P16/Ki67 dual staining versus cytology for identifying high-grade cervical intraepithelial neoplasia (CIN2+/CIN3+) in triage management of HR-HPV-positive women: a systematic review and meta-analysis.

OBJECTIVE

The co-expression of P16 and Ki67 suggests the presence of high-grade cervical intraepithelial neoplasia, which makes P16/Ki67 dual staining a promising marker in cervical cancer screening. This study provides a systemic review of the established evidence on the performance of P16/Ki67 versus cytology in detecting cervical intraepithelial neoplasia (CIN)2+/CIN3+ among high-risk human papillomavirus (HR-HPV)-positive women and HR-HPV-positive individuals with cytology-negative results for triage management.

METHODS

Studies published from database inception to April 26, 2024, were systematically searched. A total of 26 studies were eventually included in the study, comprising 26,424 women, with 14,625 classified as P16/Ki67-positive and 11,799 as P16/Ki67-negative.

RESULTS

In the triage management of HR-HPV-positive women, P16/Ki67 achieved sensitivities of 85% for CIN2+ and 88% for CIN3+, with specificities of 63% and 57%, respectively. In comparison, cytology showed lower sensitivities of 76% for CIN2+ and 79% for CIN3+, with lower specificities of 57% and 54%. In triage management of human papillomavirus (HPV)-positive but cytology-negative women, 18.48% of the HPV-positive patients, initially missed by cytology, were correctly retrieved by the addition of P16/Ki67. A negative P16/Ki67 test result reduced the risk of underlying CIN3+ to 4% for HR-HPV-positive individuals and 1% for the HR-HPV-positive individuals with cytology-negative results, prompting a recommendation for follow-up at 1-year intervals.

CONCLUSION

P16/Ki67 exhibits diagnostic superiority over liquid-based cytology in detecting CIN2+/CIN3+, among HR-HPV-positive women. Furthermore, its ability to identify patients missed by cytology highlights its value as a complementary tool for triage of HR-HPV-positive but cytology-negative population. By effectively reducing unnecessary colposcopy referrals, P16/Ki67 conserves healthcare resources and improves outcomes.

TRIAL REGISTRATION: PROSPERO Identifier: CRD42024567623.