Original ArticlesGenetic Basis of Extramedullary Plasmablastic Transformation of Multiple MyelomaLiu, Ying MD, PhD*; Jelloul, Fatima MD*; Zhang, Yanming MD†; Bhavsar, Tapan MD‡; Ho, Caleb MD*,§; Rao, Mamta BS†; Lewis, Natasha E. MD*; Cimera, Robert BS†; Baik, Jeeyeon BS*; Sigler, Allison BS*; Sen, Filiz MD*; Yabe, Mariko MD, PhD*; Roshal, Mikhail MD, PhD*; Landgren, Ola MD, PhD∥; Dogan, Ahmet MD, PhD*; Xiao, Wenbin MD, PhD*Author Information *Department of Pathology, Hematopathology Service †Department of Pathology, Cytogenetic Laboratory §Department of Pathology, Diagnostic Molecular Pathology Service ∥Department of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY ‡Department of Pathology, Wayne State University School of Medicine, Detroit Receiving Hospital, Detroit, MI Y.L. and F.J. contributed equally. Y.L., F.J., and W.X.: conceived the study, collected and analyzed the data, and wrote the manuscript. Y.Z., M. Rao, and R.C.: performed cytogenetic studies and interpreted the data. N.E.L.: collected data and wrote the manuscript. T.B., J.B., A.S., F.S., M.Y., and M. Roshal: collected data. C.H.: annotated the sequencing data. O.L. and A.D.: interpreted the data. All the authors approved the final version of the manuscript. Part of the data was presented in abstract form at the 106th Annual Meeting of the United States and Canadian Association for Pathologists, Vancouver, BC, Canada in March 2018. Present address: Tapan Bhavsar, Department of Pathology, George Washington University Medical Center, 900 23rd Street, Washington, DC 20037. Conflicts of Interest and Source of Funding: Supported in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 and MSK SPORE in lymphoma (P50 CA192937). A.D. has received consultancy fees from Roche, Corvus Pharmaceuticals, Physicians’ Education Resource, Seattle Genetics, Peerview Institute, Oncology Specialty Group, Pharmacyclics, Celgene, Novartis, Takeda, EUSAPharma, and research grants from Roche. W.X. has received research support from Stemline Therapeutics. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Wenbin Xiao, MD, PhD, Department of Pathology, Hematopathology Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (e-mail: [email protected]). The American Journal of Surgical Pathology: June 2020 - Volume 44 - Issue 6 - p 838-848 doi: 10.1097/PAS.0000000000001459 Buy Metrics Abstract In patients with multiple myeloma, plasmablastic transformation in the bone marrow is rare and associated with poor outcomes. The significance of discordant extramedullary plasmablastic transformation in patients with small, mature clonal plasma cells in the bone marrow has not been well studied. Here, we report the clinicopathologic, cytogenetic, and molecular features of 10 such patients (male/female: 6/4, median age: 65 y, range: 48 to 76 y) with an established diagnosis of multiple myeloma in the bone marrow composed of small, mature plasma cells in parallel with a concurrent or subsequent extramedullary plasmablastic transformation. Eight patients with available survival data showed an overall aggressive clinical course with a median survival of 4.5 months after the diagnosis of extramedullary plasmablastic transformation, despite aggressive treatment and even in patients with low-level bone marrow involvement. Pathologically, the extramedullary plasmablastic myeloma were clonally related to the corresponding bone marrow plasma cells, showed high levels of CMYC and/or P53 expression with a high Ki-67 proliferation index by immunohistochemistry and harbored more complex genomic aberrations including frequent mutations in the RAS pathway and MYC rearrangements compared with their bone marrow counterparts. In summary, although genetic and immunohistochemical studies were not uniformly performed on all cases due to the retrospective nature of this study, our data suggest that discordant extramedullary plasmablastic transformation of multiple myeloma has an aggressive clinical course and is characterized by frequent mutations in the RAS pathway and more complex genomic abnormalities. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.