International Society of Urological Pathology Consensus Conference on Current Issues in Bladder Cancer. Working Group 4

Author:

Warrick Joshua I.1ORCID,Al-Ahmadie Hikmat2,Berman David M.3,Black Peter C.4,Flaig Thomas W.5,Höglund Mattias6,Bubendorf Lukas7,van der Kwast Theodorus H.8,Cheng Liang9,

Affiliation:

1. Penn State College of Medicine, Departments of Pathology and Urology, Hershey, PA

2. Memorial Sloan Kettering Cancer Center, Department of Pathology, New York, NY

3. Department of Pathology and Molecular Medicine, Queen’s University, Kingston

4. Department of Urologic Sciences, Univeristy of British Columbia, Vancouver, British Columbia, Canada

5. Department of Medicine-Medical Oncology, University of Colorado School of Medicine, Aurora, CO

6. Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden

7. Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland

8. Anatomic Pathology, Laboratory Medicine Program, University Health Network, Toronto, ON

9. Department of Pathology and Laboratory Medicine, Brown University Warren Alpert Medical School; Lifespan Academic Medical Center, and the Legorreta Cancer Center at Brown University, Providence, RI

Abstract

Molecular subtyping has been a major focus of bladder cancer research over the past decade. Despite many promising associations with clinical outcomes and treatment response, its clinical impact has yet to be defined. As part of the 2022 International Society of Urological Pathology Conference on Bladder Cancer, we reviewed the current state of the science for bladder cancer molecular subtyping. Our review included several different subtyping systems. We derived the following 7 principles, which summarize progress and challenges of molecular subtyping: (1) bladder cancer has 3 major molecular subtypes: luminal, basal-squamous, and neuroendocrine; (2) signatures of the tumor microenvironment differ greatly among bladder cancers, particularly among luminal tumors; (3) luminal bladder cancers are biologically diverse, and much of this diversity results from differences in features unrelated to the tumor microenvironment, such as FGFR3 signaling and RB1 inactivation; (4) molecular subtype of bladder cancer associates with tumor stage and histomorphology; (5) many subtyping systems include idiosyncrasies, such as subtypes recognized by no other system; (6) there are broad fuzzy borders between molecular subtypes, and cases that fall on these fuzzy borders are often classified differently by different subtyping systems; and (7) when there are histomorphologically distinct regions within a single tumor, the molecular subtypes of these regions are often discordant. We reviewed several use cases for molecular subtyping, highlighting their promise as clinical biomarkers. Finally, we conclude that data are currently insufficient to support the routine use of molecular subtyping to guide bladder cancer management, an opinion shared with the majority of conference attendees. We also conclude that molecular subtype should not be considered an “intrinsic” property of a tumor but should instead be considered the result of a specific laboratory test, performed using a specific testing platform and classification algorithm, validated for a specific clinical application.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Pathology and Forensic Medicine,Surgery,Anatomy

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