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Diseases of the histiocyte (ie, macrophage or dendritic cell) lineage have historically been divided into five groups based on the final maturation steps from myeloid progenitor cells and clinical presentations: (1) Langerhans cell histiocytosis (LCH)/Erdheim-Chester Disease (ECD), (2) malignant histiocytosis (MH) or dendritic cell sarcomas, (3) juvenile xanthogranuloma (JXG), (4) Rosai-Dorfman-Destombes disease (RDD), and (5) hemophagocytic lymphohistiocytosis (HLH) syndromes. The distinction among these diseases is based on clinical characteristics and histopathologic staining for unique surface markers. Biological discoveries of recurrent mitogen-activated protein kinase (MAPK) pathway mutations in LCH, ECD, JXG, and RDD support reclassification as inflammatory or myeloid neoplastic disorders. LCH may present at birth or in adulthood with skin rash, bone pain, otitis externa, mucositis, gingivitis, pulmonary dysfunction, chronic diarrhea, diabetes insipidus, and marrow or liver failure. Therapy for LCH in children has been studied in clinical trials by the Histiocyte Society. Treatment for adults is based primarily on case series. MAPK pathway inhibitors have been effective in histiocytic disorders with somatic activating MAPK pathway gene mutations. Although relapses are not typically fatal, they are associated with a higher risk of endocrine and central nervous system complications. Erdheim-Chester disease and juvenile xanthogranuloma are histologically similar, although ECD arises almost exclusively in adults and juvenile xanthogranuloma occurs primarily in children. RDD presents with massive cervical lymphadenopathy in most patients but may also involve other parts of the body. Activating MAPK pathway gene mutations have also been identified in malignant histiocytosis and histiocytic sarcoma. Evidence to support treatment is limited to case series with a range of strategies and variable outcomes. HLH is quite distinct from the clonal myeloid neoplastic “histiocytic disorders” and characterized by dysfunction of T cells, activated macrophages, and pathologic inflammation. Extreme inflammation may also be associated with infections, autoimmune diseases, and/or cancer. Initial therapy is aimed at controlling inflammation with glucocorticoids, cytotoxic chemotherapy, and/or cytokine inhibition. Pediatric patients with HLH associated with inherited disorders of immune function may be cured with hematopoietic cell transplantation.

Acronyms and Abbreviations

ALL, acute lymphoblastic leukemia; ATG, anti-thymocyte globulin; CD, cluster designation; CNS, central nervous system; CT, computed tomography; DC, dendritic cell; DI, diabetes insipidus; DLCO, diffusing capacity in lung for carbon monoxide; ECD, Erdheim-Chester disease; EBV, Epstein-Barr virus; GH, growth hormone; HCT, hematopoietic cell transplantation; HLA-DR, human leukocyte antigen-D related; HLH, hemophagocytic lymphohistiocytosis; IFN, interferon; IgG4+, immunoglobulin G4-positive; IL, interleukin; JXG, juvenile xanthogranuloma; LC, Langerhans cell; LCH, Langerhans cell histiocytosis; LCH-ND, LCH-associated neurodegenerative disease; MACOP-B, methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin; MAID, mesna, doxorubicin, ifosfamide, and dacarbazine; MAPK, mitogen-activated protein kinase; MAS, macrophage activation syndrome; MRI, magnetic resonance imaging; NK, natural killer; PCR, polymerase chain reaction; PET, positron emission tomography; RDD, Rosai-Dorfman disease; RECIST, Response Evaluation Criteria in Solid Tumors; SEER, Surveillance, Epidemiology, and End Results


Histiocyte is an archaic term for tissue macrophages. The histiocytoses include diseases arising from all cells ...

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