title: Triaging borderline/mild dyskaryotic Pap cytology with p16/Ki-67 dual-stained cytology testing: cross-sectional and longitudinal outcome study.
abstract: BACKGROUND
  Women with borderline/mildly dyskaryotic (BMD) cytology smears are currently followed up with repeat testing at 6 and 18 months. The objective of this study is to analyse the cross-sectional and longitudinal performance of p16/Ki-67 dual-stained cytology for the detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) and CIN2+ in women with BMD, and to compare the results with baseline human papillomavirus (HPV) testing.
  
  
  METHODS
  Conventional Pap cytology specimens of 256 women with BMD were dual stained for p16/Ki-67 retrospectively, and compared with baseline HPV results and long-term follow-up results.
  
  
  RESULTS
  p16/Ki-67 dual-stained cytology showed a sensitivity of 100%, a specificity of 64.4% and a negative predictive value (NPV) of 100.% for CIN3+. Human papillomavirus testing demonstrated similar sensitivity (96.3%), and NPV (99.1%), but a significantly lower specificity (57.6%; P=0.024) for CIN3+. Sensitivity, specificity and NPV for CIN2+ of dual-stained cytology were 89.7%, 73.1% and 95.1%, respectively, which was similar when compared with HPV testing. Dual-stained cytology showed a significant lower referral rate than HPV testing (43.6% vs 49.1%; P=0.043). During long-term follow-up, no CIN3+ lesions developed in HPV-positive, dual-stained negative women.
  
  
  CONCLUSIONS
  Comparable sensitivity and NPV of dual-stained cytology for CIN3+, combined with a significantly higher specificity, makes p16/Ki-67 dual-stained cytology a viable alternative to HPV testing for triaging BMD.
authors: Department of Pathology, VU University Medical Center, PO BOX 7057, 1000 MB Amsterdam, The Netherlands.
authors: M H
authors: MH
authors: Uijterwaal
authors: Department of Epidemiology and Biostatistics, VU University Medical Center, PO BOX 7057, 1000 MB Amsterdam, The Netherlands.
authors: B I
authors: BI
authors: Witte
authors: Department of Pathology, Erasmus University Medical Center, PO BOX 2040, 3000 CA Rotterdam, The Netherlands.
authors: F J
authors: FJ
authors: Van Kemenade
authors: Department of Obstetrics and Gynaecology, VU University Medical Center, PO BOX 7057, 1000 MB Amsterdam, The Netherlands.
authors: D
authors: D
authors: Rijkaart
authors: Ventana Medical Systems, Inc., 1910 E Innovation Park Drive, Tucson, AZ 85755, USA.
authors: R
authors: R
authors: Ridder
authors: Department of Epidemiology and Biostatistics, VU University Medical Center, PO BOX 7057, 1000 MB Amsterdam, The Netherlands.
authors: J
authors: J
authors: Berkhof
authors: Saltro Diagnostic Centre, PO BOX 9300, 3506 GH Utrecht, The Netherlands.
authors: G A M A
authors: GA
authors: Balfoort-van der Meij
authors: Department of Pathology, VU University Medical Center, PO BOX 7057, 1000 MB Amsterdam, The Netherlands.
authors: M C G
authors: MC
authors: Bleeker
authors: Department of Pathology, VU University Medical Center, PO BOX 7057, 1000 MB Amsterdam, The Netherlands.
authors: P J F
authors: PJ
authors: Snijders
authors: Department of Pathology, VU University Medical Center, PO BOX 7057, 1000 MB Amsterdam, The Netherlands.
authors: C J L M
authors: CJ
authors: Meijer
mesh_terms: D000328:Adult; D003127:Colposcopy / Q000379:methods; D003430:Cross-Sectional Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16; D055088:Early Detection of Cancer / Q000379:methods; D005260:Female; D006801:Humans; D015994:Incidence; D019394:Ki-67 Antigen / Q000032:analysis*; D008137:Longitudinal Studies; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D065006:Papanicolaou Test / Q000379:methods; D027383:Papillomaviridae / Q000302:isolation & purification; D030361:Papillomavirus Infections / Q000175:diagnosis* / Q000821:virology; D012189:Retrospective Studies; D012307:Risk Factors; D013194:Staining and Labeling / Q000379:methods; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000473:pathology / Q000821:virology; D014626:Vaginal Smears / Q000379:methods; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis* / Q000473:pathology / Q000821:virology
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins