Original ArticlesUterine Inflammatory Myofibroblastic Tumors Proposed Risk Stratification Model Using Integrated Clinicopathologic and Molecular AnalysisLadwig, Nicholas R. MD*; Bean, Gregory R. MD, PhD†; Pekmezci, Melike MD*; Boscardin, John PhD‡; Joseph, Nancy M. MD, PhD*; Therrien, Nicole MD§; Sangoi, Ankur R. MD∥; Piening, Brian PhD¶; Rajamanickam, Venkatesh BS¶; Galvin, Matthew BS¶; Bernard, Brady PhD¶; Zaloudek, Charles MD*; Rabban, Joseph T. MD*; Garg, Karuna MD#; Umetsu, Sarah E. MD, PhD* Author Information Departments of *Pathology ‡Medicine and Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA †Department of Pathology, Stanford University School of Medicine, Stanford, CA ∥Department of Pathology, El Camino Hospital, Mountain View, CA §Department of Pathology, Logan Health, Kalispell, MT ¶Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR #Department of Pathology, Cleveland Clinic, Cleveland, OH ALK FISH and capture‐based NGS was performed at the UCSF Clinical Cancer Genomics Laboratory. RNA sequencing was performed at the at Providence St. Joseph Health Clinical Genomics Laboratory. Ann Griffin (UCSF Cancer Registry) assisted with clinical follow‐up data. Conflicts of Interest and Source of Funding: This study was funded by the UCSF Department of Pathology Clinical Research Endowment awards granted to N.R.L., K.G., and S.E.U. J.T.R. reports that his spouse receives salary and stock options from Merck and Co. For the remaining authors none were declared. Correspondence: Sarah E. Umetsu, MD, PhD, Department of Pathology, University of California, San Francisco, 505 Parnassus Avenue, P.O. Box 0102, San Francisco, CA 94143 (e-mail: [email protected]). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.ajsp.com. The American Journal of Surgical Pathology 47(2):p 157-171, February 2023. | DOI: 10.1097/PAS.0000000000001987 Buy SDC Metrics Abstract Inflammatory myofibroblastic tumor (IMT) of the uterus is a rare mesenchymal tumor with largely benign behavior; however, a small subset demonstrate aggressive behavior. While clinicopathologic features have been previously associated with aggressive behavior, these reports are based on small series, and these features are imperfect predictors of clinical behavior. IMTs are most commonly driven by ALK fusions, with additional pathogenic molecular alterations being reported only in rare examples of extrauterine IMTs. In this study, a series of 11 uterine IMTs, 5 of which demonstrated aggressive behavior, were evaluated for clinicopathologic variables and additionally subjected to capture-based next-generation sequencing with or without whole-transcriptome RNA sequencing. In the 6 IMTs without aggressive behavior, ALK fusions were the sole pathogenic alteration. In contrast, all 5 aggressive IMTs harbored pathogenic molecular alterations and numerous copy number changes in addition to ALK fusions, with the majority of the additional alterations present in the primary tumors. We combined our series with cases previously reported in the literature and performed statistical analyses to propose a novel clinicopathologic risk stratification score assigning 1 point each for: age above 45 years, size≥5 cm,≥4 mitotic figures per 10 high-power field, and infiltrative borders. No tumors with 0 points had an aggressive outcome, while 21% of tumors with 1 to 2 points and all tumors with ≥3 points had aggressive outcomes. We propose a 2-step classification model that first uses the clinicopathologic risk stratification score to identify low-risk and high-risk tumors, and recommend molecular testing to further classify intermediate-risk tumors. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.