P16INK4 expression in precursor lesions of squamous cell cervical cancer related to the presence of HPV-DNA

A.E.G Godoy,F.H Oliveira,L.B Moura,S Calegari,E.P Serafini,J Mandelli

doi:10.1590/s0100-879x2008000700006

A.E.G Godoy, F.H Oliveira + Show 4 more

Open Access

https://doi.org/10.1590/s0100-879x2008000700006

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Abstract

The purpose of the present study was to identify the expression of p16INK4 in cervical cancer precursor lesions by immunohistochemistry and to correlate it with lesion grade and presence of human papillomavirus (HPV) infection. Cervical specimens from 144 women seen consecutively at the gynecology outpatient clinic of our institution from December 2003 to May 2005 were analyzed by cytopathology, histopathology, polymerase chain reaction for HPV-DNA, and p16INK4 immunostaining. Histologically normal biopsies, HPV-DNA negative by polymerase chain reaction, were used as control. HPV-DNA prevalence, including the control group, was 68.1% and the prevalence of p16INK4 expression was 55.0%. The percentage of cells stained by p16INK4 ranged from 10 to 100%, both in the group consisting of cervical intraepithelial neoplasia (CIN)1/HPV specimens and in the group of CIN2/CIN3 specimens with P value of 0.0001. p16INK4 expression was 48.3% in the CIN1/HPV group, as opposed to 94.3% in the CIN2/CIN3 group (P = 0.001), showing a statistically significant difference between the two groups. The quantitative method used here is simple and less subjective than the different semiquantitative methods described in the literature. In view of the different definitions of a p16INK4-positive case, it is almost impossible to compare the findings reported by different investigators. This study confirms the association between p16INK4 and CIN2 and CIN3 lesions. Moreover, it shows that some low grade lesions expressed high levels of this protein. This may indicate that such low grade lesions may be predisposed to progress to high grade lesions. This means that p16INK4 may be a strong marker for "neoplastic lesions" induced by HPV and not just an infection marker.

Highlights

Cervical cancer is one of the most frequent neoplasias in the world, including Brazil, and is responsible for the death of thousands of women every year
This may indicate that CIN1 and CIN2/CIN3 represent different disease processes, CIN1 being the morphological manifestation of Human papillomavirus (HPV) infection, while CIN2/CIN3 represents, in addition to the morphological manifestation of HPV infection, www.bjournal.com.br the true pre-malignant lesion of cervical carcinoma [3,9,10]
Histopathological specimens were reviewed and classified as normal or presenting HPV infection, CIN1, CIN2 and CIN3 according to the morphological criteria described by Richart [19]

Summary

Introduction

Cervical cancer is one of the most frequent neoplasias in the world, including Brazil, and is responsible for the death of thousands of women every year. The traditional concept regarding the natural history of cervical cancer considers CIN1, CIN2 and CIN3 to be stages of a single progressive disease This concept has been challenged, since recent studies have shown that in most women with a CIN2 or CIN3 diagnosis, no alterations suggesting CIN1 were detected in previous tests. This may indicate that CIN1 and CIN2/CIN3 represent different disease processes, CIN1 being the morphological manifestation of HPV infection, while CIN2/CIN3 represents, in addition to the morphological manifestation of HPV infection, www.bjournal.com.br the true pre-malignant lesion of cervical carcinoma [3,9,10]. Interaction between these genes and the host leads to cell cycle deregulation as shown by the abnormal expression of proteins associated with the cell cycle, such as Ki-67, cyclin E and p16INK4 [11]

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