Disclosure of Relevant Financial Relationships

Transcription

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2 Disclosure of Relevant Financial Relationships USCAP requires that all faculty in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Stefano La Rosa declares he has no conflict(s) of interest to disclose

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4 G1 Mitoses Grading Ki67 index G1 m<2 Ki67<2% G2 G2 2< m <20 3%< Ki67<20% G3 m >20 Ki67 >20% G3

5 G1 Grading V. Adsay G. Klöppel D. Klimstra P. Komminoth S. La Rosa Mitoses Ki67 index G2 G1 G2 m<2 2< m <20 Ki67<3% 3%< Ki67<20% 2017 G3 m >20 Ki67 >20% G3

6 GEP system stomach Midgut-hindgut

7 GEP neuroendocrine neoplasms are a heterogeneous group of neoplastic proliferations characterized by specific clinicopathological and molecular features which mainly depend on the site of origin

8 Stomach

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10 La Rosa et al.,2011 G1-NET, rarely G3-NET

11 Take home message: Ki67 labeling index is a good prognostic marker but it should not be used alone to stratify patients in different prognostic categories; it should be considered together with clinicopathologic tumor type and stage

12 Duodenum

13 Morphology: well differentiated (176 cases) Ki-67: <2.5% (140 cases), % (31 cases) Mitoses: <2 (140 cases), 2-20 (16 cases) Grade: G1 (80%), G2 (20%) No WD-NET with Ki67>20%

14 G1 G2 GP 92% 8% Differences among NET subtypes Gatrinoma 85% 15% D-cell tumor 65% 35% NF- NET 82% 18%

15 Predictors of lymph node involvement Proliferative grading, lymphovascular invasion and level of wall invasion can effectively predict LN metastases

16 Disease specific survival Size, proliferative grade 2 and 3, lymphovascular invasion, wall invasion and stage III-IV are significantly related to worse survival.

17 Take home message: Ki67 labeling index is not useful to separate different tumor categories Ki67 labeling index is a predictor of lymph node involvement Although Ki67 labeling index is a predictor of disease free survival when considering duodenal NENs all together (G1, G2, G3), it does not discriminate alone the disease free survival between G1 and G2.

18 Upper jejunum

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20 Lower jejunum and ileum (midgut)

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22 Ki67>1% Ki67<1%

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25 Take home message Most ileal NETs are G1 and metastatic However: Ki67 is an independent predictor for tumor progression 14% increased risk for tumor progression for each increasing unit Ki67 is an independent risk factor for decreased survival Ki67 cut-off at 5% seems better to discriminate between G1 and G2

26 Appendix

27 Most tumors are G1 NETs, infiltrate the muscular layer, but very rarely metastasize 5HT S100

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29 Take home message: For appendiceal NETs reporting tumor grade is recommended by guidelines However, tumor grade is not statistically correlated with a different survival, which mainly depends on stage

30 Rectum (hindgut)

31 Reference N G1 G2 Jernman 2012 Hong 2013 Tsukamoto 2008 Kim 2013 Sohn 2015 Li 2015 Nakamura Total (93.2%) 101 (6.8%) Ki67 has been generally used for grading evaluation because mitoses are extremely rare Sohn et al. Cancer Res Treat 47:813, 2015

32 Sohn et al. Cancer Res Treat 47:813, 2015

33 L-cell NET EC-cell NET Glicentin

34 Cut-off: 3%

35 Take home message: Most rectal NETs are G1 Ki67 index is a prognostic marker The recently proposed cut-off of 3% seems the best one Ki67 index should not be used alone as a prognosticator, but in association with tumor size, lympho-vascular invasion, level of wall infiltration, and immunophenotype (L-cell versus EC-cell)

36 Important Information Regarding CME/SAMs The Online CME/Evaluations/SAMs claim process will only be available on the USCAP website until September 30, No claims can be processed after that date! After September 30, 2017 you will NOT be able to obtain any CME or SAMs credits for attending this meeting. PRESENTATION TITLE The value and pitfalls of Ki67 labeling index in gastrointestinal neuroendocrine neoplasms

37 The value and pitfalls of Ki67 labeling index in gastrointestinal neuroendocrine neoplasms References 1. Solcia E, Klöppel G, Sobin LH. Histological typing of endocrine tumours. WHO International Histological Classification of Tumours, 2 nd ed. Berlin: Springer; Hamilton SR, Aaltonen LA. WHO classification of tumours. Pathology and genetics of tumours of the digestive system. Lyon: IARC Press; De Lellis RA, Lloyd RV, Heitz PU, Eng C. WHO classification of tumours. Pathology and genetics of tumours of endocrine organs. Lyon: IARC Press; Pelosi 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 27: , La Rosa S, et al. Prognostic criteria in nonfunctioning pancreatic endocrine tumors. Virchows Arch 429: , Rindi G, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 449: , Rindi G, et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 451:757-62, Rindi G, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO classification of tumours of the digestive system. Lyon: IARC Press;

38 7. Yamaguki T, et al. Clinical validation of the gastrointestinal NET grading system: Ki67 index criteria of the WHO 2010 classification is appropriate to predict metastasis or recurrence. Diagn Pathol 8:65, Jann H, et al. Neuroendocrine tumors of midgut and hindgut: tumor-node-metastasis classification determines clinical outcome. Cancer 117: , La Rosa S, et al. Improved histologic and clinico-pathologic criteria for prognostic evaluation of pancreatic endocrine tumors. Hum Pathol 40:30-40, La Rosa S, et al. Histologic characterization and improved prognostic evaluation of 209 gastric neuroendocrine neoplasms. Hum Pathol 42: , Pape UF, et al. Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer 113: , Palazzo M, et al. Ki67 proliferation index, hepatic tumor load, and pretreatment tumor growth predict the antitumoral efficacy of lanreotide in patients with malignant digestive neuroendocrine tumors. Eur J Gastroenterol Hepatol 25: , Alexiev BA, et al. Endocrine tumors of the gastrointestinal tract and pancreas: grading, tumor size and proliferation index do not predict malignant behavior. Diagn Pathol 2:28, Rindi G, et al. Three subtypes of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma: a clinicopathologic study. Gastroenterology 104: , La Rosa S, et al. Gastric neuroendocrine neoplasms and related precursors lesions. J Clin Pathol 67: ,2014

39 16. Vanoli A, et al. Four neuroendocrine tumor types and the neuroendocrine carcinoma of the duodenum. Analysis of 203 cases. Neuroendocrinology 2016 Feb Chopin-Laly X, et al. Neuroendocrine neoplasms of the jejunum: a heterogeneous group with distinctive proximal and distal subsets. Virchows Arch 462: , Ahmed A, et al. Midgut neuroendocrine tumours with liver metastases: results of the UKINETS study. Endocr relat cancer 16: , Cunningham JL, et al. Malignant ileocaecal serotonin-producing carcinoids tumours: the presence of a solid growth pattern and/or Ki67 index above 1% identifies patients with a poorer prognosis. Acta Oncol 46: , Panzuto F, et al. Risk factors for disease progression in advances jejunoileal neuroendocrine tumors. Neuroendocrinology 96:32-40, Volante M, et al. Tumors 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: , Klimstra DS, 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 34: , Rindi G, et al. Gastroenteropancreatic (neuro)endocrine neoplasms: the histology report. Dig Liv Dis 43S:S356-S60, Jernman J, et al. The novel WHO 2010 classification for gastrointestinal neuroendocrine tumours correlates well with the metastatic potential of rectal neuroendocrine tumours. Neuroendocrinology 95: ,2012

40 25. Hong SM, et al. Prognostic significance of Ki-67 expression in recatl carcinoid tumors. Korean J gastroenterol 61:82-87, Tsukamoto S, et al. Clinicopathological characteristics and prognosis of rectal welldifferentiated neuroendocrine tumors. Int J Colorectal Dis 23: , Kim GU, et al. Clinical outcomes of rectal neuroendocrine tumors < 10 mm following endocscopic resection. Endoscopy 45: , Sohn JH, et al. Prognostic significance of defining L-cell type on the biologica behavior of rectal neuroendocrine tumors in relation with pathological parameters. Cancer Res Treat 47: , Li P, et al. Analysis of the factors affeting lymph node metastasis and the prognosis of rectal neuroendocrine tumors. Int J Clin Exp Pathol 8: , Nakamura K, et al. Short- and long-term outcomes of endoscopic resection of rectal neuroendocrine tumours: analyses according to the WHO 2010 classification. Scand J Gatroenterol 51: , Sugimoto S, et al. The Ki-67 labeling index and lymphatic/venous permeation predict the metastatic potential of rectal neuroendocrine tumors. Surg Endosc 30: ,2016