The clinical impact of using p16(INK4a) immunochemistry in cervical histopathology and cytology: an update of recent developments

Int J Cancer. 2015 Jun 15;136(12):2741-51. doi: 10.1002/ijc.28900. Epub 2014 May 12.


Cervical cancer screening test performance has been hampered by either lack of sensitivity of Pap cytology or lack of specificity of Human Papillomavirus (HPV) testing. This uncertainty can lead to unnecessary referral and treatment, which is disturbing for patients and increases costs for health care providers. The identification of p16(INK4a) as a marker for neoplastic transformation of cervical squamous epithelial cells by HPVs allows the identification of HPV-transformed cells in histopathology or cytopathology specimens. Diagnostic studies have demonstrated that the use of p16(INK4a) immunohistochemistry substantially improves the reproducibility and diagnostic accuracy of histopathologic diagnoses. p16(INK4a) cytology has substantially higher sensitivity for detection of cervical precancer in comparison to conventional Pap tests. Compared to HPV DNA tests, immunochemical detection of p16(INK4a) -stained cells demonstrates a significantly improved specificity with remarkably good sensitivity. About 15 years after the initial observation that p16(INK4a) is overexpressed in HPV-transformed cells we review the accumulated clinical evidence suggesting that p16(INK4a) can serve as a useful biomarker in the routine diagnostic work up of patients with HPV infections and associated lesions of the female anogenital tract.

Keywords: HPV; cervical cancer; cervical pathology; early detection; p16INK4a.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Cytodiagnosis / methods
  • Female
  • Host-Pathogen Interactions
  • Humans
  • Immunohistochemistry / methods*
  • Papillomaviridae / physiology
  • Papillomavirus Infections / diagnosis
  • Papillomavirus Infections / metabolism*
  • Papillomavirus Infections / virology
  • Sensitivity and Specificity
  • Uterine Cervical Neoplasms / diagnosis
  • Uterine Cervical Neoplasms / metabolism*
  • Uterine Cervical Neoplasms / virology


  • Cyclin-Dependent Kinase Inhibitor p16