scholarly journals High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2700-2703 ◽  
Author(s):  
Julien Haroche ◽  
Frédéric Charlotte ◽  
Laurent Arnaud ◽  
Andreas von Deimling ◽  
Zofia Hélias-Rodzewicz ◽  
...  
Keyword(s):  
Unknown Origin ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Juvenile Xanthogranuloma ◽  
Braf Mutations ◽  
Dendritic Cell Sarcoma ◽  
Erdheim Chester Disease ◽  
Rosai Dorfman Disease ◽  
Erdheim Chester ◽  
Chester Disease

Abstract Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAF mutations have been observed in Langerhans cell histiocytosis (LCH). We investigated the frequency of BRAF mutations in several types of histiocytoses. Histology from 127 patients with histiocytoses were reviewed. Detection of BRAFV600 mutations was performed by pyrosequencing of DNA extracted from paraffin embedded samples. Diagnoses of Erdheim-Chester disease (ECD), LCH, Rosai-Dorfman disease, juvenile xanthogranuloma, histiocytic sarcoma, xanthoma disseminatum, interdigitating dendritic cell sarcoma, and necrobiotic xanthogranuloma were performed in 46, 39, 23, 12, 3, 2, 1, and 1 patients, respectively. BRAF status was obtained in 93 cases. BRAFV600E mutations were detected in 13 of 24 (54%) ECD, 11 of 29 (38%) LCH, and none of the other histiocytoses. Four patients with ECD died of disease. The high frequency of BRAFV600E in LCH and ECD suggests a common origin of these diseases. Treatment with vemurafenib should be investigated in patients with malignant BRAFV600E histiocytosis.

Uncommon histiocytic disorders: Rosai–Dorfman, juvenile xanthogranuloma, and Erdheim–Chester disease

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 571-578 ◽  
Author(s):  
Julien Haroche ◽  
Oussama Abla
Keyword(s):  
Braf V600e Mutation ◽  
Braf V600e ◽  
Juvenile Myelomonocytic Leukemia ◽  
Juvenile Xanthogranuloma ◽  
Poor Prognostic Factor ◽  
Erdheim Chester Disease ◽  
Recurrent Mutations ◽  
Life Threatening ◽  
Erdheim Chester ◽  
Chester Disease

Rosai–Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and Erdheim–Chester disease (ECD) are non-Langerhans cell (non-LCH) disorders arising from either a dendritic or a macrophage cell. RDD is a benign disorder that presents with massive lymphadenopathy, but can have extranodal involvement. In most cases, RDD is self-limited and observation is the standard approach. Treatment is restricted to patients with life-threatening, multiple-relapsing, or autoimmune-associated disease. JXG is a pediatric histiocytosis characterized by xanthomatous skin lesions that usually resolve spontaneously. In a minority of cases, systemic disease can occur and can be life threatening. Juvenile myelomonocytic leukemia (JMML), as well as germline mutations in NF1 and NF2, have been reported in children with JXG. Recent whole-exome sequencing of JXG cases did not show the BRAF-V600E mutation, although 1 patient had PI3KCD mutation. ECD is an adult histiocytosis characterized by symmetrical long bone involvement, cardiovascular infiltration, a hairy kidney, and retroperitoneal fibrosis. Central nervous system involvement is a poor prognostic factor. Interferon-α is the standard as front-line therapy, although cladribine and anakinra can be effective in a few refractory cases. More than one-half of ECD patients carry the BRAF-V600E mutation. Currently, >40 patients worldwide with multisystemic, refractory BRAF-V600E+ ECD have been treated with vemurafenib, a BRAF inhibitor, which was found to be highly effective. Other recurrent mutations of the MAP kinase and PI3K pathways have been described in ECD. These discoveries may redefine ECD, JXG, and LCH as inflammatory myeloid neoplasms, which may lead to new targeted therapies.

Biological and Therapeutic Implications of the BRAF Pathway in Histiocytic Disorders

2014 ◽  
pp. e441-e445 ◽  
Author(s):  
Robert J. Arceci
Keyword(s):  
Dendritic Cell ◽  
Braf V600e ◽  
Current Evidence ◽  
Braf Mutations ◽  
Therapeutic Implications ◽  
Erdheim Chester Disease ◽  
Extracellular Signal ◽  
Tumor Protein P53 ◽  
Erdheim Chester ◽  
Chester Disease

Langerhans cell histiocytosis (LCH) has historically evolved in its classification from a primary immune dysregulatory disorder to what current evidence supports as a dendritic cell neoplasm with an immune-inflammatory component. A key part of the classification of LCH as a neoplasm has been the identification of BRAF V600E mutations in 35% to 60% of cases. Tumor protein p53 (TP53) and RAS mutations have also been identified, albeit in less than 2% of reported cases. Of note, over 50% of patients with another dendritic cell disease, Erdheim-Chester Disease, have also been shown to have BRAF V600E mutations. Although the BRAF mutations have not been shown to be associated with extent of disease, they may still provide a target for a molecularly guided approach to therapy. In cases of LCH in which no BRAF mutations were identified, there was evidence for activation of the RAS-RAF-MEK-extracellular signal-regulated kinases (ERK) pathway, suggesting that similar to other tumors, this pathway may be therapeutically exploitable. Anecdotal responses have been reported in a few patients with LCH and Erdheim-Chester Disease to vemurafenib, a BRAF V600E inhibitor. Although these results pave the way for careful, prospective clinical testing, selection of the optimal groups in which to test such inhibitors, alone or in combination, will be critical based on the toxicity profile thus far observed in adults with melanoma and other BRAF mutated tumors.

scholarly journals Uncommon histiocytic disorders: Rosai–Dorfman, juvenile xanthogranuloma, and Erdheim–Chester disease

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 571-578 ◽  
Author(s):  
Julien Haroche ◽  
Oussama Abla
Keyword(s):  
Braf V600e Mutation ◽  
Braf V600e ◽  
Juvenile Myelomonocytic Leukemia ◽  
Juvenile Xanthogranuloma ◽  
Poor Prognostic Factor ◽  
Erdheim Chester Disease ◽  
Recurrent Mutations ◽  
Life Threatening ◽  
Erdheim Chester ◽  
Chester Disease

Abstract Rosai–Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and Erdheim–Chester disease (ECD) are non-Langerhans cell (non-LCH) disorders arising from either a dendritic or a macrophage cell. RDD is a benign disorder that presents with massive lymphadenopathy, but can have extranodal involvement. In most cases, RDD is self-limited and observation is the standard approach. Treatment is restricted to patients with life-threatening, multiple-relapsing, or autoimmune-associated disease. JXG is a pediatric histiocytosis characterized by xanthomatous skin lesions that usually resolve spontaneously. In a minority of cases, systemic disease can occur and can be life threatening. Juvenile myelomonocytic leukemia (JMML), as well as germline mutations in NF1 and NF2, have been reported in children with JXG. Recent whole-exome sequencing of JXG cases did not show the BRAF-V600E mutation, although 1 patient had PI3KCD mutation. ECD is an adult histiocytosis characterized by symmetrical long bone involvement, cardiovascular infiltration, a hairy kidney, and retroperitoneal fibrosis. Central nervous system involvement is a poor prognostic factor. Interferon-α is the standard as front-line therapy, although cladribine and anakinra can be effective in a few refractory cases. More than one-half of ECD patients carry the BRAF-V600E mutation. Currently, >40 patients worldwide with multisystemic, refractory BRAF-V600E+ ECD have been treated with vemurafenib, a BRAF inhibitor, which was found to be highly effective. Other recurrent mutations of the MAP kinase and PI3K pathways have been described in ECD. These discoveries may redefine ECD, JXG, and LCH as inflammatory myeloid neoplasms, which may lead to new targeted therapies.

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.

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 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.

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