Chromogranin A, Serum (CGAK)

Test Code: CHRASO

Overview
Ordering
Specimen
Performing
Clinical/Interpretive
Contacts
Coding

Useful For

Aiding in monitoring disease progression during the course of disease and treatment in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET grade 1 and grade 2) when used in conjunction with other clinical methods.

This test is not indicated for use as a stand-alone monitoring assay.

Specimen Requirements

Specimen Type	Preferred Container/Tube	Acceptable Container/Tube	Specimen Volume	Specimen Minimum Volume (allows for 1 repeat)	Pediatric Minimum Volume (no repeat)
Serum	Serum Separator Tube (SST)	Red Top Tube (RTT)	0.5 mL	0.2 mL

Collection Processing Instructions

Proton pump inhibitor drugs should be discontinued for at least 2 weeks before collection.

Centrifuge and aliquot serum into plastic vial. Do NOT submit in original tube.

Specimen Stability Information

Specimen Type	Temperature	Time
Serum	Frozen (preferred)	90 days
	Ambient	48 hours
	Refrigerated	48 hours

Rejection Criteria

Gross Hemolysis

Interference

This test should not be used for cancer screening or cancer diagnosis. Furthermore, chromogranin A (CgA) is not indicated to be used as a stand-alone monitoring assay and should be used in conjunction with clinical signs and symptoms and other diagnostic evidence. In cases where the laboratory results do not agree with the clinical picture or history, additional tests should be performed.

Test results cannot be interpreted as absolute evidence for the presence or absence of malignant disease.

Drugs that stimulate secretion of neuroendocrine cells can lead to artifactual CgA elevations. In particular, proton pump inhibitors (PPI; eg, omeprazole), which are used in the treatment of esophageal and gastroduodenal ulcer disease and dyspepsia, will result in significant elevations of serum CgA levels, often to many times above the normal range. PPI should therefore be discontinued for at least 2 weeks before CgA measurements because the biological effects of PPI persist for a significant time period after the drugs are discontinued. If absolutely necessary, H2-receptor antagonists at modest doses can be substituted for PPI in such patients without risking significant false-elevations in CgA.(7)

Atrophic gastritis and pernicious anemia also lead to false elevations in serum CgA levels by the same mechanism as PPI, lack of feedback inhibition of gastrin production due to gastric achlorhydria.

CgA and its peptide fragments are cleared by a combination of hepatic metabolism and kidney excretion. Impaired kidney function is associated with elevated serum CgA to similar concentrations to those observed in patients on PPI, making single serum CgA measurements uninterpretable.(8) Serial measurements may have some value in selected patients if the impaired kidney function remains stable, in particular because CgA does not seem to change significantly following dialysis (in-house data, 24 patients; p=0.32). However, results must be interpreted with extreme caution.

Various non-neuroendocrine tumors might be associated with elevations, usually modest, in serum CgA concentrations. This possibility should be considered in patients who are evaluated or followed for neuroendocrine tumors and who show serum CgA elevations that are discordant to the clinical assessment or other biochemical and imaging tests.

Values obtained with different assay methods or kits may be different and cannot be used interchangeably.

In rare cases, some individuals can develop antibodies to mouse or other animal antibodies (often referred to as human anti-mouse antibodies [HAMA] or heterophile antibodies), which may cause interference in some immunoassays. Caution should be used in interpretation of results, and the laboratory should be alerted if the result does not correlate with the clinical presentation.

A "hook effect" can occur at extremely high CgA concentrations, resulting in a lower measured CgA concentration than is actually contained in the specimen. This assay is unlikely to be subject to hooking unless CgA concentrations in excess of 1,000,000 ng/mL are present. However, if there is a strong clinical suspicion of hooking, then retesting after further sample dilutions should be requested.

Occasional patient specimens will contain mixtures of CgA fragments that lead to nonlinearity of measurement in specimens with high concentrations of CgA that need to be diluted. It might not be possible to provide an accurate result in some of these individuals.

Performing Laboratory Information

Performing Location	Day(s) Test Performed	Report Available	Methodology/Instrumentation
Mayo Clinic Laboratories	Monday through Saturday	1 to 3 days	Immunofluorescent Assay (IFA)

Reference Lab

Mayo Clinic Laboratories

Test Information

Chromogranin A (CGA) is a 439-amino acid protein with a molecular weight of 48 to 60 kDa, depending on glycosylation and phosphorylation status. It is a member of the granin family of proteins and polypeptides. Granins are widespread in endocrine, neuroendocrine, peripheral, and central nervous tissues, where they are found in secretory granules alongside the tissue-specific secretion products. The role of granins within the granules is to maintain the regulated secretion of these signaling molecules. This includes:

-Facilitating the formation of secretory granules

-Calcium- and pH-mediated sequestration and resolubilization of hormones or neurotransmitters

-Regulation of neuropeptide and peptide hormone processing through modulation of prohormone convertase activity

In addition, granins contain multiple protease and peptidase cleavage sites, and upon intra- or extracellular cleavage give rise to a series of daughter peptides with distinct extracellular functions. Some of these have defined functions, such as pancreastatin, vasostatin, and catestatin, while others are less well characterized.(1)

Because of its ubiquitous distribution within neuroendocrine tissues, CGA can be a useful diagnostic marker for neuroendocrine neoplasms, including carcinoids, pheochromocytomas, neuroblastomas, medullary thyroid carcinomas (MTC), some pituitary tumors, functioning and nonfunctioning islet cell tumors and other amine precursor uptake and decarboxylation (APUD) tumors. It can also serve as a sensitive means for detecting residual or recurrent disease in treated patients.(2-4)

Carcinoid tumors in particular almost always secrete CgA along with a variety of specific modified amines, chiefly serotonin (5-hydroxytryptamine) and peptides.(1-4) Carcinoid tumors are subdivided into foregut carcinoids, arising from respiratory tract, stomach, pancreas or duodenum (approximately 15% of cases); midgut carcinoids, occurring within jejunum, ileum, or appendix (approximately 70% of cases); and hindgut carcinoids, which are found in the colon or rectum (approximately 15% of cases). Serum CgA and urine 5-hydroxyindolacetic acid (5-HIAA) are considered the most useful biochemical markers and are first-line tests in disease surveillance of most patients with carcinoid tumors.(2-4) Serum CgA measurements have been used in conjunction with, or alternative to, measurements of serum or whole blood serotonin, urine serotonin and 5-HIAA, and imaging studies in the differential diagnosis of isolated symptoms suggestive of carcinoid syndrome, in particular, flushing

A number of tumors that are not derived from classical endocrine or neuroendocrine tissues but contain cells with partial neuroendocrine differentiation, such as small-cell carcinoma of the lung or prostate carcinoma, may also display elevated CgA levels. However, the role of CgA measurement is not well defined in these tumors.

Reference Range Information

<93 ng/mL

Reference values apply to all ages.

Interpretation

Follow-up/Surveillance

Urine 5-hydroxyindolacetic acid (5-HIAA) and serum chromogranin A (CGA) increase in proportion to carcinoid tumor burden. Because of the linear relationship of CGA to tumor burden, its measurement also provides prognostic information.

Most mid- and hindgut tumors secrete CGA even if they do not produce significant amounts of serotonin or serotonin metabolites (5-HIAA). Guidelines recommend 3 to 12 monthly measurements of CGA or 5-HIAA in follow-up of midgut carcinoids.(2,3) Patients with foregut tumors can also be monitored with CGA or 5-HIAA measurements, if they were positive for these markers at initial diagnosis. Hindgut tumors usually do not secrete serotonin, and consequently only CGA monitoring is recommended.(1-4)

As is typical for tumor marker use in follow-up and surveillance, a 40% to 50% change in serum CGA concentrations should be considered potentially clinically significant in the absence of confounding factors (see Cautions). Much smaller changes in CGA concentrations might be considered significant if they occur over several serial measurements and are all in the same direction.

Adjunct in Diagnosis of Carcinoid Tumors

CGA is elevated in most patients (approximately 90%) with symptomatic or advanced carcinoids (carcinoid syndrome), usually to levels several times the upper limit of the reference interval. Serum CGA measurements are particularly suited for diagnosing hindgut tumors, being elevated in nearly all cases, even though serotonin and 5-HIAA are often normal. CGA is also elevated in 80% to 90% of patients with symptomatic foregut and midgut tumors.

To achieve maximum sensitivity in the initial diagnosis of suspected carcinoid tumors, serum CGA, serotonin in serum or blood, and 5-HIAA in urine should all be measured. In most cases, if none of these 3 analytes is elevated, carcinoids can usually be excluded as a cause of symptoms suggestive of carcinoid syndrome. For some cases, additional tests such as urine serotonin measurement will be required. An example would be a foregut tumor, which does not secrete CGA and only produces 5-hydroxytryptophan (5-HTP), rather than serotonin. In this case, circulating chromogranin, serotonin, and urine 5-HIAA levels would not be elevated. However, the kidneys can convert 5-HTP to serotonin, leading to high urine serotonin levels.

Adjunct in the Diagnosis of Other Neuroendocrine Tumors

In patients with suspected neuroendocrine tumors other than carcinoids, CGA is often elevated alongside any specific amine and peptide hormones or neurotransmitters that may be produced. The CGA elevations are less pronounced than in carcinoid tumors, and measurement of specific tumor secretion products is considered of greater utility. However, CGA measurements can occasionally aid in diagnosis of these tumors if specific hormone measurements are inconclusive. This is the case in particular with pheochromocytoma and neuroblastoma, where CGA levels may be substantially elevated and can, therefore, provide supplementary and confirmatory information to measurements of specific hormones. In particular, CGA measurements might provide useful diagnostic information in patients with mild elevations in catecholamines and metanephrines;(6) such mild elevations often represent false-positive test results.

Possible Adjunct in Outcome Prediction and Follow-up of Prostate Cancer

Prostate cancers often contain cells with partial neuroendocrine differentiation. These cells secrete CGA. The amounts secreted are insufficient in most cases to make this a useful marker for prostate cancer diagnosis. However, if patients with advanced prostate cancer are found to have elevated CGA levels, this indicates the tumor contains a significant neuroendocrine cell subpopulation. Such tumors are often resistant to antiandrogen therapy and have a worse prognosis. These patients should be monitored particularly closely.(5)

Outreach CPTs

CPT	Modifier (if needed)	Quantity	Description	Comments
86316

Ordering Applications

Ordering Application	Description
Cerner	Chromogranin A, Serum (CGAK)

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