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
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Akoun GM, Scarna HM, Milleron BJ, Benichou MP and Herman DP (1985) Serum neuron-specific enolase. A marker of disease extent and response to therapy for small cell lung cancer. Chest 87: 39–43
Barbosa JA, Gill BM, Takiyyuddin MA and O’Connor DT (1991) Chromogranin A: post-translational modifications in secretory granules. Endocrinology 128: 174–190
Baudin E, Gigliotti A, Ducreux M, Ropers J, Comoy E, Sabourin JC, Ridart JM, Cailleux AF, Bonacci R, Ruffie P and Schlumberger M (1998) Neuron-specific enolase and chromogranin A as markers of neuroendocrine tumours. Br J Cancer 78: 1102–1107
Bender H, Maier A, Wiedenmann B, O’Connor DT, Messner K and Schmidt-Gayk H (1992) Immunoluminometric assay of chromogranin A in serum with commercially available reagents. Clin Chem 38: 2267–2272
Blind E, Schmidt-Gayk HS, Sinn H-P, O’Connor DT and Raue F (1992) Chromogranin A as tumor marker in medullary thyroid carcinoma. Thyroid 2: 5–10
Bornstein SR, Sratakis CA and Chrousos GP (1999) Adrenocortical tumours: recent advances in basic concepts and clinical management. Ann Intern Med 130: 759–771
Canale MP and Bravo EL (1994) Diagnostic specificity of serum chromogranin-A for pheochromocytoma in patients with renal dysfunction. J Clin Endocrinol Metab 78: 1139–1144
Cetin Y and Grube D (1991) Topology of chromogranins in secretory granules of endocrine cells. Histochemistry 96: 301–310
Corti A, Gasparri A, Chen FX, Pelagi M, Brandazza A, Sidoli A and Siccardi AG (1996) Characterisation of circulating chromogranin A in human cancer patients. Br J Cancer 73: 924–932
Deftos LJ (1991) Chromogranin A: its role in endocrine function and as an endocrine and neuroendocrine tumour marker. Endocrinol Rev 12: 181–187
Deftos LJ, Linnoila RI, Carney DN, Burton DW, Leong SS, O’Connor DT, Murray SS and Gazdar AF (1988) Demonstration of chromogranin A in human neuroendocrine cell lines by immunohistology and immunoassay. Cancer 62: 92–97
Degorce F, Goumon Y, Jacquemart L, Vidaud C, Bellanger L, Pons-Anicet D, Seguin P, Metz-Boutigue MH and Aunis D (1999) A new human chromogranin A (CgA) immunoradiometric assay involving monoclonal antibodies raised against the unprocessed central domain (145–245). Br J Cancer 79: 65–71
Dillen L, De Block J, Van Lear L and Potter W (1989) Enzyme- linked immunosorbent assay for chromogranin A. Clin Chem 35: 1934–1938
Eriksson B, Arnberg H, Oberg K, Hellman U, Lundqvist G, Wernstedt C and Wilander E (1990) A polyclonal antiserum against chromogranin A and B- a new sensitive marker for neuroendocrine tumours. Acta Endocrinol 122: 145–155
Ferrari L, Seregni E, Martinetti A, Van Graafeiland B, Nerini-Molteni S, Botti C, Artale S, Cresta S and Bombardieri E (1998) Chromogranin A measurement in neuroendocrine tumours. Int. J Biol Markers 13: 3–9
Grondal S, Eriksson B, Hamberger B and Theodorsson E (1991) Plasma chromogranin A+B, neuropeptide Y and catecholamines in pheochromocytoma patients. J Intern Med 229: 453–456
Helle K and Angeletti RH (1994) Chromogranin A: multipurpose prohormone?. Acta Physiol Scand 152: 1–10
Hsiao RJ, Seeger RC, Yu AL and O’Connor DT (1990a) Chromogranin A in children with neuroblastoma: serum concentration parallels disease stage and predicts survival. J Clin Invest 85: 1555–1559
Hsiao RJ, Neumann HPH, Parmer RJ, Barbosa JA and O’Connor DT (1990b) Chromogranin A in familial pheochromocytoma: diagnostic screening value, prediction of tumour mass, and post-resection kinetics indicating two-compartment distribution. Am J Med 88: 607–612
Hsiao RJ, Parmer RJ, Takiyyuddin MA and O’Connor DT (1991) Chromogranin A storage and secretion: sensitivity and specificity for the diagnosis of pheochromocytoma. Medicine 70: 33–45
JNC VI–World Health Organization–International Society of Hypertension Guidelines for the Management of Hypertension (1999). J Hypertens 17: 151–183
Johnson PWM, Joel SP and Love S (1993) Tumour markers for prediction of survival and monitoring of remission in small cell lung cancer. Br J Cancer 67: 760–766
Kimura N, Miura W, Noshiro T, Mizunashi K, Hanew K, Shimizu K, Watanabe T, Shibukawa S, Sohn HE, Abe K, Miura Y and Nagura H (1997) Plasma chromogranin A in pheochromocytoma, primary hyperparathyroidism and pituitary adenoma in comparison with catecholamine, parathyroid hormone and pituitary hormones. Endocr J 44: 319–327
Konecki DS, Benedurn NM, Gerdes HH and Huttern WB (1987) The primary structure of human chromogranin A and pancreastin. J Biol Chem 262: 17026–17030
Krstulovic AM, Dziedzk SW, Bertan-Dziedzic L and Dirico DE (1981) Plasma catecholamines in hypertension and pheochromocytomas determined using con-pair reversed-phase chromatography with amperometric detection. J Chromatography 217: 523–537
Li Q, Johansson H, Kjellman M and Grimellius L (1998) Neuroendocrine differentiation and nerves in human adrenal cortex and cortical lesions. APMIS 106: 807–817
Metz-Boutigue MH, Garcia-Sablone P, Angeletti RH and Annis D (1993) Intracellular and extracellular processing of chromogranin-A. Determination of cleavage sites. Eur J Biochem 217: 247–257
Miettinen M (1992) Neuroendocrine differentiation in adrenocortical carcinoma Now immunohistochemical findings supported by electron microscopy. Lab Invest 66: 169–174
Nobels FRE, Kwekkeboom DJ, Coopmans W, Shoenmakers CHH, Lindemans J, De Herder WW, Krenning EP, Bouillon R and Lamberts SWJ (1997) Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the α-subunit of glicoprotein hormones. J Clin Endocrinol Metab 82: 2622–2628
Nobels FR, Kwekkeboom DJ, Bouillon R and Lamberts SW (1998) Chromogranin A: its clinical value as marker of neuroendocrine tumours. Eur J Clin Invest 28: 431–440
O’Connor DT (1985) Plasma chromogranin A. Initial studies in human hypertension. Hypertension 7: I-76–I-79
O’Connor DT and Bernstein KN (1984) Radioimmunoassay of chromogranin A in lasma as a measure of exocytotic sympathoadrenal activity in normal subjects and patients with pheochromocytoma. N Engl J Med 311: 764–770
O’Connor DT and Deftos LJ (1986) Secretion of chromogranin A by peptide producing endocrine neoplasms. N Engl J Med 314: 1145–1151
O’Connor DT, Frigon RP and Sokoloff RL (1984) Human chromogranin A. Purification and characterization from catecholamine storage vescicles of human pheochromocytoma. Hypertension 6: 2–12
Rosa P and Gerdes HH (1994) The granin protein family markers for neuroendocrine cells and tools for the diagnosis of neuroendocrine tumours. J Endocrinol Invest 17: 207–225
Simon JP and Annis D (1989) Biochemistry of the chromogranin A protein family. Biochem J 262: 1–13
Sobol RE, O’Connor DT, Addison J, Suchocki K, Royston I and Deftos LJ (1986) Elevated serum chromogranin A concentrations in small-cell lung carcinoma. Ann Intern Med 105: 698–700
Sobol RE, Memoli V and Deftos LJ (1989) Hormone-negative, chromogranin A-positive endocrine tumours. N Engl J Med 320: 444–447
Stridsberg M and Husebye ES (1997) Chromogranin A and chromogranin B are sensitive circulating markers for pheochromocytoma. Eur J Endocr 136: 67–73
Strub JM, Goumon Y, Lugardon K, Capon C, Lopez M, Moniatte M, Van Dorsselaer A, Aunis D and Metz-Boutigue MH (1996) Antibacterial activity of glycosylated and phosphorylated chromogranin A-derived peptide 173–194 from bovine adrenal medullary chromaffin granules. J Biol Chem 271: 28540–28553
Syversen U, Jacobsen MB, O’Connor DT, Ronning K and Waldum HL (1994) Immunoassay for measurement of chromogranin A and pancreastin-like immunoreactivity in humans: correspondence in patients with neuroendocrine neoplasia. Neuropeptides 26: 201–206
Totsch M, Muller LC, Hittmair A, Ofner D, Gibbs AR and Schmid KW (1992) Immunohistochemical demonstration of chromogranins A and B in neuroendocrine tumours of the lung. Hum Pathol 23: 312–316
Weiler R, Fleichtinger H, Schmid KW, Fischer-Colbrie R, Grimelius L, Cedermark B, Papotti M, Bussolati G and Winkler H (1987) Chromogranin A and B and secretogranin II in bronchial and intestinal carcinoids. Virchows Arch A 412: 103–109
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Bernini, G., Moretti, A., Ferdeghini, M. et al. A new human chromogranin ‘A’ immunoradiometric assay for the diagnosis of neuroendocrine tumours. Br J Cancer 84, 636–642 (2001). https://doi.org/10.1054/bjoc.2000.1659
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2000.1659