Viral Intrusion: Unveiling the Role of Human Papillomavirus in Primary Lung Cancer – A Systematic Review and Meta-analysis

Background : The role of human papillomavirus (HPV) in lung carcinogenesis remains debated. This systematic review and meta-analysis evaluated the association between HPV infection and lung cancer risk and its potential prognostic implications. Methods: A systematic search of PubMed, ScienceDirect, and Google Scholar (2015–2025) identified observational studies reporting HPV status in both lung cancer cases and non-cancer controls. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Heterogeneity was assessed with the I² statistic, and publication bias was examined using funnel plot and Egger’s test. Studies lacking control groups or effect sizes were narratively summarized. Results: Nine studies (n = 3,871,842) were included in the meta-analysis, showing a pooled OR of 2.62 (95% CI: 1.86–3.68), indicating higher odds of lung cancer among HPV-infected individuals. Substantial heterogeneity was observed (I² = 83.3%, p < 0.001) and publication bias was detected (Egger’s test p = 0.015). An additional 26 studies were narratively synthesized, many detecting HPV DNA mainly types 16 and 18 in lung tumors, particularly among non-smokers, females, and EGFR-mutated adenocarcinomas. Considerable variation in geographic origin, histology, detection method, and specimen type was also observed. Conclusion: HPV infection is significantly associated with an increased risk of lung cancer, suggesting its possible role as a risk and prognostic biomarker. However, the presence of publication bias and heterogeneity underscores the need for further large-scale, standardized studies to validate these findings.