Pure Large Nested Variant of Urothelial Carcinoma (LNUC) Is the Prototype of an FGFR3 Mutated Aggressive Urothelial Carcinoma with Luminal-Papillary Phenotype

Abstract

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 FGFR3 mutational status and PD-L1 status, the frequency of TERT-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 FGFR3-mutated with identical mutations in their concomitant papillary/papillary-like components. An FGFR3 mutation was found in 1/7 evaluable mixed LNUCs combined with NVUC. TERT-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, FGFR3-mutated, mostly PD-L1-negative tumor. In contrast, FGFR3 mutations seem to be rare in mixed LNUC, which may indicate a different pathway of tumor development.

Unusual Faces of Bladder Cancer

“…The large nested UC shares with the nested UC the same morphologic characteristics and clinical aggressiveness but the nests are larger ( Figure 1 b), with a growth pattern mimicking conventional inverted UC. These similarities have been advised to merge them into the same group in the last WHO classification of UC [ 12 ]. Interestingly, large nested UC displays a luminal phenotype, positive with FOXA1, GATA3, and CK 20 [ 12 ].…”

“…These similarities have been advised to merge them into the same group in the last WHO classification of UC [ 12 ]. Interestingly, large nested UC displays a luminal phenotype, positive with FOXA1, GATA3, and CK 20 [ 12 ]. FGFR3 and TERT genes are frequently mutated in this UC subtype [ 12 ].…”

“…Interestingly, large nested UC displays a luminal phenotype, positive with FOXA1, GATA3, and CK 20 [ 12 ]. FGFR3 and TERT genes are frequently mutated in this UC subtype [ 12 ].…”

Pathogenesis and Diagnosis of Genitourinary Cancer

“…These comprehensive innovative analyses have led to new molecular classification based on the genomic expression profiles and the discovery of potential diagnostic and therapeutic molecular targets. The current special series includes 11 articles by international leading researchers who are involved in the investigation of several challenging issues, particularly novel potential biomarkers in GU cancers, using a variety of innovative approaches [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

“…Large nested urothelial carcinoma (LNUC) is a new entity in the 2016 WHO classification of urothelial tumors. Weyerer et al evaluated a cohort of 25 LNUC using SNaPshot analysis and immunohistochemistry [ 18 ]. Pure LNUC is characterized by a luminal-papillary phenotype, FGFR3 -mutated, PD-L1-negative tumor, but FGFR3 mutations are rare in mixed LNUC, suggesting a different pathway of tumor development.…”