title: Follow-up of high-risk HPV positive women by combined cytology and bi-marker CADM1/MAL methylation analysis on cervical scrapes.
abstract: OBJECTIVE
  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 bi-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.
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Viola M J
authors: VM
authors: Verhoef
authors: Department of Pathology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors: Folkert J
authors: FJ
authors: van Kemenade
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Lawrence
authors: L
authors: Rozendaal
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Daniëlle A M
authors: DA
authors: Heideman
authors: Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Remko P
authors: RP
authors: Bosgraaf
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Albertus T
authors: AT
authors: Hesselink
authors: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Willem J G
authors: WJ
authors: Melchers
authors: Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Leon F A G
authors: LF
authors: Massuger
authors: Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Ruud L M
authors: RL
authors: Bekkers
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Renske D M
authors: RD
authors: Steenbergen
authors: Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors: Johannes
authors: J
authors: Berkhof
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Peter J F
authors: PJ
authors: Snijders
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: cjlm.meijer@vumc.nl.
authors: Chris J L M
authors: CJ
authors: Meijer
mesh_terms: D000328:Adult; D052685:Alphapapillomavirus / Q000302:isolation & purification; D014408:Biomarkers, Tumor / Q000235:genetics; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D008875:Middle Aged; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000235:genetics*; D030361:Papillomavirus Infections / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors; D014218:Triage / Q000379:methods; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D014626:Vaginal Smears / Q000379:methods; D002578:Uterine Cervical Dysplasia / Q000235:genetics* / Q000473:pathology / Q000821:virology
chemical_list: D014408:Biomarkers, Tumor; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; C569026:MAL protein, human; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins
keywords: Cervical intraepithelial neoplasia; Cervical scrape; Cervical screening; Cytology; DNA methylation; Human papillomavirus; Triage