Accuracy of HPV E6/E7 oncoprotein tests to detect high-grade cervical lesions: a systematic literature review and meta-analysis

Abstract

Background: Cervical carcinogenesis is mediated by the HPV-E6 and E7 oncoproteins, considered as biomarkers usable in managing screen-positive women.

Methods: We conducted a systematic review and meta-analysis assessing the accuracy of HPV-E6/E7-oncoprotein tests to detect underlying cervical-precancer and cancer. We included studies reporting data on oncoprotein test accuracy detecting cervical intraepithelial neoplasia grade 3 or worse. Random effects logistic regression models were applied for pooling absolute and relative accuracy.

Results: Twenty-two studies were included. Sensitivity and specificity estimates ranged from 54.2% (95%CI: 45.2-63.0) to 69.5% (95%CI:60.8-76.9) and from 82.8% (95%CI: 50.4-95.8) to 99.1 (95%CI: 98.8-99.3), respectively in the population irrespective of HPV status. Higher sensitivity estimates ranging from 60.8% (95%CI: 49.6-70.9) to 75.5% (95%CI: 71.7-78.9) but lower specificity estimates ranging from 83.7% (95%CI: 76.1-89.3) to 92.1% (95%CI: 88.5-94.6) were observed in studies enrolling high-risk-HPV-positive women. Studies recruiting only HIV-positive women showed a pooled sensitivity of 46.9% (95%CI: 30.6-63.9) with a specificity of 98.0% (95%CI: 96.8-98.7).

Conclusions: The high specificity of oncoprotein tests supports its use for triaging HPV-positive women. However, oncoprotein-negative women would not be recommended to undertake routine screening, requiring further follow-up. Large-scale and longitudinal studies are needed to further investigate the role of E6/E7-oncoprotein detection in predicting the risk of developing cervical pre-cancer and cancer.

Fig. 1. PRISMA* flow diagram.

*PRISMA Preferred Reporting Items for Systematic review and Meta-analysis.

Fig. 2. Accuracy of oncoprotein test for CIN3+ detection in the population irrespective of HPV status, hrHPV-positive women, in HPV16/18-positive women, and in women living with HIV.

a Population irrespective of HPV status; b hrHPV-positive women; c HPV16/18-positive women; d Women Living with HIV; ¹Testing with CncoE6; ²Testing with OncoE6E7; TP True Positives, FN False Negatives, TN True Negatives, FP False positives.

Fig. 3. Accuracy of oncoprotein testing relative to other screening tests in the population irrespective of HPV status and in hrHPV-positive women.

a Population irrespective of HPV status; b hrHPV-positive women. Results from a meta-regression using as a covariate the type of screening test. ASCH+ Atypical Squamous Cells where High-grade squamous intra-epithelial lesions cannot be excluded, ASCUS+ Atypical Squamous cells of Undetermined Significance, HC2 Hybrid Capture 2, HSIL High grade Squamous Intraepithelial Lesion, RT Real Time.