Triage strategies and colposcopy referrals in HPV-positive women with low-grade cytology 129 6 INTRODUCTION Human papillomavirus (HPV)-based cervical cancer screening has emerged as a highly sensitive method for detecting high-grade cervical intraepithelial neoplasia (CIN) and cervical cancer, surpassing the sensitivity of cytology-based screening 1, 2. However, it is important to address the issue of lower specificity, which consequently leads to a significant increase in colposcopy referrals 3, 4. Notably, a significant proportion of these referrals do not have clinically relevant disease (≤CIN1) 5, 6. To tackle this issue, triage tests for high risk (hr) HPV-positive women can reduce the number of unnecessary colposcopy referrals. Common triage tests include cytology, HPV16/18 genotyping or a combination of these tests. Despite the success of these triage tests in reducing overall colposcopy referrals, the colposcopy referral rate remains high, particularly in women with low-grade cytology (atypical squamous cells of undetermined significance (ASC-US); or low-grade squamous intraepithelial lesions (LSIL)). The prevalence of CIN3 or cancer (CIN3+) in women with an hrHPV-positive ASC-US/LSIL cytology result is about 10% underlining the unmet need for improved triage strategies. In the Netherlands, additional HPV16/18 genotyping for ASC-US/LSIL samples was introduced in 2022, with immediate referral after an HPV16/18-positive result and repeat testing after one year when a woman is found non-16/18 HPV-positive. This approach aims to reduce unnecessary colposcopy referral while ensuring early detection of clinically significant cases. Understanding the molecular mechanisms involved in cervical carcinogenesis is crucial for optimising screening strategies. In this context, it is well established that hypermethylation of promoter regions of specific tumour suppressor genes plays a pivotal role in cervical carcinogenesis 7, 8. As the methylation levels of these tumour suppressor genes increase, the risk of progression of CIN lesions to cervical cancer also increases, with the highest methylation levels observed in women with cervical cancer 9-11. DNA methylation biomarkers have emerged as potential triage tools for HPV-based cervical cancer screening, exhibiting high sensitivity for cervical cancer and “advanced CIN lesions”, which refer to CIN2/3 lesions associated with an hrHPV infection lasting over five years 7, 10-13. The effectiveness of these triage markers has been evaluated in terms of clinical performance for CIN3+ 12-18, the number of colposcopy referrals 15, 19 and the safety of a negative test, particularly the minimal risk of progression to CIN3 or carcinoma following a negative CIN2/3 result 19, 20. Previous studies have demonstrated the potential of FAM19A4/miR124-2 methylation and ASCL1/LHX8 as additional risk stratification tools in hrHPV-positive women with ASC-US/
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