Cytological screening for cervical cancer or its precursors using Papanicolaou's smear test (Pap test) has been highly efficient to reduce the morbidity and mortality of cervical cancer. However, evaluation of the Pap test relies on subjective diagnostic parameters and is affected by a high rate of false-positive and false-negative results. More objective diagnostic parameters to identify truly dysplastic or neoplastic cells in cervical smears as well as in cervical biopsy samples would therefore avoid insecurity for many patients and the high screening costs associated with repeated testing. Cervical dysplasia is induced by persistent infections through highrisk types of human papillomaviruses (HPVs). Outgrowth of dysplastic lesions is triggered by increasing expression of two viral oncogenes, E6 and E7, which both interact with various cell cycle-regulating proteins. Among these is the retinoblastoma gene product pRB, which is inactivated by E7. pRB inhibits transcription of the cyclin-dependent kinase inhibitor gene p16 INK4a . Increasing expression of the viral oncogenes in dysplastic cervical cells might thus be reflected by increased expression of p16 INK4a . In line with this hypothesis, we observed marked overexpression of p16 INK4a in all cervical intraepithelial neoplasm (CIN) I lesions (n ؍ 47) except those associated with low-risk HPV types (n ؍ 7), all CIN II lesions (n ؍ 32), all CIN III lesions (n ؍ 60) and 58 of 60 invasive cervical cancers. In contrast, no detectable expression of p16 INK4a was observed in normal cervical epithelium (n ؍ 42), inflammatory lesions (n ؍ 48) and low-grade cervical lesions (CIN I) associated with low-risk HPV types (n ؍ 7). Dysplastic cells could also be identified in cervical smears using a specific p16 INK4a monoclonal antibody. These data demonstrate that p16 INK4a is a specific biomarker to identify dysplastic cervical epithelia in sections of cervical biopsy samples or cervical smears.
It has been repeatedly shown that there is a substantial lack of interobserver reproducibility in the histologic diagnosis of cervical intraepithelial neoplasia (CIN), which might be improved by a more specific diagnostic biomarker. Cervical cancer and CIN, but not other cervical epithelia, express high levels of the cyclin-dependent kinase inhibitor p16, suggesting that staining for this marker could help to more precisely identify CIN in tissue sections and therefore reduce variation in interpretation of cervical lesions. To test this hypothesis, 194 cervical cone biopsy samples were selected from a routine histopathology laboratory. Two consecutive sections from each biopsy were stained with hematoxylin and eosin and with a p16 -specific monoclonal antibody, respectively. Five experienced cervical pathologists examined the slides. The agreement in the diagnosis between pairs or groups of observers was calculated by kappa statistics. Significant discrepancies were observed in the diagnostic interpretation of hematoxylin and eosin-stained slides, particularly for low-grade lesions (kappa value 0.60 [95% confidence interval 0.58-0.63]). There was significantly better agreement in the interpretation of p16 expression (kappa value 0.91 [95% confidence interval 0.84-0.99]). Expression of p16 was restricted to CIN 2/CIN 3, CIN 1 associated with high-risk human papillomavirus, or cervical cancer. p16 immunostaining allowed precise identification of even small CIN or cervical cancer lesions in biopsy sections and helped to reduce interobserver variation in the histopathologic interpretation of cervical biopsy specimens. Thus, p16 immunohistochemistry can reduce false-negative and false-positive biopsy interpretation and thereby significantly improve cervical (pre)-cancer diagnosis.
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