The histiocytic diseases in children and adults include three major classes of disorders. Only Langerhans cell histiocytosis (LCH), a dendritic cell disorder, is discussed in detail in this summary. Erdheim-Chester disease (primarily found in adults) and juvenile xanthogranuloma (diagnosed in children and adults) are macrophage disorders. Other disorders of the macrophage/monocytoid lineages include Rosai-Dorfman disease and hemophagocytic lymphohistiocytosis. Malignant disorders include malignant histiocytosis of various histiocyte lineages (formerly called histiocytic sarcoma) and the monocytic or myelomonocytic leukemias.
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. 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). Controversy exists regarding whether the clonal proliferation of LCH cells results from a malignant transformation or is the result of an immunologic stimulus.[2,3]
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The recent discovery that approximately 60% of LCH biopsy specimens demonstrate the V600E mutation in the BRAF oncogene, regardless of stage or organ involvement, has led to the conclusion that LCH is a clonal neoplastic disorder. The same 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. This finding has raised the possibility of future targeted therapy with inhibitors already in use in melanoma, and several trials of BRAF inhibitors are open in adults and children with BRAF V600E mutated tumors, including LCH. Regardless of the etiology of the clonal proliferation, the primary treatment is chemotherapy.
Langerhans cell histiocytosis is the terminology currently preferred over histiocytosis X, eosinophilic granuloma, Abt-Letterer-Siwe disease, Hand-Schuller-Christian disease, or diffuse reticuloendotheliosis. This is based on the observation that the pathologic histiocyte common to all of these diagnoses has the identical immunophenotypic characteristics including the presence of Birbeck granules identified by electron microscopy; in addition, the pathologic histiocyte or LCH cell has a gene expression profile more closely resembling a myeloid dendritic cell, raising the possibility that LCH cells arise from a circulating precursor cell rather than the skin LC.[5,6] (Refer to the Cytogenetic and Genomic Studies section of this summary for more information.)