Human Papillomavirus Shows Highly Variable Prevalence in Esophageal Squamous Cell Carcinoma and No Significant Correlation to p16INK4a Overexpression A Systematic Review

Introduction: This review investigates the role of p16(INK4a) as a marker of transcriptionally active human papillomavirus (HPV) in esophageal squamous cell carcinoma (ESCC) and the regional prevalence of HPV in ESCC. Methods: PubMed, EMBASE, and the Cochrane Library were systematically searched with the purpose of identifying all studies published between January 1980 and July 2013 reporting both HPV and p16(INK4a) results in a minimum of five human ESCC specimens. Results: Twelve studies were identified, providing data on a total of 1383 ESCC specimens collected between 1987 and 2009 from 10 different countries. HPV DNA was detected in 12.0% (n = 161) of 1347 specimens, and p16(INK4a) was detected in 33.9% (n = 209) of 617 specimens. The HPV presence varied from 0% to 70% among the studies. The prevalence of p16(INK4a) overexpression in HPV-positive and HPV-negative specimens demonstrated no statistically significant difference, neither for the combined data (p = 0.7507) nor for any individual study, and detection of p16(INK4a) overexpression did not affect the odds of tumors being HPV positive (odds ratio = 1.0666 with 95% confidence interval 0.7040-1.6157). In a pooled analysis, the sensitivity of p16(INK4a) overexpression as a marker of HPV DNA presence was 0.35, the specificity 0.67, and the positive predictive value 0.25. Conclusions: This systematic review reports great regional variation in the prevalence of HPV in ESCC and suggests that p16(INK4a) is not a reliable marker of HPV status in ESCC.