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Review
. 2018 Aug 30;379(9):856-868.
doi: 10.1056/NEJMra1607548.

Langerhans-Cell Histiocytosis

Carl E Allen  1 , Miriam Merad  1 , Kenneth L McClain  1
Affiliations
Review

Langerhans-Cell Histiocytosis

Carl E Allen et al. N Engl J Med. .
No abstract available

PubMed Disclaimer

Conflict of interest statement

Dr. Allen reports receiving travel support from Novimmune. No other potential conflict of interest relevant to this article was reported.

Figures

Figure 1.
Figure 1.. Clinical Spectrum of Langerhans-Cell Histiocytosis (LCH).
Positron-emission tomographic (PET) images show a single bone lesion involving the humerus (Panel A, arrow); low-risk lesions involving the orbit, lymph nodes, bone (multifocallesion), and thymus (Panel B); and high-risk lesions involving the liver, spleen, and bone marrow (Panel C). Other classic presentations include a lytic bone lesion (Panel D, arrow), cystic lung lesions (Panel E), and various skin lesions (Panels F through I). Examples of LCH lesions involving the skull and brain include multifocal skull lesions (Panel J, arrow), an orbital lesion (Panel K, arrow), a pituitary lesion (Panel L, arrow), and LCH-associated neurodegeneration (Panel M, arrow).
Figure 2.
Figure 2.. Histologic Features of LCH.
Panel A shows typical LCH lesions with large cells, pale cytoplasm, and reniform nuclei on hematoxylin and eosin staining (A1); CD207-positive immunostaining (A2); VE1-positive immunostaining for BRAF V600E protein (A3); and Birbeck granules visualized with electron microscopy (A4). Panel B shows liver involvement, which is frequently characterized by periportal infiltration by histiocytes (B1) and variable CD207-positive staining (B2). Panel C shows biopsy specimens from a patient with severe LCH-associated neurodegeneration (LCH-ND), characterized by perivascular VE1-positive staining (C1), CD163-positive staining (C2), and a P2RY12 infiltrate with occasional P2RY12-positive, tissue-resident microglia (C3). Panel D shows histiocytic lesions that are characteristic of both LCH and juvenile xanthogranuloma (JXG), with heterogeneous histologic features on hematoxylin and eosin staining (D1), including distinct cell populations that are CD207-positive (D2) and CD68-positive (D3).
Figure 3
Figure 3. Models of LCH Ontogeny and Pathogenesis.
Panel A shows physiologic Langerhans-cell (LC) and dermal dendritic-cell (DC) ontogeny and function. Under normal conditions, LC precursors arise from yolk-sac progenitors or fetal liver monocytes that seed the epidermis and are maintained locally by radioresistant epidermal LC precursors in the steady state. Circulating DC-restricted precursors are constantly recruited to the skin to replenish dermal DCs. During injury or inflammation, bone marrow–derived monocytes can differentiate into epidermal CD207+ LC-like cells or dermal DC-like cells that replenish the damaged LC and dermal DC pool. CCR7 is required for activated epidermal LCs and dermal DCs to migrate through the lymphatics to the lymph node, where they recruit and activate T cells and are ultimately cleared through various mechanisms, including apoptosis. Panel B shows the misguided-myeloid-differentiation model of LCH ontogeny. According to this model, the stage of differentiation in which the myeloid cell acquires activating MAPK mutations determines the extent of LCH. High-risk, multisystem LCH arises from self-renewing stem or progenitor cells from bone marrow; low-risk, multisystem LCH arises from MAPK activation of committed DC precursors or monocytes; and a low-risk, single lesion arises from a regional DC precursor. Clinical data support a fetal-liver origin for self-healing, congenital skin LCH and a hematopoietic origin for clonal cells that infiltrate the brain after systemic disease; a mouse model also suggests that it is possible for cells derived from the fetal yolk sac to drive neurodegeneration. Panel C shows mechanisms of LCH pathogenesis. MAPK activation in precursor cells contributes to the formation of LCH lesions through the following mechanisms: differentiation toward the LC phenotype, impaired migration through abrogation of CCR7 expression, and resistance to apoptosis, resulting in the accumulation of pathologic DCs and the development of an immune infiltrate that contributes to local and systemic inflammation.
Figure 4.
Figure 4.. Activating MAPK Pathway Mutations in LCH.
As shown in Panel A, canonical MAPK signaling transduces extracellular signal through receptor tyrosine kinase (RTK), which activates Ras, then RAF, then MEK, and then extracellular signal-regulated kinase (ERK) proteins, which in turn regulate cell-specific nuclear targets and gene transcription programs. Activating mutations such as BRAF V600E drive constitutive ERK activation and downstream transcriptional targets, including BCL2L1 (up-regulated) and CCR7 (down-regulated). The pie chart in Panel B shows the proportions of cases with specific activating MAPK mutations in a primarily pediatric series from one center.
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