Risk-Based Diagnosis and Modern Triage Strategies for Cervical Pathology in HPV-Positive Women
Keywords:
human papillomaviru, HPV, cervical pathology, HPV DNA, risk stratification, cytology, colposcopy, endocervical curettage, p16/Ki-67, genotyping, self-sampling, DNA methylationAbstract
Cervical pathology in HPV-positive women remains one of the most significant challenges in modern gynecology and gynecologic oncology. This is due not only to the high prevalence of human papillomavirus infection, but also to the fact that this group represents a major area of clinical uncertainty: some patients experience transient infection without significant morphological consequences, while others develop clinically significant lesions requiring timely diagnosis and active intervention. In recent years, universal screening and routing schemes have increasingly given way to risk-based and personalized management models. The aim of this review article was to analyze current literature data on the diagnosis of cervical pathology in HPV-positive women, focusing on the clinical heterogeneity of this group, the role of HPV DNA testing, cytology, colposcopy, targeted biopsy, and endocervical curettage, as well as the significance of new biomarkers and triage strategies. The article examines current understanding of the natural history of HPV infection, the differences between transient and persistent infection, the significance of individual highly oncogenic genotypes, and the role of age, immune status, the transformation zone, and reproductive cofactors. The article discusses in detail current approaches to HPV-based screening, the role of cytology as a triage method, the limitations of visual assessment in TZ3, and the importance of expanded genotyping, p16/Ki-67 dual stain, self-sampling, DNA methylation, E6/E7 mRNA, and oncoprotein tests as tools for more accurate risk stratification. It is concluded that modern diagnostics of cervical pathology in HPV-positive women should be built as a multi-level and personalized system, in which clinical decisions are made not based on a single test, but on a comprehensive assessment of viral, morphological, anatomical, and molecular parameters.
References
1. World Health Organization. Cervical cancer [Electronic resource]. Geneva: WHO, 2025.
2. Bray F., Laversanne M., Sung H., et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries // CA: A Cancer Journal for Clinicians. 2024.
3. World Health Organization. Human papillomavirus and cancer [Electronic resource]. Geneva: WHO, 2024.
4. World Health Organization. WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention. 2nd ed. Geneva: WHO, 2021.
5. World Health Organization. WHO guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention: Use of dual-stain cytology to triage women after a positive test for human papillomavirus (HPV). 2nd ed. Geneva: WHO, 2024.
6. Wei F., Georges D., Man I., et al. Causal attribution of human papillomavirus genotypes to invasive cervical cancer worldwide: a systematic analysis of the global literature // Lancet. 2024. Vol. 404, No. 10451. P. 435–444.
7. Bhatla N., Aoki D., Sharma D. N., Sankaranarayanan R. Cancer of the cervix uteri: 2025 update // International Journal of Gynecology and Obstetrics. 2025. Vol. 171, Suppl. 1. P. 87–108.
8. Clarke M. A., Wentzensen N., Perkins R. B., et al. Recommendations for use of p16/Ki67 dual stain for management of individuals testing positive for human papillomavirus // Journal of Lower Genital Tract Disease. 2024. Vol. 28, No. 2. P. 124–130.
9. Harper D. M., Paczos T., Ridder R., Huh W. K. p16/Ki-67 dual stain triage of individuals positive for HPV to detect cervical precancerous lesions // International Journal of Cancer. 2025. Vol. 156, No. 12. P. 2257–2264.
10. Wentzensen N., Massad L. S., Clarke M. A., et al. Self-collected vaginal specimens for HPV testing: Recommendations From the Enduring Consensus Cervical Cancer Screening and Management Guidelines Committee // Journal of Lower Genital Tract Disease. 2025. Vol. 29, No. 2. P. 144–152.
11. Massad L. S., Clarke M. A., Perkins R. B., et al. Applying results of extended genotyping to management of positive cervicovaginal human papillomavirus test results: Enduring guidelines // Journal of Lower Genital Tract Disease. 2025. Vol. 29, No. 2. P. 134–143.
12. Behrens A. S., Dietl A. K., Adler W., et al. Evaluation of endocervical curettage (ECC) in colposcopy for detecting cervical intraepithelial lesions // Archives of Gynecology and Obstetrics. 2024. Vol. 310, No. 6. P. 3037–3045.
13. Bruno M. T., Cavallaro A. G., Sudano M. C., et al. Role of endocervical curettage in detecting CIN2+ in postmenopausal women with persistent high-risk HPV and type 3 transformation zone // BMC Cancer. 2025. Vol. 25. Art. 1486.
14. Lycke K. D., Steben M., Garland S. M., et al. An updated understanding of the natural history of cervical human papillomavirus infection: clinical implications // American Journal of Obstetrics and Gynecology. 2025.
15. National Cancer Institute. Cervical cancer causes, risk factors, and prevention [Electronic resource]. 2024.
16. Ye Y., Jones T., Wang T., et al. Comprehensive overview of genotype distribution and prevalence of human papillomavirus in cervical lesions // Gynecology, Obstetrics and Clinical Medicine. 2024. Vol. 4, No. 1. Art. e000005.
17. Wang J., Zheng J., Luo X., et al. Risk factors for persistent infection of high-risk HPV in patients with cervical intraepithelial neoplasia // Cancer Management and Research. 2025.
18. Castellsagué X., Muñoz N. Cofactors in human papillomavirus carcinogenesis: role of parity, oral contraceptives, and tobacco smoking // Journal of the National Cancer Institute Monographs. 2003. No. 31. P. 20–28.
19. Massad L. S., et al. Colposcopy standards: guidelines for endocervical curettage at colposcopy // Journal of Lower Genital Tract Disease. 2023. Vol. 27, No. 1. P. 97–101.
20. Willows K., et al. 2023 Canadian Colposcopy Guideline: a risk-based approach to management and surveillance of cervical dysplasia // Current Oncology. 2023. Vol. 30, No. 6. P. 431.
21. Zhao J., et al. Retrospective analysis of cervical screening abnormalities in women with type 3 transformation zone without visible lesions // PeerJ. 2025. Vol. 13. Art. e20396.
22. Chen R., Ye C., Li Y., et al. The distribution of colposcopy directed ectocervical biopsy and endocervical curettage results: a retrospective study of 47,134 cases // Annals of Medicine. 2025. Vol. 57, No. 1. Art. 2573149.
23. Wei B., Li Q., Seery S., Qiao Y., Jiang Y., et al. Endocervical curettage for diagnosing high-grade squamous intraepithelial lesions or worse in women with type 3 transformation zone lesions: a retrospective observational study // BMC Women’s Health. 2023. Vol. 23. Art. 245.
24. Chen Y., et al. The value of endocervical curettage for diagnosis of cervical precancers or worse at colposcopy of women with atypical glandular cell cytology // Frontiers in Medicine. 2024. Vol. 11. Art. 1476361.
25. Wentzensen N., Egemen D., Clarke M. A., et al. Long-term prospective cohort study of cervical cancer screening using triage of women who are human papillomavirus-positive with dual stain and human papillomavirus genotyping // Journal of Clinical Oncology. 2026.
26. Burdier F. R., Waheed D. N., Nedjai B., et al. DNA methylation as a triage tool for cervical cancer screening: a meeting report // Preventive Medicine Reports. 2024. Art. 102678.
27. Schreiberhuber L., et al. Cervical cancer screening using DNA methylation triage in a real-world population // Nature Medicine. 2024.
28. Zhai X., Kong T., Yang X., et al. Clinical performance of triage strategies for HPV-positive women in cervical cancer screening in rural Yunnan, China // BMC Cancer. 2026. Vol. 26. Art. 57.
29. Chan K. K. L., Liu S. S., Lau L. S. K., et al. PAX1/SOX1 DNA methylation versus cytology and HPV16/18 genotyping for the triage of high-risk HPV-positive women in cervical cancer screening // BJOG. 2025. Vol. 132, No. 2. P. 197–204.
30. Sumiec E. G., et al. The current state of DNA methylation biomarkers in self-collected liquid biopsies for the early detection of cervical cancer: a literature review // Molecular Cancer. 2024.
31. Sørbye S., et al. Genotype-specific HPV mRNA triage improves CIN2+ detection efficiency compared to cytology: a population-based study of HPV DNA-positive women // Pathogens. 2025. Vol. 14, No. 8. Art. 749.
32. Downham L., Jaafar I., Rol M. L., et al. Accuracy of HPV E6/E7 oncoprotein tests to detect high-grade cervical lesions: a systematic literature review and meta-analysis // British Journal of Cancer. 2024. Vol. 130. P. 517–525.