Over the past decade, there has been a significant evolution in the scientific understanding of the biologic mechanisms leading to LCH, driven by new insights in both normal epidermal and disease-associated LC. Prior to these more recent discoveries, LCH was variably classified as a neoplasm, a reactive disorder, or an aberrant immune response and thought to arise from transformed or pathologically activated epidermal LC. Like epidermal LC, LCH lesion LC express CD1a and CD207 (langerin) surface markers. The frequency of LC within LCH lesions is highly variable, with a median of about 8%. The balance of this granulomatous lesion includes lymphocytes (primarily T cells), eosinophils, and macrophages.
Two studies demonstrated that pathologic LCH cells have clonal properties based on clonal X-chromosome inactivation. Additionally, expression studies of pathologic LCH cells from lesions and epidermal Langerhans cells found in skin have demonstrated that pathologic LCH cells have relatively increased expression of immature myeloid dendritic-cell precursors and are therefore likely to derive from abnormal bone-marrow precursor cells or their differentiated ontogeny. Further, several recent studies demonstrated that the expression of langerin/CD207 is not exclusive to epidermal LC but rather that it can be induced in cells from multiple hematopoietic lineages.
The discovery of recurrent BRAFV600E somatic mutations in LCH lesions supports a neoplastic etiology for LCH. BRAFV600E is observed in ~8% of all human cancers and also in benign neoplastic conditions such as melanocytic nevi. Constitutive activation of a MAPK pathway leads to activation of the terminal extracellular signal-related kinase (ERK). Several groups have confirmed recurrent BRAFV600E in 50% to 64% of LCH cases as well as mutually exclusive activating mutations in MAPK pathway genes (primarily alternative BRAF mutations or mutations in MAP2K1 [encodes MEK1]) (Fig. 1).
Fig1. MAPK PATHWAY MUTATIONS IN HISTIOCYTIC DISORDERS. (A) (Left) Schematic of MAPK pathway. Under physiologic conditions, growth factor (gray box) engages tyrosine kinase receptor that transduces signal to nucleus. (Right) Activating mutations (such as BRAF-V600E) drive constitutive ERK activation. In the case of Langerhans cell histiocytosis (LCH), this drives expression of anti-apoptosis BCL2L1 (BCL-xL) and inhibits CCR7. (B) Stacked bar graphs represent percentages of MAPK pathway mutations in each histologic subtype of histiocytosis. ECD, Erdheim-Chester disease; JXG, juvenile xantho granuloma; LCH, Langerhans cell histiocytosis; RDD, Rosai-Dorfman disease.
Taking advantage of the BRAFV600E discovery in LCH lesions, subsequent studies identified BRAFV600E in hematopoietic stem cells from bone-marrow aspirate and myeloid precursors from peripheral blood of patients with disseminated LCH.28 Interestingly, BRAFV600E+ peripheral blood mononuclear cells were rarely observed in patients with more limited “low risk” LCH. A pathogenic role for BRAFV600E in myeloid precursors is further supported by recapitulation of an LCH-like phenotype in mice in which BRAFV600E expression was enforced in CD11c+ cells. The “Misguided Myeloid Differentiation” model suggests that the stage of myeloid precursor in which this mutation develops is related to the differentiation potential of the pathologic cell that determines the extent and severity of disease. These observations support the reclassification of LCH as an inflammatory myeloid neoplastic disorder.
