Oncologic Outcomes in p16-Positive Oropharyngeal Squamous Cell Carcinoma With Extranodal Extension

Treatment de-escalation in HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) is controversial when extranodal extension (ENE) is present. This study evaluated whether pathologic ENE (pENE) presence and extent (microscopic vs. macroscopic) affect survival outcomes in p16-positive OPSCC treated with primary surgery.

This single-center retrospective cohort included patients with p16-positive OPSCC treated surgically with or without adjuvant treatment from September 2014 to July 2024. Outcomes included overall (OS), disease-specific (DSS), and disease-free survival (DFS). Kaplan-Meier survival curves were compared between groups using log-rank tests. Multivariable analyses used LASSO-selected variables.

Among 232 patients, pENE status was reported in 216, forming the primary multivariable cohort. pENE was present in 115 (53.2%); 69.6% were macroscopic. Five-year OS, DSS, and DFS for the full cohort were 88.5%, 94.4%, and 89.0%, respectively. pENE positivity was not significantly associated with DSS (93.3% vs. 94.6%, p = 0.86), DFS (87.7% vs. 91.7%, p = 0.46), or OS (83.2% vs. 93.4%, p = 0.052). Within pENE-positive disease, 5-year OS was 89.8% for microscopic versus 80.2% for macroscopic pENE (p = 0.22). On complete-case adjusted analysis (N = 96), macroscopic pENE had a nonsignificant 3.8-fold higher hazard of death (HR = 3.77, p = 0.063). Exploratory risk-gradient analysis showed worse OS with macroscopic pENE (HR = 3.29, p = 0.046) and clinical ENE (cENE; HR = 5.07, p = 0.040) compared to a pENE-negative/microscopic pENE reference.

Macroscopic pENE showed a directional association with worse OS, and exploratory analyses suggested a possible risk-gradient with increasing severity from microscopic pENE to cENE. Larger studies are required to determine the clinical significance of pENE extent in surgically treated HPV-associated OPSCC.