Interobserver reproducibility and accuracy of p16/Ki-67 dual-stain cytology in cervical cancer screening

Cancer Cytopathol. 2014 Dec;122(12):914-20. doi: 10.1002/cncy.21473. Epub 2014 Aug 12.

Abstract

Background: Dual-stain cytology for p16 and Ki-67 has been proposed as a biomarker in cervical cancer screening. The authors evaluated the reproducibility and accuracy of dual-stain cytology among 10 newly trained evaluators.

Methods: In total, 480 p16/Ki-67-stained slides from human papillomavirus-positive women were evaluated in masked fashion by 10 evaluators. None of the evaluators had previous experience with p16 or p16/Ki-67 cytology. All participants underwent p16/Ki-67 training and subsequent proficiency testing. Reproducibility of dual-stain cytology was measured using the percentage agreement, individual and aggregate κ values, as well as McNemar statistics. Clinical performance for the detection of cervical intraepithelial neoplasia grade 2 or greater (CIN2+) was evaluated for each individual evaluator and for all evaluators combined compared with the reference evaluation by a cytotechnologist who had extensive experience with dual-stain cytology.

Results: The percentage agreement of individual evaluators with the reference evaluation ranged from 83% to 91%, and the κ values ranged from 0.65 to 0.81. The combined κ value was 0.71 for all evaluators and 0.73 for cytotechnologists. The average sensitivity and specificity for the detection of CIN2+ among novice evaluators was 82% and 64%, respectively; whereas the reference evaluation had 84% sensitivity and 63% specificity, respectively. Agreement on dual-stain positivity increased with greater numbers of p16/Ki-67-positive cells on the slides.

Conclusions: Good to excellent reproducibility of p16/Ki-67 dual-stain cytology was observed with almost identical clinical performance of novice evaluators compared with reference evaluations. The current findings suggest that p16/Ki-67 dual-stain evaluation can be implemented in routine cytology practice with limited training.

Keywords: Ki-67; Papanicolaou test; cervical cancer screening; cytology; human papillomavirus; p16; reproducibility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Squamous Cell / diagnosis*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / virology
  • Cervical Intraepithelial Neoplasia / diagnosis*
  • Cervical Intraepithelial Neoplasia / metabolism
  • Cervical Intraepithelial Neoplasia / virology
  • Colposcopy
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cytodiagnosis
  • Early Detection of Cancer*
  • Female
  • Follow-Up Studies
  • Humans
  • Ki-67 Antigen / metabolism*
  • Neoplasm Grading
  • Neoplasm Proteins / metabolism*
  • Observer Variation
  • Papillomaviridae / isolation & purification
  • Papillomavirus Infections / diagnosis
  • Papillomavirus Infections / metabolism
  • Papillomavirus Infections / virology
  • Prognosis
  • Reference Standards
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Staining and Labeling
  • Uterine Cervical Neoplasms / diagnosis*
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / virology
  • Vaginal Smears

Substances

  • Biomarkers, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16
  • Ki-67 Antigen
  • Neoplasm Proteins
  • P16 protein, human