Use of Cytology, E6/E7 mRNA, and p16INK4a-Ki-67 to Define the Management of Human Papillomavirus (HPV)-Positive Women in Cervical Cancer Screening

Am J Clin Pathol. 2016 Jan;145(1):35-45. doi: 10.1093/ajcp/aqv019.


Objectives: We measured the accuracy of p16(INK4a)-Ki67 (CINtec PLUS, Roche, Mannheim, Germany), and E6/E7mRNA (types 16/18/31/33/45 NucliSENS easyQ, bioMérieux, Boxtel, The Netherlands) as triage test, alone and combined with cytology.

Methods: Six thousand two hundred and seventy two women were recruited in a population-based screening using HPV DNA as primary test; 396 were positive and were tested for cytology and biomarkers. All tests were performed on the same sample. Cytology-positive women were referred to colposcopy; cytology-negative women were referred to one-year HPV re-testing. The endpoint was CIN2+ at baseline or follow up.

Results: Sensitivity was 77.6% (95% confidence interval (CI) 65.3-86.7) and 53.2% (95%CI: 40.3-65.4) for cytology at atypical squamous cells of undetermined significance (ASC-US) and high-grade threshold, and 87.6% (95%CI:75.7-93.6), and 80.8% (95%CI: 67.6-89.8) for p16INK4a-Ki67, and E6/E7mRNA, respectively. Colposcopy referral was 36% (95%CI: 31.2-40.9) and 11.2% (95%CI: 7.8-14.1) for cytology at ASC-US and high-grade threshold, respectively, and 36.0% (95%CI: 29.9-29.6), and 47.5% (95%CI: 32.5-42.4) for p16(INK4a)-Ki67, and E6/E7mRNA, respectively. Strategies referring high-grade cytology or biomarker positive women to colposcopy reached sensitivity close to 100%, with modest increase in colposcopy referral.

Conclusions: The high sensitivity of combined strategies probably allows longer intervals in HPV-positive, triage-negative women.

Keywords: Accuracy; Biomarkers; Cervical cancer; E6/E7 mRNA; HPV; Screening; p16INK4a.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cyclin-Dependent Kinase Inhibitor p16 / analysis*
  • Cytodiagnosis
  • Early Detection of Cancer
  • Female
  • Humans
  • Ki-67 Antigen / analysis*
  • Middle Aged
  • Papillomaviridae / isolation & purification*
  • Papillomavirus Infections / diagnosis*
  • Sensitivity and Specificity
  • Uterine Cervical Neoplasms / diagnosis*


  • Cyclin-Dependent Kinase Inhibitor p16
  • Ki-67 Antigen