Ki-67 and P16INK4A immunoexpression strongly correlates with increasing grade of CIN and HPV infection

Montse Verdú 1,3, Ruth Roman1, Carme Pubill3, Miquel Calvo 4, August Vidal 1,3 Beatriz García1, Marta González1, Natalia Rodón1 and Xavier Puig1,2,3.

1BIOPAT. Biopatologia Molecular, SL, Grup Assistència; 2Hospital de Barcelona SCIAS, Grup Assistència; 3Histopat Laboratoris and 4Statistics Department, Universitat de Barcelona. Barcelona, Spain.

Background: MIB-1 immunoquantitative features have been correlated with the grade of dysplasia in cervical epithelium, while P16 accumulation has been related to the presence of high grade intraepithelial lesions (HSIL) and detection of human papillomavirus (HPV). The aim of this study was to assess the value of these markers in assisting CIN grading.

Method: Our series included 7 normal cases, 8 HPV-suspicious, 42 CIN I, 31 CIN II, 35 CIN III and 2 invasive cervical squamous-cell carcinomas collected from 109 women. Immunohistochemical analysis of formalin-fixed, paraffin-embedded samples was performed by ABC immunoperoxidase staining, using mouse monoclonal antibodies Ki-67 and P16INK4A. Results were reviewed by two pathologists. MIB-1 was classified in three categories according to the extension of nuclear staining within the epithelial thickness. Nuclear or nuclear and cytoplasmic diffuse strong staining was considered positive for P16. The presence of HPV was assessed by a commercial PCR-based assay and typified by hybridization to a low density microarray.

Results: A highly significant association (p<0.0001) was observed using Kendall’s tau-c between increasing grade of CIN and MIB-1 expression. Further, Chi-squared analysis of the 2 by 2 contingency table proved MIB-1 especially useful in discriminating the presence of CIN (p=1.004e-09). Equally, a significant relation (p=2.2 e-16) was found between P16 immunoexpression and the presence of HSIL lesions, with 98% specificity, 98% positive predictive value and 78% negative predictive value. P16 accumulation was also indicative of the presence of HPV which was detected in 51 out of 53 P16 positive samples. Furthermore, 50 (98%) of these HPV positive cases contained High Risk HPV.

Conclusion: The combined use of these two markers provides a valuable tool in assessing the grade of CIN, the presence of HR-HPV infection and verifying the diagnosis of equivocal cases.

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Abstract exhibited at the:

3rd Intercontinental Congress of Pathology
Barcelona, Spain May, 2008

Abstract in:

Virchows Archiv 2008; 452 (suppl. 1): S82.