Recurrences and Survival in Oropharyngeal Squamous Cell Carcinoma According to p16 Status and Extranodal Extension

Objective: Extranodal extension (ENE) is a recognized adverse prognostic factor in oropharyngeal squamous cell carcinoma (OPSCC). However, most evidence concerns clinical ENE, whereas data on pathologic ENE (pENE) are limited. With the renewed role of surgery in the management of OPSCC, this study evaluates the prognostic significance of pENE according to HPV status. Study design: Multicenter retrospective cohort conducted from 2010 to 2021. Setting: Specialized otolaryngology-head and neck surgery European departments. Methods: Patients aged 18 years or older who underwent primary surgery for OPSCC of the tonsil or base of tongue were included. HPV status was based on p16 expression assessed by immunohistochemistry. pENE was classified as present or absent. We estimated overall survival (OS), disease-free survival (DFS), and recurrence patterns, adjusting for competing risks. Results: Among 650 patients, 284 (43.7%) were p16-positive and 166 (25.5%) reported presence of pENE. In p16-negative patients, those with pENE showed a worse 5-year DFS (35.6% vs 43.5%; adjusted HR [aHR], 1.64; 95% CI, 1.09-2.46) and OS (43.3% vs 52.0%; aHR, 1.76, 95% CI, 1.14-2.73) than those without. Cumulative incidence of recurrence was significantly higher in p16-negative patients with pENE (55.8% vs 37.0%). pENE was significantly associated with increased risk of distant metastases only in p16-negative patients (21.0% vs 7.6%; aHR, 2.52; 95% CI, 1.03-625). Conclusions: The prognostic role of pENE in OPSCC appears to differ by HPV status. These findings underline the importance of considering HPV status when interpreting the prognostic significance of pENE.