Tumor-Infiltrating Lymphocytes Predict Extranodal Extension and Prognosis in Regionally Advanced Oral Cavity Cancer

<b>Background/Objectives:</b> Oral cavity squamous cell carcinoma (OCSCC) is an aggressive malignancy, often diagnosed at an advanced stage and with stagnant survival outcomes despite advances in surgical and oncologic management. Tumor-infiltrating lymphocytes (TILs) have been explored as potential prognostic markers in many solid tumors; however, their role in OCSCC remains under researched. This study aimed to assess the prognostic value of TILs in a cohort of patients with regionally advanced, p16-negative squamous cell carcinoma of all oral cavity subsites and to evaluate for any correlation of TILs and extranodal extension (ENE). <b>Methods:</b> A retrospective study was conducted on 103 consecutive patients treated with comprehensive surgical resection. TILs were quantified using the standardized method proposed by the International Immuno-Oncology Biomarkers Working Group. Statistical analyses evaluated associations with a comprehensive set of independent variables and survival endpoints. <b>Results</b>: High stromal infiltration at the invasive margin (>25%) was independently associated with significantly improved overall survival (HR 4.53, <i>p</i> = 0.005), disease-specific survival (HR 4.49, <i>p</i> = 0.008), and disease-free survival (HR 3.42, <i>p</i> = 0.025). Patients with ENE demonstrated lower TILs compared with ENE-negative patients (median 40% vs. 57.5%), a difference that reached statistical significance in both parametric and nonparametric testing (Welch's <i>t</i>-test <i>p</i> = 0.032; Mann-Whitney U <i>p</i> = 0.030). <b>Conclusions</b>: TILs quantified by this standardized method are a reliable, independent prognostic biomarker in regionally advanced OCSCC of all subsites and are also associated with extranodal extension of regional metases. This study gives rationale for consideration of inclusion of TILS into future immunotherapeutic decision-making and further investigations of TIL-ENE association.