**6. Conclusions**

Bladder cancer with UC variants and non-urothelial subtypes have been classically described as tumors with a worse prognosis in comparison with pure UCs. However, the latter is mostly explained by a higher stage at the diagnosis among non-pure UC, since data from case-series and retrospective studies seems to suggest that, among the majority of variants, the prognosis is similar to pure UC, after adjustment for the disease stage.

Current diagnosis of variant histology in BC provides clinically relevant information to the physician and a novel framework to stratify patients according to prognosis, risk of recurrence and expected response to a given therapy. However, the management of this conditions remains challenging. Currently, RC preceded, in some tumors by NAC, constitutes the recommended treatment approach for resecable disease; AC is most commonly unsuccessful and data on immunotherapy is still scant. Regarding immunotherapy, it appears that drugs active in the PD-1 pathway are independent of histology [60].

Additionally, molecular alterations unique to these variants could be of use, in the future, as targeted therapies could emerge as a treatment option. However, further investigation is still needed to understand more clearly the diagnostic criteria

to be applied in these entities. Multicenter, international, prospective collaborative efforts are needed in order to clarify the distinct prognosis of these patients and to determine optimal therapy regimens.
