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Original Investigation |

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

Jad Chahoud, MD1; Adele Semaan, MPH2; Yong Chen, PhD3; Ming Cao, BS3; Alyssa G. Rieber, MD4; Peter Rady, MD, PhD5; Stephen K. Tyring, MD, PhD, MBA5
[+] Author Affiliations
1Department of Internal Medicine, The University of Texas Health Science Center, University of Texas Medical School at Houston, Houston
2Department of Management Policy and Community Health, The University of Texas School of Public Health, Houston
3Department of Biostatistics, The University of Texas School of Public Health, Houston
4Department of General Oncology, The University of Texas MD Anderson Cancer Center, Houston
5Department of Dermatology, The University of Texas Medical School at Houston, Houston
JAMA Dermatol. Published online December 30, 2015. doi:10.1001/jamadermatol.2015.4530
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Importance  Existing epidemiological evidence remains controversial regarding the association between β-genus human papillomavirus (β-HPV) and cutaneous squamous cell carcinoma (cSCC) in immunocompetent individuals.

Objective  We aimed to clarify this association and evaluate type-specific β-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 β-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 Ottowa scale.

Main Outcomes and Measures  Pooled ORs and 95% CIs for overall β-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 elligibility; 14 studies met 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 β-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 β-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 β-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.

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Figure 1.
Flow Diagram of Systematic Literature Search for the Meta-analysis

β-HPV indicates β human papillomavirus; OR, odds ratio.

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Figure 2.
Forest Plot for the Studies on the Association of HPV 5, 8, 15, 17, and 20 With cSCC

The squares and horizontal lines correspond to the study-specific odds ratios (ORs) and 95% CIs. The diamond represents the pooled OR and 95% CI of the overall population. The vertical dashed line indicates the overall pooled OR of 1.33. cSCC, cutaneous squamous cell carcinoma; HPV, human papillomavirus; NA, not available; OR, odds ratio; RR, relative risk.

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Figure 3.
Forest Plot for Studies on the Association Between HPV 24, 36, and 38, and β-HPV and cSCC

The squares and horizontal lines correspond to the study-specific odds ratios (ORs) and 95% CIs. The diamond represents the pooled OR and 95% CI of the overall population. The vertical dashed line indicates the overall pooled OR of 1.33. cSCC, cutaneous squamous cell carcinoma; HPV, human papillomavirus; NA, not available; OR, odds ratio; RR, relative risk.

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Figure 4.
Funnel Plot for Studies on the Association Between β-HPV and cSCC

The vertical solid line represents the summary effect estimates, and the dotted lines are pseudo 95% CIs

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Figure 5.
Forest Plot for the Subgroup Meta-analysis: Seroprevalence Only

The squares and horizontal lines correspond to the study-specific ORs and 95% CIs. The diamond represents the pooled OR and 95% CI of the overall population. The vertical dashed line indicates the overall pooled OR of 1.35. HPV indicates human papillomavirus; NA, not available; OR, odds ratio

Graphic Jump Location
Place holder to copy figure label and caption
Figure 6.
Forest Plot for the Subgroup Meta-analysis: Seroprevalence Only

The squares and horizontal lines correspond to the study-specific ORs and 95% CIs. The diamond represents the pooled OR and 95% CI of the overall population. The vertical dashed line indicates the overall pooled OR of 1.35.

HPV indicates human papillomavirus; NA, not available; OR, odds ratio

Graphic Jump Location

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