p16 Immunoreactivity in unusual types of cervical adenocarcinoma does not reflect human papillomavirus infection

Histopathology. 2010 Sep;57(3):342-50. doi: 10.1111/j.1365-2559.2010.03632.x. Epub 2010 Aug 19.


Aims: The association between human papillomavirus (HPV) and cervical carcinoma is well known, with HPV being identifiable in almost all cervical squamous carcinomas and most adenocarcinomas. However, the prevalence of HPV in unusual morphological types of cervical adenocarcinoma has not been investigated extensively. The aim was to determine HPV status in a series of primary cervical adenocarcinomas, enriched for unusual morphological types. The relationship between HPV and p16 immunoreactivity in these neoplasms was also investigated, as it is generally assumed that in cervical neoplasms diffuse p16 expression is predictive of the presence of high-risk HPV.

Methods and results: Sixty-three cervical adenocarcinomas, comprising those of usual type (n = 43), minimal deviation type (n = 4), gastric type (n = 3), intestinal type (n = 3), mesonephric type (n = 3), clear cell type (n = 4), serous type (n = 2) and hepatoid type (n = 1) underwent linear array HPV genotyping and immunohistochemistry for p16. Overall, HPV was identified in 32 of 56 cases (57%) in which sufficient DNA was present for analysis. The most common HPV types were 16 and 18, with these being identified in 20 and 18 cases, respectively, either alone or in combination. Seventy-eight per cent of usual-type adenocarcinomas were HPV-positive, as was the single serous carcinoma in which there was sufficient DNA for analysis. In contrast, all minimal deviation adenocarcinomas and those of gastric, intestinal, mesonephric and clear cell types were HPV-negative, as was the single hepatoid carcinoma. All usual-type adenocarcinomas exhibited p16 immunoreactivity (diffuse staining in all but one case), as did 11 of 20 of those of unusual morphological type (five focal, six diffuse).

Conclusions: Most, but not all, cervical adenocarcinomas of usual type contain HPV, but those of unusual morphological type are almost always HPV-negative. This has implications for the efficacy of HPV vaccination in the prevention of cervical adenocarcinoma. A significant proportion of cervical adenocarcinomas are p16-positive in the absence of HPV, illustrating that in these neoplasms diffuse p16 immunoreactivity is not a reliable surrogate marker of the presence of high-risk HPV.

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Adenocarcinoma / virology*
  • Biomarkers, Tumor / metabolism*
  • Cervix Uteri / metabolism
  • Cervix Uteri / pathology
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA, Viral / metabolism
  • Female
  • Humans
  • Immunohistochemistry
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology
  • Neoplasm Proteins / metabolism*
  • Papillomavirus Infections / complications*
  • Papillomavirus Infections / metabolism
  • Papillomavirus Infections / pathology
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / virology*


  • Biomarkers, Tumor
  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA, Viral
  • Neoplasm Proteins