Worldwide bladder cancer accounts for over 200,000 deaths annually.1 About 70% present with non-muscle-invasive disease (NMIBC) and can be effectively managed with transurethral resection +/- intravesical therapy.2 However, up to half of patients with high-risk NMIBC progress to muscle-invasive bladder cancer (MIBC) and 20% of patients have MIBC at presentation.2 MIBC carries a high disease specific mortality3 and patients face a choice of radical treatment options including radical cystectomy or bladder-preservation.

The majority of bladder cancer patients have pure urothelial carcinoma (UC) but between 10 and 55% harbor variant histology.4, 5, 6 We can use the WHO 2016 classification to broadly group these into urothelial carcinoma with divergent differentiation (UCDD) and pure nonurothelial carcinomas (Fig. 1).7 In this review we will aim to evaluate the evidence for bladder-preservation in histological variants of bladder cancer.

Divergent differentiation describes cells derived from the urothelial lineage with distinct histopathological changes that usually exist alongside conventional UC in variable proportions. Prevalence is increasing as recognition of variant pathology improves, for example, from 2006 to 2016 squamous differentiation reporting increased from 21% to 40%.8, 9, 10 In general treatment is given along urothelial carcinoma protocols where this is the dominant histological pattern, but questions remain as to whether these histological changes should alter decision making.

Pure Non-urothelial carcinoma (NUC) represents a separate histological entity and whilst it may exist alongside UC or other mixed-histology it follows a more distinct clinical course. NUC is comparatively rare, frequently excluded from clinical trials and even when permitted, very small numbers prevent meaningful subgroup analysis. The combination of these challenges has led to a lack of evidence regarding optimal management of variant histology that has resulted in many defaulting to the historical preference for Radical Cystectomy (RC).