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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.[11,12] One study has shown that 1% of patients have a positive family history for LCH.[13]

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.[14,15] 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 and it is possible that this group represents a reactive process to smoking.[16] 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.[17] This study also reported nonclonal karyotypic abnormalities in three patients. An increase in chromosomal breakage was also noted.

cdr0000761346.jpg
Figure courtesy of Rikhia Chakraborty, Ph.D. Permission to reuse the figure in any form must be obtained directly from Dr. Chakraborty.

An activating mutation of the BRAF oncogene (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%).[18] A subsequent study with a larger sample size did not confirm this association.[19] The RAS signaling pathway (Figure) transmits signals from a cell surface receptor (e.g., a growth factor) through the RAS pathway (via one of the RAF proteins [A, B, or C]) to phosphorylate MEK and then ERK, which leads to nuclear signals affecting cell cycle and transcription regulation. The V600E mutation of BRAF leads to continuous phosphorylation, and thus activation, of MEK and ERK without the need for an external signal.

The RAS pathway was activated in a few samples that were tested for MEK and ERK expression, whether or not the BRAF V600E mutation was present. The BRAF V600E mutation in LCH has been demonstrated in flow-sorted CD1a-positive LCH cells from fresh lesions in 11 of 16 samples.[20] Another BRAF mutation (BRAF 600DLAT) was identified that resulted in the insertion of four amino acids and that also appeared to activate MAPK pathway signaling.[20] No clinical characteristics associated with the BRAF mutation have been identified.[18,19,20]

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