Intra-Tumour Heterogeneity Is One of the Main Sources of Inter-Observer Variation in Scoring Stromal Tumour Infiltrating Lymphocytes in Triple Negative Breast Cancer

Simple Summary The stromal tumour infiltrating lymphocytes (sTILs) within a tumour are a strong predictor of outcome for patients with triple negative breast cancer (TNBC). However, the assessment of sTILs is subject to variation and needs to be standardized in order for it to be used more widely as a biomarker. The aim of this study was to determine the level of consistency that can be achieved when an internet-based scoring aid is used to assist with evaluation of sTILs. Twenty-three breast pathologists across Europe scored sTILs in 49 cases of TNBC taken from a routine diagnostic practice using this aid. The consistency of scoring sTILs was good. However, variation in the distribution of sTILs within the tumour resulted in discordance between pathologists scoring cases, particularly as it caused variability in the selection of regions of the tumour to score. More rigorous training of pathologists is needed for standardization of sTILs assessment, which may potentially be improved using automated approaches. Stromal tumour infiltrating lymphocytes (sTILs) are a strong prognostic marker in triple negative breast cancer (TNBC). Consistency scoring sTILs is good and was excellent when an internet-based scoring aid developed by the TIL-WG was used to score cases in a reproducibility study. This study aimed to evaluate the reproducibility of sTILs assessment using this scoring aid in cases from routine practice and to explore the potential of the tool to overcome variability in scoring. Twenty-three breast pathologists scored sTILs in digitized slides of 49 TNBC biopsies using the scoring aid. Subsequently, fields of view (FOV) from each case were selected by one pathologist and scored by the group using the tool. Inter-observer agreement was good for absolute sTILs (ICC 0.634, 95% CI 0.539-0.735, p < 0.001) but was poor to fair using binary cutpoints. sTILs heterogeneity was the main contributor to disagreement. When pathologists scored the same FOV from each case, inter-observer agreement was excellent for absolute sTILs (ICC 0.798, 95% CI 0.727-0.864, p < 0.001) and good for the 20% (ICC 0.657, 95% CI 0.561-0.756, p < 0.001) and 40% (ICC 0.644, 95% CI 0.546-0.745, p < 0.001) cutpoints. However, there was a wide range of scores for many cases. Reproducibility scoring sTILs is good when the scoring aid is used. Heterogeneity is the main contributor to variance and will need to be overcome for analytic validity to be achieved.