Subject(s)
Erdheim-Chester Disease , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Mutation , Neoplasm Proteins , Erdheim-Chester Disease/blood , Erdheim-Chester Disease/diagnostic imaging , Erdheim-Chester Disease/genetics , Erdheim-Chester Disease/pathology , Female , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnostic imaging , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Middle Aged , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolismABSTRACT
The BRAF V600E mutation and BRAF inhibitor responsiveness characterize â¼50% of patients with the non-Langerhans cell histiocytosis (non-LCH) Erdheim-Chester disease (ECD). We interrogated the non-LCH molecular landscape [ECD, n = 35; Rosai-Dorfman disease (RDD), n = 3; mixed ECD/RDD, n = 1] using BRAF V600E PCR and/or next-generation sequencing [tissue and cell-free DNA (cfDNA) of plasma and/or urine]. Of 34 evaluable patients, 17 (50%) had the BRAF V600E mutation. Of 31 patients evaluable for non-BRAF V600E alterations, 18 (58%) had ≥1 alteration and 12 putative non-BRAF V600E MAPK pathway alterations: atypical BRAF mutation; GNAS, MAP2K1, MAP2K2, NF1, and RAS mutations; RAF1 or ERBB2 amplifications; LMNA-NTRK1 (TRK inhibitor-sensitive) and CAPZA2-BRAF fusions. Four patients had JAK2, MPL ASXL1, U2AF1 alterations, which can correlate with myeloid neoplasms, a known ECD predisposition, and one developed myelofibrosis 13 months after cfDNA testing. Therefore, our multimodal comprehensive genomics reveals clinically relevant alterations and suggests that MAPK activation is a hallmark of non-LCH.
Subject(s)
Cell-Free Nucleic Acids/genetics , Erdheim-Chester Disease/blood , Erdheim-Chester Disease/pathology , Genomics/methods , Histiocytosis, Sinus/blood , Histiocytosis, Sinus/pathology , Adolescent , Adult , Aged , Early Detection of Cancer/methods , Erdheim-Chester Disease/urine , Female , High-Throughput Nucleotide Sequencing , Histiocytosis, Sinus/urine , Humans , Leukemia, Myeloid/diagnosis , Male , Middle Aged , Mitogen-Activated Protein Kinases/genetics , Mutation , Polymerase Chain Reaction , Proto-Oncogene Proteins B-raf/genetics , Young AdultABSTRACT
Glomeruloid haemangioma (GH) is considered a specific marker of POEMS syndrome, despite some published GH cases unrelated to POEMS syndrome. To present two cases with GH and atypical presentations of Erdheim-Chester disease (ECD) or POEMS syndrome, as well as a retrospective monocentric study of histologically-confirmed GH. Clinical, biological and histological data of the patients is presented. In addition to the two presented cases, 11 GH histologically-confirmed cases were retrospectively identified. Six patients were female (46.2%; 95 CI: 12-64.9) and median age was 54 years (31-85). For 11 patients (84.6%; 95 CI: 65-104.2), a diagnosis of POEMS syndrome was retained, one patient had autoimmune hepatitis, and another had ECD. GH was localised to the trunk in 10 cases (76.9%; 95 CI: 54-99) and the legs in the other three. The median number of haemangiomas in the cohort was three (SD: 3.08). Median level of VEGF was 1,490 (610-12,000) ng/mL. All immunohistochemical staining for human herpesvirus 8 (HHV-8) was negative. Of the 13 cases of GH, of which two were not clear-cut POEMS syndrome, we report the first case of GH associated with ECD. In this cohort, all patients had high serum levels of VEGF but no in situ HHV-8 latent infection. We hypothesise that GH might be linked to a high level of VEGF in these two rare diseases.
Subject(s)
Erdheim-Chester Disease/blood , Hemangioma/pathology , POEMS Syndrome/blood , Skin Neoplasms/pathology , Vascular Endothelial Growth Factor A/blood , Adult , Aged , Aged, 80 and over , Erdheim-Chester Disease/complications , Female , Hemangioma/blood , Hemangioma/etiology , Humans , Male , Middle Aged , POEMS Syndrome/complications , Retrospective Studies , Skin Neoplasms/blood , Skin Neoplasms/etiology , Tumor BurdenABSTRACT
Objective- Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by the infiltration of multiple tissues with lipid-laden histiocytes. Cardiovascular involvement is frequent in ECD and leads to a severe prognosis. The objective of this study was to determine whether an alteration of lipid metabolism participates in the lipid accumulation in histiocytes and the cardiovascular involvement in ECD. Approach and Results- An analysis of plasma lipid levels indicated that male ECD patients carrying the BRAFV600E (B-Raf proto-oncogene, serine/threonine kinase) mutation exhibited hypoalphalipoproteinemia, as demonstrated by low plasma HDL-C (high-density lipoprotein cholesterol) levels. Capacity of sera from male BRAFV600E ECD patients to mediate free cholesterol efflux from human macrophages was reduced compared with control individuals. Cardiovascular involvement was detected in 84% of the ECD patients, and we reported that the presence of the BRAFV600E mutation and hypoalphalipoproteinemia is an independent determinant of aortic infiltration in ECD. Phenotyping of blood CD14+ cells, the precursors of histiocytes, enabled the identification of a specific inflammatory signature associated with aortic infiltration which was partially affected by the HDL phenotype. Finally, the treatment with vemurafenib, an inhibitor of the BRAFV600E mutation, restored the defective sera cholesterol efflux capacity and reduced the aortic infiltration. Conclusions- Our findings indicate that hypoalphalipoproteinemia in male ECD patients carrying the BRAFV600E mutation favors the formation of lipid-laden histiocytes. In addition, we identified the BRAF status and the HDL phenotype as independent determinants of the aortic involvement in ECD with a potential role of HDL in modulating the infiltration of blood CD14+ cells into the aorta.
Subject(s)
Aorta/metabolism , Aortic Diseases/genetics , Cholesterol, HDL/blood , Erdheim-Chester Disease/genetics , Histiocytes/metabolism , Hypoalphalipoproteinemias/genetics , Mutation , Proto-Oncogene Proteins B-raf/genetics , ATP Binding Cassette Transporter 1/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Aorta/drug effects , Aorta/pathology , Aortic Diseases/drug therapy , Aortic Diseases/enzymology , Biomarkers/blood , Case-Control Studies , Erdheim-Chester Disease/blood , Erdheim-Chester Disease/diagnosis , Erdheim-Chester Disease/drug therapy , Female , Genetic Predisposition to Disease , Histiocytes/drug effects , Histiocytes/pathology , Humans , Hypoalphalipoproteinemias/blood , Hypoalphalipoproteinemias/diagnosis , Hypoalphalipoproteinemias/drug therapy , Lipopolysaccharide Receptors/blood , Macrophages/metabolism , Male , Middle Aged , Phenotype , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Mas , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Risk Factors , Sex Factors , THP-1 Cells , Vemurafenib/therapeutic use , Young AdultABSTRACT
BACKGROUND: Erdheim-Chester disease (ECD) is a rare non-Langerhans cells histiocytosis associated with intense immune activation. In our clinical center, an ECD patient was treated with anakinra, IL1RA (interleukin1 receptor antagonist), resulting in clinical improvement and major decrease of pathological fatigue. The aim of the study was to evaluate changes in cytokine profile and shift of immune cells estimated by flow cytometric analysis of ECD patient before, during initial stages of anakinra treatment as well as after treatment ceased in comparison to healthy donors. METHODS: Singleplex reactions of 19 individual cytokines from serum of ECD patient were measured by FACS array. Flow cytometric analyses were performed on peripheral blood cells. RESULTS: The most striking result is substantial decrease of IL6 immediately after anakinra treatment started suggesting a major role of IL1 pathway in ECD pathophysiology. As for flow cytometric analysis, increased number of CD16+ monocytes before treatment is a new finding. CONCLUSION: Our results suggest that IL6 may be a marker of early treatment response of ECD patients treated with anakinra.
Subject(s)
Cytokines/blood , Erdheim-Chester Disease/drug therapy , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Monocytes/cytology , T-Lymphocytes/cytology , Case-Control Studies , Erdheim-Chester Disease/blood , Flow Cytometry , Humans , MaleABSTRACT
Erdheim-Chester disease (ECD) is a rare histiocytosis with a high prevalence of BRAF V600E mutation (>50% of patients). Patients with BRAF-mutant ECD can respond to BRAF inhibitors. Unfortunately, the lack of adequate archival tissue often precludes BRAF testing. We hypothesized that cell-free DNA (cfDNA) from plasma or urine can offer an alternative source of biologic material for testing. We tested for BRAF V600E mutation in cfDNA from the plasma and urine of 6 ECD patients. In patients with available archival tissue, the result of BRAF mutation analysis was concordant with plasma and urine cfDNA results in all 3 patients (100% agreement, kappa 1.00). In all 6 patients, BRAF mutation analysis of plasma and urine cfDNA was concordant in 5 of 6 patients (83% agreement, kappa 0.67). Testing for BRAF V600E mutation in plasma and urine cfDNA should be further investigated as an alternative to archival tissue mutation analysis.
Subject(s)
DNA/blood , Erdheim-Chester Disease/enzymology , Erdheim-Chester Disease/genetics , Mutation , Proto-Oncogene Proteins B-raf/genetics , Adult , Aged , DNA/genetics , DNA Mutational Analysis , Erdheim-Chester Disease/blood , Erdheim-Chester Disease/urine , Female , Humans , Male , Middle Aged , Prognosis , Prospective Studies , Proto-Oncogene Proteins B-raf/blood , Proto-Oncogene Proteins B-raf/urineABSTRACT
We describe a case of an Erdheim-Chester disease patient. First line chemotherapy treatment with 2-chlorodeoxyadenosine did not reduce fluorodeoxyglucose accumulation in pathological lesions. The patient had continuously increased CRP values of 17-20 mg/l. The disease continued to cause subfebrile temperatures and significant fatigue that made the patient to spend most of the daytime in bed. To manage the permanently increased inflammation markers, we decided to start treatment with anakinra, successfully used in some other autoinflammatory diseases (e.g. Schnitzler syndrome). We have now been able to evaluate the first 6 months of treatment. Daily subcutaneous administration of anakinra (KineretTM 100 mg daily) led to normalization of CRP values, cessation of subfebrile temperatures and, importantly, significant reduction of fatigue. Time periods the patient was able to spend out of the bed increased significantly. Consequent to the reduced fatigue, the patient was able to perform basic household tasks he was unable to undertake without treatment. After 3 months of treatment, fatigue of the same intensity returned following a short interruption of therapy. The CRP values went up again to 12 mg/l. CRP value returned back to norm and fatigue ceased after re-initiation of daily Kineret injections. Objective treatment response was assessed by measuring the degree of fluorodeoxyglucose accumulation in pathological bone lesions. PET-CT was performed before and 3 and 6 months after anakinra initiation. Intensity of accumulation did not change significantly after the first 3 months of therapy but decreased after 6 month therapy. Follow up CT of abdominal cavity was performed at the end of the 6th month of treatment. Presented CT images from before and 6 months after the treatment evidence an obvious reduction in fibroid changes in the retroperitoneum. Daily administration of anakinra to a patient with active Erdheim-Chester disease significantly reduced intensity of fatigue and improved quality of life, led to a reduction in inflammatory markers and regression in retroperitoneal fibrotization.
Subject(s)
C-Reactive Protein/analysis , Erdheim-Chester Disease/drug therapy , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Retroperitoneal Fibrosis/drug therapy , Adult , Drug Administration Schedule , Erdheim-Chester Disease/blood , Erdheim-Chester Disease/complications , Humans , Injections, Subcutaneous , Male , Retroperitoneal Fibrosis/complicationsABSTRACT
Immunopathogenesis of Erdheim-Chester disease (ECD), a rare non-Langerhans cell histiocytosis, is poorly known. In previous studies, various cytokines were detected in ECD lesions, presumably orchestrating lesional histiocyte recruitment. Because ECD lesions are frequently associated with systemic symptoms, we postulated that underlying global immune perturbations might also be revealed. We quantitatively analyzed 23 cytokines in serum samples obtained from a large single-center cohort of 37 patients with ECD, and studied the impact of treatment on cytokine production. IL-6, IL-12, interferon-α (IFN-α), and monocyte chemotactic protein-1 (MCP-1) levels were significantly higher in untreated patients than in controls, whereas interferon-γ (IFN-γ) inducible protein 10, IL-12, MCP-1, and IL-1 receptor antagonist were found significantly increased in IFN-α-treated patients. A biomathematical approach was used to rationalize multiparameter data, to generate new hypotheses, and identify global control pathways. Interestingly, cytokine profiles proved to be particularly stable at the individual level, and an "ECD signature" further distinguished patients from controls, based on their production of IFN-α, IL-12, MCP-1, IL-4, and IL-7. Altogether, our data underline the systemic immune Th-1-oriented perturbation associated with this condition and provide clues for the choice of more focused therapeutic agents in this rare disease with noncodified therapeutic management.
Subject(s)
Cytokines/blood , Cytokines/immunology , Erdheim-Chester Disease/blood , Erdheim-Chester Disease/immunology , Adult , Aged , Aged, 80 and over , Chemokines/blood , Chemokines/immunology , Cohort Studies , Erdheim-Chester Disease/drug therapy , Female , Humans , Immunohistochemistry , Immunologic Factors/therapeutic use , Interferon-alpha/therapeutic use , Male , Middle Aged , Signal Transduction/immunology , Young AdultABSTRACT
OBJECTIVE: Erdheim-Chester disease (ECD) is a rare, non-Langerhans form of histiocytosis of unknown origin, characterized by infiltration of tissues by spumous histiocytes. ECD features heterogeneous systemic manifestations, and the general prognosis remains poor despite various treatment options. METHODS: We treated 8 patients with multisystemic ECD with subcutaneous interferon-alpha (IFNalpha) at a dosage of 3-9 x 10(6) units 3 times weekly, for a median duration of 23 months (range 1-46 months). RESULTS: Treatment was generally well tolerated, and side effects remained limited to fever following injections. Treatment was discontinued in 1 patient, because of severe depression. During treatment, some manifestations of ECD disappeared (i.e., xanthelasma, exophthalmos, papilledema, and intracranial hypertension). The efficacy of IFNalpha on cardiovascular ECD was variable, however. Treatment resulted in partial regression of "coated aorta" in some cases and clear failure in others; 2 patients died. The level of C-reactive protein diminished sharply in 5 patients. CONCLUSION: IFNalpha might be a valuable first-line therapy for prolonged treatment of ECD. However, the efficacy of IFNalpha varies among patients and according to the sites of disease involvement, and symptoms may fail to respond to treatment, especially in patients with severe multisystemic forms of ECD with central nervous system and cardiovascular involvement.
Subject(s)
Erdheim-Chester Disease/drug therapy , Erdheim-Chester Disease/pathology , Immunologic Factors/therapeutic use , Interferon-alpha/therapeutic use , Adolescent , Adult , Aged , C-Reactive Protein/analysis , Dose-Response Relationship, Drug , Erdheim-Chester Disease/blood , Exophthalmos/drug therapy , Exophthalmos/pathology , Female , Histiocytes/pathology , Humans , Immunologic Factors/adverse effects , Interferon-alpha/adverse effects , Intracranial Hypertension/drug therapy , Intracranial Hypertension/pathology , Male , Middle Aged , Papilledema/drug therapy , Papilledema/pathology , Prognosis , Treatment OutcomeABSTRACT
Erdheim-Chester disease (ECD) is a rare non-Langherans form of histiocytosis characterized radiologically by symmetrical sclerosis of the metaphysis and the diaphysis of long tubular bones. Macrophages are potent interleukin-6 (IL-6) producers and elevated IL-6 serum levels have been described in pathological conditions characterized by increased bone resorption. In a patient with ECD, during the acute phase of the disease we found high serum levels of IL-6 and IL-6 soluble receptor (sIL-6R) and high levels of bone turnover markers. After 5 years of combination therapy with oral prednisone and intravenous clodronate a significant reduction in the above mentioned biological parameters was seen. We suggest that the systemic disorders present in ECD could be related to the high serum levels of IL-6 and sIL-6R. We also propose the use of bisphosphonates in the clinical management of ECD.