Langerhans Cell Histiocytosis Treatment (PDQ®)–Health Professional Version

General Information About Langerhans Cell Histiocytosis (LCH)

The histiocytic diseases in children and adults are caused by an abnormal accumulation of cells of the mononuclear phagocytic system. Only Langerhans cell histiocytosis (LCH), a myeloid-derived dendritic cell disorder, is discussed in detail in this summary.

The histiocytic diseases have been reclassified into five categories, and LCH is in the L group.[1] LCH results from the clonal proliferation of immunophenotypically and functionally immature, morphologically rounded LCH cells along with eosinophils, macrophages, lymphocytes, and, occasionally, multinucleated giant cells.[2,3] The term LCH cells is used because there are clear morphologic, phenotypic, and gene expression differences between Langerhans cells of the epidermis (LCs) and those in LCH lesions (LCH cells), despite the pathologic histiocyte having the identical immunophenotypic characteristics of normal epidermal LCs, including the presence of Birbeck granules identified by electron microscopy.

LCH cells, known for many years to be caused by a clonal proliferation, have now been shown to likely derive from a myeloid precursor whose proliferation is uniformly associated with activation of the MAPK/ERK signaling pathway.[4,5] However, the somatic mutation leading to the activation varies and is unknown in 10% to 20% of cases.[6] In the original breakthrough description of the BRAF V600E mutation occurring in approximately 60% of LCH biopsy specimens, the authors also described activation of the RAS-RAF-MEK-ERK pathway in almost all cases, regardless of stage and organ involvement.[7,8] Since then, activating mutations in several other genes in the pathway have been identified in a significant percentage of BRAF V600E–negative LCH specimens, including MAP2K1, in-frame deletions plus another leading to upregulation of BRAF, and, less frequently, the CSF-1 receptor, RAS, and ARAF.[9-11]

In accordance with these findings, the pathologic histiocyte or LCH cell has a gene expression profile closely resembling that of a myeloid dendritic cell. Studies have also demonstrated that the BRAF V600E mutation can be identified in mononuclear cells in peripheral blood and cell-free DNA, usually in patients with disseminated disease.[3,12,13] This shows that multisystem LCH arises from a somatic mutation within a marrow or circulating precursor cell, while localized disease arises from the mutation occurring in a precursor cell at the local site.[3]

The above findings have led all clinicians to agree that LCH is a myeloid neoplasm; however, discussion remains about whether it is a malignant neoplasm with varying clinical behavior. The same BRAF V600E mutation has been found in other cancers, including malignant melanoma; however, V600E-mutated BRAF is also present in benign nevi, possibly indicating the need for additional mutations to render the cell malignant.[7] Nevertheless, these findings have raised the possibility of targeted therapy with inhibitors already used in the treatment of melanoma. Several trials of BRAF inhibitors are open for adults and children with BRAF V600E–mutated tumors, including LCH.

(Refer to the Cytogenetic and Genomic Studies and Cytokine Analysis by Immunohistochemical Staining and Gene Expression Array Studies sections of this summary for more information.)

LCH may involve a single organ (single-system LCH), which may be a single site (unifocal) or involve multiple sites (multifocal); or LCH may involve multiple organs (multisystem LCH), which may involve a limited number of organs or be disseminated. Involvement of specific organs such as the liver, spleen, and hematopoietic system separates multisystem LCH into a high-risk group and a low-risk group, where risk indicates the risk of death from disease.

References

Emile JF, Abla O, Fraitag S, et al.: Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 127 (22): 2672-81, 2016. [PUBMED Abstract]
Laman JD, Leenen PJ, Annels NE, et al.: Langerhans-cell histiocytosis 'insight into DC biology'. Trends Immunol 24 (4): 190-6, 2003. [PUBMED Abstract]
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]
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]
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]
Monsereenusorn C, Rodriguez-Galindo C: Clinical Characteristics and Treatment of Langerhans Cell Histiocytosis. Hematol Oncol Clin North Am 29 (5): 853-73, 2015. [PUBMED Abstract]
Badalian-Very G, Vergilio JA, Fleming M, et al.: Pathogenesis of Langerhans cell histiocytosis. Annu Rev Pathol 8: 1-20, 2013. [PUBMED Abstract]
Badalian-Very G, Vergilio JA, Degar BA, et al.: Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 116 (11): 1919-23, 2010. [PUBMED Abstract]
Chakraborty R, Hampton OA, Shen X, et al.: Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood 124 (19): 3007-15, 2014. [PUBMED Abstract]
Nelson DS, van Halteren A, Quispel WT, et al.: MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis. Genes Chromosomes Cancer 54 (6): 361-8, 2015. [PUBMED Abstract]
Chakraborty R, Burke TM, Hampton OA, et al.: Alternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis. Blood 128 (21): 2533-2537, 2016. [PUBMED Abstract]
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]
Hyman DM, Diamond EL, Vibat CR, et al.: Prospective blinded study of BRAFV600E mutation detection in cell-free DNA of patients with systemic histiocytic disorders. Cancer Discov 5 (1): 64-71, 2015. [PUBMED Abstract]