Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
German Cancer Consortium (DKTK), Partner site Berlin, Berlin, Germany.
Mod Pathol. 2016 Oct;29(10):1155-64. doi: 10.1038/modpathol.2016.109. Epub 2016 Jul 1.
Multiple independent studies have shown that tumor-infiltrating lymphocytes (TIL) are prognostic in breast cancer with potential relevance for response to immune-checkpoint inhibitor therapy. Although many groups are currently evaluating TIL, there is no standardized system for diagnostic applications. This study reports the results of two ring studies investigating TIL conducted by the International Working Group on Immuno-oncology Biomarkers. The study aim was to determine the intraclass correlation coefficient (ICC) for evaluation of TIL by different pathologists. A total of 120 slides were evaluated by a large group of pathologists with a web-based system in ring study 1 and a more advanced software-system in ring study 2 that included an integrated feedback with standardized reference images. The predefined aim for successful ring studies 1 and 2 was an ICC above 0.7 (lower limit of 95% confidence interval (CI)). In ring study 1 the prespecified endpoint was not reached (ICC: 0.70; 95% CI: 0.62-0.78). On the basis of an analysis of sources of variation, we developed a more advanced digital image evaluation system for ring study 2, which improved the ICC to 0.89 (95% CI: 0.85-0.92). The Fleiss' kappa value for <60 vs ≥60% TIL improved from 0.45 (ring study 1) to 0.63 in RS2 and the mean concordance improved from 88 to 92%. This large international standardization project shows that reproducible evaluation of TIL is feasible in breast cancer. This opens the way for standardized reporting of tumor immunological parameters in clinical studies and diagnostic practice. The software-guided image evaluation approach used in ring study 2 may be of value as a tool for evaluation of TIL in clinical trials and diagnostic practice. The experience gained from this approach might be applicable to the standardization of other diagnostic parameters in histopathology.
多项独立研究表明，肿瘤浸润淋巴细胞（TIL）与乳腺癌的预后相关，并且可能与免疫检查点抑制剂治疗的反应相关。虽然许多研究小组正在评估 TIL，但目前还没有用于诊断应用的标准化系统。本研究报告了由免疫肿瘤生物标志物国际工作组进行的两项 TIL 环研究的结果。研究目的是确定不同病理学家评估 TIL 的组内相关系数（ICC）。在环研究 1 中，病理学家通过基于网络的系统评估了 120 张幻灯片，在环研究 2 中，病理学家使用了更先进的软件系统，该系统包括带有标准化参考图像的集成反馈。成功完成环研究 1 和 2 的预定目标是 ICC 大于 0.7（95%置信区间（CI）下限）。在环研究 1 中，未达到预定终点（ICC：0.70；95%CI：0.62-0.78）。基于对变异源的分析，我们为环研究 2 开发了一种更先进的数字图像评估系统，将 ICC 提高到 0.89（95%CI：0.85-0.92）。TIL<60%与≥60%之间的 Fleiss' kappa 值从环研究 1 的 0.45 提高到 RS2 的 0.63，平均一致性从 88%提高到 92%。这个大型的国际化标准化项目表明，在乳腺癌中可以实现 TIL 的可重复评估。这为在临床研究和诊断实践中标准化报告肿瘤免疫学参数开辟了道路。环研究 2 中使用的软件引导图像评估方法可能作为临床试验和诊断实践中评估 TIL 的工具具有价值。从这种方法中获得的经验可能适用于组织病理学中其他诊断参数的标准化。
