A combined histopathological treatment response classification is associated with survival and pretreatment immune features in head and neck squamous cell carcinoma treated with neoadjuvant chemoradiotherapy

Abstract A standardized system for assessing histopathological treatment response (HTR) in head and neck squamous cell carcinoma (HNSCC) is lacking, an issue of increasing relevance with growing interest in neoadjuvant therapies. In this retrospective study, paired pre- and post-treatment samples from 53 patients with HNSCC treated with curative-intent neoadjuvant radiotherapy or chemoradiotherapy (RT/CRT) were analyzed histopathologically and immunohistochemically for CD8, CD68, CD206, Clever-1, and PD-L1. Post-treatment histiocytic multinucleated giant cell reaction (MGC) was associated with favorable overall survival (OS) and with the pre-treatment immune microenvironment. Based on these findings, a two-tiered combined HTR (cHTR) classification integrating tumor regression grade (TRG) and MGC was developed. Good cHTR was associated with a 5-year OS of 59% versus 16% for poor cHTR (HR 0.21; 95% CI 0.09–0.47, p < 0.001). High pre-treatment tumor-cell PD-L1 expression was associated with absence of MGC, while elevated pre-treatment PD-L1 expression and CD8⁺ intraepithelial tumor infiltrating lymphocyte (iTIL) density were potential predictive markers of poor cHTR. The proposed cHTR classification provided clear OS stratification in this cohort but should be considered exploratory and requires validation in independent cohorts. CD8⁺ iTILs and PD-L1 may represent predictive biomarkers of histopathological response to neoadjuvant treatment and warrant further prospective validation.