Clinical and Molecular Features of Nested and Large Nested Urothelial Carcinoma - Expert Commentary

Nested urothelial carcinoma (NUC) and large nested urothelial carcinoma (LNUC) are aggressive but rare subtypes of urothelial carcinoma that are characterized by nested histological architecture and bland morphology, with the former exhibiting small nests and the latter exhibiting large nests. Aron et al. recently characterized the clinical and molecular features of NUC and LNUC tumors.

The investigators collected retrospective data for seventeen patients, of whom ten had LNUC, and seven had NUC. Most tumors were unifocal and commonly involved the ureter. The median tumor size was 3.3 cm in LNUC patients and 2 cm in NUC patients. Most samples exhibited various components of invasive conventional urothelial carcinoma, while 42.8% of NUC and 40% of LNUC samples were pure. A significantly higher proportion of LNUC cases exhibited low-grade surface papillary urothelial carcinoma (80%) compared to NUC cases (28.6%, p = 0.034). The median follow-up period was 9 months for NUC and 10 months for LNUC, whereby 70% of LNUC patients exhibited no evidence of disease on follow-up compared to 14.2% among NUC patients (p = 0.031).

Whole-exome sequencing of tumor samples revealed that the most common pathological alterations occurred in FGFR3, which was more common in LNUC samples compared to NUC samples (70% versus 14.2%, p = 0.049). PIK3CA mutations were only present in LNUC cases. Only LNUC samples (25%) exhibited a tumor mutational burden score above ten. RNA sequencing showed that differentially expressed genes in LNUC versus NUC samples were enriched for inflammatory, immune, and cell adhesion pathways. Upon clustering samples according to the expression of marker genes, both NUC and LNUC cases were of the luminal molecular subtype.

This report describes the distinct molecular characteristics and clinical outcomes of patients with NUC versus LNUC. Understanding how these distinct characteristics potentially impact response to cytotoxic and immunotherapeutic approaches is critical.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine


  1. Aron M, Chandrashekar DS, Canete-Portillo S, et al. Nested and Large Nested Subtypes of Urothelial Carcinoma of the Upper Urinary Tract: A Multi-Institutional Study [published online ahead of print, 2023 Sep 15]. Mod Pathol. 2023;100333. 
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