The pathogenesis of Langerhans cell histiocytosis (LCH) is a mater of debate. LCH is a rare disease that can invade tissues and spread but otherwise looks like a reactive process. There is ongoing controversy as whether it is a cancer. Supporting the reactive nature of LCH is its propensity for spontaneous remissions, the extensive secretion of multiple cytokines by dendritic cells and bystander-cells (a phenomenon known as cytokine storm), favorable prognosis and relatively good survival rate in patients without organ dysfunction or organ involvement.
On the other hand, the pathologic features of infiltration of organs by monoclonal population of pathologic cells, and the successful treatment of subset of disseminated disease using chemotherapy argue that it is neoplastic process. In addition, X chromosome–linked DNA probes appear to demonstrate a degree of monoclonality. Monoclonality is an important attribute of cancer but it does not prove that a proliferative process is neoplastic. Specific and unique cytogenetic or genomic abnormalities would also be required to demonstrate convincingly that LCH is a malignancy.
Activating mutation of a protooncogen in the Raf family, the BRAF gene, was recently 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%) and two other studies showed a similar result. Presence of this activating mutation could support the notion that LCH s a precancerous condition or a myelodysplastic disorder.
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