title: p16/Ki-67 dual-stained cytology for detecting cervical (pre)cancer in a HPV-positive gynecologic outpatient population.
abstract: Women who test positive for a high-risk type of the human papillomavirus (HPV) require triage testing to identify those women with cervical intraepithelial neoplasia grade 3 or cancer (≥CIN3). Although Pap cytology is considered an attractive triage test, its applicability is hampered by its subjective nature. This study prospectively compared the clinical performance of p16/Ki-67 dual-stained cytology to that of Pap cytology, with or without HPV16/18 genotyping, in high-risk HPV-positive women visiting gynecologic outpatient clinics (n=446 and age 18-66 years). From all women, cervical scrapes (for Pap cytology, HPV16/18 genotyping, and p16/Ki-67 dual-stained cytology) and colposcopy-directed biopsies were obtained. The sensitivity of p16/Ki-67 dual-stained cytology for ≥CIN3 (93.8%) did neither differ significantly from that of Pap cytology (87.7%; ratio 1.07 and 95% confidence interval (CI): 0.97-1.18) nor from that of Pap cytology combined with HPV16/18 genotyping (95.1%; ratio 0.99 and 95% CI: 0.91-1.07). However, the specificity of p16/Ki-67 dual-stained cytology for ≥CIN3 (51.2%) was significantly higher than that of Pap cytology (44.9%; ratio 1.14 and 95% CI: 1.01-1.29) and Pap cytology combined with HPV16/18 genotyping (25.8%; ratio 1.99 and 95% CI: 1.68-2.35). After exclusion of women who had been referred because of abnormal Pap cytology, the specificity of p16/Ki-67 dual-stained cytology for ≥CIN3 (56.7%) remained the same, whereas that of Pap cytology (60.3%) increased substantially, resulting in a similar specificity of both assays (ratio 0.94 and 95% CI: 0.83-1.07) in this sub-cohort. In summary, p16/Ki-67 dual-stained cytology has a good clinical performance and is an interesting objective microscopy-based triage tool for high-risk HPV-positive women.
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Roosmarijn
authors.initials: R
authors.lastname: Luttmer
authors.affiliation: Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Maaike G
authors.initials: MG
authors.lastname: Dijkstra
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Johannes
authors.initials: J
authors.lastname: Berkhof
authors.affiliation: Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Folkert J
authors.initials: FJ
authors.lastname: van Kemenade
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Rozendaal
authors.affiliation: Department of Obstetrics and Gynecology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Theo J M
authors.initials: TJ
authors.lastname: Helmerhorst
authors.affiliation: UMC Utrecht Cancer Center, Utrecht, The Netherlands.
authors.forename: René H M
authors.initials: RH
authors.lastname: Verheijen
authors.affiliation: Roosevelt Clinic, Leiden, The Netherlands.
authors.forename: W Abraham
authors.initials: WA
authors.lastname: Ter Harmsel
authors.affiliation: Department of Obstetrics and Gynecology, Flevo Hospital, Almere, The Netherlands.
authors.forename: W Marchien
authors.initials: WM
authors.lastname: van Baal
authors.affiliation: Department of Obstetrics and Gynecology, Sint Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Peppino G C M
authors.initials: PG
authors.lastname: Graziosi
authors.affiliation: DDL Diagnostic Laboratory, Rijswijk, The Netherlands.
authors.forename: Wim G V
authors.initials: WG
authors.lastname: Quint
authors.affiliation: Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Johan W M
authors.initials: JW
authors.lastname: Spruijt
authors.affiliation: Department of Obstetrics and Gynecology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.
authors.forename: Dorenda K E
authors.initials: DK
authors.lastname: van Dijken
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D005260:Female; D005838:Genotype; D061809:Human Papillomavirus DNA Tests; D052162:Human papillomavirus 16 / Q000235:genetics; D052161:Human papillomavirus 18 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis*; D008875:Middle Aged; D009426:Netherlands; D010045:Outpatients; D065006:Papanicolaou Test; D030361:Papillomavirus Infections / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D011230:Precancerous Conditions / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D011237:Predictive Value of Tests; D011446:Prospective Studies; D015203:Reproducibility of Results; D014218:Triage; D014626:Vaginal Smears; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000737:chemistry / Q000175:diagnosis* / Q000473:pathology / Q000821:virology
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen