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 histiocytosis (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 macrophages. 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 ÃCorrespondence 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/À Natural killer-cells STX11 CD1aÀ STXBP2 Rosai Dorfman disease (RDD) Macrophages No CD14þ, HLA-DRþ CD68þþ, CD163þ S100þ, fascinþ CD1aÀ CD207À 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 Histiocyte 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