Role of p16(INK4a) cytology testing as an adjunct to enhance the diagnostic specificity and accuracy in human papillomavirus-positive women within an organized cervical cancer screening program

Acta Cytol. 2012;56(5):506-14. doi: 10.1159/000338979. Epub 2012 Sep 27.

Abstract

Objective: We evaluated the performance of cytologic p16(INK4a) (p16) immunostaining within a cervical cancer screening program for the categories of atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LS after triage with high-risk human papillomavirus (HR-HPV) testing and atypical squamous cells, cannot exclude high-grade intraepithelial squamous lesion (ASC-H) and high-grade squamous intraepithelial lesion (HSIL). We also verified whether the routine introduction of p16 staining might enhance the specificity and positive predictive value (PPV) for cervical intraepithelial neoplasia grade 2 or higher (CIN2+) lesions predicted by a cytological screening test.

Study design: Performance of the p16 cytology test was estimated in 578 cytological samples, of which 213 were HR-HPV+ ASC-US, 186 were HR-HPV+ LSIL, 74 were ASC-H, 56 were HSIL-CIN2 and 49 were HSIL-CIN3. All samples had histological follow-up.

Results: In the ASC-US category, p16 sensitivity was 91% for CIN2+ and 100% for CIN3, while specificity was 64 and 58%, respectively, negative predictive value (NPV) was 96 and 100%, respectively, and PPV was 39%. In the LSIL category, sensitivity was 77 and 75%, respectively, for CIN2+ and CIN3, while specificity was 64 and 57%, NPV was 93 and 98% and PPV was 30%. Sensitivity for ASC-H and HSIL-CIN3 was 100% for CIN2+ and CIN3, while for HSIL-CIN2 it was 91 and 95%, respectively; NPV for ASC-H was 100%, and for HSIL-CIN2 it was 43 and 86%, respectively. Follow-up examinations of 8 cases diagnosed as p16+ ASC-H and HSIL-CIN3, but histologically negative or CIN1 on the first biopsy, showed 4 CIN2 and 4 CIN3 lesions.

Conclusions: Sensitivity, specificity, PPV and NPV confirm the importance of the utilization of p16 in the categories ASC-US and LSIL after triage with an HR-HPV test. In the ASC-H and HSIL-CIN3 lesions, p16 was shown to be an excellent marker for picking up CIN2+ lesions, especially in cases with cytohistological discordance.

MeSH terms

  • Adult
  • Biomarkers, Tumor / analysis
  • Cervix Uteri / chemistry
  • Cervix Uteri / pathology
  • Cervix Uteri / virology
  • Cyclin-Dependent Kinase Inhibitor p16 / analysis*
  • Cyclin-Dependent Kinase Inhibitor p16 / physiology
  • Early Detection of Cancer / methods
  • Female
  • Host-Pathogen Interactions
  • Humans
  • Immunohistochemistry
  • Middle Aged
  • Neoplasm Grading
  • Papillomaviridae / physiology
  • Papillomavirus Infections / diagnosis*
  • Papillomavirus Infections / metabolism
  • Papillomavirus Infections / virology
  • Predictive Value of Tests
  • Reproducibility of Results
  • Uterine Cervical Dysplasia / diagnosis*
  • Uterine Cervical Dysplasia / metabolism
  • Uterine Cervical Dysplasia / virology
  • Uterine Cervical Neoplasms / diagnosis*
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / virology

Substances

  • Biomarkers, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16