Molecular and kinetic features of transitional cell carcinomas of the bladder: biological and clinical implications

Molecular and kinetic analyses have contributed to our understanding of the biology of transitional cell carcinomas (TCC) of the bladder. The concorda nt pattern of X-chromosome inactivation of multiple TCCs appearing at diffe rent times and at different sites and concordant genetic abnormalities in a subset of muscle-invasive TCC strongly support a monoclonal origin and a h omogeneous tumor cell selection throughout the neoplasm. However, topograph ic intratumor heterogeneity results from the accumulation of genetic lesion s in tumor suppressor genes, predominantly neurofibromatosis (NF)-1-defecti ve in the superficial compartment and tumor protein p53 (TP53)-defective in the deep one, with lower proliferation and down-regulation of apoptosis in the latter. TCCs follow the general concept of multistep carcinogenesis an d proceed through two distinct genetic pathways responsible for generating different TCC morphologies. These are the inactivation of cyclin-dependent kinase inhibitors (p15, p16, and p21(WAF/CIP1)) in low-grade TCC and early TP53-mediated abnormalities in high-grade TCC. TCC progression correlates w ith genetic instability and accumulation of collaborative genetic lesions m ainly involving TP53, retinoblastoma (RB)-1, and growth factors. Distinctiv e genetic (low incidence of RB-1 and NF-1 abnormalities) and kinetic (slowe r cell turnover) profiles also correlate with a "single-file" infiltration pattern and poor survival in muscle-invasive TCCs. The underlying molecular changes of carcinoma in situ involve multiple and more extensive deletions (normally TP53-defective) than coexistent invasive TCC, suggesting an inde pendent genetic evolution, while low-grade dysplasia is mainly polyclonal a nd shows a low rate of gene deletions.