An Objective Assessment of Ki67 Proliferative Index Quantification in Gastroenteropancreatic Neuroendocrine Tumors (NETs).
Laura H Tang, Mithat Gonen, Cyrus Hedvat, Irvin M Modlin, David S Klimstra. Memorial Sloan-Kettering Cancer Center, New York, NY; Yale University, School of Medicine, New Haven, CT
Background: The pathologic prediction of prognosis of NETs is challenging. The proliferative rate is important for prognosis and is often assessed using Ki67 immunohistochemistry. A limitation to Ki67 assessment is the lack of uniformity and consistency in quantification. This is accentuated in well-differentiated NETs since differences of 1-3% can change the tumor grade with resultant treatment implications.
Design: Different Ki67 scoring techniques included: a) digital image analysis (DIA), b) manual counting (MC) of >2000 cells, c) “eyeballed” estimate (EE). 20 pathologists were involved in EE assessment. 45 Ki67 images were selected and analyzed as above. Statistical analyses were performed to evaluate: a) the concordance between methods, b) intra- and inter-observer consistency, and c) correlation of Ki67 scores with the NET grades. Agreement between scores was assessed by intraclass correlation (ICC).
Results: DIA and MC exhibited a concordance of ICC=0.98. ICC between DIA and EE on average was 0.88. Discordance occurred between observers on all cases quantified by EE (ICC 0.13). The intra-observer consistency ICC was 0.39 ± 0.26. Kappa statistic of EE demonstrated low to moderate agreement on all tumor grades proposed by ENETS (Table 1). EE was 93%±2 correct with Ki67 <1%, and 55%±7 with Ki67 of 2-3%. Incorrect assessment resulted in upgrading of all G1 group tumors (n=14); in the G2 group, downgrading of 41% occurred (n=11) when Ki67 was <5% and upgrading of 59% occurred (n=16) when Ki67 was >5%.
|All Grades (29)||0.13 (CI 0.05-0.37)||0.24 (CI 0.23-0.25)|
|Ki67 ≤ 2%, (ENETS G1), n=14||0.01 (CI 0-0.96)||0.12 (CI 0.09-0.16)|
|Ki67 3-20%, (ENETS G2), n=29||0.13 (CI 0.04-0.39)||0.20 (CI 0.07-0.26)|
|Ki67>20%, (ENETS G3) n=2||0.05 (CI n/a)||0.13 (CI n/a)|