CGA

(Chromogranin A)
Characteristics

Together with secretogranins, chromogranins comprise a family of acid calcium-binding glycoproteins closely associated with the matrix of dense-core neurosecretory granules in virtually all neuroendocrine (NE) cells and neurons. Probably, these proteins are involved in packaging and processing of neuropeptides and peptide hormones. Chromogranin A (CGA), 48-75 kDa, 439 amino acids, is the diagnostically most important of these glycoproteins, and probably the major target of the argyrophilic Grimelius staining reaction. Post-translational processing of CGA gives rise to fragments with biologic activities such as autocrine and paracrine functions. A number of CGA fragments have been identified: vasostatins (amino acid sequences 1-17/113), chromostatin (116/124-130/143), chromacin (173/176-195), WE-14 (316-329), catestatin (344-364), mid-parastatin (347/375-384), C-terminal parastatin (411-419/424), GE-25 (367-391), and N-terminal pancreastatin (250-284/301). The functions of several of these are known. Some fragments have influence on cell growth, adhesion and activation (e.g., vascular smooth muscle cell contraction or relaxation, microglial neurotoxin secretion) as well as antimicrobial activity. e.g., chromostatin and catestatin have an inhibitory effect on catecholamine release from the adrenal medulla, secretoneurin can stimulate dopamine release.

Neoplasms

CGA is found in the large majority of epithelial NE tumours: pituitary adenomas (however, prolactinoma, corticotropin-producing adenoma and null cell adenoma may be CGA negative while presenting CGB), parathyroid and pancreatic islet cell tumours (however, insulinoma and somatostatinoma may be CGA negative), medullary thyroid carcinoma, and carcinoid tumours of e.g., respiratory and gastrointestinal tract. As regards the latter, almost all foregut and midgut tumours are CGA positive, while hindgut carcinoids are frequently negative (while CGB positive). CGA is detected in most cases of small cell carcinoma (particularly from the lung, Merkel cell carcinoma, and other NE carcinomas) as well as in some cases of multiphenotypic tumours (e.g., malignant rhabdoid tumour, desmoplastic small round cell tumour). However, in the literature the proportion of these tumours reported as CGA positive is varying, e.g., 40 – 100 % in small cell lung carcinoma. This is in part depending on the Ab and the sensitivity of system combined with a variable and often low expression of CGA in these tumours. A small number of CGA positive cells may be detected in non-neuroendocrine carcinomas as a result of a partial NE differentiation (e.g. breast, prostate). In some carcinomas (e.g., prostate, colo-rectum, stomach), the occurrence of CGA positive cells has shown to be a negative prognostic marker, while in others (e.g., breast) it seems to be of no prognostic importance. CGA is found in the large majority of neuronal tumours: ganglioneuroblastoma, ganglioneuroma, ganglioglioma, phaeochromocytoma, paraganglioma (however, some parasympathic paraganglioma may be CGA negative). Primitive neuro¬ectodermal tumours (neuroblastoma etc.) are usually described as CGA negative, but CGA may be detected focally in sensitive systems. CGA is not detected in glial tumours (with the exception of some oliogodendrogliomas), meningioma, choroid plexus tumours, schwannoma, malignant melanoma, or adrenocortical tumours. Carcinomas (with the exception of the above mentioned) as well as mesotheliomas and sarcomas are always CGA negative.

Application

Together with synaptophysin, CGA is the most important marker for the identification of NE and neuronal tumours and NE/neuronal differentiation in other tumours. In optimized protocols is CGA slightly more specific than synaptophysin and slightly less sensitive.

Controls

Appendix is recommendable as positive and negative tissue control: An at least weak to moderate distinct granular staining must be seen in the axons and ganglion cells of the peripheral nerves. Neuroendocrine cells in the appendiceal mucosa should display a strong staining and diffusion of the staining in the vicinity of these cells has to be accepted. Epithelial and smooth muscle cells should be negative.
In this context it must be stressed that pancreas cannot be used as positive tissue control as recommended by some vendors. Endocrine cells in the pancreatic islets have a high level of CGA expression, which cannot reliable be used as control of sufficient sensitivity of the protocol. The low-level and limited expression of CGA in many neuroendocrine tumours and carcinomas can  consequently lead to a false negative staining result in these tumors despite positive staining reaction in pancreas.

Selected references

Hagn C, Schmid KW, Fischer-Colbrie R et al. Chromogranin A, B, and C in human adrenal medulla and endocrine tissues. Lab Invest 1986;55:405-411. Konecki DS, Benedum UM, Gerdes HH et al. The primary structure of chromogranin A and pancreastatin. J Biol Chem 1987;262:17026-17030. Lloyd RV, Cano M, Rosa P, et al. Distribution of chromogranin A and secretogranin I (chromogranin B) in neuroendocrine cells and tumors. Am J Pathol 1988;130:296-304. O’Connor DT. Chromogranin: widespread immunoreactivity in polypepetide hormone producing tissues and in serum. Regul Pept 1983;6:263-280. Portela-Gomes GM, Grimelius L, Johansson H, Wilander E, Stridsberg M. Chromogranin A in human neuroendocrine tumors. An immunohistochemical study with region-specific antibodies. Am J Surg path 2001;25:1261-7. Taupenot L, Harper KL, O’Connor DT: The chromogranin-secretogranin family. N Engl J Med 2003;3:1134-1149.

20.04.16 - HH/MV/LE