Pediatr Blood Cancer 2014;61:1329–1335

MEETING REPORT Updates on Histiocytic Disorders

1 y 2z 3# 4,5§ Sarah R. Vaiselbuh, MD, * Yenan T. Bryceson, PhD, MS, Carl E. Allen, MD, PhD, James A. Whitlock, MD, 4§ and Oussama Abla, MD

Histiocytic disorders are rare entities that are becoming more and Rosai Dorfman disease (RDD) including subsections on recognized as our understanding of the molecular pathogenesis lead pathogenesis, clinical diagnostic criteria and novel insights into to novel diagnostic tests and targeted drug development. A treatment. Details of other histiocytic disorders as well as the symposium held at the American Society of Pediatric Hematology/ standard treatment guidelines have been published elsewhere and Oncology (ASPHO) 2013 Annual Meeting discussed new insights are beyond the scope of this discussion [Haupt et al. (2013). Pediatr into histiocytic disorders. This review highlights the symposium Blood Cancer 60:175–184; Henter et al. (2007). Pediatr Blood presentations, divided into three sections encompassing Langerhans Cancer 2014;61:1329–1335. # 2014 Wiley Periodicals, Inc. cell (LCH), hemophagocytic lymphohistiocytosis (HLH)

Key words: hemophagocytic lymphohistiocytosis; Langerhans cell histiocytosis; Rosai Dorfman disease; targeted therapies

INTRODUCTION frequency ranging from 38% to 57% [8–12]. A novel somatic mutation in BRAF and germline variants of (T599A) BRAF have Histiocytoses describe a diverse group of proliferative disorders also been described in patients with LCH, though the significance of involving dentritic cells and . They include a spectrum these observations remains to be defined [10–12]. The frequency of of diseases including a reactive inflammatory accumulation of cells, the somatic BRAF-V600E mutation implies functional significance pathologic immune activation, or neoplastic clonal proliferation. in LCH pathogenesis, but no clinical correlations with BRAF Advanced molecular technologies are resulting in new break- genotype have been established. BRAF is an intermediate kinase in throughs in understanding the pathophysiology of histiocytic the RAS-RAF-MEK-ERK pathway that transduces extracellular disorders that are changing the field. The purpose of this update signals to the nucleus. Phosphorylation of BRAF induces activation report is to aid in understanding the subtle differences in of downstream extracellular signal-regulated kinase (ERK) [8]. The pathogenesis of three most common histiocytic disorders— V600E mutation renders BRAF constitutively active, impacting Langerhans cell histiocytosis (LCH), hemophagocytic lymphohis- several cell functions including cell proliferation and migration. tiocytosis (HLH), and Rosai Dorfman disease (RDD) and how new BRAF activation is insufficient to fully transform cells, as BRAF- insights lead to the hope for novel therapeutics (Table I). V600E has been identified in not only malignancies, including melanoma, papillary thyroid carcinoma, and gliomas, but also in LANGERHANS CELL HISTIOCYTOSIS (LCH) skin nevi and colon polyps [13–15]. Malignant transformation versus immune dysregulation has Pathogenesis been a major focus of LCH research for the past 40 years, with “Langerhans” in LCH refers to Dr. Paul Langerhans (1847– supporting data for both mechanisms. While molecular mecha- 1888) who first described normal epidermal dendritic cells (DCs) nisms are being further explored, many studies have investigated that later were recognized as having some similarity to LCH-lesion inflammation within the LCH lesion. In addition to the pathologic DCs, though he initially thought those cells were neuronal cells due LCs, LCH lesions are characterized by an inflammatory infiltrate to their notable dentritic processes. However, despite epidermal typically including macrophages, eosinophils and lymphocytes DCs having phenotypic features of cutaneous Langerhans cells (LCs), data comparing transcriptomes of purified epidermal LCs to CD207þ cells in LCH lesions found relatively distinct gene 1Children’s Cancer Center, Staten Island University Hospital, Staten expression profiles, with the LCH CD207þ cells having increased Island, New York; 2Center for Infectious Medicine, Karolinska expression of genes associated with immature myeloid precur- Institute, Stockholm, Sweden; 3Department of Pediatrics, Baylor sors [1]. Studies of mouse and human DCs also suggest that College of Medicine, Texas Children’s Cancer Center, Houston, Texas; 4Garron Family Cancer Center, The Hospital for Sick Children, langerin/CD207 expression is not limited to epidermal LCs, but 5 occurs in many lineages at different anatomic sites [2–4]. Ontario, Toronto, Canada; Department of Hematology/Oncology, The Hospital for Sick Children, Ontario, Toronto, Canada Therefore, it is possible that LCH may have an origin distinct † from the epidermal LC. Director, Children’s Cancer Center. The pathogenesis of LCH remains unresolved. Clonality of LCH ‡Assistant Professor. was described many years ago [5,6]. Although a key feature of a #Professor of Pediatrics, Division Head, Director. neoplasm is its clonal derivation from a single cell, clonality does § not necessarily mean malignancy. Willman et al. [7] defined the Associate Professor. clonal cells in LCH as CD1aþ dentritic cells. Advances in DNA Correspondence to: Sarah R. Vaiselbuh, Department of Pediatrics, sequencing technology enabled sensitive screening of CD1aþ cells Staten Island University Hospital, 256C Mason Ave., Staten Island, NY purified from LCH lesions, and it was discovered that BRAF-V600E 10305. E-mail: [email protected] point mutations were present in the majority of LCH lesions with a Received 3 September 2013; Accepted 10 February 2014

C 2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25017 Published online 9 March 2014 in Wiley Online Library (wileyonlinelibrary.com). 1330 Vaiselbuh et al.

TABLE I. Classification of Three Most Common Histiocytic Disorders

Histiocytic disorder Cell type Reported mutations Molecular markers Langerhans cell histiocytosis (LCH) Dentritic cells Yes (50–57%) CD207þþ BRAF-V600E CD1aþþ S100þþ Hemophagocytic lymphohistiocytosis (HLH) Macrophages PRF1 CD163þþþ CD8þ T-lymphocytes UNC13D S100þ/ Natural killer-cells STX11 CD1a STXBP2 Rosai Dorfman disease (RDD) Macrophages No CD14þ, HLA-DRþ CD68þþ, CD163þ S100þ, fascinþ CD1a CD207

with enrichment of regulatory CD4þCD25þT cells [16]. The warrant systemic treatment even as single lesions. Neurodegenera- lesion-LCs express high levels of T-cell stimulatory molecules as tive LCH seems to be a separate entity with a clinical presentation of well as pro-inflammatory cytokines. In addition to the intralesional symptoms of dysarthria, ataxia, and cognitive defects resembling cytokine storm, increased serum levels of pro-inflammatory cyto- multiple sclerosis. kines and chemokines are documented in active LCH [1,16–18]. Pathogenesis that defines disease subclasses of LCH needs further Treatment elucidation. A specific role for lL17A and its receptor in LCH Due to incomplete understanding of the pathogenesis of LCH, pathogenesis has been reported, though IL17A expression by LCH treatment has relied on empiric strategies. Outcomes have improved lesion DCs remains to be validated [19,20]. over the past decades despite few changes in the treatment backbone, possibly due to improved supportive care. In the most Diagnosis recent Society trial, LCH-III, patients with “Low-Risk” LCH had nearly 100% overall survival, while patients with “High- LCH, the most common histiocytic disorder in humans, is Risk” LCH had 84% 5-year overall survival [23]. Other important estimated to occur in approximately five children per million, but factors are the repetition of induction phase of therapy for all may arise de novo in adults [21]. No screening tests are available patients who did not achieve a very good response after the first and the diagnosis is often delayed. While the range of presentations 6 weeks of induction, and an early move to salvage therapy for poor can make LCH a challenging disease to diagnose, tissue biopsy responders who have a very high mortality otherwise. In all patients is diagnostic with pathologic CD207þ and/or CD1aþ DCs in a with LCH, optimizing therapy remains a challenge since background of inflammatory cells. Clinically, symptoms of LCH approximately one-half of all patients with MS-LCH still have depend on the organs involved. Pulmonary LCH might present with refractory/recurrent disease when treated with vinblastine/predni- dyspnea and cough, or chest pain, and shortness of breath in the case sone-based strategies [23,24], in contrast to single system disease, of pneumothorax. Bone lesions may lead to bone pain, abnormal which has a lower reactivation rate. Disease- and treatment-related swelling, or pathological fracture. Skin LCH can occur as a long-term effects are also problematic, and are more common in dermatitis rash with vesicles and bullae (more in infancy). Often patients with disease recurrence. While modifications in dose, there is a past history of unresolved seborrheic eczema and oozing duration and timing of chemotherapy along with improved of the external ear canal. Pituitary involvement with onset of supportive care may continue to achieve incremental improvements diabetes insipidus will cause increased thirst and polyuria. Fatigue, in outcomes for patients with LCH, an optimized therapeutic weight loss and low-grade fevers are signs of the general approach requires understanding of disease pathogenesis. inflammatory condition that often occurs with LCH. The clinical course of LCH is highly variable from self-healing without therapy Novel Therapeutics in LCH to potentially lethal multi-system disease [22]. Clinical stratification for LCH is based on the extent of organ BRAF targeted therapy has changed the treatment paradigm in systems involved, localization and organ dysfunction: single system refractory melanoma [25]. Two class I BRAF-inhibitors, vemur- LCH (SS-LCH) with one organ/system involved (uni- or multifo- afenib and dabrafenib, are orally available and now FDA-approved cal) and multisystem LCH (MS-LCH) with two or more organs/ for use in advanced BRAF-V600Eþ-melanoma [26,27]. In a phase 3 systems involved, with or without involvement of “Risk Organs.” randomized clinical trial comparing vemurafenib with dacarbazine Risk organs in LCH include liver, spleen, and bone marrow. The in patients with BRAF-V600þ-metastatic melanoma, vemurafenib lung has been considered for many decades a risk organ, but clinical produced improved rates of overall and progression-free surviv- data do not support a prognostic implication. Isolated pulmonary al [28]. Non-specific side effects were reported, but the most LCH can be seen in children but more often in adults, in strong worrisome is the development cutanous toxicities like squamous correlation with smoking. LCH is also classified based on the site of cell carcinoma in up to 30% of patients, usual well-differentiated initial presentation. Vertebral lesions with intraspinal growth or and easily resectable, but also de novo malignant melanoma, rare craniofacial lesions are classified as “special site” lesions and but serious [29]. Pediatr Blood Cancer DOI 10.1002/pbc Histiocytic Disorders Review 1331

The clinical potential of BRAF inhibition in patients with LCH monotherapy [33]. Progressive MS-LCH with bone marrow was revealed when two patients with Erdheim Chester disease involvement can be brought into remission with reduced intensity (ECD) and biopsy proven BRAF-V600Eþ-LCH lesions (one in bone marrow transplantation [22]. Alternatively, good responses skin, one in lymphnode) showed significant response to vemur- in refractory LCH have been obtained by salvage therapy of afenib after 1 month [30]. Although these data are promising, clofarabine [34,35]. In addition, the combination of 2CdA and validation is necessary with well-designed clinical multicenter Ara-C, although very immunosuppressive, shows promise as a studies. A multicenter Phase I/IIa pediatric trial for patients with salvage approach in patients with refractory LCH [32] (Table II). BRAF-V600þ-gliomas, LCH and papillary thyroid carcinoma is currently open for recruitment in Europe, US and Canada (clinicaltrials.gov NCT01677741) (Table II). At the Histiocyte HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Society meeting 2013, data were presented of a single-arm open (HLH) label trial to evaluate the efficacy and safety of afuresertib, an oral Pathogenesis pan-AKT inhibitor in adult and adolescents with relapsed/refractory LCH. Although 29% patients were reported as better at the 3 and/or The histiological signature of HLH is accumulation of 6 months disease assessment, afuresertib did not meet goals for in tissues, such as activated macrophages that engulf disease responses of this study. erythrocytes (hemophagocytosis) and activated cytotoxic T- Progressive MS-LCH (non-risk organ) has been successfully lymphocytes (hence lymphohistiocytosis). Different forms of treated with 2-chlorodeoxyadenosine (2CdA or cladribine) mono- HLH can be distinguished [36] (Table III). Primary (familial) therapy [31]. A nucleoside analogue like cladribine is often HLH, a familial form of this hyperimmune state, with persistent recommended as frontline therapy in adult LCH [32]. Adult LCH fever, cytopenias, hepatosplenomegaly, and hemophagocytosis with bone lesions only might benefit from cytarabine (Ara-C) as cardinal symptoms, was first described by Farquhar and

TABLE II. Newer Therapeutic Options in Histiocytic Disorders

Histiocytic disorder Name Clinical Langerhans cell histiocytosis (LCH) Vemurafenib Evaluation in process (NCT01677741) Cladribine Salvage therapy Clofarabine Salvage therapy Cytarabine Salvage therapy Hemophagocytic lymphohistiocytosis (HLH) HLH-94 protocol Standard of care Reduced intensity conditioning HSCT ATGþetoposide/dexa (hybrid immunotherapy) Evaluation in process (NCT01104025) Rituximab EBV-associated HLH Alemtuzumab Refractory disease Tocilizumab (anti-IFN monoclonal antibody) Evaluation in process (NCT02007239) Rosai Dorfman disease (RDD) Imatinib Validation needed Cladribine Refractory disease Clofarabine Refractory disease Rituximab Validation needed Azathiopine Validation needed

TABLE III. Genes Associated With Primary HLH

Required for Required for lymphocyte lymphocyte Partial Gene Syndrome Inheritance Protein cytotoxicity degranulation albinism Diagnostic cellular assay PRF1 FHL2 AR Perforin Yes No No Intracellular perforin expression in cytotoxic lymphocyte subsetsa UNC13D FHL3 AR Munc13-4 Yes Yes No Degranulation by cytotoxic lymphocyte subsets STX11 FHL4 AR Syntaxin-11 Yes Yes No Degranulation by cytotoxic lymphocyte subsets STXBP2 FHL5 AR Munc18-2 Yes Yes No Degranulation by cytotoxic lymphocyte subsets RAB27A GS2 AR RAB27A Yes Yes Yes Degranulation by cytotoxic lymphocyte subsets LYST CHS1 AR LYST Yes Yes Yes Degranulation by cytotoxic lymphocyte subsets SH2D1A XLP1 XL SAP No No No Intracellular SAP expression in T cells or NK cellsa XIAP XLP2 XL XIAP No No No Intracellular XIAP expression in lymphocytesa FHL, familial hemophagocytic lymphohistiocytosis; GS, Griscelli syndrome; CHS, Chediak–Higashi syndrome; XLP, X-linked lymphoprolifer- ative disease; AR, autosomal recessive; XL, X-linked. aCellular assays may fail to diagnose disease caused by coding mutations that impair protein function without affecting protein expression. Pediatr Blood Cancer DOI 10.1002/pbc 1332 Vaiselbuh et al.

Claireaux [36–38]. Primary HLH, in which genetic mutations in in lytic perforin/granzym granule exocytosis pathway. Mutations in HLH-associated genes are identified, usually has an early onset other genes, some of which cause also partial albinism, are also triggered by infection. Primary HLH may also be diagnosed in adult associated with HLH. Because genetic approaches typically are patients [39]. Secondary (acquired) HLH often presents later in life. limited to sequencing of the coding regions and splice-sites of HLH In the absence of a genetic cause or familial inheritance, secondary associated genes, mutations in non-coding regulatory sequences or HLH occurs in response to viral infections or autoimmunity, genetic aberrations such as inversions or deletions may not be leishmaniasis, malignancies (particularly lymphoma), as well as detected [47]. Importantly, cellular assays can provide rapid results metabolic disorders and acquired immunodeficiencies. Macro- to the clinician and can uncover defects missed by conventional phage activation syndrome (MAS) is a potentially fatal complica- genetic analysis. Assays measuring 51Cr-release by K562 target tion of rheumatic diseases that bears close resemblance to HLH cells sensitive to NK cell-mediated lysis have represented the gold [40]. standard for assessment of CTL function and still constitute one Many cases of primary HLH are now known to be caused by component of the clinical diagnostic criteria for HLH. However, defects in target cell killing by cytotoxic lymphocytes (CTL). The this assay cannot distinguish between an absence of NK cells or a major subsets of CTL in peripheral blood are CD8þ T-cells and defect in NK cell function and thus does not discriminate between natural killer (NK) cells. CTL can eliminate virus-infected and primary and secondary forms of HLH. More recently, sensitive flow transformed cells through direct release of cytotoxic granules that cytometric assays for assessment of NK cell intracellular perforin contain perforin and granzymes capable of inducing targeted cell content as well as surface expression of CD107a in response to death [41]. CTL also contribute to immune homeostasis through K562 target cells, the latter representing a measure of NK cell killing autologous, activated immune cells, thereby limiting the degranulation, have demonstrated efficacy for identification of magnitude of immune responses. Mutations in the genes encoding patients with primary HLH [48]. In a prospective study by a pan- perforin as well as other proteins required for cytotoxic granule European consortium, assessment of NK cell degranulation trafficking and release have been associated with HLH. Upon provided 96% sensitivity and 88% specificity for a primary immunological challenge, an inability of CTL to clear pathogens degranulation disorder in the perforin/granzyme pathway [48]. and control immune responses can result in a massive immune Elevated granzyme B in CTL and NK cells also represent a general activation with excessive production of proinflammatory cytokines signature of immune activation, and is elevated in HLH [49]. and influx of responding activated macrophages, manifesting as Improved diagnostic early screening tests are under development. A systemic inflammation with the classic immunopathology of HLH. modified assay that provides robust quantification of cytotoxic T- Thus, current HLH research, focused on how defects of CTL are cell degranulation may complement existing assays of NK-cell related to human diseases, has defined HLH as an immunodeficien- degranulation and further improve functional diagnostics [50]. cy disorder [42]. Combining cellular phenotypical and functional assessments with genetic analyses of patients with HLH promises to provide a better Diagnosis view of how genetic mutations or variations perturb cellular function and predispose to disease. Future studies may uncover HLH is characterized by a sepsis-like systemic inflammation. additional genes associated with HLH and provide greater The presence of five out of eight established diagnostic criteria, understanding of cases hitherto defined as patients with secondary confirms the diagnosis of HLH (fever, splenomegaly, cytopenias HLH. (2 cell lineages), hypertriglyceridemia/hypofibrinogenemia, he- mophagocytosis, low or absent NK activity, high ferritin (>500 mg/ Treatment ml) and sCD25 > 2,400 U/ml) [43]. Altered consciousness might indicate central nervous system involvement [44]. Organ-infiltrat- The basis of HLH therapy is intensive immunosuppression ing macrophages (CD163þþþ/S100þ/, Cd1a) involved in (including corticosteroids, etoposide, cyclosporin, intravenous hemophagocytosis as well as organ-infiltrating CD8þ T-cell immunoglobulin, and infliximab) and standard treatment guidelines expansions are often present. Of note, hemophagocytosis typically are available in excellent reviews [51]. The HLH 94 and HLH 2004 manifests late in the course of the disease. Thus, a failure to detect protocols represent consensus protocols developed by the Histio- hemophagocytosis does not negate a diagnosis of HLH. Hyper- cyte Society and have helped in formalizing a more standard cytokinemia, with high systemic levels of IL-6, IFN-g, and TNF, is approach for treatment of HLH [43,52]. Still, therapy is also a hallmark of HLH [45]. Upon clinical diagnosis of HLH, it is complicated by high treatment-related morbidity and early disease imperative that patients are rapidly evaluated for the possibility of recurrence. Because the risks and benefits of the addition of primary HLH, as this may determine the need for performing cyclosporine to induction is not yet established (HLH 2004), the transplantation (HSCT). Two complimen- HLH-94 study should be considered standard of care for all patients tary approaches, genetic, and cellular, can be taken to confirm a not enrolled in clinical trials [52]. In HLH-94, cyclosporine was diagnosis of primary HLH. Loss-of-function mutations in several introduced at the beginning of continuation therapy, while in HLH- genes have been associated with HLH (Table III). Autosomal 2004 cyclosporine administration began during induction therapy in recessive mutations in PRF1, encoding perforin, are linked to an effort to improve remission rates. In primary HLH the 8-week familial HLH type 2 (FHL2) [46]. Milder missense mutations in induction is used as a bridge to allogeneic hematopoietic stem cell PRF1 may not cause HLH, but are associated with hematologic transplant (HSCT), the only curative treatment available. Trans- malignancies later in life. Autosomal recessive mutations in plant-related morbidity in HLH has been reduced significantly with UNC13D, STX11, and STXBP2 are associated with FHL3, FHL4, reduced intensity conditioning for HSCT [53]. Antithymocyte and FHL5, respectively [42]. These genes encode the Munc13-4, globulin (ATG) based immunotherapy of familial HLH, in syntaxin-11, and Munc18-2 proteins, which regulate critical steps combination with corticosteroids, cyclosporine A, and intrathecal Pediatr Blood Cancer DOI 10.1002/pbc Histiocytic Disorders Review 1333 injections of methotrexate, is effective as a first treatment with a TNF-a. Systemic symptoms in RDD may be related to enhanced 73% rapid and complete response in a single center study. When production of these cytokines [64]. A cytokine-mediated migration HSCT was performed early after complete or partial response of monocytes could be involved in histiocytes accumulation induction with ATG in primary HLH, it led to a high rate of cure in and activation. This functional activation can be triggered by the same study [54]. Hybrid immunotherapy, combining ATG, hematological malignancies or autoimmune diseases. Indeed, RDD dexamethasone, and etoposide is currently in clinical trial has been reported following bone marrow transplant for precursor- (clinicaltrials.gov NCT01104025) (Table II). B acute lymphoblastic [65], and concurrently or after Hodgkin and non- [66]. Similarly, an increased Newer Therapeutic Options in HLH incidence of autoimmune hemolytic anemia, systemic lupus erythematosus and juvenile idiopathic arthritis has been docu- In regards to new therapeutic options, when combined with mented with RDD [67,68]. Histopathological features of RDD were conventional HLH therapies, the anti-CD20 monoclonal antibody, recently identified in the lymph nodes of 18/44 (41%) patients with rituximab, improves symptoms, reduces viral load, and diminishes autoimmune lymphoproliferative syndrome (ALPS) type Ia, with inflammation in patients with EBV-induced HLH if the EBV is TNFRSF6 heterozygous germline mutations affecting the gene proliferating within the B-cell [55]. However, rituximab is of no encoding Fas, that might classify some of the RDD as an value in cases with EBV-associated HLH where EBV proliferates in autoimmune disorder [69]. Patients with ALPS type Ia and RDD T-cells instead of B-lymphocytes, as shown in Japan [56]. tend to have more severe manifestations of ALPS, present at an Furthermore, a case report remission in primary HLH was achieved earlier age and are more often males. However, the RDD changes by treatment with the anti-CD52 monoclonal antibody, alemtuzu- tend to be mainly nodal and self-limited in these cases and only in mab, as a bridge to HSCT [57,58]. Alemtuzumab appears to be an a small number of patients contribute significantly to the clinical effective salvage agent for refractory HLH with 64% partial manifestations of ALPS. The transformation of RDD to a response rate in a single institution study, leading to survival to has been reported in a child with ALPS type undergo HSCT [53,58]. However, commentaries suggested that Ia [70]. Given the central role of defective Fas signaling in ALPS, alemtuzumab therapy may aid development of HLH in certain histiocytes could be another lineage at risk for neoplastic settings, possibly through elimination of CTL that usually transformation secondary to an apoptotic block. contribute to the maintenance of immune homeostasis [59]. Thus, the efficacy of anti-CD52 monoclonal antibody therapy is not clear. Finally, anti-IFN-g monoclonal antibody therapy has Diagnosis demonstrated efficacy in mouse models of HLH and a clinical trial The most common presentation of RDD is bilateral painless is currently under way (NCT01818492) [60]. massive cervical lymphadenopathy associated with fever, night sweats, fatigue, and weight loss. Mediastinal, inguinal, and ROSAI DORFMAN DISEASE (RDD) retroperitoneal nodes may also be involved. Extranodal involve- ment by RDD has been documented in 43% of cases with the most Pathogenesis frequent sites being skin, soft tissue, upper respiratory tract, The non-Langerhans cell (non-LCH) histiocytoses are a group multifocal bone, eye, and retro-orbital tissue [71]. Other reported of disorders defined by the accumulation of histiocytes that do not sites include urogenital tract, breast, gastrointestinal tract, liver, meet the phenotypic criteria for the diagnosis of LCs [61]. Systemic pancreas, and lungs. Head and neck involvement has been reported non-LCH include juvenile xanthogramuloma (JXG), ECD, and in 22% of cases, most commonly the nasal cavity followed by the RDD. The non-LCH are thought to arise from either a DC or a parotid gland [72]. Intracranial RDD usually occurs without cell line, and can be divided clinically into three major extracranial lymphadenopathy, and most intracranial lesions are groups—those that primarily affect the skin such as the JXG family attached to the dura with only few extending into the parenchyma. and , those that affect the skin but have a major Central nervous system disease can present clinically and systemic component such as and multi- radiologically as meningioma, but the presence of emperipolesis centric reticulohistiocytosis, and those that predominantly involve in the spinal fluid is usually diagnostic of Rosai–Dorfman systemic sites, although skin may also be affected, such as systemic disease [73,74]. RDD cases presenting with kidney, thyroid, JXG, ECD, and sinus histiocytosis with massive lymphadenopathy isolated mediastinal, and unifocal skeletal involvement have also or RDD. been reported [75–78]. Laboratory abnormalities are non-specific Initially described by Rosai & Dorfman in 1969, RDD is a non- with elevated sediment rate and leucocytosis, high ferritin, neoplastic, polyclonal, and self-limited non-LCH. RDD cells are hypergammaglobulinemia, and autoimmune hemolytic anemia. CD14þ, HLA-DRþ, CD68þþ, CD163þ, S100þ, and fascinþ macrophages, and they are typically negative for CD1a and Treatment langerin [62]. Histologically, RDD lymph nodes show massive sinus infiltration of large histiocytes mixed with lymphocytes and Since results with chemotherapy for RDD have not been plasma cells. The presence of emperipolesis, or the engulfment of encouraging, the use of chemotherapy is restricted to patients with intact erythrocytes, lymphocytes and plasma cells by S100þ life-threatening disease or multiple relapses. Successful targeted histiocytes, in the appropriate clinical setting is considered therapy with platelet-derived growth factor-receptor b (PDGFRB)- diagnostic but not unique of RDD [63]. RDD lesions have a inhibitors such as imatinib in a recent case report, might suggest a moderate expression of IL-6, which could be related to the role for PDGFRB and KIT in the pathogenesis of RDD [79]. Newer associated polyclonal plasmacytosis and hypergammaglobuline- cytotoxic agents such as cladribine (2-chlorodeoxyadenosine) and mia. Furthermore, the lesions tend to express strongly IL-1b and clofarabine, have been found to be effective in recurrent, refractory Pediatr Blood Cancer DOI 10.1002/pbc 1334 Vaiselbuh et al.

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