p16^INK4a immunohistochemistry is a promising biomarker to predict the outcome of low grade cervical intraepithelial neoplasia: comparison study with HPV genotyping

Abstract

ObjectiveIn cervical intraepithelial neoplasia (CIN), p16INK4a immunohistochemistry has been reported to be a useful diagnostic biomarker. However, limited information is available about the association between the p16INK4a immunohistochemistry and the outcomes of CIN. Here, we report p16INK4a immunohistochemistry as an effective biomarker to predict the outcomes of CIN.Methodsp16INK4a immunohistochemistry was performed in patients with CIN from January 2000 to August 2009. Among these patients, we have performed a retrospective analysis of the medical records to evaluate the outcome of CIN 1-2 and performed statistical analysis to determine the correlation between p16INK4a expression and the outcomes. We also performed HPV genotyping and analyzed the relation between the infecting human papillomavirus (HPV) genotype and the outcomes.ResultsA total of 244 patients, including 82 with CIN 1, 60 with CIN 2, and 102 with CIN 3, were examined. The rate of p16INK4a overexpression increased with increasing CIN grade, 20.7% for CIN 1, 80.0% for CIN 2, and 89.2% for CIN 3, with significant differences between CIN 1 and CIN 2-3 group. In the 131 CIN 1-2 patients, the progression rate was significantly higher for the patients showing p16INK4a overexpression than for those not showing p16INK4a overexpression (p=0.005); the regression rate was also found to be significantly lower for the patients showing p16INK4a overexpression (p=0.003). High-risk HPV genotypes were detected in 73 patients (73.7%). Both progression and regression rates were not significantly different between the high-risk HPV-positive and HPV-negative groups (p=0.401 and p=0.381, respectively).Conclusionp16INK4a overexpression was correlated with the outcome of CIN 1-2, and p16INK4a is considered to be a superior biomarker for predicting the outcome of CIN 1-2 compared with HPV genotyping.

p16INK4aexpression as a potential marker of low-grade cervical intraepithelial neoplasia progression

“…Therefore, our study agrees with some authors , that CIN1 lesions with p16 INK4a staining had a significantly higher tendency to progress to a high‐grade lesion and those that showed no staining for p16 INK4A had a higher tendency to regress. So, p16 INK4a may represent a useful biomarker for cells with active expression of high risk HPV oncogenes, and can identify CIN1 lesions related to progression, thus, complementing morphology.…”

Expression of the Immunohistochemical Markers p16 and Ki-67 and Their Usefulness in the Diagnosis of Cervical Intraepithelial Neoplasms

“…16 Other studies characterize a positive case by continuous staining throughout the epithelium. 17 Genovés et al 18 and Nishio et al 19 considered both moderate and diffuse staining as a positive marker. K i -67 values vary greatly in the literature and exhibit the same methodological issues in the definition of positivity, which hinders the ability to directly compare values.…”

P16INK4A as a surrogate biomarker for human papillomavirus‐associated oropharyngeal carcinoma: Consideration of some aspects

“…The functional inactivation of Rb by E7 therefore results in the release of the transcriptional factor E2F from the Rb–E2F protein complex and the promotion of cell cycle progression, and also leads to release of the p16 INK4A gene from its transcriptional inhibition, causing p16 INK4A to be expressed at a high level . Because of this molecular event, the fact that p16 INK4A turned out to be substantially overexpressed in virtually all HPV‐transformed cells in cervical lesions, p16 INK4A expression has been used for distinguishing high‐risk from low‐risk HPV infection, for ancillary confirmation and grading of histological diagnosis of cervical intraepithelial neoplasia, and for predicting progression or regression of low‐grade cervical intraepithelial neoplasia . Considering the etiological link with HPV in HNSCCs, p16 INK4A expression has been detected in many HPV‐related HNSCCs .…”

“…(2)(3)(4) Because of this molecular event, the fact that p16 INK4A turned out to be substantially overexpressed in virtually all HPV-transformed cells in cervical lesions, p16 INK4A expression has been used for distinguishing high-risk from low-risk HPV infection, (5) for ancillary confirmation and grading of histological diagnosis of cervical intraepithelial neoplasia, (6) and for predicting progression or regression of low-grade cervical intraepithelial neoplasia. (7,8) Considering the etiological link with HPV in HNSCCs, p16 INK4A expression has been detected in many HPV-related HNSCCs. (9)(10)(11)(12)(13)(14) Those investigations suggest that overexpression of p16 INK4A is caused by HPV infection, induced by dysfunction of the Rb tumor suppressor gene; also, theoretically, tumors with a high level of p16 INK4A are the result of HPV infection.…”