Histiocytic sarcoma arising from lymphomas via transdifferentiation pathway during clonal evolution

Differentiation occurs during development and involves a coordinated activation and/or suppression of genes. The pluripotent stem cells typically undergo restriction of their developmental potential, thus transforming into multipotent progenitor cells, which in turn give rise to even more developmentally restricted progenitor cells or terminally differentiated functional cells. Transdifferentiation refers to the conversion of a committed progenitor cell from one pathway of differentiation into another lineage without first reverting to a more primitive stem cell or progenitor cell [1]. The mechanism of transdifferentiation of mature cells can occur through somatic mutation, epigenetic changes, or external factors that affect gene expression. Transdifferentiation shows phenotypic, molecular changes and a substantiated lineage relationship between the original cell and the new cell type. Transdifferentiation can be partial or complete. In the case of partial transdifferentiation, transdifferentiated cells retain genes that are reminiscent of the parent cell.

Histiocytic sarcoma is a rare malignant hematopoietic neoplasm that can occur in lymph node, skin, the gastrointestinal tract, spleen, bone marrow, and thyroid; it shows morphological and immunophenotypic evidence of histocytic differentiation [2–5].

In this issue of Leukemia and Lymphoma, Wang et al. shed some light on the mechanism of histiocytic sarcoma transdifferentiation from a low-grade lymphoma [3]. The authors demonstrate that transformed histiocytic sarcomas partially retain their previous lymphoma signature, including the expression of markers such as OCT2, BCL2, and BCL6. They also show hypermutated immunoglobulin heavy chain variable region (IGH) genes in both B-cell lymphomas and histiocytic sarcomas. Furthermore, in the case of histiocytic sarcoma arising from follicular lymphoma, both histiocytic sarcoma and follicular lymphoma contain the characteristic IGH/BCL2 translocation as in the previously reported cases [2,5], which all indicates a clonal evolution of pre-existing follicular lymphoma.

The present study by Wang et al. adds to the small but growing literature on histiocytic sarcomas arising from pre-existing low-grade lymphomas. Previously it has been shown that a genotypic identity may exist between histocytic sarcomas and follicular lymphomas: a follicular lymphoma has either preceded the development of a histiocytic sarcoma or coexisted with it at the same time [2,4,5]. Recent studies revealed that the hematopoietic system has some degree of plasticity, especially between the B-cell and histocytic/dendritic cell. B-cell/myeloid precursors can differentiate into either B-cells or myelocytes based on growth conditions [6,7]. Most cases reported so far have shown a coexistent low-grade B-cell lymphoma and histiocytic sarcoma, or a low-grade B-cell lymphoma preceding a histiocytic sarcoma. These two neoplasms may share a common neoplastic progenitor, which differentiates into the B-cell and histocytic lineage at different time points. It is also possible that the neoplastic B-cell might have undergone transdifferentiation through a dedifferentiation and redifferentiation process to a histiocytic/dendritic phenotype [6,7]. In the current report of two such cases, the presence of mutated IGH genes in both low-grade B-cell lymphomas and histiocytic sarcomas, along with evidence that histiocytic sarcomas partially retain a B-cell lymphoma phenotype, supports a possible transdifferentiation pathway during cell transformation. However, the details of such a postulated mechanism of transdifferentiation remain unclear.

Declaration of interest: The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.