scholarly journals Successful treatment with cladribine of Erdheim-Chester disease with orbital and central nervous system involvement developing after treatment of langerhans cell histiocytosis

2016 ◽  
Vol 73 (1) ◽  
pp. 83-87 ◽  
Author(s):  
Predrag Peric ◽  
Branislav Antic ◽  
Slavica Knezevic-Usaj ◽  
Olga Radic-Tasic ◽  
Sanja Radovinovic-Tasic ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Langerhans Cell Histiocytosis ◽  
Braf V600e Mutation ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Cns Involvement ◽  
Erdheim Chester Disease ◽  
Erdheim Chester ◽  
Chester Disease

Introduction. Erdheim-Chester disease (ECD) is a rare, systemic form of non-Langerhans cell histiocytosis of the juvenile xantho-granuloma family with characteristic bilateral symmetrical long bone osteosclerosis, associated with xanthogranulomatous extras-keletal organ involvement. In ECD, central nervous system (CNS) and orbital lesions are frequent, and more than half of ECD patients carry the V600E mutation of the proto-oncogene BRAF. The synchronous or metachronous development of ECD and Langerhans cell histiocytosis (LCH) in the same patients is rare, and the possible connection between them is still obscure. Cladribine is a purine substrate analogue that is toxic to lymphocytes and monocytes with good hematoencephalic penetration. Case report. We presented a 23-year-old man successfully treated with cladribine due to BRAF V600E-mutation-negative ECD with bilateral orbital and CNS involvement. ECD developed metachronously, 6 years after chemotherapy for multisystem LCH with complete disease remission and remaining central diabetes insipidus. During ECD treatment, the patient received 5 single-agent chemotherapy courses of cladribine (5 mg/m2 for 5 consecutive days every 4 weeks), with a reduction in dose to 4 mg/m2 in a fifth course, delayed due to severe neutropenia and thoracic dermatomal herpes zoster infection following the fourth course. Radiologic signs of systemic and CNS disease started to resolve 3 months after the end of chemotherapy, and CNS lesions completely resolved within 2 years after the treatment. After 12-year follow-up, there was no recurrence or appearance of new systemic or CNS xanthogranu-lomatous lesions or second malignancies. Conclusion. In accordance with our findings and recommendations provided by other authors, cladribine can be considered an effective alternative treatment for ECD, especially with CNS involvement and BRAF V600E-mutation-negative status, when interferon-? as the first-line therapy fails.

scholarly journals Evaluation of Clinicopathologic Characteristics and the BRAF V600E Mutation in Erdheim-Chester Disease Among Chinese Adults

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3870-3870
Author(s):  
Xin-xin Cao ◽  
Jian Sun ◽  
Jian Li ◽  
Ding-rong Zhong ◽  
Na Niu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Disease Duration ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Radiographic Findings ◽  
Erdheim Chester Disease ◽  
Rosai Dorfman Disease ◽  
Erdheim Chester ◽  
Chester Disease

Abstract Objectives 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. Methods 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). Results Sixteen patients were diagnosed with ECD. Median age at diagnosis was 47 years (range, 22-61 years). 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 (25.0%), and ¡°hairy kidney¡± (25%). Thirteen patients displayed characteristic histological features, including foamy histiocyte infiltration of polymorphic granuloma and fibrosis or xanthogranulomatosis, with CD68-positive and CD1-¦Á- negative immunostaining. Three patients (designated 3, 5 and 10) displayed CD68-positive and CD1¦Á- negative histiocyte infiltration, but not the above histological characteristics, and were thus initially misdiagnosed as Rosai-Dorfman disease. All three cases were BRAFV600E mutation-positive, leading to revision of diagnosis as ECD. Diagnosis of ECD in each case was additionally supported by typical radiographic findings. The BRAF V600E mutation was detected in 68.8% patients using PCR and 50.0% patients with immunohistochemistry. Ten patients (62.5%) received IFN-¦Á as first-line treatment, 3 patients showed improvement, 3 remained stable, 3 were too early for evaluation and 1 died. Three patients (5, 10 and 11) underwent transsphenoidal pituitary lesion surgery but were not subjected to systemic treatment, owing to the absence of symptoms and disease activity post-surgery and remained stable after a median of 16 months (range, 6-30 months) from diagnosis. Thirteen patients (81.3%) were still alive at median follow-up of 14.5 months. Conclusion 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. Table 1. Characteristics and treatment of 16 patients with ECD Patient Sex/ age, years Disease duration, mo Main sites of involvement BRAF IH BRAF V600E Therapy Vital Status OS£¬mo 1 M/33 5 B N/A - IFN-6 MIU 3/wk Alive 15 2 M/22 43 S, B - - IFN-3 MIU 3/wk Alive 11 3 M/25 18 B, LN, CNS - + Pred Dead 13 4 F/28 3 S, B + + None Alive 16 5 M/60 27 B, PIT + + Surgery Alive 15 6 F/61 5 B, H, LV, R£¬CNS, MS, S N/A + IFN-6 MIU 3/wk Dead 25 7 F/23 67 S, B, H, LV - - IFN-3 MIU 3/wk Alive 19 8 M/60 43 B, P, LV, R N/A + IFN-6 MIU 3/wk Alive 14 9 M/46 84 CNS, B + + IFN-6 MIU 3/wk Alive 22 10 F/51 7 PIT + + Surgery Alive 6 11 F/36 72 PIT, B + + Surgery Alive 30 12 M/55 100 B, S, CNS, PIT - + IFN-6 MIU 3/wk Alive 3 13 F/50 11 B, H N/A + IFN-6 MIU 3/wk Alive 5 14 F/46 8 B, LV, P + + IFN-6 MIU 3/wk Alive 1 15 M/52 30 B, LV, R, P£¬E - - IFN-6 MIU 3/wk Alive 1 16 M/47 4 B, LV, R, LN - - None Dead 36 Age is at diagnosis£»disease duration is from the first symptom to diagnosis IH, immunohisochemistry; B, long bones; LN, lymph nodes; LV, large vessels; H, heart; S, skin; CNS, central nervous system; MS, maxillary sinus; PIT, pituitary gland; R, retroperitoneal; P, pericardial effusion; E, Exophthalmos; MIU, million international units; N/A, not available Disclosures No relevant conflicts of interest to declare.

Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation

Blood ◽  
2013 ◽  
Vol 121 (9) ◽  
pp. 1495-1500 ◽  
Author(s):  
Julien Haroche ◽  
Fleur Cohen-Aubart ◽  
Jean-François Emile ◽  
Laurent Arnaud ◽  
Philippe Maksud ◽  
...  
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Tumor Response ◽  
Braf V600e Mutation ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Erdheim Chester Disease ◽  
Key Points ◽  
Erdheim Chester ◽  
Chester Disease

Key Points Treatment with vemurafenib induced a dramatic response in 3 patients with histiocytosis harboring BRAF V600E mutations. Tumor response was observed in both Erdheim-Chester disease and Langerhans cell histiocytosis.

scholarly journals BRAF V600E mutation in Juvenile Xanthogranuloma family neoplasms of the central nervous system (CNS-JXG): a revised diagnostic algorithm to include pediatric Erdheim-Chester disease

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
J. Picarsic ◽  
T. Pysher ◽  
H. Zhou ◽  
M. Fluchel ◽  
T. Pettit ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Diagnostic Algorithm ◽  
Braf V600e ◽  
Juvenile Xanthogranuloma ◽  
Female Ratio ◽  
Integrated Diagnosis ◽  
Erdheim Chester Disease ◽  
Erdheim Chester ◽  
Chester Disease

Abstract The family of juvenile xanthogranuloma family neoplasms (JXG) with ERK-pathway mutations are now classified within the “L” (Langerhans) group, which includes Langerhans cell histiocytosis (LCH) and Erdheim Chester disease (ECD). Although the BRAF V600E mutation constitutes the majority of molecular alterations in ECD and LCH, only three reported JXG neoplasms, all in male pediatric patients with localized central nervous system (CNS) involvement, are known to harbor the BRAF mutation. This retrospective case series seeks to redefine the clinicopathologic spectrum of pediatric CNS-JXG family neoplasms in the post-BRAF era, with a revised diagnostic algorithm to include pediatric ECD. Twenty-two CNS-JXG family lesions were retrieved from consult files with 64% (n = 14) having informative BRAF V600E mutational testing (molecular and/or VE1 immunohistochemistry). Of these, 71% (n = 10) were pediatric cases (≤18 years) and half (n = 5) harbored the BRAF V600E mutation. As compared to the BRAF wild-type cohort (WT), the BRAF V600E cohort had a similar mean age at diagnosis [BRAF V600E: 7 years (3–12 y), vs. WT: 7.6 years (1–18 y)] but demonstrated a stronger male/female ratio (BRAF V600E: 4 vs WT: 0.67), and had both more multifocal CNS disease ( BRAFV600E: 80% vs WT: 20%) and systemic disease (BRAF V600E: 40% vs WT: none). Radiographic features of CNS-JXG varied but typically included enhancing CNS mass lesion(s) with associated white matter changes in a subset of BRAF V600E neoplasms. After clinical-radiographic correlation, pediatric ECD was diagnosed in the BRAF V600E cohort. Treatment options varied, including surgical resection, chemotherapy, and targeted therapy with BRAF-inhibitor dabrafenib in one mutated case. BRAF V600E CNS-JXG neoplasms appear associated with male gender and aggressive disease presentation including pediatric ECD. We propose a revised diagnostic algorithm for CNS-JXG that includes an initial morphologic diagnosis with a final integrated diagnosis after clinical-radiographic and molecular correlation, in order to identify cases of pediatric ECD. Future studies with long-term follow-up are required to determine if pediatric BRAF V600E positive CNS-JXG neoplasms are a distinct entity in the L-group histiocytosis category or represent an expanded pediatric spectrum of ECD.

Non-Langerhans cell histiocytosis with isolated CNS involvement: An unusual variant of Erdheim-Chester disease

2010 ◽  
Vol 30 (6) ◽  
pp. 634-647 ◽  
Author(s):  
Alexandria Conley ◽  
Sunil Manjila ◽  
Hui Guan ◽  
Murali Guthikonda ◽  
William J. Kupsky ◽  
...  
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Langerhans Cell ◽  
Cns Involvement ◽  
Erdheim Chester Disease ◽  
Unusual Variant ◽  
Erdheim Chester ◽  
Chester Disease

scholarly journals Classification and Prognosis of Central Nervous System Involvement in Erdheim-Chester Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4272-4272
Author(s):  
Fleur Cohen-Aubart ◽  
Ahmed Idbaih ◽  
Damien Galanaud ◽  
Bruno Law-Ye ◽  
Jean-François Emile ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Targeted Therapy ◽  
Mapk Pathway ◽  
Central Nervous System Involvement ◽  
Cns Involvement ◽  
Mek Inhibitors ◽  
Erdheim Chester Disease ◽  
Erdheim Chester ◽  
Chester Disease

Background: Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytosis, characterized by the infiltration of tissues by foamy CD68+CD1a- histiocytes, with 1500 known-cases since 90 years. Mutations activating the MAPK pathway are found in more than 80% of ECD patients, mainly the BRAFV600E in 57 to 70%. Central nervous system (CNS) involvement during ECD lead to significant morbidity and mortality. We assessed CNS manifestations in a French cohort of 253 ECD patients. Since 2012, close to 200 patients worldwide with multi-systemic and refractory ECD (e.g. heart and/or CNS involvements) have benefited from BRAF and MEK inhibitors, which have proven highly beneficial. Methods: CNS manifestations were determined by clinical examination and brain and/or spine magnetic resonance imaging (MRI). Targeted therapy efficacy was assessed using physician and radiologist global assessment. Results: Ninety-seven (38%) among the 253 of the whole cohort of ECD patients had CNS involvement. CNS involvement was significantly associated with a younger age at diagnosis (mean 55.5 years) and at symptoms onset (mean 50.5 years), and also with the presence of the BRAFV600E mutation (in 77% of cases), xanthelasma (34%), and diabetes insipidus (36%). Median survival among patients with CNS involvement was significantly lower than in ECD patients without CNS involvement (124 months versus 146 months, p=0.03). Seventy-four CNS MRI were centrally reviewed, corresponding to 3 patterns: tumoral in 66%, degenerative in 50%, and vascular in 18%. Targeted therapy (BRAF and/or MEK inhibitors) was associated with improvement of symptoms in 43% of patients, and MRI improvement in 45%. Conclusions: CNS manifestations are typically associated with a poor prognosis in ECD. Three distinct patterns may be recognized: tumoral, degenerative, and vascular. Targeted therapy leads to clinical and/or imaging improvement in almost 50% of patients. OffLabel Disclosure: Targeted therapies such as BRAF inhibitor (vemurafenib) and MEK inhibitor (cobimetinib) are used in severe histiocytosis in EU but are off label

scholarly journals Pediatric Erdheim-Chester Disease in the Molecular Era: A Multicenter Case Series

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4194-4194
Author(s):  
Francesco Pegoraro ◽  
Elena Gelain ◽  
Stefania Gaspari ◽  
Jean Donadieu ◽  
Jean-François Emile ◽  
...  
Keyword(s):  
Braf V600e Mutation ◽  
Langerhans Cell ◽  
Braf V600e ◽  
First Line ◽  
Erdheim Chester Disease ◽  
Sclerotic Bone ◽  
Hypothalamic Pituitary Axis ◽  
Incident Cases ◽  
Erdheim Chester ◽  
Chester Disease

Abstract Background: Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytic disorder that almost exclusively affects adults. Reports of pediatric-onset ECD are only anecdotal. Additionally, a comprehensive clinical and molecular characterization of pediatric ECD is lacking. Methods: All prevalent and incident cases followed at three ECD referral centers in Italy and France were considered eligible when they had: a) an age <18y at disease onset; b) a clinical presentation consistent with ECD (i.e., at least one of the following localizations: bilateral, sclerotic bone involvement; sclerotic bone lesions of facial sinuses; hairy kidneys; coated aorta; xanthelasma; tumoral atrial involvement); c) pathology consistent with ECD or mixed ECD-Langerhans cell histiocytosis (LCH); d) available data on molecular studies. Results: Ten patients were included (4 boys and 6 girls); their median age at diagnosis was 4.5 years (IQR 3-9). Bone pain, diabetes insipidus, and exophthalmos were the predominant clinical manifestations at onset. The most commonly involved sites were the hypothalamic/pituitary axis (8/10, 80%), the maxillary/facial structures (8/10, 80%), the bone (6/10, 60%), and the central nervous system (CNS; 7/10, 70%). Other less frequent localizations included the skin (3/10, 30%), the retroperitoneum (2/10, 20%), the lymph nodes (2/10, 20%), the large vessels (1/10, 10%), the heart (1/10, 10%), and the lung (1/10, 10%). The median number of involved sites was four (IQR 4-4). Four patients (of whom three were younger than nine years) had clinical or pathological features consistent with mixed histiocytosis (ECD-LCH). Molecular analysis of tissue biopsies revealed the BRAF V600E mutation in 6 patients (60%). As compared with adult series, the retroperitoneum, the heart, the lungs, and the skin seemed to be less frequently involved. Conversely, hypothalamic/pituitary and maxillary/facial involvement were apparently more frequent in our pediatric cohort. Treatments were heterogeneous. First-line regimens mainly consisted of chemotherapy deriving from LCH-based regimens: six out of the eight treated patients received chemotherapy, but only two of them achieved a transient response. Interferon-alpha was used in five patients (as first-line treatment in two and as a rescue treatment in three), with a partial response in two. Four patients with the BRAF V600E mutation received the BRAF inhibitor vemurafenib at some point (partial responses were obtained in all, in one case requiring a combination with cobimetinib). All patients were alive at last follow up (median 94 months, IQR 12-108). Chronic sequelae included end-stage kidney disease in one patient, growth retardation in two, and endocrine abnormalities in seven. Conclusions: The clinical phenotype of ECD differs between children and adults. The hypothalamic/pituitary axis and the maxillary/facial area are frequently involved in pediatric cases, whereas other localizations typically seen in adults (i.e., retroperitoneum, heart, lung, and skin) are rarer. An overlap with LCH is frequent, especially in younger patients. As for LCH, targeted treatments can be highly effective in children carrying the BRAF V600Emutation. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Rare Case of Erdheim-Chester Disease (Non-Langerhans Cell Histiocytosis) with Concurrent Langerhans Cell Histiocytosis: A Diagnostic and Therapeutic Challenge

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Hamza Hashmi ◽  
Drew Murray ◽  
John Greenwell ◽  
Marwan Shaikh ◽  
Soumit Basu ◽  
...  
Keyword(s):  
Interferon Alpha ◽  
Langerhans Cell Histiocytosis ◽  
Rare Case ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Therapeutic Challenge ◽  
Erdheim Chester Disease ◽  
Organ Systems ◽  
Erdheim Chester ◽  
Chester Disease

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.

scholarly journals Erdheim-Chester Disease: The Importance of Information Integration

2017 ◽  
Vol 10 (2) ◽  
pp. 613-619 ◽  
Author(s):  
Anna Nikonova ◽  
Khashayar Esfahani ◽  
Guillaume Chausse ◽  
Stephan Probst ◽  
Tina Petrogiannis-Haliotis ◽  
...  
Keyword(s):  
Retroperitoneal Fibrosis ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
High Dose ◽  
Related Disease ◽  
Igg4 Related Disease ◽  
Erdheim Chester Disease ◽  
History Of ◽  
Erdheim Chester ◽  
Chester Disease

Background: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis disorder that utilizes the RAS-RAF-MEK-ERK pathway. It has a highly variable clinical presentation, where virtually any organ can be involved, thus having the potential of posing a great diagnostic challenge. Over half of the reported cases have the BRAF V600E mutation and have shown a remarkable response to vemurafenib. Case Presentation: We describe herein a patient with a history of stroke-like symptoms and retroperitoneal fibrosis that on initial pathology raised the possibility of IgG4-related disease. However, the patient was refractory to high-dose steroids and progressed further, developing an epicardial soft tissue mass and recurrent neurological symptoms. Integration of the above findings with new information at another hospital about a radiological history of symmetrical lower extremities long bone lesions raised the differential diagnosis of ECD. Molecular analysis of formalin-fixed paraffin-embedded tissue of both of the patient’s retroperitoneal biopsies (the second one of which had shown a small focus of foamy histiocytes, CD68+/CD1a–) was positive for BRAF mutation, confirming the diagnosis of ECD. The patient demonstrated a dramatic and sustained metabolic response to vemurafenib on follow-up positron emission tomography scans. Conclusion: This case highlights the need for developing a high index of suspicion for presentations of retroperitoneal fibrosis that could represent IgG4-related disease but fail to respond to steroids. When unusual multisystem involvement occurs, one should consider a diagnosis of a rare histiocytosis. Vemurafenib appears to be an effective treatment for even advanced cases of both ECD and Langerhans histiocytosis bearing the BRAF V600E mutation.

Central Nervous System Complications of Erdheim-Chester Disease

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Nuh Filizoglu ◽  
Salih Ozguven ◽  
Tunc Ones ◽  
Halil Turgut Turoglu ◽  
Tanju Yusuf Erdil
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Erdheim Chester Disease ◽  
Erdheim Chester ◽  
Chester Disease
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