Thesis

Chapter 6 128 ABSTRACT BACKGROUND High-risk HPV (hrHPV)-positive women in cervical cancer screening are triaged by cytology, leading to many unnecessary colposcopy referrals. This study explores alternative (secondary) triage methods for hrHPV-positive low-grade cytology (ASC-US/ LSIL) to identify high-grade cervical intraepithelial neoplasia (CIN3+). METHODS Within the Dutch IMPROVE trial (NTR5078), 215 clinician-collected hrHPV-positive cervical samples with ASC-US/LSIL were used to evaluate triage by FAM19A4/miR1242 methylation, ASCL1/LHX8 methylation, HPV16/18 genotyping, HPV16/18/31/33/45 genotyping and combinations thereof. Performance was evaluated by positive predictive value (PPV), negative predictive value (NPV) and colposcopy referral rate. Strategies were ordered by test positivity and compared by the marginal positive predictive value for detecting one additional CIN3+ (mPPV). RESULTS FAM19A4/miR124-2 methylation and ASCL1/LHX8 methylation demonstrated improved PPV and NPV for CIN3+, with lower colposcopy rates than HPV16/18 genotyping. Three strategies with mPPV ≥ 20% were identified: 1. HPV16/18 AND FAM19A4/miR124-2 positive (mPPV = 50.0%, NPV = 90.8%); 2. HPV16/18/31/33/45 AND FAM19A4/miR124-2 positive (mPPV = 33.3%, NPV = 91.2%); 3. FAM19A4/miR124-2 positive (mPPV = 20.0%, NPV = 92.2%). Triage by ASCL1/LHX8 yielded an mPPV of 17.2% and NPV of 94.2%. Other strategies had an mPPV ≤ 10.6% and NPV ≤ 96.7%. CONCLUSION Methylation-based algorithms outperform HPV genotyping as a single triage test in hrHPV-positive ASC-US/LSIL cytology. None of the strategies had a sufficiently high NPV to warrant return to routine screening.

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