Progress in Understanding the Pathogenesis of Langerhans Cell Histiocytosis: Back to Histiocytosis X?

Br J Haematol. 2015 Apr;169(1):3-13. doi: 10.1111/bjh.13247. Epub 2014 Nov 28.


Langerhans cell histiocytosis (LCH), the most common histiocytic disorder, is characterized by the accumulation of CD1A(+) /CD207(+) mononuclear phagocytes within granulomatous lesions that can affect nearly all organ systems. Historically, LCH has been presumed to arise from transformed or pathologically activated epidermal dendritic cells called Langerhans cells. However, new evidence supports a model in which LCH occurs as a consequence of a misguided differentiation programme of myeloid dendritic cell precursors. Genetic, molecular and functional data implicate activation of the ERK signalling pathway at critical stages in myeloid differentiation as an essential and universal driver of LCH pathology. Based on these findings, we propose that LCH should be re-defined as an inflammatory myeloid neoplasia. Increased understanding of LCH pathogenesis will provide opportunities to optimize and personalize therapy through improved risk-stratification, targeted therapy and assessment of therapy response based on specific molecular features and origin of the pathological myeloid cells.

Keywords: BRAF V600E; Langerhans cell histiocytosis; extracellular signal-regulated kinase signalling pathway; inflammatory myeloid neoplasia; misguided myeloid differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antigens, CD / metabolism
  • Antigens, CD1 / metabolism
  • Cell Differentiation*
  • Histiocytosis, Langerhans-Cell* / classification
  • Histiocytosis, Langerhans-Cell* / metabolism
  • Histiocytosis, Langerhans-Cell* / pathology
  • Histiocytosis, Langerhans-Cell* / therapy
  • Humans
  • Langerhans Cells* / metabolism
  • Langerhans Cells* / pathology
  • Lectins, C-Type / metabolism
  • MAP Kinase Signaling System
  • Mannose-Binding Lectins / metabolism
  • Models, Biological*
  • Myeloid Cells* / metabolism
  • Myeloid Cells* / pathology
  • Neoplasms* / classification
  • Neoplasms* / metabolism
  • Neoplasms* / pathology
  • Neoplasms* / therapy


  • Antigens, CD
  • Antigens, CD1
  • CD1a antigen
  • CD207 protein, human
  • Lectins, C-Type
  • Mannose-Binding Lectins