Childhood Cancer Genomics (PDQ®)–Health Professional Version
Langerhans Cell Histiocytosis
Studies published in 1994 showed clonality in Langerhans cell histiocytosis (LCH) using polymorphisms of methylation-specific restriction enzyme sites on the X-chromosome regions coding for the human androgen receptor, DXS255, PGK, and HPRT.[1,2] The results of biopsies of lesions with single-system or multisystem disease showed a proliferation of LCH cells from a single clone. The discovery of recurring genomic alterations (primarily BRAF V600E) in LCH (see below) confirmed the clonality of LCH in children.
Pulmonary LCH in adults was initially reported to be nonclonal in approximately 75% of cases, while an analysis of BRAF mutations showed that 25% to 50% of adult lung LCH patients had evidence of BRAF V600E mutations.[3,4] Another study of 26 pulmonary LCH cases found that 50% had BRAF V600E mutations and 40% had NRAS mutations. Approximately the same number of mutations are polyclonal, rather than monoclonal. It has not yet been investigated whether clonality and BRAF pathway mutations are concordant in the same patients, which might suggest a reactive rather than a neoplastic condition in smoker's lung LCH and a clonal neoplasm in other types of LCH.
The genomic basis of LCH was advanced by a 2010 report of an activating mutation of the BRAF oncogene (V600E) that was detected in 35 of 61 cases (57%). Multiple subsequent reports have confirmed the presence of BRAF V600E mutations in 50% or more of LCH cases in children.[7-9] Other BRAF mutations that result in signal activation have been described.[8,10] ARAF mutations are infrequent in LCH but, when present, can also lead to RAS-MAPK pathway activation.
The RAS-MAPK signaling pathway (refer to Figure 8) 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 the extracellular signal-regulated kinase (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. Activation of ERK occurs by phosphorylation, and phosphorylated ERK can be detected in virtually all LCH lesions.[6,12]
Because RAS-MAPK pathway activation can be detected in all LCH cases, but not all cases have BRAF mutations, the presence of genomic alterations in other components of the pathway was suspected. The following genomic alterations were identified:
Whole-exome sequencing of BRAF-mutated versus BRAF–wild-type LCH biopsy tissue samples revealed that 7 of 21 BRAF–wild-type specimens had MAP2K1 mutations, while no BRAF-mutated specimens had MAP2K1 mutations. The mutations in MAP2K1 (which codes for MEK) were activating, as indicated by their induction of ERK phosphorylation.
Another study showed MAP2K1 mutations exclusively in 11 of 22 BRAF–wild-type cases.
Finally, in-frame BRAF deletions and in-frame FAM73A-BRAF fusions have occurred in the group of BRAF V600E and MAP2K1 mutation–negative cases.
Studies support the universal activation of ERK in LCH, with activation in most cases being explained by BRAF and MAP2K1 alterations.[6,12,14] Altogether, these mutations in the MAP kinase pathway account for nearly 90% of the causes of the universal activation of ERK in LCH.[6,12,14]
The presence of the BRAF V600E mutation in blood and bone marrow was studied in a series of 100 patients, 65% of whom tested positive for the BRAF V600E mutation by a sensitive quantitative polymerase chain reaction technique. Circulating cells with the BRAF V600E mutation could be detected in all high-risk patients and in a subset of low-risk multisystem patients. The presence of circulating cells with the mutation conferred a twofold increased risk of relapse. In a similar study that included 48 patients with BRAF V600E–mutated LCH, the BRAF V600E allele was detected in circulating cell-free DNA in 100% of patients with risk-organ–positive multisystem LCH, 42% of patients with risk-organ–negative LCH, and 14% of patients with single-system LCH.
The myeloid dendritic cell origin of LCH was confirmed by finding CD34-positive stem cells with the mutation in the bone marrow of high-risk patients. In those with low-risk disease, the mutation was found in more mature myeloid dendritic cells, suggesting that the stage of cell development at which the somatic mutation occurs is critical in defining the extent of disease in LCH. LCH is now considered a myeloid neoplasm.
Clinical implications of the described genomic findings include the following:
LCH joins a group of other pediatric entities with activating BRAF mutations, including select nonmalignant conditions (e.g., benign nevi)  and low-grade malignancies (e.g., pilocytic astrocytoma).[17,18] All of these conditions have a generally indolent course, with spontaneous resolution occurring in some cases. This distinctive clinical course may be a manifestation of oncogene-induced senescence.[16,19]
BRAF V600E mutations can be targeted by BRAF inhibitors (e.g., vemurafenib and dabrafenib) or by the combination of BRAF inhibitors plus MEK inhibitors (e.g., dabrafenib/trametinib and vemurafenib/cobimetinib). These agents and combinations are approved for adults with melanoma. Treatment of melanoma in adults with combinations of a BRAF inhibitor and a MEK inhibitor showed significantly improved progression-free survival outcome compared with treatment using a BRAF inhibitor alone.[20,21]
Case reports have described activity of BRAF inhibitors against LCH in adult patients [22-26] and pediatric patients, but there are insufficient data to assess the role of these agents in the treatment of children with LCH.
The most serious side effect of BRAF inhibitor therapies is the induction of cutaneous squamous cell carcinomas,[20,21] with the incidence of these second cancers increasing with age; this effect can be reduced by concurrent treatment with both BRAF and MEK inhibitors.[20,21] In a long-term study of adult patients with Erdheim-Chester disease and LCH who received vemurafenib, 85% of patients had arthralgias; 62% of patients had maculopapular rashes; and more than 40% of patients had other skin issues, including hyperkeratosis, seborrheic keratosis, and pruritus.
Circulating BRAF V600E–mutated cells have been found in 59% of patients who developed neurodegenerative-disease LCH, compared with 15% of patients who did not develop neurodegenerative-disease LCH. Detectable mutated circulating cells had a sensitivity of 0.59 and specificity of 0.86 for developing the neurodegenerative disease condition. Even after therapy, some patients with neurodegenerative-disease LCH had circulating BRAF V600E–mutated cells.
With additional research, the observation of BRAF V600E (or potentially mutated MAP2K1) in circulating cells or cell-free DNA may become a useful diagnostic tool to define high-risk versus low-risk disease. Additionally, for patients who have a somatic mutation, persistence of circulating cells with the mutation may be useful as a marker of residual disease.
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