Assessment of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Interobserver Variability and Contributing Factors.

Abstract

Background/Objectives: Tumor-infiltrating lymphocytes (TILs) are emerging as a crucial prognostic biomarker in triple-negative breast cancer (TNBC). However, their clinical utility remains constrained by the subjectivity and interobserver variability of manual scoring, despite standardization efforts by the International TILs Working Group (TIL-WG). This study aimed to evaluate the interobserver agreement among pathologists in scoring stromal and intratumoral TILs from H&E-stained TNBC slides and to identify contributing histological factors. Methods: Two consultant pathologists at Hospital Canselor Tuanku Muhriz, Kuala Lumpur, independently assessed 64 TNBC cases using TIL-WG guidelines. Interobserver agreement was quantified using the intraclass correlation coefficient (ICC) and Cohen's kappa coefficient. Cases with over 10% scoring discrepancies underwent review by a third pathologist, and a consensus discussion was held to explore the underlying confounders. Results: Our results showed moderate interobserver agreement for stromal TILs (ICC = 0.58) and strong agreement for intratumoral TILs (ICC = 0.71). Significant variability was attributed to three main confounding variables: heterogeneous TIL distribution, poorly defined tumor-stroma interface, and focal dense lymphoid infiltrates. Conclusions: These findings highlight the need for standardized TIL scoring protocols and suggest that validated AI-based tools may help mitigate observer variability in future TIL assessments.