What causes Langerhans cell histiocytosis (LCH)?

Updated: Sep 16, 2020
  • Author: Cameron K Tebbi, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP  more...
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As with other histiocytoses, the etiology of LCH is not known. Extensive searches for evidence of viral infection have been unrevealing. [193]  In one study, it was hypothesized that LCH occurs as a result of Merkel cell polyomavirus infection triggering an IL-1 activation loop.

Tyrosine phosphatase SHP-1, which binds IL-1 receptor-associated kinase 1, was found to have a significantly greater level of expression in cases of LCH with multiple organ involvement than in LCH cases impacting a single organ system. In the former group, the level of IL-17A receptor was also reported to be higher. [194]  A report from Sweden suggests that there is an increased rate of diagnosed histiocytosis in children conceived using in vitro fertilization. [195] In FLH, distinct genetic mutations have been clearly demonstrated.

Cytokines play an important role in the physiology and biology of dendritic cells and macrophages. LCH lesions contain various cytokines. [196, 147, 148] Large amounts of cytokines are produced by CD1a+ LCH and by CD3+ T cells, including IL-2, IL-4, IL-5, and TNF-alpha, which are exclusively generated by T cells. IL-1a is derived from Langerhans cells. T cells and macrophages can produce GM-CSF and INF-alpha, whereas LCHs and macrophages produce IL-10, and T cells and macrophages produce IL-3. Macrophages produce IL-7. Eosinophils are partly responsible for the production of IL-5, INF-gamma, GM-CSF, IL-10, IL-3, and IL-4. [147, 148]

Expression of abnormal leukocyte cellular adhesion molecules in LCH has been reported. [197, 149] These molecules mediate cell-to-cell and cell-to-matrix adhesion.

Using the X-linked human androgen receptor polymerase chain reaction (PCR)-based assay to assess clonality, researchers demonstrated that all forms of LCH are clonal; therefore, LCH is a clonal neoplastic disorder. Origination from a single cell is postulated to indicate neoplasia, although it does not mean that the process is histologically malignant. [198] Using this standard, LCH is considered to be a neoplastic disease rather than a reactive disorder. [199]  However, identification of a putative myeloid progenitor, along with the discovery that most patients with severe LCH have a BRAF-V600E gain-of-function mutation, may indicate that LCH is a reactive disorder with underlying neoplastic potential, possibly a myeloid neoplasm. [14, 44, 200, 201, 202, 203]

The role of genetics in LCH is not well defined. Although HHV6 has been found in LCH lesions, its etiologic significance has been questioned. [204, 205] BRAF-V600E mutations are seen in over 50% of LCH lesions. The B-Raf protein is a central kinase of the MAPK pathway and regulates major cellular functions. BRAF-V600E mutation results in constitutive activation of the downstream MAPK/ERK kinase (MEK) pathway and extracellular signal-regulated kinase (ERK) proteins.

The prevalence of MAP2K1 mutations in BRAF-V600E mutation–negative LCH is high. [206] MAP2K1, encoding the protein MEK1, is seen in 33-50% of LCH lesions, ie, those in which BRAF is not mutated. Some studies suggest that the existence of mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF indicates that ERK activation plays a central part in the pathogenesis of LCH. [200]

Identification of BRAF mutation in LCH and recognition of the importance of microenvironment in progression of this disorder provides opportunities for targeted therapy, such as treatment with vemurafenib (which is commercially available). 

The occurrence of several cases of LCH in one family is rare but has been reported. [207, 208] LCH has been reported in several monozygotic and dizygotic twins. [141, 143, 143, 144, 145, 146, 209] Some consanguinity and involvement in close relatives (cousins) has been reported. [210] Nevertheless, the relative rarity of the familial occurrence does not indicate a notable hereditary influence. Conversely, FHL, which is transmitted as autosomal recessive trait abnormalities of genes localized to bands 9q21.2-22 and 10q21-22 (perforin), is reported in some families. [147, 148] As expected, numerous familial cases of erythrophagocytic lymphohistiocytosis have been reported. [102]

The fusion of nucleophosmin (NPM) and anaplastic lymphoma kinase (ALK) genes that results in NPM-ALK fusion protein, which can be immunohistochemically demonstrated, is reported in malignant histiocytosis. A study reported three cases of histiocytosis in early infancy with enlarged liver and spleen, anemia, and thrombocytopenia. In one case, analysis had revealed TPM-3-ALK fusion. [209]

Spontaneous cytotoxicity of circulating lymphocytes is observed in patients with LCH. Antibody formation to autologous erythrocyte has also been reported. [211] Given these findings, treatment with crude calf-thymus extract, although not substantially successful, was clinically devised and used. [211, 212]

A prominent feature of patients with HLH is deficiency in NK-cell function against MHC-negative K652 target cells. Patients with FHL usually exhibit this defect at diagnosis. Patients with infection-associated hemophagocytic syndrome may have normal function, they may never have completely negative function, or they may develop negative NK-cell activity during the course of the disease. [183]

The etiologic role of impaired effector function of perforin with subsequent inability to release perforin-containing granules is demonstrated in HLH. It is similar to the mononuclear cell infiltration associated with Chediak-Higashi Syndrome and Griscelli Syndrome. [213, 214, 215]

Association of LCH with leukemias and lymphomas has been described. [216]  A study by Yokokawa et al examining the development of LCH during maintenance chemotherapy for T-cell acute lymphoblastic leukemia suggested that cells associated with both diseases arise from a common precursor cell featuring a T-cell receptor rearrangement and a single NOTCH1 mutation. [217]

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