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Histopathologic, Immunologic, and Cytogenetic Characteristics of LCH

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Comparative genomic hybridization has been used to analyze bone and pulmonary LCH cells with conflicting results.[13,15,16,17] 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.[18] 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.[19] 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.[20]

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%).[21] Activating BRAF mutations are also found in selected nonmalignant conditions (e.g., benign nevi) [22] and low-grade malignancies (e.g., pilocytic astrocytoma).[23,24] All of these conditions have in common a generally indolent course with spontaneous resolution sometimes occurring. This distinctive clinical course may be a manifestation of oncogene-induced senescence.[22,25]

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.[26,27] 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.[7] 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.[28] 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.

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