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This review summarizes current data on neuroendocrine tumors (NET), which, unlike other neoplasms, are able to produce biologically active substances (hormones, vasoactive peptides, amines). It is exactly their main characteristic that allows to unify this heterogeneous group and that may determine their clinical course. We present integrated recommendations for biochemical diagnosis and confirmation of over-secretion syndromes based on a  panel assessment of NET biochemical markers. Data from the literature are reviewed on evaluation of clinical significance of generic and specific NET markers, as well as the results of the studies performed by the authors themselves. Three hundred and thirty patients were examined with NETs of various localization (pancreas, stomach, small intestine and large intestine, lungs) and with metastatic NET disease with unknown primary location, who were treated in the N.N. Blokhin Russian Cancer Research Center. The control group included 115 healthy individuals. Before and during the treatment, plasma and serum chromogranin A (CgA) and serotonin levels, as well as 5-hydroxyindoleacetic acid (5-HIAA) in a  24-hour urine sample were measured with standardized immunoenzyme plate-based assays (“Chromogranin A ELISA kit”, Dako A/S; “Serotonin ELISA and 5-HIAA ELISA”, IBL International GMBH). We evaluated clinical importance of CgA as a generic NET marker, as well as that of serotonin and its metabolite 5-HIAA as specific markers of the carcinoid syndrome. CgA was shown to be the most efficient biochemical marker for diagnosis, assessment of prevalence and monitoring of NETs. CgA has a  high diagnostic sensitivity (63.4 to 88.9%) in various NETs. An association between CgA secretion and prevalence and biological activity of the tumor was confirmed. CgA measurement is particularly important in functionally inactive tumors, where serotonin and 5-HIAA have lower sensitivity, being specific markers of the carcinoid syndrome.

About the authors

N. V. Lyubimova

N.N. Blokhin Russian Cancer Research Center

Author for correspondence.

Doctor of Biol. Sci., Professor, Leading Research Fellow, Laboratory of Clinical Biochemistry,

24 Kashirskoe shosse, Moscow, 115478

Russian Federation

N. E. Kushlinskii

N.N. Blokhin Russian Cancer Research Center


MD, PhD, Professor, Correspondent Member of Russian Academy of Sciences, Head of Laboratory of Clinical Biochemistry,

24 Kashirskoe shosse, Moscow, 115478

Russian Federation


  1. Кушлинский НЕ, Любимова НВ. Биохимические маркеры в диагностике нейроэндокринных опухолей. Клиническая лабораторная диагностика. 2014;59(7):4–11.
  2. O'Toole D, Grossman A, Gross D, Delle Fave G, Barkmanova J, O'Connor J, Pape UF, Plöckinger U; Mallorca Consensus Conference participants; European Neuroendocrine Tumor Society. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: biochemical markers. Neuroendocrinology. 2009;90(2):194–202. doi: 10.1159/000225948.
  3. Modlin IM, Latich I, Zikusoka M, Kidd M, Eick G, Chan AK. Gastrointestinal carcinoids: the evolution of diagnostic strategies. J Clin Gastroenterol. 2006;40(7):572–82.
  4. Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, Caplin M, Delle Fave G, Kaltsas GA, Krenning EP, Moss SF, Nilsson O, Rindi G, Salazar R, Ruszniewski P, Sundin A. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9(1):61–72. doi: 10.1016/S1470-2045(07)70410-2.
  5. Ardill JE. Circulating markers for endocrine tumours of the gastroenteropancreatic tract. Ann Clin Biochem. 2008;45(Pt 6):539–59. doi: 10.1258/acb.2008.008039.
  6. Oberg K. Circulating biomarkers in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer. 2011;18 Suppl 1:S17–25. doi: 10.1530/ERC-10-0280.
  7. Ramage JK, Davies AH, Ardill J, Bax N, Caplin M, Grossman A, Hawkins R, McNicol AM, Reed N, Sutton R, Thakker R, Aylwin S, Breen D, Britton K, Buchanan K, Corrie P, Gillams A, Lewington V, McCance D, Meeran K, Watkinson A; UKNETwork for Neuroendocrine Tumours. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut. 2005;54 Suppl 4:iv1–16. doi: 10.1136/gut.2004.053314.
  8. Aunis D, Metz-Boutigue MH. Chromogranins: current concepts. Structural and functional aspects. Adv Exp Med Biol. 2000;482:21–38. doi: 10.1007/0-306-46837-9_2.
  9. Bílek R, Safarík L, Ciprová V, Vlcek P, Lisá L. Chromogranin A, a member of neuroendocrine secretory proteins as a selective marker for laboratory diagnosis of pheochromocytoma. Physiol Res. 2008;57 Suppl 1:S171–9.
  10. 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(15):1967–73. doi: 10.1200/JCO.2006.10.1535.
  11. 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(9):2427–43. doi: 10.1245/s10434-010-1006-3.
  12. Singh S, Law C. Chromogranin A: a sensitive biomarker for the detection and post-treatment monitoring of gastroenteropancreatic neuroendocrine tumors. Expert Rev Gastroenterol Hepatol. 2012;6(3):313–34. doi: 10.1586/egh.12.15.
  13. Stivanello M, Berruti A, Torta M, Termine A, Tampellini M, Gorzegno G, Angeli A, Dogliotti L. Circulating chromogranin A in the assessment of patients with neuroendocrine tumours. A single institution experience. Ann Oncol. 2001;12 Suppl 2:S73–7.
  14. 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(1):55–8.
  15. Vinik AI, Silva MP, Woltering EA, Go VL, Warner R, Caplin M. Biochemical testing for neuroendocrine tumors. Pancreas. 2009;38(8):876–89. doi: 10.1097/MPA.0b013e3181bc0e77.
  16. Zatelli MC, Torta M, Leon A, Ambrosio MR, Gion M, Tomassetti P, De Braud F, Delle Fave G, Dogliotti L, degli Uberti EC; Italian CromaNet Working Group. Chromogranin A as a marker of neuroendocrine neoplasia: an Italian Multicenter Study. Endocr Relat Cancer. 2007;14(2):473–82. doi: 10.1677/ERC-07-0001.
  17. Panzuto F, Severi C, Cannizzaro R, Falconi M, Angeletti S, Pasquali A, Corleto VD, Annibale B, Buonadonna A, Pederzoli P, Delle Fave G. Utility of combined use of plasma levels of chromogranin A and pancreatic polypeptide in the diagnosis of gastrointestinal and pancreatic endocrine tumors. J Endocrinol Invest. 2004;27(1):6–11.
  18. 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(4–5):510–9. doi: 10.1159/000152000.
  19. Welin S, Stridsberg M, Cunningham J, Granberg D, Skogseid B, Oberg K, Eriksson B, Janson ET. Elevated plasma chromogranin A is the first indication of recurrence in radically operated midgut carcinoid tumors. Neuroendocrinology. 2009;89(3):302–7. doi: 10.1159/000179900.
  20. Janson ET, Holmberg L, Stridsberg M, Eriksson B, Theodorsson E, Wilander E, Oberg K. Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center. Ann Oncol. 1997;8(7):685–90.
  21. Vinik E, Silva MP, Vinik AI. Measuring the relationship of quality of life and health status, including tumor burden, symptoms, and biochemical measures in patients with neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011;40(1):97–109, viii. doi: 10.1016/j.ecl.2010.12.008.
  22. Massironi S, Conte D, Sciola V, Spampatti MP, Ciafardini C, Valenti L, Rossi RE, Peracchi M. Plasma chromogranin A response to octreotide test: prognostic value for clinical outcome in endocrine digestive tumors. Am J Gastroenterol. 2010;105(9):2072–8. doi: 10.1038/ajg.2010.154.
  23. Pirker RA, Pont J, Pöhnl R, Schütz W, Griesmacher A, Müller MM. Usefulness of chromogranin A as a marker for detection of relapses of carcinoid tumours. Clin Chem Lab Med. 1998;36(11):837–40. doi: 10.1515/CCLM.1998.147.
  24. Braga F, Ferraro S, Mozzi R, Dolci A, Panteghini M. Biological variation of neuroendocrine tumor markers chromogranin A and neuron-specific enolase. Clin Biochem. 2013;46(1–2):148–51. doi: 10.1016/j.clinbiochem.2012.09.005.
  25. Walter T, Chardon L, Chopin-laly X, Raverot V, Caffin AG, Chayvialle JA, Scoazec JY, Lombard-Bohas C. Is the combination of chromogranin A and pancreatic polypeptide
  26. serum determinations of interest in the diagnosis and follow-up of gastro-entero-pancreatic neuroendocrine tumours? Eur J Cancer. 2012;48(12):1766–73. doi: 10.1016/j.ejca.2011.11.005.
  27. Nehar D, Lombard-Bohas C, Olivieri S, Claustrat B, Chayvialle JA, Penes MC, Sassolas G, Borson-Chazot F. Interest of Chromogranin A for diagnosis and follow-up of endocrine tumours. Clin Endocrinol (Oxf). 2004;60(5):644–52. doi: 10.1111/j.1365-2265.2004.02030.x.
  28. Lesurtel M, Soll C, Graf R, Clavien PA. Role of serotonin in the hepato-gastroIntestinal tract: an old molecule for new perspectives. Cell Mol Life Sci. 2008;65(6):940–52. doi: 10.1007/s00018-007-7377-3.
  29. Louthan O. Chromogranin A in physiology and oncology. Folia Biol (Praha). 2011;57(5): 173–81.
  30. Kema IP, de Vries EG, Muskiet FA. Measurement of 5-HIAA in urine. Ann Clin Biochem. 1995;32(Pt 1):102–4.
  31. Любимова НВ, Кушлинский НЕ. Биохимические маркеры нейроэндокринных опухолей. Вопросы биологической, медицинской и фармацевтической химии. 2014;12(1): 48–58.

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Copyright (c) 2016 Lyubimova N.V., Kushlinskii N.E.

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