SPECIAL ARTICLEInternational Society of Urological Pathology ConsensusConference on Current Issues in Bladder Cancer.WorkingGroup 4Molecular Subtypes of Bladder Cancer-Principles of Classificationand Emerging Clinical UtilityJoshua I.Warrick MD,*Hikmat Al-Ahmadie MD.David M.Berman,MD.PhD.Peter C.Black MD.$Thomas W.Flaig MD Mattias Hoglund PhD,Lukas Bubendorf MD,#Theodorus H.van der Kwast,MD.PhD,**Liang Cheng MD.PhD.and the Members of the ISUP Bladder Tumor Consensus Panelidiosyncrasies,such as subtypes recognized by no other system;Abstract:Molecular subtyping has been a major focus of bladder(6)there are broad fuzzy borders between molecular subtypes,cancer research over the past decade.Despite many promisingand cases that fall on these fuzzy borders are often classifiedassociations with clinical outcomes and treatment response,itsdifferently by different subtyping systems;and (7)when there areclinical impact has yet to be defined.As part of the 2022 Inter-histomorphologically distinct regions within a single tumor,thenational Society of Urological Pathology Conference on Bladdermolecular subtypes of these regions are often discordant.WeCancer,we reviewed the current state of the science for bladderreviewed several use cases for molecular subtyping.highlightingcancer molecular subtyping.Our review included several differ-their promise as clinical biomarkers.Finally,we conclude thatent subtyping systems.We derived the following 7 principles,data are currently insufficient to support the routine use of mo-which summarize progress and challenges of molecular subtyp-lecular subtyping to guide bladder cancer management,an1922023ing:(1)bladder cancer has 3 major molecular subtypes:luminal,opinion shared with the majority of conference attendees.Webasal-squamous,and neuroendocrine;(2)signatures of the tumoralso conclude that molecular subtype should not be consideredmicroenvironment differ greatly among bladder cancers,partic-an "intrinsic"property of a tumor but should instead be con-ularly among luminal tumors;(3)luminal bladder cancers areCX1AWsidered the result of a specific laboratory test,perfommed using abiologically diverse,and much of this diversity results from dif-specific testing platform and classification algorithm,validatedferences in features unrelated to the tumor microenvironment,for a specific clinical application.such as FGFR3 signaling and RBI inactivation;(4)molecularsubtype of bladder cancer associates with tumor stageKey Words:bladder cancer,molecular subtype,luminal,basal,and histomorphology;(5)many subtyping systems includebasal-squamous,genomically unstable,urothelial-like,micro-environmentFrom the *Penn State College of Medicine,Departments of Pathology(Am J Surg Pathol 2023;00:000-000)and Urology,Hershey,PA;Memorial Sloan Kettering CancerCenter,Department of Pathology,New York,NY:Department ofPathology and Molecular Medicine,Queen's University,Kingston;*Anatomic Pathology,Laboratory Medicine Program,UniversityHealth Network
