Clinical significance of immunohistochemical expression of «early» HPV proteins in the diagnosis of squamous intraepithelial lesions of the cervix and uterus of mild degree

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Abstract

This study evaluated the immunohistochemical expression of early HPV proteins (E1, E2, E4) for the differential diagnosis of cervical SIL. A cross-sectional study was conducted from 2022–2023 on 128 HPV-positive patients aged 18–50 years, divided into 4 groups based on histological diagnosis (no lesions, chronic cervicitis, LSIL, HSIL). Analysis showed that a history of LSIL for 2 or more years was statistically significantly more frequent in patients with HSIL (46.7%). Expression of E2 protein in the upper 2/3 layers of the cervical epithelium was more often observed in LSIL (87.5%), and in the upper 1/3 of the cervical epithelium, in HSIL (66.7%). Expression of E1+E4 proteins was statistically significantly more frequent in LSIL (50%). The sensitivity and specificity of IHC expression of HPV E2 proteins in the upper 2/3 layers of the squamous epithelium of the cervix and E1+E4 for LSIL were 87.5% and 92.9%, and 50% and 91%, respectively. The obtained results indicate the importance of using early HPV proteins E1, E2, E4 for the differential diagnosis of LSIL.

About the authors

D. A. Dobrovolskaya

FSBI «National Medical Research Center for Obstetrics, Gynecology, and Perinatology named after Academician V. I. Kulakov» of the Ministry of Health of the Russian Federation

Email: secretariat@oparina4.ru
ORCID iD: 0000-0003-4601-1330
117997, Moscow, Akademika Oparina St., 4

A. V. Asaturova

FSBI «National Medical Research Center for Obstetrics, Gynecology, and Perinatology named after Academician V. I. Kulakov» of the Ministry of Health of the Russian Federation

Email: secretariat@oparina4.ru
ORCID iD: 0000-0001-8739-5209
MD, PhD, Head of first pathology Department 117997, Moscow, Akademika Oparina St., 4

G. R. Bayramova

FSBI «National Medical Research Center for Obstetrics, Gynecology, and Perinatology named after Academician V. I. Kulakov» of the Ministry of Health of the Russian Federation

Email: secretariat@oparina4.ru
ORCID iD: 0000-0003-4826-661X
MD, PhD, of Medical Sciences, Honored Doctor of the Russian Federation, Professor of the Department of Obstetrics and Gynecology of the Department of Professional Education 117997, Moscow, Akademika Oparina St., 4

A. S. Badlaeva

FSBI «National Medical Research Center for Obstetrics, Gynecology, and Perinatology named after Academician V. I. Kulakov» of the Ministry of Health of the Russian Federation

Email: secretariat@oparina4.ru
ORCID iD: 0000-0001-5223-9767
MD, PhD, Senior Researcher at the 1st Pathology Department 117997, Moscow, Akademika Oparina St., 4

A. V. Tregubova

FSBI «National Medical Research Center for Obstetrics, Gynecology, and Perinatology named after Academician V. I. Kulakov» of the Ministry of Health of the Russian Federation

Email: secretariat@oparina4.ru
ORCID iD: 0000-0003-4601-1330
Pathologist 117997, Moscow, Akademika Oparina St., 4

References

  1. Zhang, Y., Qiu, K., Ren, J. et al. Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use. Sig Transduct Target Ther. 2025; 10, 44. https://doi.org/10.1038/s41392–024–02083-w;
  2. Байрамова Г. Р., Трофимов Д. Ю., Андреев А. О. и соавт. Сравнительный анализ результатов ВПЧ-тестирования в образцах цервикального эпителия и биопсийного материала шейки матки. Вестник РГМУ. 2024; 6: 132–138. doi: 10.24075/vrgmu.2024.073 [Bayramova G. R., Trofimov D.Yu., Andreev A. O. et al. Comparative analysis of HPV testing results in cervical epithelium and cervical biopsy material. Bulletin of the Russian State Medical University. 2024; 6: 132–138. doi: 10.24075/vrgmu.2024.073 (In Russ.)].
  3. Atla B., Uma P., Shamili M. et al. Cytological patterns of cervical pap smears with histopathological correlation. Int J Res Med Sci. 2015. https://doi.org/10.18203/2320–6012.ijrms20150300
  4. Koliopoulos G., Nyaga V.N., Santesso N. et al. Cytology versus HPV testing for cervical cancer screening in the general population. The Cochrane database of systematic reviews. 2017; 8 (8), https://doi.org/10.1002/14651858.CD008587.pub2
  5. Singhal A., Raina R., Verma S. et al. Predictive accuracy of cervical cytology and colposcopy in diagnosing premalignant and malignant cervical lesions: A hospital-­based study from the sub-­Himalayan region of Indian subcontinent. CHRISMED J Health Res. 2019; 6. https://doi.org/10.4103/cjhr.cjhr_51_18
  6. Wright T. C., Stoler M. H., Behrens C. M. et al. Interlaboratory variation in the performance of liquid-­based cytology: Insights from the ATHENA trial. Int J Cancer. 2014; 134. https://doi.org/10.1002/ijc.28514
  7. Asaturova A., Dobrovolskaya D., Magnaeva A. et al. Cervical Cytology-­Histology Correlation Based on the American Society of Cytopathology Guideline (2017) at the Russian National Medical Research Center for Obstetrics, Gynecology, and Perinatology. Diagnostics (Basel). 2022; 12 (1): 210. doi: 10.3390/diagnostics12010210
  8. Kyrgiou M., Athanasiou A., Kalliala I. E.J. et al. Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease. The Cochrane database of systematic reviews. 2017; 11 (11)^ CD012847. https://doi.org/10.1002/14651858.CD012847
  9. Kyrgiou M., Koliopoulos G., Martin-­Hirsch P. et al. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: Systematic review and meta-analysis. Lancet. 2006; 367. https://doi.org/10.1016/S0140–6736 (06) 68181-6
  10. Rufail M., Lew M., Pang J. et al. Low-grade squamous intraepithelial lesion on Papanicolaou test: follow-up rates and stratification of risk for high-grade squamous intraepithelial lesion. Journal of the American Society of Cytopathology. 2020; 9 (4); 258–265. https://doi.org/10.1016/j.jasc.2020.02.003
  11. Khuakoonratt, N., Tangjitgamol, S., Manusirivithaya, S. et al. Prevalence of high grade squamous intraepithelial lesion (HSIL) and invasive cervical cancer in patients with low grade squamous intraepithelial lesion (LSIL) at cervical pap smear. Asian Pacific journal of cancer prevention: APJCP. 2008; 9 (2): 253–257.
  12. Boonlikit S. Prevalence of high-grade cervical lesion in women with LSIL and HSIL cytology and prevalence of invasive cancer in women cytologically positive for malignancy. Asian Pacific journal of cancer prevention: APJCP. 2008; 9 (4): 715–718.
  13. Chen, E.Y., Tran, A., Raho, C J. et al. Histological ‘progression’ from low (LSIL) to high (HSIL) squamous intraepithelial lesion is an uncommon event and an indication for quality assurance review. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc. 2010; 23 (8): 1045–1051. https://doi.org/10.1038/modpathol.2010.85
  14. Woo Y. L., van den Hende M., Sterling J. C. et al. A prospective study on the natural course of low-grade squamous intraepithelial lesions and the presence of HPV16 E2-, E6- and E7-specific T-cell responses. International journal of cancer. 2010; 126 (1): 133–141. https://doi.org/10.1002/ijc.24804
  15. Xue Y., Bellanger S., Zhang W. et al. HPV16 E2 is an immediate early marker of viral infection, preceding E7 expression in precursor structures of cervical carcinoma. Cancer research. 2010; 7(13): 5316–5325. https://doi.org/10.1158/0008–5472.CAN-09–3789
  16. Ramirez N., Guerra F., Camporeale G. et al. Expressions of E2 and E7-HPV16 proteins in pre-malignant and malignant lesions of the uterine cervix. Biotechnic & histochemistry: official publication of the Biological Stain Commission. 2015; 90 (8): 573–580. https://doi.org/10.3109/10520295.2015.1047794
  17. Boulet G. A., Benoy I. H., Depuydt C. E. et al. Human papillomavirus 16 load and E2/E6 ratio in HPV16-positive women: biomarkers for cervical intraepithelial neoplasia >or 2 in a liquid-­based cytology setting? Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2009; 18 (11): 2992–2999. https://doi.org/10.1158/1055–9965.EPI-09–0025
  18. Stevenson A., Kavanagh K., Pan J. et al. Risk stratification of cervical disease using detection of human papillomavirus (HPV) E4 protein and cellular MCM protein in clinical liquid based cytology samples. Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology. 2018; 108: 19–25. https://doi.org/10.1016/j.jcv.2018.08.011
  19. Supchokpul A., Chansaenroj J., Theamboonlers A. et al. E4 expression of human papillomavirus in cervical samples with different cytology categories. The Southeast Asian journal of tropical medicine and public health. 2011; 42 (5): 1113–1118.
  20. Przybylski M., Pruski D., Millert-­Kalińska S. et al. Expression of E4 Protein and HPV Major Capsid Protein (L1) as A Novel Combination in Squamous Intraepithelial Lesions. Biomedicines. 2023; 11 (1): 225. https://doi.org/10.3390/biomedicines11010225
  21. van Baars R., Griffin H., Wu Z. et al. Investigating Diagnostic Problems of CIN1 and CIN2 Associated With High-risk HPV by Combining the Novel Molecular Biomarker PanHPVE4 With P16INK4a. The American journal of surgical pathology. 2015; 39 (11): 1518–1528. https://doi.org/10.1097/PAS.0000000000000498
  22. Leeman A., Jenkins D., Del Pino M. et al. Expression of p16 and HPV E4 on biopsy samples and methylation of FAM19A4 and miR124–2 on cervical cytology samples in the classification of cervical squamous intraepithelial lesions. Cancer medicine. 2020; 9 (7): 2454–2461. https://doi.org/10.1002/cam4.2855
  23. Stolyarova U.V., Khvorostukhina N.F., Mikheeva Yu. V. Complex treatment of cervical papillomavirus infection. [Kompleksnoe lechenie papillomavirusnoj infekcii shejki matki]. Izvestiya Samarskogo nauchnogo centra RAN. 2014; 16(5–4): 1456–8. (In Russ.).
  24. Мухамбеталиева Д. Д., Назарова Н. М., Асатурова А. В. и соавт. Клинические и морфологические аспекты в диагностике степени тяжести поражений шейки матки, ассоциированных с ВПЧ-инфекцией (Обзор литературы). Медицинский оппонент. 2023; 4 (24): 20–24. [Mukhambetalieva D. D., Nazarova N. M., Asaturova A. V. et al. Clinical and morphological aspects in the diagnosis of the severity of cervical lesions associated with HPV infection (Literature review). Meditsinskiy opponent = Medical Opponent. 2023; 4 (24): 20–24. (In Russ.)]. https://proffopponent.ru/4-2023-mo/

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