Global Prevalence and Modifiers of Human Papillomavirus Positivity in Oral Cavity Cancer: A Systematic Review and Meta-Analysis of Prevalence (1995–2024)

Background/Objectives: Human papillomavirus (HPV) is a known etiologic agent in oropharyngeal cancers, but its role in oral cavity squamous cell carcinoma (OCSCC) remains unclear. This systematic review and meta-analysis aimed to estimate the global prevalence of HPV in OCSCC and explore variation by clinicodemographic and tumor characteristics. Methods: We systematically searched multiple databases for studies reporting HPV prevalence in OCSCC. Pooled prevalence estimates were calculated, and subgroup analyses examined differences by age, gender, cancer stage, anatomical site, histologic subtype, region, and HPV type (HPV-16 and HPV-18). Heterogeneity and publication bias were assessed using standard meta-analytic techniques. Results: A total of 122 studies involving 16,311 patients were included. The pooled HPV prevalence in OCSCC was 25.8% (95% CI: 20.4–31.2), with HPV-16 and HPV-18 detected in 52.4% and 30.3% of positive cases, respectively. Prevalence varied geographically, from 73% in Singapore to 7.7% in South Korea. Younger patients (<40 years) had higher HPV positivity (29.7%) than older patients (>70 years, 23.8%). Early-stage cancers (stage I) showed higher HPV prevalence (41.8%) than advanced-stage cancers (stage IV, 10.4%). Verrucous carcinoma had the highest HPV positivity (34.1%), and moderately differentiated tumors the lowest (23.4%). HPV prevalence was highest in the lower alveolus (29.5%) and lips (25%), and lowest in the upper gingiva (3.9%). Conclusions: HPV prevalence in OCSCC demonstrates significant heterogeneity across regions and clinical subgroups. These findings emphasize the need for standardized diagnostic approaches and further research into the role of HPV in OCSCC pathogenesis and treatment.