Background: Chromogranin A (CgA) is often used in metastatic patients with nonfunctioning pancreatic neuroendocrine tumors (NF-pNET). The aim of this study is to assess the diagnostic accuracy of CgA in patients with low tumor burden. Methods: Resectable patients with NF-pNET without metastases at time of diagnosis were included between 2002 and 2013 in the Academic Medical Center of Amsterdam. CgA was determined at time of diagnosis and during follow-up according to a standardized method. The upper reference range was 94 µg/l. Results: Overall, 47 patients were included in this study. CgA was elevated preoperatively in only 10 patients (27%). In the detection of metastases during follow-up, the positive predictive value for CgA was 50% and negative predictive value was 81%. In 50% of the patients with an elevated CgA during follow-up, this test result was false-positive. Conclusions: The diagnostic accuracy of CgA was low preoperatively in patients with resectable NF-pNET and low tumor burden. In the detection of recurrent disease after curative resection of NF-pNET, the diagnostic accuracy of CgA was moderate (50%). We conclude that the routine measurement of CgA at time of diagnosis or during follow-up after curative resection had limited value in patients with resectable NF-pNET.

1.
Jensen RT, Cadiot G, Brandi ML, de Herder WW, Kaltsas G, Komminoth P, et al: ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology 2012;95:98-119.
2.
Falconi M, Bartsch DK, Eriksson B, Klöppel G, Lopes JM, O'Connor JM, et al: ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors. Neuroendocrinology 2012;95:120-134.
3.
Lukinius A, Stridsberg M, Wilander E: Cellular expression and specific intragranular localization of chromogranin A, chromogranin B, and synaptophysin during ontogeny of pancreatic islet cells: an ultrastructural study. Pancreas 2003;27:38-46.
4.
Rindi G, Villanacci V, Ubiali A: Biological and molecular aspects of gastroenteropancreatic neuroendocrine tumors. Digestion 2000;62(suppl 1):19-26.
5.
Oberg K: Circulating biomarkers in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer 2011;18(suppl 1):S17-S25.
6.
Kulke MH, Anthony LB, Bushnell DL, de Herder WW, Goldsmith SJ, Klimstra DS, et al: NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas 2010;39:735-752.
7.
Nikou GC, Marinou K, Thomakos P, Papageorgiou D, Sanzanidis V, Nikolaou P, Kosmidis C, Moulakakis A, Mallas E: Chromogranin a levels in diagnosis, treatment and follow-up of 42 patients with non-functioning pancreatic endocrine tumours. Pancreatology 2008;8:510-519.
8.
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;17:2427-2443.
9.
Nehar D, Lombard-Bohas C, Olivieri S, Claustrat B, Chayvialle JA, Penes MC, et al: Interest of Chromogranin A for diagnosis and follow-up of endocrine tumours. Clin Endocrinol (Oxf) 2004;60:644-652.
10.
Belli SH, Oneto A, Aranda C, O'Connor JM, Domenichini E, Roca E, Méndez G, Bestani MC, Parma P, Giacomi N, Marmissolle F: Chromogranin A as a biochemical marker for the management of neuroendocrine tumors: a multicenter study developed in Argentina. Acta Gastroenterol Latinoam 2009;39:184-189.
11.
Sciola V, Massironi S, Conte D, Caprioli F, Ferrero S, Ciafardini C, et al: Plasma chromogranin a in patients with inflammatory bowel disease. Inflamm Bowel Dis 2009;15:867-871.
12.
Sidhu R, McAlindon ME, Leeds JS, Skilling J, Sanders DS: The role of serum chromogranin A in diarrhoea predominant irritable bowel syndrome. J Gastrointestin Liver Dis 2009;18:23-26.
13.
Sanduleanu S, De Bruïne A, Stridsberg M, Jonkers D, Biemond I, Hameeteman W, et al: Serum chromogranin A as a screening test for gastric enterochromaffin-like cell hyperplasia during acid-suppressive therapy. Eur J Clin Invest 2001;31:802-811.
14.
O'Toole D, Grossman A, Gross D, Delle Fave G, Barkmanova J, O'Connor J, et al: ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: biochemical markers. Neuroendocrinology 2009;90:194-202.
15.
Hsiao RJ, Mezger MS, O'Connor DT: Chromogranin A in uremia: progressive retention of immunoreactive fragments. Kidney Int 1990;37:955-964.
16.
Marotta V, Nuzzo V, Ferrara T, Zuccoli A, Masone M, Nocerino L, et al: Limitations of Chromogranin A in clinical practice. Biomarkers 2012;17:186-191.
17.
Khan MO, Ather MH: Chromogranin A - serum marker for prostate cancer. J Pak Med Assoc 2011;61:108-111.
18.
Nobili E, Pezzilli R, Santini D, Campidelli C, Calculli L, Casadei R, et al: Autoimmune pancreatitis associated with high levels of chromogranin a, serotonin and 5-hydroxyindoleacetic acid. Case Rep Gastroenterol 2008;2:11-17.
19.
Levey AS, Coresh J: Chronic kidney disease. Lancet 2012;379:165-180.
20.
Rindi G, Klöppel G, Alhman H, Caplin M, Couvelard A, de Herder WW, et al: TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006;449:395-401.
21.
Bosman FT, Carneiro F, Hruban RH, Theise ND: WHO Classification of Tumours of the Digestive System, ed 4. IARC WHO Classification of Tumours, 2010, vol 3, p 417.
22.
Popovici T, Moreira B, Schlageter MH, Bories PN: Automated two-site immunofluorescent assay for the measurement of serum chromogranin A. Clin Biochem 2014;47:87-91.
23.
Nobels FR, Kwekkeboom DJ, Coopmans W, Schoenmakers CH, Lindemans J, De Herder WW, et al: 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;82:2622-2628.
24.
Ferrari L, Seregni E, Lucignani G, Bajetta E, Martinetti A, Aliberti G, Pallotti F, Procopio G, Della Torre S, Luksch R, Bombardier E: Accuracy and clinical correlates of two different methods for chromogranin A assay in neuroendocrine tumors. Int J Biol Markers 2004;19:295-304.
25.
Nölting S, Kuttner A, Lauseker M, Vogeser M, Haug A, Herrmann KA, et al: Chromogranin a as serum marker for gastroenteropancreatic neuroendocrine tumors: a single center experience and literature review. Cancers (Basel) 2012;4:141-155.
26.
Stridsberg M, Oberg K, Li Q, Engström U, Lundqvist G: Measurements of chromogranin A, chromogranin B (secretogranin I), chromogranin C (secretogranin II) and pancreastatin in plasma and urine from patients with carcinoid tumours and endocrine pancreatic tumours. J Endocrinol 1992;144:49-59.
27.
Campana D, Nori F, Piscitelli L, Morselli-Labate AM, Pezzilli R, Corinaldesi R, Tomassetti P: Chromogranin A: is it a useful marker of neuroendocrine tumors? J Clin Oncol 2007;25:1967-1973.
28.
Seregni E, Ferrari L, Bajetta E, Martinetti A, Bombardieri E: Clinical significance of blood chromogranin A measurement in neuroendocrine tumours. Ann Oncol 2001;12(suppl 2):S69-S72.
29.
Chou WC, Hung YS, Hsu JT, Chen JS, Lu CH, Hwang TL, et al: Chromogranin A is a reliable biomarker for gastroenteropancreatic neuroendocrine tumors in an Asian population of patients. Neuroendocrinology 2012;95:344-350.
30.
Tomassetti P, Migliori M, Simoni P, Casadei R, De Iasio R, Corinaldesi R, Gullo L: Diagnostic value of plasma chromogranin A in neuroendocrine tumours. Eur J Gastroenterol Hepatol 2001;13:55-58.
31.
Zatelli MC, Torta M, Leon A, Ambrosio MR, Gion M, Tomassetti P, et al: Chromogranin A as a marker of neuroendocrine neoplasia: an Italian multicenter study. Endocr Relat Cancer 2007;14:473-482.
32.
de Laat JM, Pieterman CR, Weijmans M, Hermus AR, Dekkers OM, de Herder WW, et al: Low accuracy of tumor markers for diagnosing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 patients. J Clin Endocrinol Metab 2013;98:4143-4151.
33.
Baudin E, Gigliotti A, Ducreux M, Ropers J, Comoy E, Sabourin JC, et al: Neuron-specific enolase and chromogranin A as markers of neuroendocrine tumours. Br J Cancer 1998;78:1102-1107.
34.
Nobels FR, Kwekkeboom DJ, Coopmans W, Schoenmakers CH, Lindemans J, De Herder WW, et al: 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;82:2622-2628.
35.
Stridsberg M, Eriksson B, Oberg K, Janson ET: A comparison between three commercial kits for chromogranin A measurements. J Endocrinol 2003;177:337-341.
36.
Paik WH, Ryu JK, Song BJ, Kim J, Park JK, Kim YT, Yoon YB: Clinical usefulness of plasma chromogranin a in pancreatic neuroendocrine neoplasm. J Korean Med Sci 2013;28:750-754.
37.
Eriksson B, Arnberg H, et al: Chromogranins - new sensitive markers for neuroendocrine tumors. Acta Oncol 1989;28:325-329.
38.
Lee LC, Grant CS, Salomao DR, Fletcher JG, Takahashi N, Fidler JL, et al: Small, nonfunctioning, asymptomatic pancreatic neuroendocrine tumors (PNETs): role for nonoperative management. Surgery 2012;152:965-974.
39.
Bettini R, Partelli S, Boninsegna L, Capelli P, Crippa S, Pederzoli P, et al: Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor. Surgery 2011;150:75-82.
40.
Nikou GC, Marinou K, Thomakos P, Papageorgiou D, Sanzanidis V, Nikolaou P, et al: Chromogranin a levels in diagnosis, treatment and follow-up of 42 patients with non-functioning pancreatic endocrine tumours. Pancreatology 2008;8:510-519.
41.
Abou-Saif A, Gibril F, Ojeaburu JV, Bashir S, Entsuah LK, Asgharian B, Jensen RT: Prospective study of the ability of serial measurements of serum chromogranin A and gastrin to detect changes in tumor burden in patients with gastrinomas. Cancer 2003;98:249-261.
42.
Oberg K: Biochemical diagnosis of neuroendocrine GEP tumor. Yale J Biol Med 1998;70:501-508.
43.
Böttcher J, Hansch A, Pfeil A, Schmidt P, Malich A, Schneeweiss A, et al: Detection and classification of different liver lesions: comparison of Gd-EOB-DTPA-enhanced MRI versus multiphasic spiral CT in a clinical single centre investigation. Eur J Radiol 2013;82:1860-1869.
44.
Metser U, Jones C, Jacks LM, Bernardini MQ, Ferguson S: Identification and quantification of peritoneal metastases in patients with ovarian cancer with multidetector computed tomography: correlation with surgery and surgical outcome. Int J Gynecol Cancer 2011;21:1391-1398.
45.
Yang Z, Tang LH, Klimstra DS: Effect of tumor heterogeneity on the assessment of Ki67 labeling index in well-differentiated neuroendocrine tumors metastatic to the liver: implications for prognostic stratification. Am J Surg Pathol 2011;35:853-860.
46.
Cimitan M, et al: Somatostatin receptor scintigraphy versus chromogranin A assay in the management of patients with neuroendocrine tumors of different types: clinical role. Ann Oncol 2003;14:1135-1141.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.