Etiology

Langerhans cells are epidermal dendritic cells that present antigen to, and activate, antigen-specific T lymphocytes. They are found in most organs. LCH is considered an inflammatory myeloid neoplasia. The condition is caused by a clonal proliferation of myeloid precursor cells, which differentiate into pathologic Langerhans cells in lesions.[13][14]

Activating mutations in the mitogen-activated protein kinase (MAPK) pathway, in particular BRAF (B-Raf proto-oncogene) V600E, have been identified in 50% to 60% cases of LCH.[15][16][17] BRAF is a cytoplasmic tyrosine kinase involved in growth factor signal transduction. Activating mutations, such as BRAF V600E, lead to increased transcription of BCL-2 like 1 (BCL2L1), which inhibits apoptosis, and decreased transcription of C-C motif chemokine receptor 7 (CCR7), which stimulates dendritic cell maturation and stimulates mobilization of activated Langerhans cells to draining lymph nodes.[3][18][19] The resultant accumulation of pathologic dendritic cells contributes to local and systemic inflammation, and may infiltrate or damage the surrounding tissue.[3][20]

Activating MAPK pathway mutations can occur at different stages of myeloid differentiation. Mutations in pluripotent hematopoietic stem cells (expressing CD34) are hypothesized to cause high-risk LCH, while mutations in dendritic cell precursors and monocytes (expressing CD11c or CD14) are thought to give rise to low-risk LCH.[13][16]

Pathophysiology

LCH is characterized by granulomatous lesions containing clonal proliferation of pathologic Langerhans cells, expressing CD1a, CD207 (langerin), and S100. LCH cells are large with a kidney-shaped nucleus.[14] [Figure caption and citation for the preceding image starts]: Very high magnification micrograph of Langerhans cell histiocytosis. H&E stain. It is characterized by Langerhans-type histiocytes that have a reniform (kidney-shaped) nucleus and stain with S100 and CD1aNephron. Reproduced under a creative commons license CC BY-SA 3.0: https://creativecommons.org/licenses/by-sa/3.0/deed.en [Citation ends].com.bmj.content.model.Caption@77a0c68e

Neoplastic Langerhans cells activate and recruit other inflammatory cells, leading to development of an inflammatory infiltrate including activated T cells, eosinophils, neutrophils, and macrophages.[14] Local immune dysregulation develops, characterized by increased proinflammatory cytokine expression, tissue remodeling, and neo-angiogenesis.[21] Environmental factors, such as tobacco smoke or infection, contribute to the development and persistence of the inflammation.[20][22] Tobacco smoke causes accumulation of Langerhans cells in the lungs, and induces proinflammatory cytokine production, which leads to histiocytic granuloma formation.[20]

Classification

Histiocyte Society: histiocytosis classification[1]

L (Langerhans) group

  • Langerhans cell histiocytosis (LCH)

    • LCH single system

    • LCH lung positive

    • LCH multiple systems (MS) risk organ (RO) positive

    • LCH MS RO negative

    • Associated with another myeloproliferative/myelodysplastic disorder

  • Indeterminate cell histiocytosis

    • Erdheim Chester disease (ECD) classical type

    • ECD without bone involvement

    • ECD associated with another myeloproliferative/myelodysplastic disorder

    • Extracutaneous or disseminated juvenile xanthogranuloma with mitogen-activated protein kinase (MAPK)-activating or anaplastic lymphoma kinase (ALK) translocations

  • Mixed ECD and LCH

C (cutaneous) group

  • Cutaneous non-LCH histiocytoses

    • Xanthgranuloma family

    • Non-xanthogranuloma family

  • Cutaneous non-LCH histiocytoses with a major systemic component

    • Xanthoma disseminatum

    • Multicentric reticulocytosis

M (malignant) group

  • Primary malignant histiocytosis

  • Secondary malignant histiocytosis

R (Rosai-Dorfman disease and miscellaneous noncutaneous, non-Langerhans cell histiocytoses) group

  • Familial Rosai-Dorfman disease (RDD)

  • Classical (nodal) RDD

  • Extranodal RDD

  • Neoplasia-associated RDD

  • Immune disease-associated RDD

H (hemophagocytic lymphohistiocytosis and macrophage activation syndrome) group

  • Primary hemophagocytic lymphohistiocytosis (HLH)

  • Secondary HLH

Euro Histio Net: clinical classification of pediatric LCH[2]

Single-system:

  • One organ system involved

  • Usually bone, skin, lymph nodes, lungs, or the thyroid or pituitary gland.

Multisystem:

  • 2 or more organ systems involved

  • Can be with or without involvement of risk organs.

Risk organs:

  • Specific organs are considered high-risk, because the associated mortality rates in those who do not respond to treatment are high

  • High-risk organs include the liver, spleen, and bone marrow.

Histiocyte Society: clinical classification of LCH in adults[4]

  • Unifocal LCH: solitary lesion involving any organ

  • Single-system pulmonary LCH: isolated lung involvement (predominantly smoking related)

  • Single-system multifocal LCH: >1 lesion involving any organ

  • Multisystem LCH: ≥2 organ/system involvement.

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