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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.


Histiocyte is an archaic term for tissue macrophages. The histiocytoses include diseases arising from all cells of the mononuclear phagocytic system, with diseases characterized by presumed lineage and biology into dendritic cell (DC) disorders, macrophage-related disorders, and malignant histiocytic disorders (Table 71–1). Historically the histiocytic disorders have been characterized by phenotype of disease-specific histiocytes (Table 71–2), but now recurrent mitogen-activated protein kinase (MAPK) pathway mutations in clonal myeloid cells in Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), juvenile xanthogranuloma (JXG), Rosai-Dorfman disease (RDD), and malignant histiocytoses clearly separate these inflammatory neoplasias from hemophagocytic lymphohistiocytosis (HLH), characterized by polyclonal reactive macrophages. A working group proposed reclassification based on clinical, histologic, and molecular features: Langerhans cell histiocytosis, indeterminate cell histiocytosis, and Erdheim-Chester disease in the “L” group; juvenile xanthogranuloma in the cutaneous non-LCH group “C”; Rosai-Dorfman Disease in the “R” group; an “M” group of malignant histiocytic diseases; and an “H” ...

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