Pure Large Nested Variant of Urothelial Carcinoma (LNUC) Is the Prototype of an Mutated Aggressive Urothelial Carcinoma with Luminal-Papillary Phenotype.

Since 2016, large nested urothelial carcinoma (LNUC) has been included within the WHO classification of urothelial tumors. Limited reports with mainly small case series have confirmed the malignant behavior of LNUC despite its bland morphological appearance. We evaluated, for the first time, markers for new immunooncological or targeted therapies including mutational status and PD-L1 status, the frequency of -promoter mutations and the molecular subtype in a cohort of 25 LNUC using SNaPshot analysis and immunohistochemistry. Of the 25 cases, 17 were pure LNUC, with 13 showing an additional exophytic papillary/papillary-like component. Seven mixed LNUCs presented areas of classical nested variant urothelial carcinoma (NVUC) and one showed a component of conventional urothelial carcinoma. Of the 17 evaluable pure LNUCs, 16 were -mutated with identical mutations in their concomitant papillary/papillary-like components. An mutation was found in 1/7 evaluable mixed LNUCs combined with NVUC. -promoter mutations were detected in 86.7% pure and 83.3% mixed tumors. Immunohistochemistry revealed a luminal phenotype; PD-L1 was negative in the majority of tumor cells and tumor-associated immune cells. Pure LNUC is a prime example of a luminal, -mutated, mostly PD-L1-negative tumor. In contrast, mutations seem to be rare in mixed LNUC, which may indicate a different pathway of tumor development.