title: Prospective evaluation of p16/Ki-67 dual-stained cytology for managing women with abnormal Papanicolaou cytology: PALMS study results.
abstract: BACKGROUND
  Testing for the presence of the human papillomavirus (HPV) is widely accepted for triaging Papanicolaou cytology results categorized as atypical squamous cells of undetermined significance (ASC-US). In contrast, HPV testing has limited use in triaging cytological low-grade squamous intraepithelial lesions (LSILs) due to prevalence rates of typically >80%. In the current study, the authors assessed the diagnostic performance of p16/Ki-67 dual-stained cytology in triaging ASC-US and LSIL cases within the prospective, multicentric Primary ASC-US LSIL Marker Study (PALMS).
  
  
  METHODS
  A total of 575 ASC-US cases and 529 LSIL cases from a cohort of 27,349 women who were prospectively enrolled into the PALMS study in 5 European countries were tested with p16/Ki-67 dual-stained cytology and Hybrid Capture 2 (HC2) HPV testing. Colposcopy-guided biopsy results of cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) were used as clinical endpoints.
  
  
  RESULTS
  p16/Ki-67 dual-stained cytology demonstrated comparable (ASC-US: 94.4% for dual-stained cytology vs 100% for HC2 testing; P = .317) or lower (LSIL: 85.7% for dual-stained cytology vs 98.4% for HC2 testing; P = .005) sensitivity for CIN2+, but higher levels of specificity compared with HC2 HPV testing in both ASC-US (78.7% vs 60.4%; P<.001) and LSIL (53.3% vs 15.6%; P<.001) cases. Positive predictive values for CIN2+ were substantially higher for dual-stained cytology versus HC2 HPV testing, especially in LSIL, and in ASC-US cases for women aged <30 years.
  
  
  CONCLUSIONS
  The clinical usefulness and efficiency of triaging women with ASC-US or LSIL Papanicolaou cytology results by p16/Ki-67 dual-stained cytology testing has been confirmed in this prospective, pan-European study. The high positive predictive value of dual-stained cytology for the presence of high-grade CIN may help to reduce the number of unnecessary colposcopy referrals.
authors.affiliation: Laboratoire Cerba, Cergy Pontoise, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bergeron
authors.affiliation: CytoMol, Frankfurt, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Ikenberg
authors.affiliation: European Institute of Oncology, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Sideri
authors.affiliation: North Bristol NHS Trust, Bristol, United Kingdom.
authors.forename: Karin
authors.initials: K
authors.lastname: Denton
authors.affiliation: Algemeen Medisch Laboratorium BVBA, Sonic Healthcare, Antwerp, Belgium.
authors.forename: Johannes
authors.initials: J
authors.lastname: Bogers
authors.affiliation: synlab MVZ Pathologie Mannheim GmbH, Mannheim, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schmidt
authors.affiliation: Department of Pathology, Hospital del Mar, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Alameda
authors.affiliation: Acomed statistik, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Keller
authors.affiliation: Roche mtm laboratories, Mannheim, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Rehm
authors.affiliation: Roche mtm laboratories, Mannheim, Germany.|Ventana Medical Systems Inc, Tucson, Arizona.
authors.forename: Ruediger
authors.initials: R
authors.lastname: Ridder
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D003581:Cytodiagnosis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism*; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D011446:Prospective Studies; D012372:ROC Curve; D065310:Squamous Intraepithelial Lesions of the Cervix / Q000175:diagnosis* / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D014626:Vaginal Smears; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen
keywords: CINtec PLUS; Primary ASC-US LSIL Marker Study (PALMS); atypical squamous cells of undetermined significance (ASC-US); cervical cytology; human papillomavirus (HPV); low-grade squamous intraepithelial lesion (LSIL); p16/Ki-67 dual-stained cytology; triage