P16 expression in relation to human papillomavirus in liquid-based cervical smears.
OBJECTIVE
At present, a simple and reliable cervical cancer screening test remains to be perfected. As overexpression of the protein p16 is correlated with the presence of high-risk HPV in malignant cervical lesions, this protein has been proposed as a surrogate marker of high-risk HPV infection in cervical cancer screening. Since high-risk viral DNA integration is necessary for neoplastic progression, we aimed to examine the expression of p16 in relation to the physical status of HPV (integrated or episomal) on liquid-based cervical smears.


METHODS
For each of the 241 liquid-based cervical smear included in our study, we realized a Pap test. Residual cells were processed for in situ hybridization with mucosal HPV DNA probes and for immunocytochemistry with an anti-p16 antibody. Integrated or episomal copies of HPV DNA were detected as dotted or diffuse signals, respectively.


RESULTS
In high-grade intraepithelial lesions, both the integrated form of high-risk HPV and overexpression of p16 were detected. However, we observed the presence of some p16-positive/HPV-negative normal and ASCUS smears. Moreover, some p16-negative ASCUS smears and low-grade intraepithelial lesions harbored episomal high-risk HPV.


CONCLUSIONS
If p16 was used as a surrogate marker of high-risk HPV infection, some women would be scored negative in spite of the presence of high-risk HPV. These women are more likely to undergo cancer progression, but no follow-up would be proposed to them in that screening pathway. A possible compromise for the triage of abnormal cervical smears should be a combination of both HPV and p16 testing.
Samama
Brigitte
B
Institut d'Histologie, Faculté de Médecine, Université Louis Pasteur, Strasbourg, France. Brigitte.Samama@medecine.u-strasbg.fr
Schaeffer
Christiane
C
Boehm
Nelly
N
D000328:Adult; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization; D009363:Neoplasm Proteins / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000175:diagnosis / Q000378:metabolism*; D013194:Staining and Labeling; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000821:virology*; D014626:Vaginal Smears / Q000379:methods
C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D009363:Neoplasm Proteins