Correlação entre a concentração dos linfócitos infiltrantes tumorais (TIL) no câncer de pulmão e a resposta à quimioterapia sistêmica : um estudo transversal

Abstract

lntroduction: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. Despite therapeutic advances, overall survival remains limited, especially in more advanced stages. Tumor-infiltrating lymphocytes (TILs) have emerged as potential biomarkers for prognosis and treatment response due to their association with an active immune microenvironment and improved clinica! outcomes. However, challenges such as methodological standardization and inconsistency in density cut-off points limit their clinica! implementation. Objective: To assess the relationship between TIL density, measured by hematoxylin-eosin (H&E) staining, and response to chemotherapy in patients with stage Ili and IV NSCLC treated at the thoracic oncology unit of UNACON-HGCS. The specific objectives were: (a) to compare TIL quantification by different pathologists to evaluate interobserver reproducibility; (b) to assess overall survival across subgroups defined by lymphocytic infiltration density; (c) to establish a clinically applicable TIL percentage cut-off for prognostic and/or predictive stratification; and (d) to explore the feasibility of morphologic TIL assessment as a clinica! toei in resource-limited settings. Methods: This retrospective cross-sectional study evaluated 51 patients with stage Ili-IV NSCLC. Tumor size was recorded before and after chemotherapy, and TILs were categorized into three density groups. Analysis of covariance (ANCOVA) was performed to examine the association between TIL density and tumor reduction, adjusting for age, sex, and clinica! stage. lnterobserver agreement was assessed using Cohen's kappa, Fleiss' kappa, and Krippendorffs alpha. Results: Tumor reduction differed significantly across TIL density groups, with mean decreases of 0.52 cm (low), -2.42 cm (moderate), and -3.18 cm (high). ANCOVA confirmed a strong association between TIL density and treatment response (F = 83.109; p < 0.001; 112 = 0.551), independent of confounding factors. Smaller baseline tumors also exhibited greater reductions (F = 10.347; p < 0.001). A strong inverse correlation was observed between TIL density and post-treatment tumor size (r = -0.676; p < 0.001). Higher TIL levels were associated with improved overall survival. lnterobserver agreement was substantial (mean kappa = 0.673), demonstrating the reproducibility of H&E-based TIL assessment. Conclusions: TIL density, as assessed by H&E staining, was significantly associated with chemotherapy response and overall survival in patients with advanced NSCLC. The analysis demonstrated good interobserver reproducibility, confirmed the prognostic value of TILs, and allowed the proposal of a clinically applicable cut-off for patient stratification. These results support the use of H&E-based TIL quantification as a low-cost and reproducible toei, potentially useful for identifying patients who may benefit from treatment de-escalation and personalized strategies, especially in systems where immunotherapy is inaccessible. [resumo fornecido pelo autor]