Updates on WHO classification for small round cell tumors: Ewing sarcoma vs. everything else

The WHO Classification of Soft Tissue and Bone Tumours currently recognizes four categories of undifferentiated small round cell sarcoma: Ewing sarcoma, round cell sarcoma with EWSR1-non-ETS fusions including NFATc2 and PATZ1, CIC-rearranged sarcoma, and sarcoma with BCOR genetic alterations. These neoplasms frequently pose significant diagnostic challenges due to rarity and overlapping morphologic and immunohistochemical findings.
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Updates on WHO classification for small round cell tumors: Ewing sarcoma vs. everything else Human Pathology 147 (2024) 101–113 Contents lists available at ScienceDirect Human Pathology journal homepage: www.elsevier.com/locate/humpathUpdates on WHO classification for small round cell tumors: Ewing sarcomavs. everything elseCarina A. Dehner, M.D. Ph.D., Assistant Professor a, Alexander J. Lazar, M.D. Ph.D., Professor b, c,John S.A. Chrisinger, M.D., Associate Professor d, *a Department of Anatomic Pathology and Laboratory Medicine, Indiana University, 635 Barnhill Drive, Indianapolis, IN, 46202, USAb Department of Pathology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USAc Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USAd Department of Pathology and Immunology, Division of Anatomic and Molecular Pathology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis,MO, 63110, USAA R T I C L E I N F O A B S T R A C TKeywords: The WHO Classification of Soft Tissue and Bone Tumours currently recognizes four categories of undifferentiatedEwing sarcoma small round cell sarcoma: Ewing sarcoma, round cell sarcoma with EWSR1-non-ETS fusions including NFATc2Ewing-like and PATZ1, CIC-rearranged sarcoma, and sarcoma with BCOR genetic alterations. These neoplasms frequentlyRound cell pose significant diagnostic challenges due to rarity and overlapping morphologic and immunohistochemicalCICBCOR findings. Further, molecular testing, with accompanying pitfalls, may be needed to establish a definitive diagNFATc2 nosis. This review summarizes the clinical, histologic, immunohistochemical, and molecular features of thesePATZ1 neoplasms. In addition, differential diagnosis and areas of uncertainty and ongoing investigation are discussed.Review1. Introduction 2. Ewing sarcoma Mesenchymal neoplasms frequently pose significant diagnostic Ewing sarcoma is the architype and most commonly occurringchallenges due to rarity, overlapping histologic and immunohisto member of the undifferentiated small round cell sarcoma group. Hischemical features with other mesenchymal and non-mesenchymal tu torically, chest wall tumors were designated “Askin tumor,” and casesmors, and pitfalls in interpretation of molecular analysis results. Further, with morphologic features of neuronal differentiation were designatedrecent discoveries, aided greatly by next-generation sequencing tech “(peripheral) primitive neuroectodermal tumor,” however the use ofniques, have led to rapid changes in classification and nomenclature. these terms is discouraged. Further, current evidence supports theThese issues are epitomized by the undifferentiated small round cell assertion that EWSR1::NFATc2 sarcoma, CIC-rearranged sarcoma andsarcoma group. The most recent WHO Classification of Soft Tissue and BCOR alteration sarcoma, previously known as “Ewing-like” sarcomas,Bone Tumours recognizes four categories within this group: Ewing sar are distinct entities biologically and now conceptionally in the mostcoma, round cell sarcoma with EWSR1-non-ETS fusions, CIC-rearranged recent WHO Soft Tissue and Bone Tumour Classification [1].sarcoma, and sarcoma with BCOR alterations [1]. This review summa So-called adamantinoma-like Ewing sarcomas of the head and neckrizes the clinical, histologic, immunohistochemical, and molecular fea are characterized by a monotonous proliferation of ovoid to epithelioidtures of these neoplasms (Fig. 1). Discussions of differential diagnosis, cells, nested or corded growth with peripheral palisading, prominentareas of uncertainty and ongoing investigation, and personal and insti associated stromal component, membranous CD99 immunopositivity,tutional approaches are also included. evidence of true epithelial differentiation in the form of expression of high molecular weight keratins and rarely overt squamous pearl for mation, and EWSR1::FLI1 fusions. These tumors have been previously * Corresponding author. Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8118, St. Louis,MO, 63110, USA. E-mail addresses: cadehner@iu.edu (C.A. Dehner), alazar@mdanderson.org (A.J. Lazar), jschrisi@wustl.edu (J.S.A. Chrisinger).https://doi.org/10.1016/j.humpath.2024.01.007Received 17 November 2023; Received in revised form 16 January 2024; Accepted 22 January 2024Available online 26 January 20240046-8177/© 2024 Elsevier Inc. All ...