RESUMEN
OBJECTIVES: To present 4 patients with Erdheim-Chester disease (ECD) based on clinical, radiologic, histopathologic, and molecular genetic findings who had enhancing brainstem lesions and were initially believed to have chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). METHODS: Case series. RESULTS: Although patients with ECD can demonstrate clinical and imaging features similar to CLIPPERS, refractoriness to corticosteroids, lack of fulfillment of specific MRI criteria (i.e., enhancing lesions >3 mm, T2 abnormalities that exceed areas of T1 postgadolinium enhancement), and systemic findings such as "hairy kidney" appearance and metadiaphyseal osteosclerosis on 18F-fluorodeoxyglucose PET-CT help discriminate it from CLIPPERS. DISCUSSION: ECD is a histiocytic neoplasm characterized by multiorgan infiltration of clonal histiocytes carrying activating variants of the MAPK-ERK pathway. Neurologic involvement occurs in up to 40% of ECD with frequent brainstem lesions that can mimic acquired neuroinflammatory disorders, such as CLIPPERS. ECD is an important CLIPPERS mimic with distinct pathophysiology and targeted treatments. We highlight the need to consider histiocytic disorders among other alternate diagnoses when findings are not classic for CLIPPERS.
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Enfermedad de Erdheim-Chester , Humanos , Enfermedad de Erdheim-Chester/diagnóstico , Enfermedad de Erdheim-Chester/genética , Persona de Mediana Edad , Masculino , Femenino , Diagnóstico Diferencial , Anciano , Tomografía Computarizada por Tomografía de Emisión de Positrones , Imagen por Resonancia Magnética , Adulto , Enfermedades Neuroinflamatorias/diagnóstico , Enfermedades Neuroinflamatorias/diagnóstico por imagenRESUMEN
Erdheim-Chester disease (ECD) is a rare histiocytosis that tends to co-exist with other myeloid malignancies. Here, we use genetic and transcriptomic sequencing to delineate a case of co-occurring BRAFV600E-mutated ECD and acute myeloid leukemia (AML), followed by AML remission and relapse. The AML relapse involved the extinction of clones with KMT2A-AFDN and FLT3-ITD, and the predominance of PTPN11-mutated subclones with distinct transcriptomic features. This case report has highlighted the screening for other myeloid malignancies at the diagnosis of ECD and the clinical significance of PTPN11-mutated AML subclones that require meticulous monitoring.
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Enfermedad de Erdheim-Chester , Leucemia Mieloide Aguda , Mutación , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Tirosina Quinasa 3 Similar a fms , Humanos , Enfermedad de Erdheim-Chester/genética , Enfermedad de Erdheim-Chester/complicaciones , Enfermedad de Erdheim-Chester/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Tirosina Quinasa 3 Similar a fms/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Masculino , Evolución Clonal/genética , Femenino , Proteínas Proto-Oncogénicas B-raf/genética , Persona de Mediana EdadRESUMEN
Erdheim Chester Disease (ECD) is a rare histiocytic disorder marked by infiltration of organs with CD68+ histiocytes. ECD stems from mutations of BRAF and MAP2K1 in hematopoietic stem and progenitor cells (HSPCs), which further differentiate into monocytes and histiocytes. Histopathology reveals lipid-containing histiocytes, which test positive for CD68 and CD133 in immunohistochemistry. Signs and symptoms vary and depend on the organ/s of manifestation. Definitive radiological results associated with ECD include hairy kidney, coated aorta, and cardiac pseudotumor. Treatment options primarily include anti-cytokine therapy and inhibitors of BRAF and MEK signaling.
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Enfermedad de Erdheim-Chester , Enfermedad de Erdheim-Chester/tratamiento farmacológico , Enfermedad de Erdheim-Chester/diagnóstico , Enfermedad de Erdheim-Chester/genética , Enfermedad de Erdheim-Chester/terapia , Enfermedad de Erdheim-Chester/patología , Enfermedad de Erdheim-Chester/metabolismo , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Histiocitos/patología , Histiocitos/metabolismoRESUMEN
Histiocytic diseases arise from MAPK mutations in myeloid progenitors. Depending on whether the progenitor follows a dendritic cell or macrophage/monocyte lineage the final histology results in Langerhans cell histiocytosis, Rosai-Dorfman disease or Erdheim-Chester disease. Commentary on: Friedman et al. Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy. Br J Haematol 2024;205:127-137.
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Mutación , Humanos , Enfermedad de Erdheim-Chester/genética , Enfermedad de Erdheim-Chester/patología , Enfermedad de Erdheim-Chester/diagnóstico , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/patología , Histiocitosis de Células de Langerhans/diagnóstico , Histiocitosis Sinusal/patología , Histiocitosis Sinusal/diagnóstico , Histiocitosis Sinusal/genéticaRESUMEN
Histiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai-Dorfman-Destombes disease (RDD) and Erdheim-Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy-proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty-seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non-V600-BRAF, RAF1 and a BICD2-BRAF fusion. A repeated-measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19-137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03-0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.
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Enfermedad de Erdheim-Chester , Mutación , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Enfermedad de Erdheim-Chester/genética , Enfermedad de Erdheim-Chester/tratamiento farmacológico , Anciano , Adolescente , Terapia Molecular Dirigida , Adulto Joven , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Niño , Histiocitosis Sinusal/genética , Histiocitosis Sinusal/tratamiento farmacológico , Histiocitosis Sinusal/patología , Proteínas Proto-Oncogénicas B-raf/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , PreescolarRESUMEN
RATIONALE: Erdheim-Chester disease (ECD) is a rare multisystemic disease characterized by the infiltration of multiple organs by foamy CD68â +â CD1a-histiocytes. The genetic background consists of gain-of-function somatic mutations in the mitogen-activated protein kinase pathway. The purpose of the present paper is to make a contribution to the scientific literature on ECD by reporting our experience with a complex clinical case report, along with a concise review of the literature. We discussed the unusual clinical presentation, the complex diagnostic process and the comparison with other published cases. PATIENT CONCERNS: A 70-year-old man presented with arthralgia due to multiple bone areas of sclerosis, first diagnosed with metastases of a prostatic neoplasm. Sequential thorax-abdomen, femoral and homer contrast-enhanced computed tomography (CT) showed pericardial effusion, pulmonary fibrosis, and perirenal fibrous tissue as "hairy kidneys." He underwent. Three bone biopsies were unsuccessful to reach diagnosis. DIAGNOSES: A xanthelasma biopsy showed histopathological signs compatible with ECD; genetic analysis showed the mutation BRAFV600E. INTERVENTIONS: The patient underwent targeted therapy with vemurafenib (BRAF-inhibitor), discontinued 2 weeks later due to the onset of a diffuse erythematous papular rash on the trunk and limbs. OUTCOMES: At the 1-year follow-up, there was only progression of chronic kidney disease (CKD). LESSONS: The present case report describes how ECD diagnosis could represent a challenge for clinicians, owing to its heterogeneous clinical presentation. Early diagnosis followed by prompt therapy is essential for modifying the natural history of the disease.
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Enfermedad de Erdheim-Chester , Humanos , Enfermedad de Erdheim-Chester/diagnóstico , Enfermedad de Erdheim-Chester/genética , Masculino , Anciano , Proteínas Proto-Oncogénicas B-raf/genética , Vemurafenib/uso terapéuticoRESUMEN
Erdheim-Chester disease (ECD) is a rare histiocytosis characterized by the foamy CD68+CD1a- histiocytes infiltrating multiple organs and tissues. ECD might be asymptomatic or present with variable manifestations. The diagnosis of ECD requires characteristic radiological findings and pathological features. Herein, we described a 52-year-old female patient who was admitted to our hospital for recurrent pericardial effusion for two months. She has a medical history of papillary thyroid carcinoma (PTC) and underwent a total thyroidectomy two years before admission. The radiological findings suggested a potential diagnosis of ECD. Cytological analysis of the effusion cytology specimen revealed CD68+CD1a- histiocytes, confirming the ECD diagnosis. The BRAF V600E mutation was identified in the histiocytes, prompting the administration of vemurafenib, a BRAF inhibitor. After two months of standard-dose vemurafenib treatment, the disease was well controlled with pericardial effusion regression.
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Enfermedad de Erdheim-Chester , Derrame Pericárdico , Proteínas Proto-Oncogénicas B-raf , Vemurafenib , Femenino , Humanos , Persona de Mediana Edad , Enfermedad de Erdheim-Chester/genética , Enfermedad de Erdheim-Chester/tratamiento farmacológico , Enfermedad de Erdheim-Chester/complicaciones , Enfermedad de Erdheim-Chester/patología , Enfermedad de Erdheim-Chester/diagnóstico , Histiocitos/patología , Mutación , Derrame Pericárdico/patología , Derrame Pericárdico/etiología , Valor Predictivo de las Pruebas , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Resultado del Tratamiento , Vemurafenib/uso terapéuticoRESUMEN
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.
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.
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Enfermedad de Erdheim-Chester , Imidazoles , Oximas , Proteínas Proto-Oncogénicas B-raf , Humanos , Enfermedad de Erdheim-Chester/tratamiento farmacológico , Enfermedad de Erdheim-Chester/genética , Masculino , Oximas/uso terapéutico , Imidazoles/uso terapéutico , Adulto , Proteínas Proto-Oncogénicas B-raf/genética , Esteroides/uso terapéutico , Mutación , Resultado del TratamientoRESUMEN
Histiocytoses, including Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD), are inflammatory myeloid tumors in which monocyte lineage cells aggregate in various organs, causing tissue damage. Most of these tumors harbor oncogenic mutations in mitogen-activated protein kinase (MAPK) pathway genes, typified by BRAFV600E. Some patients with LCH develop bilateral symmetrical cerebellar lesions and brain atrophy several years after diagnosis when the initial symptoms disappear, leading to cerebellar ataxia and higher cerebral dysfunction. A similar neurological disorder has also been reported in ECD. This neurological disorder can be improved with MAPK inhibitors. When patients with this neurological disorder are identified among neurodegeneration of unknown etiology or histiocytosis patients and treated early with MAPK inhibitors, the disorder can be reversible.
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Encefalopatías , Enfermedad de Erdheim-Chester , Histiocitosis de Células de Langerhans , Neoplasias , Humanos , Histiocitosis de Células de Langerhans/diagnóstico , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/patología , Enfermedad de Erdheim-Chester/diagnóstico , Enfermedad de Erdheim-Chester/genética , Enfermedad de Erdheim-Chester/patología , MutaciónRESUMEN
OBJECTIVE: The aim of this study was to characterize the distribution of skeletal involvement in Erdheim-Chester disease (ECD) by using radiography, computed tomography (CT), 18F-FDG positron emission tomography/computed tomography (PET/CT), and bone scans, as well as looking for associations with the BRAFV600E mutation. MATERIAL AND METHODS: Prospective study of 50 consecutive patients with biopsy-confirmed ECD who had radiographs, CT, 18F-FDG PET/CT, and Tc-99m MDP bone scans. At least two experienced radiologists with expertise in the relevant imaging studies analyzed the images. Summary statistics were expressed as the frequency with percentages for categorical data. Fisher's exact test, as well as odds ratios (OR) with 95 % confidence intervals (CI), were used to link imaging findings to BRAFV600E mutation. The probability for co-occurrence of bone involvement at different locations was calculated and graphed as a heat map. RESULTS: All 50 cases revealed skeletal involvement at different regions of the skeleton. The BRAFV600E mutation, which was found in 24 patients, was correlated with femoral and tibial involvement on 18F-FDG PET/CT and bone scan. The appearance of changes on the femoral, tibial, fibular, and humeral involvement showed correlation with each other based on heat maps of skeletal involvement on CT. CONCLUSION: This study reports the distribution of skeletal involvement in a cohort of patients with ECD. CT is able to detect the majority of ECD skeletal involvement. Considering the complementary nature of information from different modalities, imaging of ECD skeletal involvement is optimized by using a multi-modality strategy.