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Pathology, classification, and grading of neuroendocrine tumors arising in the digestive system

David S Klimstra, MD
Zhaohai Yang, MD, PhD
Section Editor
Richard M Goldberg, MD
Deputy Editor
Diane MF Savarese, MD


Neuroendocrine cells are distributed widely throughout the body. Neuroendocrine neoplasms, defined as epithelial neoplasms with predominant neuroendocrine differentiation, can arise in most organs. While some clinical and pathologic features of these tumors are unique to the site of origin, other characteristics are shared, regardless of site.

The classification and nomenclature of neuroendocrine neoplasms is complex and confusing, in part because most studies have focused on tumors arising in a specific organ system. Site-specific proposals for nomenclature and classification differ in terminology and in the criteria for histologic grading and staging, and this has led to morphologically similar neuroendocrine neoplasms being designated differently, depending on the site of origin. For now, there is no one single system of nomenclature, grading, or staging that is suitable for neuroendocrine neoplasms at all anatomic sites. However, features such as the proliferative rate of the tumor and the extent of local spread are shared by most classification systems.

Neuroendocrine neoplasms of the digestive system arising in the tubular gastrointestinal (GI) tract and the pancreas are relatively rare. The annual incidence in the United States is about 3.65 per 100,000 population [1]. The incidence has been rising over time. (See "Clinical characteristics of carcinoid tumors", section on 'Epidemiology'.)

The terminology of gastroenteropancreatic (GEP) neuroendocrine neoplasms has evolved over the past two decades to reflect a separation into two major categories:

Well-differentiated neuroendocrine tumors (NETs) show a solid, trabecular, gyriform, or glandular pattern, with fairly uniform nuclei, salt-and-pepper chromatin, and finely granular cytoplasm. These tumors were traditionally referred to as carcinoid and pancreatic neuroendocrine (islet cell) tumors. Although carcinoid tumors and pancreatic NETs may have similar characteristics on routine histologic evaluation, they have a different pathogenesis and biology.


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Literature review current through: Sep 2016. | This topic last updated: Oct 16, 2015.
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  1. Lawrence B, Gustafsson BI, Chan A, et al. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 2011; 40:1.
  2. Gustafsson BI, Kidd M, Chan A, et al. Bronchopulmonary neuroendocrine tumors. Cancer 2008; 113:5.
  3. Ramage JK, Davies AH, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut 2005; 54 Suppl 4:iv1.
  4. Washington MK, Tang LH, Berlin J, et al. Protocol for the examination of specimens from patients with neuroendocrine tumors (carcinoid tumors) of the small intestine and ampulla. Arch Pathol Lab Med 2010; 134:181.
  5. Washington MK, Tang LH, Berlin J, et al. Protocol for the examination of specimens from patients with neuroendocrine tumors (carcinoid tumors) of the colon and rectum. Arch Pathol Lab Med 2010; 134:176.
  6. College of American Pathologists protocol for examination of specimens from patients with carcinoma of the endocrine pancreas available online at http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2009/PancreasEndo_09protocol.pdf (Accessed on August 29, 2011).
  7. Klöppel G. Oberndorfer and his successors: from carcinoid to neuroendocrine carcinoma. Endocr Pathol 2007; 18:141.
  8. WILLIAMS ED, SANDLER M. The classification of carcinoid tum ours. Lancet 1963; 1:238.
  9. Soga J, Tazawa K. Pathologic analysis of carcinoids. Histologic reevaluation of 62 cases. Cancer 1971; 28:990.
  10. Capella C, Heitz PU, Höfler H, et al. Revised classification of neuroendocrine tumours of the lung, pancreas and gut. Virchows Arch 1995; 425:547.
  11. Heymann MF, Joubert M, Nemeth J, et al. Prognostic and immunohistochemical validation of the capella classification of pancreatic neuroendocrine tumours: an analysis of 82 sporadic cases. Histopathology 2000; 36:421.
  12. La Rosa S, Sessa F, Capella C, et al. Prognostic criteria in nonfunctioning pancreatic endocrine tumours. Virchows Arch 1996; 429:323.
  13. Solcia E, Capella C, Kloeppel G. Tumors of the pancreas. In: Atlas of tumor pathology, Rosai J, Sobin LH (Eds), AFIP, Washington, DC 1997. p.262.
  14. Klöppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci 2004; 1014:13.
  15. Schindl M, Kaczirek K, Kaserer K, Niederle B. Is the new classification of neuroendocrine pancreatic tumors of clinical help? World J Surg 2000; 24:1312.
  16. Ferrone CR, Tang LH, Tomlinson J, et al. Determining prognosis in patients with pancreatic endocrine neoplasms: can the WHO classification system be simplified? J Clin Oncol 2007; 25:5609.
  17. Ekeblad S, Skogseid B, Dunder K, et al. Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clin Cancer Res 2008; 14:7798.
  18. Formica V, Wotherspoon A, Cunningham D, et al. The prognostic role of WHO classification, urinary 5-hydroxyindoleacetic acid and liver function tests in metastatic neuroendocrine carcinomas of the gastroenteropancreatic tract. Br J Cancer 2007; 96:1178.
  19. Rindi G, Klöppel G, Alhman H, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006; 449:395.
  20. Rindi G, Klöppel 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.
  21. American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010.
  22. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas 2010; 39:707.
  23. Rindi G, Arnold R, Bosman FT, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: WHO Classification of Tumours of the Digestive System, 4th ed, Bosman TF, Carneiro F, Hruban RH, Theise ND (Eds), International Agency for Research on cancer (IARC), Lyon 2010. p.13.
  24. Hruban RH, Pitman MB, Klimstra DS. Tumors of the pancreas, ARP/AFIP, Washington, DC 2007. p.422.
  25. Basturk O, Yang Z, Tang LH, et al. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol 2015; 39:683.
  26. Sorbye H, Welin S, Langer SW, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol 2013; 24:152.
  27. Rindi G, Falconi M, Klersy C, et al. TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst 2012; 104:764.
  28. Jann H, Roll S, Couvelard A, et al. Neuroendocrine tumors of midgut and hindgut origin: tumor-node-metastasis classification determines clinical outcome. Cancer 2011; 117:3332.
  29. La Rosa S, Inzani F, Vanoli A, et al. Histologic characterization and improved prognostic evaluation of 209 gastric neuroendocrine neoplasms. Hum Pathol 2011; 42:1373.
  30. Pape UF, Jann H, Müller-Nordhorn J, et al. Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer 2008; 113:256.
  31. Strosberg J, Nasir A, Coppola D, et al. Correlation between grade and prognosis in metastatic gastroenteropancreatic neuroendocrine tumors. Hum Pathol 2009; 40:1262.
  32. 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.
  33. Panzuto F, Boninsegna L, Fazio N, et al. Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. J Clin Oncol 2011; 29:2372.
  34. Strosberg JR, Cheema A, Weber J, et al. Prognostic validity of a novel American Joint Committee on Cancer Staging Classification for pancreatic neuroendocrine tumors. J Clin Oncol 2011; 29:3044.
  35. Dolcetta-Capuzzo A, Villa V, Albarello L, et al. Gastroenteric neuroendocrine neoplasms classification: comparison of prognostic models. Cancer 2013; 119:36.
  36. Strosberg JR, Weber JM, Feldman M, et al. Prognostic validity of the American Joint Committee on Cancer staging classification for midgut neuroendocrine tumors. J Clin Oncol 2013; 31:420.
  37. Travis WD. The concept of pulmonary neuroendocrine tumours. In: Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart, Travis WD, et al (Eds), IARC Press, Lyon, France 2004. p.19.
  38. Travis WD, Rush W, Flieder DB, et al. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 1998; 22:934.
  39. Moran CA, Suster S. Neuroendocrine carcinomas (carcinoid tumor) of the thymus. A clinicopathologic analysis of 80 cases. Am J Clin Pathol 2000; 114:100.
  40. Hochwald SN, Zee S, Conlon KC, et al. Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. J Clin Oncol 2002; 20:2633.
  41. Voss SM, Riley MP, Lokhandwala PM, et al. Mitotic count by phosphohistone H3 immunohistochemical staining predicts survival and improves interobserver reproducibility in well-differentiated neuroendocrine tumors of the pancreas. Am J Surg Pathol 2015; 39:13.
  42. Brown DC, Gatter KC. Ki67 protein: the immaculate deception? Histopathology 2002; 40:2.
  43. Yerushalmi R, Woods R, Ravdin PM, et al. Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol 2010; 11:174.
  44. von Herbay A, Sieg B, Schürmann G, et al. Proliferative activity of neuroendocrine tumours of the gastroenteropancreatic endocrine system: DNA flow cytometric and immunohistological investigations. Gut 1991; 32:949.
  45. Pelosi G, Bresaola E, Bogina G, et al. Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin sections is an independent predictor for malignancy: a comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index, and other clinicopathologic variables. Hum Pathol 1996; 27:1124.
  46. La Rosa S, Klersy C, Uccella S, et al. Improved histologic and clinicopathologic criteria for prognostic evaluation of pancreatic endocrine tumors. Hum Pathol 2009; 40:30.
  47. Ohike N, Morohoshi T. Pathological assessment of pancreatic endocrine tumors for metastatic potential and clinical prognosis. Endocr Pathol 2005; 16:33.
  48. Pape UF, Berndt U, Müller-Nordhorn J, et al. Prognostic factors of long-term outcome in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer 2008; 15:1083.
  49. Klimstra DS, Modlin IR, Adsay NV, et al. Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set. Am J Surg Pathol 2010; 34:300.
  50. Couvelard A, Deschamps L, Ravaud P, et al. Heterogeneity of tumor prognostic markers: a reproducibility study applied to liver metastases of pancreatic endocrine tumors. Mod Pathol 2009; 22:273.
  51. Lejeune M, Jaén J, Pons L, et al. Quantification of diverse subcellular immunohistochemical markers with clinicobiological relevancies: validation of a new computer-assisted image analysis procedure. J Anat 2008; 212:868.
  52. López C, Lejeune M, Salvadó MT, et al. Automated quantification of nuclear immunohistochemical markers with different complexity. Histochem Cell Biol 2008; 129:379.
  53. Tang LH, Gonen M, Hedvat C, et al. Objective quantification of the Ki67 proliferative index in neuroendocrine tumors of the gastroenteropancreatic system: a comparison of digital image analysis with manual methods. Am J Surg Pathol 2012; 36:1761.
  54. McCall CM, Shi C, Cornish TC, et al. Grading of well-differentiated pancreatic neuroendocrine tumors is improved by the inclusion of both Ki67 proliferative index and mitotic rate. Am J Surg Pathol 2013; 37:1671.
  55. Deshpande V, Fernandez-del Castillo C, Muzikansky A, et al. Cytokeratin 19 is a powerful predictor of survival in pancreatic endocrine tumors. Am J Surg Pathol 2004; 28:1145.
  56. Zhang L, Smyrk TC, Oliveira AM, et al. KIT is an independent prognostic marker for pancreatic endocrine tumors: a finding derived from analysis of islet cell differentiation markers. Am J Surg Pathol 2009; 33:1562.
  57. Basturk O, Tang L, Hruban RH, et al. Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol 2014; 38:437.
  58. Shia J, Tang LH, Weiser MR, et al. Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity? Am J Surg Pathol 2008; 32:719.
  59. Vélayoudom-Céphise FL, Duvillard P, Foucan L, et al. Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr Relat Cancer 2013; 20:649.
  60. Scoazec JY, Couvelard A, Monges G, et al. Well-differentiated grade 3 digestive neuroendocrine tumors: myth or reality? The PRONET Study Group (abstract) J Clin Oncol 20121; 30 abstract 4129. Abstract available online at http://meetinglibrary.asco.org/content/100442-114.
  61. Sorbye H, Strosberg J, Baudin E, et al. Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer 2014; 120:2814.
  62. Tang LH, Untch BR, Reidy DL, et al. Well differentiated neuroendocrine tumors with a morphologically apparent high grade component: a pathway distinct from poorly differentiated neuroendocrine carcinomas. Clin Cancer Res 2015; in press.