Carcinoid Tumors

  • Diagnosis
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics

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
    • Significant elevation (10 times the upper reference limit) of urine 5-HIAA may indicate the presence of a carcinoid tumor
  • 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

  • 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

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

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.

5-Hydroxyindoleacetic Acid (HIAA), Urine 0080420
Method: Quantitative High Performance Liquid Chromatography - Tandem Mass Spectrometry

Limitations

Increased urine 5-HIAA concentration is common and may be the result of improper specimen collection, consumption of serotonin containing foods or dietary supplements, drug interference, or malabsorption syndromes

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

Chromogranin A 0080469
Method: Quantitative Enzyme Immunoassay

Limitations

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

Limitations

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

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

Chromogranin A by Immunohistochemistry 2003830
Method: Immunohistochemistry

Synaptophysin by Immunohistochemistry 2004139
Method: Immunohistochemistry

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

Gastrin by Immunohistochemistry 2003896
Method: Immunohistochemistry

Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry

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

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

Related Tests

Guidelines

NCCN Clinical Practice Guidelines in Oncology, Neuroendocrine Tumors. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Mar 2016]

O'Toole D, Grossman A, Gross D, Fave GDelle, Barkmanova J, O'Connor J, Pape U, Plöckinger U, Mallorca Consensus Conference participants, European Neuroendocrine Tumor Society. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: biochemical markers. Neuroendocrinology. 2009; 90(2): 194-202. PubMed

Plöckinger U, Gustafsson B, Ivan D, Szpak W, Davar J, Mallorca Consensus Conference participants, European Neuroendocrine Tumor Society. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: echocardiography. Neuroendocrinology. 2009; 90(2): 190-3. PubMed

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Appendix. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: February 2010. College of American Pathologists (CAP) . Northfield, IL [Accessed: Sep 2015]

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Colon and Rectum. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: June 2012. College of American Pathologists (CAP). Northfield, IL [Accessed: Sep 2015]

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Small Intestine and Ampulla. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: June 2012. College of American Pathologists (CAP). Northfield, IL [Accessed: Sep 2015]

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Stomach. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: February 2010. College of American Pathologists (CAP). Northfield, IL [Accessed: Nov 2015]

Ramage JK, Davies AH G, Ardill J, Bax N, Caplin M, Grossman A, Hawkins R, McNicol AM, Reed N, Sutton R, Thakker R, Aylwin S, Breen D, Britton K, Buchanan K, Corrie P, Gillams A, Lewington V, McCance D, Meeran K, Watkinson A, UKNETwork for Neuroendocrine Tumours. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut. 2005; 54 Suppl 4: iv1-16. PubMed

Vinik AI, Woltering EA, Warner RR P, Caplin M, O'Dorisio TM, Wiseman GA, Coppola D, Go VLiang W, North American Neuroendocrine Tumor Society (NANETS). NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas. 2010; 39(6): 713-34. PubMed

Öberg K, Knigge U, Kwekkeboom D, Perren A, ESMO Guidelines Working Group. Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012; 23 Suppl 7: vii124-30. PubMed

General References

Aggarwal G, Obideen K, Wehbi M. Carcinoid tumors: what should increase our suspicion? Cleve Clin J Med. 2008; 75(12): 849-55. PubMed

Desai KK, Khan MS, Toumpanakis C, Caplin ME. Management of gastroentero-pancreatic neuroendocrine tumors (GEP-NETs). Minerva Gastroenterol Dietol. 2009; 55(4): 425-43. PubMed

Massironi S, Sciola V, Peracchi M, Ciafardini C, Spampatti MPia, Conte D. Neuroendocrine tumors of the gastro-entero-pancreatic system. World J Gastroenterol. 2008; 14(35): 5377-84. PubMed

Pasieka JL. Carcinoid tumors. Surg Clin North Am. 2009; 89(5): 1123-37. PubMed

Pinchot SN, Holen K, Sippel RS, Chen H. Carcinoid tumors. Oncologist. 2008; 13(12): 1255-69. PubMed

Rockall AG, Reznek RH. Imaging of neuroendocrine tumours (CT/MR/US). Best Pract Res Clin Endocrinol Metab. 2007; 21(1): 43-68. PubMed

Vinik AI, Silva MP, Woltering EA, Woltering G, Go VLiang W, Warner R, Caplin M. Biochemical testing for neuroendocrine tumors. Pancreas. 2009; 38(8): 876-89. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Lin J, Goldblum JR, Bennett AE, Bronner MP, Liu X. Composite intestinal adenoma-microcarcinoid. Am J Surg Pathol. 2012; 36(2): 292-5. PubMed

Medical Reviewers

Last Update: April 2016