Morphological classification of digestive neuroendocrine neoplasms: the current concepts and controversies
https://doi.org/10.17650/2313-805X-2016-3-3-56-66
Abstract
Neuroendocrine tumors comprise the heterogeneous group of malignant epithelial neoplasms, the diagnosis of which is based on their histopathologic features and immunohistochemical profile. For neuroendocrine tumors of the digestive system in the World Health Organization (2010) classification were introduced main categories, the nomenclature, criterions for grading and staging. However, accumulating evidence demonstrates actual controversies in the histopathology of neuroendocrine neoplasms and unreserved problems in their classification. In this review we focus on some of the common features of neuroendocrine neoplasms, their classification, and differences in pathology, biology of the main categories, and the most important immunohistochemical markers.
About the Author
V. V. Delektorskaya
N. N. Blokhin Russian Cancer Reseach Center, Ministry of Health of Russia; 24 Kashirskoe Shosse, Moscow, 115478, Russia
Russian Federation
Russian Federation
References
1. Anlauf M. Neuroendocrine neoplasms of the gastroenteropancreatic system: pathology and classification. Horm Metab Res 2011;43(12):825–31. DOI: 10.1055/s-0031–1291307.
2. Yao J. C., Hassan M., Phan A. et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26(18):3063–72. DOI: 10.1200/JCO. 2007.15.4377.
3. Sandvik O. M., Søreide K., Gudlaugsson E. et al. Epidemiology and classification of gastroenteropancreatic neuroendocrine neoplasms using current coding criteria. Br J Surg 2016;103(3):226–32. DOI: 10.1002/bjs. 10034.
4. Fraenkel M., Kim M., Faggiano A. et al. Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. Endocr Relat Cancer 2014; 21(3):153–63. DOI: 10.1530/ERC-13–0125.
5. Öberg K. Neuroendocrine gastro-enteropancreatic tumors – from eminence based to evidence-based medicine – A Scandinavian view. Scand J Gastroenterol 2015;50(6):727–39. DOI: 10.3109/00365521.2015.1033001.
6. Verbeek W. H., Korse C. M., Tesselaar M. E. GEP-NETs update: Secreting gastro- enteropancreatic neuroendocrine tumours and biomarkers. Eur J Endocrinol 2016;174(1):1– 7. DOI: 10.1530/EJE-14–0971.
7. Walenkamp A., Crespo G., Fierro Maya F. et al. Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment. Endocr Relat Cancer 2014;21(6): 445– 60. DOI: 10.1530/ERC-14–0106.
8. Meeker A., Heaphy C. Gastroenteropancre atic endocrine tumors. Mol Cell Endocrinol 2014;386(1–2):101–20. DOI: 10.1016/j. mce.2013.07.015.
9. Solcia E., Klöppel G., Sobin L. et al. Histological typing of endocrine tumours. 2nd edn. World Health Organization. Berlin: Springer, 2000.
10. Klöppel G., Perren A., Heitz P. U. The gas troenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann NY Acad Sci 2004;1014:13–27. DOI: 10.1196/annals. 1294.002.
11. Klöppel G. Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer 2011;18(Suppl 1):S1–16. DOI: 10.1530/ERC-11–0013.
12. Klöppel G. Tumour biology and histopathology of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 2007;21(1): 15–31. DOI: 10.1016/j.beem.2007.01.004.
13. Bosman F. T., Carneiro F., Hruban R. H., Theise N. D. WHO classification of tumours of the digestive system. 4th edn. Lyon, France: IARC Press, 2010.
14. Schmitt A. M., Blank A., Marinoni I. et al. Histopathology of NET: Current concepts and new developments. Best Pract Res Clin Endocrinol Metab 2016;30(1):33–43. DOI: 10.1016/j. beem. 2016.02.002.
15. Strosberg J., Nasir A., Coppola D. et al. Correlation between grade and prognosis in metastatic gastroenteropancreatic neuroendocrine tumors. Hum Pathol 2009;40(9):1262–8. DOI: 10.1016/j. humpath. 2009.01.010.
16. Kidd M., Modlin I., Öberg K. Towards a new classification of gastroenteropancreatic neuroendocrine neoplasms. Nat Rev Clin Oncol 2016. DOI: 10.1038/nrclinonc. 2016.85.
17. Grillo F., Albertelli M., Annunziata F. et al. Twenty years of gastroenteropancreatic neuroendocrine tumors: is reclassification worthwhile and feasible? Endocrine 2016;53(1):58–62. DOI: 10.1007/s12020-015-0734-3.
18. Jiao Y., Shi C., Edil B. H. et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 2011;331(6021):1199–203. DOI: 10.1126/science.120060.
19. Yachida S., Vakiani E., White C. M. et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol 2012;36(2):173–84. DOI: 10.1097/PAS. 0b013e3182417d36.
20. Kim J. Y., Hong S. M. Recent Updates on neuroendocrine tumors from the gastrointestinal and pancreatobiliary tracts. Arch Pathol Lab Med 2016;140(5):437–48. DOI: 10.5858/arpa. 2015–0314-RA.
21. Gurevich L., Kazantseva I., Isakov V. A. et al. The analysis of immunophenotype of gastrin-producing tumors of the pancreas and gastrointestinal tract. Cancer 2003;98(9):1967–76. DOI: 10.1002/cncr. 11739.
22. Kim J. Y., Kim M. S., Kim K. S. et al. Clinicopathologic and prognostic significance of multiple hormone expression in pancreatic neuroendocrinetumors. Am J Surg Pathol 2015;39(5):592–601. DOI: 10.1097/PAS. 0000000000000383.
23. Minnetti M., Grossman A. Somatic and germline mutations in NETs: Implications for their diagnosis and management. Best Pract Res Clin Endocrinol Metab 2016;30(1):115–27. DOI: 10.1016/j. beem. 2015.09.007.
24. Uccella S., Sessa F., La Rosa S. Diagnostic approach to neuroendocrine neoplasms of the gastrointestinal tract and pancreas. Turk Patoloji Derg 2015;31(1)(Supp l):113–27. DOI: 10.5146/tjpath. 2015.01319.
25. Sorbye H., Strosberg J., Baudin E. et al. Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer 2014;120(18):2814–23. DOI: 10.1002/cncr.28721.
26. Basturk O., Tang L., Hruban R. H. et al. Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol 2014;38(4):437– 47. DOI: 10.1097/PAS. 0000000000000169.
27. DeLellis R. A., Shin S. J., Treaba O. D. Immunohistology of endocrine tumors. Ed. by D. J. Dabbs. In book: Diagnostic immunohistochemistry: theranostic and genomic applications. 3rd edn. Elsevier Inc, 2010. Pp. 291–329.
28. Klimstra D. S., Modlin I. R., Adsay N. V. et al. Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to thedevelopment of a minimum pathology data set. Am J Surg Pathol 2010;34(3):300–13. DOI: 10.1097/PAS.0b013e3181ce1447.
29. Saqi A., Alexis D., Remotti F., Bhagat G. Usefulness of CDX-2 and TTF-1 in differentiating gastrointestinal from pulmonary carcinoids. Am J Clin Pathol 2005;123(3):394–404. DOI: 10.1309/ukn6-pvrk-xhg4-22da.
30. Schmitt A. M., Riniker F., Anlauf M. et al. Islet 1(Isl-1) expression is a reliable marker for pancreatic endocrine tumors and their metastases. Am J Surg Pathol 2008;32(3):420–5. DOI: 10.1097/PAS.0b013e318158a397.
31. Srivastava A., Hornick J. L. Immunohistoc hemical staining for CDX-2, PDX-1, NESP-55, and TTF-1 can help distinguish gastrointestinalcarcinoid tumors from pancreatic endocrine and pulmonary carcinoid tumors. Am J Surg Pathol 2009;33(4):626–32. DOI: 10.1097/PAS.0b013e31818d7d8b.
32. Chan E. S., Alexander J., Swanson P. E. et al. PDX-1, CDX-2, TTF-1, and CK7: a reliable immunohistochemical panel for pancreatic neuroendocrineneoplasms. Am J Surg Pathol 2012;36(5):737–43. DOI: 10.1097/PAS. 0b013e31824aba59.
33. Long K. B., Srivastava A., Hirsch M. S., Hornick J. L. PAX-8 Expression in welldifferentiated pancreatic endocrine tumors: correlation with clinicopathologicfeatures and comparison with gastrointestinal and pulmonary carcinoid tumors. Am J Surg Pathol 2010;34(5):723–9. DOI: 10.1097/PAS.0b013e3181da0a20.
34. Sangoi A. R., Ohgami R. S., Pai R. K. et al. PAX-8 expression reliably distinguishes pancreatic well-differentiated neuroendocrine tumors from ileal and pulmonary welldifferentiated neuroendocrine tumors and pancreatic acinar cell carcinoma. Mod Pathol 2011;24(3):412–24. DOI: 10.1038/modpathol. 2010.176.
35. Tseng I. C., Yeh M. M., Yang C. Y., Jeng Y. M. NKX6-1 is a novel immunohistochemical marker for pancreatic and duodenal neuroendocrine tumors. Am J Surg Pathol 2015;39(6):850–7. DOI: 10.1097/PAS.0000000000000435.
36. Salaria S., Means A., Revetta F. et al. Expression of CD24, a stem cell marker, in pancreatic and small intestinal neuroendocrine tumors. Am J Clin Pathol 2015;144(4): 642– 8. DOI: 10.1309/AJCPMZY5P9TWNJJV.
37. Jamali M., Chetty R. Predicting prognosis in gastroentero-pancreatic neuroendocrine tumors: an overview and the value of Ki-67 immunostaining. Endocr Pathol 2008;19(4):282– 8. DOI: 10.1007/s12022-008-9044-0.
38. Körner M., Waser B., Reubi J. C. Does somatostatin or gastric inhibitory peptide receptor expression correlate with tumor grade and stage in gut neuroendocrine tumors? Neuroendocrinology 2015;101(1):45–57. DOI: 10.1159/000371804.
39. Делекторская В. В. Нейроэндокринные опухоли пищеварительной системы: морфологические и молекулярные особенности. Успехи молекулярной онкологии 2015;2(1):52–60. [Delektorskaya V. V. Neuroendocrine tumors of the digestive system: pathologic and molecular characteristics. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2015;2(1):52–60. (In Russ.)]. DOI: 10.17650/2313-805x. 2015.2.1.52–60.
40. Qian Z. R., Ter-Minassian M., Chan J. A. et al. Prognostic significance of MTOR pathway component expression in neuroendocrine tumors. J Clin Oncol 2013;31(27):3418–25. DOI: 10.1200/JCO.2012.46.6946.
41. Schmitt A. M., Pavel M., Rudolph T. et al. Prognostic and predictive roles of MGMT protein expression and promoter methylation in sporadic pancreatic neuroendocrine neoplasms. Neuroendocrinology 2014;100(1):35–44. DOI: 10.1159/000365514.
42. Marinoni I., Kurrer A. S., Vassella E. et al. Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology 2014;146(2):453–60. DOI: 10.1053/j.gastro.2013.10.020.
43. 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(4):395–401. DOI: 10.1007/s00428-006-0250-1.
44. Voss S. M., Riley M. P., Lokhandwala P. M. et al. Mitotic count by phosphohistone H3 immunohistochemical staining predicts survival and improvesinterobserver reproducibility in well-differentiated neuroendocrine tumors of the pancreas. Am J Surg Pathol 2015;39(1):13–24. DOI: 10.1097/PAS.0000000000000341.
45. Dhall D., Mertens R., Bresee C. et al. Ki-67 proliferative index predicts progressionfree survival of patients with well-differentiated ileal neuroendocrine tumors. Hum Pathol 2012;43(4):489–95. DOI: 10.1016/j.humpath. 2011.06.011.
46. Делекторская В. В., Козлов Н. А., Чемерис Г. Ю. Клинико-морфологический анализ новообразований гастроэнтеропанкреатической системы. Клиническая лабораторная диагностика 2013;(10):48–50; 10–3. [Delektorskaya V. V., Kozlov N. A., Chemeris G. Yu. Clinico-morphological analysis of the neuroendocrine neoplasms of the gastroenteropancreatic system. Klinicheskaya laboratornaya diagnostika = Clinical Laboratory Diagnostics 2013;(10):48–50, 10–3. (In Russ.)].
47. Делекторская В. В., Кушлинский Н. Е. Нейроэндокринные опухоли пищеварительной системы: морфологический спектр и клеточная пролиферация (индекс Ki-67). Вестник РАМН 2013;(5):28–37. [Delektorskaya V. V., Kushliskiy N. E. Neuroendocrine tumors of digestive system: morphologic spectrum and cell proliferation (Ki-67 index). Vestnik RAMN = RAMS Herald 2013;(5):28–37. (In Russ.)]. DOI: 10.15690/vramn.v68i5.660.
48. Grillo F., Albertelli M., Brisigotti M. P. et al. Grade increases in gastro-enteropancreatic neuroendocrine tumor metastases compared to the primary tumor. Neuroendocrinology 2015. http://dx.DOI: org/10.1159/000439434.
49. Kroneman T. N., Voss J. S., Lohse C. M. et al. Comparison of three Ki-67 index quantification methods and clinical significance in pancreatic neuroendocrine tumors. Endocr Pathol 2015;26(3):255–62. DOI: 10.1007/s12022-015-9379-2.
50. Blank A., Wehweck L., Marinoni I. et al. Interlaboratory variability of MIB-1 staining in well-differentiated pancreatic neuro endocrine tumors. Virchows Arch 2015;467(5):543–50. DOI: 10.1007/s00428-015-1843-3.
51. Klöppel G., Rindi G., Perren A. et al. The ENETS and ACC/UICC TNM classifications of the neuroendocrine tumors of the gastrointestinal tract and the pancreas: a statement. Virchows Arch 2010;456(6): 595–7. DOI: 10.1007/s00428-010-0924-6.
52. Edge S. B., Byrd D. R., Compton C. C. et al. AJCC cancer staging manual. 7th edn. American joint commision on cancer. New York: Springer, 2010.
53. 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(10):764–77. DOI: 10.1093/jnci/djs208.
54. Qadan M., Ma Y., Visser B. C. et al. Reassessment of the current American Joint Committee on Cancer staging system for pancreatic neuroendocrine tumors. J Am Coll Surg. 2014;218(2):188–95. DOI: 10.1016/j.jamcollsurg.2013.11.001.
55. Delle Fave G., O’Toole D., Sundin A. et al. ENETS consensus guidelines update for gastroduodenal neuroendocrine neoplasms. Neuroendocrinology 2016;103(2): 119–24. DOI: 10.1159/000443168.
56. Tang L. H., Basturk O., Sue J. J., Klimstra D. S. A practical approach to the classification of HO Grade 3 (G3) well-differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC) of the pancreas. Am J Surg Pathol 2016;40(9):1192–202. DOI: 10.1097/pas.0000000000000662.
57. Tang L. H., Untch B. R., Reidy D. L. et al. Well-differentiated neuroendocrine tumors with a morphologically apparent high-grade component: a pathway distinct from poorly differentiated neuroendocrine carcinomas. Clin Cancer Res 2016;22(4):1011–7. DOI: 10.1158/1078–0432. CCR-15–0548.
58. Milione M., Maisonneuve P., Spada F. et al. The clinicopathologic heterogeneity of Grade 3 gastroenteropancreatic neuroendocrine neoplasms: morphological differentiation and proliferation identify different prognostic categories. Neuroendocrinology 2016. DOI: 10.1159/000445165.
59. Garcia-Carbonero R., Sorbye H., Baudin E. et al. ENETS consensus guidelines for high- grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology. 2016;103(2):186–94. DOI: 10.1159/000443172.
60. La Rosa S., Sessa F., Uccella S. Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs): unifying the concept of a heterogeneous group of neoplasms. Endocr Pathol 2016. DOI: 10.1007/s12022-016-9432-9.
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Delektorskaya V.V. Morphological classification of digestive neuroendocrine neoplasms: the current concepts and controversies. Advances in Molecular Oncology. 2016;3(3):56-66. (In Russ.) https://doi.org/10.17650/2313-805X-2016-3-3-56-66
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