Triage strategies and colposcopy referrals in HPV-positive women with low-grade cytology 137 6 indicating its potential to identify lesions at the highest risk of progression to cervical cancer 10-13, 23. The status of FAM19A4/miR124-2 methylation in CIN2/3 lesions has important diagnostic implications. The absence of FAM19A4/miR124-2 methylation is associated with high likelihood of spontaneous regression in methylation-negative women with CIN2/3 lesions and the reduced risk of cervical cancer progression. This observation is supported by a prospective cohort study with a two-year follow-up period 28, 29. A Finnish study highlighted the prognostic utility of methylation analysis, capable of distinguishing between regressive and progressive CIN2 lesions 30. Moreover, a substantially lower 14year cervical cancer risk was found among hrHPV-positive women negative for FAM19A4/ miR124-2 methylation compared to hrHPV-positive, cytology-negative women 20. In the context of cervical cancer screening and triage testing of hrHPV-positive women, the performance of FAM19A4/miR124-2 methylation holds promise for identifying high-risk lesions, aiding in appropriate clinical management and minimising unnecessary invasive procedures for lesions likely to regress spontaneously. Given the two-fold increase in direct colposcopy referrals and CIN1 diagnosis following the implementation of HPV-based screening in the Netherlands 5, 6, 31, the limitation of colposcopy referral rate is pivotal in assessing the efficacy of triage strategies. Our proposed algorithm, involving FAM19A4/miR124-2 or ASCL1/LHX8 methylation, combined with HPV genotyping, as a secondary triage test for hrHPV-positive women with ASCUS/LSIL cytology, offers several advantages. Firstly, methylation provides an objective molecular test to identify clinically relevant high-grade lesions. Secondly, a methylation test significantly reduces the direct colposcopy referral rate, leading to a more efficient utilisation of healthcare resources. In this study the reduction of colposcopy referrals after FAM19A4/miR124-2 methylation was 85.6%, but also Dick et al. and Bonde et al., reported reductions of 60.0% and 66.0% in colposcopy referral rates, respectively 15, 19. Furthermore, ASCL1/LHX8 methylation showed a reduction of colposcopy referrals of 70.6%. Notably, the strategy involving HPV16/18 genotyping AND FAM19A4/miR124-2 methylation in our study even achieved a 94.8% reduction in direct colposcopy referrals. Thirdly, this approach facilitates risk stratification, enabling the identification of women at low risk of CIN3+ to reduce direct colposcopy referrals. It is essential to note that none of the strategies achieved an NPV of >98%, which has been defined as a threshold for return to routine screening in cervical cancer screening in the Netherlands 25. Hence, as indicated by Polman et al. 25, follow-up testing within 12 months is required, aimed at capturing any potentially missed CIN3 lesion. Previous studies of triage strategies in HPVbased screening showed that strategies with repeat cytology, as currently implemented
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