Epidemiology of cervical intraepithelial neoplasia: the role of human papillomavirus.

The evidence implicating specific HPV types in the aetiology of cervical cancer is now strong enough to establish a causative role. HPV infection of the cervix affects the developing immature metaplastic cells of the transformation zone. Cervical neoplasia can be viewed as the interaction of high risk papillomavirus and immature metaplastic epithelium. Once maturity is reached, there is minimal risk of subsequent development of cervical squamous neoplasia. Exposure to HPV is an extremely common event, especially in young sexually active women. Yet, despite frequent HPV exposure at that phase of life in which the cervical transformation zone is at its most vulnerable, established expressed disease is relatively uncommon. Most studies in which the natural history of CIN is not altered by cervical biopsy reveal a progression rate from low to high grade CIN of less than one third. Where viral type is taken into account, however, the progression rate from normal but high risk HPV-infected cervical epithelium to CIN 2 or 3 is higher. Despite this, most cervical abnormalities will not transform into invasive cancer, even if left untreated. The variance between the high rate of HPV infection, the intermediate rate of CIN and the relatively low rate of cervical cancer establishes a stepwise gradient of disease of increasing severity with decreasing prevalence. In an immunocompetent host, HPV infection alone does not appear to be sufficient to induce the step from high grade CIN to invasion. Epidemiological studies indicating that HPV infection with oncogenic viral types is far more common than cervical neoplasia suggest the necessity of cofactors in cervical carcinogenesis. The long time-lag between initial infection and eventual malignant conversion suggests that random events may be necessary for such conversion, and the spontaneous regression of many primary lesions suggests that most patients are not exposed to these random events. Potential cofactors include cigarette smoking, hormonal effects of oral contraceptives and pregnancy, dietary deficiencies, immunosuppression and chronic inflammation. In those women who develop cervical cancer, malignant progression is rarely rapid, more commonly taking many years or decades. Malignant progression has been documented in patients who presented initially with only low grade HPV-induced atypia. On the other hand, progression may be a misnomer, as 'apparent' progression may really represent adjacent 'de novo' development of higher grade CIN. Although most cervical cancers contain high risk HPV types, up to 15% of such cancers test negative for HPV, raising the possibility that a few, usually more aggressive, cervical cancers may arise from from a non-viral source.(ABSTRACT TRUNCATED AT 400 WORDS)