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Under the term histiocytoses, we consider a group of disorders that have in common the proliferation of cells of the mononuclear phagocytic system and the dendritic cell (DC) system. Normally, histiocytes (tissue macrophages) and DCs are involved in immune and inflammatory responses. The histiocytoses are each characterized by localized or generalized reactive or neoplastic proliferation of cells similar, if not identical, to one of these cell types. They are diagnosed on the basis of characteristic signs, symptoms, and laboratory findings that, in combination with specific histological features, satisfy diagnostic criteria. In the case of Langerhans cell histiocytosis (LCH), the proliferating cell is the Langerhans cell, and in hemophagocytic lymphohistiocytosis (HLH), the macrophage accumulates.

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Pathophysiology and Genetics

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The diagnosis of Langerhans cell histiocytosis (LCH) is based on hematologic and histological criteria established by the international Histiocyte Society and subsequently revised by Favara and colleagues.1,2 They feature a monoclonal population of CD1a+ histiocytes with a phenotype akin to that of cells of the antigen-presenting Langerhans cell (LC) family. T lymphocytes, macrophages, eosinophils, together with multinucleated giant cells, are variably present. The CD1a+ LCH cells, required for a definitive diagnosis, in contrast to normal LC, are actively proliferating and have a round rather than dendritic shape. They have a moderate amount of homogeneous, pink, granular cytoplasm and distinct cell margins, and they express several distinctive antigenic markers. The nucleus is folded with indistinct nucleoli. Birbeck granules, typically rod- or racket-shaped intracytoplasmic granules demonstrable on electron microscopy, are only found in LC. High levels of Langerin/CD207 are expressed in the LCH cells in association with Birbeck granules.3

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A central feature of normal immunological regulation involves the production and local action of cytokines. However, this action is normally short lived. In cases of immunologic dysregulation, as is thought to occur in LCH, the overproduction of cytokines can lead to pathologic consequences. LCH is characterized by a lesional “cytokine storm,” so called because of the high level and diversity of cytokines produced locally.4 The inappropriate accumulation of LC at various anatomic sites in LCH, commonly including skin, bone, and lymph nodes as well as nearly all other organs, has shown that the LCH cells are likely to use chemokine-mediated mechanisms to traffic to aberrant anatomical sites or to maintain the persistence of LCH lesions. Chemokines function both by autocrine and paracrine mechanisms; they not only may cause the retention of lesional LCH cells but are also instrumental in the recruitment and retention of bystander cells such as eosinophils and activated T cells.5 The increased levels of cytokines probably reflect the immune activation of the various inflammatory cell types involved in LCH lesions. Although the increased levels of cytokines in LCH lesions might be a secondary phenomenon, it is highly likely that they play a fundamental role in propagating the inflammatory responses responsible for tissue damage. Coury and colleagues reported that the CD1a+ LCH cells spontaneously express ...

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