• Histiocytic disorders are derived from mononuclear phagocytic cells and dendritic cells. They are divided into three groups.
    • Dendritic cell disorders (e.g., Langerhans cell histiocytosis [LCH], juvenile xanthogranuloma [JXG], Erdheim-Chester disease)
    • Macrophage-related disorders (e.g., hemophagocytic lymphohistiocytosis [HLH], macrophage activation syndrome [MAS], Rosai-Dorfman disease)
    • Malignant histiocytosis (lymphoma subtype)
  • LCH (the focus of this chapter) results from the clonal proliferation of immature myeloid dendritic cells that share similar morphologic expression to skin LCH cells.
  • Other names include the following (Langerhans cell histiocytosis is the preferred terminology):
    • Histiocytosis X, Hand-Schüller-Christian syndrome, Letterer-Siwe disease, eosinophilic granuloma
    • Hashimoto-Pritzker syndrome: infant dermatologic involvement, often self-limited


  • 2 to 10 cases per million children
  • LCH may occur at any age. Median age is 30 months.
  • Single-system disease in 55% of patients; multisystem disease is more common in children 1 to 3 years of age.
  • Male-to-female ratio approximately 1
  • May be more common in whites of northern European descent than African Americans



  • No evidence that relatives of LCH patients are at increased risk of disease.
  • Very rare reports of recurrence within families
  • Specific HLA alleles associated with disease phenotype in some case series


  • Single-system LCH: limited to one organ system; most commonly bone, followed by skin
  • Multisystem LCH involves two or more organs/systems with or without risk organs.
  • Risk organs include hematopoietic system, liver, and/or spleen and portend a worse prognosis. Lungs are no longer considered a risk organ.
  • CNS risk lesions: Lesions in the facial or anterior or middle cranial fossa bones are associated with 3 times increased risk of CNS involvement.
  • CNS lesions can include mass lesions, pituitary stalk involvement, or neurodegenerative disease.


LCH etiology is incompletely understood. BRAFV600E mutations are found in ~60% of cases but are not prognostic. Activation of the RAS/MAPK/MEK/ERK pathway is common regardless of BRAF mutation status. Inflammatory infiltrates and abnormal cytokine production in lesions are common, although role in disease remains unclear.

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