Molecular mechanisms of squamous differentiation in urothelial cell carcinoma: A paradigm for molecular subtyping of urothelial cell carcinoma of the bladder

Background: Recent molecular characterization studies focusing on bladder cancer have provided a wealth of information, including the identification of specific molecular subtypes of this disease. Interestingly, a particular molecular subtype identified by several different groups is characterized, at least in part, by the presence of squamous differentiation (SqD) in a significant fraction of primary tumors. Tumors that exhibit SqD are extremely aggressive. Moreover, conflicting reports exist relative to the sensitivity of bladder tumors exhibiting SqD to multimodal treatment. Bladder cancers that exhibit SqD appear to be distinct clinical entities and are often associated with a specific molecular subtype; therefore, it is important to understand the molecular drivers of this process. Purpose: Because presence of SqD is closely associated with a basal molecular phenotype, we review the evidence for specific pathways in SqD. In addition, we pose key areas for future exploration.