Cancer of the uterine cervix: Integration of molecular evaluation into management strategy and the concept of biological staging

Carcinoma of the uterine cervix is the most common malignancy affecting Indian women. The biological behaviour of invasive cervical cancer is not always predictable. Even when the lesion is localized to the cervix, 15–20% of the patients have recurrences. The evaluation of cervical precancer is even more complex and the current approach is to assess malignant potential based on histological and cytological criteria. However, lesions at any point in the spectrum of premalignancy have been associated with subsequent invasion, reflecting the limitations of histological grading for predicting the risk of progression. Biological markers are measures of cellular events associated with specific stages of carcinogenesis. This definition indicates that the risk of tumour progression and/or biological behaviour could correlate with the quantitative degree and pattern of biomarker expression. A number of such markers are now available for the evaluation of cervical lesions. Molecular, biological and histopathological investigations of preinvasive and invasive carcinoma of the uterine cervix have shown the role of human papillomavirus (HPV) infection in cervical carcinogenesis. Molecular analysis of HPV DNAs has also provided information on their genomic organization, protein function and transcriptional regulation. Studies on the expression of E6 and E7 transforming proteins of certain high-risk HPVs have shown that these viruses play a role in carcinogenic progression by forming complexes with products of the tumor suppressor genes, Rb and p53. Studies have also shown the association of the oncogenes, ras and myc with HPV and cervical carcinoma. The role of HPV infection, E6–E7 transforming proteins, oncogenes and tumour suppressor genes in cervical carcinogenesis are discussed in this paper. Evaluation of these molecular markers can thus be used to elaborate the existing grading system for cervical lesions and could play a vital role in the management of cervical precancer and cancer.