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      Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net

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          Langerhans Cell Histiocytosis (LCH) is an orphan disease of clonal dendritic cells which may affect any organ of the body. Most of the knowledge about the diagnosis and therapy is based on pedriatic studies. Adult LCH patients are often evaluated by physicians who focus on only the most obviously affected organ without sufficient evaluation of other systems, resulting in patients being underdiagnosed and/or incompletely staged. Furthermore they may be treated with pediatric-based therapies which are less effective and sometimes more toxic for adults. The published literature on adult LCH cases lacks a comprehensive discussion on the differences between pediatric and adult patients and there are no recommendations for evaluation and comparative therapies. In order to fill this void, a number of experts in this field cooperated to develop the first recommendations for management of adult patients with LCH. Key questions were selected according to the clinical relevance focusing on diagnostic work up, therapy, and follow up. Based on the available literature up to December 2012, recommendations were established, drafts were commented by the entire group, and redrafted by the executive editor. The quality of evidence of the recommendations is predominantly attributed to the level of expert opinion. Final agreement was by consensus.

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          Most cited references 66

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          Recurrent BRAF mutations in Langerhans cell histiocytosis.

          Langerhans cell histiocytosis (LCH) has a broad spectrum of clinical behaviors; some cases are self-limited, whereas others involve multiple organs and cause significant mortality. Although Langerhans cells in LCH are clonal, their benign morphology and their lack (to date) of reported recurrent genomic abnormalities have suggested that LCH may not be a neoplasm. Here, using 2 orthogonal technologies for detecting cancer-associated mutations in formalin-fixed, paraffin-embedded material, we identified the oncogenic BRAF V600E mutation in 35 of 61 archived specimens (57%). TP53 and MET mutations were also observed in one sample each. BRAF V600E tended to appear in younger patients but was not associated with disease site or stage. Langerhans cells stained for phospho-mitogen-activated protein kinase kinase (phospho-MEK) and phospho-extracellular signal-regulated kinase (phospho-ERK) regardless of mutation status. High prevalence, recurrent BRAF mutations in LCH indicate that it is a neoplastic disease that may respond to RAF pathway inhibitors.
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            Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules.

            We have identified a type II Ca2+-dependent lectin displaying mannose-binding specificity, exclusively expressed by Langerhans cells (LC), and named Langerin. LC are uniquely characterized by Birbeck granules (BG), which are organelles consisting of superimposed and zippered membranes. Here, we have shown that Langerin is constitutively associated with BG and that antibody to Langerin is internalized into these structures. Remarkably, transfection of Langerin cDNA into fibroblasts created a compact network of membrane structures with typical features of BG. Langerin is thus a potent inducer of membrane superimposition and zippering leading to BG formation. Our data suggest that induction of BG is a consequence of the antigen-capture function of Langerin, allowing routing into these organelles and providing access to a nonclassical antigen-processing pathway.
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              Langerhans'-cell histiocytosis (histiocytosis X)--a clonal proliferative disease.

              The lesions of Langerhans'-cell histiocytosis (histiocytosis X), a proliferative histiocytic disorder of unknown cause, contain histiocytes similar in phenotype to dendritic Langerhans' cells. The disease ranges in severity from a fatal leukemia-like disorder to an isolated lytic lesion of bone. Intermediate forms of the disease are usually characterized by multiorgan involvement, diabetes insipidus, and a chronic course. To determine whether Langerhans' histiocytosis is a polyclonal reactive disease or a clonal disorder, we used X-linked polymorphic DNA probes (HUMARA, PGK, M27 beta[DXS255], and HPRT) to assess clonality in lesional tissues and control leukocytes from 10 female patients with various forms of the disease. Lymphoid clonality was also assessed by analysis of rearrangements at immunoglobulin and T-cell-receptor gene loci. The HUMARA assay detected clonal cells in the lesions of 9 of the 10 patients: 3 patients had acute disseminated disease, 3 had unifocal disease, and 3 had intermediate forms. The percentage of clonal cells closely approximated the percentage of CD1a-positive histiocytes in each lesion. Clonality was also confirmed in two of nine cases with the PGK or M27 beta probe. Extreme constitutional lyonization precluded assessment of clonality in the 10th case. Lymphoid clonality was ruled out in all cases. The detection of clonal histiocytes in all forms of Langerhans'-cell histiocytosis indicates that this disease is probably a clonal neoplastic disorder with highly variable biologic behavior. Thus, genetic mutations that promote clonal expansion of Langerhans' cells or their precursors may now be identified.

                Author and article information

                Orphanet J Rare Dis
                Orphanet J Rare Dis
                Orphanet Journal of Rare Diseases
                BioMed Central
                14 May 2013
                : 8
                : 72
                [1 ]Department of Medicine I, Center of Hematology an Stem Cell Transplantation, Hemostasis and Medical Oncology Internal Medicine I, Elisabethinen Hospital, Fadinger Str. 1 4010, Linz, Austria
                [2 ]Department of Pediatric Hematology Oncology, Azienda Ospedaliero Universitaria A. Meyer, Florence, Italy
                [3 ]Departament of Respiratory Medicine, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
                [4 ]Imperial NHS Trust, London, UK
                [5 ]Clinic for Internal Medicine, Protestant Clinics, Gelsenkirchen, Germany
                [6 ]Paracelsus Klinik, Osnabrück, Germany
                [7 ]Service de Medicine Interne, Groupe Hospitalier Pitie-Salpetiere, Paris, France
                [8 ]Department of Pathophysiology, University of Athens School of Medicine, Athens, Greece
                [9 ]Department of Endocrinology and Diabetes, 251 Hellenic Air Force & VA General Hospital, Athens, Greece
                [10 ]U.O. Dermatologia, Fondazione IRCCS Ca´ Granda-Ospedale Maggiore Policlinico, Milano, Italy
                [11 ]Department of Internal Medicine, Hospital Saint Louis, Paris, France
                [12 ]Department of Radiotherapy and Radiation Oncology, Franziskus Hospital, Bielefeld, Germany
                [13 ]Radiation Oncology Center, Hamburg, Germany
                [14 ]Pulmonolgy Department, Saint Louis Teaching Hospital, Paris, France
                [15 ]Texas Children’s Cancer Center/Hematology Service, Houston, TX, USA
                Copyright ©2013 Girschikofsky et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


                Infectious disease & Microbiology

                adult, histiocytosis, langerhans


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