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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 ...