Background: To detail two cases of sarcomatoid urothelial carcinoma (UC) with rapid progression, disseminated metastases, and early death, detailing the results of somatic tumor profiling using next-generation sequencing (NGS). Case Series: The first case presented is a rare case of UC of the renal pelvis with osteosarcomatous differentiation and venous tumor thrombus in a 65-year-old man found to have a heterozygous germline variant of unknown significance in the neurofibromatosis-1 gene. The second case is a 72-year-old woman with sarcomatoid UC of the bladder. Herein, we discuss the presentation and clinical course, histology, immunohistochemical profiles, and somatic tumor testing results. We then review the literature regarding this rare and aggressive entity, detail options for optimal management, and address the role of molecular profiling in these cases. Conclusion: Sarcomatoid UC is a rare and aggressive entity. NGS may be useful in these cases to guide systemic therapy.

Keywords: Sarcomatoid, urothelial carcinoma, bladder cancer, renal mass, next-generation sequencing.