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Langerhans Cell Histiocytosis Treatment (PDQ®)

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Histopathologic, Immunologic, and Cytogenetic Characteristics of LCH

Cell of Origin and Biologic Correlates
Immunologic Abnormalities
Etiology
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 divides 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 cells that express the monocyte marker CD14, which is not found on normal skin Langerhans cells (LCs).[3] 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.[4] Rather it is likely to be a myeloid dendritic cell, which expresses the same antigens (CD1a and CD207) as the skin LC. 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.[5]

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.[6]

Immunologic Abnormalities

Normally, the LC is a primary presenter of antigen to naïve T-lymphocytes. However, in LCH, the LCH cell does not efficiently stimulate primary T-lymphocyte responses.[7] 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.[3,7,8] 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 LCH patients has been reported.[8] 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 LCH patients than in controls and returned to a normal level when patients were in remission.[8]

Etiology

The etiology of LCH is unknown. Efforts to define a viral cause have not been successful.[9,10] One study has shown that 1% of patients have a positive family history for LCH.[11]

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.[12,13] 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.[14] 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.[15] This study also reported nonclonal karyotypic abnormalities in three patients. An increase in chromosomal breakage was also noted.

Comparative genomic hybridization has been used to analyze bone and pulmonary LCH cells with conflicting results.[14,16-18] Thus, there is some doubt if comparative genomic hybridization can reliably identify mutations in LCH.

One report has shown significantly shortened telomeres in lesional LCH cells compared with LCs in inflammatory disorders such as dermatopathic lymphadenitis.[19] However, another group found telomere length of LCH cells from skin multisystem lesions were long compared with those from bone lesions that were heterogeneous in length.[20] Telomerase was more often expressed in skin LCH lesions than in bone lesions. In another study evaluation of peripheral blood leukocyte DNA from high-risk LCH patients showed polymorphisms of two cytokine genes (IL-4 and interferon gamma), which were associated with high-expressor phenotypes.[21]

Activating mutation of the BRAF gene (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%).[22] This was confirmed by a group that tested flow-sorted CD1a cells from fresh lesions and found 10 of 16 samples had a pathogenic BRAF mutation.[23] Nine cases had the BRAF V600E mutation, and one additional case had a novel mutation, BRAF 600 DLAT, which demonstrated upregulation of ERK. These authors could not identify any clinical characteristics associated with the BRAF mutant genotype, even when they added their population (N = 16) to those previously reported (N = 61). A study of pulmonary lesions from five adults with lung LCH using a next-generation sequencing method to identify mutational hot spots in 46 cancer genes found two of five patients had the BRAF V600E mutation in all nodules tested.[24]

Activating BRAF mutations are also found in selected nonmalignant conditions (e.g., benign nevi) [25] and low-grade malignancies (e.g., pilocytic astrocytoma).[26,27] 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.[25,28]

Cytokine Analysis by Immunohistochemical Staining and Gene Expression Array Studies

Immunohistochemical staining of LCH lesions have shown apparent upregulation of the chemokines CCR6 and possibly CCR7.[29,30] 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.[8] 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 LCH patients.[31] 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.[4]

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.[4] 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.[32]

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.[33] 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.[34]

References
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  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. 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]

  5. 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]

  6. 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]

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  10. 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]

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

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  17. Chikwava KR, Hunt JL, Mantha GS, et al.: Analysis of loss of heterozygosity in single-system and multisystem Langerhans' cell histiocytosis. Pediatr Dev Pathol 10 (1): 18-24, 2007 Jan-Feb.  [PUBMED Abstract]

  18. da Costa CE, Szuhai K, van Eijk R, et al.: No genomic aberrations in Langerhans cell histiocytosis as assessed by diverse molecular technologies. Genes Chromosomes Cancer 48 (3): 239-49, 2009.  [PUBMED Abstract]

  19. Bechan GI, Meeker AK, De Marzo AM, et al.: Telomere length shortening in Langerhans cell histiocytosis. Br J Haematol 140 (4): 420-8, 2008.  [PUBMED Abstract]

  20. da Costa CE, Egeler RM, Hoogeboom M, et al.: Differences in telomerase expression by the CD1a+ cells in Langerhans cell histiocytosis reflect the diverse clinical presentation of the disease. J Pathol 212 (2): 188-97, 2007.  [PUBMED Abstract]

  21. De Filippi P, Badulli C, Cuccia M, et al.: Specific polymorphisms of cytokine genes are associated with different risks to develop single-system or multi-system childhood Langerhans cell histiocytosis. Br J Haematol 132 (6): 784-7, 2006.  [PUBMED Abstract]

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

  23. 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]

  24. Yousem SA, Dacic S, Nikiforov YE, et al.: Pulmonary Langerhans cell histiocytosis: profiling of multifocal tumors using next-generation sequencing identifies concordant occurrence of BRAF V600E mutations. Chest 143 (6): 1679-84, 2013.  [PUBMED Abstract]

  25. 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]

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  29. 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]

  30. 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]

  31. 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]

  32. 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]

  33. 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]

  34. 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]