p16 INK4a immunostaining identifies occult CIN lesions in HPV-positive women

Int J Gynecol Pathol. 2009 Jan;28(1):90-7. doi: 10.1097/PGP.0b013e31817e9ac5.


To evaluate whether p16 staining could help to recognize underestimated cervical intraepithelial neoplasia (CIN) in women positive for high-risk human papillomavirus (HR-HPV) with negative biopsy. Out of 1,259 women undergoing a histologic study and a simultaneous HR-HPV detection using the Hybrid Capture 2 test, we selected all patients testing positive for HR-HPV and having a negative biopsy (n=139), as well as all women testing negative for HR-HPV with a biopsy of either CIN 1 (26 cases) or CIN 2 to 3 (11 cases). Of the remaining 1,083 women, we randomly selected for the purpose of controls, 50 cases negative for HR-HPV with negative biopsy and 100 cases positive for HR-HPV and with biopsy of CIN (50 CIN 1, 50 CIN 2-3). In all cases, immunohistochemical staining for p16 and a second evaluation of the initial biopsy was carried out. Thirty-four out of 139 biopsies (24.5%) testing positive for HR-HPV but having a negative biopsy were positive for p16. Thirty of these cases (21.6%) were classified as harboring a CIN (11 CIN 1, 19 CIN 2/3) after reevaluation. Both the number of cases reclassified as CIN of any grade, or as CIN 2/3, were significantly higher for cases with HR-HPV load above 100 relative light unit (P<0.005). Particular attention should be paid to biopsies from patients having positive Hybrid Capture 2. The risk of harboring undetected CIN of any type or CIN 2/3 is significantly higher for patients with high HR-HPV load. Immunostaining with p16 should be considered as a highly desirable addition to the histologic evaluation of cervical biopsy specimens in HR-HPV-positive women.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / analysis*
  • Cervical Intraepithelial Neoplasia / metabolism*
  • Cervical Intraepithelial Neoplasia / pathology
  • Cervical Intraepithelial Neoplasia / virology
  • Cyclin-Dependent Kinase Inhibitor p16 / biosynthesis*
  • Female
  • Humans
  • Immunohistochemistry
  • Middle Aged
  • Papillomaviridae
  • Papillomavirus Infections / metabolism*
  • Papillomavirus Infections / pathology
  • Papillomavirus Infections / virology
  • Uterine Neoplasms / metabolism*
  • Uterine Neoplasms / pathology
  • Uterine Neoplasms / virology


  • Biomarkers, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16