Lipid-Rich Urothelial Carcinoma

Lipid-rich urothelial carcinoma (LR-UC) is a rare subtype, with ∼65 cases reported in the literature. Here, we report the largest case series of bladder LR-UC, including 40 patients. Clinical follow-up was available for 29 patients. Twenty-seven patients had at least 2-years follow-up, 15 of whom were alive (55.6%) at 2 years. Twenty-six patients had at least 5-years follow-up, 12 of whom were alive (46%) at 5 years. Definitive resection was associated with improved overall survival (OS) (P=0.0188). Neoadjuvant treatment showed a trend towards improved OS compared with resection alone. Patients with a higher percentage of LR-UC (>10%) showed a trend of decreased OS. Positive MDM2 immunostain in both LR-UC and adjacent UC was observed in 6 of 8 tumors, with MDM2 gene amplification confirmed by FISH in one case and MDM2 RNA-ISH overexpression in one additional case. RNA-seq was performed on 9 paired microdissected LR-UC and adjacent UC samples. Principal component analysis demonstrated LR-UC clustered with its paired UC more than with the LR component of other patients. PRSS3P2 was the only component detected to be higher in LR-UC than in UC. GSEA analysis demonstrated that 59.1% of positively enriched genes were metabolism-related, and 57.6% of negatively enriched genes were immune/inflammation-related. In summary, we report the largest LR-UC series to date, highlighting its aggressive clinical behavior, and suggesting a possible benefit of definitive surgical resection and neoadjuvant therapy. MDM2 expression in UC with lipoblast-like cells may pose a diagnostic pitfall and transcriptomic profiling confirm the UC origin lipoblast-like cells.