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

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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, UnitéMixte de Recherche 5239, Laboratoire de Biologie Moléculairede la Cellule, Lyon, France; 2Ecole Normale Supérieurede Lyon, Lyon, France; 3Université de Lyon, Lyon, France; 4Université 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.

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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 unacceptable side appear warranted. effects from long-lasting steroid exposure.11 Since the early 1990s, an international cooperative group of pediatric hematology-oncology specialists met the challenge of conducting 3 consecutive randomized trials in this orphan disease. Overall, these studies provided LCH: inflammatory or neoplastic? meaningful lessons: First, in LCH-I, which was a comparison of Although it has only localized manifestations in most cases, LCH 6-month therapy with vinblastine or etoposide together with an ini- must be considered a systemic disease. Unlike leukemia, LCH does tial 3-day pulse of prednisone, all patients with multisystem LCH not seem to arise from the bone marrow and to spread elsewhere. The (MS-LCH) were equivalent with respect to response, survival, disease basic lesion, the granuloma—the morphology of which has already reactivation, permanent consequences, and toxicity. However, early been exhaustively described by nineteenth-century pathologists—is response and prevention of disease reactivation were inferior to results characteristically enriched in dendritic cells (DCs), reminiscent of of the more aggressive (5-drug combination) and longer (12 months) the typical pattern of tissue reaction to an intracellular pathogen of DAL-HX 83 and DAL-HX 90 protocols, suggesting a need to which the tuberculous granuloma is the prototype. Again, it is since intensify treatment.12,13 Second, in LCH-II, MS-LCH patients were the nineteenth century that an infectious origin of LCH had been stratified by risk (high risk being those with age ,2 years and/or surmised but never proven, and extensive epidemiological studies involvement of a risk organ such as liver, spleen, hematopoietic system, have failed to identify significant infectious associations.19 However, and lung) and were randomly assigned to the standard combination since the early 1990s, it has been claimed that clonal cell populations of prednisone and vinblastine vs additional etoposide. In both treatment are present based on analysis through an X-linked marker (eg, the arms, patients showed faster disease resolution and a higher survival human androgen receptor assay; Humara) of lesional tissue from rate than those in LCH-I, although the 44% reactivation rate was still females with LCH.22 This finding is, per se, nonconclusive of cancer, high. Lack of advantage, together with its reported leukemogenic because although cancer must be clonal, not every clonal population potential, caused the discontinuation of study of etoposide in patients is cancer; indeed, clonal populations have been observed in benign 14 fi with MS-LCH. Third, in the LCH-III successor study, the ef cacy disorders. Unexplained remission can occur in neoplasms, excep- of increasing intensity by adding methotrexate in risk-organ patients tionally even in widely metastatic cases; but spontaneous healing in (treated for 12 months) and prolonging initial intense therapy if only LCH is not exceptional: on top of what is frequently seen in skin and a partial response was achieved by 6 weeks was tested but did not bone lesion of children, the provocative observation that some young provide a better outcome; otherwise, extending the duration of adult patients with pulmonary LCH remit after smoking cessation is treatment to 12 months proved superior to 6 months in reducing one of the fascinating and incompletely understood features of LCH, the rate of disease reactivation in children who had achieved suggesting that there may be many pathobiologic contributions to the 15 disease control. disease process. As a result of these trials, the former intuition, that patients with The fact that an animal model of LCH has been lacking for a long LCH should be stratified according to their very different risk of pro- time has been a forceful stimulus to investigating pathogenesis by ex 16 gression and treatment failure, has been validated. Patients with vivo studies and by looking for biomarkers. Clinical manifestations localized disease should be treated conservatively with very limited of LCH—aggressive chronic granuloma formation, bone resorp- exceptions; patients with multisystem disease without involvement tion, and soft tissue lesions with occasional neurodegeneration— of vital organs should be treated with the combination of vinblastine show similarities with those observed in other interleukin-17A and prednisone for a total duration of at least 12 months, which (IL-17A) –related human diseases (Mycobacterium infection, Crohn’s represents the standard of care in pediatric LCH, aimed at limiting the disease, rheumatoid arthritis, and multiple sclerosis). In one study, disease course and also permanent consequences. Yet there are still peripheral blood samples from patients with LCH were put in culture; additional unmet clinical needs: about one third of patients who the resulting monocyte-derived DCs showed extended life span and achieve complete control of the disease will suffer relapse during the propensity to undergo cell fusion, leading to the formation of multi- following months, most often within the same tissue or organ(s) nucleated giant cells. These features make them excellent candidates type(s) involved at presentation. Fortunately, whereas in childhood to be at the origin of the characteristic granuloma. Remarkably, both leukemia relapse is usually associated with very unfavorable prognosis, of these properties—extended life span and propensity to fuse—were From www.bloodjournal.org by guest on November 4, 2014. For personal use only.

BLOOD, 7 AUGUST 2014 x VOLUME 124, NUMBER 6 LANGERHANS CELL HISTIOCYTOSIS 869

Figure 1. Major cell, cytokine, and protease players in LCH lesion. This simplified overview indicates the main cytokines, chemokines, and proteases found in an LCH lesion that may play a major role in cell recruitment, survival, fusion, and inflammatory and tissue-aggressive activities, supported by proinflammatory cytokines and matrix metalloproteinases (MMPs), respectively. The origin of the pathogenic DC in an LCH lesion is still a matter of debate. Recent results argue that pathogenic DCs do not arise from Langerhans cells but from accumulation of bone marrow–derived immature myeloid cells able to differentiate into DCs such as monocytes, macrophage and DC precursor (MDP), or CD1351 lympho-myeloid progenitor (LMP). CCL, chemokine (C-C motif) ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; RANKL, receptor activator of nuclear factor k-B ligand; TNF, tumor necrosis factor; Treg, regulatory T cell. reproduced in culture by exposing normal control DCs to IL-17A; this In spite of much recent progress on LCH that has just been phenomenon could be suppressed by exposure to anti-IL-17 antibodies reviewed, there remain three major questions to which we have only and restored by re-exposure to IL-17A, suggesting an autocrine role partial answers. for this cytokine with respect to granuloma formation.23 In the same 1. Why does a monocyte-derived DC become an LCH cell? The study, patients with LCH were found to have high levels of IL-17A. long-lasting question of a triggering pathogen in LCH has been However, a second group was unable to detect IL-17A messenger revitalized by Murakami et al,29 who recently reported elevated RNA (mRNA) or protein in samples from LCH patients.24 The amounts of Merkel cell polyomavirus DNA in the peripheral blood authors suggested that the initial finding could be attributed to lack of specificity of the anti-IL-17A antibody. Subsequently, this laboratory cells of 2 of 3 LCH patients with high-risk organ involvement, but not failed to identify any cells in LCH lesions with IL-17A gene expression, in the blood cells of 12 of 12 patients with low-risk LCH. Yet with concluding that evidence for IL-17A as a significant factor in LCH lower viral loads, an elevated number of Merkel cell polyomavirus remained inadequate, thus beginning an IL-17 controversy in LCH.25 DNA sequences was detected in 12 LCH tissues compared with Yet the DC fusion activity of IL-17A in vitro was not dependent on controls other than patients with dermatopathic lymphadenopathy. an IL-17A antibody and has not been challenged, suggesting that Previous studies of peripheral blood chromosomes showed that patients IL-17A secreted by other cells might play a pathogenic role in LCH with LCH display an excess of spontaneous chromosomal breaks that 30 fi to foster tissue-aggressive giant myeloid inflammatory cell formation are more evident during the acute phase of the disease ;these ndings (Figure 1). Recently, Murakami et al26 confirmed higher levels of resemble the genomic instability induced by respiratory syncytial virus 30,31 IL-17A in 38 patients with LCH compared with controls. Furthermore, (RSV), hepatitis C virus (HCV), or Epstein-Barr virus (EBV). Lourda et al27 found an increased frequency of IL-17A1 mononuclear 2. What are the key signals that drive monocyte-derived DCs 32 cells in the bloodstream of LCH patients by using intracellular cytokine to form a granuloma? Hutter et al showed that JAG2-mediated staining followed by flow cytometry analysis. The majority of the NOTCH activation confers phenotypic and functional aspects of 1 33 IL-17A cells were monocytes, which by reverse-transcription poly- LCH to DCs. Olsson et al found that monocyte-derived DCs merase chain reaction (RT-PCR) showed higher levels of both IL-17A treated with IL-17A express BCL2A1/BFL1, a prosurvival mem- and retinoic acid orphan receptor C (RORC) mRNA, which is ber of the Bcl-2 family. They also proposed that exposure to anti- associated with higher disease activity. The finding that monocytes IL-17A may decrease BFL1 and synergize with chemotherapy to play a central role in this process appears to reconcile the controversy eradicate LCH DCs.34 Identification of BRAFV600E mutation in 35 and agrees with the recent report of an immature marrow–based DC (57%) of 61 archived specimens of LCH tissue opened a novel of origin in LCH.28 research avenue in LCH.35 This finding was confirmed by a French From www.bloodjournal.org by guest on November 4, 2014. For personal use only.

870 DELPRAT and ARICO` BLOOD, 7 AUGUST 2014 x VOLUME 124, NUMBER 6

Figure 2. Mechanisms of accumulation of LCH pathogenic DCs through proliferation and prolonged survival. (A) DC survival is basically regulated by exogenous concentration of GM-CSF on CSF2R. Low GM-CSF concentration (black) stimulates the selective activation of Ser585/14-3-3/PI-3 kinase (PI3K), the “survival only” pathway, and high GM-CSF concentration (red) can give rise to assembling of CSF2R chains40 in dodecamer, thus involving the Jak/STAT, Ras/mitogen- activated protein kinase (MAPK), and PI3K pathways (middle) downstream of Ser585 and Tyr577 phosphory- lation (red bullet). In the IL-17A inflammatory microen- vironment (green), monocyte-derived DC survival can be prolonged for weeks by IL-17A treatment.33 The TRAF6-dependent IL-17R transduction is able to activate both PI3K/Akt and nuclear factor kB (NF-kB) pathways.41 S, serine; Y, tyrosine. (B) In LCH patients, although low concentration of GM-CSF will normally induce PI3K/Akt (black), other molecular specificities turn DC survival and phenotype into aggressive myeloid cells: the presence of IL-17A activates both PI3K/Akt and NF-kB pathways (green), leading to increased survival, inflammation, and DC fusion. In addition, pathogenic LCH DCs express JAG2 and activate transduction downstream of its receptor NOTCH (brown),32 which may account for tissue destruction via MMP expression. BRAFV600E mutation will ensure constitutive activation of the MAPK pathway (red). It will be important in the future to explore the Jak2/Stat5 pathway, which may be absent in LCH DCs. From this recent knowledge, new therapeutic interven- tions in LCH may neutralize IL-17A, inhibit NOTCH and BRAFV600E/MAPK pathways, and possibly activate the Jak2/Stat5 pathway to reverse LCH DC phenotype toward normal DC phenotype until we better understand the origin of this impairment of DC differentiation.

group,36 which has not yet been able to document BRAFV600E in was sufficient to drive LCH-like disease. In summary, although peripheral blood cells of patients with LCH, which would confirm expression of BRAFV600E in marrow DC progenitors was found to that it is a somatic mutation within the lesional cells.37 In both recapitulate the human high-risk LCH, BRAFV600E expression in studies, BRAFV600E did not seem to correlate with age, clinical differentiated DCs resembled low-risk LCH.39 On the basis of these presentation, or outcome. Yet those data were not conclusive: (1) findings, we propose classification of LCH as a myeloid neoplasia. only about 40% of LCH patients have somatic mutations of BRAF, Taking into account this collection of data, it is tempting to propose (2) retroviral transduction of BRAFV600E in myeloid cells resulted in a working model for the impairment of transduction pathways driving growth arrest and cell death, and (3) in genetically engineered LCH pathogenic DC development (Figure 2).40,41 mouse models, BRAFV600E mutation in mature Langerhans cells 3. Why do some people develop LCH? Studies of familial was insufficient to develop LCH.38 In a very recent study of 100 clustering of the disease have documented that about 1% of patients LCH lesions, of which 64 carried the BRAFV600E mutation within with LCH have another affected member in the family. When focusing infiltrating CD2071 DCs, patients with active, high-risk LCH on twin pairs, the rate of concordance is as high as 10% in nonidentical 1 were found to carry BRAFV600E in circulating CD11c and twins and an impressive 92% in identical twins.42,43 These data CD141 fractions and in bone marrow CD341 hematopoietic cell strongly point to a genetic component predisposing to LCH,42-46 even progenitors, but the mutation was restricted to lesional CD2071 though efforts by Egeler et al to identify an LCH-associated locus DCs in low-risk patients. In a new mouse model, the expression through a genome-wide screening have not been successful.47 of conditional BRAFV600E enforced under the langerin promoter Interestingly, in this study, all patients had diploid genomes, From www.bloodjournal.org by guest on November 4, 2014. For personal use only.

BLOOD, 7 AUGUST 2014 x VOLUME 124, NUMBER 6 LANGERHANS CELL HISTIOCYTOSIS 871 which, if anything, casts additional doubt on the neoplastic origin of LCH. Acknowledgment In conclusion, from the clinical point of view, LCH is a rare disorder with widely variable manifestations. After decades in which its The authors thank Prof Lucio Luzzatto (Istituto Toscano Tumori, pathogenesis remained elusive, recent findings suggest that somatic Firenze, Italy) for fruitful discussion and contribution to manuscript mutation occurring in a bone marrow myeloid progenitor drive writing, and Associazione Italiana Ricerca Istiocitosi for supporting a neoplastic process, although the same somatic mutation occurring the research. at a more differentiated stage drives a self-limiting, inflammatory disorder. The finding of BRAFV600E mutation in all concurrent pulmonary nodules48 suggests either multiple independent events or a true spread within the affected lungs. The monocyte/DC plays Authorship a pivotal role and might have been genetically predisposed42-46 to becoming overstimulated by an infectious trigger. Contribution: M.A. designed and wrote the manuscript; and C.D. Until now, improved outcomes for patients with LCH have accrued contributed to data interpretation, drew the figures, and contributed from empirically adopted chemotherapeutic regimens; recent exciting to writing the manuscript. advances in the pathogenesis of LCH may suggest incorporating in Conflict-of-interest disclosure: The authors declare no competing a therapeutic trial prospective validation of the association of BRAFV600E financial interests. mutation with multisystem aggressive LCH and higher risk of Correspondence: Maurizio Arico,` Istituto Toscano Tumori, treatment failure and exploring the use of first-line target therapy with V.le G. Pieraccini 6, Building 27/B, 50139 Firenze, Italy; e-mail: vemurafenib49 in accurately defined subgroups of patients with LCH. [email protected].

References

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