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Virchows Archiv

, Volume 472, Issue 3, pp 341–349 | Cite as

Ki67 labeling index: assessment and prognostic role in gastroenteropancreatic neuroendocrine neoplasms

  • Günter Klöppel
  • Stefano La Rosa
Review and Perspectives

Abstract

In 1983, a monoclonal antibody, Ki67, was generated, that labeled the nuclei of proliferating non-neoplastic and neoplastic cells. The name Ki67 derived from the city of Kiel (Ki) where the antibody was produced in the university department of pathology and refers to the number of the original clone (67). Systematic assessment of the proliferative activity of tumors using Ki67 started in the 1990s, when Ki67, which only worked on frozen tissue, was complemented by the antibody MIB-1 that also worked in formalin-fixed tissues. Pancreatic neuroendocrine neoplasms (PanNENs) were the first endocrine tumors whose proliferative activity was assessed with Ki67. This approach was so successful that Ki67 was included as prognostic marker in the 2000 and 2004 WHO classifications of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In 2010, the WHO classification of GEP-NENs introduced a three-tiered grading, originally proposed by ENETS in 2006 that was mainly based on the Ki67 index. As it has subsequently been shown that the Ki67 index is the most reliable factor in the prognostic evaluation of GEP-NENs, especially of PanNENs, the 2017 WHO classification of PanNENs requires its use and strongly recommends exact assessment of the proportion Ki67-labeled cells as basis for the calculation of the Ki67 index. Problems in assessing the Ki67 index include intertumoral and intratumoral staining heterogeneity and counting methods. Despite such problems, the Ki67 index has emerged as indispensable for the prognostic and therapeutic stratification of the majority of GEP-NENs and can barely be replaced by counting mitoses. In future, however, it can be anticipated that the Ki67 cut-offs experience refinement in relation to the type of tumor, its location, and its response to therapy. It is also possible that the prognostic risk of an individual tumor is calculated for each Ki67 unit and not for an “a priori” fixed Ki67 class.

Keywords

Ki67 History Assessment Prognostic marker Neuroendocrine neoplasms Pancreas Stomach Intestine 

Notes

Compliance with ethical standards

This work does not violate any ethical standards.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Adsay V (2012) Ki67 labeling index in neuroendocrine tumors of the gastrointestinal and pancreatobiliary tract: to count or not to count is not the question, but rather how to count. Am J Surg Pathol 36:1743–1746.  https://doi.org/10.1097/PAS.0b013e318272ff77 CrossRefPubMedGoogle Scholar
  2. 2.
    Ahmed A, Turner G, King B, Jones L, Culliford D, McCance D, Ardill J, Johnston BT, Poston G, Rees M, Buxton-Thomas M, Caplin M, Ramage JK (2009) Midgut neuroendocrine tumours with liver metastases: results of the UKINETS study. Endocr Relat Cancer 16:885–894.  https://doi.org/10.1677/erc-09-0042 CrossRefPubMedGoogle Scholar
  3. 3.
    Araujo PB, Cheng S, Mete O, Serra S, Morin E, Asa SL, Ezzat S (2013) Evaluation of the WHO 2010 grading and AJCC/UICC staging systems in prognostic behavior of intestinal neuroendocrine tumors. PloS one 8:e61538.  https://doi.org/10.1371/journal.pone.0061538 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Basturk O, Yang Z, Tang LH, Hruban RH, Adsay V, McCall CM, Krasinskas AM, Jang KT, Frankel WL, Balci S, Sigel C, Klimstra DS (2015) 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 39:683–690.  https://doi.org/10.1097/PAS.0000000000000408 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Blank A, Wehweck L, Marinoni I, Boos LA, Bergmann F, Schmitt AM, Perren A (2015) Interlaboratory variability of MIB1 staining in well-differentiated pancreatic neuroendocrine tumors. Virchows Arch 467:543–550.  https://doi.org/10.1007/s00428-015-1843-3 CrossRefPubMedGoogle Scholar
  6. 6.
    Capella C, Heitz PU, Höfler H, Solcia E, Klöppel G (1995) Revised classification of neuroendocrine tumours of the lung, pancreas and gut. Virchows Arch 425:547–560CrossRefPubMedGoogle Scholar
  7. 7.
    Clift AK, Faiz O, Al-Nahhas A, Bockisch A, Liedke MO, Schloericke E, Wasan H, Martin J, Ziprin P, Moorthy K, Frilling A (2016) Role of staging in patients with small intestinal neuroendocrine tumours. J Gastrointest Surg 20:180–188; discussion 188.  https://doi.org/10.1007/s11605-015-2953-6 CrossRefPubMedGoogle Scholar
  8. 8.
    Clift AK, Faiz O, Goldin R, Martin J, Wasan H, Liedke MO, Schloericke E, Malczewska A, Rindi G, Kidd M, Modlin IM, Frilling A (2017) Predicting the survival of patients with small bowel neuroendocrine tumours: comparison of 3 systems. Endocr Connect 6:71–81.  https://doi.org/10.1530/ec-16-0114 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Combs SE, Han G, Mani N, Beruti S, Nerenberg M, Rimm DL (2016) Loss of antigenicity with tissue age in breast cancer. Lab Invest 96:264–269.  https://doi.org/10.1038/labinvest.2015.138 CrossRefPubMedGoogle Scholar
  10. 10.
    Cunningham JL, Grimelius L, Sundin A, Agarwal S, Janson ET (2007) Malignant ileocaecal serotonin-producing carcinoid tumours: the presence of a solid growth pattern and/or Ki67 index above 1% identifies patients with a poorer prognosis. Acta Oncol 46:747–756.  https://doi.org/10.1080/02841860701218659 CrossRefPubMedGoogle Scholar
  11. 11.
    Cuylen S, Blaukopf C, Politi AZ, Muller-Reichert T, Neumann B, Poser I, Ellenberg J, Hyman AA, Gerlich DW (2016) Ki-67 acts as a biological surfactant to disperse mitotic chromosomes. Nature 535:308–312.  https://doi.org/10.1038/nature18610 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Gerdes J, Schwab U, Lemke H, Stein H (1983) Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer 31:13–20CrossRefPubMedGoogle Scholar
  13. 13.
    Gonzalez RS, Liu EH, Alvarez JR, Ayers GD, Washington MK, Shi C (2014) Should mesenteric tumor deposits be included in staging of well-differentiated small intestine neuroendocrine tumors? Mod Pathol 27:1288–1295.  https://doi.org/10.1038/modpathol.2013.232 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Grozinsky-Glasberg S, Thomas D, Strosberg JR, Pape UF, Felder S, Tsolakis AV, Alexandraki KI, Fraenkel M, Saiegh L, Reissman P, Kaltsas G, Gross DJ (2013) Metastatic type 1 gastric carcinoid: a real threat or just a myth? World J Gastroenterol 19:8687–8695.  https://doi.org/10.3748/wjg.v19.i46.8687 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hong SM, Kim YS, Moon JS, Kim JN, Oh MK, Kwon SO, Jeong SY, Hong SW, Kang YK (2013) Prognostic significance of Ki-67 expression in rectal carcinoid tumors. Korean J Gastroenterol 61:82–87CrossRefPubMedGoogle Scholar
  16. 16.
    Jernman J, Valimaki MJ, Louhimo J, Haglund C, Arola J (2012) The novel WHO 2010 classification for gastrointestinal neuroendocrine tumours correlates well with the metastatic potential of rectal neuroendocrine tumours. Neuroendocrinology 95:317–324.  https://doi.org/10.1159/000333035 CrossRefPubMedGoogle Scholar
  17. 17.
    Kim GU, Kim KJ, Hong SM, Yu ES, Yang DH, Jung KW, Ye BD, Byeon JS, Myung SJ, Yang SK, Kim JH (2013) Clinical outcomes of rectal neuroendocrine tumors≤ 10 mm following endoscopic resection. Endoscopy 45:1018–1023.  https://doi.org/10.1055/s-0033-1344860 CrossRefPubMedGoogle Scholar
  18. 18.
    Klöppel G (2011) Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer 18(Suppl 1):S1–16.  https://doi.org/10.1530/erc-11-0013 CrossRefPubMedGoogle Scholar
  19. 19.
    Klöppel G, Perren A, Heitz PU (2004) The gastroenteropancreatic neuroendocrine cell system and its tumors. The WHO classification. Ann NY Acad Sci 1014:13–27CrossRefPubMedGoogle Scholar
  20. 20.
    Konukiewitz B, Schlitter AM, Jesinghaus M, Pfister D, Steiger K, Segler A, Agaimy A, Sipos B, Zamboni G, Weichert W, Esposito I, Pfarr N, Klöppel G (2017) Somatostatin receptor expression related to TP53 and RB1 alterations in pancreatic and extrapancreatic neuroendocrine neoplasms with a Ki67-index above 20. Mod Pathol.  https://doi.org/10.1038/modpathol.2016.217
  21. 21.
    Kreipe H, Heidebrecht HJ, Hansen S, Rohlk W, Kubbies M, Wacker HH, Tiemann M, Radzun HJ, Parwaresch R (1993) A new proliferation-associated nuclear antigen detectable in paraffin-embedded tissues by the monoclonal antibody Ki-S1. Am J Pathol 142:3–9PubMedPubMedCentralGoogle Scholar
  22. 22.
    La Rosa S, Inzani F, Vanoli A, Klersy C, Dainese L, Rindi G, Capella C, Bordi C, Solcia E (2011) Histologic characterization and improved prognostic evaluation of 209 gastric neuroendocrine neoplasms. Hum Pathol 42:1373–1384.  https://doi.org/10.1016/j.humpath.2011.01.018 CrossRefPubMedGoogle Scholar
  23. 23.
    La Rosa S, Sessa F, Capella C, Riva C, Leone BE, Klersy C, Rindi G, Solcia E (1996) Prognostic criteria in nonfunctioning pancreatic endocrine tumours. Virchows Arch 429:323–333CrossRefPubMedGoogle Scholar
  24. 24.
    La Rosa S, Sessa F, Uccella S (2016) Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs): unifying the concept of a heterogeneous group of neoplasms. Endocr Pathol 27:284–311.  https://doi.org/10.1007/s12022-016-9432-9 CrossRefPubMedGoogle Scholar
  25. 25.
    La Rosa S, Vanoli A (2014) Gastric neuroendocrine neoplasms and related precursor lesions. J Clin Pathol 67:938–948.  https://doi.org/10.1136/jclinpath-2014-202515 CrossRefPubMedGoogle Scholar
  26. 26.
    Lardiere-Deguelte S, de Mestier L, Appere F, Vullierme MP, Zappa M, Hoeffel C, Noaves M, Brixi H, Hentic O, Ruszniewski P, Cadiot G, Panis Y, Kianmanesh R (2016) Toward a preoperative classification of lymph node metastases in patients with small intestinal neuroendocrine tumors in the era of intestinal-sparing surgery. Neuroendocrinology 103:552–559.  https://doi.org/10.1159/000441423 CrossRefPubMedGoogle Scholar
  27. 27.
    Li P, Wu F, Zhao H, Dou L, Wang Y, Guo C, Wang G, Zhao D (2015) Analysis of the factors affecting lymph node metastasis and the prognosis of rectal neuroendocrine tumors. Int J Clin Exp Pathol 8:13331–13338PubMedPubMedCentralGoogle Scholar
  28. 28.
    Lloyd RV, Osamura RY, Klöppel G, Rosai J (2017) WHO Classification of Tumours of Endocrine Organs. IARC Press, LyonGoogle Scholar
  29. 29.
    Milione M, Maisonneuve P, Spada F, Pellegrinelli A, Spaggiari P, Albarello L, Pisa E, Barberis M, Vanoli A, Buzzoni R, Pusceddu S, Concas L, Sessa F, Solcia E, Capella C, Fazio N, La Rosa S (2017) The clinicopathologic heterogeneity of grade 3 gastroenteropancreatic neuroendocrine neoplasms: morphological differentiation and proliferation identify different prognostic categories. Neuroendocrinology 104:85–93.  https://doi.org/10.1159/000445165 CrossRefPubMedGoogle Scholar
  30. 30.
    Modlin IM, Gustafsson BI, Pavel M, Svejda B, Lawrence B, Kidd M (2010) A nomogram to assess small-intestinal neuroendocrine tumor (‘carcinoid’) survival. Neuroendocrinology 92:143–157.  https://doi.org/10.1159/000319784 CrossRefPubMedGoogle Scholar
  31. 31.
    Nakamura K, Osada M, Goto A, Iwasa T, Takahashi S, Takizawa N, Akahoshi K, Ochiai T, Nakamura N, Akiho H, Itaba S, Harada N, Iju M, Tanaka M, Kubo H, Somada S, Ihara E, Oda Y, Ito T, Takayanagi R (2016) Short- and long-term outcomes of endoscopic resection of rectal neuroendocrine tumours: analyses according to the WHO 2010 classification. Scand J Gastroenterol 51:448–455.  https://doi.org/10.3109/00365521.2015.1107752 CrossRefPubMedGoogle Scholar
  32. 32.
    Norlen O, Stalberg P, Oberg K, Eriksson J, Hedberg J, Hessman O, Janson ET, Hellman P, Akerstrom G (2012) Long-term results of surgery for small intestinal neuroendocrine tumors at a tertiary referral center. World J Surg 36:1419–1431.  https://doi.org/10.1007/s00268-011-1296-z CrossRefPubMedGoogle Scholar
  33. 33.
    O’Toole D, Kianmanesh R, Caplin M (2016) ENETS 2016 consensus guidelines for the management of patients with digestive neuroendocrine tumors: an update. Neuroendocrinology 103:117–118.  https://doi.org/10.1159/000443169 CrossRefPubMedGoogle Scholar
  34. 34.
    Panzuto F, Boninsegna L, Fazio N, Campana D, Pia Brizzi M, Capurso G, Scarpa A, De Braud F, Dogliotti L, Tomassetti P, Delle Fave G, Falconi M (2011) Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. J Clin Oncol 29:2372–2377.  https://doi.org/10.1200/jco.2010.33.0688 CrossRefPubMedGoogle Scholar
  35. 35.
    Panzuto F, Campana D, Fazio N, Brizzi MP, Boninsegna L, Nori F, Di Meglio G, Capurso G, Scarpa A, Dogliotti L, De Braud F, Tomassetti P, Delle Fave G, Falconi M (2012) Risk factors for disease progression in advanced jejunoileal neuroendocrine tumors. Neuroendocrinology 96:32–40.  https://doi.org/10.1159/000334038 CrossRefPubMedGoogle Scholar
  36. 36.
    Pape UF, Jann H, Müller-Nordhorn J, Bockelbrink A, Berndt U, Willich SN, Koch M, Röcken C, Rindi G, Wiedenmann B (2008) Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer 113:256–265CrossRefPubMedGoogle Scholar
  37. 37.
    Pape UF, Niederle B, Costa F, Gross D, Kelestimur F, Kianmanesh R, Knigge U, Oberg K, Pavel M, Perren A, Toumpanakis C, O’Connor J, Krenning E, Reed N, O’Toole D (2016) ENETS consensus guidelines for neuroendocrine neoplasms of the appendix (excluding goblet cell carcinomas). Neuroendocrinology 103:144–152.  https://doi.org/10.1159/000443165 CrossRefPubMedGoogle Scholar
  38. 38.
    Pelosi G, Bresaola E, Bogina G, Pasini F, Rodella S, Castelli P, Iacono C, Serio G, Zamboni G (1996) 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 27:1124–1134CrossRefPubMedGoogle Scholar
  39. 39.
    Pelosi G, Rindi G, Travis WD, Papotti M (2014) Ki-67 antigen in lung neuroendocrine tumors: unraveling a role in clinical practice. J Thorac Oncol 9:273–284.  https://doi.org/10.1097/jto.0000000000000092 CrossRefPubMedGoogle Scholar
  40. 40.
    Ramage JK, De Herder WW, Delle Fave G, Ferolla P, Ferone D, Ito T, Ruszniewski P, Sundin A, Weber W, Zheng-Pei Z, Taal B, Pascher A (2016) ENETS consensus guidelines update for colorectal neuroendocrine neoplasms. Neuroendocrinology 103:139–143.  https://doi.org/10.1159/000443166 CrossRefPubMedGoogle Scholar
  41. 41.
    Reid MD, Bagci P, Ohike N, Saka B, Erbarut Seven I, Dursun N, Balci S, Gucer H, Jang KT, Tajiri T, Basturk O, Kong SY, Goodman M, Akkas G, Adsay V (2015) Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies. Mod Pathol 28:686–694.  https://doi.org/10.1038/modpathol.2014.156 CrossRefPubMedGoogle Scholar
  42. 42.
    Rindi G, Azzoni C, La Rosa S, Klersy C, Paolotti D, Rappel S, Stolte M, Capella C, Bordi C, Solcia E (1999) ECL cell tumor and poorly differentiated endocrine carcinoma of the stomach: prognostic evaluation by pathological analysis. Gastroenterology 116:532–542CrossRefPubMedGoogle Scholar
  43. 43.
    Rindi G, Arnold R, Bosman FT, Capella C, Klimstra DS, Kloppel G et al. (2010) Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, Theise ND (eds) WHO Classification of Tumours of the Digestive system, 4th edn. IARC, Lyon, pp 13–14 Google Scholar
  44. 44.
    Rindi G, Falconi M, Klersy C, Albarello L, Boninsegna L, Buchler MW, Capella C, Caplin M, Couvelard A, Doglioni C, Delle Fave G, Fischer L, Fusai G, de Herder WW, Jann H, Komminoth P, de Krijger RR, La Rosa S, Luong TV, Pape U, Perren A, Ruszniewski P, Scarpa A, Schmitt A, Solcia E, Wiedenmann B (2012) TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst 104:764–777.  https://doi.org/10.1093/jnci/djs208 CrossRefPubMedGoogle Scholar
  45. 45.
    Rindi G, Klöppel G, Ahlman H, Caplin M, Couvelard A, de Herder WW, Eriksson B, Falchetti A, Falconi M, Komminoth P, Körner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B, participants aaoFCC (2006) TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 449:395–401CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Rindi G, Klöppel G, Couvelard A, Komminoth P, Körner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B (2007) TNM staging of midgut and hindgut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 451:757–762CrossRefPubMedGoogle Scholar
  47. 47.
    Rindi G, Luinetti O, Cornaggia M, Capella C, Solcia E (1993) Three subtypes of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma: a clinicopathologic study. Gastroenterology 104:994–1006CrossRefPubMedGoogle Scholar
  48. 48.
    Rosentraeger MJ, Garbrecht N, Anlauf M, Raffel A, Knoefel WT, Wiedenmann B, Klöppel G (2016) Syndromic versus non-syndromic sporadic gastrin-producing neuroendocrine tumors of the duodenum: comparison of pathological features and biological behavior. Virchows Arch 468:277–287.  https://doi.org/10.1007/s00428-015-1890-9
  49. 49.
    Rudolph P, Kellner U, Chassevent A, Collin F, Bonichon F, Parwaresch R, Coindre JM (1997) Prognostic relevance of a novel proliferation marker, Ki-S11, for soft-tissue sarcoma. A multivariate study. Am J Pathol 150:1997–2007PubMedPubMedCentralGoogle Scholar
  50. 50.
    Scarpa A, Mantovani W, Capelli P, Beghelli S, Boninsegna L, Bettini R, Panzuto F, Pederzoli P, delle Fave G, Falconi M (2010) Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol 23:824–833.  https://doi.org/10.1038/modpathol.2010.58 CrossRefPubMedGoogle Scholar
  51. 51.
    Scherübl H, Jensen RT, Cadiot G, Stölzel U, Klöppel G (2011) Management of early gastrointestinal neuroendocrine neoplasms. World J Gastrointest Endosc 3:133–139.  https://doi.org/10.4253/wjge.v3.i7.133
  52. 52.
    Sobecki M, Mrouj K, Camasses A, Parisis N, Nicolas E, Lleres D, Gerbe F, Prieto S, Krasinska L, David A, Eguren M, Birling MC, Urbach S, Hem S, Dejardin J, Malumbres M, Jay P, Dulic V, Lafontaine D, Feil R, Fisher D (2016) The cell proliferation antigen Ki-67 organises heterochromatin. eLife 5:e13722.  https://doi.org/10.7554/eLife.13722 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Sohn JH, Cho MY, Park Y, Kim H, Kim WH, Kim JM, Jung ES, Kim KM, Lee JH, Chan HK, Park DY, Joo M, Kim S, Moon WS, Kang MS, Jin SY, Kang YK, Yoon SO, Han H, Choi E (2015) Prognostic significance of defining L-cell type on the biologic behavior of rectal neuroendocrine tumors in relation with pathological parameters. Cancer Res Treat 47:813–822.  https://doi.org/10.4143/crt.2014.238 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Strosberg JR, Weber JM, Feldman M, Coppola D, Meredith K, Kvols LK (2013) Prognostic validity of the American Joint Committee on Cancer staging classification for midgut neuroendocrine tumors. J Clin Oncol 31:420–425.  https://doi.org/10.1200/jco.2012.44.5924 CrossRefPubMedGoogle Scholar
  55. 55.
    Sugimoto S, Hotta K, Shimoda T, Imai K, Yamaguchi Y, Nakajima T, Oishi T, Mori K, Takizawa K, Kakushima N, Tanaka M, Kawata N, Matsubayashi H, Ono H (2016) The Ki-67 labeling index and lymphatic/venous permeation predict the metastatic potential of rectal neuroendocrine tumors. Surg Endosc 30:4239–4248.  https://doi.org/10.1007/s00464-015-4735-3 CrossRefPubMedGoogle Scholar
  56. 56.
    Tang LH, Basturk O, Sue JJ, Klimstra DS (2016) A practical approach to the classification of WHO grade 3 (G3) well-differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC) of the pancreas. Am J Surg Pathol 40:1192–1202.  https://doi.org/10.1097/pas.0000000000000662 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Tang LH, Gonen M, Hedvat C, Modlin IM, Klimstra DS (2012) 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 36:1761–1770.  https://doi.org/10.1097/PAS.0b013e318263207c CrossRefPubMedGoogle Scholar
  58. 58.
    Tsukamoto S, Fujita S, Yamaguchi T, Yamamoto S, Akasu T, Moriya Y, Taniguchi H, Shimoda T (2008) Clinicopathological characteristics and prognosis of rectal well-differentiated neuroendocrine tumors. Int J Color Dis 23:1109–1113.  https://doi.org/10.1007/s00384-008-0505-1 CrossRefGoogle Scholar
  59. 59.
    Vanoli A, La Rosa S, Klersy C, Grillo F, Albarello L, Inzani F, Maragliano R, Manca R, Luinetti O, Milione M, Doglioni C, Rindi G, Capella C, Solcia E (2017) Four neuroendocrine tumor types and neuroendocrine carcinoma of the duodenum: analysis of 203 cases. Neuroendocrinology 104:112–125.  https://doi.org/10.1159/000444803 CrossRefPubMedGoogle Scholar
  60. 60.
    Vinik AI, Woltering EA, Warner RR, Caplin M, O’Dorisio TM, Wiseman GA, Coppola D, Go VL (2010) NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas 39:713–734.  https://doi.org/10.1097/MPA.0b013e3181ebaffd CrossRefPubMedGoogle Scholar
  61. 61.
    Volante M, Daniele L, Asioli S, Cassoni P, Comino A, Coverlizza S, De Giuli P, Fava C, Manini C, Berruti A, Papotti M (2013) Tumor staging but not grading is associated with adverse clinical outcome in neuroendocrine tumors of the appendix: a retrospective clinical pathologic analysis of 138 cases. Am J Surg Pathol 37:606–612.  https://doi.org/10.1097/PAS.0b013e318275d1d7 CrossRefPubMedGoogle Scholar
  62. 62.
    von Herbay A, Sieg B, Schurmann G, Hofmann WJ, Betzler M, Otto HF (1991) Proliferative activity of neuroendocrine tumours of the gastroenteropancreatic endocrine system: DNA flow cytometric and immunohistological investigations. Gut 32:949–953CrossRefGoogle Scholar
  63. 63.
    Yachida S, Vakiani E, White CM, Zhong Y, Saunders T, Morgan R, de Wilde RF, Maitra A, Hicks J, Demarzo AM, Shi C, Sharma R, Laheru D, Edil BH, Wolfgang CL, Schulick RD, Hruban RH, Tang LH, Klimstra DS, Iacobuzio-Donahue CA (2012) 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 36:173–184.  https://doi.org/10.1097/PAS.0b013e3182417d36 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Yang Z, Tang LH, Klimstra DS (2011) 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 35:853–860.  https://doi.org/10.1097/PAS.0b013e31821a0696 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Deutschland 2017

Authors and Affiliations

  1. 1.Institute of Pathology, Consultation Center for Pancreatic and Endocrine TumorsTechnical University of MunichMunichGermany
  2. 2.Service of Clinical Pathology, Institute of PathologyLausanne University HospitalLausanneSwitzerland

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