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

Abstract

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.

Keywords: BRAF L485F mutation; Divergent evolution; Histiocytic sarcoma; Lineage plasticity; Multiple myeloma; Transdifferentiation.

Fig. 1.

a–c CT images demonstrating a heterogeneous L4 lucent lesion with large left paraspinal soft tissue mass with likely extension into the neural foramen. d Bone marrow biopsy showing sheets of plasma cells (H&E. stain; ×20), which are highlighted by CD138 immunostain (×20) (e). FISH analysis showing one red signal representing heterozygous deletion of RB1 (13q14.2) (green – control signal) (f), loss of 1p (green) and gain of 1q (red) with 3 copies (g), and fusion of IGH (14q32.3)/MAF (16q23) with atypical signal pattern (one fusion, 2 IGH) in 24.5% of cells (IGH – green, MAF – red) (h). Skin punch biopsy showing dense dermal infiltrate of large atypical histiocytic cells mixed with neutrophils (H&E. stain; ×20) (i). By immunohistochemistry, these cells exhibited bright CD163 (×20) (j) and moderate Ki-67 proliferation index (×40) (k). FISH studies revealed gain of 1q21/CKS1B (red) (l) and deletion of RB1(13q14) (red) (m).

Fig. 2.

a IGH and IGK gene rearrangement results from bone marrow (A–D) and skin tissue (E–H). The IGH rearrangement was assessed by targeting the FR2 and FR3 regions of the VH region, and the JH region shown in panels A, B, E and F. IGK rearrangement was assessed by targeting Vk and Jk regions (panels C, G), and Kde rearrangement with Vk and the intragenic Jk-Ck region (panels D, H). The presence of similar clonal peaks in bone marrow and skin tissue (see D, H, asterisks) indicates clonal relationship between MM and HS. Several IGH/IGK peaks were present exclusively in HS. One possible interpretation is that additional immunoglobulin rearrangements occurred in HS during its development. However, this is unlikely, as the observed Vk-Jk rearrangement (panel G) occurring after a Vk-Kde or Jk-Ck intron-Kde rearrangement (panels D, H) is improbable. A more plausible explanation is that during divergent evolution from the common GCB precursor (see text), MM underwent additional SHM or IGH alterations which may abolish PCR primer-binding sites, thus interfering with IGH rearrangement detection. b Proposed model of transdifferentiation of MM to HS: a GCB-harboring RB1 deletion, BRAF L485F mutation, and 1p/1q abnormalities acquire an IGH::MAF translocation as a result of faulty CSR, leading to the development of MM. Under therapeutic pressure, a lineage switch of this GCB also occurs, followed by transformation to HS subsequent to CDKN2A/B loss. b Created with BioRender.com. IGH, immunoglobulin heavy chain; IGK, immunoglobulin kappa light chain; Kde, kappa-deleting element.