title: Triaging HPV-positive women with normal cytology by p16/Ki-67 dual-stained cytology testing: baseline and longitudinal data.
abstract: Primary human papillomavirus (HPV)-based screening results in a 2-5% lower specificity for cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) compared to Pap cytology. To identify HPV-positive women with CIN2+, we retrospectively evaluated the cross-sectional and longitudinal performance of p16/Ki-67 dual-stained cytology in HPV-positive women with normal cytology participating in population-based cervical screening. Conventional Pap cytology specimens of 847 of these women derived from the VUSA-Screen study were dual-stained for p16/Ki-67. Cross-sectional clinical performance in detecting CIN3 or worse (CIN3+), and CIN2+ was compared to that of baseline HPV genotyping. Moreover, 5-year cumulative incidence risks (CIR) for CIN3+ (CIN2+) were determined. The sensitivity of p16/Ki-67 dual-stained cytology for CIN3+ (CIN2+) was 73.3% (68.8%) with a specificity of 70.0% (72.8%). HPV16/18 genotyping showed a sensitivity for CIN3+ (CIN2+) of 46.7% (43.8%), with a specificity of 78.3% (79.4%). The 5-year CIR for CIN3+ in HPV-positive women with normal cytology was 6.9%. Testing these women with p16/Ki-67 dual-stained cytology resulted in a significantly lower CIN3+ 5-year CIR of 3.3% (p = 0.017) in case of a negative test result. A negative HPV16/18 genotyping test result also led to a lower 5-year CIN3+ CIR of 3.6%. p16/Ki-67 dual-stained cytology detects more than 70% of underlying CIN3+ lesions in HPV-positive women with normal cytology at baseline and is therefore suitable for triaging these women to colposcopy. Furthermore, the CIN3+ 5-year CIR of 3.3% after a negative dual-stain result is significantly lower compared to the 5-year CIR of 6.9% in women without p16/Ki-67 dual-stained cytology triage.
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Margot H
authors.initials: MH
authors.lastname: Uijterwaal
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Polman
authors.forename: Birgit I
authors.initials: BI
authors.lastname: Witte
authors.forename: Folkert J
authors.initials: FJ
authors.lastname: van Kemenade
authors.forename: Dorien
authors.initials: D
authors.lastname: Rijkaart
authors.forename: Johannes
authors.initials: J
authors.lastname: Berkhof
authors.forename: G A M A
authors.initials: GA
authors.lastname: Balfoort-van der Meij
authors.forename: Ruediger
authors.initials: R
authors.lastname: Ridder
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
mesh_terms: D000328:Adult; D019941:Cyclin-Dependent Kinase Inhibitor p16; D003588:Cytopathogenic Effect, Viral; D055088:Early Detection of Cancer / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis*; D008137:Longitudinal Studies; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D065006:Papanicolaou Test; D027383:Papillomaviridae / Q000235:genetics* / Q000378:metabolism; D030361:Papillomavirus Infections / Q000175:diagnosis / Q000821:virology*; D012307:Risk Factors; D014218:Triage / Q000379:methods*; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000821:virology; D014626:Vaginal Smears / Q000379:methods; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis / Q000378:metabolism* / Q000821:virology
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins
keywords: cervical cytology; genotyping; human papillomavirus; p16/Ki-67 dual-stained cytology