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 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