• Viola M J Verhoef, Folkert J van Kemenade, Lawrence Rozendaal, Daniëlle A M Heideman, Remko P Bosgraaf, Albertus T Hesselink, Willem J G Melchers, Leon F A G Massuger, Ruud L M Bekkers, Renske D M Steenbergen, Johannes Berkhof, Peter J F Snijders, and Chris J L M Meijer.
• Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
• Gynecol. Oncol. 2015 Apr 1; 137 (1): 55-9.

ObjectivesTriage of HPV screen-positive women is needed to identify those with underlying cervical intraepithelial neoplasia grade 2/3 or worse (CIN2/3+). Presently, cytology on a physician-taken cervical scrape is mostly accepted as triage test, but needs follow-up testing in order not to miss severe disease. Here, we evaluated the performance of combined cytology and bi-marker CADM1/MAL-methylation analysis as triage test on physician-taken cervical scrapes of HPV positive women.MethodsIn this post-hoc analysis, we used 364 left-over HPV positive cytology triage samples of participants of a randomized controlled trial (PROHTECT-3: n=46,001) performed in population-based cervical screening. Study endpoints were CIN2+ and CIN3+ detection. Cytology testing with and without methylation marker analysis was evaluated with regard to sensitivity, specificity, positive and negative predictive value, and referral rate.ResultsBi-marker CADM1/MAL-methylation positivity increased proportionally with severity of underlying lesions. Overall, cytology and bi-marker CADM1/MAL-methylation analysis yielded similar performances with regard to CIN3+ detection, yet in combination a significantly higher sensitivity for CIN3+ (88.7%) was obtained at a specificity of 53.6% and a colposcopy referral rate of 53.6%. The combined strategy detected all six cervical cancers, whereas triage by cytology alone failed to detect two of them.ConclusionsCytology and bi-marker CADM1/MAL-methylation analysis perform complementary for CIN2+/CIN3+ detection when used as triage tool on cervical scrapes of HPV positive women. This approach not only results in a higher CIN3+ sensitivity than cytology triage with an acceptable referral rate, but also seems to reduce the risk of missing cervical cancers and advanced high-grade lesions.Copyright © 2015 Elsevier Inc. All rights reserved.

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