akusherstvoObstetrics, Gynecology and ReproductionАкушерство, Гинекология и Репродукция2313-73472500-3194IRBIS LLC10.17749/2313-7347/ob.gyn.rep.2026.642akusherstvo-2717Research ArticleREVIEW ARTICLESНАУЧНЫЕ ОБЗОРЫOnce again about HPV and cervical neoplasia: biology and pathogenesisЕще раз о ВПЧ и цервикальной неоплазии: биология и патогенезhttps://orcid.org/0009-0004-3139-7765ЩукинВ. Ю.ShchukinV. Yu.

Щукин Владимир Юрьевич

443031 Самара, Солнечная ул., д. 50

Vladimir Yu. Shchukin - MD.

51 Solnechnaya Str., Samara 443031

https://orcid.org/0000-0001-9092-7149ГерфановаЕ. В.GerfanovaE. V.

Герфанова Евгения Викторовна - к.м.н.

117997 Москва, ул. Академика Опарина, д. 4

Evgeniya V. Gerfanova - MD, PhD.

4 Academika Oparina Str., Moscow 117997

evgeniyagerf@gmail.comhttps://orcid.org/0000-0002-4654-9512БабаеваН. А.BabaevaN. A.

Бабаева Наталья Александровна - д.м.н.

117997 Москва, ул. Академика Опарина, д. 4

Nataliya A. Babaeva - MD, Dr Sci Med.

4 Academika Oparina Str., Moscow 117997

https://orcid.org/0000-0002-2957-3940АлешиковаО. И.AleshikovaO. I.

Алешикова Ольга Ивановна - к.м.н.

117997 Москва, ул. Академика Опарина, д. 4

Olga I. Aleshikova - MD, PhD.

4 Academika Oparina Str., Moscow 117997

https://orcid.org/0000-0002-8285-9091МухсинзодаН. А.MukhsinzodaN. A.

Мухсинзода Нилуфар Абдукаххоровнa - к.м.н.

734026 Душанбе, проспект Исмоила Сомони, д. 59а

Nilufar A. Mukhsinzoda - MD, PhD.

59a Ismail Somoni Avenue, Dushanbe 734026

https://orcid.org/0000-0002-4721-3420КиселевВ. И.KiselevV. I.

Киселев Всеволод Иванович - д.м.н. - проф., академик РАН.

117997 Москва, ул. Академика Опарина, д. 4

Vsevolod I. Kiselev - MD, Dr Sci Med, Prof., Corresponding Member of RAS.

4 Academika Oparina Str., Moscow 117997

https://orcid.org/0000-0001-6396-4948АшрафянЛ. А.AshrafyanL. A.

Ашрафян Лев Андреевич - д.м.н., проф., член-корр. РАН.

117997 Москва, ул. Академика Опарина, д. 4

Lev A. Ashrafyan - MD, Dr Sci Med, Prof., Academician of RAS.

4 Academika Oparina Str., Moscow 117997

ГБУЗ «Самарский областной клинический онкологический диспансер»РоссияSamara Regional Clinical Oncology DispensaryRussian FederationФГБУ «Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии имени академика В.И. Кулакова» Министерства здравоохранения Российской ФедерацииРоссияAcademician Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian FederationRussian FederationГУ «Республиканский онкологический научный центр»ТаджикистанRepublican Oncology Research CenterTajikistan202612032026201192203Copyright © Shchukin V.Y., Gerfanova E.V., Babaeva N.A., Aleshikova O.I., Mukhsinzoda N.A., Kiselev V.I., Ashrafyan L.A., 20262026Щукин В.Ю., Герфанова Е.В., Бабаева Н.А., Алешикова О.И., Мухсинзода Н.А., Киселев В.И., Ашрафян Л.А.Shchukin V.Y., Gerfanova E.V., Babaeva N.A., Aleshikova O.I., Mukhsinzoda N.A., Kiselev V.I., Ashrafyan L.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.gynecology.su/jour/article/view/2717

Human papillomavirus (HPV) is the main risk factor for developing cervical cancer (CC). About 70–75 % of all invasive CC cases worldwide are associated with HPV 16 and 18 genotypes, 20–25 % cases being related to HPV 31, 33, 35, 45, 52, and 58 genotypes. Currently, there are more than 100 tests for HPV diagnostics, but up to now, it has been difficult to establish and evaluate sensitivity of cytological examination for detecting pre-invasive and invasive cervical squamous and glandular lesions. The use of biomarkers for a more objective diagnostics of squamous intraepithelial lesions (SIL) was investigated in numerous studies. The most widely used biomarker is the p16INK4a (p16) antibody that flags E7-induced high-risk HPV-caused cell proliferation. The diagnosis of SIL upon cervical biopsy is also highly variable convincingly supported by the documented evidence. The intermediate category, cervical intraepithelial neoplasia grade 2 (CIN2), provides the least reproducible results. The use of immunohistochemistry p16, alone or in combination with the proliferation marker Ki-67, increases the effectiveness of differentiation between SIL and its benign imitators. Thus, a high degree of variability still is observed between the data of cervical cytology and biopsy due to both sampling errors and the expertise of medical works involved in data interpretation. Atypical squamous cells of undetermined significance (ASC-US) represent the primary source of such variability.

Вирус папилломы человека (ВПЧ) является основным фактором риска развития рака шейки матки (РШМ). Около 70–75 % всех наблюдений инвазивного РШМ в мире связано с 16-м и 18-м генотипами ВПЧ, 20–25 % – с 31-м, 33-м, 35-м, 45-м, 52-м и 58-м генотипами. В настоящее время имеется более 100 тестов для диагностики ВПЧ, но вплоть до настоящего времени трудно установить и оценить в широких пределах чувствительность цитологического исследования для выявления преинвазивных и инвазивных плоскоклеточных и железистых поражений шейки матки. Использование биомаркеров для более объективной диагностики плоскоклеточных интраэпителиальных поражений (англ. squamous intraepithelial lesions, SIL) является объектом многочисленных исследований. Наиболее широко используемым биомаркером является антитело p16INK4a (p16), маркер Е7-обусловленной пролиферацией клеток, вызванной ВПЧ высокого риска. Диагностика SIL при биопсии шейки матки также весьма вариабельна, что убедительно подтверждено документальными доказательствами. Промежуточная категория – цервикальная интраэпителиальная неоплазия 2-й степени (англ. cervical intraepithelial neoplasia, CIN2) обладает самой плохой воспроизводимостью. Использование иммуногистохимии p16 отдельно или в сочетании с маркером пролиферации Ki-67 повышает результативность дифференцирования SIL и его доброкачественных имитаторов. Таким образом, высокая вариабельность между результатами цервикальной цитологии и биопсии сохраняется, что объясняется как ошибками при взятии образцов материала, так и квалификацией врачей-специалистов, интерпретирующих полученные результаты, при этом клетки плоского эпителия с атипией неясного значения (англ. atypical squamous cells of undetermined significance, ASC-US) представляют собой наибольший источник вариабельности.

вирус папилломы человекаВПЧрак шейки маткиРШМцитологическое исследованиетерминология системы Бетесдаhuman papillomavirusHPVcervical cancerCCcytological examinationBethesda system terminologyАвторы заявляют об отсутствии финансовой поддержкиThe authors declare no fundingReferencesWHO classification of tumours of female reproductive organs. Eds. R.J. Kurman, M.L. Carcangiu, C.S. Herrington, R.H. Young. 4th ed. Lyon: IARC, 2014. 307 р.WHO classification of tumours of female reproductive organs. Eds. R.J. Kurman, M.L. Carcangiu, C.S. Herrington, R.H. Young. 4th ed. Lyon: IARC, 2014. 307 р.Haghshenas M.R., Mousavi T., Kheradmand M. et al. Efficacy of human papillomavirus L1 protein vaccines (Cervarix and Gardasil) in reducing the risk of cervical intraepithelial neoplasia: a meta-analysis. Int J Prev Med. 2017;8:44. https://doi.org/10.4103/ijpvm.IJPVM_413_16.Haghshenas M.R., Mousavi T., Kheradmand M. et al. Efficacy of human papillomavirus L1 protein vaccines (Cervarix and Gardasil) in reducing the risk of cervical intraepithelial neoplasia: a meta-analysis. Int J Prev Med. 2017;8:44. https://doi.org/10.4103/ijpvm.IJPVM_413_16.Krishnamurti U., Unger E.R. Pathobiology of human papillomaviruses in human immunodeficiency virus-infected persons. Semin Diagn Pathol. 2017;34(4):364–70. https://doi.org/10.1053/j.semdp.2017.04.005.Krishnamurti U., Unger E.R. Pathobiology of human papillomaviruses in human immunodeficiency virus-infected persons. Semin Diagn Pathol. 2017;34(4):364–70. https://doi.org/10.1053/j.semdp.2017.04.005.Thomison J., Thomas L.K., Shroyer K.R. Human papillomavirus: molecular and cytologic/histologic aspects related to cervical intraepithelial neoplasia and carcinoma. Hum Pathol. 2008;39(2):154–66. https://doi.org/10.1016/j.humpath.2007.11.002.Thomison J., Thomas L.K., Shroyer K.R. Human papillomavirus: molecular and cytologic/histologic aspects related to cervical intraepithelial neoplasia and carcinoma. Hum Pathol. 2008;39(2):154–66. https://doi.org/10.1016/j.humpath.2007.11.002.Baseman J.G., Koutsky L.A. The epidemiology of human papillomavirus infections. J Clin Virol. 2017;32 Suppl 1:S16–24. https://doi.org/10.1016/j.jcv.2004.12.008.Baseman J.G., Koutsky L.A. The epidemiology of human papillomavirus infections. J Clin Virol. 2017;32 Suppl 1:S16–24. https://doi.org/10.1016/j.jcv.2004.12.008.Lee L.-Y., Garland S.M. Human papillomavirus vaccination: the population impact. F1000Res. 2017;6:866. https://doi.org/10.12688/f1000research.10691.1.Lee L.-Y., Garland S.M. Human papillomavirus vaccination: the population impact. F1000Res. 2017;6:866. https://doi.org/10.12688/f1000research.10691.1.Doorbar J. Host control of human papillomavirus infection and disease. Best Pract Res Clin Obstet Gynaecol. 2017;47:27–41. https://doi.org/10.1016/j.bpobgyn.2017.08.001.Doorbar J. Host control of human papillomavirus infection and disease. Best Pract Res Clin Obstet Gynaecol. 2017;47:27–41. https://doi.org/10.1016/j.bpobgyn.2017.08.001.Schiffman M., Castle P.E., Jeronimo J. et al. Human papillomavirus and cervical cancer. Lancet. 2007;370(9590):890–907. https://doi.org/10.1016/S0140-6736(07)61416-0.Schiffman M., Castle P.E., Jeronimo J. et al. Human papillomavirus and cervical cancer. Lancet. 2007;370(9590):890–907. https://doi.org/10.1016/S0140-6736(07)61416-0.Doorbar J., Quint W., Banks L. et al. The biology and life-cycle of human papillomaviruses. Vaccine. 2012;30 Suppl 5:F55–70. https://doi.org/10.1016/j.vaccine.2012.06.083.Doorbar J., Quint W., Banks L. et al. The biology and life-cycle of human papillomaviruses. Vaccine. 2012;30 Suppl 5:F55–70. https://doi.org/10.1016/j.vaccine.2012.06.083.Mirkovic J., Howitt B.E., Roncarati P. et al. Carcinogenic HPV infection in the cervical squamo-columnar junction. J Pathol. 2015;236(3):265–71. https://doi.org/10.1002/path.4533.Mirkovic J., Howitt B.E., Roncarati P. et al. Carcinogenic HPV infection in the cervical squamo-columnar junction. J Pathol. 2015;236(3):265–71. https://doi.org/10.1002/path.4533.Burd E.M. Human papillomavirus and cervical cancer. Clin Microbiol Rev. 2003;16(1):1–17.Burd E.M. Human papillomavirus and cervical cancer. Clin Microbiol Rev. 2003;16(1):1–17.Committee on Practice Bulletins – Gynecology. Practice Bulletin No. 168: cervical cancer screening and prevention. Obstet Gynecol. 2016;128(4):e111–e130. https://doi.org/10.1097/AOG.0000000000001708.Committee on Practice Bulletins – Gynecology. Practice Bulletin No. 168: cervical cancer screening and prevention. Obstet Gynecol. 2016;128(4):e111–e130. https://doi.org/10.1097/AOG.0000000000001708.Khan M.J., Castle P.E., Lorincz A.T. et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2015;97(14):1072–9. https://doi.org/10.1093/jnci/dji187.Khan M.J., Castle P.E., Lorincz A.T. et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2015;97(14):1072–9. https://doi.org/10.1093/jnci/dji187.Schiffman M., Burk R.D., Boyle S. et al. A study of genotyping for management of human papillomavirus-positive, cytology-negative cervical screening results. J Clin Microbiol. 2015;53(1):52–9. https://doi.org/10.1128/JCM.02116-14.Schiffman M., Burk R.D., Boyle S. et al. A study of genotyping for management of human papillomavirus-positive, cytology-negative cervical screening results. J Clin Microbiol. 2015;53(1):52–9. https://doi.org/10.1128/JCM.02116-14.Arbyn M., Snijders P.J.F., Meijer C.J.L.M. et al. Which high-risk HPV assays fulfil criteria for use in primary cervical cancer screening? Clin Microbiol Infect. 2015;21(9):817–26. https://doi.org/10.1016/j.cmi.2015.04.015.Arbyn M., Snijders P.J.F., Meijer C.J.L.M. et al. Which high-risk HPV assays fulfil criteria for use in primary cervical cancer screening? Clin Microbiol Infect. 2015;21(9):817–26. https://doi.org/10.1016/j.cmi.2015.04.015.Zhao C., Moriarty A.T., Ghofrani M. et al. Human papillomavirus testing and reporting rates in 2012: results of a College of American Pathologists national survey. Arch Pathol Lab Med. 2014;139(6):757–61. https://doi.org/10.5858/arpa.2014-0393-CP.Zhao C., Moriarty A.T., Ghofrani M. et al. Human papillomavirus testing and reporting rates in 2012: results of a College of American Pathologists national survey. Arch Pathol Lab Med. 2014;139(6):757–61. https://doi.org/10.5858/arpa.2014-0393-CP.de Thurah L., Bonde J., Lam J.U.H., Rebolj M. Concordant testing results between various human papillomavirus assays in primary cervical cancer screening: systematic review. Clin Microbiol Infect. 2017;24:29–36. https://doi.org/10.1016/j.cmi.2017.05.020.de Thurah L., Bonde J., Lam J.U.H., Rebolj M. Concordant testing results between various human papillomavirus assays in primary cervical cancer screening: systematic review. Clin Microbiol Infect. 2017;24:29–36. https://doi.org/10.1016/j.cmi.2017.05.020.Mills A.M., Dirks D.C., Poulter M.D. et al. HR-HPV E6/E7 mRNA in situ hybridization: validation against PCR, DNA in situ hybridization, and p16 immunohistochemistry in 102 samples of cervical, vulvar, anal, and head and neck neoplasia. Am J Surg Pathol. 2017;41(5):607–15. https://doi.org/10.1097/PAS.0000000000000800.Mills A.M., Dirks D.C., Poulter M.D. et al. HR-HPV E6/E7 mRNA in situ hybridization: validation against PCR, DNA in situ hybridization, and p16 immunohistochemistry in 102 samples of cervical, vulvar, anal, and head and neck neoplasia. Am J Surg Pathol. 2017;41(5):607–15. https://doi.org/10.1097/PAS.0000000000000800.The Bethesda system for reporting cervical cytology: definitions, criteria, and explanatory notes. Eds. R. Nayar, D.C. Wilbur. 3rd ed. Cham: Springer, 2015. 345 p. https://doi.org/10.1007/978-3-319-11074-5.The Bethesda system for reporting cervical cytology: definitions, criteria, and explanatory notes. Eds. R. Nayar, D.C. Wilbur. 3rd ed. Cham: Springer, 2015. 345 p. https://doi.org/10.1007/978-3-319-11074-5.Darragh T.M., Colgan T.J., Cox J.T. et al. The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med. 2012;136(10):1266–97. https://doi.org/10.5858/arpa.LGT200570.Darragh T.M., Colgan T.J., Cox J.T. et al. The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med. 2012;136(10):1266–97. https://doi.org/10.5858/arpa.LGT200570.Massad L.S., Einstein M.H., Huh W.K. et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013;121(4):829–46. https://doi.org/10.1097/AOG.0b013e3182883a34.Massad L.S., Einstein M.H., Huh W.K. et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013;121(4):829–46. https://doi.org/10.1097/AOG.0b013e3182883a34.Doorbar J. Model systems of human papillomavirus-associated disease. J Pathol. 2016;238(2):166–79. https://doi.org/10.1002/path.4656.Doorbar J. Model systems of human papillomavirus-associated disease. J Pathol. 2016;238(2):166–79. https://doi.org/10.1002/path.4656.McCluggage W.G., Walsh M.Y., Thornton C.M. et al. Inter-andintraobserver variation in the histopathological reporting of cervical squamous in intraepithelial lesion using a modified Bethesda grading system. BJOG. 2009;105(2):206–10. https://doi.org/10.1111/j.1471-0528.1998.tb10054.x.McCluggage W.G., Walsh M.Y., Thornton C.M. et al. Inter-andintraobserver variation in the histopathological reporting of cervical squamous in intraepithelial lesion using a modified Bethesda grading system. BJOG. 2009;105(2):206–10. https://doi.org/10.1111/j.1471-0528.1998.tb10054.x.Carreon J.D., Sherman M.E., Guillйn D. et al. CIN2 is a much less reproducible and less valid diagnosis than CIN3: results from a histological review of population-based cervical samples. Int J Gynecol Pathol. 2017;26(4):441–6. https://doi.org/10.1097/pgp.0b013e31805152ab.Carreon J.D., Sherman M.E., Guillйn D. et al. CIN2 is a much less reproducible and less valid diagnosis than CIN3: results from a histological review of population-based cervical samples. Int J Gynecol Pathol. 2017;26(4):441–6. https://doi.org/10.1097/pgp.0b013e31805152ab.Castle P.E, Stoler M.H., Solomon D., Schiffmanx M. The relationship of community biopsy-diagnosed cervical intraepithelial neoplasia grade 2 to the quality control pathology-reviewed diagnoses: an ALTS report. Am J Clin Pathol. 2017;127(5):805–15. https://doi.org/10.1309/PT3PNC1QL2F4D2VL.Castle P.E, Stoler M.H., Solomon D., Schiffmanx M. The relationship of community biopsy-diagnosed cervical intraepithelial neoplasia grade 2 to the quality control pathology-reviewed diagnoses: an ALTS report. Am J Clin Pathol. 2017;127(5):805–15. https://doi.org/10.1309/PT3PNC1QL2F4D2VL.Stoler M.H., Schiffman M., for the Atypical Squamous Cells of Undetermined Significance-Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS) Group. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL triage study. JAMA. 2019;285(11):1500–5. https://doi.org/10.1001/jama.285.11.1500.Stoler M.H., Schiffman M., for the Atypical Squamous Cells of Undetermined Significance-Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS) Group. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL triage study. JAMA. 2019;285(11):1500–5. https://doi.org/10.1001/jama.285.11.1500.Galgano M.T., Castle P.E., Atkins K.A. et al. Using biomarkers as objective standards in the diagnosis of cervical biopsies. Am J Surg Pathol. 2020;34(8):1077–87. https://doi.org/10.1097/PAS.0b013e3181e8b2c4.Galgano M.T., Castle P.E., Atkins K.A. et al. Using biomarkers as objective standards in the diagnosis of cervical biopsies. Am J Surg Pathol. 2020;34(8):1077–87. https://doi.org/10.1097/PAS.0b013e3181e8b2c4.Group T.A. A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol. 2023;188(6):1393–400. https://doi.org/10.1067/mob.2003.462.Group T.A. A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol. 2023;188(6):1393–400. https://doi.org/10.1067/mob.2003.462.Van Baars R., Griffin H., Wu Z. et al. Investigating diagnostic problems of CIN 1 and 2 associated with high-risk HPV by combining the novel molecular biomarker PanHPV E4 with P16INK4a. Am J Surg Pathol. 2015;39(11):1518–28. https://doi.org/10.1097/PAS.0000000000000498.Van Baars R., Griffin H., Wu Z. et al. Investigating diagnostic problems of CIN 1 and 2 associated with high-risk HPV by combining the novel molecular biomarker PanHPV E4 with P16INK4a. Am J Surg Pathol. 2015;39(11):1518–28. https://doi.org/10.1097/PAS.0000000000000498.Tsoumpou I., Arbyn M., Kyrgiou M. et al. p16(INK4a) immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. Cancer Treat Rev. 2019;35(3):210–20. https://doi.org/10.1016/j.ctrv.2008.10.005.Tsoumpou I., Arbyn M., Kyrgiou M. et al. p16(INK4a) immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. Cancer Treat Rev. 2019;35(3):210–20. https://doi.org/10.1016/j.ctrv.2008.10.005.WHO/ICO Information Centre on HPV and Cancer. Russian Federation: Human Papillomavirus and Related Cancers, Fact Sheet. 2017. 334 p.WHO/ICO Information Centre on HPV and Cancer. Russian Federation: Human Papillomavirus and Related Cancers, Fact Sheet. 2017. 334 p.Conesa-Zamora P., Domenech-Peris A., Orantes-Casado F.J. et al. Effect of human papillomavirus on cell cycle-related proteins p16, Ki-67, cyclin D1, p53, and ProEx C in precursor lesions of cervical carcinoma: a tissue microarray study. Am J Clin Pathol. 2019;132(3):378–90. https://doi.org/10.1309/AJCPO0WY1VIFCYDC.Conesa-Zamora P., Domenech-Peris A., Orantes-Casado F.J. et al. Effect of human papillomavirus on cell cycle-related proteins p16, Ki-67, cyclin D1, p53, and ProEx C in precursor lesions of cervical carcinoma: a tissue microarray study. Am J Clin Pathol. 2019;132(3):378–90. https://doi.org/10.1309/AJCPO0WY1VIFCYDC.Bergeron C., Ordi J., Schmidt D. et al. Conjunctive p16INK4a testing significantly increases accuracy in diagnosing high-grade cervical intraepithelial neoplasia. Am J Clin Pathol. 2021;133(3):395–406. https://doi.org/10.1309/AJCPXSVCDZ3D5MZM.Bergeron C., Ordi J., Schmidt D. et al. Conjunctive p16INK4a testing significantly increases accuracy in diagnosing high-grade cervical intraepithelial neoplasia. Am J Clin Pathol. 2021;133(3):395–406. https://doi.org/10.1309/AJCPXSVCDZ3D5MZM.Pinto A.P., Schlecht N.F., Woo T.Y.C. et al. Biomarker (ProEx C, p16(INK4A), and MiB-1) distinction of high-grade squamous intraepithelial lesion from its mimics. Mod Pathol. 2018;21(9):1067–74. https://doi.org/10.1038/modpathol.2008.101.Pinto A.P., Schlecht N.F., Woo T.Y.C. et al. Biomarker (ProEx C, p16(INK4A), and MiB-1) distinction of high-grade squamous intraepithelial lesion from its mimics. Mod Pathol. 2018;21(9):1067–74. https://doi.org/10.1038/modpathol.2008.101.Dijkstra M.G., Heideman D.A.M., de Roy S.C. et al. p16(INK4a) immunostaining as an alternative to histology review for reliable grading ofcervical intraepithelial lesions. J Clin Pathol. 2021;63(11):972–7. https://doi.org/10.1136/jcp.2010.078634.Dijkstra M.G., Heideman D.A.M., de Roy S.C. et al. p16(INK4a) immunostaining as an alternative to histology review for reliable grading ofcervical intraepithelial lesions. J Clin Pathol. 2021;63(11):972–7. https://doi.org/10.1136/jcp.2010.078634.Pinto A.P., Crum C.P., Hirsch M.S. Molecular markers of early cervical neoplasia. Diagn Histopathol (Oxf). 2022;16(10):445–54. https://doi.org/10.1016/j.mpdhp.2010.06.012.Pinto A.P., Crum C.P., Hirsch M.S. Molecular markers of early cervical neoplasia. Diagn Histopathol (Oxf). 2022;16(10):445–54. https://doi.org/10.1016/j.mpdhp.2010.06.012.Maniar K.P., Sanchez B., Paintal A. et al. Role of the biomarker p16 in downgrading – IN 2 diagnoses and predicting higher-grade lesions. Am J Surg Pathol. 2015;39(12):1708–18. https://doi.org/10.1097/PAS.0000000000000494.Maniar K.P., Sanchez B., Paintal A. et al. Role of the biomarker p16 in downgrading – IN 2 diagnoses and predicting higher-grade lesions. Am J Surg Pathol. 2015;39(12):1708–18. https://doi.org/10.1097/PAS.0000000000000494.del Pino M., Garcia S., Fuste V. et al. Value of p16(INK4a) as a marker of progression/regression in cervical intraepithelial neoplasia grade 1. Am J Obstet Gynecol. 2009;201(5):488.e1–7. https://doi.org/10.1016/j.ajog.2009.05.046.del Pino M., Garcia S., Fuste V. et al. Value of p16(INK4a) as a marker of progression/regression in cervical intraepithelial neoplasia grade 1. Am J Obstet Gynecol. 2009;201(5):488.e1–7. https://doi.org/10.1016/j.ajog.2009.05.046.Quint K.D., de Koning M.N.C., Quint W.G.V., Pirog E.C. Progression of cervical low grade squamous intraepithelial lesions: in search of prognostic biomarkers. Eur J Obstet Gynecol Reprod Biol. 2023;170(2):501–6. https://doi.org/10.1016/j.ejogrb.2013.07.012.Quint K.D., de Koning M.N.C., Quint W.G.V., Pirog E.C. Progression of cervical low grade squamous intraepithelial lesions: in search of prognostic biomarkers. Eur J Obstet Gynecol Reprod Biol. 2023;170(2):501–6. https://doi.org/10.1016/j.ejogrb.2013.07.012.Wang S.S., Trunk M., Schiffman M. et al. Validation of p16INK4a as a marker of oncogenic human papillomavirus infection in cervical biopsies from a population-based cohort in Costa Rica. Cancer Epidemiol Biomarkers Prev. 2014;13(8):1355–60.Wang S.S., Trunk M., Schiffman M. et al. Validation of p16INK4a as a marker of oncogenic human papillomavirus infection in cervical biopsies from a population-based cohort in Costa Rica. Cancer Epidemiol Biomarkers Prev. 2014;13(8):1355–60.Sagasta A., Castillo P., Saco A., Torne A. et al. p16 staining has limited value in predicting the outcome of histological low-grade squamous intraepithelial lesions of the cervix. Mod Pathol. 2016;29(1):51–9. https://doi.org/10.1038/modpathol.2015.126.Sagasta A., Castillo P., Saco A., Torne A. et al. p16 staining has limited value in predicting the outcome of histological low-grade squamous intraepithelial lesions of the cervix. Mod Pathol. 2016;29(1):51–9. https://doi.org/10.1038/modpathol.2015.126.Moyer V.A. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2022;156(12):880–91. https://doi.org/10.7326/0003-4819-156-12-201206190-00424.Moyer V.A. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2022;156(12):880–91. https://doi.org/10.7326/0003-4819-156-12-201206190-00424.Saslow D., Solomon D., Lawson H.W. et al.; ACS-ASCCP-ASCP Cervical Cancer Guideline Committee. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012;62(3):147–72. https://doi.org/10.3322/caac.21139.Saslow D., Solomon D., Lawson H.W. et al.; ACS-ASCCP-ASCP Cervical Cancer Guideline Committee. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012;62(3):147–72. https://doi.org/10.3322/caac.21139.Bernstein S.J., Sanchez-Ramos L., Ndubisi B. Liquid-based cervical cytologic smear study and conventional Papanicolaou smears: a metaanalysis of prospective studies comparing cytologic diagnosis and sample adequacy. Am J Obstet Gynecol. 2001;185(2):308–17. https://doi.org/10.1067/mob.2001.116736.Bernstein S.J., Sanchez-Ramos L., Ndubisi B. Liquid-based cervical cytologic smear study and conventional Papanicolaou smears: a metaanalysis of prospective studies comparing cytologic diagnosis and sample adequacy. Am J Obstet Gynecol. 2001;185(2):308–17. https://doi.org/10.1067/mob.2001.116736.Negri G., Menia E., Egarter-Vigl E. et al. ThinPrep versus conventional Papanicolaou smear in the cytologic follow-up of women with equivocal cervical smears. Cancer. 2003;99(6):342–5. https://doi.org/10.1002/cncr.11856.Negri G., Menia E., Egarter-Vigl E. et al. ThinPrep versus conventional Papanicolaou smear in the cytologic follow-up of women with equivocal cervical smears. Cancer. 2003;99(6):342–5. https://doi.org/10.1002/cncr.11856.Schiffman M., Solomon D. Screening and prevention methods for cervical cancer. JAMA. 2009;302(16):1809–10. https://doi.org/10.1001/jama.2009.1573.Schiffman M., Solomon D. Screening and prevention methods for cervical cancer. JAMA. 2009;302(16):1809–10. https://doi.org/10.1001/jama.2009.1573.Kessler T.A. Cervical cancer: prevention and early detection. Semin Oncol Nurs. 2017;33(2):172–83. https://doi.org/10.1016/j.soncn.2017.02.005.Kessler T.A. Cervical cancer: prevention and early detection. Semin Oncol Nurs. 2017;33(2):172–83. https://doi.org/10.1016/j.soncn.2017.02.005.Cibas E.S., Ducatman B.S. Cervical andv aginal cytology. In: Cytology. Diagnostic principles and clinical correlates. 4th ed. Philadelphia: Saunders, 2014. 7–8.Cibas E.S., Ducatman B.S. Cervical andv aginal cytology. In: Cytology. Diagnostic principles and clinical correlates. 4th ed. Philadelphia: Saunders, 2014. 7–8.Jones B.A., Novis D.A. Cervical biopsy-cytology correlation. A College of American Pathologists Q-Probes study of 22439 correlations in 348 laboratories. Arch Pathol Lab Med. 1996;120(6):523–31.Jones B.A., Novis D.A. Cervical biopsy-cytology correlation. A College of American Pathologists Q-Probes study of 22439 correlations in 348 laboratories. Arch Pathol Lab Med. 1996;120(6):523–31.Eversole G.M., Moriarty A.T., Schwartz M.R. et al. Practices of participants in the College of American Pathologists interlaboratory comparison program in cervicovaginal cytology, 2006. Arch Pathol Lab Med. 2010;134(3):331–5. https://doi.org/10.5858/134.3.331.Eversole G.M., Moriarty A.T., Schwartz M.R. et al. Practices of participants in the College of American Pathologists interlaboratory comparison program in cervicovaginal cytology, 2006. Arch Pathol Lab Med. 2010;134(3):331–5. https://doi.org/10.5858/134.3.331.Sherman M.E., Castle P.E., Solomon D. Cervical cytology of a typical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (ASC-H): characteristics and histologic outcomes. Cancer. 2006;108(5):298–305. https://doi.org/10.1002/cncr.21844.Sherman M.E., Castle P.E., Solomon D. Cervical cytology of a typical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (ASC-H): characteristics and histologic outcomes. Cancer. 2006;108(5):298–305. https://doi.org/10.1002/cncr.21844.Thomas C., Wright J., Cox J.T. et al.; ASCCP-Sponsored Consensus Conference. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287(16):2120–9. https://doi.org/10.1001/jama.287.16.2120.Thomas C., Wright J., Cox J.T. et al.; ASCCP-Sponsored Consensus Conference. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287(16):2120–9. https://doi.org/10.1001/jama.287.16.2120.Vizcaino A.P., Moreno V., Bosch F.X. et al. International trends in incidence of cervical cancer: II. Squamous-cell carcinoma. Int J Cancer. 2000;86(3):429–35. https://doi.org/10.1002/(sici)1097-0215(20000501)86:3<429::aid-ijc20>3.0.co;2-d.Vizcaino A.P., Moreno V., Bosch F.X. et al. International trends in incidence of cervical cancer: II. Squamous-cell carcinoma. Int J Cancer. 2000;86(3):429–35. https://doi.org/10.1002/(sici)1097-0215(20000501)86:3<429::aid-ijc20>3.0.co;2-d.Walboomers J.M., Jacobs M.V., Manos M.M., et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189(1):12–9. https://doi.org/10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F.Walboomers J.M., Jacobs M.V., Manos M.M., et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189(1):12–9. https://doi.org/10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F.De Sanjose S., Quint W.G., Alemany L. et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective crosssectional worldwide study. Lancet Oncol. 2010;11(11):1048–56. https://doi.org/10.1016/S1470-2045(10)70230-8.De Sanjose S., Quint W.G., Alemany L. et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective crosssectional worldwide study. Lancet Oncol. 2010;11(11):1048–56. https://doi.org/10.1016/S1470-2045(10)70230-8.Brinck U., Jakob C., Bau O., Fuzesi L. Papillary squamous cell carcinoma of the uterine cervix: report of three cases and a review of its classification. Int J Gynecol Pathol. 2000;19(3):231–5. https://doi.org/10.1097/00004347-200007000-00006.Brinck U., Jakob C., Bau O., Fuzesi L. Papillary squamous cell carcinoma of the uterine cervix: report of three cases and a review of its classification. Int J Gynecol Pathol. 2000;19(3):231–5. https://doi.org/10.1097/00004347-200007000-00006.Koenig C., Turnicky R.P., Kankam C.F., Tavassoli F.A. Papillary squamotransitional cell carcinoma of the cervix: a report of 32 cases. Am J Surg Pathol. 1997;21(8):915–21. https://doi.org/10.1097/00000478199708000-00005.Koenig C., Turnicky R.P., Kankam C.F., Tavassoli F.A. Papillary squamotransitional cell carcinoma of the cervix: a report of 32 cases. Am J Surg Pathol. 1997;21(8):915–21. https://doi.org/10.1097/00000478199708000-00005.Randall M.E., Andersen W.A., Mills S.E., Kim J.A. Papillary squamous cell carcinoma of the uterine cervix: a clinicopathologic study of nine cases. Int J Gynecol Pathol. 1986;5(1):1–10. https://doi.org/10.1097/00004347198603000-00001.Randall M.E., Andersen W.A., Mills S.E., Kim J.A. Papillary squamous cell carcinoma of the uterine cervix: a clinicopathologic study of nine cases. Int J Gynecol Pathol. 1986;5(1):1–10. https://doi.org/10.1097/00004347198603000-00001.Zbroch T., Grzegorz Knapp P., Knapp P.A. Verrucous carcinoma of the cervix – diagnostic and therapeutic difficulties with regards to HPV status. Case report. Eur J Gynaecol Oncol. 2005;26(2):227–30.Zbroch T., Grzegorz Knapp P., Knapp P.A. Verrucous carcinoma of the cervix – diagnostic and therapeutic difficulties with regards to HPV status. Case report. Eur J Gynaecol Oncol. 2005;26(2):227–30.Grayson W., Cooper K. A reappraisal of “basaloid carcinoma” of the cervix, and the differential diagnosis of basaloid cervical neoplasms. Adv Anat Pathol. 2002;9(5):290–300. https://doi.org/10.1097/00125480200209000-00003.Grayson W., Cooper K. A reappraisal of “basaloid carcinoma” of the cervix, and the differential diagnosis of basaloid cervical neoplasms. Adv Anat Pathol. 2002;9(5):290–300. https://doi.org/10.1097/00125480200209000-00003.Park J.J., Sun D., Quade B.J. et al. Stratified mucin-producing intraepithelial lesions of the cervix: adenosquamous or columnar cell neoplasia? Am J Surg Pathol. 2000;24(10):1414–9. https://doi.org/10.1097/00000478-200010000-00012.Park J.J., Sun D., Quade B.J. et al. Stratified mucin-producing intraepithelial lesions of the cervix: adenosquamous or columnar cell neoplasia? Am J Surg Pathol. 2000;24(10):1414–9. https://doi.org/10.1097/00000478-200010000-00012.Lastra R.R., Park K.J., Schoolmeester J.K. Invasive stratified mucinproducing carcinoma and stratified mucin-producing intraepithelial lesion (SMILE): 15 cases presenting a Spectrum of cervical neoplasia with description of a distinctive variant of invasive adenocarcinoma. Am J Surg Pathol. 2016;40(2):262–9. https://doi.org/10.1097/PAS.0000000000000543.Lastra R.R., Park K.J., Schoolmeester J.K. Invasive stratified mucinproducing carcinoma and stratified mucin-producing intraepithelial lesion (SMILE): 15 cases presenting a Spectrum of cervical neoplasia with description of a distinctive variant of invasive adenocarcinoma. Am J Surg Pathol. 2016;40(2):262–9. https://doi.org/10.1097/PAS.0000000000000543.Mikami Y., Kiyokawa T., Hata S. et al. Gastrointestinal immunophenotype in adenocarcinomas of the uterine cervix and related glandular lesions: a possible link between lobular endocervical glandular hyperplasia/pyloric gland metaplasia and 'adenoma malignum'. Mod Pathol. 200417(8):962–72. https://doi.org/10.1038/modpathol.3800148.Mikami Y., Kiyokawa T., Hata S. et al. Gastrointestinal immunophenotype in adenocarcinomas of the uterine cervix and related glandular lesions: a possible link between lobular endocervical glandular hyperplasia/pyloric gland metaplasia and 'adenoma malignum'. Mod Pathol. 200417(8):962–72. https://doi.org/10.1038/modpathol.3800148.Kawauchi S., Kusuda T., Liu X.P. et al. Is lobular endocervical glandular hyperplasia a cancerous precursor of minimal deviation adenocarcinoma?: А comparative molecular-genetic and immunohistochemical study. Am J Surg Pathol. 2008;32(12):1807–15. https://doi.org/10.1097/PAS.0b013e3181883722.Kawauchi S., Kusuda T., Liu X.P. et al. Is lobular endocervical glandular hyperplasia a cancerous precursor of minimal deviation adenocarcinoma?: А comparative molecular-genetic and immunohistochemical study. Am J Surg Pathol. 2008;32(12):1807–15. https://doi.org/10.1097/PAS.0b013e3181883722.Talia K.L., Stewart C.J.R., Howitt B.E. et al. HPV-negative gastric type adenocarcinoma in situ of the cervix: a spectrum of rare lesions exhibiting gastric and intestinal differentiation. Am J Surg Pathol. 2017;41(8):1023–33. https://doi.org/10.1097/PAS.0000000000000855.Talia K.L., Stewart C.J.R., Howitt B.E. et al. HPV-negative gastric type adenocarcinoma in situ of the cervix: a spectrum of rare lesions exhibiting gastric and intestinal differentiation. Am J Surg Pathol. 2017;41(8):1023–33. https://doi.org/10.1097/PAS.0000000000000855.Biscotti C.V., Hart W.R. Apoptotic bodies: a consistent morphologic feature of endocervical adenocarcinoma in situ. Am J Surg Pathol. 1998;22(4):434–9. https://doi.org/10.1097/00000478-199804000-00007.Biscotti C.V., Hart W.R. Apoptotic bodies: a consistent morphologic feature of endocervical adenocarcinoma in situ. Am J Surg Pathol. 1998;22(4):434–9. https://doi.org/10.1097/00000478-199804000-00007.Pirog E.C., Lloveras B., Molijn A. et al. HPV prevalence and genotypes in different histological subtypes of cervical adenocarcinoma, a worldwide analysis of 760 cases. Mod Pathol. 2014;27(12):1559. https://doi.org/10.1038/modpathol.2014.55.Pirog E.C., Lloveras B., Molijn A. et al. HPV prevalence and genotypes in different histological subtypes of cervical adenocarcinoma, a worldwide analysis of 760 cases. Mod Pathol. 2014;27(12):1559. https://doi.org/10.1038/modpathol.2014.55.Iwasawa A., Nieminen P., Lehtinen M., Paavonen J. Human papillomavirus DNA in uterine cervix squamous cell carcinoma and adenocarcinoma detected by polymerase chain reaction. Cancer. 1996;77(11):2275–9. https://doi.org/10.1002/(SICI)1097-0142(19960601)77:11<2275::AID-CNCR14>3.0.CO;2-U.Iwasawa A., Nieminen P., Lehtinen M., Paavonen J. Human papillomavirus DNA in uterine cervix squamous cell carcinoma and adenocarcinoma detected by polymerase chain reaction. Cancer. 1996;77(11):2275–9. https://doi.org/10.1002/(SICI)1097-0142(19960601)77:11<2275::AID-CNCR14>3.0.CO;2-U.An H.J., Kim K.R., Kim I.S. et al. Prevalence of human papillomavirus DNA in various histological subtypes of cervical adenocarcinoma: a population-based study. Mod Pathol. 2005;18(4):528–34. https://doi.org/10.1038/modpathol.3800316.An H.J., Kim K.R., Kim I.S. et al. Prevalence of human papillomavirus DNA in various histological subtypes of cervical adenocarcinoma: a population-based study. Mod Pathol. 2005;18(4):528–34. https://doi.org/10.1038/modpathol.3800316.Bibbo M., Wilbur D. Comprehensive cytopathology.4th ed. Philadelphia: Saunders, 2014. 161 p.Bibbo M., Wilbur D. Comprehensive cytopathology.4th ed. Philadelphia: Saunders, 2014. 161 p.Levine P.H., Elgert P.A., Mittal K. False-positive squamous cell carcinoma in cervical smears: cytologic-histologic correlation in 19 cases. Diagn Cytopathol. 2003;28(1):23–7. https://doi.org/10.1002/dc.10220.Levine P.H., Elgert P.A., Mittal K. False-positive squamous cell carcinoma in cervical smears: cytologic-histologic correlation in 19 cases. Diagn Cytopathol. 2003;28(1):23–7. https://doi.org/10.1002/dc.10220.Andersson S., Rylander E., Larsson B. et al. The role of human papillomavirus in cervical adenocarcinoma carcinogenesis. Eur J Cancer. 2001;37(2):246–50. https://doi.org/10.1016/s0959-8049(00)00376-2.Andersson S., Rylander E., Larsson B. et al. The role of human papillomavirus in cervical adenocarcinoma carcinogenesis. Eur J Cancer. 2001;37(2):246–50. https://doi.org/10.1016/s0959-8049(00)00376-2.Solomon D., Frable W.J., Vooijs G.P. et al. ASCUS and AGUS criteria. International Academy of Cytology Task Force summary. Diagnostic Cytology Towards the 21st Century: An International Expert Conference and Tutorial. Acta Cytol. 1998;42(1):16–24. https://doi.org/10.1159/000331531.Solomon D., Frable W.J., Vooijs G.P. et al. ASCUS and AGUS criteria. International Academy of Cytology Task Force summary. Diagnostic Cytology Towards the 21st Century: An International Expert Conference and Tutorial. Acta Cytol. 1998;42(1):16–24. https://doi.org/10.1159/000331531.Amin M.B., Greene F.L., Edge S.B. et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging. CA Cancer J Clin. 2017;67(2):93–9. https://doi.org/10.3322/caac.21388.Amin M.B., Greene F.L., Edge S.B. et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging. CA Cancer J Clin. 2017;67(2):93–9. https://doi.org/10.3322/caac.21388.

The authors declare that there are no conflicts of interest present.