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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 (BRAF V600E 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., (©2020 Society for Leukocyte Biology.)

Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation., (© 2021 by The American Society of Hematology.)

To calculate the prevalence of sinonasal and ear involvement in an Erdheim-Chester disease (ECD) population, to describe the different ear, nose and throat (ENT) manifestations and to study the association between ENT involvement, other organ involvement, and BRAF mutations. We led a retrospective monocentric study in the national referral center for ECD. One hundred and sixty-two patients with ECD and ENT data were included between January 1, 1980 and December 31, 2020. Ear and nose clinical and radiological findings were noted. We described and studied the prevalence of ENT involvement in ECD population. The association between sinonasal and ear involvement, other organ involvement, and BRAF mutations was calculated. The prevalence of ENT manifestations is around 45%. No clinical rhinologic or otologic signs were specific to ECD. Sinus imaging was abnormal in 70% of cases. A bilateral maxillary sinus frame osteosclerosis was highly specific of ECD. Associations were found between the sinus MRI imaging type and BRAF status, central nervous system involvement, cerebellum involvement and xanthelasma. Sinonasal or ear involvement is frequent in ECD and has specific imaging features for sinuses. Trial registration: #2011-A00447-34., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Objectives: Erdheim-Chester disease (ECD) is a rare form of histiocytosis characterised by uncontrolled chronic inflammation. The oncogenic BRAF(V600E) mutation has been reported in biopsies in 19 out of 37 patients with ECD from the largest published cohort, but never found in the patients' peripheral blood. Also, the role of the mutation in the pathogenesis of the disease has not been elucidated yet. BRAF(V600E) has been associated with oncogene-induced senescence (OIS), a protective mechanism against oncogenic events, characterised by the induction of proinflammatory pathways., Methods: We verified the BRAF status in biopsies and peripheral blood from 18 patients with ECD from our cohort and matched controls by means of immunohistochemistry and of an ultrasensitive assay, based on the combination of a locked nucleic acid PCR and pyrosequencing. Droplet digital PCR was used to confirm the findings. We also evaluated the presence of senescence markers in ECD histiocytes., Results: BRAF(V600E) mutation was present in all the biopsy and peripheral blood samples from patients with ECD and in none of the controls. ECD histiocytes and a fraction of circulating monocytes from patients with ECD showed signs of a constitutive activation of the MAPK pathway. Moreover, BRAF-mutated histiocytes expressed markers of OIS., Conclusions: 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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

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 (ECD) is characterized by excessive production and accumulation of histiocytes within multiple tissues and organs. ECD patients harbor recurrent mutations of genes associated with the RAS/RAF/MEK/ERK signaling pathway, particularly, the BRAF V600E mutation. Following our previous finding that miR-15a-5p is the most prominently downregulated microRNA in ECD patients compared to healthy individuals, we elucidated its role in ECD pathogenesis. Bioinformatics analysis followed by a luciferase assay showed that chemokine ligand 10 (CXCL10) is a target gene regulated by miRNA-15a-5p. This was confirmed in 24/34 ECD patients that had low expression of miR-15a-5p concurrent with upregulated CXCL10. Overexpression of miR-15a-5p in cell lines harboring BRAF or RAS mutations (Ba/F3, KG-1a and OCI-AML3) resulted in CXCL10 downregulation, followed by LIN28a and p-ERK signaling downregulation and let-7 family upregulation. Overexpression of miR-15a-5p inhibited cell growth and induced apoptosis by decreasing Bcl-2 and Bcl-xl levels. Analysis of sequential samples from 7 ECD patients treated with MAPK inhibitors (vemurafenib/cobimetinib) for 4 months showed miR-15a-5p upregulation and CXCL10 downregulation. Our findings suggest that miR-15a-5p is a tumor suppressor in ECD through the CXCL10-ERK-LIN28a-let7 axis, highlighting another layer of post-transcriptional regulation in this disease. Upregulation of miR-15a-5p in ECD patients may have a potential therapeutic role., (© 2021. The Author(s).)

Erdheim-Chester disease (ECD) is a rare disorder characterized by accumulation of non-Langerhans cell histiocytes in multiple organs. The clinical manifestations are protean and vary from asymptomatic focal disease to potentially fatal multisystem disorder. The commonest presentation is symmetric osterosclerotic lesions of lower extremity long bones; other organs, including cardiovascular, nervous, and endocrine system may be affected. Central nervous system involvement can occur in up to 50% cases and is associated with poor prognosis. The disease pathogenesis involves organ involvement secondary to histiocytic infiltration and systemic inflammation driven by Th1 cytokine activation. The recent discovery of activating mutations in proto-oncogene B-rapidly accelerated fibrosarcoma (BRAF) V600E and other genes involved in mitogen-activated protein kinase (MAPK) pathways has led to redefinition of ECD as a myeloid neoplastic disorder. The diagnosis requires histochemical and molecular analysis of histiocytes in tissue biopsies in patients with compatible clinical and imaging features. The treatment options include interferon-alpha, anakinra, and immunosuppressive therapies. Better understanding of disease pathogenesis has led to development of novel targeted and effective therapies including BRAF and MEK inhibitors. The rarity of the disease and variable clinical features and course often results in diagnostic errors and delays. Rare primary neurological presentation can occur mimicking CNS inflammatory, neoplastic, or demyelinating disorders. We report an unusual case of ECD presenting with progressive encephalopathy and ataxia along with multifocal brainstem and cerebellar lesions. A comprehensive review of clinical and neuroimaging features and immunohistochemical and molecular characteristic of ECD are presented along with review of neuroimaging findings in two previously reported cases., (© 2020 American Society of Neuroimaging.)

Erdheim-Chester disease (ECD) is a proliferative disorder of non-Langerhans histiocytes with a higher incidence in the fifth to seventh decades and rarer occurrence in the pediatric population. Although ECD typically involves bone, it can also affect the central nervous system, cardiovascular system, retro-orbital space, retroperitoneal space, and kidneys, lungs, and skin. A 13-year-old Syrian girl who presented with multisystemic involvement was diagnosed with ECD. The B-Raf proto-oncogene V600E mutation was not detected in ECD lesions. Response to the high-dose interferon-α therapy was excellent in this pediatric patient. In this article, pediatric ECD case reports are also reviewed.

Key Clinical Message: Diagnosis of Erdheim–Chester disease (ECD) requires the clinician to be familiar with its various manifestations, classic radiologic and histologic features. This case highlights the significance of considering ECD in any patient presenting with bone pain and symmetric osteosclerosis of long bones of extremities to allow for early diagnosis and treatment. Erdheim–Chester disease (ECD) is a rare non‐Langerhans histiocytic disorder with diverse clinical manifestations, ranging from indolent, localized presentation to life‐threatening, multi‐systemic disease. Delayed or erroneous diagnosis is common. The presence of classic radiographic finding along with foamy histiocytes that is positive for CD68 but negative for CD1a on histologic examination establishes the diagnosis. We report a second case of ECD from Ethiopia. A 50‐year‐old Ethiopian man presented with a 13‐year history of bilateral lower leg bone pain, cold intolerance, somnolence, constipation, impotence, decreased libido, and secondary infertility. The diagnosis was suspected when skeletal X‐ray revealed bilateral symmetric sclerosis of metadiaphysis of femur, tibia, and humerus. The demonstration of foamy histiocytes that were positive for CD68 but negative for CD1a on histologic examination with immunohistochemical staining confirmed the diagnosis. Evaluation for the extent of the disease revealed coated aorta sign, hairy kidney sign, and cystic lesion with ground glass opacity of lung, primary hypothyroidism, and hypergonadotropic hypogonadism. ECD is rare histiocytic neoplasm with wide range of clinical features which often delay the diagnosis. Clinician should be mindful of the various presentations and the classic radiographic and histologic features of ECD. This case highlights the significance of entertaining ECD in any patient presenting with lower leg bone pain and symmetric osteosclerosis of long bones of lower extremities to allow for early diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Introduction: Erdheim-Chester disease (ECD) is a rare disease that belongs to the group of Dendritic and histiocytic neoplasms. Only 2000 cases have been reported worldwide. It can present with a wide range of symptoms, making a differential diagnosis especially difficult. The primary and most important diagnostic tool is a biopsy of the affected organ/tissue. Nowadays the analysis of different mutations affecting the BRAF and MAPK pathways makes it possible to use targeted treatments, such as vemurafenib, dabrafenib, or cobimetinib. Objective: Our aim is to present the results of three male patients treated in our hematology department. Results: Our BRAF mutation-positive patient presented with retroperitoneal tissue proliferation and diabetes insipidus. The initial therapy of choice was dabrafenib. After 3 months of treatment, 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) scans showed regression, and after 2 years of treatment, no disease activity was detected. In our second patient, a recurrent febrile state (not explained by other reasons) and diabetes insipidus suggested the diagnosis. A femoral bone biopsy confirmed BRAF-negative ECD. The first-line therapy was interferon-alpha. After 3 months of treatment, no response was observed on 18FDG-PET/CT, and treatment with cobimetinib was started. The control 18FDG-PET/CT imaging was negative. Our third patient was evaluated for dyspnea, and a CT scan showed fibrosis with hilar lymphadenomegaly. A lung biopsy confirmed BRAF-negative ECD. We started treatment with interferon-alpha, but unfortunately, no improvement was observed. Second-line treatment with cobimetinib resulted in a partial metabolic response (PMR) according to control 18FDG-PET/CT. Conclusions: Our results demonstrate that an appropriately chosen treatment can lead to a good therapeutic response, but dose reduction may be necessary due to side effects. With advanced targeted therapeutic treatment options, survival and quality of life are significantly improved. [ABSTRACT FROM AUTHOR]

Erdheim-Chester disease (ECD) is an exceedingly rare non–Langerhans cell CD68+ CD1a- S100- histiocytic multi-organ disease. Diagnosis of ECD is often delayed due to non-specific radiographic findings and heterogeneous lesional tissue. Increasingly, the role of genomic alterations is being recognized for both diagnosis and treatment of ECD. More than half of ECD patients harbor the BRAFV600E mutation. Evaluation for this mutation be can falsely negative on immunohistochemical staining and confirmation with molecular analyses is recommended. We present a case of the 44 year-old male with BRAFV600E-positive ECD treated successfully with steroids followed by single-agent dabrafenib. Plain language summary Erdheim-Chester disease (ECD) is an exceedingly rare type of histiocytosis (a disorder of white blood cells). The diagnosis of ECD can be challenging because tissue biopsy may not provide a definitive diagnosis. Currently, genetic mutations can be used to support both diagnosis and treatment. We present a case of the 44 year-old male with BRAF V600E -positive ECD who was treated successfully with steroids followed by dabrafenib. Executive summary Erdheim-Chester Disease (ECD) is exceedingly rare. ECD with central nervous system involvement can be refractory to conventional therapies. Steroids may be therapeutic for ECD. Molecular profiling should be obtained to assess for BRAFV600E mutation, regardless of a negative immunohistochemical BRAF immunohistochemical staining. BRAF inhibitors should be considered as first-line therapy for BRAFV600E-positive ECD patients. [ABSTRACT FROM AUTHOR]

Background: Histiocytoses are rare disorders manifested by increased proliferation of pathogenic myeloid cells sharing histological features with macrophages or dendritic cells and accumulating in various organs, i.a., bone and skin. Pre-clinical in vitro models that could be used to determine molecular pathways of the disease are limited, hence research on histiocytoses is challenging. The current study compares cytophysiological features of progenitor, stromal-like cells derived from histiocytic lesions (sl-pHCs) of three pediatric patients with different histiocytoses types and outcomes. The characterized cells may find potential applications in drug testing. Methods: Molecular phenotype of the cells, i.e. expression of CD1a and CD207 (langerin), was determined using flow cytometry. Cytogenetic analysis included GTG-banded metaphases and microarray (aCGH) evaluation. Furthermore, the morphology and ultrastructure of cells were evaluated using a confocal and scanning electron microscope. The microphotographs from the confocal imaging were used to reconstruct the mitochondrial network and its morphology. Basic cytophysiological parameters, such as viability, mitochondrial activity, and proliferation, were analyzed using multiple cellular assays, including Annexin V/7-AAD staining, mitopotential analysis, BrdU test, clonogenicity analysis, and distribution of cells within the cell cycle. Biomarkers potentially associated with histiocytoses progression were determined using RT-qPCR at mRNA, miRNA and lncRNA levels. Intracellular accumulation of histiocytosis-specific proteins was detected with Western blot. Cytotoxicyty and IC50 of vemurafenib and trametinib were determined with MTS assay. Results: Obtained cellular models, i.e. RAB-1, HAN-1, and CHR-1, are heterogenic in terms of molecular phenotype and morphology. The cells express CD1a/CD207 markers characteristic for dendritic cells, but also show intracellular accumulation of markers characteristic for cells of mesenchymal origin, i.e. vimentin (VIM) and osteopontin (OPN). In subsequent cultures, cells remain viable and metabolically active, and the mitochondrial network is well developed, with some distinctive morphotypes noted in each cell line. Cell-specific transcriptome profile was noted, providing information on potential new biomarkers (non-coding RNAs) with diagnostic and prognostic features. The cells showed different sensitivity to vemurafenib and trametinib. Conclusion: Obtained and characterized cellular models of stromal-like cells derived from histiocytic lesions can be used for studies on histiocytosis biology and drug testing. [ABSTRACT FROM AUTHOR]

Objective: Rare disease. Background: Erdheim-Chester disease (ECD), a form of non-Langerhans-cell histiocytosis, is extremely rare. The mean age of individuals with ECD is in their 50s. Histiocytic infiltration of vital organ systems is a potential cause of substantial morbidity, which is associated with the multisystemic form of ECD. This report presents the first case of ECD with renal abnormalities in Palestine. Case Report: A 54-year-old woman with no medical or surgical history presented with 6 months of bilateral flank pain with no radiation or fever. A physical examination revealed only bilateral flank pain. Urine tests showed microhematuria. Laboratory test results showed increased serum creatinine levels (1.21 mg/dL) and microcytic anemia. A CT scan revealed significant multi-organ abnormalities, including renal abnormalities with a hairy kidney sign, pericardial effusion, and an osteolytic lesion of the spine. The hairy kidney sign is pathognomonic for ECD, so the renal mass was biopsied to confirm the diagnosis. The biopsy showed foamy histiocytes, lymphocytes, and plasma cells. Foamy histiocytes were CD68-positive and negative for S100, CD1a, and HMB45. PAx5 and CD3 immunostaining showed T-predominant B-lymphocyte mixtures. Conclusions: In the setting of systemic symptoms and imaging abnormalities such as presence of the hairy kidney sign, pericardial effusion, and osteolytic lesion of the spine, it is necessary to examine the possibility of ECD and proceed with a biopsy for confirmation. This is the first case in Palestine to be reported and the second case worldwide with a renal mass as an atypical presentation. [ABSTRACT FROM AUTHOR]

Histiocytoses encompass a wide spectrum of diseases, all characterized by tissue infiltration by CD68+ histiocytes. Most adult histiocytoses are considered clonal diseases because they highlight recurrent somatic mutations in the MAP-kinase pathway gene, primarily BRAF. The presence of BRAF mutation is associated with widespread disease in children with Langerhans cell histiocytosis (LCH) or cardiovascular/neurological involvement in Erdheim-Chester disease (ECD). Nevertheless, few data are available on adult clonal histiocytosis. This is why we have conducted a retrospective study of all patients with clonal histiocytosis in our institution and present the data according to the presence of BRAF mutation. Among 27 adult patients (10 ECD, 10 LCH, 5 Rosai-Dorfman disease (RDD), and 3 mixed ECD/LCH), 11 (39%) have BRAFmutation with gain of function (n = 9) and deletion (n = 2). Those patients had frequent multicentric disease with risk organ involvement, especially the brain and cardiovascular system. They had frequent associated myeloid neoplasms (mostly chronic myelomonocytic leukemia) and received more frequently targeted therapy as the front-line therapy. Nevertheless, its presence did not affect the overall survival or relapse-free survival probably due to the emergence of efficient therapies. To conclude, rapid and accurate molecular establishment in adult clonal histiocytoses is crucial because BRAFV600E mutation correlates with multicentric disease with organ involvement and incomplete metabolic response. [ABSTRACT FROM AUTHOR]

Purpose: To provide a comprehensive review of ocular and orbital manifestations of Erdheim-Chester Disease (ECD) and compare clinical outcomes with vemurafenib (INN) to historical treatments (HT). Primary outcomes are ophthalmic findings on presentation, changes in visual acuity, and mortality rate. Secondary outcomes include the progression of ocular findings, systemic involvements, and treatment modalities. Methods: All published literature from January 1983 to March 2021 was searched for ophthalmic manifestations of ECD. Clinical outcomes following HT were collected and compared with INN. Results: Forty-seven patients with ECD and ophthalmic presentations were identified. The mean age was 49.6 years (SD = 15.0). Proptosis (65.6%) and extraocular muscle restrictions (42.5%) were the most common presenting signs. Of 41 (87.2%) patients with orbital masses on radiologic examination, 90.2% were bilateral, and 53.7% were located in the intraconal space. Ophthalmic examination was significant for xanthelasma (27.2%), optic disc edema (34.0%), and subretinal changes (21.3%). Common treatments were systemic steroids (76.6%), interferon-a (17.0%), and cyclophosphamide (14.9%). INN was less commonly used (12.8%). The mean change in logMAR visual acuity declined with HT (29.9%) but improved with INN (79.1%) (p > 0.05). The proportion of eyes with complete vision loss increased after HT (p < 0.05). The overall mortality rate was 27.7% and notably higher in the HT group (29.3%) when compared to the INN group (16.7%) (p > 0.05). Conclusion: ECD presents with many ophthalmic manifestations. Although the intraocular treatments remain controversial, INN should be highly considered in treating orbital ECD patients with BRAF-V600E mutations to prevent and reverse vision loss. [ABSTRACT FROM AUTHOR]

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by xanthoma/xanthogranuloma infiltration in various organs and a broad spectrum of clinical presentations, including bone lesions, central diabetes insipidus and renal failure. BRAF V600E mutation is seen in almost half of the cases of ECD; the BRAF inhibitor vemurafenib is recommended treatment in the United States and the European Union. However, the indication for vemurafenib in Japan is limited to unresectable malignant melanoma with BRAF mutation. Although glucocorticoids, interferon, chemotherapy, and radiation therapy are treatment options, no standard therapy for ECD has yet been established in Japan. We describe here a patient with central diabetes insipidus and retroperitoneal lesions who was successfully treated with prednisolone. Glucocorticoid therapy is therefore a plausible alternative for ECD with BRAF V600E mutation when the BRAF inhibitor vemurafenib cannot be used. [ABSTRACT FROM AUTHOR]

Erdheim-Chester disease is characterized by the infiltration of foamy histiocytes in tissues. Lesional tissue biopsy is recommended to confirm diagnosis and establish the BRAF mutational status. A 52-yearold man presented to our hospital with hydronephrosis. Computed tomography showed enhancement of soft shadows around the left renal pelvis transition area and the aorta. He was treated with prednisolone 0.2 mg/kg for 1 year; however, no improvement was observed. 18Fluorodeoxyglucose-positron emission tomography/computed tomography revealed increased fluorodeoxyglucose uptake in various body parts, including the maxillary sinuses, indicative of Erdheim-Chester disease. He refused further examination, and the maxillary sinus lesions were treated with antibiotics and intranasal steroids, but no improvement was observed. Two years later, he underwent biopsy with endoscopic sinus surgery of the maxillary sinus, which showed the highest increase in fluorodeoxyglucose uptake on repeat 18Fluorodeoxyglucose-positron emission tomography/computed tomography. Endoscopic findings showed only nonspecific inflammatory findings, but pathological findings revealed the proliferation of cells with abundant foamy cytoplasms. Sufficient tumor volume was available to perform PCR for BRAF V600E mutation analysis, which was positive and resulted in a diagnosis of Erdheim-Chester disease with the BRAF V600E mutation. This is the first case of a patient with Erdheim-Chester disease with the BRAF V600E mutation identified in a sinus lesion. Endoscopic sinus surgery biopsy of the paranasal sinuses was considered to contribute to the histological and genetic diagnosis of Erdheim-Chester disease, particularly following the notable increase in fluorodeoxyglucose uptake. [ABSTRACT FROM AUTHOR]

In summary, despite ECD being a rare neurological disease, neurologists must consider this entity as a putative cause of the cerebellar syndrome with dentate nuclei involvement in cerebral MRI, which is potentially treatable (Video 2). The Dentate Nucleus Is the Clue: Erdheim-Chester Disease as a Cause of Cerebellar Syndrome The brain MRI presented T2 hyperintense lesions involving the dorsal part of the pons, lower midbrain tegmentum, middle cerebellar peduncles, and bilateral dentate nuclei, without gadolinium enhancement (Fig. Keywords: dentate nucleus; Erdheim-Chester disease; cerebellar syndrome EN dentate nucleus Erdheim-Chester disease cerebellar syndrome S17 S20 4 09/20/22 20220903 NES 220903 Erdheim-Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis, most commonly affecting bones, skin, retroperitoneum, heart, orbit, lung, and brain. [Extracted from the article]

Background: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis characterized by infiltration of lipid-laden foamy macrophages within different tissues. Clinical manifestations of ECD are highly heterogeneous. Bone lesions are found in 80%-95% of patients, while extraosseous lesions usually involve the cardiovascular system, retroperitoneum, central nervous system (CNS), and skin. Pancreatic involvement in ECD has barely been reported.Case Presentation: A 29-year-old female initially presented with menoxenia, diabetes insipidus and diabetes mellitus. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) revealed hypermetabolic foci in the bilateral frontal lobe, saddle area, and pancreas. A 99mTc-MDP bone scrintigraphy scan revealed symmetrical increased uptake in distal femoral and proximal tibial metaphysis, which was confirmed to be osteosclerosis by high-resolution peripheral quantitative computed tomography. The patient underwent incomplete resection of the sellar mass. Histological examination of biopsies showed histiocytic aggregates, which were positive for S100 and negative for CD1a and CD207 on immunohistochemistry. Enhanced abdominal CT scan showed hypointense nodules within the body and tail of the pancreas. Endoscopic ultrasonography guided fine-needle aspiration (EUS-FNA) found no evidence of malignancy. She was diagnosed with ECD and treated with high-dose IFN-α. Repeated examinations at three-and eight-months post treatment revealed markedly reduction of both intracranial and pancreatic lesions.Conclusions: ECD is a rare histiocytic neoplasm that can involve almost every organ, whereas pancreatic involvement has barely been reported to date. Here, we present the rare case of pancreatic lesions in ECD that responded well to interferon-α. We further reviewed reports of pancreatic involvement in histiocytic disorders and concluded the characteristics of such lesions to help diagnosis and treatment, in which these lesions mimicked pancreatic adenocarcinoma and caused unnecessary invasive surgeries. [ABSTRACT FROM AUTHOR]

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis caused by the expression of CD68-positive and CD1a-negative foam tissue cells, which is polar in pediatric patients. The study reports a case of an 8-year-old Chinese boy who presented with polydipsia and polyuria for 4 years, followed by central nervous system symptoms. Magnetic resonance imaging (MRI) showed a large lesion in the lateral ventricle. The histiocytes stained positively for CD68, CD163 and negatively for CD1a, glial fibrillary acidic protein (GFAP) and langerin, and were partially positive for S100 by immunohistochemical assay. More importantly, BRAFV 600E staining was positive in tissue, and the BRAF V600E mutations was also detected by real-time quantitative PCR (RT-qPCR) in the intracranial lesion tissue. According to our review of the literature, this is a rare case of ECD in the ventricle, with a younger age. [ABSTRACT FROM AUTHOR]

Erdheim-Chester disease (ECD) is a rare and systemic non-Langerhans cell histiocytosis. Recently, ECD was classified as an inflammatory medullary tumor that affects a diverse group of organ systems. The purpose of this report is to present the radiological features of this disease in a 51-year-old man with intestinal obstruction as the initial presentation. In this case, X-ray computed tomography (CT) and emission computed tomography (ECT) clearly showed lesions in various systems, especially in the skeletal images. The survival benefit of treatment with interferon α (IFN-α) and BRAF inhibitors is well established, while other treatments focus on symptom relief. [ABSTRACT FROM AUTHOR]

Erdheim–Chester disease (ECD) is a rare non-Langerhans cell histiocytosis associated with BRAFV600E mutations in more than 50% of cases and presenting with 95% with skeletal lesions. However, cutaneous, pulmonary, large vessels and central nervous system involvement can also occur. We report a case of a 25-year-old woman who was admitted in 2018 for exploration of diffuse bone pain and rashes on the face. Her current symptoms had started 14 months earlier and consisted of bone pain, affecting the legs. She had periodic low-grade fever, asthenia and xanthelasma-like papules appeared on face. At admission, physical examination showed bilateral and symmetrical long bone pain, especially in the knees and multiple xanthelasma-like papules around the eyelids, cheeks and chin. Laboratory tests revealed elevated erythrocyte sedimentation rate and C-reactive protein. Magnetic resonance (MR) imaging showed multiple mixed bone lesions with a hyperintensive MR signal on PD FS and hypointense signal on T1of the femur and tibia. Bone scintigraphy indicated bilateral and symmetrical metaphyseal and diaphyseal increased uptake. Abdominal computed tomography (CT) scan showed infiltration of the perirenal fat. Biopsy of the skin revealed histiocytic infiltration, which was CD68-positive and CD100-positive, confirming the diagnosis of ECD. Patient was treated with interferon-α (IFN-α) plus methylprednisolone. After 6 months of treatment her clinical condition partly improved: a reduction of pain on visual analogue scale (VAS) scale, significant decrease of methylprednisolone dose and specific dynamics according to bone MR imaging data, however, no change in symptoms attributed to skin rash was noted. We also provide the literature review results of IFN-α treatment efficacy in Erdheim–Chester disease involving the skin and musculoskeletal system with MR imaging changes. [ABSTRACT FROM AUTHOR]

Purpose of Review: Erdheim-Chester disease (ECD) is a very rare neoplasm of the non-Langerhans cell histiocytes. Pericardial involvement is uncommon, and we aim to review the current knowledge on the epidemiology, clinical manifestations, and management of recurrent pericarditis due to ECD. We also aim to raise awareness of the importance of considering ECD as a differential diagnosis for recurrent pericarditis in the appropriate clinical settings. Recent Findings: The prevalence of pericardial involvement in ECD is estimated to be 40% and is getting more recognized recently. Up to 68% of patients carry the BRAFV600E mutation, and targeted treatment with vemurafenib, an inhibitor of BRAF kinase, showed an excellent response in those who carry this mutation. Summary: Pericardial disease appears to be the most common cardiac presentation (in 80% of cases). Although pericardial involvement is frequently asymptomatic, patients with ECD can present with typical pericarditis chest pain and signs of right heart failure if constriction is present. The diagnosis of ECD requires a biopsy of the pericardium or another affected organ. If BRAFV600E mutation is absent, limited data exist, and many medications have been tried, like interferon alfa, anakinra, and infliximab. [ABSTRACT FROM AUTHOR]

Objective: To characterize the spectrum of neurologic involvement in Erdheim–Chester Disease (ECD), a treatable inflammatory neoplasm of histiocytes. Methods: Sixty‐two patients with ECD were prospectively enrolled in a natural history study that facilitated collection of clinical, imaging, laboratory, neurophysiologic, and pathologic data. Results: Ninety‐four percent of the patients had neurologic abnormalities on examination or imaging, and 22% had neurologic symptoms as the initial presentation of ECD. The most common neurologic findings were cognitive impairment, peripheral neuropathy, pyramidal tract signs, cranial nerve involvement, and cerebellar ataxia. Imaging revealed atrophy and demyelination along with focal lesions that were located throughout the nervous system, dura, and extra‐axial structures. The BRAF V600E variant correlated with cerebral atrophy. Brain pathology revealed lipid‐laden, phagocytic macrophages (histiocytes) accompanied by demyelination and axonal degeneration. Interpretation: In patients with ECD, neurologic morbidity is common and contributes significantly to disability. Since neurologic symptoms can be the presenting feature of ECD and, given the mean delay in ECD diagnosis is 4.2 years, it is critical that neurologists consider of ECD and other histiocytosis in patients with inflammatory, infectious, or neoplastic‐appearing white matter. Furthermore, given the broad spectrum of neurologic involvement, neurologists have an important role in a team of specialists treating ECD patients. [ABSTRACT FROM AUTHOR]

Purpose of Review: This report provides an overview of the current knowledge of molecular characterization, clinical description, and treatment of Erdheim-Chester disease (ECD), a multi-systemic adult histiocytosis of the L group. Recent Findings: The recent identification of several MAPK mutations in histiocytes of ECD lesions. Leading to targeted therapies. Summary: The discovery of the BRAFV600E mutation in ECD lesions followed by several other kinase mutations in the MAPK pathway has revolutionized our understanding of the disease pathogenesis and led to trials with targeted therapies that demonstrated robust efficacy. [ABSTRACT FROM AUTHOR]

Purpose of Review: Provide an overview of recent progress in decoding the pathogenesis and treatment of systemic histiocytoses. Recent Findings: Advances in molecular techniques over the last few years, enabling the identification of several MAPK mutations in lesion histiocytes, have revolutionized our understanding of histiocytosis that led to a revised classification and new treatments. Summary: Since the 2010 discovery of the BRAFV600E mutation in 57% of Langerhans cell histiocytosis (LCH) lesions, several other kinase mutations have been found, mostly in the MAPK pathway, and also in other key signaling pathways, in LCH, Erdheim–Chester Disease (ECD) and, less frequently, Destombes–Rosai–Dorfman disease (RDD). Those revolutionary breakthroughs enhanced our understanding of the pathogenesis of histiocytosis and led to trials with targeted therapies that demonstrated notable efficacy. [ABSTRACT FROM AUTHOR]

Objectives: To use magnetic resonance imaging (MRI) and computed tomography (CT) to define abdominal involvement in Erdheim-Chester disease (ECD), and to investigate the association between these findings and the BRAFV600E mutation.Methods: This prospective study was performed on 61 ECD patients (46 men). The MRI and CT imaging studies were reviewed independently by two experienced radiologists. The association between BRAFV600E mutation and imaging findings was analysed using Fisher's exact test, and odds ratios with 95% confidence intervals.Results: Perinephric infiltration was the most common finding (67%), followed by involvement of proximal ureters (61%). In 56% of cases, infiltration extended to the renal sinuses, and in 38% caused hydronephrosis. Adrenal gland infiltration was present in 48% of patients. Infiltration of renal artery (49%) and aorta (43%) were the most common vascular findings, followed by sheathing of celiac, superior mesenteric artery (SMA) or inferior mesenteric artery (IMA) (23%). The BRAFV600E mutation was positive in 53% of patients with interpretable BRAF sequencing. There was a statistically significant association between this mutation and perinephric infiltration (p = 0.003), renal sinus involvement (p < 0.001), infiltration of proximal ureters (p < 0.001), hydronephrosis (p < 0.001), adrenal gland involvement (p < 0.001), periaortic infiltration (p = 0.03), sheathing or stenosis of renal artery (p < 0.001) and sheathing of other aortic branches (p = 0.04).Conclusions: Renal and vascular structures are the most commonly affected abdominal organs in ECD patients. Some of these findings have significant positive association with the BRAFV600E mutation.Key Points: • Abdominal imaging plays a crucial role in management of Erdheim-Chester disease. • Significant associations exist between BRAF V600E mutation and several abdominal imaging findings. • Considering several associations, evaluating BRAFV600E mutation status is recommended in ECD patients. [ABSTRACT FROM AUTHOR]

p16 activation caused by oncogenic mutations may represent oncogene‐induced senescence (OIS), a protective mechanism against oncogenic events. However, OIS can contribute to tumor development via tissue remodeling in some tumors. Erdheim–Chester disease (ECD), a rare non‐Langerhans cell histiocytosis, is one such tumor. Its clinical and histological features vary, making it difficult to diagnose. Herein, we describe an autopsy of an ECD patient. The patient underwent radiological examinations, including 18F‐fluorodeoxyglucose (FDG)‐positron emission tomography/computed tomography (PET/CT), bone scintigraphy and CT. A biopsy from the lesion with the highest FDG accumulation confirmed the presence of foamy macrophages, a diagnostic clue for ECD. Based on this finding and the clinical features, ECD was diagnosed. However, the patient died from heart dysfunction. After the autopsy, each radiologically different site showed various histological findings regarding the morphology of macrophages, fibrosis, inflammation, and p16 expression. OIS‐induced histological progression can cause certain changes observed in radiological images. In addition, in order to evaluate the increase in glucose metabolism, which can affect FDG accumulation, the expression of glucose transporter 1 and hexokinase II was also analyzed. Summarizing the radio‐histological correlation can help further both the understanding and diagnosis of ECD. [ABSTRACT FROM AUTHOR]

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocyte disorder most commonly characterized by multifocal osteosclerotic lesions of the long bones demonstrating sheets of foamy histiocyte infiltrates on biopsy with or without histiocytic infiltration of extraskeletal tissues. ECD can be difficult to diagnose since it is a very rare disease that can affect many organ systems. Diagnosis is based on the pathologic evaluation of involved tissue interpreted within the clinical context. Patients who have the BRAF V600E mutation are treated first line with vemurafenib. For those without the mutation with symptomatic ECD, conventional or PEGylated interferon alpha is recommended. For patients who are either intolerant or nonresponsive to interferon alpha, systemic chemotherapy with or without corticosteroids can be used. We present a rare case of Erdheim-Chester disease with concurrent Langerhans cell histiocytosis which occurs in only one fifth of the cases and often presents as a diagnostic and therapeutic challenge. [ABSTRACT FROM AUTHOR]

Background: Leukoencephalopathies with prominent involvement of cerebellum and brainstem, henceforward called prominent infratentorial leukoencephalopathies (PILs), encompass a variety of inherited and acquired white matter diseases. Erdheim–Chester disease (ECD) is a rare non-Langerhans cell histiocytosis likely under-diagnosed as cause of adult PIL.Methods: We reviewed the clinical and laboratory information of ten consecutive sporadic adult patients with PIL of unknown origin, who were investigated for ECD.Results: There were seven males and three females; mean age at clinical onset was 49.6 years (range 38–59); cerebellar ataxia with or without other neurological symptoms was the only or the main clinical manifestation; diabetes insipidus was present in three individuals. Eight patients had white matter focal supratentorial abnormalities, in addition to the infratentorial white matter changes. Six out of eight patients had spinal cord lesions. Thoraco-abdominal CT showed periaortic sheathing in two patients, whole-body FDG-PET revealed increased glucose uptake in the long bones of the legs in five patients, brain FDG-PET showed overt infratentorial hypermetabolism in one patient. In eight patients, ECD was confirmed by bone scintigraphy, pathological data, or both. Two ECD patients treated with vemurafenib showed a marked improvement of neurological symptoms and brain MRI abnormalities at 1 year follow-up.Conclusions: Symptoms of PIL can be the only clinical manifestation of ECD. Adult patients with PIL of unknown origin should undergo investigations aimed at unveiling ECD, including bone scintigraphy and whole-body FDG-PET. The early diagnosis allows starting disease-modifying therapies of an otherwise life-threatening disease. [ABSTRACT FROM AUTHOR]

Erdheim-Chester disease (ECD) is a rare histiocytic disorder, characterized by the xanthomatous infiltration of tissues by CD68-positive and CD1a-/CD100-negative foamy histiocytes. In childhood, ECD is exceptionally rare, and only a dozen cases have been published so far. The cooccurence of Langerhans cell histiocytosis (LCH) and ECD is even rarer. Here, we report a 2-year-old boy, the youngest patient in the literature so far, who was diagnosed with concomitant BRAF mutation-positive LCH and ECD. In his case, conventional LCH treatment proved to be ineffective, but he is the youngest patient who was successfully treated with the BRAF inhibitor vemurafenib. [ABSTRACT FROM AUTHOR]

Erdheim-Chester disease (ECD) is a rare form of histiocytosis with a broad, non-specific clinical spectrum. Here, we retrospectively evaluated the clinical and pathologic characteristics, presence of the BRAF V600E mutation, treatment options, and outcomes of Chinese patients diagnosed with ECD at our center. Patients diagnosed with ECD between January 2010 and April 2015 at Peking Union Medical College Hospital were included for study. We evaluated baseline characteristics, reviewed histological material, and tested for the presence of the BRAF V600E mutation using immunohistochemistry and polymerase chain reaction (PCR). Sixteen patients were diagnosed with ECD. Median disease duration (from the first symptom to diagnosis) was 22.5 months (range, 3-100 months). The main sites of involvement included bone (93.8 %), cardiovascular region (43.8 %), skin (31.3 %), central nervous system (25 %), and "hairy kidney" (25 %). The BRAF V600E mutation was detected in 68.8 % patients using PCR and 50 % patients with immunohistochemistry. Three patients could not be diagnosed using histological analysis owing to similarities with Rosai-Dorfman disease, and diagnosis in these cases was confirmed based on the BRAF V600E mutation status. Ten patients (62.5 %) received IFN-α as first-line treatment. Thirteen patients (81.3 %) were still alive at median follow-up of 14.5 months. ECD remains a largely overlooked disease, and increased recognition by clinicians and pathologists is necessary for effective diagnosis and treatment. The presence of the BRAF V600E mutation may facilitate discrimination of ECD from other non-Langerhans cell histiocytoses. [ABSTRACT FROM AUTHOR]

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Erdheim- Chester disease is a multi-system histiocyte disorder characterised by histological xanthogranulomatous inflammation. We report a 67-year-old man who had fatal multi-systemic Erdheim-Chester disease involvement, including retroperitoneal fibrosis, dilated cardiomyopathy and bone pain that was diagnosed late in its course and was refractory to interferon-alfa. A pathogenic BRAFV600E mutation, identified after death in this patient, provides insights into pathogenesis and opens potential lines of treatment. [ABSTRACT FROM AUTHOR]

Erdheim–Chester disease (ECD) is a life-threatening multi-systemic non-Langerhans histiocytosis with cardiovascular complications as the leading cause of death. ECD affects the kidneys in up to 30% of cases, with fibrotic tissue deposition in the perirenal fat and renal hilum. Diagnosis is usually based on histological analysis of the pathologic tissue, which typically shows xanthogranulomatous infiltrates of foamy CD68+/CD1a- histiocytes surrounded by fibrosis. A consistent percentage of patients affected by ECD develop renal failure and hypertension as a consequence of renal artery stenosis and hydronephrosis. These conditions have been generally treated with the placement of stents and nephrostomies that frequently led to disappointing outcomes. Before the introduction of interferon-alpha (IFNα) treatment, the mortality rate was as high as 57% in the long term. Recent studies have granted new insights into the pathogenesis of ECD, which seems to bear a dual component of clonal and inflammatory disease. These advances led to use specific therapies targeting either the oncogenes (BRAFV600E) or the effectors of the immune response implicated in ECD (IL-1, TNFα). Drugs such as anakinra (recombinant human IL-1 receptor antagonist), infliximab (monoclonal antibody against TNFα) and vemurafenib (inhibitor of mutant BRAF) showed promising results in small single-centre series. Although larger trials will be needed to address the impact of these drugs on ECD prognosis and to select the most effective treatment, targeted therapies hold the premises to drastically change the outcome of this condition. [ABSTRACT FROM AUTHOR]

Erdheim-Chester disease (ECD) is a rare form of systemic histiocytosis characterized by the diffuse infiltration of tissues by lipid-laden macrophages. As the clinical course and prognosis are highly influenced by site of disease involvement, ECD course ranges from asymptomatic to life threatening, with a reported global 5-year mortality of 30-40%. Whether ECD is an inflammatory or clonal disease in its nature has long been debated. The disease is characterized by a network of pro-inflammatory cyto/chemokines responsible for the recruitment and activation of histiocytes into ECD lesions, similarly to what reported in Langerhans cell histiocytosis (LCH). Growing evidence supports a central role of the oncogenic BRAFV600E mutation in histiocytosis pathogenesis, and suggests oncogene-induced senescence (OIS), a major protective mechanism against oncogenic events characterized by cell-cycle arrest and the induction of pro-inflammatory molecules, as the possible link between the oncogenic mutation and the observed inflammation. Indeed, ECD recapitulates in vivo the molecular events associated with OIS, i.e., cell-cycle arrest and a potent local inflammatory response. Accordingly, the infiltration of different tissues by macrophages and the inflammatory local and systemic effects observed in ECD likely represent a drawback of OIS. Therefore, these findings delineate a new conception of OIS as a new pathogenic mechanism intrinsically responsible for disease development. [ABSTRACT FROM AUTHOR]

Simple Summary: In the last two decades, new molecules, named microRNAs, have been identified. Impairment of microRNA function can lead to the development of diseases such as cancer; therefore, analyzing microRNAs expression, may help to explain the development of diseases. Moreover, these molecules can be obtained easily from blood, with little discomfort to the patient, and this may help to develop them as substances that could help to diagnose diseases and determine response to treatment. Here, we studied how microRNAs are involved in a rare clonal hematological malignancy named Erdheim–Chester disease (ECD). We found a differential expression microRNA signature between ECD patients and healthy controls. Our analysis suggests that reduced expression of microRNAs in ECD results in upregulation of target genes that participate in cell survival signaling and inflammation. This study expands our knowledge of the molecular basis of ECD and may enable improved treatment for affected patients. The pathogenesis of histiocytic neoplasms is driven by mutations activating the MAPK/ERK pathway, but little is known about the transcriptional and post-transcriptional alterations involved in these neoplasms. We analyzed microRNA (miRNA) expression in plasma samples and tissue biopsies of Erdheim–Chester disease (ECD) and Langerhans cell histiocytosis (LCH) patients. In silico analysis revealed a potential role of miRNAs in regulating gene expression in these neoplasms as compared with healthy controls (HC). NanoString analysis revealed 101 differentially expressed plasma miRNAs in 16 ECD patients as compared with 11 HC, 95% of which were downregulated. MiRNAs-15a-5p, -15b-5p, -21-5p, -107, -221-3p, -320e, -630, and let-7 family miRNAs were further evaluated by qRT-PCR in an extended cohort of 32 ECD patients, seven LCH and 15 HC. Six miRNAs (let-7a, let-7c, miR-15a-5p, miR-15b-5p, miR-107 and miR-630) were highly expressed in LCH plasma and tissue samples as compared with ECD. Pathway enrichment analysis indicated the miRNA contribution to inflammatory and pro-survival signaling pathways. Moreover, the let-7 family members were downregulated in untreated ECD patients as compared with HC, while treatment with MAPK/ERK signaling inhibitors for 16 weeks resulted in their upregulation, which was in parallel with the radiologic response seen by PET-CT. The study highlights the potential contribution of miRNA to the inflammatory and neoplastic characteristics of ECD and LCH. [ABSTRACT FROM AUTHOR]