title: The clinical value of HPV genotyping in triage of women with high-risk-HPV-positive self-samples.
abstract: Cytology alone, or combined with HPV16/18 genotyping, might be an acceptable method for triage in hrHPV-cervical cancer screening. Previously studied HPV-genotype based triage algorithms are based on cytology performed without knowledge of hrHPV status. The aim of this study was to explore the value of hrHPV genotyping combined with cytology as triage tool for hrHPV-positive women. 520 hrHPV-positive women were included from a randomised controlled self-sampling trial on screening non-attendees (PROHTECT-3B). Eighteen baseline triage strategies were evaluated for cytology and hrHPV genotyping (Roche Cobas 4800) on physician-sampled triage material. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), referral rate, and number of referrals needed to diagnose (NRND) were calculated for CIN2+ and CIN3+. A triage strategy was considered acceptable if the NPV for CIN3+ was ≥98%, combined with maintenance or improvement of sensitivity and an increase in specificity in reference to the comparator, being cytology with a threshold of atypical cells of undetermined significance (ASC-US). Three triage strategies met the criteria: HPV16+ and/or ≥LSIL; HPV16+ and/or ≥HSIL; (HPV16+ and/or HPV18+) and/or ≥HSIL. Combining HPV16+ and/or ≥HSIL yielded the highest specificity (74.9%, 95% CI 70.5-78.9), with a sensitivity (94.4%, 95% CI 89.0-97.7) similar to the comparator (93.5%, 95% CI 87.7-97.1), and a decrease in referral rate from 52.2% to 39.5%. In case of prior knowledge of hrHPV presence, triage by cytology testing can be improved by adjusting its threshold, and combining it with HPV16/18 genotyping. These strategies improve the referral rate and specificity for detecting CIN3+ lesions, while maintaining adequate sensitivity.
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, HB, 6500, The Netherlands.
authors.forename: Renée M F
authors.initials: RM
authors.lastname: Ebisch
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, HB, 6500, The Netherlands.
authors.forename: Gabriëlle M
authors.initials: GM
authors.lastname: de Kuyper-de Ridder
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, HB, 6500, The Netherlands.|Department of Obstetrics and Gynaecology, Jeroen Bosch Hospital, 's-Hertogenbosch, ME, 5200, The Netherlands.
authors.forename: Remko P
authors.initials: RP
authors.lastname: Bosgraaf
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, HB, 6500, The Netherlands.
authors.forename: Leon F A G
authors.initials: LF
authors.lastname: Massuger
authors.affiliation: Institute for Health Sciences, Radboud University Medical Center, Nijmegen, HB, 6500, The Netherlands.
authors.forename: Joanna
authors.initials: J
authors.lastname: IntHout
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, MB, 1007, The Netherlands.
authors.forename: Viola M J
authors.initials: VM
authors.lastname: Verhoef
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, MB, 1007, The Netherlands.
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, MB, 1007, The Netherlands.
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, MB, 1007, The Netherlands.
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
authors.affiliation: Department of Pathology, Erasmus MC, University Medical Center, Rotterdam, CA, 3000, The Netherlands.
authors.forename: Folkert J
authors.initials: FJ
authors.lastname: van Kemenade
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, HB, 6500, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Bulten
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, HB, 6500, The Netherlands.
authors.forename: Albert G
authors.initials: AG
authors.lastname: Siebers
authors.affiliation: Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, HB, 6500, The Netherlands.
authors.forename: Ruud L M
authors.initials: RL
authors.lastname: Bekkers
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, HB, 6500, The Netherlands.
authors.forename: Willem J G
authors.initials: WJ
authors.lastname: Melchers
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D005838:Genotype; D006801:Humans; D008403:Mass Screening; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D027383:Papillomaviridae / Q000145:classification / Q000235:genetics*; D030361:Papillomavirus Infections / Q000175:diagnosis / Q000453:epidemiology* / Q000821:virology*; D012680:Sensitivity and Specificity; D014218:Triage / Q000379:methods; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control; D014626:Vaginal Smears; D002578:Uterine Cervical Dysplasia / Q000453:epidemiology / Q000209:etiology / Q000473:pathology
keywords: cervical carcinoma; cervical intraepithelial neoplasia; genotyping; human papillomavirus; screening; triage