P16INK4a immunohistochemistry improves the reproducibility of the histological diagnosis of cervical intraepithelial neoplasia in cone biopsies

Gynecol Oncol. 2008 Oct;111(1):120-4. doi: 10.1016/j.ygyno.2008.06.032. Epub 2008 Aug 9.


Objective: Cervical cancer is currently the most frequently occurring cancer among women in Mexico. Mexican cervical cancer prevention programs have been unsatisfactory in part because the tests used to diagnose precursor lesions have poor reproducibility. The implementation of specific biomarkers may overcome these limitations. Here, we analyzed whether immunohistochemistry for p16(INK4a) could improve the reproducibility of histopathological diagnoses of cervical precancerous lesions.

Methods: Serial sections of 78 specimens were stained for H&E and p16(INK4a) and independently interpreted by three Mexican pathologists. Specimens were interpreted and categorized in two ways: 1) four diagnostic categories including negative lesions, CIN1, CIN2, and CIN3, or 2) two diagnostic categories; either lesions that do not require therapy (negative, CIN1), or lesions that require therapy (>or=CIN2). The agreement in diagnoses between pairs of observers was evaluated by kappa statistics.

Results: The best concordance in diagnosing was observed with two categories and p16(INK4a) staining. Interestingly, the overall diagnostic discordances of higher than one CIN grade were 26.1% for H&E and 9.20% for p16(INK4a) (P<0.001). Using four diagnostic categories, weighted kappa values for each pair of observers were 0.28, 0.15, and 0.36 for H&E and 0.34, 0.35, and 0.60 for p16(INK4a) stains. Using two diagnostic categories, kappa values were 0.36, 0.12, and 0.18 for H&E and 0.59, 0.70, and 0.59, p16(INK4a) stains.

Conclusion: These data show that p16(INK4a) immunohistochemistry substantially improved the reproducibility of interpreting histological slides. This approach may result in more accurate diagnoses and improved clinical management of patients with cervical precancerous lesions in Mexico and elsewhere.

MeSH terms

  • Adult
  • Biomarkers, Tumor / metabolism*
  • Conization
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Eosine Yellowish-(YS) / chemistry
  • Female
  • Hematoxylin / chemistry
  • Humans
  • Immunohistochemistry
  • Neoplasm Staging
  • Observer Variation
  • Reproducibility of Results
  • Staining and Labeling / methods
  • Uterine Cervical Dysplasia / diagnosis*
  • Uterine Cervical Dysplasia / metabolism
  • Uterine Cervical Dysplasia / pathology
  • Uterine Cervical Neoplasms / diagnosis*
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology


  • Biomarkers, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16
  • Eosine Yellowish-(YS)
  • Hematoxylin