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Independent development of lymphoid and histiocytic malignancies from a shared early precursor

Leukemia volume 30, pages 955–958 (2016)Cite this article

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Histiocytic neoplasms are tumors that develop from macrophages and dendritic cells and are also called histiocytes. Histiocytic sarcoma is a malignant tumor derived from mature histiocytes that are characterized by the expression of one or more histiocytic markers (CD163, CD68 or lysozyme) and the absence of Langerhans cell, follicular dendritic cell and myeloid cell markers (CD1a, langerin, CD21, CD35, CD33, CD13 and myeloperoxidase).1, 2 Non-Langerhans cell histiocytosis describes a very diverse group of histiocytic proliferations for which the cells do not meet the criteria for Langerhans cells (CD1a+, Langerin+ and S100+).3 The genetic etiology of these tumors has not been described as yet, but considering the cell types involved, the presumption is that these tumors derive from a myeloid stem cell. Both histiocytic sarcoma and non-Langerhans cell histiocytosis are very rare and mostly affect adults. A few pediatric and young adult cases have been described, and in these cases, the histiocytic tumor often co-occurred or developed subsequently to lymphoid neoplasms such as lymphoma and B-lineage or T-lineage acute lymphoblastic leukemia (T-ALL) (Pagni et al.,4 Feldman et al.,5 Kumar et al.6 and McClure et al.,7 and references therein). Hematopoiesis is postulated as the unidirectional maturation of stem cells into lineage-committed cells. However, immunoglobulin and T-cell receptor gene rearrangements (TR rearrangements) typical for lymphoid cells were also identified in histiocytic tumors (Vos et al.,2 Pagni et al.,4 Feldman et al.,5 Kumar et al.,6 McClure et al.7 and Brunner et al.,8 and references therein). This apparent lineage switch of lymphoid cells might have occurred through (1) transdifferentiation, defined as the transformation of one cell type into another without passing an intermediate pluripotent state or progenitor cell type, or (2) de-differentiation, defined as the transformation via an intermediate pluripotent state or progenitor cell type. Alternatively, these tumors may have developed from a multipotent stem cell that is capable of differentiating into both myeloid and lymphoid precursors.9, 10, 11 In this letter, we describe a child with three tumors from two different lineages in which genetic analysis shows that the tumors were derived from a common precursor cell showing lineage plasticity for both lymphoid and myeloid development.

We isolated genomic DNA from skin fibroblasts, from a bone marrow sample taken at the time of T-ALL diagnosis and from biopsy specimens from the non-Langerhans cell histiocytosis and the histiocytic sarcoma, after informed consent and approval by the medical ethics committee/institutional board (CMO, study 2012/271) of the Radboudumc. To investigate the clonal relationship between the malignancies, we determined the TR gene rearrangements (Supplementary Methods). All samples showed a VDJ-rearranged TRB gene, an incomplete DJ TRB gene rearrangement and two (biallelic) VJ-rearranged TRG genes (Figure 1d). The four clonal rearrangements were of identical size in the three specimens, which suggests that the three tumors originate from the same precursor cell.

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Acknowledgements

We acknowledge Prof Dr Jacques van Dongen and Prof Dr Robert Arceci for their expert advice on the treatment of this patient. We thank Dr Charles Mullighan for helpful discussions and Ingrid Vogelaar, Christian Gilissen and Eugène Verwiel for technical assistance. We thank the members of the Genomic Disorders Group Nijmegen and the Radboud Genomics Technology Center for their technical support. EW is a KWF fellow from the Dutch Cancer Society (KUN2012-5366), AH is supported by the Netherlands Organization for Health Research and Development (ZonMW 916-12-095) and RPK is funded by Stichting Kinderen Kankervrij (KiKa project 150).

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Author notes

  1. R P Kuiper and D M W M te Loo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands

    E Waanders, E J Kamping, A Simons, A Hoischen, M C J Jongmans & R P Kuiper

  2. Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands

    K M Hebeda & P J T A Groenen

  3. Princess Máxima Center for Pediatric Oncology, De Bilt, The Netherlands

    P M Hoogerbrugge

  4. Department of Pediatric Oncology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands

    F N van Leeuwen & D M W M te Loo

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  1. E Waanders
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  2. K M Hebeda
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  9. F N van Leeuwen
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Correspondence to D M W M te Loo.

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Waanders, E., Hebeda, K., Kamping, E. et al. Independent development of lymphoid and histiocytic malignancies from a shared early precursor. Leukemia 30, 955–958 (2016). https://doi.org/10.1038/leu.2015.193

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