HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis

Background We aimed to provide updated information about the global estimates of attributable fraction and type distribution of human papillomavirus (HPV) in head and neck squamous cell carcinomas by doing a systematic review and meta-analysis. Methods We did a literature search on PubMed to identify studies that used PCR for detection of HPV DNA in head and neck squamous cell carcinomas with information about HPV genotype distribution. We included studies that tested 20 or more biopsies per cancer site and were published between July 15, 1990, and Feb 29, 2012. We collected information about sex, risk factors, HPV detection methods, and biomarkers of potentially HPV-induced carcinogenesis (E6/E7 mRNA and p16(INK4a)). If it was not possible to abstract the required information directly from the paper, we contacted the authors. We did a meta-analysis to produce pooled prevalence estimates including a meta-regression to explore sources of heterogeneity. Findings 148 studies were included, contributing data for 12 163 cases of head and neck squamous cell carcinoma from 44 countries. HPV DNA was detected in 3837 cases. HPV16 accounted for 82.2% (95% CI 77.7-86.4) of all HPV DNA positive cases. By cancer site, pooled HPV DNA prevalence estimates were 45.8% (95% CI 38.9-52.9) for oropharynx, 22.1% (16.4-28.3) for larynx (including hypopharynx), and 24.2% (18.7-30.2) for oral cavity. The percent positivity of p16(INK4a) positive cases in HPV-positive oropharyngeal cancer cases was 86.7% (95% CI 79.2-92.9) and of E6/E7 mRNA positive cases was 86.9% (73.2-96.8). The estimate of HPV attributable fraction in oropharyngeal cancer defined by expression of positive cases of E6/E7 mRNA was 39.8% and of p16(INK4a) was 39.7%. Of subsites, tonsils (53.9%, 95% CI 46.4-61.3) had the highest HPV DNA prevalence. HPV DNA prevalence varied significantly by anatomical site, geographic region, but not by sex or tobacco or alcohol consumption. Interpretation The contribution of HPV prevalence in head and neck squamous cell carcinoma and in particular that of HPV16 in the oropharynx shows the potential benefit of prophylactic vaccines.