Diagnosing Carcinoid Tumors and Carcinoid Syndrome

Neuroendocrine Tumor Biomarkers

Biochemical markers are hormones, or amines, secreted by neuroendocrine tumors (NET) that circulate in the blood, are excreted in the urine, and are used to assist in the diagnosis of NET.1 Each of these substances can cause a specific clinical syndrome, including carcinoid syndrome (serotonin), Zollinger-Ellison syndrome (gastrin), and hypoglycemia (insulin).2 Specific markers for these syndromes include urinary 5-hydroxyindoleacetic acid (5-HIAA), serum or plasma gastrin, insulin, vasoactive intestinal peptide (VIP), and glucagon.2 Other potential biomarkers for patients with pancreatic NET (PNET) include synaptophysin, neurokinin A, pancreastatin, substance P, serotonin, and pancreatic polypeptide.3,4

Elevated serum levels of biomarkers such as chromogranin A (CgA), and pancreatic polypeptide are frequently used to diagnose non-functional PNET in patients without clinical syndromes (neuron-specific enolase [NSE]).4,5

Chromogranin A

Chromogranins are a family of glycoproteins with dense-core secretory vesicles that are found in neuronal and endocrine tissues.3 Despite certain limitations, CgA is currently the most useful circulating marker for carcinoid tumors and PNET5 and is elevated in 60% to 100% of NET.4

Sensitivity and specificity of CgA for the detection of NET is 68% and 86%, respectively.6 Levels of CgA are measured in the serum and are also correlated with tumor burden.3,6,7 However, false-positive tests can occur in patients with renal or hepatic impairment, atrophic gastritis, and proton pump inhibitor use (due to enterochromaffin-like cells hyperplasia).3

5-Hydroxyindoleacetic Acid

Urinary 5-HIAA, a metabolite of serotonin, is the principal laboratory test for the measurement of serotonin overproduction by carcinoid tumors (Figure 7).6 Measurement of 5-HIAA has a sensitivity of 64% and a specificity of 98% for carcinoid tumors.8 The consumption of serotonin-rich foods (bananas, pineapples, or nuts) may alter urinary 5-HIAA levels, resulting in false positives.6 These foods should be avoided during the 5-HIAA specimen collection.8

Image Chart

Reproduced from Zuetenhorst JM, Taal BG. Oncologist. 2005;10:123-131, with permission from ALPHAMED PRESS, INC. in the format Internet posting via Copyright Clearance Center.

Neuron-specific enolase

NSE is an enzyme that is present in the cytoplasm of most neuroendocrine cells.3,7 The sensitivity and specificity of NSE in carcinoid tumors is 33% and 100%, respectively. 9 The advantage of NSE is that it is not associated with tumor secretory activity and is useful for the follow-up and monitoring of patients with NET.7 The disadvantage is that NSE is nonspecific, due to its presence in other tumors such as fibroadenomas of the breast, carcinomas, and lymphomas.7 Immunohistochemistry with NSE aids in the diagnosis of carcinoid tumors; however, NSE enzyme-linked immunosorbent assay does not assist in diagnosis or follow-up.10

Biochemical markers can also be used as prognostic indicators and measures of disease progression.11 (Table 6). High levels of CgA are a predictor of poor prognosis,11 whereas high levels of pancreastatin indicate active progressive liver disease.4

Table 6. Specific Biomarkers for Carcinoid Tumors4
Site Carcinoid Type Marker Specificity
All   CgA and CgB High
PP, NSE, neurokinin, neurotensin Intermediate
HCG α and β Low
Thymus Foregut carcinoid ACTH Intermediate


Foregut carcinoid, small-cell lung carcinoma

ACTH, ADH, serotonin, 5-HIAA Intermediate
Histamine, GRP, GHRH, VIP, PTH-rP Low
Stomach Foregut carcinoid, gastrinoma, Histamine, gastrin Intermediate
ghrelinoma Ghrelin Low
Pancreas Gastrinoma, insulinoma, glucagonoma, somatostatinoma, PPoma, VIPoma Gastrin, insulin, proinsulin, glucagon somatostatin, VIP High
C-peptide, neurotensin, PTH-rP, calcitonin Low
Duodenum Gastrinoma, somatostatinoma Gastrin, somatostatin High
Ileum Midgut carcinoid Serotonin, 5-HIAA High
Neurokinin A, neuropeptide K, SP Intermediate
Colon and rectum Hindgut carcinoid Peptide YY, somatostatin Intermediate
Cardiac involvement Carcinoid BNP Intermediate
5-HIAA, 5-hydroxyindoleacetic acid; ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; BNP, brain natriuretic peptide; CgA, chromogranin A; GHRH, growth hormone-releasing hormone; GRP, gastrin-releasing peptide; HCG, human chorionic gonadotropin; NSE, neuron-specific enolase, PP, pancreatic polypeptide; PTH-rP, parathyroid hormone-related protein; SP, substance P; VIP, vasoactive intestinal peptide.

Reproduced with permission from Vinik AI, Woltering EA, Warner RR, Caplin M, O'Dorisio TM, Wiseman GA, Coppola D, Go VL; North American Neuroendocrine Tumor Society (NANETS). NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas. 2010;39(6):713-734.

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  1. Ramage JK, Davies AH, Ardill J et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut. 2005;54 Suppl 4:iv1-16.
  2. Oberg K, Castellano D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev. 2011;30(suppl 1):3-7.
  3. Strosberg JR, Nasir A, Hodul P, Kvols L. Biology and treatment of metastatic gastrointestinal neuroendocrine tumors. Gastrointest Cancer Res. 2008;2:113-125.
  4. Vinik AI, Woltering EA, Warner RR et al. NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas. 2010;39:713-734.
  5. Diagnosing NET: CgA testing. The Neuroendocrine Tumor Alliance Web site. http://neuroendocrinetumor.com/health-care-professional/diagnosing-nets/explore/biochemical-tests.jsp. Accessed June 27, 2016
  6. Zuetenhorst JM, Taal BG. Metastatic carcinoid tumors: a clinical review. Oncologist. 2005;10:123-131.
  7. Jensen RT, Doherty GM. Section 6. Carcinoid tumors and the carcinoid syndrome (Chapter 34.6 Cancer of the Endocrine System) In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer Principles and Practice of Oncology. 7th ed. New York, NY: Lippincott, Williams & Wilkins; 2005;1813-1833.
  8. Feldman JM. Urinary serotonin in the diagnosis of carcinoid tumors. Clin Chem. 1986;32:840-844.
  9. Seregni E, Ferrari L, Bajetta E, Martinetti A, Bombardieri E. Clinical significance of blood chromogranin A measurement in neuroendocrine tumours. Ann Oncol. 2001;12 Suppl 2:S69-72
  10. ARUP Laboratories. The physicians guide to laboratory test selection and interpretation. Carcinoid tumors: Indications for laboratory testing. https://arupconsult.com/content/carcinoid-tumors. Accessed June 27, 2016.
  11. Ardill JE, O'Dorisio TM. Circulating biomarkers in neuroendocrine tumors of the enteropancreatic tract: application to diagnosis, monitoring disease, and as prognosticindicators. Endocrinol Metab Clin North Am. 2010;39:777-790.