Prognostic value of human papillomavirus biomarkers in the differential diagnosis of squamous intraepithelial lesions of the cervix

DOI

https://dx.doi.org/10.18565/aig.2022.6.20-25

Dobrovolskaya D.A., Bairamova G.R., Asaturova A.V., Tevryukova N.S.
Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, Moscow, Russian Federation

In the modern world, cervical diseases associated with high-risk human papillomavirus (HR-HPV) are one of the urgent problems discussed by researchers. In most HR-HPV-infected women, the virus is known to eliminate on its own within two years, and only in 10–15% papillomavirus infection becomes persistent and is able to cause cellular changes leading to the development of squamous intraepithelial lesions (SIL) and cervical cancer. Therefore, the identification of patients in the early stages of SIL development is extremely important and promising. The study of HPV L1 and E4 biomarkers is an important component in the differential diagnosis between the cytological findings of atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion (HSIL) and in the sorting of women for further treatment and follow-up.
Conclusion: Thus, there is a need for further investigations of these biomarkers to predict the development of cervical SIL, which will create personalized management tactics in terms of HPV biology.

human papillomavirus (HPV)

molecular genetic biomarkers

low-grade squamous intraepithelial lesions of the cervix

squamous intraepithelial lesion (LSIL)

HPV L1 and HPV E4

Full text (in Russian)

Chen G., Zheng P., Gao L., Zhao J., Wang Y, Qin W. Prevalence and genotype distribution of human papillomavirus in women with cervical cancer or cervical intraepithelial neoplasia in Henan province, central China. J. Med. Virol. 2020; 92(12): 3743-9. https://dx.doi.org/10.1002/jmv.25670.
The International Agency for Research on Cancer (IARC) World Health Organization. 2021. Available at: https://gco.iarc.fr/today/online-analysis
Stelzle D., Tanaka L.F., Lee K.K., Khalil A.I., Baussano I., Shah A.S. et al. Estimates of the global burden of cervical cancer associated with HIV. Lancet Glob. Health. 2021; 9(2): e161-9. https://dx.doi.org/10.1016/S2214-109X(20)30459-9.
Ferlay J., Colombet M., Soerjomataram I., Mathers C., Parkin D.M., Piñeros M., Znaor A., Bray F. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int. J. Cancer. 2019; 144(8): 1941-53. https://dx.doi.org/10.1002/ijc.31937.
Каприн А.Д., Старинский В.В., Шахзадова А.О., ред. Состояние онкологической помощи населению России в 2019 году. М.: МНИОИ им. ТП.А. Герцена − филиал ФГБУ «НМИЦ радиологии» Минздрава России; 2020. 239 с. [Kaprin A.D., Starinsky V.V., Shakhzadova A.O., ed. The state of oncological care for the population of Russia in 2019. Moscow: MNIOI im. P.A. Gertsen – branch of the Federal State Budgetary Institution "NMITs Radiology" of the Ministry of Health of Russia; 2020. 239 p. (in Russian)].
Петрова Г.В. Рак шейки матки. Динамика основных статистических показателей. Исследования и практика в медицине. 2016; Спецвыпуск (Тезисы 1-го Национального конгресса «Онкология репродуктивных органов: от профилактики и раннего выявления к эффективному лечению». 19-21 мая 2016. Москва): 134. [Petrova G.V. Cancer of the cervix. Dynamics of the main statistical indicators. Research'n Practical Medicine Journal. 2016; Special issue. (in Russian)].
Scott-Wittenborn N., Fakhry C. Epidemiology of HPV related malignancies. Semin. Radiat. Oncol. 2021; 31(4): 286-96. https://dx.doi.org/10.1016/j.semradonc.2021.04.001.
Obeid D.A., Almatrrouk S.A., Alfageeh M.B., Al-Ahdal M.N., Alhamlan F.S. Human papillomavirus epidemiology in populations with normal or abnormal cervical cytology or cervical cancer in the Middle East and North Africa: a systematic review and meta-analysis. J. Infect. Public Health. 2020; 13(9):1304-13. https://dx.doi.org/10.1016/j.jiph.2020.06.012.
Šarenac T., Mikov M. Cervical cancer, different treatments and importance of bile acids as therapeutic agents in this disease. Front. Pharmacol. 2019; 10: 484. https://dx.doi.org/10.3389/fphar.2019.00484.
Magalhães G.M., Vieira É.C., Garcia L.C., De Carvalho-Leite M.L.R., Guedes A.C.M., Araújo M.G. Update on human papilloma virus – part I: epidemiology, pathogenesis, and clinical spectrum. An. Bras. Dermatol. 2021; 96(1): 1-16. https://dx.doi.org/10.1016/j.abd.2020.11.003.
Zhang S., Xu H., Zhang L., Qiao Y. Cervical cancer: epidemiology, risk factors and screening. Chin. J. Cancer Res. 2020; 32(6): 720-28. https://dx.doi.org/10.21147/j.issn.1000-9604.2020.06.05.
Pankaj S., Kumari A., Kumari S., Choudhary V., Kumari J., Anjili Kumari A. et al. Evaluation of sensitivity and specificity of pap smear, LBC and HPV in screening of cervical cancer. Indian J. Gynecol. Oncol. 2018; 16: 49. https://dx.doi.org/10.1007/s40944-018-0221-x.
Najib F.S., Hashemi M., Shiravani Z., Poordast T., Sharifi S., Askary E. Diagnostic accuracy of cervical pap smear and colposcopy in detecting premalignant and malignant lesions of cervix. Indian J. Surg. Oncol. 2020; 11(3): 453-8. https://dx.doi.org/10.1007/s13193-020-01118-2.
Fontham E.T., Wolf A.M., Church T.R., Etzioni R., Flowers C.R., Herzig A. et al. Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society. CA Cancer J. Clin. 2020; 70(5): 321-46. https://dx.doi.org/10.3322/caac.21628.
Perkins R.B., Guido R.S., Castle P.E., Chelmow D., Einstein M.H., Garcia F. et al. 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors. J. Low. Genit. Tract Dis. 2020; 24(2): 102-31. https://dx.doi.org/10.1097/LGT.0000000000000525.
Vale D.B., Silva M.T., Discacciati M.G., Polegatto I., Teixeira J. C., Zeferino LC. Is the HPV-test more cost-effective than cytology in cervical cancer screening? An economic analysis from a middle-income country. PloS One. 2021; 16(5): E0251688. https://dx.doi.org/10.1371/journal.pone.0251688.
Ronco G., Dillner J., Elfström K.M., Tunesi S., Snijders P.J., Arbyn M. et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014; 383(9916): 524-32. https://dx.doi.org/10.1016/S0140-6736(13)62218-7.
Maver P.J., Poljak M. Primary HPV-based cervical cancer screening in Europe: implementation status, challenges, and future plans. Clin. Microbiol. Infect. 2020; 26(5): 579-83. https://dx.doi.org/10.1016/j.cmi.2019.09.006.
Bouvard V., Wentzensen N., Mackie A., Berkhof J., Brotherton J., Giorgi-Rossi P. et al. The IARC perspective on cervical cancer screening. N. Engl. J. Med. 2021; 385(20): 1908-18. https://dx.doi.org/10.1056/NEJMsr2030640.
Monsonego J. HPV testing in prevention of cervical cancer: practices and current trends. Ann. Biol. Clin. (Paris). 2013; 71(1): 27-32. https://dx.doi.org/10.1684/abc.2013.0907.
Chesson H.W., Meites E., Ekwueme D.U., Saraiya M., Markowitz L.E. Updated medical care cost estimates for HPV-associated cancers: implications for cost-effectiveness analyses of HPV vaccination in the United States. Hum. Vaccin. Immunother. 2019; 15(7-8): 1942-8. https://dx.doi.org/10.1080/21645515.2019.1603562.
Liu Y., Sigel K., Gaisa M.M. Human papillomavirus genotypes predict progression of anal low-grade squamous intraepithelial lesions. J. Infect. Dis. 2018; 218(11): 1746-52. https://dx.doi.org/10.1093/infdis/jiy463.
Wright T.C. Jr, Stoler M.H., Parvu V., Yanson K., Cooper C., Andrews J. Risk detection for high-grade cervical disease using Onclarity HPV extended genotyping in women, ≥ 21 years of age, with ASC-US or LSIL cytology. Gynecol. Oncol. 2019; 154(2): 360-7. https://dx.doi.org/10.1016/j.ygyno.2019.05.012.
Kyrgiou M., Kalliala I., Mitra A., Fotopoulou C., Ghaem-Maghami S., Martin-Hirsch P.P. et al. Immediate referral to colposcopy versus cytological surveillance for minor cervical cytological abnormalities in the absence of HPV test. Cochrane Database Syst. Rev. 2017; 1(1): CD009836. https://dx.doi.org/10.1002/14651858.CD009836.pub2.
Bruno M.T., Cassaro N., Bica F., Boemi S. Progression of CIN1/LSIL HPV persistent of the cervix: actual progression or CIN3 coexistence. Infect. Dis. Obstet. Gynecol. 2021; 2021: 6627531. https://dx.doi.org/10.1155/2021/6627531.
Ding L., Song L., Zhao W., Li X., Gao W., Qi Z. et al. Predictive value of p16INK4a, Ki 67 and ProExC immuno qualitative features in LSIL progression into HSIL. Exp. Ther. Med. 2020; 19(4): 2457-66. https://dx.doi.org/10.3892/etm.2020.8496.
Kaur G., Balasubramaniam S.D., Lee Y.J., Balakrishnan V., Oon C.E. Minichromosome maintenance complex (MCM) genes profiling and MCM2 protein expression in cervical cancer development. Asian Pac. J. Cancer Prev. 2019; 20(10): 3043-9. https://dx.doi.org/10.31557/APJCP.2019.20.10.3043.
Giannos P., Kechagias K.S., Bowden S., Tabassum N., Paraskevaidi M., Kyrgiou M. PCNA in cervical intraepithelial neoplasia and cervical cancer: aniInteraction network analysis of differentially expressed genes. Front. Oncol. 2021; 11: 779042. https://dx.doi.org/10.3389/fonc.2021.779042.
Ершов В.А., Чирский В.С., Лисянская А.С. Изменения ядерного митотического аппарата как признак цервикальной неоплазии, ассоциированной с вирусом папилломы человека высокого канцерогенного риска. Онкология. Журнал им. П.А. Герцена. 2015; 2: 24-8. [Ershov V.A, Chirsky V.S., Lisyanskaya A.S. Changes in the nuclear mitotic apparatus as a sign of cervical neoplasia associated with human papillomavirus high carcinogenic risk. Oncology. Journal them. P.A. Herzen. 2015; 2: 24-8. (in Russian)]. https://dx.doi.org/10.17116/onkolog20154224-28.
Doorbar J., Quint W., Banks L., Bravo I.G., Stoler M., Broker T.R. et al. The biology and life-cycle of human papillomaviruses. Vaccine. 2012; 30(Suppl. 5): F55-70. https://dx.doi.org/10.1016/j.vaccine.2012.06.083.
Del Moral-Hernández O., Hernández-Sotelo D., Alarcón-Romero L.D., Mendoza-Catalán M.A., Flores-Alfaro E., Castro-Coronel Y. et al. TOP2A/MCM2, p16INK4a, and cyclin E1 expression in liquid-based cytology: a biomarkers panel for progression risk of cervical premalignant lesions. BMC Cancer. 2021; 21: 39. https://dx.doi.org/10.1186/s12885-020-07740-1.
Alrajjal A., Pansare V., Choudhury M.S., Khan M.Y., Shidham V.B. Squamous intraepithelial lesions (SIL: LSIL, HSIL, ASCUS, ASC-H, LSIL-H) of uterine cervix and bethesda system. Cytojournal. 2021; 18: 16. https://dx.doi.org/10.25259/Cytojournal_24_2021.
Yemelyanova A., Gravitt P.E., Ronnett B.M., Rositch A.F., Ogurtsova A., Seidman J. et al. Immunohistochemical detection of human papillomavirus capsid proteins L1 and L2 in squamous intraepithelial lesions: potential utility in diagnosis and management. Mod. Pathol. 2013; 26(2): 268-74. https://dx.doi.org/10.1038/modpathol.2012.156.
Lee S.J., Lee A.W., Kang C.S., Park J.S., Park D.C., Ki E.Y. et al. Clinicopathological implications of human papilloma virus (HPV) L1 capsid protein immunoreactivity in HPV16-positive cervical cytology. Int. J. Med. Sci. 2014; 11(1): 80. https://dx.doi.org/10.7150/ijms.5585.
Shen-Gunther J., Cai H., Zhang H., Wang Y. Abundance of HPV L1 intra-genotype variants with capsid epitopic modifications found within low-and high-grade Pap smears with potential implications for vaccinology. Front. Genet. 2019; 10: 489. https://dx.doi.org/10.3389/fgene.2019.00489.
Ki E.Y., Park J.S., Lee A., Kim T.J., Jin H.T., Seo Y.B. et al. Utility of human papillomavirus L1 capsid protein and HPV test as prognostic markers for cervical intraepithelial neoplasia 2+ in women with persistent ASCUS/LSIL cervical cytology. Int. J. Med. Sci. 2019; 16(8): 1096. https://dx.doi.org/10.7150/ijms.31163.
Griesser H., Sander H., Hilfrich R., Moser B., Schenck U. Correlation of immunochemical detection of HPV L1 capsid protein in pap smears with regression of high-risk HPV positive mild/moderate dysplasia. Anal. Quant. Cytol. Histol. 2004; 26(5): 241-5.
Rauber D., Mehlhorn G., Fasching P.A., Beckmann M.W., Ackermann S. Prognostic significance of the detection of human papilloma virus L1 protein in smears of mild to moderate cervical intraepithelial lesions. Eur. J. Obstet. Gynecol. Reprod. Biol. 2008; 140(2): 258-62. https://dx.doi.org/10.1016/j.ejogrb.2008.05.003.
Mehlhorn G., Obermann E., Negri G., Bubendorf L., Mian C., Koch M. et al. HPV L1 detection discriminates cervical precancer from transient HPV infection: a prospective international multicenter study. Mod. Pathol. 2013; 26(7): 967-74. https://dx.doi.org/10.1038/modpathol.2012.233.
Hu H., Zhao J., Yu W., Zhao J., Wang Z., Jin L. et al. Human papillomavirus DNA, HPV L1 capsid protein and p16 INK4a protein as markers to predict cervical lesion progression. Arch. Gynecol. Obstet. 2019; 299(1): 141-9. https://dx.doi.org/10.1007/s00404-018-4931-1.
Yoshida T., Sano T., Kanuma T., Owada N., Sakurai S., Fukuda T. et al. Immunochemical analysis of HPV L1 capsid protein and p16 protein in liquid‐based cytology samples from uterine cervical lesions. Cancer Cytopathol. 2008; 114(2): 83-8. https://dx.doi.org/10.1002/cncr.23366.
van Bogaert L.J. Cervical preneoplasia biomarkers: a conundrum for the community based gynecologic surgical pathologist. J. Gynecol. Oncol. 2014; 25(1): 3-5. https://dx.doi.org/10.3802/jgo.2014.25.1.3.
Liu C., Du H., Wang C., Belinson J. L., Yang B., Zhang W. et al. HPV L1 and P16 expression in CIN1 to predict future CIN2. Int. J. Gynecol. Pathol. 2017; 36(3): 281-8. https://dx.doi.org/10.1097/PGP.0000000000000326.
Huang M.Z., Li H.B., Nie X.M., Wu X.Y., Jiang X.M. An analysis on the combination expression of HPV L1 capsid protein and p16INK4a in cervical lesions. Diagn. Cytopathol. 2010; 38(8): 573-8. https://dx.doi.org/10.1002/dc.21258.
Lee H., Lee K.J., Jung C.K., Hong J.H., Lee Y.S., Choi Y.J. et al. Expression of HPV L1 capsid protein in cervical specimens with HPV infection. Diagn. Cytopathol. 2008; 36(12): 864-7. https://dx.doi.org/10.1002/dc.20922.
Бурменская О.В., Назарова Н.М., Сычева Е.Г., Прилепская В.Н., Трофимов Д.Ю., Сухих Г.Т. Применение молекулярно-генетических методов для диагностики и прогноза развития дисплазии тяжелой степени и рака шейки матки. Акушерство и гинекология. 2021; 10: 85-92. [Burmenskaya O.V., Nazarova N.M., Sycheva E.G., Prilepskaya V.N., Trofimov D.Yu., Sukhikh G.T. Application of molecular genetic methods for the diagnosis and prognosis of the development of severe dysplasia and cervical cancer. Obstetrics and Gynecology. 2021; 10: 85-92 (in Russian)]. https://dx.doi.org/10.18565/aig.2021.10.85-92.
Doorbar J. The E4 protein; structure, function and patterns of expression. Virology. 2013; 445(1-2): 80-98. https://dx.doi.org/10.1016/j.virol.2013.07.008.
Zummeren M.V., Kremer W.W., Leeman A., Bleeker M.C., Jenkins D., Sandt M.V.D. et al. HPV E4 expression and DNA hypermethylation of CADM1, MAL, and miR124-2 genes in cervical cancer and precursor lesions. Mod. Pathol. 2018; 31(12): 1842-50. https://dx.doi.org/10.1038/s41379-018-0101-z.
Louvanto K., Aro K., Nedjai B., Bützow R., Jakobsson M., Kalliala I. et al. Methylation in predicting progression of untreated high-grade cervical intraepithelial neoplasia. Clin. Infect. Dis. 2020; 70(12): 2582-90. https://dx.doi.org/10.1093/cid/ciz677.
Verlaat W., Van Leeuwen R.W., Novianti P.W., Schuuring E., Meijer C.J., Van Der Zee A.G. et al. Host-cell DNA methylation patterns during high-risk HPV-induced carcinogenesis reveal a heterogeneous nature of cervical pre-cancer. Epigenetics. 2018; 13(7): 769-78. https://dx.doi.org/10.1080/15592294.2018.1507197.
Vink F.J., Dick S., Heideman D.A.M., De Strooper L.M.A., Steenbergen R.D.M., Lissenberg-Witte B.L.W. et al. Classification of high-grade CIN by p16 ink4a, Ki-67, HPV E4 and FAM19A4/miR124-2 methylation status demonstrates considerable heterogeneity with potential consequences for management. Int. J. Cancer. 2021; 49(3): 707-16. https://dx.doi.org/10.1002/ijc.33566.

Received 01.04.2022

Accepted 11.05.2022

Darya A. Dobrovolskaya, postgraduate student of the Scientific Polyclinic Department, V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia, +7(916)400-67-68, dashaGRI@yandex.ru, https://orcid.org/0000-0002-1409-9959, 117997, Russia, Moscow, Akademika Oparina str., 4.
Guldana R. Bayramova, Dr. Med. Sci., Professor of the Department of Obstetrics and Gynecology of the Department of Professional Education, Head of Clinical Work
of the Scientific Polyclinic Department, V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia, +7(495)438-18-66 (ex. 1489), bayramova@mail.ru,
https://orcid.org/0000-0003-4826-661X, 117997, Russia, Moscow, Akademika Oparina str., 4.
Aleksandra V. Asaturova, Dr. Med. Sci., Head of the 1st Pathology Department, V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia,
+7(495)438-23-11 (ex. 2438), a_asaturova@oparina4.ru, https://orcid.org/0000-0001-8739-5209, 117997, Russia, Moscow, Akademika Oparina str., 4.
Nadezhda S. Tevryukova, PhD (Bio), Senior Researcher at the 1st Pathology Department, V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia,
+7(495)438-23-11 (ex. 2438), n.s.tevrukova@yandex.ru, https://orcid.org/0000-0003-3305-8543, 117997, Russia, Moscow, Akademika Oparina str., 4.
Corresponding author: Darya A. Dobrovolskaya, dashaGRI@yandex.ru

Authors' contributions: Bairamova G.R., Asaturova A.V., Dobrovolskaya D.A. – concept and design of the investigation; Dobrovolskaya D.A., Asaturova A.V., Tevryukova N.S. – review of literature data; Dobrovolskaya D.A. – writing the original text; Bairamova G.R., Asaturova A.V. – editing, final approval of the manuscript.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The investigation has been conducted with financial support from the Russian Foundation for Basic Research and the Government of Moscow within the framework of Science Project No. 21-315-70048. Agreement No. 21-315-70048 "Study of a role of viral replication proteins of the early response of human papillomavirus in the modulation of the signaling pathways of cervical epitheliocytes in the early forms of intraepthelial squamous lesions using the methods of neural network analysis".
For citation: Dobrovolskaya D.A., Bairamova G.R., Asaturova A.V., Tevryukova N.S.
Prognostic value of human papillomavirus biomarkers in the differential diagnosis
of squamous intraepithelial lesions of the cervix.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2022; 6: 20-25 (in Russian)
https://dx.doi.org/10.18565/aig.2022.6.20-25

Prognostic value of human papillomavirus biomarkers in the differential diagnosis of squamous intraepithelial lesions of the cervix

Dobrovolskaya D.A., Bairamova G.R., Asaturova A.V., Tevryukova N.S.

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