Association of Multiple High-Risk Human Papillomavirus Infections with High-Grade Cervical Intraepithelial Lesions

Öz

Aim:Cervical cancer is the fourth most common malignancy among women worldwide. Almost all cases are attributed to Human Papillomavirus (HPV) infection, with approximately 70% caused by HPV types 16 and 18. However, data remain limited regarding whether concurrent infection with HPV 16 and other genotypes further increases cervical cancer risk. This study aimed to evaluate the association between combined HPV infections and the presence of high-grade squamous intraepithelial lesions (HSIL). Material and Methods: Medical records of HPV-positive women who underwent colposcopic examination were retrospectively reviewed. Women aged 25–65 years were included, while those with a history of malignancy, autoimmune disease, or immunosuppressive therapy were excluded. Data regarding HPV genotype, colposcopic findings, and histopathological results were collected from medical records. Results: A total of 107 patients met the inclusion criteria; 69 (64.5%) had HPV 16 alone, and 38 (35.5%) had HPV 16 with other genotypes. Both groups showed similar baseline characteristics. We also evaluated the relationship between HPV 16 infection, alone or combined with other types, and the presence of HSIL lesions. When pathology results were compared according to HPV types, 27 patients (33.8%) without HSIL had combined HPV types, whereas 11 patients (40.7%) with HSIL had both HPV 16 and other types detected (p = .512). Conclusion: In our study, the combination of HPV 16 with other HPV types was not found to confer an additional risk for the development of HSIL lesions. Therefore, colposcopic evaluation should be performed in all patients with HPV 16 positivity, even in the absence of coexisting HPV types.

Anahtar Kelimeler

• HPV
• High-risk HPV
• HSIL
• Cervical cancer

Birden Fazla Yüksek Riskli İnsan Papilloma Virüsü Enfeksiyonlarının Yüksek Dereceli Servikal İntraepitelyal Lezyonlarla İlişkisi

Öz

Amaç: Serviks kanseri, dünya genelinde kadınlarda en sık görülen dördüncü malignitedir. Olguların neredeyse tamamı persistan yüksek riskli İnsan Papilloma Virüsü (HPV) enfeksiyonuna bağlıdır ve vakaların yaklaşık %70’i HPV tip 16 ve 18 ile ilişkilidir. HPV 16’nın yüksek dereceli servikal lezyonlarla güçlü ilişkisi bilinmekle birlikte, HPV 16’ya eşlik eden diğer HPV genotiplerinin varlığının yüksek dereceli skuamöz intraepitelyal lezyon (HSIL) riskini artırıp artırmadığına dair veriler sınırlıdır. Bu çalışmanın amacı, kombine HPV enfeksiyonları ile HSIL varlığı arasındaki ilişkiyi değerlendirmektir. Gereç ve Yöntem: Kolposkopik değerlendirme yapılan HPV pozitif kadın hastaların tıbbi kayıtları retrospektif olarak incelendi. Çalışmaya 25–65 yaş arası kadınlar dâhil edildi; malignite öyküsü, otoimmün hastalık veya immünsüpresif tedavi öyküsü olan hastalar dışlandı. HPV genotipleri, kolposkopik bulgular ve histopatolojik sonuçlara ait veriler hasta dosyalarından elde edildi. Bulgular: Çalışma kriterlerini karşılayan toplam 107 hasta analiz edildi. Hastaların 69’unda (%64,5) yalnızca HPV 16 saptanırken, 38’inde (%35,5) HPV 16’ya ek olarak diğer HPV genotipleri mevcuttu. Her iki grubun demografik ve klinik özellikleri benzerdi. Histopatolojik sonuçlar değerlendirildiğinde, HSIL saptanmayan hastaların 27’sinde (%33,8) kombine HPV enfeksiyonu bulunurken, HSIL saptanan 11 hastada (%40,7) HPV 16’ya ek olarak diğer HPV tipleri mevcuttu. Gruplar arasında istatistiksel olarak anlamlı fark saptanmadı (p = 0,512). Sonuç: HPV 16’ya eşlik eden diğer HPV genotiplerinin varlığı, HPV 16 enfeksiyonu tek başına olan hastalara kıyasla HSIL gelişme riskini artırmamaktadır. Bu bulgular, HSIL gelişimi açısından HPV 16 pozitifliğinin, ek HPV tiplerinin varlığından bağımsız olarak temel belirleyici olduğunu göstermektedir. Bu nedenle, HPV 16 pozitifliği saptanan tüm hastalarda, eşlik eden diğer HPV tiplerinin varlığına bakılmaksızın kolposkopik değerlendirme yapılmalıdır.

Anahtar Kelimeler

• HPV
• Yüksek riskli HPV
• HSIL
• Serviks kanseri

Kaynakça

1. McCluggage WG, Singh N, Gilks CB. Key changes to the World Health Organization (WHO) classification of female genital tumours introduced in the 5th edition (2020). Histopathology. 2022 Apr;80(5):762-778. doi: 10.1111/his.14609. Epub 2022 Feb 20. PMID: 34996131.
2. Thrall MJ, McCarthy E, Mito JK, Rao J; Clinical Practice Committee of the American Society of Cytopathology. Triage options for positive high-risk HPV results from HPV-based cervical cancer screening: a review of the potential alternatives to Papanicolaou test cytology. J Am Soc Cytopathol. 2025 Jan-Feb;14(1):11-22. doi: 10.1016/j.jasc.2024.09.00 Epub 2024 Sep 19. PMID: 39395892.3.
3. Fontham ETH, Wolf AMD, Church TR, 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):321-346. doi:10.3322/caac.21628.
4. Perkins RB, Guido RS, Castle PE, 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):102-131. doi:10.1097/LGT.00000000000005252013 Apr;121(4):829-846. doi: 10.1097/AOG.0b013e3182883a34. PMID: 23635684.
5. Li M, Du X, Lu M, 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.253316.
6. Senapati R, Nayak B, Kar SK, Dwibedi B. HPV genotypes co-infections associated with cervical carcinoma: Special focus on phylogenetically related and non-vaccine targeted genotypes. PLoS One. 2017;12(11):e0187844. Published 2017 Nov 21. doi:10.1371/journal.pone.01878447.
7. Ye Y, Jones T, Wang T, Zeng X, Liu Y, Zhao C. Comprehensive overview of genotype distribution and prevalence of human papillomavirus in cervical lesions. Gynecol Obstet Clin Med. 2024 Apr;4(1):e000005. doi: 10.1136/gocm-2024-000005. PMID: 38650896; PMCID: PMC11034807.
8. Laake I, Feiring B, Jonassen CM, Pettersson JHO, Frengen TG, Kirkeleite IØ, Trogstad L. Concurrent Infection With Multiple Human Papillomavirus Types Among Unvaccinated and Vaccinated 17-Year-Old Norwegian Girls. J Infect Dis. 2022 Sep 4;226(4):625-633. doi: 10.1093/infdis/jiaa709. PMID: 33205203; PMCID: PMC9441200.

9. Alcı, A., Yalcın, N., Gokkaya, M., Ekin Sarı, G., Turkmenoglu, H. R., Ureyen, I., & Toptas, T. (2025). Does Co-Infection With HPV 16 Have a Worse Effect on Cervical Pathology Than HPV 16 Alone?. Med Bull Sisli Etfal Hosp, 59(3), 338-344. https://doi.org/10.14744/SEMB.2025.34682.
10. Kim M, Park NJ, Jeong JY, Park JY. Multiple Human Papilloma Virus (HPV) Infections Are Associated with HSIL and Persistent HPV Infection Status in Korean Patients. Viruses. 2021 Jul 12;13(7):1342. doi: 10.3390/v13071342. PMID: 34372548; PMCID: PMC8310096.
11. Khan MJ, Castle PE, Lorincz AT, 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. 2005 20;97(14):1072-9.
12. Wheeler CM, Hunt WC, Cuzick J, Langsfeld E, Robertson M, Castle PE; New Mexico HPV Pap Registry Steering Committee. The influence of type-specific human papillomavirus infections on the detection of cervical precancer and cancer: A population-based study of opportunistic cervical screening in the United States. Int J Cancer. 2014 Aug 1;135(3):624-34. doi: 10.1002/ijc.28605. Epub 2014 Apr 15. PMID: 24226935; PMCID: PMC4020996.
13. Winer RL, Kiviat NB, Hughes JP, Adam DE, Lee SK, Kuypers JM, et al. Development and duration of human papillomavirus lesions, after initial infection. J Infect Dis 2005;191:731–8.
14. Saslow D, Runowicz CD, Solomon D, Moscicki AB, Smith RA, Eyre HJ, et al. American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin 2002;52:342–62.
15. Woodman CB, Collins S, Winter H, Bailey A, Ellis J, Prior P, et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study. Lancet 2001;357:1831–6.
16. Herrero R, Castle PE, Schiffman M, Bratti MC, Hildesheim A, Morales J, et al. Epidemiologic profile of type-specific human papillomavirus infection and cervical neoplasia in Guanacaste, Costa Rica. J Infect Dis. 2005;191(11):1796–807.
17. Adcock R, Cuzick J, Hunt WC, McDonald RM, Wheeler CM. Role of HPV genotype, multiple infections and viral load on the risk of high-grade cervical neoplasia. Cancer Epidemiol Biomark Prev. 2019;28(11):1816–24.
18. Cuzick J, Ho L, Terry G, Kleeman M, Giddings M, Austin J, et al. Individual detection of 14 high risk human papilloma virus genotypes by the PapType test for the prediction of high grade cervical lesions. J Clin Virol. 2014;60(1):44–9.
19. Oyervides-Muñoz MA, Pérez-Maya AA, Sánchez-Domínguez CN, et al. Multiple HPV Infections and Viral Load Association in Persistent Cervical Lesions in Mexican Women. Viruses. 2020;12(4):380. Published 2020 Mar 31. doi:10.3390/v1204038020.
20. Salazar KL, Zhou HS, Xu J, et al. Multiple Human Papilloma Virus Infections and Their Impact on the Development of High-Risk Cervical Lesions. Acta Cytol. 2015;59(5):391-398. doi:10.1159/000442512