Erdheim-Chester disease: a rapidly evolving disease model.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis with a putative neoplastic and inflammatory nature. The disease is driven by mutations in proto-oncogenes such as BRAF and MEK, while immune-mediated mechanisms contribute to disease development and progression. The clinical presentation of ECD is highly heterogeneous, ranging from smouldering unifocal forms to multiorgan life-threatening disease. Almost any organ can be involved, but the most common lesions include long-bone involvement, retroperitoneal fibrosis, interstitial lung disease, pericardial and myocardial infiltration, CNS, retro-orbital, and large-vessel involvement. These manifestations may mimic those of neoplastic and systemic immune-mediated diseases. Overlap with these conditions represents an emerging challenge for the clinician. A variety of treatments are efficacious for ECD, targeting both the MAPK-pathway and the immune-mediated pathomechanisms. The traditional approach is based on immunomodulatory agents (interferon-α), but recent alternatives-including anti-cytokine therapies (IL1- and TNFα-blockers) and immunosuppressants (mTOR-inhibitors)-showed promising results. However, since the detection of MAPK pathway activation in most patients and the dramatic efficacy of BRAF and MEK inhibitors, these targeted treatments represent the first-line approach in patients with severe disease forms. High rates of radiologic responses do not often mean clinical remission, especially for CNS involvement, which often results in chronic disability. This review will outline the main clinical features of ECD, with emphasis on the emerging challenges in pathogenesis and management, and on the role of recent targeted approaches.

Erdheim-Chester disease: An in vivo human model of Mϕ activation at the crossroad between chronic inflammation and cancer.

Erdheim-Chester disease (ECD) is a rare histiocytosis characterized by infiltration of multiple tissues by CD68+ foamy Mϕs (or 'histiocytes'). Clinical manifestations arise from mass-forming lesions or from tissue and systemic inflammation. ECD histiocytes harbor oncogenic mutations along the MAPK-kinase signaling pathway (BRAFV600E in more than half of the patients), and secrete abundant pro-inflammatory cytokines and chemokines. Based on these features, ECD is considered an inflammatory myeloid neoplasm, and is accordingly managed with targeted kinase inhibitors or immunosuppressive and cytokine-blocking agents. Evidence is emerging that maladaptive metabolic changes, particularly up-regulated glycolysis, represent an additional, mutation-driven feature of ECD histiocytes, which sustains deregulated and protracted pro-inflammatory activation and cytokine production. Besides translational relevance to the management of ECD patients and to the development of new therapeutic approaches, recognition of ECD as a natural human model of chronic, maladaptive Mϕ activation instructs the understanding of Mϕ dysfunction in other chronic inflammatory conditions.

Pulmonary histiocytosis: beyond Langerhans cell histiocytosis related to smoking. / Histiocitosis pulmonar: más allá de la histiocitosis de células de Langerhans relacionada con el tabaco.

OBJECTIVE: To review the imaging findings for the different types of pulmonary histiocytosis. In particular, in addition to the well-known pulmonary Langerhans cell histiocytosis related to smoking and its possible appearance in nonsmokers, we focus on non-Langerhans cell histiocytosis in Rosai-Dorfman disease and Erdheim-Chester disease. We also review the etiopathogenesis, histology, clinical presentation, and treatment of pulmonary histiocytosis. CONCLUSION: Langerhans cell histiocytosis, Rosai-Dorfman disease, and Erdheim-Chester disease are idiopathic diseases in which the proliferation and infiltration of histiocytes is the histologic finding that confirms the diagnosis. Langerhans cell histiocytosis manifests as nodules and cysts that spare the costophrenic angles; it typically appears in smokers. Although it is uncommon in nonsmokers, Langerhans cell histiocytosis should also be considered in nonsmokers treated with chemotherapy and radiotherapy in whom cavitated nodules appear and should be included in the differential diagnosis together with metastatic disease and opportunistic infections. Rosai-Dorfman disease and Erdheim-Chester disease present with less specific thoracic findings such as adenopathies, interstitial thickening, and pleural effusion. In Erdheim-Chester disease, the characteristic extrathoracic manifestations are usually key for the diagnosis.

Erdheim-Chester disease associated with a novel, complex BRAF p.Thr599_Val600delinsArgGlu mutation.

BRAF mutation testing to determine eligibility for treatment with vemurafenib was performed on archival skin lesions of a 54-year-old patient diagnosed with Erdheim-Chester disease (ECD) in 1999. Sanger sequencing of DNA extracted from a 2008 skin lesion identified two non-contiguous base substitutions in BRAF, which were shown by next-generation sequencing (NGS) to be located in the same allele. Due to its long-standing duration, molecular evolution of disease was possible; however, both Sanger and NGS of a 2000 skin lesion were unsuccessful due to the poor quality of DNA. Finally, droplet digital PCR using a probe specific for this novel mutation detected the complex BRAF mutation in both the 2000 and 2008 lesions, indicating this case to be ECD with a novel underlying BRAF p.Thr599_Val600delinsArgGlu mutation. Although well at present, molecular modelling of the mutant BRAF suggests suboptimal binding of vemurafenib and hence reduced therapeutic effectiveness.

Erdheim-Chester disease: a comprehensive review.

Erdheim-Chester disease is a rare form of non-Langerhans' cell histiocytosis characterized by multi-system infiltration by xanthogranulomas composed of foamy histiocytes surrounded by fibrosis. Approximately 400 cases have been reported in the literature, and the recent increase in the number of cases is likely due to the increased awareness of its associated morbidity and mortality. The etiology of this disease remains unknown, the clinical course is variable and treatment is still not well-established. The objective of this review is to describe the pathogenesis, clinical manifestations, and diagnosis of this rare disorder, and to review its prognosis and treatment. Erdheim-Chester disease (ECD) is a rare form of non-Langerhans' cell histiocytosis. It was first described in 1930. Approximately 400 cases have been reported in the literature.

Erdheim-Chester disease: characteristics and management.

Erdheim-Chester disease is a rare CD68(+), CD1a(-) non-Langerhans cell histiocytosis with multiorgan involvement. The etiology of Erdheim-Chester disease is unclear; there are no known associated infectious or hereditary genetic abnormalities. However, somatic BRAF mutations have recently been identified in these patients. Historically, the literature regarding the management of Erdheim-Chester disease consisted of case reports and small case series with anecdotal therapeutic responses to agents including, but not limited to, cytotoxic chemotherapy, bone marrow transplantation, cladribine, corticosteroids, IFN-α, the BCR-ABL/KIT inhibitor imatinib mesylate, the IL-1 receptor antagonist anakinra, the TNF-inhibitor infliximab, and recently the BRAF inhibitor vemurafenib. We performed a search of the literature using PubMed with the terms Erdheim Chester disease, without date limitations, including case reports, case series, original articles, and previous review articles. In the absence of large-scale studies, experience-based management prevails. The present review details our approach to the management of patients with Erdheim-Chester disease.

[Cardiovascular involvement in Erdheim-Chester syndrome: clinical and therapeutic implications]. / Coinvolgimento cardiovascolare nella sindrome di Erdheim-Chester: aspetti clinici e terapeutici.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans' cell histiocytosis of unknown etiology and its incidence is constantly increasing. ECD is characterized by a xantomatous or xanthogranulomatous infiltration of various tissues by foamy histiocytes surrounded by fibrosis. ECD is characterized by multi-organ involvement and is generally associated with a poor prognosis with a median survival of 32 months after diagnosis. Cardiovascular involvement concerns mainly the thoraco-abdominal aorta and pericardium. Less frequently, infiltration affects the myocardial tissue, especially the right atrium, and the valvular endocardium. Recently, the involvement of the vena cava has also been described. The diagnosis of ECD is made by the identification of foamy histiocytes CD68 positive and CD1a/S100 negative embedded in a polymorphic inflammatory tissue on biopsy. Despite the adoption of several therapeutic strategies until now prognosis has remained poor. Interferon-α can be considered the first line therapy, but its effects on central nervous system and cardiovascular localization have been shown to be often poor. In this context a combined treatment with the anti-TNFα monoclonal antibody infliximab and methotrexate seems to be effective and well tolerated.

Erdheim-Chester disease associated with intramedullary spinal cord lesion.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis. We present a case of a 56-year-old male with ECD. As time progressed, involvement of the orbital fossa, cranial convexity, spinal cord, brain stem, thyroid, lung, retroperitoneum, lower extremity bones and skin were found. Previously reported cases reveal the frequency of ECD with spinal cord involvement is rare. Although this was a presumed diagnosis based on other lesions, our case is the first in which both intramedullary and epidural masses are present.

Langerhans cell histiocytosis and Erdheim-Chester disease.

PURPOSE OF REVIEW: To provide an updated overview of the pathogenesis and treatment of Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD). RECENT FINDINGS: There is ongoing debate as to the exact pathogenesis of these disorders and their classification as reactive versus neoplastic. Proinflammatory cytokines are known to play a role in both LCH and ECD and strengthen the hypothesis that, at least in part, they are disorders of immune dysregulation. The recent discovery of activating mutations in the proto-oncogene BRAF in a subset of LCH patients suggests that LCH is in fact a neoplastic disorder. Understanding of the mechanisms that promote proliferation and migration of histiocytes has led researchers to explore targeted immune-modulatory therapies for ECD. Similarly for LCH, alternative chemotherapeutic agents and reduced-intensity hematopoietic stem cell transplant are being evaluated for refractory disease. SUMMARY: More research is needed to better understand the cause of these disorders and may help in identifying new targeted therapies, particularly for patients with refractory or relapsed disease. Multinational trials are ongoing for LCH and are urgently needed for ECD.

[Etiology and outcome of liver granulomatosis: a retrospective study of 21 cases]. / Etiologies et évolution des hépatites granulomateuses : étude rétrospective de 21 cas consécutifs.

PURPOSE: To assess the etiologies and outcome of liver granulomatosis. METHODS: We analyzed all consecutive liver granulomatosis diagnosed in our internal medicine department from 2000 to 2008. RESULTS: Among 471 liver biopsies, 21 disclosed evidence of liver granulomatosis (4.5%), in sixteen women (76%) and five men, with a median age of 41years. Thirteen were caucasians (62%). At the time of diagnosis, six (28.5%) had isolated abnormal liver function tests, and fifteen (71.4%) presented with clinical manifestations. The underlying cause was identified in 18 cases (85.7%). Eleven (52.3%) were systemic diseases: five (23.8%) primary biliary cirrhosis, two (9.5%) primary sclerosing cholangitis, two (9.5%) common variable immunodeficiency, one (4.7%) Sjögren's syndrome, and one (4.7%) Behçet's disease. Two (9.5%) patients had sarcoidosis. Three (14.3%) liver granulomatosis were of infectious origin (tuberculosis, schistosomiasis, and hepatitis C virus), two (9.5%) were neoplastic (Hodgkin's lymphoma and liver cell adenoma), and three (14.3%) were idiopathic. With a median of 38 months of follow-up, four patients (19%, two common variable immunodeficiency and two sarcoidosis) developed portal hypertension, independently of cirrhosis. One patient died of cryptococcosis. CONCLUSION: In accordance with other European studies, systemic diseases are the main causes of hepatic granulomas. Liver granulomatosis related to common variable immunodeficiency and sarcoidosis are at risk of portal hypertension.

Pituitary tumours: inflammatory and granulomatous expansive lesions of the pituitary.

Inflammatory and granulomatous diseases of the pituitary are rare causes of sellar masses. Lymphocytic hypophysitis is the most relevant of these disorders, and it is characterised by autoimmune pathogenesis with focal or diffuse inflammatory infiltration and varying degrees of pituitary gland destruction. Endocrine symptoms may include partial or total hypopituitarism, with adrenocorticotropic hormone (ACTH) deficiency being the earliest and most frequent alteration. Pituitary abscess is a rare but potentially life-threatening disease and, in 30-50% of patients, anterior pituitary hormone deficiencies or central diabetes insipidus (DI) at onset may be observed: the earliest manifestation being growth hormone deficiency (GHD), followed by follicle-stimulating hormone (FSH)/luteinising hormone (LH), thyroid-stimulating hormone (TSH) and ACTH deficiencies. Fungal infections of the pituitary are also very rare and include aspergillosis and coccidioidomycosis. Concerning pituitary involvement in systemic diseases, in sarcoidosis endocrine complications are rare, but the hypothalamus and pituitary are the glands most commonly affected. DI is reported in approximately 25-33 % of all neurosarcoidosis cases and is the most frequently observed endocrine disorder. Hyperprolactinaemia and anterior pituitary deficiencies may also occur. Rarely, partial or global anterior pituitary dysfunction may be present also in Wegener's granulomatosis, either at onset or in the course of the disease, resulting in deficiency of one or more of the pituitary axes. Other forms of granulomatous pituitary lesions include idiopathic giant cell granulomatous hypophysitis, Takayasu's disease, Cogan's syndrome and Crohn's disease. The hypotalamic-pituitary system is involved mainly in children with Langerhans' cells histiocytosis who develop DI, which is the most common endocrine manifestation. Anterior pituitary dysfunction is found more rarely and is almost invariably associated with DI. Pituitary involvement may also be observed in another form of systemic hystiocitosis, that is, Erdheim-Chester disease. Tuberculosis is a rare cause of hypophysitis, which may present with features of anterior pituitary dysfunction, such as hypopituitarism with hyperprolactinaemia. In conclusion, in patients with a sellar mass and unusual clinical presentation (DI, neurological symptoms), aggressiveness and onset and in the presence of systemic diseases, inflammatory and granulomatous pituitary lesions should be carefully considered in differential diagnosis.