The natural history of cervical intraepithelial neoplasia: an argument for intermediate endpoint biomarkers

Cervical cancer is the second most common malignancy in women worldwide and remains a significant health problem for women, especially minority women in the United States. Despite morbid and costly treatment with whole pelvic radiotherapy, radical surgery, and chemotherapy, the overall survival remains 40%. While the epidemiological risk factors are well known, little is known of the pathobiology of cervical carcinogenesis. Prevention of cervical cancer and its precursors is an important objective. New strategies, both clinical and laboratory based, are desperately needed. Cellular and molecular characteristics of the pathobiology of cervical cancer and its precursors need to be quantified, thereby providing insights into the multistep process of cervical carcinogenesis, identifying those precancerous lesions at high risk for progression to invasion, providing potential targets for intervention, and providing intermediate end point biomarkers for chemopreventive therapies. The premise for this strategy in cervical cancer prevention is that squamous cancers of the female genital tract have a well defined preinvasive stage, and that carcinogenesis is a multistep genetic process which involves increasing dysregulation of proliferation and differentiation as lesions progress from normal to human papillomavirus infected tissue to cervical intraepithelial neoplasia to cancer.