Low methylation levels among HPV-vaccinated women with cervical HSIL 159 7 among unvaccinated women, regardless of the age 8-10, 12. However, given the absence or low level of methylation in our study, it is likely that histologically confirmed HSIL cases in these young, HPV-vaccinated women have a very low progression potential. Nevertheless, with the S5-classifier, which combines results on viral genes and host-cell gene EPB41L3, a significant difference was detected between HPV-vaccinated HSIL cases and controls. However, the mean levels of the S5-classifier were relatively low. Altogether, our findings lead to a debate whether HPV-vaccinated women with HSIL lesions could potentially regress spontaneously without the need for LEEP and associated risks and complications. The main strength of our study lies in the longitudinal follow-up of women who all received a full three-dose bivalent vaccine at the age of 12-15 years old. Additionally, due to the well-established original Finnish community and individually randomised trial cohort, we were able to structure a case-control setting where both age and community at the time of vaccination were utilised. This study also represents the first evaluation of methylation markers among HSIL lesions in HPV-vaccinated women. However, our study has also several limitations. These include the small sample size of HSIL lesions and the young age of the women at time of HSIL detection. Additionally, under the current Bethesda guidelines, abnormal histology is reported based on a two-tier stratification of LSIL (formerly CIN1) or HSIL (formerly CIN2 and CIN3). Therefore, we were unable to further stratify the HSIL lesions into CIN2 or CIN3 in this study 31, 32. Our results require validation in the future with a larger number of HSIL lesions, as well as the inclusion of older HPV-vaccinated women. As HPV-vaccinated women enter cervical cancer screening programs, a new era in screening approaches is forthcoming. To determine the need and frequency to screen HPV-vaccinated women, we must consider all potential harms and benefits of this new era. Based on these first findings, moving away from a one-size-fits-all strategy is anticipated, taking the HPV vaccination status into account, allowing for the direction of screening resources to those at highest risk and using less intensive screening for those with lower risk. Our findings suggest that active surveillance may be suitable for HPVvaccinated women with cervical HSIL, given the potential for lesion regression. However, further validation of these results in larger cohorts of HPV-vaccinated women with longer follow-up is needed.
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