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Histiocytic disorders

Abstract

The historic term ‘histiocytosis’ meaning ‘tissue cell’ is used as a unifying concept for diseases characterized by pathogenic myeloid cells that share histological features with macrophages or dendritic cells. These cells may arise from the embryonic yolk sac, fetal liver or postnatal bone marrow. Prior classification schemes align disease designation with terminal phenotype: for example, Langerhans cell histiocytosis (LCH) shares CD207+ antigen with physiological epidermal Langerhans cells. LCH, Erdheim–Chester disease (ECD), juvenile xanthogranuloma (JXG) and Rosai–Dorfman disease (RDD) are all characterized by pathological ERK activation driven by activating somatic mutations in MAPK pathway genes. The title of this Primer (Histiocytic disorders) was chosen to differentiate the above diseases from Langerhans cell sarcoma and malignant histiocytosis, which are hyperproliferative lesions typical of cancer. By comparison LCH, ECD, RDD and JXG share some features of malignant cells including activating MAPK pathway mutations, but are not hyperproliferative. ‘Inflammatory myeloproliferative neoplasm’ may be a more precise nomenclature. By contrast, haemophagocytic lymphohistiocytosis is associated with macrophage activation and extreme inflammation, and represents a syndrome of immune dysregulation. These diseases affect children and adults in varying proportions depending on which of the entities is involved.

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Fig. 1: Mutations found in histiocytic disorders.
Fig. 2: Physiopathology of Langerhans cell histiocytosis7,61,73.
Fig. 3: Clinical presentations of LCH, ECD, JXG and RDD.
Fig. 4: Manifestations of LCH.
Fig. 5: Clinical presentations of ECD.
Fig. 6: Rashes in JXG.
Fig. 7: Clinical presentations in RDD.
Fig. 8: Diagnostic algorithm for HLH.
Fig. 9: Clinical presentations of HLH.
Fig. 10: Histological characteristics of LCH, JXG and RDD.
Fig. 11: Histology of HLH.

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Acknowledgements

The TXCH Histiocytosis Program is supported by a research grant from the HistioCure Foundation (C.E.A. and K.L.M.). The North American Consortium for Histiocytosis is supported by a Consortium grant from St. Baldrick’s Foundation (C.E.A. and K.L.M.). Additional support was received from: National Institutes of Health (NIH) grants CA154947 (M.M. and C.E.A.) and NCI SPORE in Lymphoma P50CA126752 (C.E.A.); Cancer Research UK (CRUK) grant C30484/A21025 (to M.C.); a St. Baldrick’s Foundation Innovation grant (C.E.A.); and the Leukaemia and Lymphoma Society TRP (C.E.A.)

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All authors reviewed the review concept and finalized the manuscript. Specific areas of focus: Introduction (C.E.A. and K.L.M.); Epidemiology (K.B.R. and K.L.M.); Mechanisms/pathophysiology (C.B., J.H., R.A.M., M.M., J.P., C.E.A. and K.L.M.); Diagnosis, screening and prevention (J.H., R.A.M., J.P., C.E.A. and K.L.M.); Management (J.H., R.A.M., C.E.A. and K.L.M.); Quality of life (J.H., R.M., C.E.A. and K.L.M.); Outlook (M.C. and C.E.A.); Overview of Primer (K.L.M.).

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Correspondence to Kenneth L. McClain.

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K.L.M. and C.E.A. have served on advisory committees for SOBI Corporation. All other authors declare no competing interests.

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Nature Reviews Disease Primers thanks B. Durham, A. Fischer, C. Hutter, T. Imamura and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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McClain, K.L., Bigenwald, C., Collin, M. et al. Histiocytic disorders. Nat Rev Dis Primers 7, 73 (2021). https://doi.org/10.1038/s41572-021-00307-9

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