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Histiocytic disorders arise from abnormal development or function of histiocytes, which literally means “tissue cells.” However, we remain loyal to the archaic nomenclature for histiocytosis that is meant to encompass all cells of the mononuclear phagocytic system. The histiocytic umbrella therefore covers a wide range of disorders, from physiologic reaction to inflammatory stimuli to dysregulated differentiation and proliferation. This chapter will focus on the most common histiocytic disorders in children, including Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), Rosai-Dorfman disease, and hemophagocytic lymphohistiocytosis (HLH).



Historical diagnoses of Hand-Schüller-Christian disease (pituitary and bone lesions), Letterer-Siwe disease (disseminated disease), or eosinophilic granuloma (bone lesions) are now collectively classified as LCH. While LCH is often thought of as a rare disease, it is actually as common as pediatric rhabdomyosarcoma and pediatric Hodgkin lymphoma, with an estimated 5 cases per 1 million children. The median age at diagnosis is 1.8 years, although it can present at any age. Males are affected slightly more than females by a 1.3-to-1 ratio. No inherited risk factors have been identified, though LCH arises more frequently in people with Hispanic ethnicity and is relatively rare in people with African ancestry.


Langerhans cell histiocytosis lesions have a characteristic appearance on hematoxylin and eosin (H&E) stain, with the histiocytes having coffee-bean–shaped nuclei surrounded by an inflammatory infiltrate (Fig. 459-1A). The pathologic dendritic cells in LCH lesions have a shared histology with epidermal Langerhans cells, which stain with CD1a+/CD207 (Fig. 459-1B). Based on shared histology, LCH was initially hypothesized to arise from abnormally activated or transformed epidermal Langerhans cells.

Figure 459-1

Langerhans cell histiocytosis (LCH) lesion histology. A: LCH lesion demonstrating foamy histiocytes with grooved nuclei on a polymorphous inflammatory infiltrate background composed of abundant eosinophils, lymphocytes, neutrophils. B: CD207+ (langerin) antibody stain on an LCH lesion demonstrating strong positivity with associated multinucleated giant cells from an LCH lesion. C: Juvenile xanthogranuloma lesion demonstrating multinucleated Touton giant cells and xanthomatous cells in background. D: Biopsy of an enlarged lymph node from a child with significant bilateral cervical lymphadenopathy. This image demonstrates emperipolesis, a characteristic of Rosai-Dorfaman disease, where viable lymphocytes traffic through with histiocytes (clear background). E: Bone marrow aspirate from a patient with hemophagocytic lymphohistiocytosis, demonstrating characteristic vacuolated macrophages engulfing red blood cells (hemophagocytosis) and lymphocytes.

Multiple studies have identified specific clonal LCH histiocytes within LCH lesions. Additionally, recent discoveries of somatic mutations in LCH lesion histiocytes have advanced our understanding of the pathogenesis of LCH. Approximately 60% of LCH biopsy samples are found to have a recurrent mutation in BRAF V600E, an oncogene that constitutively activates the mitogen-activated protein kinase (MAPK) signal transduction pathway (Fig. 459-2). In patients without BRAF V600E, ...

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