Transdifferentiation of Multiple Myeloma into Histiocytic Sarcoma: Case Report of a Highly Unusual Phenomenon

Introduction: Transdifferentiation of multiple myeloma (MM) into histiocytic sarcoma (HS) is exceptionally rare. We report a unique case, confirming this phenomenon through cytogenetics and molecular analyses. Case Presentation: A 46-year-old woman with high-risk light chain MM developed extramedullary disease despite multiple lines of therapy. Biopsies revealed atypical histiocytic proliferation consistent with HS. Shared immunoglobulin gene rearrangements, cytogenetic alterations, and gene mutations, including a rare BRAF L485F, confirmed clonal relatedness between the two neoplasms. IGH::MAF translocation specific to MM and IGVH somatic hypermutation in HS suggests divergent evolution from a putative germinal center B-cell (GCB) precursor. Conclusions: This case highlights lineage plasticity of MM to undergo HS transdifferentiation, potentially mediated through a mutated common GCB precursor antecedent to the plasma cell stage, and the subsequent development of HS and MM through acquisition of additional genetic events. Recognition of this exceptional phenomenon and understanding its underlying mechanism have implications for diagnosis, classification, and personalized treatment.