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Immunohistochemical Expression of p16^INK4a and bcl-2 According to HPV Type and to the Progression of Cervical Squamous Intraepithelial Lesions

Márcia C.M. Guimarães, Maria Alice G. Gonçalves, Christiane P. Soares, Jussara S.R. Bettini, Roberta A. Duarte and Edson G. Soares

Department of Pathology (MCMG,JSRB,EGS), Division of Clinical Immunology (MAGG), School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo Brazil; and Department of Clinical Analyses (CPS,RAD), School of Pharmaceutical Sciences of Araraquara, University of São Paulo State, Araraquara, Brazil

Correspondence to: Maria Alice Guimarães Gonçalves, Department of Pathology, School of Medicine of Ribeirão Preto, University of São Paulo Av. Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil. E-mail: epigin{at}uol.com.br or soarescp{at}hotmail.com

Inactivation of the cell cycle inhibitor gene p16MTS1 seems to be involved in human papillomavirus (HPV)-related carcinogenesis because E6 and E7 oncoproteins may impair p16^INK4a and, indirectly, bcl-2 functions. In this study, we analyzed the role of immunohistochemical expression of p16^INK4a and bcl-2 in HPV-infected cervical biopsies as prognostic markers of the progression of squamous intraepithelial lesion (SIL). Sixty-five cervical biopsies were stratified into two subgroups according to the second biopsy: 27 of them maintained a low-grade (LG)-SIL diagnosis, and 38 progressed from LG-SIL to high-grade (HG)-SIL. p16^INK4a and bcl-2 quantitative expression levels were measured by the immunoperoxidase method. PCR-DNA techniques were used to detect and type HPV. The Wilcoxon and Fisher exact tests were employed for the statistical analysis. In the group with an LG-SIL diagnosis at the second biopsy, no significant associations were found between p16^INK4a and bcl-2 expression and presence of HPV16/18. In the group that progressed to HG-SIL, a significant association was observed between p16^INK4a overexpression and HPV16/18 presence (p=0.021), but none with bcl-2 levels. It is concluded that immunohistochemical bcl-2 expression may not be useful for predicting the progression of HPV-related SIL. In contrast, p16^INK4a overexpression seemed to be associated with HPV 16 and 18, suggesting that it may be a good marker for predicting SIL progression.

(J Histochem Cytochem 53:509–516, 2005)

Key Words: human papillomavirus • p16^INK4a • bcl-2 • squamous intraepithelial • lesions • carcinogenesis

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