Urothelial Cancers with Small Cell Variant Histology Have Confirmed High Tumor Mutational Burden, Frequent TP53 and RB Mutations, and a Unique Gene Expression Profile.

Although predominantly urothelial, some bladder cancer and upper tract urothelial cancer (BC/UTUC) harbor histologic variants. Small cell BC (SCBC) variants comprised ˜5% of The Cancer Genome Atlas BC cohort, with a poor prognosis. We describe genomic profiles of BC/UTUC with small cell/neuroendocrine features identified in the Foundation Medicine database from June 2012 to September 2018. Of 3368 BC/UTUC samples, 3.92% (132) harbored small cell/neuroendocrine features by immunohistochemistry. Mutations were noted in: TP53 (92%), RB1 (75%), combined TP53/RB1 (72%), and TERT promoter (68%). Of the samples, 6.5% had TMB ≥ 10 mutations/Mb. RNA expression profiling of 24 pure SCBC and 51 urothelial BC (UBC) muscle-invasive samples evaluated from a separate cohort revealed a large number of differentially expressed genes with suppression of several inflammatory pathways in SCBC compared with UBC. This largest reported SCBC dataset to date confirms enrichment of signatures in SCBC similar to small cell lung cancer and describes unique gene expression compared with UBC. These findings may explain aggressive SCBC phenotype. PATIENT SUMMARY: Small cell bladder cancer (SCBC) is an aggressive subtype that microscopically resembles aggressive small cell lung cancer (SCLC). This study confirms that SCBC shares DNA changes similar to SCLC and that SCBC expresses many genes that urothelial bladder cancer does not, possibly explaining aggressive SCBC activity.

Update on bladder cancer molecular subtypes.

In 2014, there was a burst of studies on the molecular subtypes of bladder cancer in the published literature that was made possible by the advances in high-throughput technologies. Based on gene expression profiling, the major molecular classification subdivisions were basal and luminal subtypes, which resembled to those observed in breast cancers. These basal and luminal subtypes were further subdivided by TCGA into squamous, infiltrated, luminal-papillary, luminal/genomically unstable (GU), and neuronal/small cell carcinoma (SCC) subtypes. Recently, an international subtypes consensus project further expanded on the TCGA subtypes by defining a consensus molecular classification (CMC). A multidisciplinary team of experts generated CMC to overcome the difficulties of clinical applications due to several published bladder cancer molecular classifications with various nomenclatures and molecular features. It included six molecular subtypes with the addition of one more luminal subtype (luminal nonspecified) compared to the TCGA subtype classification. The initial research efforts have focused on the characterization of each subtype at the molecular and histopathologic levels, but more recent studies have examined their significance in terms of clinical utility, i.e., biomarkers that inform prognostication and/or to predict therapeutic responses to be tested in future clinical trials. This review provides an overview of recent investigations into the relationship between molecular subtypes and the clinical management of patients with bladder cancer.