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Patients with head and neck squamous cell carcinoma (HNSCC) are at elevated risk of second primary malignancies (SPM), most commonly of the head and neck (HN), lung, and esophagus. Our objectives were to identify HNSCC subsite-specific differences in SPM risk and distribution and to describe trends in risk over 3 decades, before and during the era of human papillomavirus (HPV) –associated oropharyngeal SCC.

Population-based cohort study of 75,087 patients with HNSCC in the Surveillance, Epidemiology, and End Results (SEER) program. SPM risk was quantified by using standardized incidence ratios (SIRs), excess absolute risk (EAR) per 10,000 person-years at risk (PYR), and number needed to observe. Trends in SPM risk were analyzed by using joinpoint log-linear regression.

In patients with HNSCC, the SIR of second primary solid tumor was 2.2 (95% CI, 2.1 to 2.2 …