tumors

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Protein Gene Product (PGP) 9.5 by Immunohistochemistry 2004091
Method: Immunohistochemistry

Aid in diagnosing carcinoid tumors

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Neuron Specific Enolase 0098198
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Not useful for diagnosis or monitoring of carcinoid tumors

Cortisol, Saliva 0081117
Method: Quantitative Enzyme Immunoassay

Screen for thymic and bronchial carcinoid tumors

Adrenocorticotropic Hormone 0070010
Method: Quantitative Chemiluminescent Immunoassay

Screen for thymic and bronchial carcinoid tumors

Serotonin, Serum 0080397
Method: Quantitative High Performance Liquid Chromatography

Diagnose carcinoid tumors