Association Between β-Genus Human Papillomavirus and Cutaneous Squamous Cell Carcinoma in Immunocompetent Individuals-A Meta-analysis

IMPORTANCE Existing epidemiological evidence remains controversial regarding the association between beta-genus human papillomavirus (beta-HPV) and cutaneous squamous cell carcinoma (cSCC) in immunocompetent individuals. OBJECTIVE We aimed to clarify this association and evaluate type-specific beta-HPV involvement. DATA SOURCES We performed a systematic literature search of MEDLINE and EMBASE for studies in humans through June 18, 2014, with no restriction on publication date or language. The following search terms were used: " human papillomavirus" and " cutaneous squamous cell carcinoma or skin squamous cell carcinoma or cSCC or nonmelanoma skin neoplasms." STUDY SELECTION Articles were independently assessed by 2 reviewers. We only included case-control or cohort studies, in immunocompetent individuals, that calculated the odds ratio (OR) for cSCC associated with overall and type-specific beta-HPV. DATA EXTRACTION AND SYNTHESIS We first assessed the heterogeneity among study-specific ORs using the Q statistic and I2 statistic. Then, we used the random-effects model to obtain the overall OR and its 95% CI for all studies as well as for each type of HPV. We also tested and corrected for publication bias by 3 funnel plot-based methods. The quality of each study was assessed with the Newcastle Ottawa Scale. MAIN OUTCOMES AND MEASURES Pooled ORs and 95% CIs for overall beta-HPV and HPV types 5, 8, 15, 17, 20, 24, 36, and 38 association with skin biopsy proven cSCC. RESULTS Seventy-nine articles were assessed for eligibility; 14 studiesmet inclusion criteria for the meta-analysis and included 3112 adult immunocompetent study participants with cSCC and 6020 controls. For all detection methods, the overall association between beta-HPV and cSCC was significant with an adjusted pooled OR (95% CI) of 1.42 (1.18-1.72). As for the type-specific analysis, types 5, 8, 15, 17, 20, 24, 36, and 38 showed a significant association with adjusted pooled ORs (95% CIs) of 1.4 (1.18-1.66), 1.39 (1.16-1.66), 1.25 (1.04-1.50), 1.34 (1.19-1.52), 1.38 (1.21-1.59), 1.26 (1.09-1.44), 1.23 (1.01-1.50), and 1.37 (1.13-1.67) respectively. Our subgroup analysis in studies using only serology for HPV detection showed a significant association between overall beta-HPV and HPV subtypes 5, 8, 17, 20, 24, and 38 with an increased risk of cSCC development. CONCLUSIONS AND RELEVANCE This study serves as added evidence supporting beta-HPV as a risk factor for cSCC in healthy individuals. The subgroup analysis highlights this significant association for HPV 5, 8, 17, 20, and 38, which may help to direct future prevention efforts.