ВПЧ-ассоциированный рак шейки матки: современное состояние и перспективы

Ежегодно в мире диагностируется 570 000 новых случаев рака шейки матки (РШМ), и 311 000 человек погибают от этого заболевания. РШМ – четвёртый по распространённости вид рака и, соответственно, четвёртая по распространённости причина смерти от рака у женщин во всём мире. Многочисленные данные о возникновении и развитии РШМ свидетельствуют об ассоциации в большинстве случаев (до 90 %) с вирусами папилломы человека (ВПЧ) высокого канцерогенного риска (ВКР).
В свою очередь стратегии профилактики РШМ основаны на скрининге, а смертельные исходы от данной онкопатологии представляется возможным предотвратить путём проведения вакцинопрофилактики и лечения при раннем обнаружении заболевания.
В представленном обзоре большое внимание уделяется актуальным в настоящее время вопросам выявления и профилактики ВПЧ-ассоциированных патологий, в частности рака шейки матки, с целью обобщения и анализа последних международных литературных данных по данной проблематике. В результате проведения настоящего исследования показано, что для стран, реализующих Национальную программу вакцинации против ВПЧ ВКР, зарегистрировано снижение заболеваемости как патологиями шейки матки различной степени тяжести, так и другими онкозаболеваниями, ассоциированными с носительством данного вируса.
Несмотря на то, что эффективное использование накопленного на сегодняшний день опыта и будущих достижений вакцинопрофилактики папилломавирусной инфекции может позволить всем странам перейти к высокому уровню охвата, который необходим для окончательной ликвидации ВПЧ-ассоциированной патологии, полученные результаты также свидетельствуют о том, что путь к полной ликвидации рака шейки матки как глобальной проблемы общественного здравоохранения может оказаться чрезвычайно трудным в силу ряда существующих ограничений.

1. Almeida AM, Queiroz JA, Sousa F, Sousa Â. Cervical cancer and HPV infection: Ongoing therapeutic research to counteract the action of E6 and E7 oncoproteins. Drug Discov Today. 2019; 24(10): 2044-2057. doi: 10.1016/j.drudis.2019.07.011

2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Сancer J Clin. 2021; 71(3): 209-249. doi: 10.3322/caac.21660

3. Jalil AT, Kadhum WR, Faryad Khan MU, Karevskiy A, Hanan ZK, Suksatan W, et al. Cancer stages and demographical study of HPV16 in gene L2 isolated from cervical cancer in DhiQar province, Iraq. Appl Nanosci. 2021; 13: 3627. doi: 10.1007/s13204-021-01947-9

4. Mutombo AB, Benoy I, Tozin R, Bogers J, van Geertruyden JP, Jacquemyn Y. Prevalence and distribution of human papillomavirus genotypes among women in Kinshasa, the Democratic Republic of the Congo. J Glob Oncol. 2019; 5:1-9. doi: 10. 1200/JGO.19.00110

5. Zoa Assoumou S, Ndjoyi Mbiguino A, Mabika Mabika B, Nguizi Ogoula S, El Mzibri M, Khattabi A, et al. Human papillomavirus genotypes distribution among Gabonese women with normal cytology and cervical abnormalities. Infect Agent Cancer. 2016; 11(1): 1-8. doi: 10.1186/s13027-016-0046-0

6. Khodakarami N, Hosseini SJ, Yavari P, Farzaneh F, Etemad K, Salehpour S, et al. Human papillomavirus infection prevalence in women referred to health clinic of Shahid Beheshti University of Medical Sciences, Tehran, Iran. Iranian Journal of Epidemiology. 2012; 7(4): 35-42.

7. Zhang X, Li J, Xie B, Wu B, Lei S, Yao Y, et al. Comparative metabolomics analysis of cervicitis in human patients and a phenol mucilage-induced rat model using liquid chromatography tandem mass spectrometry. Front Pharmacol. 2018; 9: 282. doi: 10.3389/fphar.2018.00282

8. Li M, Du X, Lu M, Zhang W, Sun Z, Li L, et al. Prevalence characteristics of single and multiple HPV infections in women with cervical cancer and precancerous lesions in Beijing, China. J Med Virol. 2019; 91(3): 473-481. doi: 10.1002/jmv.25331

9. Короленкова Л.И. Цервикальные интраэпителиальные неоплазии и ранние формы рака шейки матки: клинико-морфологическая концепция цервикального канцерогенеза. М., 2017.

10. Joshi S, Parikh R. PAP smear and HPV co-testing-need of the hour. Int J Health Sci Res. 2021; 11(1): 48-53.

11. Šarenac T, Mikov M. Cervical cancer, different treatments and importance of bile acids as therapeutic agents in this disease. Front Pharmacol. 2019; 10: 484. doi: 10.3389/fphar.2019.00484

12. Alkilani YG, Apodaca-Ramos I. Cervical polyps. StatPearls Publishing; 2020.

13. Kucukyıldız I, Karaca M, Akgor U, Turkyılmaz M, Keskinkılıc B, Kara F, et al. Endocervical polyps in high risk human papillomavirus infections. Ginekol Pol. 2022; 93(1): 7-10. doi: 10.5603/GP.a2021.0207

14. Major AL, Dvořák V, Schwarzová J, Skřivánek A, Malík T, Pluta M, et al. Efficacy and safety of an adsorbent and anti-oxidative vaginal gel on CIN1 and 2, on high-risk HPV, and on p16/Ki-67: A randomized controlled trial. Arch Gynecol Obstet. 2021; 303(2): 501-511. doi: 10.1007/s00404-020-05816-8

15. Ye J, Cheng XD, Cheng B, Cheng YF, Chen XJ, Lu WG, et al. MiRNA detection in cervical exfoliated cells for missed high-grade lesions in women with LSIL/CIN1 diagnosis after colposcopyguided biopsy. BMC Cancer. 2019; 19(1): 1-9. doi: 10.1186/s12885-019-5311-3

16. Liu M, Yan X, Zhang M, Li X, Li S, Jing M. Influence of human papillomavirus infection on the natural history of cervical intraepithelial neoplasia 1: A meta-analysis. BioMed Res Int. 2017; 2017: 8971059. doi: 10.1155/2017/8971059

17. Santana BN, Baro RS, Orozco R, Arranz JP. Cervical vaporization in LSIL and persistent HPV infection. Taiwan J Obstet Gynecol. 2018; 57(4): 475-478. doi: 10.1016/j.tjog.2018.06.010

18. Tang Y, Zheng L, Yang S, Li B, Su H, Zhang LP. Epidemiology and genotype distribution of human papillomavirus (HPV) in Southwest China: A cross-sectional five years study in nonvaccinated women. Virol J. 2017; 14(1): 1-10. doi: 10.1186/s12985-017-0751-3

19. Yang W, Luo N, Ma L, Dai H, Cheng Z. The changes of surgical treatment for symptomatic uterine myomas in the past 15 years. Gynecol Minim Invasive Ther. 2018; 7(1): 10. doi: 10.4103/GMIT.GMIT_11_17

20. Bonde J, Bottari F, Parvu V, Pedersen H, Yanson K, Iacobone AD, et al. Bayesian analysis of baseline risk of CIN2 and CIN3 by HPV genotype in a European referral cohort. Int J Cancer. 2019; 145(4): 1033-1041. doi: 10.1002/ijc.32291

21. Sand FL, Munk C, Frederiksen K, Junge J, Iftner T, Dehlendorff C, et al. Risk of CIN3 or worse with persistence of 13 individual oncogenic HPV types. Int J Cancer. 2019; 144(80): 1975-1982. doi: 10.1002/ijc.31883

22. Celiešiūtė J, Vitkauskaitė A, Jusevičiūtė V, Paškauskas S, Jarienė K, Čižauskas A, et al. Low, medium and high-risk HPV type distribution in cervical carcinoma in situ. Int J Gynecol Cancer. 2017; 27(4): 1747.

23. Lu J, Song E, Ghoneim A, Alrashoud M. Machine learning for assisting cervical cancer diagnosis: An ensemble approach. Future Generation Computer Systems. 2020; 106: 199-205. doi: 10.1016/j.future.2019.12.033

24. Wang X, Huang X, Zhang Y. Involvement of human papillomaviruses in cervical cancer. Front Microbiol. 2018; 9: 2896. doi: 10.3389/fmicb.2018.02896

25. Wang R, Pan W, Jin L, Huang W, Li Y, Wu D, et al. Human papillomavirus vaccine against cervical cancer: Opportunity and challenge. Cancer Lett. 2020; 471: 88-102. doi: 10.1016/j.canlet.2019.11.039

26. Ono A, Koshiyama M, Nakagawa M, Watanabe Y, Ikuta E, Seki K, Oowaki M, et al. The preventive effect of dietary antioxidants on cervical cancer development. Medicina. 2020; 56(11): 604. doi: 10.3390/medicina56110604

27. Almeida AM, Queiroz JA, Sousa F, Sousa Â. Cervical cancer and HPV infection: Ongoing therapeutic research to counteract the action of E6 and E7 oncoproteins. Drug Discov Today. 2019;24(10): 2044-2057. doi: 10.1016/j.drudis.2019.07.011

28. Li W, Tian S, Wang P, Zang Y, Chen X, Yao Y, et al. The characteristics of HPV integration in cervical intraepithelial cells. J Cancer. 2019; 10(12): 2783. doi: 10.7150/jca.31450

29. Hu Z, Ma D. The precision prevention and therapy of HPV‐related cervical cancer: New concepts and clinical implications. Cancer Med. 2018; 7(10): 5217-5236. doi: 10.1002/cam4.1501

30. Zhou L, Qiu Q, Zhou Q, Li J, Yu M, Li K, et al. Long-read sequencing unveils high-resolution HPV integration and its oncogenic progression in cervical cancer. Nat Commun. 2022; 13(1):2563. doi: 10.1038/s41467-022-30190-1

31. Ribeiro J, Teixeira D, Marinho-Dias J, Monteiro P, Loureiro J, Baldaque I, et al. Characterization of human papillomavirus genotypes and HPV-16 physical status in cervical neoplasias of women from northern Portugal. Int J Gynecol Obstet. 2014; 125(2): 107-110. doi: 10.1016/j.ijgo.2013.10.011

32. Oyervides-Muñoz MA, Pérez-Maya AA, Rodríguez-Gutiérrez HF, Gómez-Macias GS, Fajardo-Ramírez OR, Treviño V, et al. Understanding the HPV integration and its progression to cervical cancer. Infect Genet Evol. 2018; 61: 134-144. doi: 10.1016/j.meegid.2018.03.003

33. Kamal M, Lameiras S, Deloger M, Morel A, Vacher S, Lecerf C, et al. Human papilloma virus (HPV) integration signature in cervical cancer: Identification of MACROD2 gene as HPV hot spot integration site. Br J Cancer. 2021; 124(4): 777-785. doi: 10.1038/s41416-020-01153-4

34. Bodelon C, Vinokurova S, Sampson JN, den Boon JA, Walker JL, Horswill MA, et al. Chromosomal copy number alterations and HPV integration in cervical precancer and invasive cancer. Carcinogenesis. 2016; 37(2): 188-196. doi: 10.1093/carcin/bgv171

35. Wipperman J, Neil T, Williams T. Cervical cancer: Evaluation and management. Am Fam Physician. 2018; 97(7): 449-454.

36. Wang R, Pan W, Ji L, Huang W, Li Y, Wu D. Human papillomavirus vaccine against cervical cancer: Opportunity and challenge. Cancer Lett. 2020; 471: 88-102. doi: 10.1016/j.canlet.2019.11.039

37. Nagelhout G, Ebisch RM, van der Hel O, Meerkerk GJ, Magnée T, de Bruijn T, et al. Is smoking an independent risk factor for developing cervical intra-epithelial neoplasia and cervical cancer? A systematic review and meta-analysis. Expert Rev Anticancer Ther. 2021; 21(7): 781-794. doi: 10.1080/14737140.2021.1888719

38. Litviakov NV, Ibragimova MK, Tsyganov MM, Shpileva OV, Churuksaeva ON, Kolomiets LA. Changes in the genetic landscape during the malignization of high grade squamous intraepithelial lesion into cervical cancer. Curr Probl Cancer. 2020; 44(5): 100567. doi: 10.1016/j.currproblcancer.2020.100567

39. Zhang H, Lu J, Lu Y, Cai Q, Liu H, Xu C. Cervical microbiome is altered in cervical intraepithelial neoplasia after loop electrosurgical excision procedure in china. Sci Rep. 2018; 8(1): 1-8. doi: 10.1038/s41598-018-23389-0

40. De Vincenzo R, Ricci C, Conte C, Scambia G. HPV vaccine cross-protection: Highlights on additional clinical benefit. Gynecol Oncol. 2013; 130(3): 642-651. doi: 10.1016/j.ygyno.2013.05.033

41. Ranjeva SL, Baskerville EB, Dukic V, Villa LL, Lazcano-Ponce E, Giuliano AR, et al. Recurring infection with ecologically distinct HPV types can explain high prevalence and diversity. Proceedings of the National Academy of Sciences. 2017; 114(51): 13573-13578. doi: 10.1073/pnas.1714712114

42. Wang R, Pan W, Jin L, Huang W, Li Y, Wu D, et al. Human papillomavirus vaccine against cervical cancer: Opportunity and challenge. Cancer Lett. 2020; 471: 88-102. doi: 10.1016/j.canlet.2019.11.039

43. Giorgi Rossi P, Carozzi F, Ronco G, Allia E, Bisanzi S, Gillio-Tos A, et al. p16/ki67 and E6/E7 mRNA accuracy and prognostic value in triaging HPV DNA-positive women. JNCI: J Nati Cancer Inst. 2021; 113(3): 292-300. doi: 10.1093/jnci/djaa105

44. Zhao J, Cao H, Zhang W, Fan Y, Shi S, Wang R. SOX14 hypermethylation as a tumour biomarker in cervical cancer. BMC Cancer. 2021; 21(1): 1-10. doi: 10.1186/s12885-021-08406-2

45. Park S, Eom K, Kim J, Bang H, Wang HY, Ahn S, et al. MiR-9, miR-21, and miR-155 as potential biomarkers for HPV positive and negative cervical cancer. BMC Cancer. 2017; 17(1): 1-8. doi: 10.1186/s12885-017-3642-5

46. Kim HJ, Kim CY, Jin J, Bae MK, Kim YH, Ju W, et al. Aberrant single‐minded homolog 1 methylation as a potential biomarker for cervical cancer. Diagn Cytopathol. 2018; 46(1): 15-21. doi: 10.1002/dc.23838

47. Jiao X, Zhang S, Jiao J, Zhang T, Qu W, Muloye GM, et al. Promoter methylation of SEPT9 as a potential biomarker for early detection of cervical cancer and its overexpression predicts radioresistance. Clin Epigeneicst. 2019; 11(1): 1-14. doi: 10.1186/s13148-019-0719-9

48. Li N, He Y, Mi P, Hu Y. ZNF582 methylation as a potential biomarker to predict cervical intraepithelial neoplasia type III/worse:

49. A meta-analysis of related studies in Chinese population. Medicine. 2019; 98(6): e14297. doi: 10.1097/MD.0000000000014297

50. Fang C, Wang SY, Liou YL, Chen MH, Ouyang W, Duan KM. The promising role of PAX1 (aliases: HUP48, OFC2) gene methylation in ancer screening. Mol Genet Genomic Med. 2019; 7(3): e506. doi: 10.1002/mgg3.506

51. Zhang L, Yu J, Huang W, Zhang H, Xu J, Cai H. A. Sensitive and simplified classifier of cervical lesions based on a methylationspecific PCR assay: A Chinese cohort study. Cancer Manag Res. 2020; 12: 2567-2576. doi: 10.2147/CMAR.S246103

52. Gutiérrez-Hoya A, Soto-Cruz I. Role of the JAK/STAT pathway in cervical cancer: It’s relationship with HPV E6/E7 oncoproteins. Cells. 2020; 9(10): 2297. doi: 10.3390/cells9102297

53. Rodrigues C, Joy LR, Sachithanandan SP, Krishna S. Notch signalling in cervical cancer. Expl Cell Res. 2019; 385(2): 111682. doi: 10.1016/j.yexcr.2019.111682

54. Ramachandran D, Schürmann P, Mao Q, Wang Y, Bretschneider LM, Speith LM, et al. Association of genomic variants at the human leukocyte antigen locus with cervical cancer risk, HPV status and gene expression levels. Int J Cancer. 2020; 147(9): 2458-2468. doi: 10.1002/ijc.33171

55. Lei J, Ploner A, Elfström KM, Wang J, Roth A, Fang F, et al. HPV vaccination and the risk of invasive cervical cancer. N Engl J Med. 2020; 383(14): 1340-1348. doi: 10.1056/NEJMoa1917338

56. Brisson M, Kim JJ, Canfell K, Drolet M, Gingras G, Burger EA, et al. Impact of HPV vaccination and cervical screening on cervical cancer elimination: A comparative modeling analysis in 78 low-income and lower-middle-income countries. Lancet. 2020; 395(10224): 575-590. doi: 10.1016/S0140-6736(20)30068-4

57. Ngoma M, Autier P. Cancer prevention: cervical cancer. Ecancermedicalscience. 2019; 13: 952. doi: 10.3332/ecancer.2019.952

58. Simms KT, Hanley SJ, Smith MA, Keane A, Canfell K. Impact of HPV vaccine hesitancy on cervical cancer in Japan: A modelling study. Lancet Public Health. 2020; 5(4): e223-e234. doi: 10.1016/S2468-2667(20)30010-4

59. Canfell K. Towards the global elimination of cervical cancer. Papillomavirus Res. 2019; 8: 100170. doi: 10.1016/j.pvr.2019.100170

60. Palmer T, Wallace L, Pollock KG, Cuschieri K, Robertson C, Kavanagh K, et al. Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12–13 in Scotland: Retrospective population study. BMJ. 2019; 365: 1161. doi: 10.1136/bmj.l1161

61. Tanaka H, Shirasawa H, Shimizu D, Sato N, Ooyama N, Takahashi O, et al. Preventive effect of human papillomavirus vaccination on the development of uterine cervical lesions in young Japanese women. J Obstet Gynaecol Res. 2017; 43(10): 1597-1601. doi: 10.1111/jog.13419

62. Gertig DM, Brotherton JM, Budd AC, Drennan K, Chappell G, Saville AM. Impact of a population-based HPV vaccination program on cervical abnormalities: A data linkage study. BMC Med. 2013; 11(1): 1-12. doi : 10.1186/1741-7015-11-227

63. Mahmud SM, Kliewer EV, Lambert P, Bozat-Emre S, Demers AA. Effectiveness of the quadrivalent human papillomavirus vaccine against cervical dysplasia in Manitoba, Canada. J Clin Oncol. 2014; 32(5): 438-443. doi: 10.1200/JCO.2013.52.4645

64. Wang R, Pan W, Jin L, Huang W, Li Y, Wu D, et al. Human papillomavirus vaccine against cervical cancer: Opportunity and challenge.Cancer Lett. 2020; 471: 88-102. doi: 10.1016/j.canlet.2019.11.039

65. Bruni L, Saura-Lázaro A, Montoliu A, Brotons M, Alemany L, Diallo MS, et al. HPV vaccination introduction worldwide and WHO and UNICEF estimates of national HPV immunization coverage 2010–2019. Prev Med. 2021; 144: 106399. doi: 10.1016/j.ypmed.2020.106399

66. Tsu VD, LaMontagne DS, Atuhebwe P, Bloem PN, Ndiaye C. National implementation of HPV vaccination programs in lowresource countries: Lessons, challenges, and future prospects. Prev Med. 2021; 144: 106335. doi: 10.1016/j.ypmed.2020.106335

67. Oyedeji O, Maples JM, Gregory S, Chamberlin SM, Gatwood JD, Wilson AQ, et al. Pharmacists’ perceived barriers to human papillomavirus (HPV) vaccination: A systematic literature review. Vaccines. 2021; 9(11): 1360. doi: 10.3390/vaccines9111360

68. Toh ZQ, Russell FM, Garland SM, Mulholland EK, Patton G, Licciardi PV. Human papillomavirus vaccination after COVID-19. JNCI Cancer Spectr. 2021; 5(2): pkab011. doi: 10.1093/jncics/pkab011

69. Coleman D, Day N, Douglas G, Farmery E, Lynge E, Philip J. European guidelines for quality assurance in cervical cancer screening. Europe against cancer programme. Part A. Eur J Cancer. 1993; 29: 298-299.

70. Chrysostomou AC, Stylianou DC, Constantinidou A, Kostrikis LG. Cervical cancer screening programs in Europe: The transition towards HPV vaccination and population-based HPV testing. Viruses. 2018; 10(12): 729. doi: 10.3390/v10120729

71. Цервикальная интраэпителиальная неоплазия, эрозия и эктропион шейки матки: клинические рекомендации. 2022.

72. Sroczynski G, Esteban E, Widschwendter A, Oberaigner W, Borena W, von Laer D, et al. Reducing overtreatment associated with overdiagnosis in cervical cancer screening – A model-based benefit-harm analysis for Austria. Int J Cancer. 2020; 147(4): 1131-1142. doi: 10.1002/ijc.32849

73. Jolidon V, De Prez V, Willems B, Bracke P, Cullati S, BurtonJeangros C. Never and under cervical cancer screening in Switzerland and Belgium: Trends and inequalities. BMC Public Health. 2020; 20(1): 1-11. doi: 10.1186/s12889-020-09619-z

74. Altova A, Kulhánová I, Bruha L, Lustigova M. Breast and cervical cancer screening attendance among Czech women. Cent Eur J Public Health. 2021; 29(2): 90-95. doi: 10.21101/cejph.a6623

75. Pedersen K, Fogelberg S, Thamsborg LH, Clements M, Nygård M, Kristiansen IS, et al. An overview of cervical cancer epidemiology and prevention in Scandinavia. Acta Obstet GynecolScand. 2018; 97(7): 795-807. doi: 10.1111/aogs.13313

76. Ojamaa K, Innos K, Baburin A, Everaus H, Veerus P. Trends in cervical cancer incidence and survival in Estonia from 1995 to 2014. BMC Cancer. 2018; 18(1): 1-9. doi: 10.1186/s12885-018-5006-1

77. De Rycke Y, Tubach F, Lafourcade A, Guillo S, Dalichampt M, Dahlab A, et al. Cervical cancer screening coverage, management of squamous intraepithelial lesions and related costs in France. PloS One. 2020; 15(2): e0228660. doi: 10.1371/journal.pone.0228660

78. de Munter AC, Klooster TM, van Lier A, Akkermans R, de Melker HE, Ruijs WLM. Determinants of HPV-vaccination uptake and subgroups with a lower uptake in the Netherlands. BMC Public Health. 2021; 21(1): 1-13. doi: 10.1186/s12889-021-11897-0

79. Osowiecka K, Yahuza S, Szwiec M, Gwara A, Kasprzycka K, Godawska M, et al. Students’ knowledge about cervical cancer prevention in Poland. Medicina. 2021; 57(10): 1045. doi: 10.3390/medicina57101045

80. Kramer J. Eradicating cervical cancer: Lessons learned from Rwanda and Australia. Int J Gynecol Obstet. 2021; 154(2): 270-276. doi: 10.1002/ijgo.13601

81. Fernandes C, Alves J, Rodrigues A, Azevedo J. Group for the study of HPV vaccines. Epidemiological impact of the human papillomavirus vaccination program on genital warts in Portugal: A retrospective, chart review study. Vaccine. 2022; 40(2): 275-281. doi: 10.1016/j.vaccine.2021.11.070

82. Maver PJ, Poljak M. Primary HPV-based cervical cancer screening in Europe: Implementation status, challenges, and future plans. Clin Microbiol Infect. 2020; 26(5): 579-583. doi: 10.1016/j.cmi.2019.09.006