Cross-site and higher-order human papillomavirus-related multiple primary cancers: A long-term risk assessment using the Surveillance, Epidemiology, and End Results database

Multiple primary cancers (MPCs), particularly those arising at human papillomavirus (HPV)-related sites, represent a growing concern in cancer survivorship. Despite the rising incidence of HPV-related site MPCs, long-term surveillance strategies remain underdeveloped, especially for cross-site cancers such as oral/oropharyngeal and genital/anal tumors. In this retrospective cohort study, data from the SEER-8, SEER-17, and SEER-21 registries were analyzed to assess the incidence, latency, and cross-site associations of HPV-related MPCs, including higher-order cases involving three or more distinct primaries. Among 15.8 million retrieved cases, 2.8 million were MPCs, of which 4.1–4.6% were higher-order, underscoring their increasing prevalence. Most HPV-related site cancers demonstrated significantly elevated standardized incidence ratios, particularly more than 10 years after initial diagnosis, and notable cross-site associations were observed (e.g., tongue-to-vulva, anal-to-tonsil). These findings highlight that HPV-related site MPCs, including those with long latencies and higher-order patterns, pose a growing burden for cancer management. Lifelong, minimally invasive, and multidisciplinary surveillance is warranted to facilitate earlier detection and improved outcomes. The proposed frequency analysis method offers a novel framework to identify high-risk survivors and supports the development of integrated follow-up strategies that can enhance quality of life and reduce late detection risks.