Nested (NUC) and large nested (LNUC) subtypes of urothelial carcinoma of the upper urinary tract are exceedingly rare. This has contributed to the paucity of information regarding their clinicopathological and molecular characteristics.
To address this knowledge gap, we explored the largest cohort to date of these rare tumors, comprising of resection specimens of 10 LNUC and 7 NUC, from seven participating institutions. Clinicopathological data was retrieved and documented. Whole exome sequencing and RNA sequencing was performed on the Illumina NovaSeq 6000 sequencer. The data generated was analyzed using the genome analysis toolkit pipeline. Somatic mutations were annotated using funcotator tool to identify pathogenic/likely-pathogenic variants. Tumor mutational burden was calculated using python based "pyTMB" tool. Microsatellite instability analysis was done using MSI sensor2 and the IdyllaTM platform. Differential expression analysis of genes in LNUC and NUC, along with mRNA expression-based molecular subtyping was performed, by analyzing expression pattern of markers used in the cancer genome atlas subclassification of bladder carcinoma. Both tumor types were more common in older males, were unifocal, and occurred more commonly mixed with minor components of predominantly conventional urothelial carcinoma. Overlying low-grade papillary urothelial carcinoma was significantly more common in LNUC (p=0.034). On follow-up (LNUC: median= 10 months, range 3-84; NUC: median=9 months, range 2-48) LNUC had better clinical outcomes (p=0.031). Pathogenic mutations in FGFR3 and PIK3CA were significantly more common in LNUC (p= 0.049 and p=0.044), with the latter present exclusively in LNUC. 75% of the cases showed TMB of <10, and all cases were microsatellite stable. FGFR3 mutations were also more common in low stage tumors. This study expands on the clinicopathological spectrum of NUC and LNUC of the upper urinary tract and is the first to comprehensively analyze the molecular profile of these tumors, highlighting pathogenic genetic alterations of potential therapeutic and prognostic value.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2023 Sep 15 [Epub ahead of print]
Manju Aron, Darshan S Chandrashekar, Sofia Canete-Portillo, Fadi Brimo, Sean R Williamson, Adeboye O Osunkoya, Maria Rosaria Raspollini, Lakshmi P Kunju, Sooryanarayana Varambally, Alexander C Mackinnon, Shuko Harada, George J Netto
Departments of Pathology and Urology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA., Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA., Department of Pathology, McGill University, Montreal, Quebec, Canada., Department of Pathology, Cleveland Clinic, Cleveland, Ohio, USA., Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, Georgia, USA., Department of Pathology, University Hospital Careggi, Firenze, Italy, USA., Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA., Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA. Electronic address: ., Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/37717923