New developments in our understanding of the aetiology and pathology of cervical neoplasia

Abstract

Invasive cervical carcinoma is the second commonest malignancy in women worldwide. The major aetiological factor is human papillomavirus (HPV) infection of the cervix. ‘Low risk’ HPV types undergo ‘vegetative’ or ‘permissive’ replication in the squamous epithelium of the cervix, and cause the lesions recognised by histopathologists as koilocytosis and cervical intraepithelial neoplasia grade 1 (CIN1). ‘High risk’ HPV types may cause koilocytosis and CIN1, but also have the potential to cause high grade CIN (CIN2/3). This potential is related to the viral E6 protein, which in high risk HPV types has many functions including binding to and inactivating the host p53 tumour suppressor protein. High grade intraepithelial lesions are vulnerable to further genetic damage, not directly HPV-related, which may result in the acquisition of an invasive phenotype. Most cervical HPV infections do not cause CIN or carcinoma, and there are important host and environmental co-factors which determine the outcome of HPV infection. These co-factors include genetic factors: CIN and carcinoma show familial clustering, and some HLA alleles are positively associated with CIN and carcinoma. The host immune response to HPV infection is of central importance in the control of HPV infection. Cigarette smoking is one of the major factors involved in the progression of high grade CIN to carcinoma. Hormonal factors and the oral contraceptive pill may be involved in the development of CIN. HPV typing has much potential use in routine screening for cervical neoplasia. There is potential for the development of both prophylactic and therapeutic vaccines to HPV.