High Frequency of Clonal Immunoglobulin Receptor Gene Rearrangements in Sporadic Histiocytic/Dendritic Cell Sarcomas

Abstract

The diagnosis of histiocytic/dendritic cell (H/DC) sarcomas is currently based on morphology and the presence of immunophenotypic features of H/DC differentiation. The issue whether clonal immunoglobulin receptor gene rearrangements are present in H/DC sarcomas has been debated over decades until the recent data by Feldman et al, which provided compelling evidence that patients with follicular lymphoma and concurrent/synchronous H/DC sarcoma share identical genotypic features, suggested the possibility of transdifferentiation or dedifferentiation of 2 otherwise morphologically and immunophenotypically distinctive neoplasms. Here we investigated the molecular characteristics of 23 patients with sporadic H/DC sarcoma. Nine of the 23 cases (39%) showed clonal IGH (+/-IGK) gene rearrangements, whereas 2 (9%) cases showed only clonal IGK gene rearrangements, which were further validated and confirmed by direct DNA sequencing. One histiocytic sarcoma showed t(14;18) by quantitative-polymerase chain reaction, which was confirmed by fluorescence in situ hybridization analysis showing IGH/BCL2 fusions in neoplastic histiocytes. Notably, all IGH/IGK-positive H/DC sarcomas were negative for B-cell-associated transcription factors PAX5 and BOB.1, whereas 4 of 7 IGH/IGK-positive histiocytic sarcoma cases were positive for Oct2. In addition, no evidence of Epstein-Barr virus infection was detected in 8 of 11 IGH/IGK-positive H/DC sarcoma cases by in situ hybridization, suggesting that Epstein-Barr virus infection may not play an important role in the pathogenesis of these tumors. This study provides evidence that clonal immunoglobulin receptor gene rearrangements may be detected at a high frequency in sporadic H/DC sarcomas. The findings suggest that a large subset of H/DC sarcomas have inherited B-cell genotypes, thus providing new insights for the pathogenesis of these rare but aggressive neoplasms.

The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications

“…Recent studies have shown identical clonal rearrangements in T-cell lymphoblastic leukemias and subsequent Langerhans cell histiocytosis or in FLs lymphomas and associated histiocytic tumors, indicating a common clonal origin in tumors of different lineages. [118][119][120] This phenomenon recapitulates in a clinical setting the plasticity of hematopoietic cells observed in experimental models, in which modulation of specific transcription factors can reprogram cells to enter disparate differentiation pathways. 121 106 The biology of lymphoid cells and the tumors derived from these cells is complex.…”

Histiocytic Sarcoma : An Updated Literature Review Based on the 2008 WHO Classification

“…Of interest, Chen et al recently reported that 4 of 7 sporadic HS cases with detectable clonal IG gene rearrangement expressed OCT-2. 13 Association of viral infection such as Epstein-Barr virus has not been detected.…”

Lymphoma classification and the tools of our trade: an introduction to the 2012 USCAP Long Course

“…Monoclonality is not necessarily equivalent to the diagnosis of a malignant lymphoma and lack of a demonstrable clone is not equivalent to assurance that a B-or T-cell proliferation is benign. If a clonal population is present and detected, the molecular studies may still be misleading by suggesting the 'wrong' lineage (eg, IGH@ rearrangements in some histiocytic/dendritic neoplasms [28][29][30][31] ) or they may lead to a diagnostic error by identifying a clone that is less important than something else present (eg, finding a restricted T-cell population without a demonstrable immunoglobulin gene rearrangement in a B-cell neoplasm).…”