Clinical trial of HPV mRNA testing for uterine cervical cancer screening in Kitakyushu city

Background: We investigated the clinical usefulness of HPV (Human Papillomavirus) mRNA testing for uterine cervical cancer screening in Kitakyushu City. Methods: Based on the guidelines, cervical cancer screening through cytology was conducted for women aged 20 and above. Among those screened, HPV mRNA testing (Aptima HPV) was performed on 763 women aged 30–69 years who consented to the screening between 23 June and 06 October 2022. Results: Of the 2456 patients who underwent cervical cancer screening, 24 (0.98%) showed abnormal cytological results: ASC-US (atypical squamous cells of undetermined significance) (9 cases), LSIL (low-grade squamous intraepithelial lesion) (8 cases), HSIL (high-grade squamous intraepithelial lesion) (3 cases), ASC-H (atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion) (3 cases) and AGC (atypical glandular cells) (1 case). Among the 763 individuals who underwent HPV mRNA testing, 35 (4.6%) tested positive for HPV. Statistical analysis revealed a significant difference in HPV mRNA positivity rates across age groups (p < 0.001). The positivity rates were highest in the 30s age group (13.4%) and lowest in the 60s age group (2.2%). The HPV mRNA positivity rate observed in this study was lower compared to HPV DNA testing methods reported in other studies. This suggests that the HPV mRNA test may have different performance characteristics compared to traditional HPV DNA tests. Conclusions: Based on these findings, Kitakyushu City is considering the introduction of HPV mRNA testing for cervical cancer screening, as it may offer a unique perspective on HPV detection and could potentially enhance detection rates and screening coverage.

Cancer screening; HPV mRNA testing; Uterine cervical cancer; Kitakyushu city

[1] Katanoda K, Hori M, Saito E, Shibata A, Ito Y, Minami T, et al. Updated trends in cancer in japan: incidence in 1985–2015 and mortality in 1958–2018—a sign of decrease in cancer incidence. Journal of Epidemiology. 2021; 31: 426–450.

[2] Jain M, Yadav D, Jarouliya U, Chavda V, Yadav AK, Chaurasia B, et al. Epidemiology, molecular pathogenesis, immuno-pathogenesis, immune escape mechanisms and vaccine evaluation for HPV-associated carcinogenesis. Pathogens. 2023; 12: 1380.

[3] Perkins RB, Wentzensen N, Guido RS, Schiffman M. Cervical cancer screening: a review. JAMA. 2023; 330: 547–558.

[4] OECD Data Explorer. Quality and outcomes of care. Cancer screening. 2023. Available at: https://www.oecd-ilibrary.org/social-issues-migration-health/health-at-a-glance-2023_7a7afb35-en (Accessed: 01 July 2024).

[5] Matsuura Y, Kawagoe T, Toki N, Sugihara K, Kashimura M. Low grade cervical intraepithelial neoplasia associated with human papillomavirus infection. Long-term follow-up. Acta Cytologica. 1998; 42: 625–630.

[6] Hortlund M, van Mol T, Van de Pol F, Bogers J, Dillner J. Human papillomavirus load and genotype analysis improves the prediction of invasive cervical cancer. International Journal of Cancer. 2021; 149: 684–691.

[7] Gilham C, Sargent A, Crosbie EJ, Peto J. Long-term risks of invasive cervical cancer following HPV infection: follow-up of two screening cohorts in Manchester. British Journal of Cancer. 2023; 128: 1933–1940.

[8] Wang W, Arcà E, Sinha A, Hartl K, Houwing N, Kothari S, et al. Cervical cancer screening guidelines and screening practices in 11 countries: a systematic literature review. Preventive Medicine Reports. 2022; 28: 101813.

[9] National Cancer Center Japan. Guidelines for cervical cancer screening based on effectiveness evaluation. 2020. Available at: https://www.ncc.go.jp/jp/information/pr_release/2020/0729/index.html (Accessed: 01 July 2024).

[10] Monsonego J, Hudgens MG, Zerat L, Zerat JC, Syrjänen K, Halfon P, et al. Evaluation of oncogenic human papillomavirus RNA and DNA tests with liquid-based cytology in primary cervical cancer screening: the FASE study. International Journal of Cancer. 2011; 129: 691–701.

[11] Viveros-Carreño D, Fernandes A, Pareja R. Updates on cervical cancer prevention. International Journal of Gynecological Cancer. 2023; 33: 394–402.

[12] 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. Preventive Medicine. 2021; 144: 106399.

[13] Singh D, Vignat J, Lorenzoni V, Eslahi M, Ginsburg O, Lauby-Secretan B, et al. Global estimates of incidence and mortality of cervical cancer in 2020: a baseline analysis of the WHO Global Cervical Cancer Elimination Initiative. The Lancet Global Health. 2023; 11: e197–e206.

[14] Nelson CW, Mirabello L. Human papillomavirus genomics: understanding carcinogenicity. Tumour Virus Research. 2023; 15: 200258.

[15] Zonta MA, Liljander A, Roque KB, Schillert A, Kai M, Dos Santo FA, et al. Prevalence of sexually transmitted infections and human papillomavirus in cervical samples from incarcerated women in São Paulo, Brazil: a retrospective single-center study. Frontiers in Public Health. 2024; 12: 1353845.

[16] Shami S, Coombs J. Cervical cancer screening guidelines: an update. Journal of the American Academy of Physician Assistants. 2021; 34: 21–24.

[17] Ronco G, Dillner J, Elfström KM, Tunesi S, Snijders PJF, Marc Arbyn M, et al. International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. The Lancet. 2014; 383: 524–532.

[18] Muresu N, Sotgiu G, Marras S, Gentili D, Sechi I, Cossu A, et al. Cervical screening in North Sardinia (Italy): genotype distribution and prevalence of HPV among women with ASC-US cytology. International Journal of Environmental Research and Public Health. 2022; 19: 693.

[19] Katki, HA, Kinney WK, Fetterman B, Lorey T, Poitras NE, Cheung L, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. The Lancet Oncology. 2011; 12: 663–672.

[20] Wright TC III, Stoler MH, Behrens CM, Sharma A, Sharma K, Apple R. Interlaboratory variation in the performance of liquid-based cytology: insights from the ATHENA trial. International Journal of Cancer. 2014; 134: 1835–1843.

[21] Sørbye SW, Suhrke P, Revå BW, Berland J, Maurseth RJ, Al-Shibli K. Accuracy of cervical cytology: comparison of diagnoses of 100 Pap smears read by four pathologists at three hospitals in Norway. BMC Clinical Pathology. 2017; 17: 18.

[22] Kitchener HC, Almonte M, Thomson C, Wheeler P, Sargent A, Stoykova B, et al. HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial. The Lancet Oncology. 2009; 10: 672–682.

[23] Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Palma PD, Mistro AD, et al. New technologies for cervical cancer screening (NTCC) working group. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. The Lancet Oncology. 2010; 11: 249–257.

[24] Morisada T, Teramoto K, Takano H, Sakamoto I, Nishio H, Iwata T, et al. CITRUS, cervical cancer screening trial by randomization of HPV testing intervention for upcoming screening: design, methods and baseline data of 18,471 women. Cancer Epidemiology. 2017; 50: 60–67.

[25] Ogilvie GS, van Niekerk D, Krajden M, Smith LW, Cook D, Gondara L, et al. Effect of screening with primary cervical HPV testing vs cytology testing on high-grade cervical intraepithelial neoplasia at 48 months: the HPV FOCAL randomized clinical trial. JAMA. 2018; 320: 43–52.

[26] Kurokawa T, Onuma T, Shinagawa A, Chino Y, Kobayashi M, Yoshida Y. The ideal strategy for cervical cancer screening in Japan: result from the Fukui cervical cancer screening study. Cytopathology. 2018; 29: 361–367.

[27] Kono K, Morisada T, Saika K, Aoki ES, Miyagi E, Ito K, et al. The first-round results of a population-based cohort study of HPV testing in Japanese cervical cancer screening: baseline characteristics, screening results, and referral rate. Journal of Gynecologic Oncology. 2021; 32: e29.

[28] Wright TC III, Stoler MH, Sharma A, Zhang G, Behrens C, Wright TL. ATHENA (addressing THE need for advanced HPV diagnostics) study group. Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV+ cytology-negative results. American Journal of Clinical Pathology. 2011; 136: 578–586.

[29] Reid JL, Wright Jr TC, Stoler MH, Cuzick J, Castle PE, Dockter J, et al. Human papillomavirus oncogenic mRNA testing for cervical cancer screening: baseline and longitudinal results from the CLEAR study. American Journal of Clinical Pathology. 2015; 144: 473–483.

[30] Rad A, Sørbye SW, Tiwari S, Løchen ML, Skjeldestad FE. Risk of intraepithelial neoplasia grade 3 or worse (CIN3+) among women examined by a 5-type HPV mRNA test during 2003 and 2004, followed through 2015. Cancers. 2023; 15: 3106.

[31] Ting J, Smith JS, Myers ER. Cost-effectiveness of high-risk human papillomavirus testing with messenger RNA versus DNA under United States guidelines for cervical cancer screening. Journal of Lower Genital Tract Disease. 2019; 19: 333–339.

[32] Ge Y, Christensen P, Luna E, Armylagos D, Schwartz MR, Mody DR. Performance of Aptima and Cobas HPV testing platforms in detecting high-grade cervical dysplasia and cancer. Cancer Cytopathology. 2017; 125: 652–657.

[33] Arbyn M, Simon M, de Sanjosé S, Clarke MA, Poljak M, Rezhake R, et al. Accuracy and effectiveness of HPV mRNA testing in cervical cancer screening: a systematic review and meta-analysis. The Lancet Oncology. 2022; 23: 950–960.

[34] Ton M, Swami N, Germar MJV, Dee EC. HPV mRNA testing in cervical cancer screening: implications for low- and middle-income countries. International Journal of Gynecological Cancer. 2022; 32: 1632–1633.

[35] Li A, Li J, Austin RM, Wang T, Ashman D, Zhang H, et al. Aptima HPV messenger RNA testing and histopathologic follow-up in women with HSIL cytology: a study emphasizing additional review of HPV-negative cases. Cancer Cytopathology. 2021; 129: 622–631.

[36] Kir G, Dokmeci Guney D, Seneldir H. Comparison of the clinical performance of Aptima HPV Assay and the Cobas 4800 platform in women with normal cytology and positive high-risk HPV. Acta Cytologica. 2023; 67: 395–402.

[37] Perkins RB, Guido RL, Saraiya M, Sawaya GF, Wentzensen N, Schiffman M, et al. Summary of current guidelines for cervical cancer screening and management of abnormal test results: 2016–2020. Journal of Women’s Health. 2021; 30: 5–13.

[38] Wiser A, Quinlan JD, Batur P. Risk-based guidelines: redefining management of abnormal cervical cancer screening results. Cleveland Clinic Journal of Medicine. 2021; 88: 556–560.

[39] Perkins RB, Guido RS, Castle PE, Chelmow D, Einstein MH, Garcia F, et al.; 2019 ASCCP risk-based management consensus guidelines committee. 2019 ASCCP risk-based management consensus guidelines: updates through 2023. Journal of Lower Genital Tract Disease. 2024; 28: 3–6.

[40] Muresu N, Sotgiu G, Saderi L, Sechi I, Cossu A, Marras V, et al. Italian observational study on HPV infection, E6, and p16 expression in men with penile cancer. Virology Journal. 2020; 17: 161.