Mark V. Dahl, MD
LCH limited to skin and LCH affecting internal organs appear to originate from separate mutations with different degrees of risk for death.
Patients with Langerhans cells histiocytosis (LCH) accumulate CD207+ dendritic cells (DCs) in skin, vital organs, or both. Previously, experts considered these cells to be transformed or activated Langerhans cells, because many of them contain Birbeck granules or langerin. Recent studies dispute this; these Langerhans-like cells may be immature myeloid DC precursors. LCH prognosis depends on involvement of the internal organs, regardless of skin disease severity. If LCH involves bone marrow, liver, spleen, or other “high-risk” organs, patients have a >20% risk for related mortality; those with cutaneous disease alone have related mortality rates of almost zero.
Recent reports identify recurrent somatic mutations of BRAF-V600E in skin lesions and blood of LCH patients. These authors assessed BRAF-V600E status in samples of 130 LCH lesions from 100 patients. BRAF-V600E mutation did not correlate with age, sex, single versus multiple lesions, high-risk versus low-risk clinical assessment, location, or other clinical factors; it was associated with a twofold increased risk for recurrence or relapse but not with overall survival. When BRAF-V600E mutation was present in one LCH lesion, the mutation was invariably found in other lesions from the same patient. Not all Langerin+ cells contained the mutation. Circulating cells with BRAF-V600E mutations were found in some patients, always associated with mutated BRAF-V600E in lesions. Mutated cells in blood were particularly likely to be found in patients with high-risk disease and not in any patient with wild-type BRAF in lesions. The investigators generated a severe LCH phenotype in mice by inducing physiologic expression of BRAF-V600E in bone marrow dendritic cell precursors. They conclude that LCH is a myeloid neoplasm and suggest that high-risk LCH arises from mutations of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.
Citation(s):
Berres ML et al. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med 2014 Apr 7; 211:669.
