Neuroendocrine Tumor (NET) of Gastrointestinal Tract, Lung, and Thymus – Carcinoid Tumors

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

Indications for Testing

  • Carcinoid syndrome marked by symptoms of flushing and diarrhea, wheezing, right-sided congestive heart failure

Laboratory Testing

  • Guidelines suggest that laboratory testing for biochemical markers be guided by symptoms (NCCN, 2016)
  • Testing for hormones produced by neuroendocrine tumor may include
    • Urinary 5-hydroxyindoleacetic acid (5-HIAA) – for flushing
      • 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
    • Gastrin – fasting concentrations, off proton-pump inhibitors 1 week
      • Prognostic marker in gastric tumors with hypergastrinemia syndrome
    • ACTH/cortisol – useful in thymic and bronchial tumors with Cushing syndrome
    • Serotonin – whole blood preferred over serum
      • Highly specific for carcinoid identification
      • Not frequently used

Histology

  • Definitive diagnosis requires biopsy and pathologist examination

Imaging Studies

  • CT/MRI
    • Abdomen and pelvis
  • Echocardiography
    • For bronchopulmonary
    • Evaluate valvular thickening and leaflet damage
  • Endoscopy
    • As indicated by location (esophagogastroduodenoscopy [EGD], colonoscopy)
  • Other imaging as indicated
    • Bronchoscopy
    • CT chest
    • CT enterography or capsule endoscopy
    • Endorectal MRI
    • Endoscopic ultrasound
    • Fluorodeoxyglucose positron emission tomography (FDG-PET)/CT and brain imaging with CT/MRI for poorly differentiated carcinomas
    • MRI with gadoxetate
    • Nuclear imaging (octreotide scan)

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
        • CT recommended every 6 months for 2-3 years in NSCLC (NCCN, 2017)
      • Echocardiogram – every 2-3 years

Carcinoid tumors are rare, slow-growing tumors. Some may be functional neuroendocrine tumors (NETs) of the gastrointestinal system, lungs, or thymus and release hormones or vasoactive substances. These factors cause clinical syndromes characterized by flushing and diarrhea (gastrointestinal) or wheezing and right heart effects (bronchopulmonary). Carcinoid syndromes usually do not occur until tumors metastasize to the liver. 

Epidemiology

  • Incidence
    • 2-4/100,000 in U.S. (NCCN, 2017)
    • 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

  • 15-20% of NETs are related to genetic syndromes 
    • 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
    • Tuberous sclerosis

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

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

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

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

Ki-67, MIB-1, by Immunohistochemistry 2004519
Method: Immunohistochemistry

Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry

Thyroid Transcription Factor (TTF-1) by Immunohistochemistry 2004166
Method: Immunohistochemistry

CDX2 by Immunohistochemistry 2003821
Method: Immunohistochemistry

PAX8 by Immunohistochemistry 2010787
Method: Immunohistochemistry

Guidelines

Fave D, O'Toole D, Sundin A, Taal B, Ferolla P, Ramage JK, Ferone D, Ito T, Weber W, Zheng-Pei Z, De Herder WW, Pascher A, Ruszniewski P, Vienna Consensus Conference participants. ENETS Consensus Guidelines Update for Gastroduodenal Neuroendocrine Neoplasms. Neuroendocrinology. 2016; 103(2): 119-24. PubMed

Garcia-Carbonero R, Sorbye H, Baudin E, Raymond E, Wiedenmann B, Niederle B, Sedlackova E, Toumpanakis C, Anlauf M, Cwikla JB, Caplin M, O'Toole D, Perren A, Vienna Consensus Conference participants. ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas. Neuroendocrinology. 2016; 103(2): 186-94. PubMed

Kunz PL, Reidy-Lagunes D, Anthony LB, Bertino EM, Brendtro K, Chan JA, Chen H, Jensen RT, Kim MK, Klimstra DS, Kulke MH, Liu EH, Metz DC, Phan AT, Sippel RS, Strosberg JR, Yao JC, North American Neuroendocrine Tumor Society. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013; 42(4): 557-77. PubMed

NCCN Clinical Practice Guidelines in Oncology, Neuroendocrine Tumors. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jan 2017]

Niederle B, Pape U, Costa F, Gross D, Kelestimur F, Knigge U, Öberg K, Pavel M, Perren A, Toumpanakis C, O'Connor J, O'Toole D, Krenning E, Reed N, Kianmanesh R, Vienna Consensus Conference participants. ENETS Consensus Guidelines Update for Neuroendocrine Neoplasms of the Jejunum and Ileum. Neuroendocrinology. 2016; 103(2): 125-38. PubMed

Pape U, Niederle B, Costa F, Gross D, Kelestimur F, Kianmanesh R, Knigge U, Öberg K, Pavel M, Perren A, Toumpanakis C, O'Connor J, Krenning E, Reed N, O'Toole D, Vienna Consensus Conference participants. ENETS Consensus Guidelines for Neuroendocrine Neoplasms of the Appendix (Excluding Goblet Cell Carcinomas). Neuroendocrinology. 2016; 103(2): 144-52. 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: Jan 2016. College of American Pathologists (CAP) . Northfield, IL [Revised Oct 2013; Accessed: Dec 2016]

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: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised Jan 2016; Accessed: Dec 2016]

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: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised Oct 2013; Accessed: Dec 2016]

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: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised Oct 2013; Accessed: Dec 2016]

Ramage JK, Davies AH, 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

Ramage JK, De Herder WW, Fave D, Ferolla P, Ferone D, Ito T, Ruszniewski P, Sundin A, Weber W, Zheng-Pei Z, Taal B, Pascher A, Vienna Consensus Conference participants. ENETS Consensus Guidelines Update for Colorectal Neuroendocrine Neoplasms. Neuroendocrinology. 2016; 103(2): 139-43. 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

Koo J, Dhall D. Problems with the diagnosis of metastatic neuroendocrine neoplasms. Which diagnostic criteria should we use to determine tumor origin and help guide therapy? Semin Diagn Pathol. 2015; 32(6): 456-68. PubMed

Massironi S, Sciola V, Peracchi M, Ciafardini C, Spampatti MP, 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

Schmitt AM, Blank A, Marinoni I, Komminoth P, Perren A. Histopathology of NET: Current concepts and new developments. Best Pract Res Clin Endocrinol Metab. 2016; 30(1): 33-43. PubMed

Vinik AI, Silva MP, Woltering EA, Woltering G, Go VL, 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®

Clark Z, Cutler J, Frank E. Practical LC-MS/MS Method for 5-Hydroxyindoleacetic Acid in Urine. The Journal of Applied Laboratory Medicine. [Accepted Oct 2016; Accessed: May 2017]

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

Content Reviewed: 
March 2017

Last Update: May 2017