Diagnostic markers of human papillomavirus persistence and progression of cervical intraepithelial neoplasia

Cervical intraepithelial neoplasia is widespread among patients of the reproductive period, the peak of the incidence occurs at a young age, often when the reproductive function has not yet been performed. The oncological alertness of the medical community is justified: the incidence of cervical cancer has increased by 24.6% over the past ten years, and in the structure of cancer mortality in the age group of 30–39 years cervical cancer occupies the 1st place accounting for 23%. Тhe same time aggressive management of the disease in patients who have not yet performed their reproductive function is associated with the loss of significant volume of cervical tissues and an increase in the frequency of premature birth. The most acute issue is the tactics of managing cervical neoplasia of the second degree of severity, when there is still hope for the regression of the disease, but at the same time there is a high risk of transition to dysplasia of the third degree of severity and subsequently to invasive cancer. The search for diagnostic markers that allow predicting the probability of regression and, conversely, the unfavorable course of the disease is the most important task solution of which will allow optimizing tactics in controversial clinical cases and avoiding unnecessary surgical aggression, improving the perinatal outcomes of patients undergoing surgical treatment. The search for new economically feasible and diagnostically valuable markers allowing us to predict the course of the disease and determine the amount of necessary surgical treatment continues, but the most significant at this moment is still the determination of the coexpression of p16 and Ki-67 in immunocytochemical studies and p16INK4a in immunohistochemical studies. The diagnostic sensitivity of determining the co-expression of p16INK4a/Ki67 is 98.5%, and the expression of p16INK4a in CIN II indicates that in 81% of cases there is a tendency to a progressive course of the disease.

1. Kaprin A.D., Starinsky V.V., Petrova G.V. (eds.). Malignant neoplasms in Russia in 2017 (morbidity and mortality). Moscow: Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Center; 2018. 250 p. (In Russ.) Available at: https://oncologyassociation.ru/wp-content/uploads/2020/09/2018.pdf.

2. Kaprin A.D. Starinsky V.V., Petrova G.V. (eds.). The state of oncological care for the population of Russia in 2018. Moscow: Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Center; 2019. 236 p. (In Russ.) Available at: http://www.demoscope.ru/weekly/2019/0817/biblio03.php.

3. Broutet N., O’Neal Eckert L., Ullrich A., Bloem P. Comprehensive Cervical Cancer Control. A guide to essential practice. 2nd ed. World Health Organization; 2014. 408 p. Available at: https://apps.who.int/iris/bitstream/handle/10665/144785/9789241548953_eng.pdf?sequence=1.

4. Bekos C., Schwameis R., Heinze G., Gärner M., Grimm C., Joura E. et al. Influence of age on histologic outcome of cervical intraepithelial neoplasia during observational management: results from large cohort, systematic review, meta-analysis. Sci Rep. 2018;8(1):6383. https://doi.org/10.1038/ s41598-018-24882-2.

5. Krasnopolsky V.I., Logutova L.S., Zarochentseva N.V., Dzhadzhikhia L.K. Cervical intraepithelial neoplasia (diagnosis, treatment, prevention). Moscow: Politekhnika-Servis; 2015. 71 p. (In Russ.) Available at: https://intelmed.ru/files/science_item/70/Учебное%20пособие%20для%20Московской%20 области%202015%20г%20диагностики%20и%20лечения%20РШМ.pdf.

6. Bruni L., Albero G., Serrano B., Mena M., Gómez D., Muñoz J. et al. ICO/IARC Information Centre on HPV and Cancer (HPV Information Centre). Human Papillomavirus and Related Diseases in the WORLD. Summary Report. 2021. Available at: https://hpvcentre.net/statistics/reports/XWX.pdf.

7. Lyubasovskaya L.A., Melkumyan A.R., Dubodelov D.V., Rodchenko Yu.V., Muravyeva V.V., Kondrakhin A.P. et al. Experience of using feminine hygiene products containing the probiotic strain Lactobacillus acidophilus in women of reproductive age and in postmenopausal women for the prevention of opportunistic vaginal infections. Akusherstvo i ginekologiya = Obstetrics and Gynecology. 2018;(9):126–131. (In Russ.) https://doi.org/10.18565/aig.2018.9.

8. Bayramova G.R., Fayzullin L.Z., Korolkova A.I., Poloznikov A.A., Kiselev V.I. Screening of cervical cancer: what is new in world practice. Akusherstvo i ginekologiya = Obstetrics and Gynecology. 2016;(7):17–21. (In Russ.) https://doi.org/10.18565/aig.2016.7.17-21.

9. Lowy D.R. HPV vaccination to prevent cervical cancer and other HPVassociated disease: from basic science to effective interventions. J Clin Invest. 2016;126(1):5–11. https://doi.org/10.1172/JCI85446.

10. Rao Q., Shen Q., Zhou H., Peng Y., Li J., Lin Z. Aberrant microRNA expression in human cervical carcinomas. Med Oncol. 2012;29(2):1242–1248. https://doi.org/10.1007/s12032-011-9830-2.

11. Wyber R., Vaillancourt S., Perry W., Mannava P., Folaranmi T., Celi L.A. Big data in global health: improving health in low- and middle-income countries. Bull World Health Organ. 2015;93(3):203–208. https://doi. org/10.2471/BLT.14.139022.

12. Brico N.I., Lopukhov P.D. Need to Control HPV-Associated Diseases. Epidemiologiya i vaktsinoprofilaktika = Epidemiology and Vaccinal Prevention. 2017;16(2):10–15. (In Russ.) https://doi.org/10.31631/2073- 3046-2017-16-2-10-15.

13. Serova O.F., Zarochentseva N.V., Vazhnova V.M., Kesh’yan L.V. Pregnancy in women after treatment of cervical intraepithelial neoplasia. Effektivnaya farmakoterapiya = Effective Pharmacotherapy. 2010;(1):28–32. (In Russ.) Available at: https://umedp.ru/upload/iblock/0ab/stada.pdf.

14. Maleva T.M. (ed.). Monthly monitoring of the socio-economic situation and well-being of the population: 2015 – November 2018. Moscow: Russian Presidential Academy of National Economy and Public Administration; 2018. 58 p. (In Russ.) Available at: http://socinst.ru/sites/default/files/ news/Мониторинг_полный_15-06-2018.pdf.

15. Methodological recommendations for the prevention of cervical cancer. Moscow; 2018. (In Russ.) Available at: http://khmrb.ru/spetsialistam/ recom/recom_PRSHM.docx.

16. Rogovskaya S.I., Lipova E.V. (eds.). The cervix, the vagina, the vulva. Physiology, pathology, colposcopy, aesthetic correction: a guide for practicing physicians. Moscow: StatusPraesens; 2014. 832 p. (In Russ.).

17. Adamyan L.V., Artymuk N.V., Ashrafyan L.A., Baranov I.I., Bayramova G.R., Belokrinitskaya T.E. et al. Benign and precancerous diseases of the cervix from the perspective of cancer prevention: clinical guidelines (patient management protocols). Moscow; 2017. 54 p. (In Russ.) Available at: https://kraszdrav.ru/assets/documents/Protokol_po_sheyke_matke_MZ_RF_ ot_02.11.201707.11.2017%2014:05.pdf.

18. Mezhevitinova E.A., Abakarova P.R., Khlebkova Yu.S. Precancerous cervical lesions. Meditsinskiy sovet = Medical Council. 2016;(12):112–118. (In Russ.) https://doi.org/10.21518/2079-701X-2016-12-112-118.

19. Dimitriadi T.A., Burtsev D.V., Dzhenkova E.A., Gudtskova T.N., Dvadnenko K.V. Prognostic relevance of Ki-67 and P16/INK4a markers in histological diagnosis of cervical dysplasia. Research’n Practical Medicine Journal. 2020;7(1):8–15. (In Russ.) https://doi.org/10.17709/2409-2231- 2020-7-1-1.

20. Curty G., de Carvalho P.S., Soares M.A. The Role of the Cervicovaginal Microbiome on the Genesis and as a Biomarker of Premalignant Cervical Intraepithelial Neoplasia and Invasive Cervical Cancer. Int J Mol Sci. 2019;21(1):222. https://doi.org/10.3390/ijms21010222.

21. Podzolkova N.M., Sozaeva L.G., Osadchev V.B. Papillomavirus and herpetic infections in obstetrics and gynecology. Moscow: Russian Medical Academy of Postgraduate Education; 2009. 49 p. (In Russ.).

22. Voznesenskaya N.V., Nasyrov R.A., Trubnikova L.I., Savinova N.A., Kometova V.V. On the role of viral infection in the development of dysplastic processes in the cervix. Ul’yanovskiy mediko-biologicheskiy zhurnal = Ulyanovsk Medical and Biological Journal. 2012;(3):48–54. (In Russ.) Available at: http://medbio.ulsu.ru/images/numbers/2012/3-2012.pdf

23. Ewaisha R., Panicker G., Maranian P., Unger E.R., Anderson K.S. Serum Immune Profiling for Early Detection of Cervical Disease. Theranostics. 2017;7(16):3814–3823. https://doi.org/10.7150/thno.21098.

24. Mikeska T., Craig J.M. DNA methylation biomarkers: cancer and beyond. Genes (Basel). 2014;5(3):821–864. https://doi.org/10.3390/genes5030821.

25. Kim M.K., Lee I.H., Lee K.H., Lee Y.K., So K.A., Hong S.R. et al. DNA methylation in human papillomavirus-infected cervical cells is elevated in highgrade squamous intraepithelial lesions and cancer. J Gynecol Oncol. 2016;27(2):e14. https://doi.org/10.3802/jgo.2016.27.e14.

26. Lorincz A.T. Virtues and Weaknesses of DNA Methylation as a Test for Cervical Cancer Prevention. Acta Cytol. 2016;60(6):501–512. https://doi. org/10.1159/000450595.

27. Agodi A., Barchitta M., Quattrocchi A., Maugeri A., Vinciguerra M. DAPK1 Promoter Methylation and Cervical Cancer Risk: A Systematic Review and a Meta-Analysis. PLoS ONE. 2015;10(8):e0135078. https://doi. org/10.1371/journal.pone.0135078.

28. Kocsis A., Takács T., Jeney C., Schaff Z., Koiss R., Járay B. et al. Performance of a new HPV and biomarker assay in the management of hrHPV positive women: Subanalysis of the ongoing multicenter TRACE clinical trial (n > 6,000) to evaluate POU4F3 methylation as a potential biomarker of cervical precancer and cancer. Int J Cancer. 2017;140(5):1119–1133. https://doi.org/10.1002/ijc.30534.

29. Wu Y., Shi B., Ding X., Liu T., Hu X., Yip K.Y. et al. Improved prediction of RNA secondary structure by integrating the free energy model with restraints derived from experimental probing data. Nucleic Acids Res. 2015;43(15):7247–7259. https://doi.org/10.1093/nar/gkv706.

30. Nassirpour R., Mehta P.P., Yin M.J. miR-122 regulates tumorigenesis in hepatocellular carcinoma by targeting AKT3. PLoS ONE. 2013;8(11):e79655. https://doi.org/10.1371/journal.pone.0079655.

31. Wang W.T., Zhao Y.N., Yan J.X., Weng M.Y., Wang Y., Chen Y.Q., Hong S.J. Differentially expressed microRNAs in the serum of cervical squamous cell carcinoma patients before and after surgery. J Hematol Oncol. 2014;7:6. https://doi.org/10.1186/1756-8722-7-6.

32. Knyazeva M.S., Prisyazhnaya Т.S., Zabegina L.M., Smirnova О.A., Mikhetko A.A., Berlev I.V., Malek A.V. Prognostic value of microRNA assessment in cervical epithelial cells of patients with mild dysplasia. Opukholi zhenskoy reproduktivnoy sistemy = Tumors of Female Reproductive System. 2020;16(4):66–75. (In Russ.) https://doi.org/10.17650/1994-4098-2020-16-4-66-75.