Giant Cell Urothelial Carcinoma: Morphometric Insights and Associations With Aggressive Clinical Features

Giant cell urothelial carcinoma (GCUC) is an exceedingly rare histologic subtype with 50+ reported cases. To date, 3 case series have been reported. Scant chemotherapy and immunotherapy responses were reported with variable results. We report the largest GCUC series, including 27 GCUC and 27 matched control urothelial carcinoma (CoUC) patients, most (>90%) of whom had more than 5 years of follow-up, including neoadjuvant and adjuvant therapy status. We further characterized the nuclear size ratio of giant tumor cells to background tumor cells and analyzed urothelial differentiation markers (GATA3, CK5/6), p53, tumor-infiltrating lymphocytes (CD19 and CD3), and therapeutic targets (TROP2, Nectin4, PDL1, and HER2). Morphometric analysis of giant tumor cells demonstrated that they were, on average, 12 times larger than surrounding nongiant tumor cells. GCUC showed many histologic and immunophenotypic features similar to CoUC. GCUC was enriched for higher stages (T3/4 and metastatic disease) than CoUC and showed a trend toward worse OS than conventional urothelial carcinoma, but was similar to urothelial carcinoma with variant histology. GCUC included 3 low-stage (T1/2) patients, who had significantly worse OS than low-stage CoUC, suggesting early extensive workup and oncologic intervention. Chemotherapy slightly improved OS in both GCUC and CoUC patients without statistical significance. Compared with CoUC, GCUC appeared to have more tumor-infiltrating T cells, but without statistical significance. There were no expression differences in TROP2, Nectin4, PDL1, and HER2. However, a subset of GCUC patients might benefit from target therapies (PDL1, Nectin4), warranting more cohort studies.