Predictive value of p16/Ki-67 immunocytochemistry for triage of women with abnormal Papanicolaou test in cervical cancer screening: a systematic review and meta-analysis

Ann Saudi Med. 2016 Jul-Aug;36(4):245-51. doi: 10.5144/0256-4947.2016.245.


Background: The Papanicolaou (Pap) test is one screening strategy used to prevent cervical cancer in developed countries. The p16/Ki-67 immunocytochemistry is a triage test performed on Pap smears in women with atypical squamous cells of undetermined significance (ASCUS) or low grade squamous intraepithelial lesion.

Objective: Our objective was to review studies investigating the diagnostic performance of p16/Ki-67 dual stain for triage of women with abnormal Pap tests.

Design: We conducted a systematic review and meta-analysis of diagnostic test accuracy studies.

Settings: We followed the protocol of systematic review of diagnostic accuracy studies.

Patients and methods: We searched PubMed, The Cochrane Library, BioMed Central, and for relevant studies. We included research that assessed the accuracy of p16/Ki-67 dual stain and high risk human papillomavirus testing for triage of abnormal Pap smears. Review articles and studies that provided insufficient data to construct 2.2 tables were excluded. Data synthesis was conducted using a random-effects model.

Main outcome measures: Sensitivity and specificity.

Results: In seven studies encompassing 2628 patients, the pooled sensitivity and specificity of p16/Ki-67 for triage of abnormal Pap smear results were 0.91 (95% CI, 0.89 to 0.93) and 0.64 (95% CI, 0.62 to 0.66), respectively. No study used a case-control design. A subgroup analysis involving liquid-based cytology showed a sensitivity of 0.91 (95%CI, 0.89 to 0.93) and specificity of 0.64 (95%CI, 0.61 to 0.66).

Conclusions: Our meta-analysis of p16/Ki-67 dual stain studies showed that the test achieved high sensitivity and moderate specificity for p16/Ki-67 immunocytochemistry for high-grade squamous intraepi.thelial lesion and cervical cancer. We suggest that p16/Ki-67 dual stain might be a reliable ancillary method identifying high-grade squamous intraepithelial lesions in women with abnormal Pap tests.

Limitations: No study in the meta-analysis examined the accuracy of the p16/Ki-67 dual stain for inter.pretation of glandular neoplasms.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Atypical Squamous Cells of the Cervix / chemistry*
  • Cyclin-Dependent Kinase Inhibitor p16 / analysis*
  • Early Detection of Cancer / methods*
  • Female
  • Humans
  • Ki-67 Antigen / analysis*
  • Papanicolaou Test
  • Predictive Value of Tests
  • Squamous Intraepithelial Lesions of the Cervix / diagnosis*
  • Squamous Intraepithelial Lesions of the Cervix / metabolism
  • Triage
  • Uterine Cervical Neoplasms / chemistry*
  • Uterine Cervical Neoplasms / diagnosis*
  • Vaginal Smears


  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Ki-67 Antigen