Sandbox: Langerhans

Pathogenesis

• Langerhans cell histiocytosis arises from epidermal dendritic cells, which are normally involved in the process of antigen presentation to lymphocytic cells.
• Langerhans cells originally arise from the bone marrow, then the cells migrate to other organs such as:

• Skin
• Lymph nodes
• Lungs
• Hypothalamic pituitary axis
• Gastrointestinal tract
• CNS
• Oral cavity

• The malignant organ involvement is variable among patients with Langerhans cell histiocytosis. The disease process may range from an isolated cutaneous or bone involvement to a life-threatening multi-system condition.
• The skeletal distribution of Langerhans cell histiocytosis involves the following sites:

• The skull (most common bone involved)
• Ribs
• Humerus
• Vertebra

• The exact pathogenesis of Langerhans cell histiocytosis is not fully understood. It is thought that Langerhans cell histiocytosis is the result of either a true neoplastic process or a reactive immune condition.
• Facts consistent with the neoplastic process hypothesis include the following:

• The infiltration of organs by monoclonal population of pathologic cells
• The presence of specific recurrent cytogenetic and genomic abnormalities
• The successful treatment of a subset of disseminated Langerhans cell histiocytosis using chemotherapeutic regimens

• Facts consistent with the reactive immune condition hypothesis include the following:

• The evidence of spontaneous remissions that may occur among certain cases of Langerhans cell histiocytosis
• The extensive secretion of multiple cytokines by dendritic cells and bystander-cells (a phenomenon known as cytokine storm)
• The favorable prognosis and relatively good survival rate among patients with no organ dysfunction

• The excessive Langerhans cells clonal proliferation will initiate a non-specific inflammatory response, which will lead to the accumulation of various immune system cells such as:

• Eosinophils
• Macrophages
• Lymphocytes
• Multinucleated giant cells

• Langerhans cell histiocytosis may result in bone marrow failure due to malignant cell infiltration of the bone marrow. This can manifest as:

• Anemia
• Recurrent bleeding
• Recurrent Infections

• The infiltration of the hypothalamic pituitary axis by malignant Langerhans cells will lead to a deficiency in both anterior and posterior pituitary hormones, which may result in:

• Central diabetes insipidus
• Growth retardation
• Delayed puberty

• Langerhans cell histiocytosis may also infiltrate the lymph nodes, spleen, and liver.

Genetics

• Development of Langerhans cell histiocytosis is the result of multiple genetic mutations.
• Genes commonly involved in the pathogenesis of Langerhans cell histiocytosis include:

• BRAF gene mutation located on Chromosome 7
• MAP2K1 gene mutation located on Chromosome 15

Associated Conditions

• Langerhans cell histiocytosis is associated with a number of syndromes that include:

• Hand-Schüller-Christian triad
• Hashimoto-Pritzker disease
• Letterer-Siwe disease

Gross Pathology

• On gross pathology, scaly erythematous, red papules, and extensive eruptions located on the scalp are characteristic finding of Langerhans cell histiocytosis.
• The image below demonstrates the cutaneous lesions observed among Langerhans cell histiocytosis patients:

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Microscopic Pathology

• Characteristic findings of Langerhans cell histiocytosis on light microscopy may include:

• Langerhans cells histiocytes
• Clusters of cells
• Kidney-shaped nucleus
• Abundant foamy cytoplasm
• Fine, granular chromatin pattern
• Prominent eosinophils
• Fibrosis
• Other inflammatory cells may be present (neutrophils, plasma cells, and multinucleated giant cells)