PET/CT Diagnostic Accuracy for Synchronous Primary HPV-Positive Oropharyngeal Tumors: A Multi-Institutional Study.

BACKGROUND: The incidence of human papillomavirus-associated (HPV) oropharyngeal squamous cell carcinoma (OPSCC) is rising, making accurate detection of synchronous primary tumors essential for staging and treatment planning. METHODS: This multi-institutional retrospective cohort study (2019-2026) included adult participants across three academic tertiary centers who underwent PET/CT and subsequent biopsy or surgical resection with histopathological confirmation of p16-positive disease. RESULTS: Among 306 patients meeting inclusion criteria, PET/CT identified 15 suspicious for synchronous primary tumors; seven (mean age 58.90 ± 11.48 years) were pathologically confirmed. PET/CT demonstrated 77.78% sensitivity, 97.31% specificity, 46.67% positive predictive value (PPV), and 99.31% negative predictive value (NPV). False positives were attributed to physiologic bilateral uptake, reactive lymphoid tissue, or inflammation. CONCLUSIONS AND RELEVANCE: PET/CT demonstrates excellent NPV for excluding synchronous primary tumors in HPV-positive OPSCC and moderate PPV for identifying them. In settings of multifocal fluorodeoxyglucose uptake, pathologic confirmation is warranted prior to definitive management.