This distinction is more than semantic because it better reflects the pathological and biological differences among these tumors and reinforces the importance of reporting both the presence and relative proportion of each component.
Although these tumors have long been recognized as aggressive, their rarity and frequent exclusion from prospective clinical trials have limited our ability to develop evidence-based, subtype-specific treatment strategies. Consequently, many management decisions continue to rely on retrospective studies and institutional experience rather than high-level evidence. We undertook this review to bring together the available pathological, molecular, and clinical data into a practical resource for clinicians managing these uncommon but important disease entities.1
One of the clearest conclusions from the review is that the different histological subtypes are distinct from one another in clinically significant ways. Small cell neuroendocrine carcinoma consistently benefits from platinum-etoposide chemotherapy, whereas the evidence for conventional cisplatin-based chemotherapy against squamous, plasmacytoid, micropapillary, sarcomatoid, and adenocarcinoma tumors is considerably more heterogeneous. Similarly, the role of bladder preservation appears to differ by subtype, reinforcing that these tumors should not be approached using a uniform treatment strategy.
Another recurring theme is the rapid progress in our understanding of the molecular biology underlying these histological subtypes. Genomic profiling has identified characteristic alterations across several subtypes, including ERBB2, FGFR3, and CDH1, while retrospective studies suggest activity of immune checkpoint inhibitors and antibody-drug conjugates in selected patients. However, these observations have not yet translated into standardized treatment algorithms.
Perhaps the greatest challenge moving forward is how these tumors should be managed as the treatment landscape of clinically localized muscle-invasive bladder cancer rapidly evolves. While newer systemic regimens have changed the standard of care for conventional urothelial carcinoma, subtype-specific outcomes remain largely unavailable.
Consequently, we do not yet know whether these approaches should be applied uniformly across histological subtypes or adapted according to the biology and treatment sensitivity of each entity. Answering this question will require prospective studies that intentionally include these rare tumors rather than merely extrapolating from conventional urothelial carcinoma.
Ultimately, we hope this review serves as both a practical summary of the current evidence and a framework for future research. Standardized pathological reporting, including the relative proportion of each histological subtype or differentiated component, collaborative international efforts, and subtype-enriched clinical trials will be essential to developing evidence-based management strategies for these biologically distinct tumors.
Written by: Can Aydogdu,1,2 Roger Li3
- Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Urology, LMU Klinikum, Ludwig-Maximilians-University of Munich, Munich, Germany
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
- Aydogdu C, Bukavina L, Cheng L, et al. Histological Subtypes and Divergent Differentiation of Urothelial Carcinoma: Histology, Genomics, and Management Implications. Eur Urol. 2026. doi:10.1016/j.eururo.2026.05.030.
- Netto GJ, Amin MB, Berney DM, et al. The 2022 World Health Organization classification of tumors of the urinary system and male genital organs, Part B: Prostate and urinary tract tumors. Eur Urol. 2022;82:469-482.