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Multicenter Study
. 2025 Jul 1;151(7):655-664.
doi: 10.1001/jamaoto.2025.0848.

A Proposal for HPV-Associated Oropharyngeal Carcinoma in the Ninth Edition Clinical TNM Classification

Shao Hui Huang  1 , Jie Su  2 , Shlomo A Koyfman  3 , David Routman  4 , Frank Hoebers  5 , Houda Bahig  6 , Eugene Yu  7 , Eric Bartlett  7 , Anna Spreafico  8 , Jonathan Lee  9 , Sarah Stock  9 , Robin Davis  3 , Neil M Woody  3 , Kristoff Nelson  10 , Danny Lavigne  6 , Phuc Felix Nguyen-Tan  6 , Laurent Létourneau-Guillon  10 , Edith Filion  6 , Alex A Nagelschneider  11 , Daniel Ma  4 , Kathryn M Van Abel  12 , Alida A Postma  13   14 , Walter M Palm  13 , Ann Hoeben  15 , William Lydiatt  16 , Snehal G Patel  17 , Melvin L K Chua  18 , Wei Xu  2 , Brian O'Sullivan  1
Affiliations
Multicenter Study

A Proposal for HPV-Associated Oropharyngeal Carcinoma in the Ninth Edition Clinical TNM Classification

Shao Hui Huang et al. JAMA Otolaryngol Head Neck Surg. .

Abstract

Importance: A subset of Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) eighth edition TNM stage I and II human papillomavirus-positive oropharyngeal carcinoma has undesirable outcomes, which might have contributed to a lack of success in phase III deintensification trials. Refining clinical stage groups, especially in the overabundant cN1/stage I group, has become important for treatment selection.

Objective: To assess the prognostic importance of pretreatment lymph node (LN) characteristics to optimize case distribution and outcome homogeneity within the N classification system.

Design, setting, and participants: This is an international multi-institutional retrospective prognostic cohort study. Analysis of human papillomavirus-positive oropharyngeal carcinoma treated curatively from 4 institutions (International Collaboration of Oropharyngeal Cancer Network for N-Classification [ICON-N] dataset) provided a refined clinical staging proposal; an independent dataset (Centre Hospitalier de l'Université de Montréal [CHUM] dataset) validated the proposal. Neuroradiologists reviewed pretreatment computed tomography and/or magnetic resonance imaging for nodal features, including presence or absence of abnormal LN(s), retropharyngeal LN, laterality, number of abnormal LN, and imaging-detected extranodal extension (iENE). Data were collected from February to May 2023, and data were analyzed from June to July 2023.

Exposures: Definitive chemoradiotherapy/radiotherapy or definitive surgery with or without postoperative chemoradiotherapy/radiotherapy.

Main outcomes and measures: The primary end point was overall survival. A Cox proportional hazards multivariable model was used to estimate adjusted hazard ratios (AHRs) and to derive an optimal clinical TNM stage classification (AHR-stage schema) incorporating the strongest prognostic nodal features within the UICC/AJCC eighth edition TNM framework after confirming the prognostication of iENE status. The performance (according to overall normalized scores and ranking) of the AHR-stage schema against the current UICC/AJCC eighth edition TNM staging system was evaluated for hazard consistency, hazard discrimination, prognostic importance, and sample size balance. Validation was performed in the CHUM dataset.

Results: The ICON-N dataset comprised 2053 patients, including 1898 (92.5%) with cN-positive disease and 155 (7.5%) with cN0 disease; a total of 298 (14.5%) were female, and the mean (SD) age was 60.6 (9.3) years. iENE-positive disease was identified in 710 of 1898 patients with cN-positive disease (37.4%). The median (range) follow-up was 5.1 (0.1-14.7) years. iENE was the strongest prognostic nodal feature in multivariable analysis; the AHR for iENE-positive vs iENE-positive disease was 2.43 (95% CI, 1.96-3.03) in the ICON-N dataset and 2.04 (95% CI, 1.28-3.23) in the CHUM dataset (n = 451). Reclassifying iENE-positive cases 1 stratum higher for N categorization without altering iENE-negative cases yielded an AHR-stage schema that outperformed the current TNM staging system in disease-free and overall survival with a lower (ie, better) overall normalized score (2 vs 3).

Conclusions and relevance: In this study, reclassifying each N category 1 stratum higher for iENE-positive disease resulted in better disease-free and overall survival. The proposed new classification outperformed the currently TNM staging system in risk stratification and may facilitate future clinical trial design, outcomes research, and patient care.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Koyfman reported personal fees from Merck, BMS, Regeneron, Castle Biosciences, Galera Therapeutics, Varian Medical Systems, and UpToDate outside the submitted work. Dr Routman reported nonfinancial support from Naveris during the conduct of the study; serves on the advisory board for Adela outside the submitted work; has a patent for DNA methylation licensed to Exact Sciences; and is supported by the Paul Calabresi Program in Clinical/Translational Research at the Mayo Clinic Comprehensive Cancer Center. Dr Bahig reported personal fees from AstraZeneca and grants from Varian outside the submitted work. Dr Spreafico reported grants from Merck, GSK, BMS, Symphogen, AstraZeneca, Bayer, Surface Oncology, Array Biopharma/Pfizer, Oncorus, Treadwell, Regeneron, Alkermes, Amgen, Roche, Seagen, Teva Therapeutics, Merus, and ALX Oncology as well as personal fees from Merck, GSK, and BeiGene outside the submitted work. Dr Davis reported support from the Melvin Markey Discovery Fund at the Cleveland Clinic during the conduct of the study. Dr Letourneau-Guillon reported grants from Fonds de Recherche du Quebec en Sante and Fondation de l’Association des Radiologistes du Quebec Clinical Research Scholarship–Junior 1 Salary Award outside the submitted work. Dr Postma reported grants from Siemens Healthineers outside the submitted work. Dr Patel reported a patent for PCT/US2016/026717 issued, a patent for US10,016,238 B2 issued, a patent for PCT/US2014/073053 issued, a patent for PCT/US2015/065816 issued, a patent for PCT/US2016/066969 issued, and a patent for WO2019212945A1 issued. No other disclosures were reported.

References

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