Chromogranin A

CPT: 86316
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Special Instructions

Values obtained with different assay methods should not be used interchangeably in serial testing. It is recommended that only one assay method be used consistently to monitor each patient's course of therapy. If serial monitoring is required, please use Chromogranin A (Serial Monitor) [480847] to order.


Expected Turnaround Time

3 - 5 days


Related Information


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Specimen Requirements


Specimen

Serum


Volume

0.5 mL


Minimum Volume

0.3 mL (Note: This volume does not allow for repeat testing.)


Container

Gel-barrier tube


Collection

Transfer separated serum to a plastic transport tube.


Storage Instructions

Room temperature


Stability Requirements

Temperature

Period

Room Temperature

7 days

Refrigerated

14 days

Frozen

3 months

Freeze/thaw cycles

Stable x4


Causes for Rejection

Gross icterus; gross hemolysis; gross lipemia


Test Details


Use

An aid in the detection and monitoring of neuroendocrine cancers including pheochromocytomas, medullary thyroid carcinomas, functioning and nonfunctioning islet cell and gastrointestinal amine precursor uptake and decarboxylation tumors, and pituitary adenomas. A possible adjunct in outcome prediction and follow-up in advanced prostate cancer.


Limitations

Elevated CGA levels may be seen in non-NEN malignancies including hepatocellular carcinoma41 and breast cancer.42

Circulating CgA is increased in several common, non-neoplastic conditions associated with tissue damage and remolding.5,43-46 These include:

• Gastrointestinal disorders such as chronic atrophic gastritis, Helicobacter pylori infection, liver cirrhosis, chronic hepatitis, pancreatitis, inflammatory bowel diseases and irritable bowel syndrome.

• Cardiovascular disorders such as hypertension, chronic heart failure, acute coronary syndromes.

• Rheumatoid diseases such as giant cell arteritis, rheumatoid arthritis, systemic lupus erythematosus and pulmonary obstructive disease.

• Kidney and liver functional impairment ostensibly due to reduced clearance.5

• Endocrine disorders of non-neuroendocrine nature, such as hyperthyroidism, likely due to enhanced sympathetic activity which pairs with attenuation of the vagal tone.

Chronic use of proton pump inhibitors can produce CGA elevations, often to many times above the normal range.5,47

Sensitivity of circulating CgA is a relatively poor marker for poorly differentiated NETs.5,43 The level of circulation CgA is often normal in patients with localized, non-functional (non-secretory) NETs, such as those of the appendix, pancreas, lungs, duodenum and rectum.5

CgA may not be increased in patients with multiple endocrine neoplasia type 1(MEN).5

As with all immunometric assays there is a low, but definite, possibility of false-positive results in patients with heterophile antibodies.


Methodology

The Thermofisher/BRAHMS KRYPTOR® assay employs Time-Resolved Amplified Cryptate Emission Cryptate Emission (TRACE) technology based on a non-radioactive energy transfer between a donor (europium cryptate) and an acceptor (XL665) in a sandwich immunofluorescent format using two mouse monoclonal antibodies.37-40 This assay is calibrated against recombinant human CG, and according to the manufacturer's package insert.1


Reference Interval

0.0 – 101.8 ng/mL


Additional Information

Chromogranin A1 is a hydrophilic glycoprotein that is stored in the chromaffin granules of the neuroendocrine cells.2 The physiologic role of CgA has not been fully elucidated, but studies suggest that it serves as a precursor to other biologically active peptides and facilitates the production of other hormones and neuropeptides.2-4 In healthy individuals, most of the CgA found in the circulation is derived from enterocromaffin- like (ECL) cells5 found in the gastric glands of the stomach in the vicinity of parietal cells. ECL cells serve to stimulate the production of gastric acid via the neuroendocrine release of histamine.5

Neuroendocrine cells receive neuronal input that stimulates them to release a variety of molecules (in many cases including CgA). Neuroendocrine cells are ubiquitous throughout the body and can be found in numerous organs including the gastrointestinal (GI) tract (in the small intestine, rectum, stomach, colon, esophagus and appendix), the gallbladder, the pancreas (islet cells) and the thyroid (C cells). Neuroendocrine cells are also found in the lungs and airways into the lungs (bronchi), as well as the respiratory tract of the head and neck. The pituitary gland, the parathyroid glands and the inner layer of the adrenal gland (adrenal medulla) are largely made up of neuroendocrine cells. Other locations of neuroendocrine cells include the thymus, kidneys, liver, prostate, skin, cervix, ovaries and testicles.

Neuroendocrine neoplasms (NENs) can originate from any of the neuroendocrine cells that are scattered throughout the body. Because many NENs are secretory, the measurement of circulating biomarkers can be helpful for their diagnosis as well as for estimating tumor burden, assessing tumor response to treatment, monitoring disease progression, and predicting outcomes.5-19 Patients with well-differentiated NENs frequently express elevated blood levels of CgA. Numerous studies have documented the utility of measuring circulating CgA levels in patients with a variety of NENs, including carcinoids,21 tumors of the gastroenteropancreatic tract,5,15,20,24-26 pheochromocytomas,22,23 neuroblastomas,27 islet cell tumors,16,28 and other amine precursor uptake and decarboxylation (APUD) tumors.15,29,30 CGA can be elevated in patients with multiple endocrine neoplasia, type 1 (MEN1) and is used for the routine surveillance of this condition.31,32

Prostate cancers often contain cells with partial neuroendocrine differentiation. The value of CgA as a biomarker of prostate cancer has been extensively evaluated with several studies suggesting that it has prognostic utility in certain cases, such as in combination with NSE assessment or in patients treated with certain specific therapies.33-36


Footnotes

1. BRAHMS CgA II KRYPTOR® IFU-839R-USA [package insert]. Middletown, VA: Fisher Scientific Company LLC; 2015.
2. Borges R, Daz-Vera J, Domnguez N, Arnau MR, Machado JD. Chromogranins as regulators of exocytosis. J Neurochem. 2010 Jul;114(2):335-343.20456013
3. D'amico MA, Ghinassi B, Izzicupo P, Manzoli L, Di Baldassarre A. Biological function and clinical relevance of chromogranin A and derived peptides. Endocr Connect. 2014 Apr 29;3(2):R45-54.24671122
4. Bartolomucci A, Possenti R, Mahata SK, Fischer-Colbrie R, Loh YP, Salton SR. The extended granin family: structure, function, and biomedical implications. Endocr Rev. 2011 Dec;32:755-797.21862681
5. Ardill JE, O'Dorisio TM. Circulating biomarkers in neuroendocrine tumors of the enteropancreatic tract: application to diagnosis, monitoring disease, and as prognostic indicators. Endocrinol Metab Clin North Am. 2010 Dec;39(4):777-790.21095544
6. Strosberg JR, Halfdanarson TR, Bellizzi AM, et al. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Midgut Neuroendocrine Tumors. Pancreas. 2017 Jul;46(6):707-714.28609356
7. Citterio D, Pusceddu S, Facciorusso A, et al. Primary tumour resection may improve survival in functional well-differentiated neuroendocrine tumours metastatic to the liver. Eur J Surg Oncol. 2017 Feb;43(2):380-387.27956320
8. Gut P, Czarnywojtek A, Fischbach J, et al. Chromogranin A - unspecific neuroendocrine marker. Clinical utility and potential diagnostic pitfalls. Arch Med Sci. 2016 Feb 1;12(1):1-9.26925113
9. Yao JC, Pavel M, Lombard-Bohas C, et al. Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: Overall survival and circulating biomarkers from the randomized, Phase III RADIANT-3 Study. J Clin Oncol. 2016 Nov 10;34(32):3906-3913.27621394
10. Yang X, Yang Y, Li Z, et al. Diagnostic value of circulating chromogranin a for neuroendocrine tumors: A systematic review and meta-analysis. PLoS One. 2015 2015 Apr 20;10(4):e0124884.25894842
11. Kanakis G, Kaltsas G. Biochemical markers for gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Best Pract Res Clin Gastroenterol. 2012 Dec;26(6):791-802.23582919
12. Kunz PL, Reidy-Lagunes D, Anthony LB, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013 May;42(4):557-577.23591432
13. Lawrence B, Gustafsson BI, Kidd M, Pavel M, Svejda B, Modlin IM. The clinical relevance of chromogranin A as a biomarker for gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011 Mar;40(1):111-134.21349414
14. Ramage JK, Ahmed A, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut. 2012 Jan;61(1):6-32.22052063
15. Boudreaux JP, Klimstra DS, Hassan MM, et al. The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the Jejunum, Ileum, Appendix, and Cecum. Pancreas. 2010 Aug;39(6):753-766.20664473
16. Oberg K. Circulating biomarkers in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer. 2011 Oct 17;18 Suppl 1:S17-25.22005113
17. Kocha W, Maroun J, Kennecke H, et al. Consensus recommendations for the diagnosis and management of well- differentiated gastroenterohepatic neuroendocrine tumours: A revised statement from a Canadian National Expert Group. Curr Oncol. 2010 Jun;17(3):49-64.20567626
18. Massironi S, Conte D, Sciola V, et al. Plasma chromogranin A response to octreotide test: Prognostic value for clinical outcome in endocrine digestive tumors. Am J Gastroenterol. 2010 Sep;105(9):2072-2078.20372113
19. Arnold R, Wilke A, Rinke A, et al. Plasma chromogranin A as marker for survival in patients with metastatic endocrine gastroenteropancreatic tumors. Clin Gastroenterol Hepatol. 2008 Jul;6(7):820-827.18547872
20. O'Toole D, Grossman A, Gross D, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biochemical markers. Neuroendocrinology. 2009;90(2):194-202.19713711
21. Kulke MH. Clinical presentation and management of carcinoid tumors. Hematol Oncol Clin North Am. 2007 Jun; 21(3):433-455; vii-viii.17548033
22. Shah MH, Goldner WS, Halfdanarson TR, et al. NCCN Guidelines Insights: Neuroendocrine and Adrenal Tumors, Version 2.2018. J Natl Compr Canc Netw. 2018 Jun;16(6):693-702.29891520
23. Algeciras-Schimnich A, Preissner CM, Young WF Jr, Singh RJ, Grebe SK. Plasma chromogranin A or urine fractionated metanephrines follow-up testing improves the diagnostic accuracy of plasma fractionated metanephrines for pheochromocytoma. J Clin Endocrinol Metab. 2008 Jan;93(1):91-95.17940110
24. Jun E, Kim SC, Song KB, et al. Diagnostic value of chromogranin A in pancreatic neuroendocrine tumors depends on tumor size: A prospective observational study from a single institute. Surgery. 2017 Jul;162(1):120-130.28262254
25. Chou WC, Chen JS, Hung YS, et al. Plasma chromogranin A levels predict survival and tumor response in patients with advanced gastroenteropancreatic neuroendocrine tumors. Anticancer Res. 2014 Oct;34(10):5661-5669.25275071
26. Singh S, Law C. Chromogranin A: a sensitive biomarker for the detection and post-treatment monitoring of gastroenteropancreatic neuroendocrine tumors. Expert Rev Gastroenterol Hepatol. 2012 Jun;6(3):313-334.22646254
27. Georgantzi K, Skoldenberg EG, Stridsberg M, et al. Chromogranin A and neuron-specific enolase in neuroblastoma: Correlation to stage and prognostic factors. Pediatr Hematol Oncol. 2018 Mar;35(2):156-165.29737901
28. Nanno Y, Toyama H, Matsumoto I, et al. Baseline plasma chromogranin A levels in patients with well-differentiated neuroendocrine tumors of the pancreas: A potential predictor of postoperative recurrence. Pancreatology. 2017 Mar-Apr;17(2):291-294.28043759
29. Anthony LB, Stosberg JR, Klimstra DS, et al. The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors (nets): well-differentiated nets of the distal colon and rectum. Pancreas. 2010 Aug;39(6):767-774.20664474
30. Kulke MH, Benson AB 3rd, Bergsland E, et al. Neuroendocrine tumors. J Natl Compr Canc Netw. 2012 Jun 1;10(6):724-764.22679117
31. Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012 Sep;97(9):2990-3011.22723327
32. Ahmed A, Turner G, King B, et al. Midgut neuroendocrine tumours with liver metastases: results of the UNIKETS study. Endocr Relat Cancer. 2009 Sep;16(3):885-894.19458024
33. Heck MM, Thaler MA, Schmid SC, et al. Chromogranin A and neurone-specific enolase serum levels as predictors of treatment outcome in patients with metastatic castration- resistant prostate cancer undergoing abiraterone therapy. BJU Int. 2017 Jan;119(1):30-37.27037533
34. Niedworok C, Tschirdewahn S, Reis H, et al. Serum Chromogranin A as a Complementary Marker for the Prediction of Prostate Cancer-Specific Survival. Pathol Oncol Res. 2017 Jul;23(3):643-650.28012116
35. Fan L, Wang Y, Chi C, et al. Chromogranin A and neurone-specific enolase variations during the first 3 months of abiraterone therapy predict outcomes in patients with metastatic castration-resistant prostate cancer. BJU Int. 2017 Aug;120(2):226-232.28107595
36. Appetecchia M, Mecule A, Pasimeni G, et al. Incidence of high chromogranin A serum levels in patients with non metastatic prostate adenocarcinoma. J Exp Clin Cancer Res. 2010 Dec 17;29:166.21162758
37. Krabbe JG, Monaghan PJ, Russell J, de Rijke YB. Analytical evaluation of a second generation assay for chromogranin A; a dual-site study. Clin Chem Lab Med. 2016 Apr;54(4):e139-142.26393331
38. Ferraro S, Borille S, Panteghini M. Reference intervals for the Kryptor second-generation chromogranin A assay. Clin Chem Lab Med. 2016 Nov 1;54(11):e335-e337.27092653
39. van der Knaap RHP, Kwekkeboom DJ, Ramakers CRB, de Rijke YB. Evaluation of a new immunoassay for chromogranin A measurement on the Kryptor system. Pract Lab Med. 2015 Mar 10;1:5-11.28932793
40. Wolf M, Riedlinger I, Lehmann R, Häring HU, Schleicher E, Peter A. Comparison of the automated KRYPTOR chromogranin A assay with the DAKO ELISA. Clin Lab. 2014;60(12):2103-2106.25651748
41. Spadaro A, Ajello A, Morace C, et al. Serum chromogranin-A in hepatocellular carcinoma: diagnostic utility and limits. World J Gastroenterol. 2005 Apr 7;11(13):1987-1990.15800991
42. Giovanella L, Marelli M, Ceriani L, Giardina G, Garancini S, Colombo L. Evaluation of chromogranin A expression in serum and tissues of breast cancer patients. Int J Biol Markers. 2001 Oct-Dec;16(4):268-272.11820723
43. Marotta V, Zatelli MC, Sciammarella C, et al. Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: More flaws than fame. Endocr Relat Cancer. 2018 Jan;25(1):R11-R29.29066503
44. Modlin IM, Gustafsson BI, Moss SF, Pavel M, Tsolakis AV, Kidd M. Chromogranin A—biological function and clinical utility in neuro endocrine tumor disease. Ann Surg Oncol. 2010 Sep;17(9):2427-2443.20217257
45. Molina R, Alvarez E, Aniel-Quiroga A, et al. Evaluation of chromogranin A determined by three different procedures in patients with benign diseases, neuroendocrine tumors and other malignancies. Tumour Biol. 2011 Feb;32(1):13-22.20730520
46. Kidd M, Bodei L, Modlin IM. Chromogranin A: any relevance in neuroendocrine tumors? Curr Opin Endocrinol Diabetes Obes. 2016 Feb;23(1):28-37.26627724
47. Mosli HH, Dennis A, Kocha W, Asher LJ, Van Uum SH. Effect of short-term proton pump inhibitor treatment and its discontinuation on chromogranin A in healthy subjects. J Clin Endocrinol Metab. 2012 Sep;97(9):E1731-1735.22723311

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
140848 Chromogranin A 9811-1 140853 Chromogranin A ng/mL 9811-1

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