Current understanding of the biology of advanced bladder cancer

Transitional cell carcinoma (TCC) is reported to be the fifth most common solid malignancy in the U.S. Although radical cystectomy will cure a substantial number of patients with minimally invasive TCC, many patients with deeply muscle-invasive or extravesical disease who are treated with radical cystectomy alone die of metastatic TCC, as do patients with metastatic disease. The differing clinical course and the limited value of established prognosticators make analysis of new molecular parameters of interest in predicting the prognosis of patients with bladder cancer, particularly those in high-risk groups who are at risk of disease progression and recurrence. In the current review, a comprehensive MEDLINE/PubMed search of articles pertaining to the biology of TCC from 1965 to the present was performed, as well as a bibliographic review of cross references. TCC follow the general concept of multistep carcinogenesis and proceed through two distinct genetic pathways responsible for generating different TCC morphologies, namely the inactivation of cyclin-dependent kinase inhibitors in low-grade TCC and early p53-mediated abnormalities in high-grade TCC. TCC progression correlates with genetic instability and the accumulation of collaborative genetic lesions mainly involving p53, retinoblastoma, and growth factors. The bulk of these data are derived from cases of localized/locally advanced disease and none are ready yet for routine clinical application; however, the current knowledge has led to the clinical testing of novel biologic observations in several important trials. Understanding of the molecular biology of advanced bladder cancer continues to improve. It is likely that in the new millennium, real breakthroughs in the identification and therapy of high-risk, poor-prognosis patients will come from an integration of molecular modalities in the clinical application.