Neuroendocrine Neoplasms of the Gastrointestinal Tract

Matthias Schott

Günter Klöppel

Andreas Raffel

Andreas Saleh

Wolfram Knoefel

Werner Scherbaum

^{Klinik für Endokrinologie, Diabetologie und Rheumatologie, Universitätsklinikum Düsseldorf}

^{Institut für Pathologie, Technische Universität München}

^{Klinik für Allgemein-, Viszeral- und Kinderchirurgie, Universitätsklinikum Düsseldorf}

^{Institut für Radiologie, Universitätsklinikum Düsseldorf}

*Klinik für Endokrinologie, Diabetologie und Rheumatologie, Universitätsklinik Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany, ed.frodlesseud-inu.dem@ttohcs.saihttam, www.endokrines-Tumorzentrum.de

Received 2009 Jun 22; Accepted 2010 Jun 21.

Abstract

Background

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are complex tumors whose incidence is rising and whose treatment requires precise classification and risk stratification.

Method

Selective review of the relevant literature, including recently published guidelines.

Results

GEP-NENs are initially classified by their degree of histological differentiation and their graded cell proliferation (Ki-67 index). In addition, there are GEP-NEN specific TNM staging protocols. The laboratory assessment includes the measurement of general tumor markers (synaptophysin, chromogranin A) as well as specific ones (hormones). The most important imaging technique for diagnosis is octreotide scintigraphy. The surgical treatment of GEP-NEN is based on oncological resection criteria whose aim is to achieve locally radical resection while preserving as much organ function as possible. Metastases, too, may be amenable to resection. The treatment options for unresectable metastases include radiofrequency ablation and chemoembolization, both of which are palliative methods of reducing tumor volume and hormone production. Other chemotherapeutic and nuclear-medical treatments can be applied depending on the extent of metastatic spread, the proliferation index, and the degree of hormone production by the tumor.

Conclusion

The accurate diagnosis and appropriate treatment of GEP-NET currently gives most patients with this tumor a good prognosis, as long as it is discovered early. Early GEP-NETs have a favorable prognosis. Further advances in the diagnosis and treatment of this disease may result from structural changes in patient care, including the establishment of NET centers.

Abstract

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), also known as carcinoids and islet cell tumors, arise from the neuroendocrine cells of the gastroenteropancreatic system. This cell system and its tumors are characterized by the expression of cell-type-specific peptide hormones and general markers (synaptophysin, chromogranin A). All GEP-NENs are included in one common classification. The incidence of these tumors, reported to be 1 to 2 per 100 000 head of population per year (for insulinomas, the reported incidence is around 4 per 1 million persons per year) seems to be on the rise, which is probably due to improvements and intensification of efforts in diagnostic endoscopy (1). As the prevalence of GEP-NENs has increased, so have the questions about their prognosis and treatment. This article aims to give general practitioners a general overview of the classification, prognosis, and treatment of GEP-NENs including practical hints for patient management. A selective literature search was carried out and guidelines from, among others, the European Neuroendocrine Tumor Society (ENETS) were taken into account.

Acknowledgments

Translated from the original German by Kersti Wagstaff, MA.

The authors wish to thank Dr. Andreas Bockisch, Director of the Department of Nuclear Medicine at Essen University Hospital, and Dr. T. D. Pöppel for critical reading of this article and valuable suggestions for improvement, especially in the section on nuclear medicine.

The authors also thank Dr. M. Anlauf of the Institute of Pathology, Düsseldorf University Hospital, for critical reading of the manuscript.

Acknowledgments

Footnotes

Conflict of interest statement

The authors declare that no conflict of interest exists.

Footnotes

References

1. Modlin IM, Oberg K, Chung DC, et al Gastroenteropancreatic neuroendocrine tumors. Lancet Oncol. 2008;9:61–72.[PubMed][Google Scholar]
2. Garbrecht N, Anlauf M, Schmitt A, et al Somatostatin-producing neuroendocrine tumors of the duodenum and pancreas: incidence, types, biological behavior, association with inherited syndromes, and functional activity. Endocr Relat Cancer. 2008;15:229–241.[PubMed][Google Scholar]
3. Moller JE, Connolly HM, Rubin J, Seward JB, Modesto K, Pellikka PAFactors associated with progression of carcinoid heart disease. N Engl J Med. 2003;348:1005–1015.[PubMed][Google Scholar]
4. Williams ED, Sandler MThe classification of carcinoid tumors. Lancet. 1963;1(7275):238–239.[PubMed][Google Scholar]
5. Kloppel G, Rindi G, Anlauf M, Perren A, Komminoth PSite-specific biology and pathology of gastroenteropancreatic neuroendocrine tumors. Virchows Arch. 2007;451(Suppl 1):9–27.[PubMed][Google Scholar]
6. Rindi G, Arnold R, Bosman FT. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, et al., editors. WHO classification of tumors of the digestive system. Lyon: IARC; 2010. [PubMed]
7. Rindi G, Kloppel G, Couvelard A, et al TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2007;451:757–762.[PubMed][Google Scholar]
8. Rindi G, Luinetti O, Cornaggia M, Capella C, Solcia EThree sub-types of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma: a clinicopathologic study. Gastroenterology. 1993;104:994–1006.[PubMed][Google Scholar]
9. O’Toole D, Grossman A, Gross D, et al ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: biochemical markers. Neuroendocrinology. 2009;90:194–202.[PubMed][Google Scholar]
10. Raffel A, Krausch MM, Anlauf M, et al Diffuse nesidioblastosis as a cause of hyperinsulinemic hypoglycemia in adults: a diagnostic and therapeutic challenge. Surgery. 2007;141:179–184.[PubMed][Google Scholar]
11. Sundin A, Vullierme MP, Kaltsas G, Plockinger UENETS consensus guidelines for the standards of care in neuroendocrine tumors: radiological examinations. Neuroendocrinology. 2009;90:167–183.[PubMed][Google Scholar]
12. Dromain C, de BT, Lumbroso J, et al Detection of liver metastases from endocrine tumors: a prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging. J Clin Oncol. 2005;23:70–78.[PubMed][Google Scholar]
13. Buchmann I, Henze M, Engelbrecht S, et al Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2007;34:1617–1626.[PubMed][Google Scholar]
14. Tonelli F, Fratini G, Nesi G, et al Pancreatectomy in multiple endocrine neoplasia type 1-related gastrinomas and pancreatic endocrine neoplasias. Ann Surg. 2006;244:61–70.[Google Scholar]
15. Anlauf M, Garbrecht N, Henopp T, et al Sporadic versus hereditary gastrinomas of the duodenum and pancreas: distinct clinico-pathological and epidemiological features. World J Gastroenterol. 2006;12:5440–5446.[Google Scholar]
16. Anlauf M, Bauersfeld J, Raffel A, et al Insulinomatosis: a multicentric insulinoma disease that frequently causes early recurrent hyperinsulinemic hypoglycemia. Am J Surg Pathol. 2009;33:339–346.[PubMed][Google Scholar]
17. Marrache F, Vullierme MP, Roy C, et al Arterial phase enhancement and body mass index are predictors of response to chemo-embolisation for liver metastases of endocrine tumors. Br J Cancer. 2007;96:49–55.[Google Scholar]
18. Mazzaglia PJ, Berber E, Milas M, Siperstein AELaparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery. 2007;142:10–19.[PubMed][Google Scholar]
19. Rinke A, Muller HH, Schade-Brittinger C, et al Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27:4656–4663.[PubMed][Google Scholar]
20. Plockinger U, Rindi G, Arnold R, et al. Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumors. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS) Neuroendocrinology. 2004;80:394–424.[PubMed]
21. Eriksson B, Annibale B, Bajetta E, et al ENETS consensus guidelines for the standards of care in neuroendocrine tumors: chemotherapy in patients with neuroendocrine tumors. Neuroendocrinology. 2009;90:214–219.[PubMed][Google Scholar]
22. Eriksson B, Kloppel G, Krenning E, et al Consensus guidelines for the management of patients with digestive neuroendocrine tumors—well-differentiated jejunal-ileal tumor/carcinoma. Neuroendocrinology. 2008;87:8–19.[PubMed][Google Scholar]
23. Kwekkeboom DJ, Krenning EP, Lebtahi R, et al ENETS consensus guidelines for the standards of care in neuroendocrine tumors: peptide receptor radionuclide therapy with radiolabeled somatostatin analogs. Neuroendocrinology. 2009;90:220–226.[PubMed][Google Scholar]
24. Kwekkeboom DJ, Teunissen JJ, Bakker WH, et al Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol. 2005;23:2754–2762.[PubMed][Google Scholar]
25. Kwekkeboom DJ, de Herder WW, Kam BL, et al Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–2130.[PubMed][Google Scholar]
26. Pape UF, Berndt U, Muller-Nordhorn J, et al Prognostic factors of long-term outcome in gastroenteropancreatic neuroendocrine tumors. Endocr Relat Cancer. 2008;15:1083–1097.[PubMed][Google Scholar]
27. Jacobsen MB, Nitter-Hauge S, Bryde PE, Hanssen LECardiac manifestations in mid-gut carcinoid disease. Eur Heart J. 1995;16:263–268.[PubMed][Google Scholar]
28. Rindi G, Kloppel G, Alhman H, et al TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2006;449:395–401.[Google Scholar]
29. Rindi G, Luinetti O, Cornaggia M, Capella C, Solcia EThree subtypes of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma: a clinicopathologic study. Gastroenterology. 1993;104:994–1006.[PubMed][Google Scholar]
30. Anderson MA, Carpenter S, Thompson NW, Nostrant TT, Elta GH, Scheiman JMEndoscopic ultrasound is highly accurate and directs management in patients with neuroendocrine tumors of the pancreas. Am J Gastroenterol. 2000;95:2271–2277.[PubMed][Google Scholar]
31. Krenning EP, Kwekkeboom DJ, Bakker WH, et al Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med. 1993;20:716–731.[PubMed][Google Scholar]
32. Boy C, Heusner A, Müller M, et al Normal values in Ga-68-DOTATOC PET/CT-imaging. Nuklearmedizin. 2009 abstract. [PubMed][Google Scholar]
33. Koopmans KP, Neels ON, Kema IP, et al Molecular imaging in neuroendocrine tumors: Molecular uptake mechanisms and clinical results. Clin Rev Oncol Hematol. 2009;71:199–213.[PubMed][Google Scholar]
34. Gabriel M, Decristoforo C, Kendler D, et al 68Ga-DOTA-Tyr3-Octreotide PET in neurondocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J Nucl Med. 2007;48:508–518.[PubMed][Google Scholar]
35. de BT, Deschamps F, Teriitheau C, et al Transarterial chemoembolization of liver metastases from well differentiated gastroenteropancreatic endocrine tumors with doxorubicin-eluting beads: preliminary results. J Vasc Interv Radiol. 2008;19:855–861.[PubMed][Google Scholar]
36. Yao JC, Shah MH, Ito T, et al Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514–523.[Google Scholar]
37. Raymond E, Dahan L, Raoul JL, et al Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501–513.[PubMed][Google Scholar]
38. Ahlman H, Nilsson O, McNicol AM, et al Poorly-differentiated endocrine carcinomas of midgut and hindgut origin. Neuroendocrinology. 2008;87:40–46.[PubMed][Google Scholar]