Histopathologic, Molecular, and Clinical Profiling of Lymphoepithelioma-like Carcinoma of the Bladder

Lymphoepithelioma-like urothelial carcinoma of the urinary bladder (LELC-B) is a rare histologic subtype characterized by strong immune cell infiltrates. A better prognosis and favorable response rates to immune-checkpoint inhibitors (ICI) have been described. We aimed to characterize the molecular profiles and immune cell infiltration of LELC-B for a better understanding and its therapeutic implications. We identified eleven muscle-invasive bladder cancer cases with pure and mixed LELC-B. PD-L1 expression and mismatch-repair (MMR) proteins were evaluated using immunohistochemistry. We calculated the tumor-mutational burden (TMB) and characterized mutational profiles using whole exome DNA-sequencing data. Transcriptomic signatures were detected using the NanoString nCounter PanCancer IO360 panel. Multiplex immunofluorescence of tumor microenvironment (PD-L1, PanCK, aSMA, Vimentin, CD45, Ki67) and T-cells (CD4, CD3, PD-1, CD163, CD8, FoxP3) was used to quantify cell populations. All LELC-B cases were highly positive for PD-L1 (median TPS/TC 70%; range 20-100; median CPS 100; range 50-100), MMR-proficient and negative for Epstein-Barr virus infection. Immune cell infiltrates were characterized by high CD8+ T-cell count and high PD-1/PD-L1 expression on immune and tumor cells. LELC-B showed upregulation of signaling pathways involved in immune cell response. Most common mutations were found in chromatin remodeling genes causing epigenetic dysregulation. All LELC-B cases showed high TMB of 39 Mut/Mb (IQR 29-66). In conclusion, LELC-B is a highly immunogenic tumor, showing strong upregulation of PD1/PD-L1 and making ICI a promising treatment option.