Validation and refinement of the AJCC 8th edition ypStage in esophageal squamous cell carcinoma after neoadjuvant...

The AJCC 8th edition post-neoadjuvant pathologic stage (ypStage) shows limited prognostic discrimination in esophageal squamous cell carcinoma (ESCC). Alternative strategies have been proposed, but most were limited by small samples and lack of inclusion of patients treated with immunotherapy. This study aimed to validate the AJCC 8th edition ypStage and develop a refined ypStage system with improved prognostic performance for ESCC.

This was a large retrospective cohort study including 1848 consecutive ESCC patients treated with neoadjuvant therapy followed by esophagectomy between June 2018 and September 2023. Patients were randomly assigned to training (n = 1108) and validation (n = 740) cohorts. A refined ypStage was developed using recursive partitioning analysis (RPA). Survival outcomes were evaluated using Kaplan-Meier curves and log-rank tests, and multivariable Cox proportional hazards regression was used to confirm independent prognostic value. Prognostic performance of the RPA and AJCC 8th edition ypStage systems was compared using the Groome criteria: hazard consistency, hazard discrimination, sample balance, outcome prediction, and overall score. Subgroup analyses were performed by neoadjuvant therapy type.

The AJCC 8th edition ypStage showed a reversal of the expected survival hierarchy between ypStage II and IIIA [3-year overall survival (OS): II, 80.1%; IIIA, 90.7%]. RPA identified three groups: ypStage I (ypT0-2N0-1), II (ypT0-2N2-3 or ypT3-4bN0-1), and III (ypT3-4bN2-3). In the validation cohort, RPA ypStage demonstrated clear survival separation (3-year OS: I, 91.2%; II, 79.1%; III, 60.5%; pairwise P < 0.01). Multivariable analysis confirmed its independent prognostic value [II vs I: Hazard Ratio (HR) = 2.44, 95% Confidence Interval (CI): 1.68-3.52; III vs I: HR = 3.67, 95% CI: 2.28-5.90; both P < 0.001]. RPA ypStage outperformed AJCC ypStage across all evaluation metrics. Subgroup analyses further supported its robustness, particularly in patients receiving chemotherapy or chemo-immunotherapy.

The RPA-derived ypStage provides improved prognostic stratification compared with the AJCC 8th edition in ESCC patients following neoadjuvant therapy. Further external validation is warranted for potential incorporation into future staging guidelines.