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Langerhans Cell Histiocytosis Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Histopathologic, Immunologic, and Cytogenetic Characteristics of LCH

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Etiology

The etiology of LCH is unknown. Efforts to define a viral cause have not been successful.[9,10] One study has shown that 1% of patients have a positive family history for LCH.[11]

Cytogenetic and Genomic Studies

Studies showing clonality in LCH using polymorphisms of methylation-specific restriction enzyme sites on the X-chromosome regions coding for the human androgen receptor, DXS255, PGK, and HPRT were published in 1994.[12,13] Biopsies of lesions with single-system or multisystem disease were found to have a proliferation of LCH cells from a single clone. Pulmonary LCH in adults is usually nonclonal.[14] Cytogenetic abnormalities in LCH have rarely been reported. One study described an abnormal clone t(7;12)(q11.2;p13) from a vertebral lesion of one patient.[15] This study also reported nonclonal karyotypic abnormalities in three patients. An increase in chromosomal breakage was also noted.

Comparative genomic hybridization has been used to analyze bone and pulmonary LCH cells with conflicting results.[14,16,17,18] Thus, there is some doubt if comparative genomic hybridization can reliably identify mutations in LCH.

One report has shown significantly shortened telomeres in lesional LCH cells compared with LCs in inflammatory disorders such as dermatopathic lymphadenitis.[19] However, another group found telomere length of LCH cells from skin multisystem lesions were long compared with those from bone lesions that were heterogeneous in length.[20] Telomerase was more often expressed in skin LCH lesions than in bone lesions. In another study evaluation of peripheral blood leukocyte DNA from high-risk LCH patients showed polymorphisms of two cytokine genes (IL-4 and interferon gamma), which were associated with high-expressor phenotypes.[21]

Activating mutation of the BRAF gene (V600E) 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%).[22] This was confirmed by a group that tested flow-sorted CD1a cells from fresh lesions and found 11 of 16 had the BRAF mutation.[23] They also identified another mutation, BRAF 600 DLAT, which demonstrated upregulation of ERK. These authors could not identify any clinical characteristics that were significantly associated with the BRAF mutation even when they added their population (N = 16) to those previously reported (N = 61). A study of pulmonary lesions from five adults with lung LCH using a next-generation sequencing method to identify mutational hot spots in 46 cancer genes found two of five patients had the BRAF V600E mutation in all nodules tested.[24]

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