Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis. Recent findings suggest that ECD is a clonal disorder, marked by recurrent BRAFV600E mutations in >50% of patients, in which chronic uncontrolled inflammation is an important mediator of disease pathogenesis. Although ∼500 to 550 cases have been described in the literature to date, increased physician awareness has driven a dramatic increase in ECD diagnoses over the last decade. ECD frequently involves multiple organ systems and has historically lacked effective therapies. Given the protean clinical manifestations and the lack of a consensus-derived approach for the management of ECD, we provide here the first multidisciplinary consensus guidelines for the clinical management of ECD. These recommendations were outlined at the First International Medical Symposium for ECD, comprised of a comprehensive group of international academicians with expertise in the pathophysiology and therapy of ECD. Detailed recommendations on the initial clinical, laboratory, and radiographic assessment of ECD patients are presented in addition to treatment recommendations based on critical appraisal of the literature and clinical experience. These formalized consensus descriptions will hopefully facilitate ongoing and future research efforts in this disorder. (Blood. 2014;124(4):483-492)

It has been suggested that members of HSP families represent the surface target of immune responses leading to tumor rejection in mice. Here we report that tumor cells, compared with normal cells, constitutively expressed 2- to 10-fold higher levels of intracellular HSP90. Moreover, in the absence of environmental stress, 2 lines (out of 6) expressed the "inducible" HSP72, which was also detectable in fresh tumor cells. HSP72 expression was not regulated during the cell cycle, in contrast with what has been observed with normal cells. Both HSP90 and HSP72 proteins exhibited a heterogeneous pattern of intracellular distribution in most cells, HSP72 being confined mainly to the nuclear compartment. Finally, we could detect both HSP90 and, to a lesser extent, HSP72 (that are generally believed to be located intracellularly) at the surface of some tumor cell lines. We conclude that tumor cells differ from normal cells in their pattern of HSP expression; this might imply a role of HSPs in eliciting an immune response against cancer.

No abstract

Objective. Erdheim-Chester disease (ECD) is a rare form of non-Langerhans' cell histiocytosis (LCH) of unknown etiology, characterized by diffuse histiocyte infiltration of bones and soft tissue. The purpose of this study was to assess cell proliferation and expression of cytokines, chemokines, and chemokine receptors that may potentially be important in histiocyte accumulation in ECD lesions.Methods. Biopsies were performed on 3 patients with ECD. The diagnosis of the disease was based on clinical signs including typical radiologic osteosclerosis, and on the detection of foamy CD68؉,CD1a؊ nonLangerhans' cell histiocytes on histologic examination. The expression of the proliferation marker Ki-67 as well as of selected chemokine/chemokine receptor pairs and cytokines was analyzed by immunohistochemistry.Results. In all samples, Ki-67 was undetectable in CD68؉ histiocytes. Conversely, these cells expressed the chemokines CCL2 (monocyte chemotactic protein 1), CCL4/macrophage inflammatory protein 1␤ (MIP-1␤), CCL5/RANTES, CCL20/MIP-3␣, and CCL19/MIP-3␤, and their counter-receptors CCR1, CCR2, CCR3, CCR5, CCR6, and CCR7. Moreover, ECD histiocytes expressed interferon-␥-inducible 10-kd protein (CXCL10), which is specifically induced by interferon-␥, and interleukin-6 and RANKL, which are both implicated in bone remodeling. Finally, all cases showed a Th1-type lymphocyte infiltrate.Conclusion. Our data indicate that, similar to LCH, ECD lesions are characterized by a complex cytokine and chemokine network, which may orchestrate histiocyte activation and accumulation through an autocrine loop and contribute to the pathogenesis of the disease.Erdheim-Chester disease (ECD) is a rare form of systemic non-Langerhans' cell histiocytosis (LCH), with ϳ250 cases described so far. The disease represents a distinct pathologic entity characterized by nearly pathognomonic osteosclerosis, especially of the long bones, and frequently by extraskeletal involvement. Histologically, the lesions consist of diffuse infiltration of bones and soft tissue (kidney, retroperitoneal space, skin, brain, and lung) by foamy CD68ϩ,CD1aϪ nonLangerhans' cell histiocytes (1-3).The etiopathogenesis of the disease is unknown; in particular, at variance with LCH (4), attempts to demonstrate the clonality of histiocytes in ECD have shown inconclusive results (5). Moreover, the mechanisms leading to histiocyte accumulation in ECD lesions have not been elucidated. In this regard, it is well known that leukocyte migration to tissues may be driven by chemokines via interaction with their specific receptors

The oncogenic BRAF(V600E) mutation is present in biopsies and in the peripheral blood from all patients with ECD who were evaluated and is associated with OIS. These findings have significant implications for the pathogenesis, diagnosis and treatment of ECD.