Molecular determinants of tumor recurrence in the urinary bladder

Tumor recurrence is a major clinical concern for patients with urothelial carcinoma of the urinary bladder. Traditional morphological analysis is of limited utility for identifying cases in which recurrence will occur. However, molecular and genetic analyses offer new perspectives on the prediction of bladder tumor recurrence. Recent studies have suggested that urothelial carcinogenesis occurs as a 'field effect' that can involve any number of sites in the bladder mucosa. Accumulating evidence supports the notion that resident urothelial stem cells in the affected field are transformed into cancer stem cells by acquiring genetic alterations that lead to tumor formation through clonal expansion. Both initial and recurrent tumors are derived from cancer stem cells in the affected field via two distinct molecular pathways. These provide a genetic framework for understanding urothelial carcinogenesis, tumor recurrence and progression: the FGFR3-associated pathway and the TP53-associated pathway. These two pathways are characterized by different genomic, epigenetic and gene-expression alterations. Their outcomes correlate with the markedly different clinical and pathologic features of both relatively indolent low-grade cancers and the aggressive high-grade cancers. As such, these molecular findings are potentially useful for counseling patients and for assessing risk of recurrence or biological aggressiveness of the patient's tumor. The molecular changes may additionally prove useful for developing preventive and therapeutic strategies for urothelial bladder cancer. A unifying model of urothelial carcinogenesis, tumor recurrence and progression is proposed in this review.