Skip to main content

Biochemical Testing for Neuroendocrine Tumors

  • Chapter
  • First Online:
Book cover Endocrine Pathology:

Abstract

In this chapter, we focus on the use of biochemical markers for the diagnosis of neuroendocrine tumors (NETs) and exclusion of conditions that masquerade as NETs. In addition, we outline the use of biochemical markers for followup, response to intervention and prognosis. Previous publications have focused only on markers specific to certain tumor types, but the uniqueness of this chapter is that it presents a new approach ranging from biochemical markers that relate to symptomatology, to the use of markers that facilitate decision making with regard to optimizing the choices of therapy from the complex arrays of intervention, The sequence of presentation in this chapter is, first to provide the usual view i.e. biochemical markers of each tumor type and thereafter, the diagnosis of the underlying condition or exclusion thereof and finally, the algorithm for their use from the clinical presentation to the suspected diagnosis and the biochemical markers to monitor progression and therapeutic choice. There is also a specific description of the properties of the most important biochemical markers, and, two complications, bone metastasis and carcinoid heart disease from the biochemical point of view.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Massironi S, Sciola V, Peracchi M, Ciafardini C, Spampatti MP, Conte D (2008) Neuroendocrine tumors of the gastro-entero-pancreatic system. World J Gastroenterol 14:5377–5384

    Article  PubMed  Google Scholar 

  2. Eriksson B, Oberg K, Stridsberg M (2000) Tumor markers in neuroendocrine tumors. Digestion 62(Suppl. 1):33–38

    Article  CAS  PubMed  Google Scholar 

  3. Lamberts SWJ, Hofland LJ, Nobels FRE (2001) Neuroendocrine tumor markers. Front Neuroendocrinol 22:309–339

    Article  CAS  PubMed  Google Scholar 

  4. Vinik A, O'Dorisio T, Woltering E, Go VL (2006) Neuroendocrine tumors: a comprehensive guide to diagnosis and management, 1st edn. Interscience Institute, Inglewood

    Google Scholar 

  5. Vinik A, Moattari AR (1989) Use of somatostatin analog in management of carcinoid syndrome. Dig Dis Sci 34:14S–27S

    Article  CAS  PubMed  Google Scholar 

  6. Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, Caplin M, Delle FG, Kaltsas GA, Krenning EP, Moss SF, Nilsson O, Rindi G, Salazar R, Ruszniewski P, Sundin A (2008) Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 9:61–72

    Article  CAS  PubMed  Google Scholar 

  7. Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM (2008) Bronchopulmonary neuroendocrine tumors. Cancer 113:5–21

    Article  CAS  PubMed  Google Scholar 

  8. Oberg K, Jelic S (2008) Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up. Ann Oncol 19(Suppl. 2):ii102–ii103

    Article  PubMed  Google Scholar 

  9. Stachura T, Strzalka M, Bolt L (2003) Type 1 carcinoids and ECL-cell hyperplasia of the gastric mucosa. Przegl Lek 60:782–788

    PubMed  Google Scholar 

  10. le Roux CW, Patterson M, Vincent RP, Hunt C, Ghatei MA, Bloom SR (2005) Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects. J Clin Endocrinol Metab 90:1068–1071

    Article  PubMed  Google Scholar 

  11. Ariga H, Imai K, Chen C, Mantyh C, Pappas TN, Takahashi T (2008) Does ghrelin explain accelerated gastric emptying in the early stages of diabetes mellitus? Am J Physiol Regul Integr Comp Physiol 294:R1807–R1812

    CAS  PubMed  Google Scholar 

  12. Tsolakis AV, Stridsberg M, Grimelius L, Portela-Gomes GM, Falkmer SE, Waldum HL, Janson ET (2008) Ghrelin immunoreactive cells in gastric endocrine tumors and their relation to plasma ghrelin concentration. J Clin Gastroenterol 42:381–388

    Article  CAS  PubMed  Google Scholar 

  13. de Herder WW, Niederle B, Scoazec JY, Pauwels S, Kloppel G, Falconi M, Kwekkeboom DJ, Oberg K, Eriksson B, Wiedenmann B, Rindi G, O'Toole D, Ferone D (2006) Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology 84:183–188

    Article  PubMed  Google Scholar 

  14. Hirshberg B, Livi A, Bartlett DL, Libutti SK, Alexander HR (2000) Forty-eight-hour fast: the diagnostic test for insulinoma. J Clin Endocrinol Metab 85:3222–3226

    Article  CAS  PubMed  Google Scholar 

  15. Quinkler M, Strelow F, Pirlich M, Rohde W, Biering H, Lochs H, Gerl H, Strasburger CJ, Ventz M (2007) Assessment of suspected insulinoma by 48-hour fasting test: a retrospective monocentric study of 23 cases. Horm Metab Res 39:507–510

    Article  CAS  PubMed  Google Scholar 

  16. Jensen RT, Niederle B, Mitry E, Ramage JK, Steinmuller T, Lewington V, Scarpa A, Sundin A, Perren A, Gross D, O'Connor JM, Pauwels S, Kloppel G (2006) Gastrinoma (duodenal and pancreatic). Neuroendocrinology 84:173–182

    Article  CAS  PubMed  Google Scholar 

  17. Kaltsas GA, Besser GM, Grossman AB (2004) The diagnosis and medical management of advanced neuroendocrine tumors. Endocr Rev 25:458–511

    Article  CAS  PubMed  Google Scholar 

  18. O'Toole D, Salazar R, Falconi M, Kaltsas G, Couvelard A, de Herder WW, Hyrdel R, Nikou G, Krenning E, Vullierme MP, Caplin M, Jensen R, Eriksson B (2006) Rare functioning pancreatic endocrine tumors. Neuroendocrinology 84:189–195

    Article  PubMed  Google Scholar 

  19. Kloppel G (2007) Tumour biology and histopathology of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 21:15–31

    Article  PubMed  Google Scholar 

  20. Bolanowski M, Jarzab B, Handkiewicz-Junak D, Jeziorski A, Kos-Kudla B, Zajecki W (2008) Neuroendocrine tumors of the small intestine and the appendix –anagement guidelines (recommended by The Polish Network of Neuroendocrine Tumors). Endokrynol Pol 59:87–96

    PubMed  Google Scholar 

  21. Tseng WW, Liu CD (2002) Peptide YY and cancer: current findings and potential clinical applications. Peptides 23:389–395

    Article  CAS  PubMed  Google Scholar 

  22. Guller U, Turek J, Eubanks S, DeLong ER, Oertli D, Feldman JM (2006) Detecting pheochromocytoma: defining the most sensitive test. Ann Surg 243:102–107

    Article  PubMed  Google Scholar 

  23. Giovanella L, Squin N, Ghelfo A, Ceriani L (2006) Chromogranin A immunoradiometric assay in diagnosis of pheochromocytoma: comparison with plasma metanephrines and 123I-MIBG scan. Q J Nucl Med Mol Imaging 50:344–347

    CAS  PubMed  Google Scholar 

  24. Bilek R, Safarik L, Ciprova V, Vlcek P, Lisa L (2008) Chromogranin A, a member of neuroendocrine secretory proteins as a selective marker for laboratory diagnosis of pheochromocytoma. Physiol Res 57(Suppl. 1):S171–S179

    CAS  PubMed  Google Scholar 

  25. Klein RD, Lloyd RV, Young WF (2008) Hereditary paraganglioma-pheochromocytoma syndromes. In: Gene reviews

    Google Scholar 

  26. Ageciras-Schimnich A, Preissner CM, Young WF Jr, Singh RJ, Grebe SK (2008) Plasma chromogranin A or urine fractionated metanephrines follow-up testing improves the diagnostic accuracy of plasma fractionated metanephrines for pheochromocytoma. J Clin Endocrinol Metab 93(1):91–95

    Article  Google Scholar 

  27. Young WF Jr (2006) Paragangliomas: clinical overview. Ann N Y Acad Sci 1073:21–29

    Article  CAS  PubMed  Google Scholar 

  28. Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S, Crocetti U, Attard M, Maranghi M, Torlontano M, Filetti S (2007) Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab 92:450–455

    Article  CAS  PubMed  Google Scholar 

  29. Cohen R, Campos JM, Salaun C, Heshmati HM, Kraimps JL, Proye C, Sarfati E, Henry JF, Niccoli-Sire P, Modigliani E (2000) Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d'Etudes des Tumeurs a Calcitonine (GETC). J Clin Endocrinol Metab 85:919–922

    Article  CAS  PubMed  Google Scholar 

  30. Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH (2000) Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 88:1139–1148

    Article  CAS  PubMed  Google Scholar 

  31. Etit D, Faquin WC, Gaz R, Randolph G, DeLellis RA, Pilch BZ (2008) Histopathologic and clinical features of medullary microcarcinoma and C-cell hyperplasia in prophylactic thyroidectomies for medullary carcinoma: a study of 42 cases. Arch Pathol Lab Med 132:1767–1773

    PubMed  Google Scholar 

  32. Elisei R (2008) Routine serum calcitonin measurement in the evaluation of thyroid nodules. Best Pract Res Clin Endocrinol Metab 22:941–953

    Article  CAS  PubMed  Google Scholar 

  33. Scheuba C, Kaserer K, Moritz A, Drosten R, Vierhapper H, Bieglmayer C, Haas O, Niederle B (2008) Sporadic hypercalcitoninemia: clinical and therapeutic consequences. Endocr Relat Cancer

    Google Scholar 

  34. Colombo P, Locatelli F, Travaglini P (2006) Useful and limits of the biochemical markers for the diagnosis of thyroid carcinoma. Ann Ital Chir 77(3):209–214

    PubMed  Google Scholar 

  35. Schley E, Shin S, Nakave AA, Perry R, Vinik AI (2009) Symptomatic isolated C-Cell hyperplasia: masquerading as carcinoid syndrome. Pancreas

    Google Scholar 

  36. Marx SJ, Agarwal SK, Kester MB, Heppner C, Kim YS, Skarulis MC, James LA, Goldsmith PK, Saggar SK, Park SY, Spiegel AM, Burns AL, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Emmert-Buck MR, Guru SC, Manickam P, Crabtree J, Erdos MR, Collins FS, Chandrasekharappa SC (1999) Multiple endocrine neoplasia type 1: clinical and genetic features of the hereditary endocrine neoplasias. Recent Prog Horm Res 54:397–438

    CAS  PubMed  Google Scholar 

  37. Piecha G, Chudek J, Wiecek A (2008) Multiple endocrine neoplasia type 1. Eur J Intern Med 19:99–103

    Article  CAS  PubMed  Google Scholar 

  38. Perry R (2006) Multiple endocrine neoplasia type 1 and MEN II. Diffuse hormonal systems and endocrine tumor syndromes

    Google Scholar 

  39. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr, Marx SJ (2001) Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86:5658–5671

    Article  CAS  PubMed  Google Scholar 

  40. Gertner ME, Kebebew E (2004) Multiple endocrine neoplasia type 2. Curr Treat Options in Oncol 5:315–325

    Article  Google Scholar 

  41. Fialkowski EA, DeBenedetti MK, Moley JF, Bachrach B (2008) RET proto-oncogene testing in infants presenting with Hirschsprung disease identifies 2 new multiple endocrine neoplasia 2A kindreds. J Pediatr Surg 43:188–190

    Article  PubMed  Google Scholar 

  42. Raue F, Frank-Raue K (2007) Multiple endocrine neoplasia type 2: 2007 update. Horm Res 68(Suppl. 5):101–104

    Article  PubMed  Google Scholar 

  43. Vinik AI (2008) Carcinoid syndrome. Diffuse hormonal systems and endocrine tumor syndromes

    Google Scholar 

  44. Cunningham JL, Janson ET, Agarwal S, Grimelius L, Stridsberg M (2008) Tachykinins in endocrine tumors and the carcinoid syndrome. Eur J Endocrinol 159(3):275–282

    Article  CAS  PubMed  Google Scholar 

  45. Won JG, Tseng HS, Yang AH, Tang KT, Jap TS, Lee CH, Lin HD, Burcus N, Pittenger G, Vinik A (2006) Clinical features and morphological characterization of 10 patients with noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS). Clin Endocrinol (Oxf) 65:566–578

    Article  Google Scholar 

  46. Cohen RM (1971) Factors responsible for the carcinoid spectrum. A review. Calif Med 114:1–6

    CAS  PubMed  Google Scholar 

  47. Montenegro F, Lawrence GD, Macon W, Pass C (1980) Metastatic glucagonoma. Improvement after surgical debulking. Am J Surg 139:424–427

    Article  CAS  PubMed  Google Scholar 

  48. Conlon JM (1980) The glucagon-like polypeptides – order out of chaos? Diabetologia 18:85–88

    Article  CAS  PubMed  Google Scholar 

  49. Vinik AI (2004) Glucagonoma syndrome. Diffuse hormonal systems and endocrine tumor syndromes. In: Neuroendocrine tumors: a comprehensive guide to diagnosis and management. Inter Science Institute, Inglewood

    Google Scholar 

  50. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM (2008) The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 93:1526–1540

    Article  CAS  PubMed  Google Scholar 

  51. Taupenot L, Harper KL, O'Connor DT (2003) The chromogranin-secretogranin family. N Engl J Med 348:1134–1149

    Article  CAS  PubMed  Google Scholar 

  52. Nobels FR, Kwekkeboom DJ, Bouillon R, Lamberts SW (1998) Chromogranin A: its clinical value as marker of neuroendocrine tumours. Eur J Clin Invest 28:431–440

    Article  CAS  PubMed  Google Scholar 

  53. Stridsberg M, Eriksson B, Fellstrom B, Kristiansson G, Tiensuu JE (2007) Measurements of chromogranin B can serve as a complement to chromogranin A. Regul Pept 139:80–83

    Article  CAS  PubMed  Google Scholar 

  54. Takiyyuddin MA, Cervenka JH, Hsiao RJ, Barbosa JA, Parmer RJ, O'Connor DT (1990) Chromogranin A. Storage and release in hypertension. Hypertension 15:237–246

    CAS  PubMed  Google Scholar 

  55. Oberg K (1997) Biochemical diagnosis of neuroendocrine GEP tumor. Yale J Biol Med 70:501–508

    CAS  PubMed  Google Scholar 

  56. Nobels FR, Kwekkeboom DJ, Coopmans W, Schoenmakers CH, Lindemans J, de Herder WW, Krenning EP, Bouillon R, Lamberts SW (1997) Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones. J Clin Endocrinol Metab 82:2622–2628

    Article  CAS  PubMed  Google Scholar 

  57. Zatelli MC, Torta M, Leon A, Ambrosio MR, Gion M, Tomassetti P, De BF, Delle FG, Dogliotti L, Ggli Uberti EC (2007) Chromogranin A as a marker of neuroendocrine neoplasia: an Italian Multicenter Study. Endocr Relat Cancer 14:473–482

    Article  CAS  PubMed  Google Scholar 

  58. Panzuto F, Severi C, Cannizzaro R, Falconi M, Angeletti S, Pasquali A, Corleto VD, Annibale B, Buonadonna A, Pederzoli P, Delle FG (2004) 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 27:6–11

    CAS  PubMed  Google Scholar 

  59. Bajetta E, Ferrari L, Martinetti A, Celio L, Procopio G, Artale S, Zilembo N, Di BM, Seregni E, Bombardieri E (1999) Chromogranin A, neuron specific enolase, carcinoembryonic antigen, and hydroxyindole acetic acid evaluation in patients with neuroendocrine tumors. Cancer 86:858–865

    Article  CAS  PubMed  Google Scholar 

  60. Jensen EH, Kvols L, McLoughlin JM, Lewis JM, Alvarado MD, Yeatman T, Malafa M, Shibata D (2007) Biomarkers predict outcomes following cytoreductive surgery for hepatic meta­stases from functional carcinoid tumors. Ann Surg Oncol 14:780–785

    Article  PubMed  Google Scholar 

  61. Stronge RL, Turner GB, Johnston BT, McCance DR, McGinty A, Patterson CC, Ardill JE (2008) A rapid rise in circulating pancreastatin in response to somatostatin analogue therapy is associated with poor survival in patients with neuroendocrine tumours. Ann Clin Biochem 45:560–566

    Article  CAS  PubMed  Google Scholar 

  62. Bloomston M, Al-Saif O, Klemanski D, Pinzone JJ, Martin EW, Palmer B, Guy G, Khabiri H, Ellison EC, Shah MH (2007) Hepatic artery chemoembolization in 122 patients with metastatic carcinoid tumor: lessons learned. J Gastrointest Surg 11:264–271

    Article  PubMed  Google Scholar 

  63. Turner GB, Johnston BT, McCance DR, McGinty A, Watson RG, Patterson CC, Ardill JE (2006) Circulating markers of prognosis and response to treatment in patients with midgut carcinoid tumours. Gut 55:1586–1591

    Article  CAS  PubMed  Google Scholar 

  64. Lipton A, Costa L, Ali S, Demers L (2001) Use of markers of bone turnover for monitoring bone metastases and the response to therapy. Semin Oncol 28:54–59

    Article  CAS  PubMed  Google Scholar 

  65. Brown JE, Cook RJ, Major P, Lipton A, Saad F, Smith M, Lee KA, Zheng M, Hei YJ, Coleman RE (2005) Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 97:59–69

    Article  CAS  PubMed  Google Scholar 

  66. Roberts WC (1997) A unique heart disease associated with a unique cancer: carcinoid heart disease [article online]. Am J Cardiol 80(2):251–256

    Article  CAS  PubMed  Google Scholar 

  67. Fox DJ, Khattar RS (2004) Carcinoid heart disease: presentation, diagnosis, and management. Heart 90:1224–1228

    Article  PubMed  Google Scholar 

  68. Woltering EA, Salvo VA, O'Dorisio TM, Lyons J III, Li G, Zhou Y, Seward JR, Go VL, Vinik AI, Mamikunian P, Mamikunian G (2008) Clinical value of monitoring plasma octreotide levels during chronic octreotide long-acting repeatable therapy in carcinoid patients. Pancreas 37:94–100

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Aaron I. Vinik .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Vinik, A.I., Silva, M.P. (2010). Biochemical Testing for Neuroendocrine Tumors. In: Lloyd, R. (eds) Endocrine Pathology:. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1069-1_26

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-1069-1_26

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4419-1068-4

  • Online ISBN: 978-1-4419-1069-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics