858 Background: Urothelial carcinoma with trophoblastic differentiation (TUC) represents a rare and aggressive variant that has been previously reported in both the upper and lower urinary tract. Although isolated cases have described its distinct histopathological and immunohistochemical (IHC) features, comprehensive characterization of this variant remains limited. Genomic data on TUC is exceedingly scarce, making its clinical behavior difficult to characterize. In this study, our objective is to define the genomic features of this uncommon histologic variant by evaluating results from clinical next-generation sequencing. Methods: From our institution-based data set, we retrospectively reviewed patients diagnosed with TUC on surgical pathology report between 2020 to 2025. Patients were included if they had undergone standard-of-care comprehensive whole exome genomic profiling (Altera, Caris, Foundation One, or other). Patient, clinical, and pathological findings were collected. Tumor mutational burden (TMB) was retrieved from assay reports and categorized as low (≤5 mut/Mb), intermediate (6–19 mut/Mb), or high (≥20 mut/Mb). Data was extracted from PDF reports and converted to CSV format manually or with PythonV3.13.5 and subsequently analyzed. Median time to follow up, overall and recurrence free survival analysis were performed. Results: Eighteen patients were diagnosed with confirmed TUC; five had available genomic data. The median age was 74 years, and all patients were non-Hispanic White. Smoking history included two active and three former users. Three tumors originated in the bladder and two in the ureter, with pathological stages pT1 (n = 2), pT2 (n = 2), and pT3 (n = 1). At last follow-up, three patients were alive with disease, and two had no evidence of disease. Genomic profiling revealed low-to-intermediate TMB. Pathogenic and recurrent alterations most frequently involved TERT (~80%), FGFR3 (~40%), ERCC2 (~40%), KMT2D (~40%), and TP53 (~40%). Interestingly, one patient harbored coexisting KRAS and BRAF mutations—a rare finding in UC—suggesting potential clonal divergence in this variant. Median overall survival and recurrence-free survival were not reached and median time to follow up was 18.5 months. Conclusions: This study represents one of the first reports of real-world genomic profiling in the TUC variant. We highlight the notable inter-patient heterogeneity and genomic diversity of this variant with an interesting take on TERT mutation coappearing with KRAS and BRAF mutations. These findings emphasize the need for further comprehensive genomic investigation to improve the interpretation of its biological behavior and to guide the development of targeted therapeutic strategies.
Diaz et al. (Sun,) studied this question.