Correlation of tumor-infiltrating lymphocyte spatial distribution patterns with HER2 expression status and prognostic significance in gastric adenocarcinoma: a retrospective study based on digital pathology.

Abstract

Background: The spatial distribution of tumor-infiltrating lymphocytes (TILs) has prognostic value in solid tumors, but its relationship with HER2 status in gastric adenocarcinoma remains poorly characterized.

Methods: TIL densities in the tumor center (CT) and at the invasive margin (IM) were assessed on H&E-stained slides using QuPath, and the edge/center ratio (E/C ratio = IM-TILs/CT-TILs) was calculated. The optimal cut-off for E/C ratio was determined by maximizing the log-rank statistic. Survival analyses were performed using Kaplan-Meier and Cox regression.

Results: The HER2-positive group (n = 35) exhibited significantly lower CT-TILs (11.92% vs. 20.98%, P < 0.001) and a higher E/C ratio (2.11 vs. 1.25, P < 0.001) than the HER2-negative group (n = 165). Using an optimal cut-off of 1.57, high E/C ratio was associated with significantly worse overall survival (OS) in the whole cohort (median 14.64 vs. 42.87 months; log-rank P < 0.001). Multivariate Cox regression, adjusting for clinicopathological factors, revealed that the E/C ratio as a continuous variable was independently prognostic (HR = 1.398, P < 0.001), and a significant interaction between HER2 status and E/C ratio was observed (HR = 1.844, P = 0.001). Dichotomization at E/C > 1.57 provides significant prognostic stratification, an effect that is modified by HER2 status; however, due to the small HER2-positive subgroup, these findings require validation in larger independent cohorts.

Conclusions: HER2-positive gastric adenocarcinoma exhibits an "edge-limiting" immune phenotype with elevated E/C ratio. Digital assessment of TILs on routine H&E sections is simple and promising for clinical translation.