Clinical implications

LCH is included in a group of other pediatric tumors with activating BRAF variants, such as select nonmalignant conditions (e.g., benign nevi) [21] and low-grade malignancies (e.g., pilocytic astrocytoma).[22,23] 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.[21,24]

In some pediatric studies, BRAF V600E variants have been associated with more severe multisystem disease, treatment failure, increased reactivations, and an increased risk of neurodegeneration (see below).[25] These clinical correlates were recently investigated for non-BRAF V600E variants in an international study. Similar to the BRAF V600E cohort, all patients with multisystem risk organ–positive LCH had detectable variants in peripheral blood mononuclear cells. Of seven patients with multisystem risk organ–negative LCH, four had detectable variants. No patients with single-system disease had detectable variants in peripheral blood mononuclear cells. The authors concluded that other MAPK pathway variants are associated with risk status, similar to BRAF V600E variants.[17]BRAF V600E variants 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 outcomes compared with treatment using a BRAF inhibitor alone.[26,27]Several case reports and two case series have also demonstrated the efficacy of BRAF inhibitors for the treatment of LCH in children.[28-33] However, the long-term role of this therapy is complicated because most patients will relapse when the inhibitors are discontinued. For more information, see the sections on Treatment of recurrent, refractory, or progressive high-risk disease: multisystem LCH and Targeted therapies for the treatment of single-system and multisystem disease.

Circulating BRAF V600E–altered 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 altered circulating cells had a sensitivity of 0.59 and specificity of 0.86 for developing the neurodegenerative disease. Even after therapy, some patients with neurodegenerative-disease LCH had circulating BRAF V600E–altered cells.[34]

With additional research, the observation of the BRAF V600E variant (or potentially MAP2K1 variants) in circulating cells or cell-free DNA may become a useful diagnostic tool to define high-risk versus low-risk disease.[2] Additionally, for patients who have a somatic variant, persistence of circulating cells with the variant may be useful as a marker of residual disease.[2]