title: Toward a molecular pathologic classification of urothelial carcinoma.
abstract: We recently defined molecular subtypes of urothelial carcinomas according to whole genome gene expression. Herein we describe molecular pathologic characterization of the subtypes using 20 genes and IHC of 237 tumors. In addition to differences in expression levels, the subtypes show important differences in stratification of protein expression. The selected genes included biological features central to bladder cancer biology, eg, cell cycle activity, cellular architecture, cell-cell interactions, and key receptor tyrosine kinases. We show that the urobasal (Uro) A subtype shares features with normal urothelium such as keratin 5 (KRT5), P-cadherin (P-Cad), and epidermal growth factor receptor (EGFR) expression confined to basal cells, and cell cycle activity (CCNB1) restricted to the tumor-stroma interface. In contrast, the squamous cell cancer-like (SCCL) subtype uniformly expresses KRT5, P-Cad, EGFR, KRT14, and cell cycle genes throughout the tumor parenchyma. The genomically unstable subtype shows proliferation throughout the tumor parenchyma and high ERBB2 and E-Cad expression but absence of KRT5, P-Cad, and EGFR expression. UroB tumors demonstrate features shared by both UroA and SCCL subtypes. A major transition in tumor progression seems to be loss of dependency of stromal interaction for proliferation. We present a simple IHC/histology-based classifier that is easy to implement as a standard pathologic evaluation to differentiate the three major subtypes: urobasal, genomically unstable, and SCCL. These three major subtypes exhibit important prognostic differences.
authors.affiliation: Department of Clinical Sciences, Division of Oncology, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Gottfrid
authors.initials: G
authors.lastname: Sjödahl
authors.forename: Kristina
authors.initials: K
authors.lastname: Lövgren
authors.forename: Martin
authors.initials: M
authors.lastname: Lauss
authors.forename: Oliver
authors.initials: O
authors.lastname: Patschan
authors.forename: Sigurdur
authors.initials: S
authors.lastname: Gudjonsson
authors.forename: Gunilla
authors.initials: G
authors.lastname: Chebil
authors.forename: Mattias
authors.initials: M
authors.lastname: Aine
authors.forename: Pontus
authors.initials: P
authors.lastname: Eriksson
authors.forename: Wiking
authors.initials: W
authors.lastname: Månsson
authors.forename: David
authors.initials: D
authors.lastname: Lindgren
authors.forename: Mårten
authors.initials: M
authors.lastname: Fernö
authors.forename: Fredrik
authors.initials: F
authors.lastname: Liedberg
authors.forename: Mattias
authors.initials: M
authors.lastname: Höglund
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000145:classification* / Q000235:genetics / Q000473:pathology*; D019459:Urothelium / Q000378:metabolism / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger