Traditional and new molecular methods for early detection of cervical cancer

Abstract

Disadvantages of the traditional Papanicolaou-method for the cytological detection of cervical carcinomas and their precursors can be overcome by the use of specific molecular markers for nuclear attypicality. High grade HR-HPV induced cervical dysplasia is initiated by deregulated expression of viral oncogenes in replicating epithelial stem cells. Here, the E6-E7 gene products gain control of cell cycle and mitotic activity first and induce multistep mutagenesis with severe genomic instability in successin. The detailed molecular analysis of these activities has allowed the development of biomarkers for dysplastic cervical cells. The marked over-expression of the cyclin dependent kinase inhibitor p16INK4a is regularly observed in HR-HPV induced malignant lesions and indicates an active expression of the viral oncogene E7 in dysplastic cells. Morphologically, these molecular deregulations are reflected mainly in an altered nuclear-cytoplasmic ratio, anisonucleosis, and hyperchromasia. With p16INK4a immunostaining--as reported in the literature--dysplastic and atypical cells can be easily detected even under low magnification and differentiated by higher magnification from occasional positive atrophic or metaplastic cells by their atypical nuclear structure. In questionable cases the additional use of proliferation markers could eliminate false interpretation. The results with these new molecular techniques can by further optimized by applying the ThinPrep-method for the preparation of the cytological slides to ensure overlying blood, mucus or inflammatory cells do not mask atypical cells. With these new methods we can expect to lower the rate of false-positive and false-negative cytology tests as experienced with the traditional Papanicolaou-method, of not eliminate them completely, gaining thereby great advantages for patients and for cost-efficiency.