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High-Risk HPV Infection and CIN Grade Correlates to the Expression of c-myc, CD4+, FHIT, E-cadherin, Ki-67, and p16INK4a

Samir, Raghad MD1; Asplund, Anna PhD2; Tot, Tibor PhD3; Pekar, Gyula MD3; Hellberg, Dan MD, PhD4,5

Journal of Lower Genital Tract Disease: October 2011 - Volume 15 - Issue 4 - p 280-286
doi: 10.1097/LGT.0b013e318215170c
Original Articles

Objective: This study aimed to investigate correlations between a panel of biomarkers/tumor markers and high-risk (HR) human papillomavirus (HPV)-positive versus HR-HPV-negative cervical lesions.

Materials and Methods: The study included 188 women who consecutively attended a colposcopy clinic because of PAP smears suggesting cervical intraepithelial neoplasia (CIN), and 40 women with normal vaginal cytology. Tissue microarray blocks were prepared from representative cervical cone or punch biopsies. Sections were stained for 12 biological markers, previously shown to be relevant in cervical neoplasms, and expression was correlated to the presence or absence of HR-HPV in cervical lesions.

Results: No correlations between expression of biomarkers and HPV status were found in normal epithelium. Expression of c-myc, CD4+, Ki-67, and p16INK4a correlated significantly to HR-HPV-infected epithelium compared with HR-HPV-negative epithelium. When adjustment was made for CIN grade, only the expression of Ki-67 correlated significantly with HPV status and CIN grade. Human papillomavirus status was stratified to normal epithelium, low-grade CIN, and high-grade CIN. Fragile histidine triad (FHIT), E-cadherin, Rb, Ki-67, and p16INK4a expression was significantly increased in HPV-positive tissue by increasing CIN grade. No correlation to tumor marker expression was observed in the HPV-negative tissue.

Conclusions: This study described correlations, previously not investigated, between HPV status and tumor marker expression, that is, E-cadherin, Rb, and fragile histidine triad. Surprisingly, p16INK4a was not, although Ki-67 expression was, independently correlated to HPV positivity. The results of this study suggest that p16INK4a instead correlates independently with increasing CIN grade.

Correlations between human papillomavirus status and expression of E-cadherin, Rb, FHIT, p16INK4a, and Ki-67 were found but could be confounded by increasing cervical intraepithelial neoplasia grade.

1Department of Obstetrics and Gynecology, Falun Hospital, Falun; 2Department of Genetics and Pathology, Uppsala University, Uppsala; 3Department of Pathology and Clinical Cytology, Falun Hospital, Falun; 4Center for Clinical Research, Falun; and 5Department of Women's and Children's Health, Akademiska Hospital, Uppsala University, Uppsala, Sweden

Reprint requests to: Raghad Samir, MD, Department of Obstetrics and Gynecology, Falun Hospital, 79182 Falun, Sweden. E-mail

©2011The American Society for Colposcopy and Cervical Pathology