Molecular basis for advances in cervical screening

Human papillomaviruses (HPVs) cause cervical lesions, which can, in some instances, progress to high-grade neoplasia and cancer. Around half a million cases of cervical cancer occur each year, with most occurring in developing countries where cervical cancer is a major cause of cancer-related death. The reduction in cervical cancer incidence in developed countries is largely attributed to the introduction of cervical screening. Cervical screening currently depends on the identification by cytology of abnormalities in cells taken from the surface of the cervix. The standard Pap test was developed >50 years ago, and despite modifications, still forms the basis of the test currently in use in most routine screening laboratories. Advances in our understanding of the molecular mechanisms that lead to the development of cervical cancer have been slow to impact on screening, despite the relatively high false-negative rates that can be associated with the conventional Pap smear. Improvements in screening strategies fall into a number of categories. Methods that improve cell presentation and attempt to eliminate artefacts/obscuring debris can be combined with image analysis systems in order to enhance diagnostic accuracy. Such approaches still rely on cytological evaluation and do not incorporate advances in our knowledge of how HPV causes cancer. By contrast, markers of virus infection or cell cycle entry, particularly those that offer some degree of prognostic significance, may be able to highlight abnormal cells more reliably than cytology, and could be combined with cytology to improve the detection rate. Our understanding of the molecular biology of HPV infection and the organization of the HPV life-cycle during cancer progression provides a rational basis for marker selection. The general assumption that persistent active infection by high-risk HPV types is the true precursor of cervical cancer provides the rationale for HPV DNA testing in conjunction with enhanced cytology, while the development of RNA-based approaches should allow active infections to be distinguished from those that are latent. The detection in superficial cells of marker combinations at the level of RNA or protein has the potential to predict disease status more precisely than the detection of markers in isolation. There is also a need for better prognostic markers if the predictive value of screening is to be improved. The potential to control infection by vaccination should reduce the incidence of HPV-associated neoplasia in the population, and this may cause a change in the way that screening is carried out. Nevertheless, the lack of a therapeutic vaccine, and the difficulties associated with eliminating infection by multiple high-risk HPV types, means that some form of screening will still be required as a preventive measure for the control of cervical cancer for the foreseeable future.