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Langerhans-Zell-Histiozytose (LCH)
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Langerhans cell histiocytosis (LCH) is a rare systemic disorder characterized by the accumulation of CD1a+/Langerin + LCH cells and wide‐ranging organ involvement. LCH was formerly referred to as Histiocytosis X, until it was renamed in 1987. LCH ßwas named for its morphological similarity to skin Langerhans cells. Studies have demonstrated that LCH cells originate from myeloid dendritic cells rather than skin Langerhans cells. There has been significant debate regarding whether LCH should be defined as an immune disorder or a neoplasm. A breakthrough in understanding the pathogenesis of LCH occurred in 2010 when a gain‐of‐function mutation in BRAF (V600E) was identified in more than half of LCH patient samples. Studies have since demonstrated that 100% of LCH cases exhibit ERK phosphorylation, indicating that LCH is likely to be a clonally expanding myeloid neoplasm. LCH is now defined as inflammatory myeloid neoplasms in the revised 2016 Histiocyte Society classification. Randomized trials and novel approaches have led to improved outcomes for pediatric patients, but no well‐defined treatments for adult patients have been developed to date. Although LCH is not fatal in all cases, delayed diagnosis or treatment can result in serious impairment of organ function and decreased quality of life. This study summarizes recent advances in the pathophysiology and treatment of adult LCH, to raise awareness of this “orphan disease”.
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Pulmonary Langerhans' cell histiocytosis (PLCH) is a rare disorder of unknown cause characterised by the infiltration of the lungs and other organs by the bone marrow derived Langerhans' cells, which carry mutations of BRAF gene and/or NRAS, KRAS and MAP2K1 genes. It occurs predominantly in young smokers, without gender predominance. The disease is characterised by formation of eosinophilic granulomas with the presence of Langerhans' cells infiltrating and destroying distal airways. High-resolution computed tomography of the chest (HRCT) plays an outstanding role in PLCH diagnosis. The typical radiological picture of PLCH is the presence of small intralobular nodules, often forming 'tree in bud' lesions, cavitated nodules, thin- and thick-walled cystic lesions frequently confluent. Definite diagnosis requires the finding of characteristic lesions in histological examination and demonstration of antigen CD1a or CD207 presenting cells in immunohistochemistry. Smoking cessation is the most important recommendation for PLCH patients. There are no evidence based data regarding systemic steroid therapy. The treatment of progressive PLCH is based on cladribine or cytarabine as salvage therapy. The prognosis is good, and over 85% of patients survive 10 years.
Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207(+) dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207(+) DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c(+) and CD14(+) fractions and in bone marrow (BM) CD34(+) hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207(+) DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.
A variety of processes can cause interstitial lung disease-like patterns but are not forms of ILD. These include fibrosis secondary to chronic alveolar hemorrhage, which most commonly is associated with underlying vasculitis, Kaposi sarcoma, some lymphomas, leukemias that involve the lung, and lymphangitic carcinoma. In addition, a lung that is collapsed or crushed can mimic ILD even though the parenchyma is completely normal.
The classification of the histiocytoses has evolved based on new understanding of the cell of origin as a bone marrow precursor. Although the pathologic features of the histiocytoses have not changed per se, molecular genetic information now needs to be integrated into the diagnosis. The basic lesions of the most common histiocytoses, their patterns in different sites, and ancillary diagnostics are now just one part of the classification. As more is understood about the cell of origin and molecular biology of the histiocytoses, future classifications will be refined.
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