Artificial Intelligence Model for Imaging-Based Extranodal Extension Detection and Outcome Prediction in Human Papillomavirus−Positive Oropharyngeal Cancer

Importance Although not included in the eighth edition of the American Joint Committee on Cancer Staging System , there is growing evidence suggesting that imaging-based extranodal extension (iENE) is associated with worse outcomes in HPV-associated oropharyngeal carcinoma (OPC). Key challenges with iENE include the lack of standardized criteria, reliance on radiological expertise, and interreader variability. Objective To develop an artificial intelligence (AI)−driven pipeline for lymph node segmentation and iENE classification using pretreatment computed tomography (CT) scans, and to evaluate its association with oncologic outcomes in HPV-positive OPC. Design, Setting, and Participants This was a single-center cohort study conducted at a tertiary oncology center in Montreal, Canada, of adult patients with HPV-positive cN + OPC treated with up-front (chemo)radiotherapy from January 2009 to January 2020. Participants were followed up until January 2024. Data analysis was performed from March 2024 to April 2025. Exposures Pretreatment planning CT scans along with lymph node gross tumor volume segmentations performed by expert radiation oncologists were extracted. For lymph node segmentation, an nnU-Net model was developed. For iENE classification, radiomic and deep learning feature extraction methods were compared. Main Outcomes and Measures iENE classification accuracy was assessed against 2 expert neuroradiologist evaluations using area under the receiver operating characteristic curve (AUC). Subsequently, the association of AI-predicted iENE with oncologic outcomes—ie, overall survival (OS), recurrence-free survival (RFS), distant control (DC), and locoregional control (LRC)—was assessed. Results Among 397 patients (mean [SD] age, 62.3 [9.1] years; 80 females [20.2%] and 317 males [79.8%]), AI-iENE classification using radiomics achieved an AUC of 0.81. Patients with AI-predicted iENE had worse 3-year OS (83.8% vs 96.8%), RFS (80.7% vs 93.7%), and DC (84.3% vs 97.1%), but similar LRC. AI-iENE had significantly higher Concordance indices than radiologist-assessed iENE for OS (0.64 vs 0.55), RFS (0.67 vs 0.60), and DC (0.79 vs 0.68). In multivariable analysis, AI-iENE remained independently associated with OS (adjusted hazard ratio [aHR], 2.82; 95% CI, 1.21-6.57), RFS (aHR, 4.20; 95% CI, 1.93-9.11), and DC (aHR, 12.33; 95% CI, 4.15-36.67), adjusting for age, tumor category, node category, and number of lymph nodes. Conclusions and Relevance This single-center cohort study found that an AI-driven pipeline can successfully automate lymph node segmentation and iENE classification from pretreatment CT scans in HPV-associated OPC. Predicted iENE was independently associated with worse oncologic outcomes. External validation is required to assess generalizability and the potential for implementation in institutions without specialized imaging expertise.