An International Ki67 Reproducibility Study
An International Ki67 Reproducibility Study
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DOI：
10.1093/jnci/djt306
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发表时间：
2013-12-01
影响因子：
10.3
通讯作者：
Nielsen, Torsten O.
中科院分区：
文献类型：
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作者：
Polley, Mei-Yin C.;Leung, Samuel C. Y.;Nielsen, Torsten O.
在乳腺癌中，使用Ki67标记物对增殖进行免疫组化评估在研究和临床管理中都有潜在用途。然而，实验室之间缺乏一致性限制了Ki67的价值。成立了一个工作组来制定一项策略，以协调Ki67分析并提高评分的一致性。为了实现这一目标，我们进行了一项Ki67可重复性研究。八个实验室收到了100例乳腺癌病例，这些病例被制成1毫米的芯组织微阵列——一组由参与实验室染色，另一组由中心实验室染色，都使用MIB - 1抗体。每个实验室使用自己的方法将Ki67评分为阳性染色的浸润性肿瘤细胞的百分比。六个实验室在3个不同的日子对50例本地染色的病例重复评分。使用对数2转换测量的随机效应模型分析变异来源。通过组内相关系数（ICC）量化可重复性，并提供了这些实验中真实组内相关系数的近似双侧95%置信区间（CIs）。实验室内可重复性较高（ICC为0.94；95%CI为0.93 - 0.97）。实验室间可重复性仅为中等（中心染色：ICC为0.71，95%CI为0.47 - 0.78；本地染色：ICC为0.59，95%CI为0.37 - 0.68）。100例病例中每个实验室的Ki67值的几何平均值，中心染色为7.1% - 23.9%，本地染色为6.1% - 30.1%。导致实验室间不一致的因素包括肿瘤区域选择、计数方法以及对染色阳性的主观评估。正式计数方法比目测估计能给出更一致的结果。在一些世界上最有经验的实验室中观察到Ki67评分存在很大差异。如果不标准化评分方法，Ki67值和用于临床决策的截断值无法在实验室之间转移，因为分析有效性有限。
In breast cancer, immunohistochemical assessment of proliferation using the marker Ki67 has potential use in both research and clinical management. However, lack of consistency across laboratories has limited Ki67s value. A working group was assembled to devise a strategy to harmonize Ki67 analysis and increase scoring concordance. Toward that goal, we conducted a Ki67 reproducibility study.Eight laboratories received 100 breast cancer cases arranged into 1-mm core tissue microarraysuone set stained by the participating laboratory and one set stained by the central laboratory, both using antibody MIB-1. Each laboratory scored Ki67 as percentage of positively stained invasive tumor cells using its own method. Six laboratories repeated scoring of 50 locally stained cases on 3 different days. Sources of variation were analyzed using random effects models with log2-transformed measurements. Reproducibility was quantified by intraclass correlation coefficient (ICC), and the approximate two-sided 95% confidence intervals (CIs) for the true intraclass correlation coefficients in these experiments were provided.Intralaboratory reproducibility was high (ICC 0.94; 95% CI 0.93 to 0.97). Interlaboratory reproducibility was only moderate (central staining: ICC 0.71, 95% CI 0.47 to 0.78; local staining: ICC 0.59, 95% CI 0.37 to 0.68). Geometric mean of Ki67 values for each laboratory across the 100 cases ranged 7.1% to 23.9% with central staining and 6.1% to 30.1% with local staining. Factors contributing to interlaboratory discordance included tumor region selection, counting method, and subjective assessment of staining positivity. Formal counting methods gave more consistent results than visual estimation.Substantial variability in Ki67 scoring was observed among some of the worlds most experienced laboratories. Ki67 values and cutoffs for clinical decision-making cannot be transferred between laboratories without standardizing scoring methodology because analytical validity is limited.