Cancer Health Center

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 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 (DC) which expresses the same antigens (CD1a and CD207) as the skin LC.

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.[5]

Immunologic Abnormalities

Normally, the LC is a primary presenter of antigen to na�ve T-lymphocytes. However, in LCH, the LCH cell does not efficiently stimulate primary T-lymphocyte responses.[6] Antibody staining for the DC markers, CD80, CD86, and class II antigens, has been used to show that in LCH, the abnormal cells are immature DCs that present antigen poorly and are proliferating at a low rate.[3,6,7] Transforming growth factor-beta (TGF-beta) as well as 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.[7] 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.[7]

Etiology

The etiology of LCH is unknown. Efforts to define a viral cause have not been successful.[8,9] One study has shown that 1% of patients have a positive family history for LCH.[10]

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.[11,12] 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.[13] 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.[14] This study also reported nonclonal karyotypic abnormalities in three patients. An increase in chromosomal breakage was also noted.