HER2 expression and genomic alterations in plasmacytoid urothelial carcinoma: Results from a large real-world institutional cohort.

Abstract

803 Background: Plasmacytoid urothelial carcinoma (PUC) is a rare and aggressive histologic subtype of urothelial carcinoma (UC), characterized by discohesive growth, frequent peritoneal dissemination, and poor response to conventional systemic therapies. Despite its distinct clinical behavior, the molecular features of PUC remain poorly characterized. The prevalence and clinical significance of HER2 expression and ERBB2 alterations in PUC are unclear. Given the availability of FGFR3- and HER2-directed systemic therapies in UC, characterizing the molecular landscape of PUC may provide biological insight into its aggressive behavior and reveal novel therapeutic targets. We hypothesized that HER2 overexpression and other genomic alterations underlie the aggressive phenotype of PUC. Methods: This retrospective cohort study included patients diagnosed with histologically confirmed plasmacytoid urothelial carcinoma (PUC) at our institution between 2019 and 2025. Clinicopathologic data, HER2 immunohistochemistry (IHC; Ventana 4B5 assay, Roche), and comprehensive genomic profiling (CGP; Altera, Caris, FoundationOne, or other platforms) were collected. Tumor mutational burden (TMB) was categorized as low (≤5 mut/Mb), intermediate (6–19 mut/Mb), or high (≥20 mut/Mb). Overall survival (OS) was estimated using the Kaplan-Meier method, and all other data were summarized descriptively. Results: A total of 125 patients with plasmacytoid urothelial carcinoma (PUC) were identified (median age 72 y [IQR 65–79]; 78% male). Median follow-up was 19.8 months (95% CI 15.0–30.4, and median overall survival across all stages was 23.6 months (95% CI 17.6–NR). Clinical T-stage distribution at diagnosis was 33% ≤T1, 32% T2, 22% T3, and 12% T4. HER2 IHC and CGP findings are summarized in Table 1, highlighting frequent HER2 overexpression, ERBB2 alterations, and common co-mutations in TERT , TP53 , and RB1 . Conclusions: HER2 positivity (IHC 3+) and ERBB2 were frequently present in pts with PUC. These findings suggest a potential role for systematic HER2 IHC assessment and warrant exploration of HER2-directed therapies in pts with PUC. Molecular and genomic characteristics of plasmacytoid urothelial carcinoma (PUC). Feature n (%)/Description HER2 IHC (n = 62)  HER2 3+ (positive) 13 (21%)  HER2 2+ (equivocal) 25 (40%) CGP (n = 24)  ERBB2 alterations 4 (17%)  CDH1 alterations 3 (13%) TMB High in 25%, intermediate in 4% Frequent pathogenic alterations TERT (71%), TP53 (54%), RB1 (33%), ARID1A (29%), KDM6A (25%)