Incidence of HPV-independent second primary malignancies following treatment of HPV-associated malignancy

Second primary tumors after HPV-associated oropharyngeal squamous cell carcinoma (HPV + OPSCCa) are generally assumed to share the same HPV status as the index lesion, and current pathology guidelines discourage repeat HPV testing in recurrent disease. We retrospectively reviewed records from a tertiary academic center (2010-2024) to identify patients with a history of HPV + OPSCCa who subsequently developed an HPV-independent second primary head and neck squamous cell carcinoma. HPV status was determined by p16 immunohistochemistry, high-risk HPV DNA PCR, or RNA in situ hybridization. Eleven patients developed metachronous HPV-independent malignancies, representing an incidence of 2.5 %. The median interval between tumors was 8.8 years (range, 3.2-16.0 years). Second primaries most often arose in the contralateral base of tongue (55 %) or oral cavity (27 %). All patients had received definitive or adjuvant radiation for the initial tumor, and 73 % received concurrent chemotherapy. Four patients (36 %) reported a smoking history >10 pack-years. Most tumors at both time points were T1 or T2, but node-positive disease was more frequent in first primaries (82 % vs 18 %). Two patients developed a third HPV-independent primary tumor. These findings demonstrate that biologically discordant second primary head and neck cancers can emerge years after HPV + OPSCCa, challenging the assumption of HPV concordance and underscoring the need for long-term surveillance and reconsideration of repeat HPV testing in this population.