Special ArticlesReport From the International Society of Urological Pathology (ISUP) Consultation Conference On Molecular Pathology Of Urogenital Cancers. II. Molecular Pathology of Bladder Cancer Progress and ChallengesWarrick, Joshua I. MD*; Knowles, Margaret A. PhD†; Yves, Allory MD, PhD‡; van der Kwast, Theo MD, PhD§; Grignon, David J. MD∥; Kristiansen, Glen MD¶; Egevad, Lars MD, PhD#; Hartmann, Arndt MD**; Cheng, Liang MD∥Author Information *Department of Pathology, Penn State College of Medicine, Hershey, PA †Divison of Molecular Medicine, Leeds Institute of Molecular Research at St James’s, St James’s University Hospital, Leeds, UK ‡Department of Pathology, CHU Henri Mondor, Creteil, France §Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada ∥Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN ¶Institute of Pathology, University Hospital Bonn, Bonn, Germany #Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden **Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany All authors are members of the International Society of Urological Pathology Working Group on Molecular Pathology of Bladder Cancer. Conflicts of Interest and Source of Funding: A.H.: Advisory board Meetings and lectures for MSD, BMS, Janssen, Roche, AstraZeneca, Novartis, QIAGEN, Cepheid, Illumina, IPSEN; research support by Cepheid, Roche, AstraZeneca, Janssen. T.v.d.K.: consultation fees from Janssen Canada. M.A.K.: consultation fees from Janssen Europe. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Joshua I. Warrick, MD, Department of Pathology, Milton S. Hershey Medical Center, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033 (e-mail: [email protected]). The American Journal of Surgical Pathology: July 2020 - Volume 44 - Issue 7 - p e30-e46 doi: 10.1097/PAS.0000000000001453 Buy Metrics Abstract During the 2019 International Society of Urological Pathology Consultation Conference on Molecular Pathology of Urogenital Cancer, the Working Group on Bladder Cancer presented the current status and made recommendations on the diagnostic use of molecular pathology, incorporating a premeeting survey. Bladder cancers are biologically diverse and can be separated into “molecular subtypes,” based on expression profiling. These subtypes associate with clinical behavior, histology, and molecular alterations, though their clinical utility has not been demonstrated at present and use in bladder cancer is not recommended. Mutations in the TERT promoter are present in the majority of bladder cancers, including the noninvasive stage of tumor evolution, but not in reactive conditions. Mutational analysis of the TERT promoter thus distinguishes histologically deceptive cancers from their benign mimics in some cases. A minority of pathologists employ this test. FGFR3 mutations are common in bladder cancer, and metastatic urothelial carcinoma (UC) with such mutations frequently responds to erdafitinib, an FGFR inhibitor. Testing for FGFR3 alterations is required before using this drug. Metastatic UC responds to immune-oncology (IO) agents in 20% of cases. These are approved as first and second-line treatments in metastatic UC. Several biological parameters associate with response to IO agents, including tumor mutational burden, molecular subtype, and infiltration by programmed death-ligand 1–positive lymphocytes, detected by immunohistochemistry. Programmed death-ligand 1 immunohistochemistry is mandatory before administering IO agents in the first-line setting. In conclusion, much has been learned about the biology of bladder cancer, and this understanding has improved the care of patients with the disease. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.