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
1996 2006/2007 2017 2000 2000 2004 2010
G1 Mitoses Grading Ki67 index G1 m<2 Ki67<2% G2 G2 2< m <20 3%< Ki67<20% G3 m >20 Ki67 >20% G3
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
GEP system stomach Midgut-hindgut
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
Stomach
La Rosa et al.,2011 G1-NET, rarely G3-NET
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
Duodenum
Morphology: well differentiated (176 cases) Ki-67: <2.5% (140 cases), 2.5-20% (31 cases) Mitoses: <2 (140 cases), 2-20 (16 cases) Grade: G1 (80%), G2 (20%) No WD-NET with Ki67>20%
G1 G2 GP 92% 8% Differences among NET subtypes Gatrinoma 85% 15% D-cell tumor 65% 35% NF- NET 82% 18%
Predictors of lymph node involvement Proliferative grading, lymphovascular invasion and level of wall invasion can effectively predict LN metastases
Disease specific survival Size, proliferative grade 2 and 3, lymphovascular invasion, wall invasion and stage III-IV are significantly related to worse survival.
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.
Upper jejunum
Lower jejunum and ileum (midgut)
Ki67>1% Ki67<1%
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
Appendix
Most tumors are G1 NETs, infiltrate the muscular layer, but very rarely metastasize 5HT S100
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
Rectum (hindgut)
Reference N G1 G2 Jernman 2012 Hong 2013 Tsukamoto 2008 Kim 2013 Sohn 2015 Li 2015 Nakamura 2016 72 37 23 79 972 147 170 61 33 17 79 906 137 166 11 4 6 0 66 10 4 Total 1500 1399 (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
Sohn et al. Cancer Res Treat 47:813, 2015
L-cell NET EC-cell NET Glicentin
Cut-off: 3%
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)
Important Information Regarding CME/SAMs The Online CME/Evaluations/SAMs claim process will only be available on the USCAP website until September 30, 2017. 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
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; 2000 2. Hamilton SR, Aaltonen LA. WHO classification of tumours. Pathology and genetics of tumours of the digestive system. Lyon: IARC Press; 2000 1. De Lellis RA, Lloyd RV, Heitz PU, Eng C. WHO classification of tumours. Pathology and genetics of tumours of endocrine organs. Lyon: IARC Press; 2004 2. 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 27:1124-1134,1996 3. La Rosa S, et al. Prognostic criteria in nonfunctioning pancreatic endocrine tumors. Virchows Arch 429:323-333,1996 4. Rindi G, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 449:395-401,2006 5. Rindi G, et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 451:757-62,2007 6. 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; 2010. 13-4.
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