Skull Base Manifestations of Erdheim-Chester Disease: A Case Series and Systematic Review

AbstractBACKGROUNDErdheim-Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis. Up to 50% of patients develop central nervous system involvement, and a subset of these patients can present with isolated tumor-like masses.OBJECTIVETo describe the skull base manifestations of ECD with an emphasis on aspects most pertinent to surgeons who may be referred such patients for primary evaluation.METHODSScopus, Web of Science, and PubMed were searched from database inception to May 1, 2018 for articles reporting skull base ECD. An institutional retrospective analysis of all patients treated at the authors’ institution since January 1, 1996 was also performed to supplement these data.RESULTSOf 465 retrieved articles, 18 studies totaling 20 patients met inclusion criteria. Institutional review identified an additional 7 patients. Collectively, the median age at diagnosis was 49 yr (interquartile range, 42-58) with a 4:1 male-to-female ratio. Patients frequently presented with diplopia (48%), headache (30%), dysarthria (22%), and vertigo or imbalance (22%), though trigeminal hypesthesia (11%), facial nerve paresis (7%), hearing loss (7%), and trigeminal neuralgia (7%) were also observed. ECD commonly mimicked meningioma (33%), trigeminal schwannoma (8%), neurosarcoidosis (8%), and skull base lymphoma (8%).CONCLUSIONDiscrete skull base lesions frequently mimic more common pathology such as meningioma or cranial nerve schwannomas. Medical therapy comprises the initial treatment for symptomatic skull base disease. Surgical resection is not curative and the utility of surgical intervention is largely limited to biopsy to establish diagnosis and/or surgical debulking to relieve mass effect.

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Erdheim-Chester disease mimicking an intracranial trigeminal schwannoma: case report

Journal of Neurosurgery Pediatrics ◽

10.3171/2014.10.peds14441 ◽

2015 ◽

Vol 15 (5) ◽

pp. 493-498 ◽

Cited By ~ 11

Author(s):

Maysam Alimohamadi ◽

Christian Hartmann ◽

Vincenzo Paterno ◽

Madjid Samii

Keyword(s):

Central Nervous System Involvement ◽

Multiple Organ ◽

Imaging Features ◽

Aged Patients ◽

Trigeminal Schwannoma ◽

Erdheim Chester Disease ◽

Meningeal Involvement ◽

Organ Systems ◽

Erdheim Chester ◽

Chester Disease

Erdheim-Chester disease (ECD) is non-Langerhans histiocytosis that can affect multiple organ systems. It usually affects middle-aged patients, and only a few reports of ECD in children appear in the literature. Central nervous system involvement is a common feature that usually occurs as infiltration of the hypothalamus-pituitary axis, cerebellum, and/or brainstem. Meningeal involvement occurs less commonly. In this article, the authors discuss a rare pediatric case of ECD presenting as an infiltrative mass of the trigeminal nerve and resembling the clinical and imaging features of a trigeminal schwannoma.

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Skull Base Manifestations of Erdheim-Chester Disease: A Case Series and Systematic Review

10.1055/s-0039-1679640 ◽

2019 ◽

Author(s):

P. Peters ◽

J. Marinelli ◽

A. Vaglio ◽

J. Van Gompel ◽

J. Lane ◽

...

Keyword(s):

Systematic Review ◽

Skull Base ◽

Case Series ◽

Erdheim Chester Disease ◽

Erdheim Chester ◽

Chester Disease

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Central nervous system involvement in Erdheim-Chester disease

Neurology ◽

10.1212/wnl.0000000000010748 ◽

2020 ◽

Vol 95 (20) ◽

pp. e2746-e2754 ◽

Cited By ~ 1

Author(s):

Fleur Cohen Aubart ◽

Ahmed Idbaih ◽

Damien Galanaud ◽

Bruno Law-Ye ◽

Jean-François Emile ◽

...

Keyword(s):

Targeted Therapy ◽

Central Nervous System Involvement ◽

Class Iii ◽

Cns Involvement ◽

Erdheim Chester Disease ◽

Younger Age ◽

Spine Mri ◽

Erdheim Chester ◽

Chester Disease

ObjectiveCNS involvement in Erdheim-Chester disease (ECD) leads to substantial morbidity and mortality. To assess CNS manifestations in a French cohort of 253 patients with ECD, we determined clinical characteristics and outcomes, including those under targeted therapies.MethodsThis was a retrospective longitudinal study. CNS manifestations were determined by clinical examination and brain or spine MRI. Targeted therapy efficacy was assessed using global assessment from a physician and a radiologist. The study was approved by the ethics committee Comité de Protection des Personnes Ile de France III.ResultsNinety-seven of 253 patients (38%) with ECD had CNS involvement. CNS involvement was significantly associated with a younger age at diagnosis (mean 55.5 years) and at symptom onset (mean 50.5 years), as well as 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 that of patients with ECD without CNS involvement (124 months vs 146 months, p = 0.03). Seventy-four CNS MRIs were centrally reviewed, which showed 3 patterns: tumoral in 66%, pseudo-degenerative in 50%, and vascular in 18%. Targeted therapy (BRAF or MEK inhibitors) was associated with improved symptoms in 43% of patients and MRI improvement in 45%.ConclusionsCNS manifestations are typically associated with poor prognosis in patients with ECD. Three distinct patterns can be recognized: tumoral, pseudodegenerative, and vascular.Classification of evidenceThis study provides Class III evidence that targeted therapy leads to clinical or imaging improvement in almost 50% of patients.

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AB0982 Analysis of the treatment efficacy for retroperitoneal fibrosis - a case series. suspicion of erdheim-chester disease in a patient with an initial diagnosis of retroperitoneal fibrosis, refractory to standard treatment

10.1136/annrheumdis-2017-eular.5960 ◽

2017 ◽

Author(s):

J Koblowski ◽

A Juszkiewicz ◽

M Kania-Pudło ◽

W Tlustochowicz

Keyword(s):

Treatment Efficacy ◽

Standard Treatment ◽

Retroperitoneal Fibrosis ◽

Case Series ◽

Initial Diagnosis ◽

Erdheim Chester Disease ◽

Erdheim Chester ◽

Chester Disease

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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

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0811-6 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 8

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.

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Intracranial mass lesions and skin discoloration in the armpits as unusual clues to Erdheim-Chester disease: a case report

BMC Neurology ◽

10.1186/s12883-021-02107-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Pedro Gustavo Barros Rodrigues ◽

Isabelle de Sousa Pereira ◽

Valter Barbalho Lima Filho ◽

Daniel Aguiar Dias ◽

Paulo Ribeiro Nóbrega ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Central Nervous System Involvement ◽

Skin Lesions ◽

Neurological Signs ◽

Intracranial Mass ◽

Erdheim Chester Disease ◽

Mass Lesions ◽

Erdheim Chester ◽

Chester Disease

Abstract Background Erdheim–Chester disease (ECD) is a non-Langerhans histiocytosis that results in multi-organ disease involving the skin, bones, lungs and kidneys. Central nervous system (CNS) involvement occurs in about 50 % of patients, and diabetes insipidus, visual disturbances, and cerebellar ataxia are the most frequent neurological signs. We report a case of Erdheim-Chester disease with central nervous system involvement in the form of enhancing intracranial mass lesions with massive edema. Case presentation The patient presented with vertigo, ataxia, encephalopathy and pyramidal signs. Diagnosis was suggested by xanthomatous skin lesions and a biopsy was compatible with Erdheim-Chester disease demonstrating xanthogranulomas CD68 positive (clone KP1) and CD1a and S100 negative. Testing for BRAF mutation was negative, which precluded treatment with Vemurafenib. Treatment with steroids and interferon resulted in improvement of neurological signs and regression of edema on MRI. Conclusions The diagnosis of Erdheim-Chester disease should be considered in intracranial mass lesions. Xanthomatous skin lesions are a clue to the diagnosis.

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

Blood ◽

10.1182/blood-2019-130606 ◽

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

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Erdheim-Chester disease

Blood ◽

10.1182/blood.2019002766 ◽

2020 ◽

Vol 135 (16) ◽

pp. 1311-1318 ◽

Cited By ~ 6

Author(s):

Julien Haroche ◽

Fleur Cohen-Aubart ◽

Zahir Amoura

Keyword(s):

Mapk Pathway ◽

Myeloproliferative Neoplasms ◽

Acquired Resistance ◽

Central Nervous System Involvement ◽

Long Bone ◽

Interferon Α ◽

Braf Mutations ◽

Erdheim Chester Disease ◽

Erdheim Chester ◽

Chester Disease

Abstract 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.

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P25 Erdheim-Chester disease: a rare histocytosis masked as IgG4 disease

Rheumatology ◽

10.1093/rheumatology/keaa111.024 ◽

2020 ◽

Vol 59 (Supplement_2) ◽

Author(s):

Dhivya Das ◽

Sharon Jones

Keyword(s):

Bone Pain ◽

Retroperitoneal Fibrosis ◽

Female Ratio ◽

Ifn Alpha ◽

Erdheim Chester Disease ◽

Cranial Nerve Palsies ◽

Xanthogranulomatous Inflammation ◽

History Of ◽

Erdheim Chester ◽

Chester Disease

Abstract Background Erdheim-Chester disease (ECD) is a rare non-inherited, non-Langerhans form histiocytosis reclassified as a histiocytic neoplasm was first described in 1930 by Jakob Erdheim and William Chester. Only 500 cases were reported. Onset is usually between 50 to 70 years old. Male to female ratio is 3:1. Symptoms include long bone pain, fever, weight loss, exophthalmos, papilledema, headaches, cranial nerve palsies and sensory disturbances. Skeletal Abnormalities includes bilateral and symmetric cortical osteosclerosis of long bones. Cardiovascular involvement includes a ‘coated aorta’ which can involve renal arteries leading to reno-vascular hypertension. Pulmonary and retroperitoneal fibrosis has been reported. Methods We present a 90 year old gentleman with a complicated history of diplopia, proptosis with large retrobulbar orbital masses (confirmed on CT orbits) increasing in size over 2 years. He was symptomatic with bone pain, recurrent falls, dizziness and shortness of breath. He had a background history of pulmonary embolism, atrial fibrillation, hypertension and osteoporosis. On examination, no joint synovitis or lymphadenopathy noted. Chest examination revealed mild inspiratory crackles. Results CRP was recorded at 150mg/L. ANA, ENA, ANCA, anti-DsDNA, RF, anti-MCV antibodies were negative. IgG4 levels were normal. Pulmonary Function tests showed a restrictive Pattern - FEV1/FVC - 64%, FVC - 68%, TLC - 75%, TLCO - 68% predicted. CT Chest reported aortitis and mild undifferentiated pulmonary fibrosis. CT aorta done subsequently reported extensive soft tissue changes of the abdominal and thoracic Aorta which extended to the renal hila causing bilateral hydronephrosis. There was confirmed retroperitoneal Fibrosis and widespread para-aortic lymphadenopathy. He was stented by the urologists for hydronephrosis. Orbital biopsy of his left eye revealed xanthogranulomatous inflammation with widespread foamy histiocytes (CD68 positive). S100 and CD1a were negative. This confirms a clinical correlation of ECD. Further multidisciplinary discussions suggested that he stays on high dose prednisolone of 30mg daily. Localised radiotherapy was successful in debulking his orbital lesions. Chemotherapy was discussed but he does not wish for this. Conclusion Differential diagnoses for ECD include IgG4 disease, Granulomatosis with polyangiitis, Takayasu’s arteritis, Langherhan Cell histiocytosis, or malignancies. Tissue diagnosis describes infiltration of foamy histiocytes, lymphocytes and lipid laden macrophages. It is distinguished by immunohistological characteristics (ECD positive for CD68, negative for CD1a and S-100 protein) in 80 percent of cases. Serum Assay Samples can show high IFN-alpha, IL1, IL-6 and IL-12 titres. First line treatment is pegylated IFN-alpha. Bisphosphonates can alleviate bone pain. Cladribine has helped those with orbital involvement. Anakinra or Inflixamab improves symptoms of mild forms of ECD. Vemurafenib is used for patients with the BRAFV600 proto-oncogene mutation. PET scans are recommended for disease activity assessment. ECD has a variable prognosis but poorer in those with CNS involvement. With treatment, the mortality rate is 26% and 5-year survival is 68%. Disclosures D. Das None. S. Jones None.

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