Introduction:

Plasmacytoid urothelial carcinoma (PUC) is a rare and aggressive histological subtype of bladder cancer, defined by discohesive growth, high metastatic potential, and poor response to chemotherapy. Its genomic landscape is incompletely characterized, and the spectrum of actionable alterations remains underexplored. This study aims to characterize the genetic landscape of this variant histology through analysis of standard-of-care comprehensive genomic profiling results.

Methods:

We retrospectively identified patients with histologically confirmed plasmacytoid urothelial carcinoma (PUC) from our institutional database (2019–2025) who had undergone standard-of-care comprehensive genomic profiling (Altera, Caris, FoundationOne, or other). Clinicopathological characteristics (age, sex, stage) were summarized descriptively. Variants were classified as pathogenic/likely pathogenic or variants of uncertain significance (VUS) per AMP/ASCO/CAP guidelines. HER2 status was determined from ERBB2 amplification (copy number ≥6), pathogenic mutations, or IHC overexpression. Loss of heterozygosity (LOH) was obtained from assay reports, with ≥16% classified as high. Variant allele frequencies (VAF) for pathogenic and VUS alterations were visualized by patient and gene using heatmaps. 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 were extracted from PDF reports and converted to CSV format manually or with Python. Statistical analyses were performed in Python.

Results:

A total of 23 patients with histologically confirmed PUC were included and analyzed. Median age was 69 years (interquartile range, 60–79), and 73.9% were male. T‑stage distribution was 4.3% (T1), 34.8% (T2), 26.1% (T3), and 34.8% (T4), respectively. HER2 positivity (ERBB2 mutation and/or IHC overexpression) was identified in 21.7% (5/23) of patients. TMB was low in 56.5% (13/23), intermediate in 39.1% (9/23), and high in 4.3% (1/23). LOH status (available for 11 patients) was high in 27.3% (3/11), low in 54.5% (6/11), and equivocal in 18.2% (2/11). Pathogenic alterations were most frequently observed in TERT (60.9%), TP53 (47.8%), RB1 (34.8%), ARID1A (30.4%), and KDM6A (21.7%). Variants of uncertain significance (VUS) were most common in ERBB3, DYNC1H1, and AHNAK. No correlation was observed between TMB category and the number of pathogenic variants.

Conclusion:

Given the high frequency of HER2 positivity (21.7%) in PUC, both comprehensive genomic profiling and HER2 IHC testing are warranted to identify candidates for targeted treatment. Our findings broaden the molecular characterization of this aggressive variant and support the potential role of HER2‑directed antibody–drug conjugates as an important therapeutic option in selected PUC patients.

Funding: N/A