The Distinct Molecular Profile of the Small-Cell Bladder Cancer Variant - Expert Commentary

Urothelial carcinoma variants are rare and some are associated with poor clinical outcomes. The small-cell variant comprises less than 1% of all bladder cancers. These cancers are more aggressive and have poorer prognoses than conventional urothelial carcinoma.

A recent study in European Urology Oncology investigated urothelial carcinomas of the bladder and the upper tract with small cell or neuroendocrine variant histology.1 The investigators included 3368 samples for genomic profiling and identified small cell/neuroendocrine histological features in 132/3368 (3.92%). Targeted exome sequencing identified 92% harbored TP53 mutations, 75% harbored RB1 mutations, 72% had both mutations, and 68% had mutations in the telomerase reverse transcriptase (TERT) promoter. 6.5% had TMB ≥ 10 mutations/Mb.

The RNA expression profile of 24 pure small-cell bladder cancers and 51 urothelial muscle-invasive bladder cancers from a separate cohort revealed a distinct gene expression profile in small cell bladder cancer. This profile was characterized by dysregulation of several inflammatory pathways, including interferon-gamma.

This study adds to our understanding of the distinct molecular characteristics of this important urothelial cancer variant. This knowledge can potentially lead to trials testing variant-specific treatment strategies in the future.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York


1. Hoffman-Censits, Jean, Woonyoung Choi, Sumanta Pal, Edouard Trabulsi, William Kevin Kelly, Noah M. Hahn, David McConkey et al. "Urothelial Cancers with Small Cell Variant Histology Have Confirmed High Tumor Mutational Burden, Frequent TP53 and RB Mutations, and a Unique Gene Expression Profile." European Urology Oncology (2020). 

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