Original ArticlesRecurrent Loss of SMARCA4 in Sinonasal TeratocarcinosarcomaRooper, Lisa M. MD*; Uddin, Nasir MBBS†; Gagan, Jeffrey MD, PhD‡; Brosens, Lodewijk A.A. MD, PhD§; Magliocca, Kelly R. DDS, MPH∥; Edgar, Mark A. MD∥; Thompson, Lester D.R. MD¶; Agaimy, Abbas MD#; Bishop, Justin A. MD‡Author Information *Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD †Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi, Pakistan ‡Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX §Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands ∥Department of Pathology, Emory University Hospital, Atlanta, GA ¶Southern California Permanente Medical Group, Department of Pathology, Woodland Hills Medical Center, Woodland Hills, CA #Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital, Erlangen, Germany A portion of this data was presented in abstract form at the 2020 USCAP Annual Meeting in Los Angeles, CA. Funded in part by the Jane B. and Edwin P. Jenevein, MD Endowment for Pathology at UT Southwestern Medical Center. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Justin A. Bishop, MD, Department of Pathology, University of Texas Southwestern Medical Center, MC 9073, 5323 Harry Hines Boulevard, Dallas, TX 75390-9073 (e-mail: [email protected]). The American Journal of Surgical Pathology: October 2020 - Volume 44 - Issue 10 - p 1331-1339 doi: 10.1097/PAS.0000000000001508 Buy Metrics Abstract Molecular analysis has reshaped the landscape of high grade sinonasal tumors by defining novel entities and identifying recurrent mutations in established tumor types. However, sinonasal teratocarcinosarcoma (TCS), a rare and aggressive tumor with intermixed teratomatous, carcinomatous, and sarcomatous elements, remains poorly understood. The multiphenotypic differentiation of TCS has engendered persistent controversy about its histogenesis and leads to diagnostic overlap with several other malignancies. In this study, we evaluated the molecular underpinnings of TCS to clarify its pathogenesis and diagnosis. We performed SMARCA4 immunohistochemistry (IHC) on 22 TCS and 153 other sinonasal tumors. We identified loss of SMARCA4 expression in 18 TCS (82%), including 15 (68%) with complete loss and 3 (14%) with partial loss. Although we also identified partial SMARCA4 loss in 1 of 8 SMARCB1-deficient sinonasal carcinomas (13%), SMARCA4 was intact in all other sinonasal carcinomas and neuroendocrine tumors. We then selected 3 TCS with complete SMARCA4 loss by IHC for a targeted next-generation sequencing panel that included 1425 cancer-related genes. We confirmed biallelic somatic inactivation of SMARCA4 without other known oncogenic mutations in these 3 cases. Overall, these findings suggest that SMARCA4 inactivation may be the dominant genetic event in TCS, expanding understanding of this gene’s role in sinonasal tumorigenesis. They also raise the possibility that TCS is on a diagnostic spectrum with the newly described SMARCA4-deficient sinonasal carcinoma, blurring the lines between established and emerging sinonasal entities. In addition, SMARCA4 IHC may provide a useful adjunct for confirming a diagnosis of TCS in limited material. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.