title: Combined CADM1/MAL methylation and cytology testing for colposcopy triage of high-risk HPV-positive women.
abstract: Primary screening for high-risk human papillomavirus (hrHPV) requires a triage protocol. Repeat cytology testing at baseline and after 6 to 12 months has emerged as a reasonable triage approach, but carries the risk of loss to follow-up. Repeat cytology testing may be omitted if cytology is supplemented with another, complementary triage test at baseline. In this study, the performance of combined triage by cytology and DNA methylation analysis was assessed. In hrHPV-positive cervical scrapes (n = 250), cytology [threshold: atypical squamous cells of undetermined significance (ASCUS)], bi-marker CADM1/MAL methylation testing (at different assay thresholds), and combinations of both were evaluated for endpoints cervical intraepithelial neoplasia grade 2 or worse (CIN2(+)) and grade 3 or worse (CIN3(+)). At a predefined methylation threshold of 70% specificity for CIN3(+), combined triage revealed a CIN3(+) sensitivity of 86.8% [95% confidence interval (CI), 76.1-97.6] compared with 65.8% (95% CI, 50.7-80.9) for sole cytology triage testing. Corresponding CIN3(+) specificity was 64.8% (95% CI, 58.1-71.5) for combined triage and 78.6% (95% CI, 72.8-84.3) for sole cytology triage testing. For CIN2(+), the sensitivity of combined triage testing was 84.5% (95% CI, 75.2-93.8) compared with 65.5% (95% CI, 53.3-77.7) for sole cytology triage, with corresponding specificities of 69.9% (95% CI, 63.1-76.6) and 83.5% (95% CI, 78.0-89.0), respectively. In conclusion, combined triage reached substantially higher CIN2(+)/3(+) sensitivities compared with sole cytology at a slight drop in specificity. Therefore, it is an attractive triage strategy for colposcopy of hrHPV-positive women with a high reassurance for cervical cancer and advanced CIN lesions.
authors: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Lise M A
authors: LM
authors: De Strooper
authors: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Albertus T
authors: AT
authors: Hesselink
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: Chris J L M
authors: CJ
authors: Meijer
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.
authors: Renske D M
authors: RD
authors: Steenbergen
authors: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands. dam.heideman@vumc.nl.
authors: Daniëlle A M
authors: DA
authors: Heideman
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics*; D003127:Colposcopy / Q000379:methods; D019175:DNA Methylation; D055088:Early Detection of Cancer; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D008875:Middle Aged; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000235:genetics*; D027383:Papillomaviridae / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000235:genetics* / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000821:virology*; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000235:genetics / 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