Detection of Human Papillomavirus in Lung Cancer: Systematic Review and Meta-analysis

Background: Since the first reports (in 1979) suggesting an etiological role for human papillomavirus (HPV) in bronchial squamous cell carcinoma, literature reporting HPV detection in lung cancer has expanded rapidly, but a comprehensive meta-analysis has yet to be published. We performed a systematic review and formal meta-analysis of the literature reporting on HPV detection in lung cancer. Materials and Methods: MEDLINE and Current Contents were searched through April 2012. The effect size was calculated as event rates and their 95% Confidence intervals (CI), with homogeneity testing using Cochran's Q and I-2 statistics. Meta-regression was used to test the impact of study-level co-variates (HPV detection method, geographical origin of study, cancer histology) on effect size, and potential publication bias was estimated using funnel plot symmetry (Begg and Mazumdar rank correlation, Egger's: regression, and Duval and Tweedie's trim and fill method). Results: One hundred studies were eligible, covering 7,381 lung cancer cases from different geographical regions. Altogether, 1,653 (22.4%) samples tested HPV-positive; effect size was 0.348 (95% CI=0.333-0.363; fixed-effects model), and 0.220 (95% CI=0.18-0.259; random effects model). There was significant heterogeneity between the studies stratified by HPV detection technique, but the random effects in between-strata comparison was not significant (p=0.193). When stratified by i) different geographical regions, and ii) different histological types, the between-strata comparison was significant (p=0.0001). However, in meta-regression, HPV detection method (p=0.473), geographical origin (p=0298) and histological type (p=0.589) were not significant study-level co-variates. No evidence for significant publication bias was found in funnel plot symmetry testing. In sensitivity analysis, all meta-analytic results seemed robust to all one-by-one study removals. Conclusion: These meta-analytic results imply that the reported variability in HPV detection rates in lung cancer is better explained by geographical study origin and histological types of cancer than by the HPV detection method itself. In formal meta-regression, however, none of these three factors were significant study-level co-variates accounting for the heterogeneity of the summary effect size estimates, i.e. HPV prevalence in lung cancer.