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    Langerhans Cell Histiocytosis Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Histopathologic, Immunologic, and Cytogenetic Characteristics of LCH


    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]

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