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

Veronika Weyerer,Yves Allory,Eva Compérat,Markus Eckstein,Robert Stöhr,Simone Bertz,Arndt Hartmann,Bernd Wullich,Morgan Rouprêt,Nadine T Gaisa,Hendrik Juette

doi:10.3390/cancers12030763

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.

Highlights

Urothelial bladder cancer presents as urothelial carcinoma (UC) in 80%–90% of patients; the remaining patients present with non-urothelial tumors
We found 25 urothelial carcinomas that met the histomorphological criteria of large nested urothelial carcinoma (LNUC) as originally described by Cox and Epstein [3]
We present the first analysis of clinically relevant molecular alterations in LNUC, including pure and mixed tumors combined with other UC components

Summary

Introduction

Urothelial bladder cancer presents as urothelial carcinoma (UC) in 80%–90% of patients; the remaining patients present with non-urothelial tumors. The large nested variant of urothelial carcinoma (LNUC) was first described in 2011 by Cox and Epstein [3] and has only recently been included in the. 2016 World Health Organization (WHO) Classification system within the nested variant of urothelial carcinoma (NVUC) [4]. LNUC usually presents with large-sized well-delineated or irregular tumor nests with a bland cytology invading the detrusor muscle [3]. The growth pattern of LNUC is similar to the nested variant of urothelial carcinoma, with tumor nests lacking inflammatory and/or desmoplastic stroma reaction. This was probably the reason for combining LNUC and NVUC into one group in the WHO classification. To date, no molecular data on LNUC have been available

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