Validation of the 9th edition cTNM classification for HPV-positive oropharyngeal carcinoma in a non-endemic Chinese cohort

Purpose: The UICC/AJCC ninth edition (TNM9) incorporated imaging-detected extranodal extension (iENE) as a new cN modifier for HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). This single-institutional study evaluates the prognostic value of iENE and the applicability of the revised cTNM in a non-endemic Chinese cohort. Methods: All patients with non-metastatic HPV-positive OPSCC treated with definitive radiotherapy/chemoradiotherapy (RT/CRT) from 2011 to 2022 were included. The iENE status was evaluated on pre-treatment scans by radiologists to reclassify cN categories and overall stage, which were then compared with the TNM8 cTNM for stage distribution and prognostic performance. Results: Among 191 consecutively-treated cases, 66 (34.6%) were iENE-positive and 125 were iENE-negative, including 8 with N0 disease. Median follow-up was 44.0 months (IQR 34.1-53.8). iENE-positive patients had inferior 3-year progression-free survival (PFS) vs iENE-negative (70.8% vs. 96.8%, p < 0.001) and overall survival (OS) (82.6% vs. 98.3%, p < 0.05). On multivariable analysis (adjusted for smoking and TNM8 stage), iENE remained independently prognostic for PFS (HR 6.67, 95% CI 2.36-18.84, p = 0.001). TNM9 reclassified 22.9% (27/118) of TNM8-cN1 to TNM9-cN2 and 41.5% (17/41) of TNM8-cN2 to TNM9-cN3, corresponding to 21.9% (21/96) stage I-to-II and 29.3% (17/58) stage II-to-III shifts. TNM9 stage classification improved PFS discrimination (C-index: cN 0.754 vs 0.673; stage 0.760 vs 0.714). Conclusion: The 9th edition cTNM classification provides better risk stratification and more balanced stage distribution in this Chinese cohort of HPV-positive OPSCC. Validation in a larger cohort is warranted.