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Langerhans Cell Histiocytosis Treatment (PDQ®)

Health Professional Version
Last Modified: 06/04/2014

Histopathologic, Immunologic, and Cytogenetic Characteristics of LCH

Cell of Origin and Biologic Correlates
Immunologic Abnormalities
Cytogenetic and Genomic Studies
Cytokine Analysis by Immunohistochemical Staining and Gene Expression Array Studies
Human Leukocyte Antigen (HLA) Type and Association With LCH

Cell of Origin and Biologic Correlates

Modern classification of the histiocytic diseases subdivides them into dendritic cell–related, monocyte/macrophage-related, or true malignancies. Langerhans cell histiocytosis (LCH) is a dendritic cell disease.[1,2] The Langerhans cells (LCH cells) in LCH lesions are immature dendritic cells making up less than 10% of the cells present in LCH lesions.[3,4] Comprehensive gene expression array data analysis on LCH cells is consistent with the concept that the skin LC is not the cell of origin for LCH.[5] Rather it is likely to be a myeloid dendritic cell, which expresses the same antigens (CD1a and CD207) as the skin LC.[6] This concept was further supported by a study reporting that the transcription profile of LCH cells was distinct from myeloid and plasmacytoid dendritic cells, as well as epidermal LCs.[6,7]

LCH lesions also contain lymphocytes, macrophages, neutrophils, eosinophils, fibroblasts, and sometimes multinucleated giant cells. In the brain, the following three types of histopathologic findings have been described in LCH:

  • Mass lesions in meninges or choroid plexus with CD1a-positive LCH cells and predominantly CD8-positive lymphocytes.

  • Mass lesions in connective tissue spaces with CD1a-positive LCH cells and predominantly CD8-positive lymphocytes causing an inflammatory response and neuronal loss.

  • Predominantly CD8+ lymphocyte infiltration with neuronal degeneration, microglial activation, and gliosis.[8]

Immunologic Abnormalities

Normally, the LC is a primary presenter of antigen to naïve T-lymphocytes. However, in LCH, the pathologic dendritic cell does not efficiently stimulate primary T-lymphocyte responses.[9] Antibody staining for the dendritic cell markers, CD80, CD86, and class II antigens, has been used to show that in LCH, the abnormal cells are immature dendritic cells that present antigen poorly and are proliferating at a low rate.[3,9,10] Transforming growth factor-beta (TGF-beta) and interleukin (IL)-10 are possibly responsible for preventing LCH cell maturation in LCH.[3] The expansion of regulatory T cells in patients with LCH has been reported.[10] The population of CD4-positive CD25(high) FoxP3(high) cells was reported to comprise 20% of T cells and appeared to be in contact with LCH cells in the lesions. These T cells were present in higher numbers in the peripheral blood of patients with LCH than in controls and returned to a normal level when patients were in remission.[10]


The etiology of LCH is unknown. Efforts to define a viral cause have not been successful.[11,12] One study has shown that 1% of patients have a positive family history for LCH.[13]

Cytogenetic and Genomic Studies

Studies showing clonality in LCH using polymorphisms of methylation-specific restriction enzyme sites on the X-chromosome regions coding for the human androgen receptor, DXS255, PGK, and HPRT were published in 1994.[14,15] Biopsies of lesions with single-system or multisystem disease were found to have a proliferation of LCH cells from a single clone. Pulmonary LCH in adults is usually nonclonal and it is possible that this group represents a reactive process to smoking.[16] Cytogenetic abnormalities in LCH have rarely been reported. One study described an abnormal clone t(7;12)(q11.2;p13) from a vertebral lesion of one patient.[17] This study also reported nonclonal karyotypic abnormalities in three patients. An increase in chromosomal breakage was also noted.

BRAF-RAS pathway
Figure courtesy of Rikhia Chakraborty, Ph.D. Permission to reuse the figure in any form must be obtained directly from Dr. Chakraborty.

An activating mutation of the BRAF oncogene (V600E) was detected in 35 of 61 (57%) LCH biopsy samples, with mutations being more common in patients younger than 10 years (76%) than in patients aged 10 years and older (44%).[18] A subsequent study with a larger sample size did not confirm this association.[19] The RAS signaling pathway (Figure) 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 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.

The RAS pathway was activated in a few samples that were tested for MEK and ERK expression, whether or not the BRAF V600E mutation was present. The BRAF V600E mutation in LCH has been demonstrated in flow-sorted CD1a-positive LCH cells from fresh lesions in 11 of 16 samples.[20] Another BRAF mutation (BRAF 600DLAT) was identified that resulted in the insertion of four amino acids and that also appeared to activate MAPK pathway signaling.[20] No clinical characteristics associated with the BRAF mutation have been identified.[18-20]

A series of 135 biopsies from 100 patients were tested for the BRAF V600E mutation by a sensitive quantitative polymerase chain reaction technique and found the mutation in 65% of patients.[19] Circulating cells with the BRAF V600E mutation could be detected in all high-risk patients and in a subset of low-risk multisystem patients. Presence of the circulating cells with the mutation conferred a twofold increased risk of relapse. The myeloid dendritic cell origin of LCH was confirmed by finding CD34+ stem cells with the mutation in the bone marrow of high-risk patients. Those with low-risk disease had more mature myeloid dendritic cells with the mutation, but not the stem cells suggesting the stage of cell development is critical in defining the clinical characteristics of LCH, which can now be considered a myeloid neoplasia.

Activating BRAF mutations are also found in selected 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 sometimes occurring. This distinctive clinical course may be a manifestation of oncogene-induced senescence.[21,24]

Cytokine Analysis by Immunohistochemical Staining and Gene Expression Array Studies

Immunohistochemical staining of LCH lesions has shown apparent upregulation of the chemokines CCR6 and possibly CCR7.[25,26] In an analysis of gene expression in LCH by gene array techniques, 2,000 differentially expressed genes were identified. Of 65 genes previously reported to be associated with LCH, only 11 were found to be upregulated in the array results. The most highly upregulated gene in both CD207 and CD3-positive cells was osteopontin; other genes that activate and recruit T cells to sites of inflammation are also upregulated. The expression profile of the T cells was that of an activated regulatory T-cell phenotype with increased expression of FOXP3, CTLA4, and osteopontin. These findings support a previous report on the expansion of regulatory T cells in LCH.[10] There was pronounced expression of genes associated with early myeloid progenitors including CD33 and CD44, which is consistent with an earlier report of elevated myeloid dendritic cells in the blood of patients with LCH.[27] A model of "Misguided Myeloid Dendritic Cell Precursors" has been proposed, whereby myeloid dendritic cell precursors are recruited to sites of LCH by an unknown mechanism and the dendritic cells in turn recruit lymphocytes by excretion of osteopontin, neuropilin-1, and vannin-1.[5]

Several investigators have published studies evaluating the level of various cytokines or growth factors in the blood of patients with LCH that have included many of the genes found not to be upregulated by the gene expression results discussed above.[5] One explanation for elevated levels of these proteins is a systemic inflammatory response with the cytokines/growth factors being produced by cells outside the LCH lesions. A second possible explanation is that macrophages in the LCH lesions produce the cytokines measured in the blood or are concentrated in lesions.

IL-1 beta and prostaglandin GE2 levels were measured in the saliva of patients with oral LCH lesions or multisystem high-risk patients with and without oral lesions; levels of both were higher in patients with active disease and decreased after successful therapy.[28]

Human Leukocyte Antigen (HLA) Type and Association With LCH

Specific associations of LCH with distinct HLA types and extent of disease have been reported. In a study of 84 Nordic patients, those with only skin or bone involvement more frequently had HLA-DRB1*03 type than those with multisystem disease.[29] In 29 patients and 37 family members in the United States, the Cw7 and DR4 types were significantly more prevalent in Caucasians with single-bone lesions.[30]

  1. Laman JD, Leenen PJ, Annels NE, et al.: Langerhans-cell histiocytosis 'insight into DC biology'. Trends Immunol 24 (4): 190-6, 2003.  [PUBMED Abstract]

  2. Jaffe R: The diagnostic histopathology of langerhans' cell histiocytosis. In: Weitzman S, Egeler R M, eds.: Histiocytic Disorders of Children and Adults. Cambridge, United Kingdom: Cambridge University Press, 2005, pp 14-39. 

  3. Geissmann F, Lepelletier Y, Fraitag S, et al.: Differentiation of Langerhans cells in Langerhans cell histiocytosis. Blood 97 (5): 1241-8, 2001.  [PUBMED Abstract]

  4. Berres ML, Allen CE, Merad M: Pathological consequence of misguided dendritic cell differentiation in histiocytic diseases. Adv Immunol 120: 127-61, 2013.  [PUBMED Abstract]

  5. Allen CE, Li L, Peters TL, et al.: Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells. J Immunol 184 (8): 4557-67, 2010.  [PUBMED Abstract]

  6. Ginhoux F, Merad M: Ontogeny and homeostasis of Langerhans cells. Immunol Cell Biol 88 (4): 387-92, 2010 May-Jun.  [PUBMED Abstract]

  7. Hutter C, Kauer M, Simonitsch-Klupp I, et al.: Notch is active in Langerhans cell histiocytosis and confers pathognomonic features on dendritic cells. Blood 120 (26): 5199-208, 2012.  [PUBMED Abstract]

  8. Grois N, Prayer D, Prosch H, et al.: Neuropathology of CNS disease in Langerhans cell histiocytosis. Brain 128 (Pt 4): 829-38, 2005.  [PUBMED Abstract]

  9. Yu RC, Morris JF, Pritchard J, et al.: Defective alloantigen-presenting capacity of 'Langerhans cell histiocytosis cells'. Arch Dis Child 67 (11): 1370-2, 1992.  [PUBMED Abstract]

  10. Senechal B, Elain G, Jeziorski E, et al.: Expansion of regulatory T cells in patients with Langerhans cell histiocytosis. PLoS Med 4 (8): e253, 2007.  [PUBMED Abstract]

  11. McClain K, Jin H, Gresik V, et al.: Langerhans cell histiocytosis: lack of a viral etiology. Am J Hematol 47 (1): 16-20, 1994.  [PUBMED Abstract]

  12. Jeziorski E, Senechal B, Molina TJ, et al.: Herpes-virus infection in patients with Langerhans cell histiocytosis: a case-controlled sero-epidemiological study, and in situ analysis. PLoS One 3 (9): e3262, 2008.  [PUBMED Abstract]

  13. Aricò M, Nichols K, Whitlock JA, et al.: Familial clustering of Langerhans cell histiocytosis. Br J Haematol 107 (4): 883-8, 1999.  [PUBMED Abstract]

  14. Willman CL, Busque L, Griffith BB, et al.: Langerhans'-cell histiocytosis (histiocytosis X)--a clonal proliferative disease. N Engl J Med 331 (3): 154-60, 1994.  [PUBMED Abstract]

  15. Yu RC, Chu C, Buluwela L, et al.: Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis. Lancet 343 (8900): 767-8, 1994.  [PUBMED Abstract]

  16. Dacic S, Trusky C, Bakker A, et al.: Genotypic analysis of pulmonary Langerhans cell histiocytosis. Hum Pathol 34 (12): 1345-9, 2003.  [PUBMED Abstract]

  17. Betts DR, Leibundgut KE, Feldges A, et al.: Cytogenetic abnormalities in Langerhans cell histiocytosis. Br J Cancer 77 (4): 552-5, 1998.  [PUBMED Abstract]

  18. Badalian-Very G, Vergilio JA, Degar BA, et al.: Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 116 (11): 1919-23, 2010.  [PUBMED Abstract]

  19. Berres ML, Lim KP, Peters T, et al.: BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med 211 (4): 669-83, 2014.  [PUBMED Abstract]

  20. Satoh T, Smith A, Sarde A, et al.: B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease. PLoS One 7 (4): e33891, 2012.  [PUBMED Abstract]

  21. Michaloglou C, Vredeveld LC, Soengas MS, et al.: BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436 (7051): 720-4, 2005.  [PUBMED Abstract]

  22. Jones DT, Kocialkowski S, Liu L, et al.: Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68 (21): 8673-7, 2008.  [PUBMED Abstract]

  23. Pfister S, Janzarik WG, Remke M, et al.: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118 (5): 1739-49, 2008.  [PUBMED Abstract]

  24. Jacob K, Quang-Khuong DA, Jones DT, et al.: Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin Cancer Res 17 (14): 4650-60, 2011.  [PUBMED Abstract]

  25. Fleming MD, Pinkus JL, Fournier MV, et al.: Coincident expression of the chemokine receptors CCR6 and CCR7 by pathologic Langerhans cells in Langerhans cell histiocytosis. Blood 101 (7): 2473-5, 2003.  [PUBMED Abstract]

  26. Annels NE, Da Costa CE, Prins FA, et al.: Aberrant chemokine receptor expression and chemokine production by Langerhans cells underlies the pathogenesis of Langerhans cell histiocytosis. J Exp Med 197 (10): 1385-90, 2003.  [PUBMED Abstract]

  27. Rolland A, Guyon L, Gill M, et al.: Increased blood myeloid dendritic cells and dendritic cell-poietins in Langerhans cell histiocytosis. J Immunol 174 (5): 3067-71, 2005.  [PUBMED Abstract]

  28. Preliasco VF, Benchuya C, Pavan V, et al.: IL-1 beta and PGE2 levels are increased in the saliva of children with Langerhans cell histiocytosis. J Oral Pathol Med 37 (9): 522-7, 2008.  [PUBMED Abstract]

  29. Bernstrand C, Carstensen H, Jakobsen B, et al.: Immunogenetic heterogeneity in single-system and multisystem langerhans cell histiocytosis. Pediatr Res 54 (1): 30-6, 2003.  [PUBMED Abstract]

  30. McClain KL, Laud P, Wu WS, et al.: Langerhans cell histiocytosis patients have HLA Cw7 and DR4 types associated with specific clinical presentations and no increased frequency in polymorphisms of the tumor necrosis factor alpha promoter. Med Pediatr Oncol 41 (6): 502-7, 2003.  [PUBMED Abstract]