Sarcomatoid urothelial carcinoma (sUC) is associated with poor clinical outcomes. Herein, we evaluated clinicopathologic features (including PD-L1 expression) for institutional cases.
Sixty-five patients with sUC treated by radical cystectomy were matched for age, sex, and pathologic stage to 190 patients with pure urothelial carcinoma (UC). Outcomes were evaluated using the Kaplan-Meier method. Immunohistochemistry (IHC) results for tumor-specific PD-L1 expression in sUC were quantified using H-scores (range, 0-300). Cases with constitutive PD-L1 expression (cPD-L1; H-score ≥240) were evaluated for amplification events using fluorescence in situ hybridization (n = 28), mate-pair sequencing (Mpseq; n = 6), RNA sequencing (n = 5), and targeted next-generation sequencing (n = 8). PD-L1 regulatory pathways were evaluated using gene set enrichment analysis in the Cancer Hallmark dataset.
Most patients with sUC had advanced disease (≥pT2, 62/65, 95%), without significant differences in overall and cancer-specific survival, when matched to pure UC. Median PD-L1 H-scores using different clones were 100 (SP142), 120 (SP263), and 195 (22C3). cPD-L1 was seen in 43% (28/65) of cases of sUC that were enriched for TP53, TERT, and CDKN2A/B alterations. PD-L1 amplification was identified in 7 (of 28, 25%) of these cases. Bionformatics analysis consistently identified IL6-JAK-STAT3 and interferon α/γ signaling in sUC with cPD-L1 expression.
Our results suggest that cPD-L1 expression in most sUC occurs secondary to IL6-JAK-STAT3 and interferon α/γ signaling. This provides a biologic rationale for evaluating response to immunotherapy in this patient population.
American journal of clinical pathology. 2026 Apr 03 [Epub]
Sounak Gupta, Farhad Kosari, Prabin Thapa, Stephen J Murphy, Sarah H Johnson, Patricia T Greipp, Nooshin K Dashti, Burak Tekin, Jabra G Zarka, Surendra Dasari, Benjamin R Kipp, Vidit Sharma, Paras H Shah, Jacob J Orme, Igor Frank, R Jeffrey Karnes, Stephen A Boorjian, George Vasmatzis, John C Cheville
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States., Department of Molecular Medicine, Mayo Clinic, Rochester, MN, United States., Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States., Biomarker Discovery Laboratory, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States., Department of Pathology, Dartmouth Hitchcock Medical Center, Lebanon, NH, United States., Department of Medical Oncology, Mayo Clinic, Rochester, MN, United States., Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States., Department of Urology, Mayo Clinic, Rochester, MN, United States.