Derivation and validation of the AJCC9V pathological stage classification for HPV-positive oropharyngeal carcinoma: a...

Modernisation of the American Joint Committee on Cancer and Union for International Cancer Control (AJCC/UICC) staging for HPV-positive oropharyngeal carcinoma has strengthened its fundamental role to convey prognosis and guide treatment decisions. Implementation has nonetheless revealed imbalances. An AJCC committee reappraised HPV-positive oropharyngeal carcinoma pathological staging to advance prognostic accuracy and improve clinical applicability.

For this analysis, US registry data from the National Cancer Database were divided into derivation and validation cohorts. Eligible cases encompassed surgically treated adult patients aged 18 years or older with HPV-positive oropharyngeal carcinoma. The primary objective was to derive and validate an optimised HPV-positive oropharyngeal carcinoma pathological staging classification based on determinants of overall survival. Multivariable Cox regression models were used to assess lymph node characteristics for overall survival. Non-linear associations between metastatic lymph node number and survival were modelled with restricted cubic splines. Adjusted hazard ratios (AHRs) and recursive partitioning analysis methods were applied to generate optimal classification groups. Performance was evaluated with Groome's criteria.

Overall, 14 447 patients across 984 facilities in the USA met the criteria for inclusion, and were divided into a derivation cohort (n=7768) and validation cohort (n=6679). Patients were treated between 2010 and 2019; 12 276 (85·0%) were male, 2171 (15·0%) were female, 13 594 (94·1%) were White, and 4552 patients (31·5%) had pathological extranodal extension (pENE). Median follow-up was 52·4 months (95% CI 51·5-53·3). Mortality risk increased with each additional metastatic lymph node (HR 1·20 [95% CI 1·11-1·29], p<0·0001), up to an optimal cutoff at 4·3 lymph nodes. Multivariable analysis confirmed the association of pENE with increased mortality risk (HR 1·47 [95% CI 1·30-1·65], p<0·0001), but no significant prognostic changes were shown by the extent of pENE (minor vs major). AHR approaches derived and validated optimised pN and pTNM stage categories (N1a: 1 positive lymph node and pENE-negative; N1b: 2-4 positive lymph nodes and pENE-negative; N2: >4 positive lymph nodes and pENE-negative or 1-4 positive lymph nodes and ENE-positive; N3: >4 positive lymph nodes and ENE-positive; Stage I: T0-2N0-1M0; Stage II: T0-2N2-3M0 or T3N0-2M0; Stage III: T3N3M0 or T4N0-3MO); Stage IV: M1. AJCC9V showed superior hazard consistency, outcome prediction, and balance, but not hazard discrimination, compared to AJCC8E. The AJCC Expert Panel on HPV-positive oropharyngeal carcinoma endorsed the proposal by Delphi consensus.

The AJCC9V HPV-positive oropharyngeal carcinoma staging classification confers an improved schema for guiding prognostication and management compared to AJCC8E. Incorporating ENE and correcting imbalances will enhance clinical relevance and align pathological staging in a condition whose management continues to evolve.

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