Post-Radiation PET Shows Higher Diagnostic Accuracy in HPV-Negative Head and Neck Cancers

Background: Post-treatment evaluation of residual neck disease in head and neck squamous cell carcinoma (HNSCC) is challenging because of treatment-related changes and biological differences between HPV-positive and HPV-negative tumors. Methods: We performed a prospective single-center study of 58 node-positive HNSCC patients treated with definitive chemoradiotherapy (CRT) followed by 18F-FDG PET/CT. PET-positive patients underwent neck dissection, while PET-negative patients were followed clinically for at least two years. Diagnostic performance was analyzed by p16 status. Results: PET/CT showed high overall accuracy (sensitivity 94%, specificity 83%, PPV 70%, NPV 97%). In p16-negative cases, sensitivity was 93%, specificity 80%, PPV 81%, and NPV 92%. In p16-positive cases, sensitivity and NPV reached 100%, but PPV was only 43%, indicating frequent false positives. Residual disease requiring neck dissection was associated with significantly worse survival (p = 0.008). Conclusions: PET/CT is reliable for post-treatment assessment, especially in p16-negative HNSCC. In p16-positive cases, careful interpretation and standardized PET/CT criteria are needed to reduce false positives and avoid unnecessary surgery.