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, this is followed by the migration of the cells to other organs such as:

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

• 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

Microscopic Pathology

There are ongoing investigations to determine whether Langerhans cell histiocytosis is a reactive (non-cancerous) or neoplastic (cancerous) process. Arguments supporting the reactive nature of Langerhans cell histiocytosis include the occurrence of spontaneous remissions, the extensive secretion of multiple cytokines by dendritic cells and bystander-cells (a phenomenon known as cytokine storm) in the lesional tissue, favorable prognosis, and relatively good survival rate in patients without organ dysfunction.[14][15]

On the other hand, the infiltration of organs by monoclonal population of pathologic cells, and the successful treatment of subset of disseminated disease using chemotherapeutic regimens are all consistent with a neoplastic process.[16][17][18]

In addition, a demonstration, using X chromosome–linked DNA probes, of LCH as a monoclonal proliferation provided additional support for the neoplastic origin of this disease.[19] While clonality is an important attribute of cancer, its presence does not prove that a proliferative process is neoplastic. Recurrent cytogenetic or genomic abnormalities would also be required to demonstrate convincingly that LCH is a malignancy.

Activating mutation of a protooncogen in the Raf family, the BRAF gene, was detected in 35 of 61 (57%) LCH biopsy samples with mutations being more common in patients younger than 10 years (76%) than in patients aged 10 years and older (44%).[20] This study documented the first recurrent mutation in LCH samples. Two independent studies have confirmed this finding.[21][22] Presence of this activating mutation could support the notion to characterize LCH as myeloproliferative disorder.

Langerhans cell histiocytosis (LCH) is a rare disease involving clonal proliferation of Langerhans cells, abnormal cells deriving from bone marrow and capable of migrating from skin to lymph nodes. Clinically, its manifestations range from isolated bone lesions to multisystem disease. LCH is part of a group of clinical syndromes called histiocytoses, which are characterized by an abnormal proliferation of histiocytes (an archaic term for activated dendritic cells and macrophages). These diseases are related to other forms of abnormal proliferation of white blood cells, such as leukemias and lymphomas.

The disease spectrum results from clonal accumulation and proliferation of cells resembling the epidermal dendritic cells called Langerhans cells, sometimes called Dendritic Cell Histiocytosis. These cells in combination with lymphocytes, eosinophils, and normal histiocytes form typical LCH lesions that can be found in almost any organ.[2] A similar set of diseases has been described in canine histiocytic diseases.