Original ArticlesToward Biological Subtyping of Papillary Renal Cell Carcinoma With Clinical Implications Through Histologic, Immunohistochemical, and Molecular AnalysisSaleeb, Rola M. MD*,†; Brimo, Fadi MD, FRCPC‡; Farag, Mina MD*; Rompré-Brodeur, Alexis MD§; Rotondo, Fabio BSc*; Beharry, Vidya BSc*; Wala, Samantha MSc*; Plant, Pamela PhD*; Downes, Michelle R. MD, FRCPC†,∥; Pace, Kenneth MD, MSc, FRCPC¶; Evans, Andrew MD, PhD, FRCPC†,#; Bjarnason, Georg MD, FRCPC(C)**; Bartlett, John M.S. BSc, PhD††; Yousef, George M. MD, PhD, FRCPC (Path)*,†Author Information *Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael’s Hospital †Department of Laboratory Medicine and Pathobiology, University of Toronto ∥Department of Pathology **Division of Medical Oncology and Hematology, Sunnybrook Health Sciences Centre ¶Department of Surgery, Division of Urology, St. Michael’s Hospital #Department of Pathology, University Health Network ††Ontario Institute for Cancer Research, Toronto, ON Departments of ‡Pathology §Urology, McGill University Health Center, Montreal, QC, Canada Conflicts of Interest and Source of Funding: Supported by grants from the Kidney Cancer Research Network of Canada and the Canadian Urology Oncology group (KCRNC/CUOG) research trainee award, the Ontario Institute of Cancer Research (Transformative Pathology Fellowship award RFTP-004), and Ontario Molecular Pathology Research Network (OMPRN stream 1 grant #CPTRG-004). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: George M. Yousef, MD, PhD, FRCPC (Path), Department of Laboratory Medicine, St. Michael’s Hospital, 30 Bond Street, Toronto, ON, Canada M5B 1W8 (e-mail: email@example.com). The American Journal of Surgical Pathology: December 2017 - Volume 41 - Issue 12 - p 1618-1629 doi: 10.1097/PAS.0000000000000962 Buy SDC Metrics Abstract Papillary renal cell carcinoma (PRCC) has 2 histologic subtypes. Almost half of the cases fail to meet all morphologic criteria for either type, hence are characterized as PRCC not otherwise specified (NOS). There are yet no markers to resolve the PRCC NOS category. Accurate classification can better guide the management of these patients. In our previous PRCC study we identified markers that can distinguish between the subtypes. A PRCC patient cohort of 108 cases was selected for the current study. A panel of potentially distinguishing markers was chosen from our previous genomic analysis, and assessed by immunohistochemistry. The panel exhibited distinct staining patterns between the 2 classic PRCC subtypes; and successfully reclassified the NOS (45%) cases. Moreover, these immunomarkers revealed a third subtype, PRCC3 (35% of the cohort). Molecular testing using miRNA expression and copy number variation analysis confirmed the presence of 3 distinct molecular signatures corresponding to the 3 subtypes. Disease-free survival was significantly enhanced in PRCC1 versus 2 and 3 (P=0.047) on univariate analysis. The subtypes stratification was also significant on multivariate analysis (P=0.025; hazard ratio, 6; 95% confidence interval, 1.25-32.2). We propose a new classification system of PRCC integrating morphologic, immunophenotypical, and molecular analysis. The newly described PRCC3 has overlapping morphology between PRCC1 and PRCC2, hence would be subtyped as NOS in the current classification. Molecularly PRCC3 has a distinct signature and clinically it behaves similar to PRCC2. The new classification stratifies PRCC patients into clinically relevant subgroups and has significant implications on the management of PRCC. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.