Follow-up of high-risk HPV positive women by combined cytology and bi-marker CADM1/MAL methylation analysis on cervical scrapes

VMJ Verhoef, Folkert van Kemenade, L Rozendaal, DAM Heideman, RP Bosgraaf, AT Hesselink, WJG Melchers, LFAG Massuger, RLM Bekkers, RDM Steenbergen, J Berkhof, PJF Snijders, CJLM Meijer

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Objectives. Triage 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 hi-marker CADM1/MAL-methylation analysis as triage test on physician-taken cervical scrapes of HPV positive women. Methods. In 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. Results. Bi-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. Conclusions. Cytology 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. (C) 2015 Elsevier Inc. All rights reserved.
Original languageUndefined/Unknown
Pages (from-to)55-59
Number of pages5
JournalGynecologic Oncology
Issue number1
Publication statusPublished - 2015

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  • EMC MM-03-24-01

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