Possible contributing role of Epstein-Barr virus (EBV) as a cofactor in human papillomavirus (HPV)-associated cervical carcinogenesis.

ABSTRACT

BACKGROUND: Persistent infection with EBV has been linked to the development of malignancies including HPV-associated cervical carcinoma. However, the role of EBV in HPV-associated cervical cancer is still poorly understood. OBJECTIVE: To determine the possible contributing role of EBV in HPV-associated cervical carcinogenesis according to HPV genotypes, HPV genome status and EBV localization. STUDY DESIGN: Cervical tissues, including 82 with no squamous intraepithelial lesions (noSILs), 85 low-grade SILs (LSILs), 85 high grade SILs (HSILs) and 40 squamous cell carcinoma samples (SCC) were investigated using PCR and dot blot hybridization for EBV detection and PCR and reverse line blot hybridization for HPV genotyping. The amplification of papillomavirus oncogene transcripts assay and in situ hybridization were used to determine HPV physical status and EBV EBER localization, respectively. RESULTS: EBV was detected increasingly from noSIL (13.4%), LSIL (29.4%) to HSIL (49.4%) samples. The prevalence of HPV-EBV co-infection was significantly higher in any grade of lesion than in noSIL samples (p<0.05) including noSIL (1.2%; 95% confidence intervals [CI]=0.0-3.6%, relative risk [RR]=1), LSIL (18.8%, 95% CI=10.5-27.1%, RR=15.4), HSIL (41.2%, 95% CI=30.7-51.6%, RR=33.8) and SCC (30.0%, 95% CI=15.8-44.2%, RR=24.6). Interestingly, HPV-EBV co-infection was more common in cases with episomal forms of high-risk (HR) HPV whereas HPV alone was more common in cases with integrated HR-HPV. In addition, EBER staining demonstrated that EBV was mainly present in infiltrating lymphocytes. CONCLUSION: Infiltrating EBV-infected lymphocytes may play a role in cancer progression of cervical lesion containing episomal HR-HPV.