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Nature Reviews. Disease Primers Oct 2021The historic term 'histiocytosis' meaning 'tissue cell' is used as a unifying concept for diseases characterized by pathogenic myeloid cells that share histological... (Review)
Review
The historic term 'histiocytosis' meaning 'tissue cell' is used as a unifying concept for diseases characterized by pathogenic myeloid cells that share histological features with macrophages or dendritic cells. These cells may arise from the embryonic yolk sac, fetal liver or postnatal bone marrow. Prior classification schemes align disease designation with terminal phenotype: for example, Langerhans cell histiocytosis (LCH) shares CD207 antigen with physiological epidermal Langerhans cells. LCH, Erdheim-Chester disease (ECD), juvenile xanthogranuloma (JXG) and Rosai-Dorfman disease (RDD) are all characterized by pathological ERK activation driven by activating somatic mutations in MAPK pathway genes. The title of this Primer (Histiocytic disorders) was chosen to differentiate the above diseases from Langerhans cell sarcoma and malignant histiocytosis, which are hyperproliferative lesions typical of cancer. By comparison LCH, ECD, RDD and JXG share some features of malignant cells including activating MAPK pathway mutations, but are not hyperproliferative. 'Inflammatory myeloproliferative neoplasm' may be a more precise nomenclature. By contrast, haemophagocytic lymphohistiocytosis is associated with macrophage activation and extreme inflammation, and represents a syndrome of immune dysregulation. These diseases affect children and adults in varying proportions depending on which of the entities is involved.
Topics: Erdheim-Chester Disease; Histiocytosis, Langerhans-Cell; Histiocytosis, Sinus; Humans; Inflammation; Xanthogranuloma, Juvenile
PubMed: 34620874
DOI: 10.1038/s41572-021-00307-9 -
Blood Apr 2020Erdheim-Chester disease (ECD) is characterized by the infiltration of tissues by foamy CD68+CD1a- histiocytes, with 1500 known cases since 1930. Mutations activating the... (Review)
Review
Erdheim-Chester disease (ECD) is characterized by the infiltration of tissues by foamy CD68+CD1a- histiocytes, with 1500 known cases since 1930. Mutations activating the MAPK pathway are found in more than 80% of patients with ECD, mainly the BRAFV600E activating mutation in 57% to 70% of cases, followed by MAP2K1 in close to 20%. The discovery of BRAF mutations and of other MAP kinase pathway alterations, as well as the co-occurrence of ECD with LCH in 15% of patients with ECD, led to the 2016 revision of the classification of histiocytoses in which LCH and ECD belong to the "L" group. Both conditions are considered inflammatory myeloid neoplasms. Ten percent of ECD cases are associated with myeloproliferative neoplasms and/or myelodysplastic syndromes. Some of the most striking signs of ECD are the long bone involvement (80%-95%), as well as the hairy kidney appearance on computed tomography scan (63%), the coated aorta (40%), and the right atrium pseudo-tumoral infiltration (36%). Central nervous system involvement is a strong prognostic factor and independent predictor of death. Interferon-α seems to be the best initial treatment of ECD. Since 2012, more than 200 patients worldwide with multisystem or refractory ECD have benefitted from highly effective therapy with BRAF and MEK inhibitors. Targeted therapies have an overall, robust, and reproducible efficacy in ECD, with no acquired resistance to date, but their use may be best reserved for the most severe manifestations of the disease, as they may be associated with serious adverse effects and as-yet-unknown long-term consequences.
Topics: Animals; Erdheim-Chester Disease; Humans; Leukemia, Myeloid; MAP Kinase Kinase 1; Mutation; Myelodysplastic Syndromes; Myeloproliferative Disorders; Prognosis; Proto-Oncogene Proteins B-raf
PubMed: 32107533
DOI: 10.1182/blood.2019002766 -
Neuro-oncology Sep 2021Histiocytoses are heterogeneous hematopoietic diseases characterized by the accumulation of CD68(+) cells with various admixed inflammatory infiltrates. The... (Review)
Review
Histiocytoses are heterogeneous hematopoietic diseases characterized by the accumulation of CD68(+) cells with various admixed inflammatory infiltrates. The identification of the pivotal role of the mitogen-activated protein kinase (MAPK) pathway has opened new avenues of research and therapeutic approaches. We review the neurologic manifestations of 3 histiocytic disorders with frequent involvement of the brain and spine: Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman-Destombes disease (RDD). Central nervous system (CNS) manifestations occur in 10%-25% of LCH cases, with both tumorous or neurodegenerative forms. These subtypes differ by clinical and radiological presentation, pathogenesis, and prognosis. Tumorous or degenerative neurologic involvement occurs in 30%-40% of ECD patients and affects the hypothalamic-pituitary axis, meninges, and brain parenchyma. RDD lesions are typically tumorous with meningeal or parenchymal masses with strong contrast enhancement. Unlike LCH and ECD, neurodegenerative lesions or syndromes have not been described with RDD. Familiarity with principles of evaluation and treatment both shared among and distinct to each of these 3 diseases is critical for effective management. Refractory or disabling neurohistiocytic involvement should prompt the consideration for use of targeted kinase inhibitor therapies.
Topics: Central Nervous System; Erdheim-Chester Disease; Histiocytosis, Langerhans-Cell; Histiocytosis, Sinus; Humans; Prognosis
PubMed: 33993305
DOI: 10.1093/neuonc/noab107 -
Blood May 2020Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK... (Review)
Review
Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600-mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.
Topics: Clinical Trials as Topic; Erdheim-Chester Disease; Female; Histiocytosis, Langerhans-Cell; Humans; MAP Kinase Signaling System; Male; Molecular Targeted Therapy; Mutation; Prognosis; Proto-Oncogene Proteins B-raf
PubMed: 32187362
DOI: 10.1182/blood.2019003507 -
Clinical Lymphoma, Myeloma & Leukemia Jan 2021Histiocytic disorders are an exceptionally rare group of diseases with diverse manifestations and a paucity of approved treatments, thereby leading to various challenges... (Review)
Review
Highlights of the Management of Adult Histiocytic Disorders: Langerhans Cell Histiocytosis, Erdheim-Chester Disease, Rosai-Dorfman Disease, and Hemophagocytic Lymphohistiocytosis.
Histiocytic disorders are an exceptionally rare group of diseases with diverse manifestations and a paucity of approved treatments, thereby leading to various challenges in their diagnosis and management. With the discovery of novel molecular targets and the incorporation of targeted agents in the management of various adult histiocytic disorders, their management has become increasingly complex. In an attempt to improve the understanding of the clinical features and management of common adult histiocytic disorders (Langerhans cell histiocytosis, Erdheim-Chester disease, Rosai-Dorfman disease, and hemophagocytic lymphohistiocytosis), we created this document based on existing literature and expert opinion.
Topics: Adult; Drug Therapy, Combination; Erdheim-Chester Disease; Histiocytosis, Langerhans-Cell; Histiocytosis, Sinus; Humans; Lymphohistiocytosis, Hemophagocytic; Treatment Outcome
PubMed: 32943371
DOI: 10.1016/j.clml.2020.08.007 -
AJNR. American Journal of Neuroradiology May 2023Erdheim-Chester disease is a rare non-Langerhans cell histiocytosis. The disease is widely variable in its severity, ranging from incidental findings in asymptomatic...
Erdheim-Chester disease is a rare non-Langerhans cell histiocytosis. The disease is widely variable in its severity, ranging from incidental findings in asymptomatic patients to a fatal multisystem illness. CNS involvement occurs in up to one-half of patients, most often leading to diabetes insipidus and cerebellar dysfunction. Imaging findings in neurologic Erdheim-Chester disease are often nonspecific, and the disease is commonly mistaken for close mimickers. Nevertheless, there are many imaging manifestations of Erdheim-Chester disease that are highly suggestive of the disease, which an astute radiologist could use to accurately indicate this diagnosis. This article discusses the imaging appearance, histologic features, clinical manifestations, and management of Erdheim-Chester disease.
Topics: Humans; Erdheim-Chester Disease
PubMed: 36997288
DOI: 10.3174/ajnr.A7832 -
European Journal of Internal Medicine May 2015Erdheim-Chester disease (ECD) is rare form of non-Langerhans cells histiocytosis with multiorgan involvement. Individuals are more frequently affected in their fifth... (Review)
Review
Erdheim-Chester disease (ECD) is rare form of non-Langerhans cells histiocytosis with multiorgan involvement. Individuals are more frequently affected in their fifth decade and there is a slight male prevalence. Recent studies have demonstrated that ECD patients bare mutations in the proto-oncogene BRAF (and more rarely in other genes involved in the MAPK activation pathway), suggesting a critical role of this pathway in the pathogenesis and a possible clonal origin of the disease. Clinical manifestations are extremely protean and virtually every organ system can be affected. The most common clinical features include skeletal involvement with typical bilateral osteosclerotic lesions of long bones of the lower limbs, diabetes insipidus, cardiovascular involvement with circumferential thickening of the aorta ("coated aorta"), and retroperitoneal fibrosis ("hairy kidney"). Cardiovascular and central nervous system (CNS) involvement are associated with the worst prognosis. Biopsy is necessary to establish a definite diagnosis with the identification of CD68+/CD1a-/S100- foamy histiocytes. Currently, interferon-α is the first-line treatment in ECD, as it has been clearly demonstrated to increase overall survival. Anakinra and infliximab have also led to encouraging results and should be taken into consideration when treatment with interferon-α fails. More recently, the BRAF-inhibitor vemurafenib has been used in small groups of ECD patients with optimal efficacy in all treated cases. Nevertheless, its adverse effects and the scanty data on its long-term efficacy and safety still discourage its use as a first-line option. Further studies are still warranted to better understand and treat this neglected and overlooked disease.
Topics: Biopsy; Diagnosis, Differential; Erdheim-Chester Disease; Female; Humans; Indoles; Interferon-alpha; Male; Mutation; Prognosis; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Sex Ratio; Sulfonamides; Vemurafenib
PubMed: 25865950
DOI: 10.1016/j.ejim.2015.03.004 -
JAMA Oncology Mar 2018The histiocytic neoplasms Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are highly enriched for BRAF V600 mutations and have been previously...
Vemurafenib for BRAF V600-Mutant Erdheim-Chester Disease and Langerhans Cell Histiocytosis: Analysis of Data From the Histology-Independent, Phase 2, Open-label VE-BASKET Study.
IMPORTANCE
The histiocytic neoplasms Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are highly enriched for BRAF V600 mutations and have been previously shown to be responsive to treatment with vemurafenib, an inhibitor of the BRAF V600 kinase. However, the long-term efficacy and safety of prolonged vemurafenib use in these patients are not defined. Here we analyze the final efficacy and safety data for vemurafenib in patients with ECD and LCH enrolled in the VE-BASKET study.
OBJECTIVE
To determine the efficacy and safety of vemurafenib in adults with ECD or LCH enrolled in the VE-BASKET study.
DESIGN, SETTING, AND PARTICIPANTS
The VE-BASKET study was an open-label, nonrandomized, multicohort study for patients with nonmelanoma cancers harboring the BRAF V600 mutation. Patients with BRAF V600-mutant ECD or LCH were enrolled in an "other solid tumor" cohort of the VE-BASKET study, and they were enrolled in the present study.
INTERVENTIONS
Patients received vemurafenib, 960 mg, twice daily continuously until disease progression, study withdrawal, or occurrence of intolerable adverse effects.
MAIN OUTCOMES AND MEASURES
The primary end point was confirmed objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Secondary end points included progression-free survival (PFS), overall survival (OS), metabolic response by modified positron-emission tomography (PET) Response Criteria in Solid Tumors (PERCIST) using 18F-fluorodeoxyglucose (FDG)-PET/computed tomography (CT), and safety.
RESULTS
A total of 26 patients from the VE-BASKET trial (22 with ECD, 4 with LCH) were included in the present study (14 women and 12 men; median age, 61 years; age range, 51-74 years). The confirmed ORR was 61.5% (95% CI, 40.6%-79.8%) in the overall cohort and 54.5% (95% CI, 32.2%-75.6%) in patients with ECD. All evaluable patients achieved stable disease or better. The median PFS and OS had not been reached in the overall cohort at study closure despite a median follow-up of 28.8 months; 2-year PFS was 86% (95% CI, 72%-100%), and 2-year OS was 96% (95% CI, 87%-100%). All 15 patients evaluated by FDG-PET/CT achieved a metabolic response, including 12 patients (80%) with a complete metabolic response. The most common adverse events (AEs) in the overall cohort included arthralgia, maculopapular rash, fatigue, alopecia, prolonged QT interval, skin papilloma, and hyperkeratosis. Hypertension and dermatologic AEs occurred at higher rates than those reported in metastatic melanoma.
CONCLUSIONS AND RELEVANCE
In this study, vemurafenib had prolonged efficacy in patients with BRAF V600-mutant ECD and LCH and warrants consideration as a new standard of care for these patients.
Topics: Aged; Amino Acid Substitution; Erdheim-Chester Disease; Female; Fluorodeoxyglucose F18; Histiocytosis, Langerhans-Cell; Humans; Male; Middle Aged; Mutation, Missense; Positron Emission Tomography Computed Tomography; Prognosis; Proto-Oncogene Proteins B-raf; Survival Analysis; Treatment Outcome; Valine; Vemurafenib
PubMed: 29188284
DOI: 10.1001/jamaoncol.2017.5029 -
Internal Medicine (Tokyo, Japan) Jan 2020
PubMed: 31554755
DOI: 10.2169/internalmedicine.3324-19 -
The British Journal of Radiology Dec 2019Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis which can have a broad range of clinical and radiological presentations. Typically, ECD affects... (Review)
Review
Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis which can have a broad range of clinical and radiological presentations. Typically, ECD affects multiple organ systems, with skeletal involvement present in almost all ECD patients and cardiothoracic manifestations in more than half. Cardiac and thoracic involvement contributes significantly to morbidity and mortality in affected patients and may have prognostic implications. The diagnosis of ECD can be challenging due to its rarity and similarity to other systemic disease processes. Although the diagnosis can be suggested on imaging, histopathology and immunohistochemistry are required for confirmation. We describe the multimodal imaging features of mediastinal, cardiac, pleural and lung parenchymal ECD. This review identifies the most common radiological manifestations of cardiac and thoracic ECD on contrast-enhanced CT, fluorine-fludeoxyglucose positron emission tomography/CT and cardiac MRI, and highlights the role of these cross-sectional techniques in disease diagnosis.
Topics: Contrast Media; Erdheim-Chester Disease; Fluorodeoxyglucose F18; Heart Diseases; Humans; Lung Diseases; Magnetic Resonance Imaging; Mediastinal Diseases; Multimodal Imaging; Pleural Diseases; Positron Emission Tomography Computed Tomography; Radiopharmaceuticals; Tomography, X-Ray Computed
PubMed: 31386554
DOI: 10.1259/bjr.20190473