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Blood Spotlight on Langerhans Cell Histiocytosis From www.bloodjournal.org by guest on November 4, 2014. For personal use only. 2014 124: 867-872 doi:10.1182/blood-2014-02-556407 originally published online June 3, 2014 Blood spotlight on Langerhans cell histiocytosis Christine Delprat and Maurizio Aricò Updated information and services can be found at: http://www.bloodjournal.org/content/124/6/867.full.html Articles on similar topics can be found in the following Blood collections Blood Spotlight (30 articles) Myeloid Neoplasia (1270 articles) Pediatric Hematology (361 articles) Phagocytes, Granulocytes, and Myelopoiesis (484 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved. From www.bloodjournal.org by guest on November 4, 2014. For personal use only. Blood Spotlight Blood spotlight on Langerhans cell histiocytosis Christine Delprat1-5 and Maurizio Aric`o6 1Centre National de la Recherche Scientifique, Unit´eMixte de Recherche 5239, Laboratoire de Biologie Mol´eculairede la Cellule, Lyon, France; 2Ecole Normale Sup´erieurede Lyon, Lyon, France; 3Universit´e de Lyon, Lyon, France; 4Universit´e de Lyon 1, Villeurbanne, France; 5Institut Universitaire de France, Paris, France; and 6Pediatric Oncology Network, Istituto Toscano Tumori, Firenze, Italy Langerhans cell histiocytosis (LCH) is a apoptosis and inflammation in lesional in the field of myeloid neoplasm remains to rare disease affecting people of any age, dendritic cells. Recently somatic BRAF V600E be determined. Altogether, these findings with widely variable clinical manifestations mutation in myeloid precursor dendritic suggest that future therapeutic strategy and different outcomes. The precise chain cells was associated with the more aggres- might incorporate a screening of this ge- of events driving lesional granuloma for- sive form of the disease, although the same netic mutation for high-risk patients poten- mation has remained elusive for many mutation in a more differentiated dendritic tially suitable for target therapy. (Blood. years. There is evidence for inherited cell might drive a less aggressive disease. 2014;124(6):867-872) predisposition to and derangement of Whether this picture convincingly put LCH Introduction Langerhans cell histiocytosis (LCH) is a rare disease mainly seen in outcome or, sometimes, to late postinflammatory fibrosis (sclerosing children, but it can present at any age.1,2 The clinical manifestations cholangitis). In a minority of these patients, liver transplantation range from a solitary, asymptomatic osteolytic lesion called “eosino- may prove curative, but in many, the disease reactivates in the philic granuloma” that tends to heal spontaneously to multiple osteolytic transplanted organ.4 Pulmonary involvement is one of the most lesions of the skull, intriguingly associated with exophthalmos and puzzling features of LCH. Children may have disseminated diabetes insipidus (DI), formerly called “Hand-Schuller-Christian¨ ” interstitial pulmonary nodules and cysts that are responsive to systemic disease. In addition, in a small proportion of patients, especially therapy.5 Conversely, isolated pulmonary LCH is by far the most toddlers, an ominous form of LCH (once described as “Abt-Letterer- frequent manifestation in adults. A correlation with cigarette Siwe” disease) may run an acute course with dissemination to various smoking has been clearly documented. Yet, in most cases, smoking organs other than bones (particularly liver and spleen), thus shaping cessation is not sufficient to stop the inflammatory process, and these a multisystem disease as life-threatening as childhood acute young adults may show progression to multicystic metaplasia and fi lymphoblastic leukemia. Based on solid pathology ndings and on become oxygen dependent. In such patients, the role of LCH-directed a bit of intuition, Lichtenstein suggested in 1953 that these three chemotherapy remains unclear, because existing reports are on small conditions were part of a common disease spectrum, and he coined series, and no prospective studies have been conducted.6 End-stage the term histiocytosis X, conveying the message that dysregulated organ failure often requires lung transplantation, and here too, disease proliferation of a histiocytic cell was at the heart of the problem but that 3 recurrence may take place. the trigger for this was unknown. DI, resulting from destruction of the supraoptic-paraventricular fi The diagnosis of LCH is based on nding in a biopsy, usually of nuclei in which vasopressin is produced,7 occurs in about 12% to 15% skin or bone, a granuloma consisting of pale histiocytic cells with of patients with disseminated LCH. Osteolytic lesions of the skull infolded nuclei, eosinophils, and multinucleated giant cells. base and facial bones predispose to DI, likely because of local Staining of the histiocytic cells for CD1a (and CD207 langerin) vascular dissemination. Once DI is established, reversal may be has become part of the diagnosis (the demonstration of Birbeck exceptional.8 Thus, DI can be a disabling sequela, and it may granules by electron microscopy is no longer required).1,3 The progress to multiple anterior pituitary hormone deficiency.9 A small morphology of individual lesions is so uniform as to make it number of patients with LCH, especially among those with DI, may impossible for the pathologist to know whether a biopsy was from develop bilateral symmetric alterations in the cerebellar gray matter, a patient with unifocal or multifocal disease, from a child or an in the basal ganglia, and in the brainstem. Histopathology from adult, and whether the disease was clinically indolent or life- threatening; thus, after more than half a century, Lichtenstein’s cerebellar biopsies and from autopsies revealed neuronal loss, fl notion is fully vindicated. axonal degeneration, and a profound T-cell in ammation. Its pathogenesis remains unsolved, but propagation from long- standing granulomatous lesions of the craniofacial bones to the Systemic manifestations of LCH intracranial space, with stimulation of chemokine/cytokine tissue damage or initiation of an autoimmune response to brain Skin and bone lesions are the most frequent but fortunately the least components have been suggested.10 Neurodegenerative LCH threatening manifestations of LCH. At the other end of the spectrum, may be devastating and, unfortunately, no effective therapy is massive liver involvement and dysfunction may lead to rapidly fatal available so far. Submitted February 13, 2014; accepted May 28, 2014. Prepublished online as © 2014 by The American Society of Hematology Blood First Edition paper, June 3, 2014; DOI 10.1182/blood-2014-02-556407. BLOOD, 7 AUGUST 2014 x VOLUME 124, NUMBER 6 867 From www.bloodjournal.org by guest on November 4, 2014. For personal use only. 868 DELPRAT and ARICO` BLOOD, 7 AUGUST 2014 x VOLUME 124, NUMBER 6 relapsed LCH is usually amenable to treatment with the same agents Treatment of LCH used before, or even with anti-inflammatory agents. For this reason, the term “reactivation,” which has been proposed since 1982,16 is 17 LCH tends to run a favorable course in the large majority of patients; now preferred to the term “relapse.” Beyond disease reactivation, a 16 indeed, most patients with solitary lesions do not need treatment as number of permanent consequences, including DI, neurodegener- long as the lesion remains solitary (although it must be acknowl- ation, sclerosing cholangitis, pulmonary failure, reduced linear growth edged that even biopsy itself may exert some therapeutic effect and and other endocrine dysfunctions, and bone deformities, represent 17,18 may speed up the healing process). However, in a minority of cases, quite a heavy burden for the quality of life of patients cured of LCH. the disease may be aggressive and even life threatening. For a long But even more compelling is the remaining minority (20%) of time, the management of patients was conducted on an empirical MS-LCH patients with involvement of liver, spleen, bone marrow basis, reflecting the different views and the uncertainty that have whofailtorespondwithin2to3weeks,whostillfacean 12-15 prevailed regarding the nature of the disease. Leukemia-oriented unacceptably high risk of early mortality in the range of 40%. chemotherapy was used in children with disseminated disease by the In these patients, very intensive chemotherapy, similar to that used 19 Austrian-German group during the 1980s, with favorable response. for acute myeloid leukemia, turned out to be useful, whereas the role 20 Conversely, based on the concept of an inflammatory disease, anti- of hematopoietic stem cell transplantation remains uncertain. But fi inflammatory agents, especially steroids, were used by the British this is de nitely the subset of patients for whom novel experimental group; although this achieved disease control in most cases, children therapies derived from improved knowledge of LCH pathogenesis with chronic and/or reactivating LCH developed
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