Higher-order multiple primary cancers and persistent cross-site risk across human papillomavirus-related anatomical sites in the United States: a population-based Surveillance, Epidemiology, and End Results study.

Objective: Survivors of cancers at human papillomavirus (HPV)-related sites are at increased risk of subsequent malignancies, but the burden and patterns of higher-order (≥3 primaries) multiple primary cancers (MPCs) and long-term cross-site risk patterns remain poorly understood. This study characterized these patterns and evaluated implications for cancer prevention and early detection. Methods: This population-based retrospective cohort study analyzed data from the United States Surveillance, Epidemiology, and End Results (SEER)-8, SEER-17, and SEER-21 registries from 1975 to 2022. We evaluated the incidence and distribution of MPCs as well as latency-specific standardized incidence ratios and cross-site associations across HPV-related sites. Results: Among 15.9 million cancer cases, 2.8 million (17.6%) were MPCs. Higher-order MPCs accounted for 4.1%-4.6% of diagnoses. Most HPV-related sites showed significantly elevated risk of higher-order MPCs, and the risk of MPCs persisted for ≥10 years of latency. Bidirectional cross-site associations included anus-to-tonsil and tongue-to-vulva associations at latency intervals of ≥10 years. Conclusions: Higher-order MPCs represent a substantial and underrecognized component of overall cancer burden. Survivors of cancers at HPV-related sites carry persistent, long-term cross-site risks. Current organ-specific follow-up strategies may be insufficient and suggest the need for more integrated, long-term surveillance and prevention strategies in this population.