Cancer and Metastasis Reviews

, Volume 30, Supplement 1, pp 3–7 | Cite as

Current knowledge on diagnosis and staging of neuroendocrine tumors

  • Kjell ÖbergEmail author
  • Daniel Castellano


Neuroendocrine tumors (NETs) consist of a heterogeneous group of malignancies with various clinical presentations and growth rates. The incidence has been estimated to 2.5–5 per 100,000 people per year and prevalence of 35 per 100,000. The largest group is the gastroenteropancreatic NETs. Small intestinal NETs are the most common followed by pancreatic NETs in the gastrointestinal tract. A classification system (World Health Organization) was established in year 2000 and recently updated in 2010, taking into consideration the histopathology and tumor biology of the tumors. To further refine the classification a “tumor node metastasis” staging has been suggested by the European Neuroendocrine Tumor Society. The same organization has also proposed a grading system (G1, G2, and G3). The diagnosis of a NET is based on histopathology on tumor specimens, circulating biomarkers as well as imaging. Traditional radiology, such as computerized tomography and magnetic resonance imaging, is still the basis but is complemented with somatostatin receptor scintigraphy and positron emission tomography with specific isotopes such 68Ga-DOTA-octreotate, F18-dopamine, or C11-5 hydroxytryptamine. Molecular imaging will increase in importance in the near future. There is still an unmet need for more sensitive biomarkers for diagnosis and follow-up.


Neuroendocrine tumor GEP-NETs WHO classification TNM staging Molecular imaging Biomarkers 



The authors acknowledge Dr. Fernando Sánchez-Barbero from HealthCo SL (Madrid, Spain) for his assistance in the preparation of this manuscript and Pfizer Spain for the financial support of medical writing services.

Conflicts of interest

The authors declare that they do not have any conflict of interest that may influence this work.


  1. 1.
    Lubarsch, O. (1867). Ueber den primaren Krebs des Ileum, nebst Bemerkungen über das gleichzeitige Vorkommen von Krebs und Tuberkuolose. Virchow Archiv Pathol Anatom Physiol Klin Med, 111, 280–317.CrossRefGoogle Scholar
  2. 2.
    Modlin, I. M., Oberg, K., Chung, D. C., et al. (2008). Gastroenteropancreatic neuroendocrine tumours. The Lancet Oncology, 9(1), 61–72.PubMedCrossRefGoogle Scholar
  3. 3.
    Modlin, I. M., Lye, K. D., & Kidd, M. (2003). A 5-decade analysis of 13,715 carcinoid tumors. Cancer, 97(4), 934–59.PubMedCrossRefGoogle Scholar
  4. 4.
    Modlin, I. M., Kidd, M., Latich, I., et al. (2005). Current status of gastrointestinal carcinoids. Gastroenterology, 128(6), 1717–51.PubMedCrossRefGoogle Scholar
  5. 5.
    Oberg, K. (2005). Somatostatin-receptor mediated diagnosis and treatment in gastrointestinal neuroendocrine tumours (GEP-NET’s). Roczniki Akademii Medycznej w Bialymstoku, 50, 62–8.PubMedGoogle Scholar
  6. 6.
    Reubi, J. C., & Waser, B. (2003). Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. European Journal of Nuclear Medicine and Molecular Imaging, 30(5), 781–93.PubMedCrossRefGoogle Scholar
  7. 7.
    Guillemin, R. (2005). Hypothalamic hormones a.k.a. hypothalamic releasing factors. The Journal of Endocrinology, 184(1), 11–28.PubMedCrossRefGoogle Scholar
  8. 8.
    Oberg, K. E., Reubi, J. C., Kwekkeboom, D. J., et al. (2010). Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. Gastroenterology, 139(3), 742–53. 753 e1.PubMedCrossRefGoogle Scholar
  9. 9.
    Welin, S. V., Janson, E. T., Sundin, A., et al. (2004). High-dose treatment with a long-acting somatostatin analogue in patients with advanced midgut carcinoid tumours. European Journal of Endocrinology, 151(1), 107–12.PubMedCrossRefGoogle Scholar
  10. 10.
    Waldherr, C., Pless, M., Maecke, H. R., et al. (2002). Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq (90)Y-DOTATOC. Journal of Nuclear Medicine, 43(5), 610–6.PubMedGoogle Scholar
  11. 11.
    Oberg, K. (1999). Neuroendocrine gastrointestinal tumors—a condensed overview of diagnosis and treatment. Annals of Oncology, 10(Suppl 2), S3–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Stridsberg, M., Eriksson, B., Oberg, K., et al. (2003). A comparison between three commercial kits for chromogranin A measurements. The Journal of Endocrinology, 177(2), 337–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Eriksson, B., Arnberg, H., Oberg, K., et al. (1989). Chromogranins—new sensitive markers for neuroendocrine tumors. Acta Oncológica, 28(3), 325–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Leja, J., Essaghir, A., Essand, M., et al. (2009). Novel markers for enterochromaffin cells and gastrointestinal neuroendocrine carcinomas. Modern Pathology, 22(2), 261–72.PubMedCrossRefGoogle Scholar
  15. 15.
    Duerr, E. M., Mizukami, Y., Ng, A., et al. (2008). Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis. Endocr Relat Cancer, 15(1), 243–56.PubMedCrossRefGoogle Scholar
  16. 16.
    Kloppel, G., Perren, A., & Heitz, P. U. (2004). The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Annals of the New York Academy of Sciences, 1014, 13–27.PubMedCrossRefGoogle Scholar
  17. 17.
    Ekeblad, S., Skogseid, B., Dunder, K., et al. (2008). Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clinical Cancer Research, 14(23), 7798–803.PubMedCrossRefGoogle Scholar
  18. 18.
    Rindi, G., Kloppel, G., Alhman, H., et al. (2006). TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Archiv, 449(4), 395–401.PubMedCrossRefGoogle Scholar
  19. 19.
    Rindi, G., Kloppel, G., Couvelard, A., et al. (2007). TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Archiv, 451(4), 757–62.PubMedCrossRefGoogle Scholar
  20. 20.
    Fischer, L., Kleeff, J., Esposito, I., et al. (2008). Clinical outcome and long-term survival in 118 consecutive patients with neuroendocrine tumours of the pancreas. The British Journal of Surgery, 95(5), 627–35.PubMedCrossRefGoogle Scholar
  21. 21.
    Pape, U. F., Jann, H., Muller-Nordhorn, J., et al. (2008). Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer, 113(2), 256–65.PubMedCrossRefGoogle Scholar
  22. 22.
    Eriksson, B., Oberg, K., & Stridsberg, M. (2000). Tumor markers in neuroendocrine tumors. Digestion, 62(Suppl 1), 33–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Oberg, K., Janson, E. T., & Eriksson, B. (1999). Tumour markers in neuroendocrine tumours. Italian Journal of Gastroenterology and Hepatology, 31(Suppl 2), S160–2.PubMedGoogle Scholar
  24. 24.
    Leja, J., Nilsson, B., Yu, D., et al. (2010). Double-detargeted oncolytic adenovirus shows replication arrest in liver cells and retains neuroendocrine cell killing ability. PLoS ONE, 5(1), e8916.PubMedCrossRefGoogle Scholar
  25. 25.
    Modlin, I. M., Gustafsson, B. I., & Kidd, M. (2007). Gastrointestinal carcinoid tumors. In C. W. Howden, J. Baillie, A. L. Buchman, D. C. Metz, & I. M. Modlin (Eds.), Advances in digestive disease (pp. 203–218). Bethesda: AGA Institute Press.Google Scholar
  26. 26.
    Anderson, M. A., Carpenter, S., Thompson, N. W., et al. (2000). Endoscopic ultrasound is highly accurate and directs management in patients with neuroendocrine tumors of the pancreas. The American Journal of Gastroenterology, 95(9), 2271–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Gibril, F., Reynolds, J. C., Doppman, J. L., et al. (1996). Somatostatin receptor scintigraphy: its sensitivity compared with that of other imaging methods in detecting primary and metastatic gastrinomas. A prospective study. Annals of Internal Medicine, 125(1), 26–34.PubMedGoogle Scholar
  28. 28.
    Adams, S., Baum, R., Rink, T., et al. (1998). Limited value of fluorine-18 fluorodeoxyglucose positron emission tomography for the imaging of neuroendocrine tumours. European Journal of Nuclear Medicine, 25(1), 79–83.PubMedGoogle Scholar
  29. 29.
    Koopmans, K. P., de Vries, E. G., Kema, I. P., et al. (2006). Staging of carcinoid tumours with 18F-DOPA PET: a prospective, diagnostic accuracy study. The Lancet Oncology, 7(9), 728–34.PubMedCrossRefGoogle Scholar
  30. 30.
    Orlefors, H., Sundin, A., Garske, U., et al. (2005). Whole-body (11)C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and computed tomography. The Journal of Clinical Endocrinology and Metabolism, 90(6), 3392–400.PubMedCrossRefGoogle Scholar
  31. 31.
    Koukouraki, S., Strauss, L. G., Georgoulias, V., et al. (2006). Evaluation of the pharmacokinetics of 68Ga-DOTATOC in patients with metastatic neuroendocrine tumours scheduled for 90Y-DOTATOC therapy. European Journal of Nuclear Medicine and Molecular Imaging, 33(4), 460–6.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Endocrine OncologyUppsala University HospitalUppsalaSweden
  2. 2.Medical Oncology DepartmentUniversity Hospital 12 de OctubreMadridSpain

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