[712] 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%.

Table 1. Correlation of EE Assessment of Ki67 and Tumor Grades (using DIA as gold standard)

	ICC	Kappa Value
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)

Conclusions: DIA and MC are the gold standards for Ki67 assessment. Given the inherent discordance in determining the grade (especially for NETs bordering between low and intermediate grade), the use of an “eyeballed” Ki67 index alone requires critical reevaluation. Determination of therapeutic strategies should be guided by an amalgamation of clinicopathological characteristics of an individual tumor.
Category: Gastrointestinal

Tuesday, March 1, 2011 1:00 PM

Poster Session IV # 65, Tuesday Afternoon