Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Mar;84(5):636–642. doi: 10.1054/bjoc.2000.1659

A new human chromogranin 'A' immunoradiometric assay for the diagnosis of neuroendocrine tumours

G P Bernini 1, A Moretti 1, M Ferdeghini 2, S Ricci 2, C Letizia 3, E D'Erasmo 3, G F Argenio 1, A Salvetti 1
PMCID: PMC2363780  PMID: 11237384

Abstract

We investigated whether plasma chromogranin A (CgA), measured by a new immunoradiometric assay, may be a sensitive and specific marker of phaeochromocytoma and of other neuroendocrine tumours. This study involved 121 patients of whom 20 with phaeochromocytoma, 28 with other neuroendocrine tumours (19 gastroenteropancreatic tumors, 3 medullary thyroid and 6 small cell lung carcinomas), 25 with solid nonfunctioning adrenocortical tumours and 48 with essential hypertension. In addition, 130 normal subjects were taken as controls. Plasma catecholamines were measured by using high-performance liquid chromatography, and CgA by a two-site sandwich immunoradiometric assay involving monoclonal antibodies raised against the unprocessed central domain (145–245) of human CgA. Plasma CgA in controls (49.0 ± 3.1 ng ml–1, mean ± SE) and in essential hypertensives (50.8 ± 3.5 ng ml–1) was lower (P< 0.0001) than in adrenocortical tumours (91.8 ± 13.2 ng ml–1), in phaeochromocytomas (254 ± 49 ng ml–1) and in patients with other neuroendocrine tumours (469 ± 84 ng ml–1). Plasma CgA and catecholamines identified 13 and 18 out of 20 phaeochromocytomas with sensitivity of 65% and 90%, respectively. Combined measurement of both markers improved sensitivity up to 100%. In the other neuroendocrine tumours, CgA was abnormal in 23/28 cases (sensitivity 82%) and in 6 it was the only circulating marker of disease. In gastroenteropancreatic tumours, CgA measurement identified all cases (sensitivity 100%). Specificity of CgA in patients with essential hypertension was 98%. In conclusion, CgA determination showed high sensitivity in identifying gastroenteropancreatic tumours and, in association with catecholamines, in detecting patients with phaeochromocytoma. CgA sometimes appeared to be the only circulating marker of disease. Since the specificity of CgA proved to be excellent, this assay may be useful for diagnosis both of functioning and non-functioning neuroendocrine tumours. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: chromogranin A, phaeochromocytoma, neuroendocrine tumours

Full Text

The Full Text of this article is available as a PDF (99.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akoun G. M., Scarna H. M., Milleron B. J., Bénichou M. P., Herman D. P. Serum neuron-specific enolase. A marker for disease extent and response to therapy for small-cell lung cancer. Chest. 1985 Jan;87(1):39–43. doi: 10.1378/chest.87.1.39. [DOI] [PubMed] [Google Scholar]
  2. Barbosa J. A., Gill B. M., Takiyyuddin M. A., O'Connor D. T. Chromogranin A: posttranslational modifications in secretory granules. Endocrinology. 1991 Jan;128(1):174–190. doi: 10.1210/endo-128-1-174. [DOI] [PubMed] [Google Scholar]
  3. Baudin E., Gigliotti A., Ducreux M., Ropers J., Comoy E., Sabourin J. C., Bidart J. M., Cailleux A. F., Bonacci R., Ruffié P. Neuron-specific enolase and chromogranin A as markers of neuroendocrine tumours. Br J Cancer. 1998 Oct;78(8):1102–1107. doi: 10.1038/bjc.1998.635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bender H., Maier A., Wiedenmann B., O'Connor D. T., Messner K., Schmidt-Gayk H. Immunoluminometric assay of chromogranin A in serum with commercially available reagents. Clin Chem. 1992 Nov;38(11):2267–2272. [PubMed] [Google Scholar]
  5. Blind E., Schmidt-Gayk H., Sinn H. P., O'Connor D. T., Raue F. Chromogranin A as tumor marker in medullary thyroid carcinoma. Thyroid. 1992 Spring;2(1):5–10. doi: 10.1089/thy.1992.2.5. [DOI] [PubMed] [Google Scholar]
  6. Bornstein S. R., Stratakis C. A., Chrousos G. P. Adrenocortical tumors: recent advances in basic concepts and clinical management. Ann Intern Med. 1999 May 4;130(9):759–771. doi: 10.7326/0003-4819-130-9-199905040-00017. [DOI] [PubMed] [Google Scholar]
  7. Corti A., Gasparri A., Chen F. X., Pelagi M., Brandazza A., Sidoli A., Siccardi A. G. Characterisation of circulating chromogranin A in human cancer patients. Br J Cancer. 1996 Apr;73(8):924–932. doi: 10.1038/bjc.1996.183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Deftos L. J. Chromogranin A: its role in endocrine function and as an endocrine and neuroendocrine tumor marker. Endocr Rev. 1991 May;12(2):181–187. doi: 10.1210/edrv-12-2-181. [DOI] [PubMed] [Google Scholar]
  9. Deftos L. J., Linnoila R. I., Carney D. N., Burton D. W., Leong S. S., O'Connor D. T., Murray S. S., Gazdar A. F. Demonstration of Chromogranin A in human neuroendocrine cell lines by immunohistology and immunoassay. Cancer. 1988 Jul 1;62(1):92–97. doi: 10.1002/1097-0142(19880701)62:1<92::aid-cncr2820620117>3.0.co;2-t. [DOI] [PubMed] [Google Scholar]
  10. Degorce F., Goumon Y., Jacquemart L., Vidaud C., Bellanger L., Pons-Anicet D., Seguin P., Metz-Boutigue M. H., Aunis D. A new human chromogranin A (CgA) immunoradiometric assay involving monoclonal antibodies raised against the unprocessed central domain (145-245). Br J Cancer. 1999 Jan;79(1):65–71. doi: 10.1038/sj.bjc.6690013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dillen L., De Block J., Van Lear L., De Potter W. Enzyme-linked immunosorbent assay for chromogranin A. Clin Chem. 1989 Sep;35(9):1934–1938. [PubMed] [Google Scholar]
  12. Eriksson B., Arnberg H., Oberg K., Hellman U., Lundqvist G., Wernstedt C., Wilander E. A polyclonal antiserum against chromogranin A and B--a new sensitive marker for neuroendocrine tumours. Acta Endocrinol (Copenh) 1990 Feb;122(2):145–155. doi: 10.1530/acta.0.1220145. [DOI] [PubMed] [Google Scholar]
  13. Ferrari L., Seregni E., Martinetti A., Van Graafeiland B., Nerini-Molteni S., Botti C., Artale S., Cresta S., Bombardieri E. Chromogranin A measurement in neuroendocrine tumors. Int J Biol Markers. 1998 Jan-Mar;13(1):3–9. doi: 10.1177/172460089801300102. [DOI] [PubMed] [Google Scholar]
  14. Gröndal S., Eriksson B., Hamberger B., Theodorsson E. Plasma chromogranin A + B, neuropeptide Y and catecholamines in pheochromocytoma patients. J Intern Med. 1991 May;229(5):453–456. doi: 10.1111/j.1365-2796.1991.tb00374.x. [DOI] [PubMed] [Google Scholar]
  15. Helle K. B., Angeletti R. H. Chromogranin A: a multipurpose prohormone? Acta Physiol Scand. 1994 Sep;152(1):1–10. doi: 10.1111/j.1748-1716.1994.tb09779.x. [DOI] [PubMed] [Google Scholar]
  16. Hsiao R. J., Neumann H. P., Parmer R. J., Barbosa J. A., O'Connor D. T. Chromogranin A in familial pheochromocytoma: diagnostic screening value, prediction of tumor mass, and post-resection kinetics indicating two-compartment distribution. Am J Med. 1990 Jun;88(6):607–613. doi: 10.1016/0002-9343(90)90526-j. [DOI] [PubMed] [Google Scholar]
  17. Hsiao R. J., Parmer R. J., Takiyyuddin M. A., O'Connor D. T. Chromogranin A storage and secretion: sensitivity and specificity for the diagnosis of pheochromocytoma. Medicine (Baltimore) 1991 Jan;70(1):33–45. [PubMed] [Google Scholar]
  18. Hsiao R. J., Seeger R. C., Yu A. L., O'Connor D. T. Chromogranin A in children with neuroblastoma. Serum concentration parallels disease stage and predicts survival. J Clin Invest. 1990 May;85(5):1555–1559. doi: 10.1172/JCI114604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Johnson P. W., Joel S. P., Love S., Butcher M., Pandian M. R., Squires L., Wrigley P. F., Slevin M. L. Tumour markers for prediction of survival and monitoring of remission in small cell lung cancer. Br J Cancer. 1993 Apr;67(4):760–766. doi: 10.1038/bjc.1993.138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kimura N., Miura W., Noshiro T., Mizunashi K., Hanew K., Shimizu K., Watanabe T., Shibukawa S., Sohn H. E., Abe K. Plasma chromogranin A in pheochromocytoma, primary hyperparathyroidism and pituitary adenoma in comparison with catecholamine, parathyroid hormone and pituitary hormones. Endocr J. 1997 Apr;44(2):319–327. doi: 10.1507/endocrj.44.319. [DOI] [PubMed] [Google Scholar]
  21. Konecki D. S., Benedum U. M., Gerdes H. H., Huttner W. B. The primary structure of human chromogranin A and pancreastatin. J Biol Chem. 1987 Dec 15;262(35):17026–17030. [PubMed] [Google Scholar]
  22. Krstulović A. M., Dziedzic S. W., Bertani-Dziedzic L., DiRico D. E. Plasma catecholamines in hypertension and pheochromocytoma determined using ion-pair reversed-phase chromatography with amperometric detection: investigation of the separation mechanism and clinical methodology. J Chromatogr. 1981 Nov 6;217:523–537. doi: 10.1016/s0021-9673(00)88103-0. [DOI] [PubMed] [Google Scholar]
  23. Li Q., Johansson H., Kjellman M., Grimelius L. Neuroendocrine differentiation and nerves in human adrenal cortex and cortical lesions. APMIS. 1998 Aug;106(8):807–817. doi: 10.1111/j.1699-0463.1998.tb00227.x. [DOI] [PubMed] [Google Scholar]
  24. Metz-Boutigue M. H., Garcia-Sablone P., Hogue-Angeletti R., Aunis D. Intracellular and extracellular processing of chromogranin A. Determination of cleavage sites. Eur J Biochem. 1993 Oct 1;217(1):247–257. doi: 10.1111/j.1432-1033.1993.tb18240.x. [DOI] [PubMed] [Google Scholar]
  25. Miettinen M. Neuroendocrine differentiation in adrenocortical carcinoma. New immunohistochemical findings supported by electron microscopy. Lab Invest. 1992 Feb;66(2):169–174. [PubMed] [Google Scholar]
  26. Nobels F. R., Kwekkeboom D. J., Bouillon R., Lamberts S. W. Chromogranin A: its clinical value as marker of neuroendocrine tumours. Eur J Clin Invest. 1998 Jun;28(6):431–440. doi: 10.1046/j.1365-2362.1998.00305.x. [DOI] [PubMed] [Google Scholar]
  27. Nobels F. R., Kwekkeboom D. J., Coopmans W., Schoenmakers C. H., Lindemans J., De Herder W. W., Krenning E. P., Bouillon R., Lamberts S. W. Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones. J Clin Endocrinol Metab. 1997 Aug;82(8):2622–2628. doi: 10.1210/jcem.82.8.4145. [DOI] [PubMed] [Google Scholar]
  28. O'Connor D. T., Bernstein K. N. Radioimmunoassay of chromogranin A in plasma as a measure of exocytotic sympathoadrenal activity in normal subjects and patients with pheochromocytoma. N Engl J Med. 1984 Sep 20;311(12):764–770. doi: 10.1056/NEJM198409203111204. [DOI] [PubMed] [Google Scholar]
  29. O'Connor D. T., Deftos L. J. Secretion of chromogranin A by peptide-producing endocrine neoplasms. N Engl J Med. 1986 May 1;314(18):1145–1151. doi: 10.1056/NEJM198605013141803. [DOI] [PubMed] [Google Scholar]
  30. O'Connor D. T., Frigon R. P., Sokoloff R. L. Human chromogranin A. Purification and characterization from catecholamine storage vesicles of human pheochromocytoma. Hypertension. 1984 Jan-Feb;6(1):2–12. doi: 10.1161/01.hyp.6.1.2. [DOI] [PubMed] [Google Scholar]
  31. Rosa P., Gerdes H. H. The granin protein family: markers for neuroendocrine cells and tools for the diagnosis of neuroendocrine tumors. J Endocrinol Invest. 1994 Mar;17(3):207–225. doi: 10.1007/BF03347721. [DOI] [PubMed] [Google Scholar]
  32. Simon J. P., Aunis D. Biochemistry of the chromogranin A protein family. Biochem J. 1989 Aug 15;262(1):1–13. doi: 10.1042/bj2620001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sobol R. E., Memoli V., Deftos L. J. Hormone-negative, chromogranin A-positive endocrine tumors. N Engl J Med. 1989 Feb 16;320(7):444–447. doi: 10.1056/NEJM198902163200707. [DOI] [PubMed] [Google Scholar]
  34. Sobol R. E., O'Connor D. T., Addison J., Suchocki K., Royston I., Deftos L. J. Elevated serum chromogranin A concentrations in small-cell lung carcinoma. Ann Intern Med. 1986 Nov;105(5):698–700. doi: 10.7326/0003-4819-105-5-698. [DOI] [PubMed] [Google Scholar]
  35. Stridsberg M., Husebye E. S. Chromogranin A and chromogranin B are sensitive circulating markers for phaeochromocytoma. Eur J Endocrinol. 1997 Jan;136(1):67–73. doi: 10.1530/eje.0.1360067. [DOI] [PubMed] [Google Scholar]
  36. Strub J. M., Goumon Y., Lugardon K., Capon C., Lopez M., Moniatte M., Van Dorsselaer A., Aunis D., Metz-Boutigue M. H. Antibacterial activity of glycosylated and phosphorylated chromogranin A-derived peptide 173-194 from bovine adrenal medullary chromaffin granules. J Biol Chem. 1996 Nov 8;271(45):28533–28540. doi: 10.1074/jbc.271.45.28533. [DOI] [PubMed] [Google Scholar]
  37. Syversen U., Jacobsen M. B., O'Connor D. T., Rønning K., Waldum H. L. Immunoassays for measurement of chromogranin A and pancreastatin-like immunoreactivity in humans: correspondence in patients with neuroendocrine neoplasia. Neuropeptides. 1994 Mar;26(3):201–206. doi: 10.1016/0143-4179(94)90131-7. [DOI] [PubMed] [Google Scholar]
  38. Tötsch M., Müller L. C., Hittmair A., Ofner D., Gibbs A. R., Schmid K. W. Immunohistochemical demonstration of chromogranins A and B in neuroendocrine tumors of the lung. Hum Pathol. 1992 Mar;23(3):312–316. doi: 10.1016/0046-8177(92)90113-h. [DOI] [PubMed] [Google Scholar]
  39. Weiler R., Feichtinger H., Schmid K. W., Fischer-Colbrie R., Grimelius L., Cedermark B., Papotti M., Bussolati G., Winkler H. Chromogranin A and B and secretogranin II in bronchial and intestinal carcinoids. Virchows Arch A Pathol Anat Histopathol. 1987;412(2):103–109. doi: 10.1007/BF00716181. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES