p16 overexpression identifies HPV-positive vulvar squamous cell carcinomas

Am J Surg Pathol. 2006 Nov;30(11):1347-56. doi: 10.1097/01.pas.0000213251.82940.bf.


Two types of vulvar squamous cell carcinomas (VSCCs) are recognized according to their relationship to human papillomavirus (HPV). Basaloid or warty carcinomas are considered HPV-associated tumors, whereas differentiated keratinizing neoplasms are considered non-HPV-associated. Recently, immunohistochemical detection of p16 and p53 has been proposed to differentiate these 2 types of VSCCs. We conducted a histologic study with immunohistochemical evaluation of p16 and p53 and HPV detection and typing by polymerase chain reaction using 2 different sets of primers in 92 cases of VSCCs to evaluate the usefulness of immunohistochemistry in the classification of VSCCs and to describe the clinico-pathologic characteristics of both types of VSCCs. HPV was detected in 16/92 (17.4%) specimens, HPV16 being identified in 75% of positive cases. A significant number of discrepancies between histology and HPV detection were observed, with 37.5% of HPV-positive tumors being keratinizing and 9.2% of HPV-negative carcinomas showing basaloid or warty features. Diffuse positivity for p16 and p53 was observed in 100% and 6.2% of HPV-positive tumors and in 2.3% and 64.5% of HPV-negative neoplasms, respectively. The sensitivity and specificity of p16 immunostaining to detect HPV-associated carcinomas (100% and 98.7%, respectively) were better than those of histologic criteria (93.8% and 35.5%) and of p53 negative stain (62.5% and 93.4%). Vulvar intraepithelial neoplasia grade 3 of basaloid/warty type was identified in 53.8% HPV-positive tumors, including 3 keratinizing tumors. All these cases were p16 positive and p53 negative. Vulvar intraepithelial neoplasia grade 3 of differentiated type was observed in 45.6% of HPV-negative cases; 90.8% of them were positive for p53 but all were negative for p16. No differences in age, stage, or development of recurrence were observed between HPV-positive and negative tumors. In summary, the current morphologic criteria to discriminate HPV-positive and negative VSCCs have a significant overlap. Immunostaining for p16 is a reliable marker for HPV-positive VSSCs, which improves the results of histologic classification.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / analysis*
  • Carcinoma, Squamous Cell / classification
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / virology*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • DNA Primers
  • Female
  • Humans
  • Immunohistochemistry
  • Papillomavirus Infections / complications*
  • Papillomavirus Infections / metabolism
  • Precancerous Conditions / virology
  • Sensitivity and Specificity
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Virus Infections / complications
  • Tumor Virus Infections / metabolism
  • Vulvar Neoplasms / classification
  • Vulvar Neoplasms / metabolism
  • Vulvar Neoplasms / virology*


  • Biomarkers, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA Primers
  • Tumor Suppressor Protein p53