p16INK4a immunohistochemistry in cervical biopsy specimens: A systematic review and meta-analysis of the interobserver agreement

Am J Clin Pathol. 2014 Dec;142(6):767-72. doi: 10.1309/AJCP3TPHV4TRIZEK.


Objectives: The interpretation of cervical biopsy specimens guides management of women with suspected cervical cancer precursors. However, morphologic evaluation is subjective and has low interobserver agreement. Addition of p16(INK4a) immunohistochemistry may improve interpretation.

Methods: We performed a systematic review and meta-analysis of published data on interobserver agreement of p16(INK4a) positivity using p16(INK4a) immunohistochemistry and of cervical intraepithelial neoplasia grade 2 (CIN2+) and CIN grade 3 (CIN3+) classification using H&E morphology in conjunction with p16(INK4a) in comparison with H&E morphology alone.

Results: The literature search revealed five eligible articles. The results show strong agreement of pathologists' interpretation of cervical biopsy specimens as p16(INK4a) positive or negative (pooled κ = 0.90; 95% confidence interval [CI], 0.88-0.92) and significantly higher agreement for a CIN2+ diagnosis with H&E morphology in conjunction with p16(INK4a) (κ = 0.73; 95% CI, 0.67-0.79) compared with H&E morphology alone (κ = 0.41; 95% CI, 0.17-0.65). Also, a slightly higher agreement for CIN3+ can be observed (κ = 0.66; 95% CI, 0.39-0.94 for H&E morphology in conjunction with p16(INK4a) and κ = 0.61; 95% CI, 0.44-0.78 for H&E morphology alone), but this difference was not statistically significant.

Conclusions: The published literature indicates improved interobserver agreement of the diagnosis of CIN2+ with the conjunctive use of H&E morphology with p16(INK4a) immunohistochemistry compared with H&E morphology alone.

Keywords: Agreement; Cervical intraepithelial neoplasia; Histopathology; Reproducibility; p16INK4a.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Biomarkers, Tumor / analysis*
  • Cyclin-Dependent Kinase Inhibitor p16 / analysis*
  • Female
  • Humans
  • Immunohistochemistry
  • Observer Variation
  • Uterine Cervical Dysplasia / diagnosis*
  • Uterine Cervical Dysplasia / epidemiology
  • Uterine Cervical Neoplasms / diagnosis*
  • Uterine Cervical Neoplasms / epidemiology


  • Biomarkers, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16