Jing Nicola, Fang Catherine, Williams David S
Department of Pathology, Austin Health, Heidelberg, Australia; Melbourne Medical School, University of Melbourne, Parkville, Australia.
School of Cancer Medicine, Olivia Newton-John Cancer Research Institute, Latrobe University, Heidelberg, Australia.
Pathology. 2017 Jun;49(4):371-378. doi: 10.1016/j.pathol.2017.02.001. Epub 2017 Apr 24.
Ki-67 is a prognostic and predictive biomarker in oestrogen receptor positive breast cancer. However, its measurement is not well standardised. This study compared the validity, intra- and inter-observer reproducibility and reporting time of five methods of Ki-67 assessment on tissue microarrays (TMA) and whole slides. Ki-67 labelling index (LI) was assessed on 71 breast carcinomas of no special type (NST), using five methods: manual counting (gold standard), unaided visual estimation, visual estimation aided by reference photographs, semi-manual digital image analysis (DIA) and fully automated DIA (Aperio platform). On TMA, semi-manual DIA demonstrated the closest agreement with the gold standard [intra-class correlation coefficient (ICC)=0.99 (95% confidence interval 0.98-0.99)]. All other methods also demonstrated close agreement [unaided estimation ICC=0.92 (0.90-0.93), aided estimation ICC=0.93 (0.92-0.95), fully automated DIA ICC=0.97 (0.96-0.97)]. On whole slides, both aided estimation and semi-manual DIA demonstrated excellent agreement with the gold standard [aided visual estimation ICC=0.91 (0.85-0.94), semi-manual DIA ICC=0.94 (0.89-0.96)]. Aided visual estimation significantly improved inter-observer reproducibility compared to unaided estimation [unaided ICC=0.87 (0.80-0.92); aided ICC=0.96 (0.93-0.97)] and corrected the underestimation bias seen in unaided estimation. Importantly, validity and reproducibility on whole slides were lower than on TMA for all methods of assessment, suggesting that field selection is an important source of variability in Ki-67 assessment. Values close to clinically used cut-off values therefore should be interpreted with caution.
Ki-67是雌激素受体阳性乳腺癌的一种预后和预测生物标志物。然而，其测量方法尚未得到很好的标准化。本研究比较了五种在组织微阵列（TMA）和全切片上评估Ki-67的方法的有效性、观察者内和观察者间的可重复性以及报告时间。使用五种方法对71例非特殊类型（NST）乳腺癌的Ki-67标记指数（LI）进行评估：手工计数（金标准）、无辅助视觉估计、参考照片辅助视觉估计、半自动数字图像分析（DIA）和全自动DIA（Aperio平台）。在TMA上，半自动DIA与金标准的一致性最接近[组内相关系数（ICC）=0.99（95%置信区间0.98 - 0.99）]。所有其他方法也显示出密切的一致性[无辅助估计ICC = 0.92（0.90 - 0.93），辅助估计ICC = 0.93（0.92 - 0.95），全自动DIA ICC = 0.97（0.96 - 0.97）]。在全切片上，辅助视觉估计和半自动DIA与金标准均显示出极好的一致性[辅助视觉估计ICC = 0.9（0.85 - 0.94），半自动DIA ICC = 0.94（0.89 - 0.96）]。与无辅助估计相比，辅助视觉估计显著提高了观察者间的可重复性[无辅助ICC = 0.87（0.80 - 0.92）；辅助ICC = 0.96（0.93 - 0.97）]，并纠正了无辅助估计中出现的低估偏差。重要的是，所有评估方法在全切片上的有效性和可重复性均低于在TMA上，这表明视野选择是Ki-评估中变异性的一个重要来源。因此，对于接近临床使用临界值的值应谨慎解释。
