Maladie d'Erdheim-Chester

doi:10.1016/j.lpm.2007.04.032

La Presse Médicale

Volume 36, Issue 11, Part 2, November 2007, Pages 1663-1668

https://doi.org/10.1016/j.lpm.2007.04.032 Get rights and content

Key points

Erdheim-Chester disease is a non-Langerhans cell histiocytosis, classically thought to be rare, but diagnosed more frequently nowadays (250 published cases).

Histiocytes of Erdheim-Chester disease are positive for CD68 but not for CD1a, contrary to Langerhans cell histiocytosis.

Two signs highly evocative of this diagnosis are nearly constant tracer uptake by the long bones on ⁹⁹Tc bone scintigraphy and a “hairy kidney” appearance on abdominal CT scan.

A more “elegant” diagnostic method is ultrasound-guided biopsy of the perirenal infiltration.

Cardiovascular involvement, which affects the aorta (“coated aorta”) as well as all the cardiac layers, leads to one third of the deaths related to this disease.

Central nervous system infiltration (especially cerebellar) is severe and difficult to treat.

The prognosis is extremely variable and is often worse when there is a cardiovascular and/or central nervous system involvement.

The treatment, decided upon on a case-by-case basis at a specialist center, often begins with interferon alpha.

Points essentiels

La maladie d'Erdheim-Chester est une histiocytose non langerhansienne, classiquement rare, mais plus fréquemment diagnostiquée aujourd'hui (250 cas publiés).

Les histiocytes de la maladie d'Erdheim-Chester marquent le CD68 mais pas le CD1a, contrairement à ceux de l'histiocytose langerhansienne.

Deux signes hautement évocateurs du diagnostic sont l'hyperfixation des os longs sur la scintigraphie osseuse au ⁹⁹Tc (quasiment constante) et l'aspect de “rein chevelu” sur la tomodensitométrie abdominale.

Une méthode diagnostique “élégante” de la maladie est la biopsie échoguidée de l'infiltration périrénale.

L'atteinte cardiovasculaire, qui touche aussi bien l'aorte (“manchon périaortique”) que l'ensemble des tuniques cardiaques, est à l'origine d'un tiers des décès.

L'atteinte neurologique centrale (notamment cérébelleuse) est sévère et difficile à traiter.

Le pronostic, extrêmement variable d'une forme à l'autre, est souvent péjoratif en présence d'une atteinte cardiovasculaire et/ou neurologique centrale.

Le traitement, discuté au cas par cas en centre spécialisé, fait souvent appel en première intention à l'interféron alpha.

Section snippets

Diagnostic positif

Le diagnostic de maladie d'Erdheim-Chester est fondé sur l'association de critères anatomopathologiques et radiologiques évocateurs. Ceux-ci ont été retenus pour les 2 grandes séries publiées par notre équipe, et s'appliquent aussi à nos observations ultérieures :

•
une histologie typique (figure 1) comportant la présence d'histiocytes spumeux au sein d'un granulome polymorphe et d'une fibrose ou une image de xanthogranulome avec un marquage constant des histiocytes par le CD68 alors que le CD1a

Manifestations cliniques

Notre expérience personnelle repose actuellement sur l'analyse de 24 observations de maladie d'Erdheim-Chester suivies dans le service de médecine interne de la Pitié-Salpêtrière entre 1992 et 2006.

La maladie d'Erdheim-Chester se caractérise par des manifestations systémiques très hétérogènes. La symptomatologie révélatrice est très variable d'un patient à l'autre, qu'il s'agisse de douleurs osseuses, d'un diabète insipide, d'une exophtalmie, de xanthélasmas, ou encore de signes neurologiques

Marqueurs biologiques

Un syndrome inflammatoire biologique est présent chez 84 % des patients. Il n'y a pas de marqueur biologique spécifique de la maladie d'Erdheim-Chester.

Diagnostics différentiels

Les histiocytes de l'histiocytose langerhansienne marquent le CD1a et sont CD68-, ce qui permet aisément de les différentier des cellules de la maladie d'Erdheim-Chester. Même si certaines atteintes sont communes aux 2 maladies (diabète insipide, pneumopathie interstitielle), les aspects clinique et radiologique permettent souvent de distinguer ces 2 affections. Rappelons que le squelette axial et la mandibule sont classiquement respectés dans la maladie d'Erdheim-Chester.

L'infiltration

Traitement

Le traitement de la maladie d'Erdheim-Chester, mal codifié, doit être discuté au cas par cas dans un centre spécialisé.

De nombreux traitements ont été proposés comprenant les corticoïdes, diverses chimiothérapies, les biphosphonates et la radiothérapie. L'évaluation de l'efficacité de ces thérapeutiques était néanmoins rendue souvent difficile par leur association, le petit nombre de patients traités (1 ou 2), et/ou le faible recul disponible. Dans notre expérience, la maladie d'Erdheim-Chester

Pronostic

Le pronostic de la maladie d'Erdheim-Chester est extrêmement variable d'une forme à l'autre. Il dépend largement de la présence d'une atteinte cardiovasculaire et/ou neurologique centrale. Parmi les 24 patients suivis dans le service, 4 sont décédés après un suivi compris entre 1 et 4,6 ans après le diagnostic, 2 décès résultant de l'atteinte cardiovasculaire spécifique. Cette mortalité, très inférieure à celle rapportée dans la littérature 1, 2, traduit probablement l'amélioration récente de

Conclusion

Depuis quelques années, le diagnostic de maladie d'Erdheim-Chester est plus souvent porté grâce à une meilleure connaissance de la maladie par les anatomopathologistes, les radiologues et les internistes. Environ 200 nouveaux cas ont ainsi été rapportés depuis 10 ans. Le cadre des fibroses rétropéritonéales et médiastinales dites idiopathiques doit certainement être révisé pour en exclure certaines formes de la maladie d'Erdheim-Chester. Un avis en centre spécialisé est justifié tant pour

Références (20)

F. Braiteh et al.
Successful treatment of Erdheim-Chester disease, a non-Langerhans cell histiocytosis, with Interferon-alpha
Blood
(2005)
P. Ammann et al.
Cardiac tumor due to Erdheim-Chester disease
Am J Med
(2001)
E.J. Yun et al.
Erdheim-Chester disease: case report and review of associated urological, radiological and histological features
J Urol
(2003)
C. Veyssier-Belot et al.
Erdheim-Chester disease. Clinical and radiologic characteristics of 59 cases
Medicine (Baltimore)
(1996)
J. Haroche et al.
Cardiovascular involvement, an overlooked feature of Erdheim-Chester disease: report of 6 new cases and a literature review
Medicine (Baltimore)
(2004)
J. Wechsler et al.
Erdheim-Chester disease: a form of xanthogranulomatosis
Ann Dermatol Venereol
(1989)
W. Chester
Über lipoidgranulomatose
Virchows Arch Pathol Anat.
(1930)
M. Bisceglia et al.
Erdheim-Chester disease: clinical and pathologic spectrum of four cases from the Arkadi M. Rywlin slide seminars
Adv Anat Pathol
(2003)
E. Dion et al.
Bone involvement in Erdheim-Chester disease: imaging findings including periostitis and partial epiphyseal involvement
Radiology
(2006)
J. Serratrice et al.
“Coated aorta”: a new sign of Erdheim-Chester disease
J Rheumatol
(2000)

There are more references available in the full text version of this article.

Cited by (53)

Successful treatment of non-Langerhans cell histiocytosis with the MEK inhibitor trametinib: a multicenter analysis
2023, Blood Advances
Erdheim-Chester disease (ECD) and Rosai-Dorfman disease (RDD) are rare non-Langerhans cell histiocytoses (non-LCHs), for which therapeutic options are limited. MAPK pathway activation through BRAFV600E mutation or other genomic alterations is a histiocytosis hallmark and correlates with a favorable response to BRAF inhibitors and the MEK inhibitor cobimetinib. However, there has been no systematic evaluation of alternative MEK inhibitors. To assess the efficacy and safety of the MEK inhibitor trametinib, we retrospectively analyzed the outcomes of 26 adult patients (17 with ECD, 5 with ECD/RDD, 3 with RDD, and 1 with ECD/LCH) treated with orally administered trametinib at 4 major US care centers. The most common treatment-related toxicity was rash (27% of patients). In most patients, the disease was effectively managed at low doses (0.5-1.0 mg trametinib daily). The response rate of the 17 evaluable patients was 71% (73% [8/11] without a detectable BRAFV600E achieving response). At a median follow-up of 23 months, treatment effects were durable, with a median time-to-treatment failure of 37 months, whereas the median progression-free and overall survival were not reached (at 3 years, 90.1% of patients were alive). Most patients harbored mutations in BRAF (either classic BRAF^V600E or other BRAF alterations) or alterations in other genes involved in the MAPK pathway, eg, MAP2K, NF1, GNAS, or RAS. Most patients required lower than standard doses of trametinib but were responsive to lower doses. Our data suggest that the MEK inhibitor trametinib is an effective treatment for ECD and RDD, including those without the BRAFV600E mutation.
A rare case of Erdheim-chester disease reported from Nepal
2022, Annals of Medicine and Surgery
Erdheim-Chester Disease (ECD) is a rare non-Langerhans cell histiocytosis with a propensity to involve multiple organs.
We report a case of a patient in mid-60s with occipital headache and ataxia. Following the radiological and immunohistochemical investigations and genomic studies, a diagnosis of ECD was made with two intracerebral lesions. Brain lesions were resected and the patient was discharged with the medication Vemurafenib. After 3 years of diagnosis and 13 years of initial presentation, patient passed away.
ECD frequently presents with Diabetes Insipidus as initial presentation, long bone osteosclerosis as the most common presentation, and has multi-system predisposition. ECD can be differentiated from Langerhans Cell Histiocytosis (LCH) with immunohistochemistry images of the biopsy specimens. Further, with genomic analysis of ECD, the neoplastic nature has been highlighted and targeted therapies like Vemurafenib and Cobimetinib are shown to be effective.
Good clinical judgement and supporting investigations can aid in diagnosing rare entities like ECD even in resource-limited settings.
Erdheim–Chester disease
2020, Best Practice and Research: Clinical Rheumatology
Erdheim–Chester disease (ECD) is a rare but increasingly recognized multi-system disorder. Its diagnosis and treatment require integration of clinical information, imaging studies, and pathology studies. Of note, ECD can now be defined as a clonal myeloid disorder due to mutations which activate mitogen-activated protein kinase (MAPK) pathways and where an inflammatory milieu is important in the pathogenesis and clinical manifestations of the disease. Biopsy demonstrating characteristic histopathologic features in addition to clinical and radiographic features, most often sclerosing long bone involvement, is required to establish a diagnosis. Detection of somatic MAPK pathway mutations can also assist in the differential diagnosis of ECD and related histiocytic neoplasms. Also, genetic analysis establishing BRAF and RAS mutational status is critical in all ECD patients, as these features will impact therapy with MAPK inhibition. Therapy is recommended at diagnosis in all patients, except for those patients with minimally symptomatic disease. Prospective therapeutic trials are essential to furthering therapeutic progress in ECD.
Erdheim-Chester disease: Consensus recommendations for evaluation, diagnosis, and treatment in the molecular era
2020, Blood
Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600–mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.
Erdheim-chester disease
2020, Blood
Citation Excerpt :
Childhood ECD is rare (<20 reported cases)17 and usually spares the heart. In 2006, a preliminary study reported a time between symptom onset and diagnosis of between several months and 25 years.18 The time to diagnosis has since decreased, undoubtedly because of greater awareness of the disease.
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 BRAF^V600E 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.
Erdheim-Chester disease (ECD), an inflammatory myeloid neoplasia
2017, Presse Medicale
Dans un contexte clinique évocateur, le diagnostic de maladie d’Erdheim-Chester (MEC) repose sur l’analyse des histiocytes tissulaires : ils sont volontiers spumeux, CD68+ CD1a–, alors que dans l’histiocytose langerhansienne (HL), l’immunomarquage est CD68+ CD1a+. Les formes de chevauchement sont fréquentes. La fixation intense des os longs sur la scintigraphie osseuse au ⁹⁹Tc est très évocatrice de MEC ; l’aspect de « reins chevelus » est retrouvé dans plus de la moitié des cas sur le scanner abdominal. L’atteinte du système nerveux central dans la MEC est un facteur pronostique indépendant prédictif de mortalité. Le traitement de première intention de la MEC est l’interféron α (et/ou l’interféron α pégylé), dont l’administration prolongée augmente significativement la survie ; sa tolérance est cependant médiocre. L’anakinra, l’infliximab et le sirolimus ont une efficacité possible, et sont principalement efficaces pour des formes modérées de la maladie. La MEC est associée à une réaction systémique inflammatoire, intéressant principalement les voies de l’IFNα, IL-1/IL1-RA, IL-6, IL-12, et MCP-1, en rapport avec une réponse immunitaire de type Th1. Cinquante-sept à 75 % des patients avec une MEC sont porteurs de la mutation BRAF^V600E, une mutation activatrice du proto-oncogène BRAF. Une cinquantaine de patients ayant une atteinte réfractaire et multisystémique de MEC (parfois associée à une HL), mutés BRAF^V600E, ont été traité avec succès par le vemurafenib, un inhibiteur de BRAF. D’autres mutations fréquentes de la voie des MAP kinases (NRAS, MAP2K1) et de PIK3CA ont été identifiées chez des patients ayant une MEC. Des mutations récurrentes de la voie des MAP kinases étant fréquemment retrouvées dans la MEC et l’HL, nous pensons que ces deux pathologies pourraient être « reclassifiées » comme des néoplasies myéloïdes inflammatoires.
In a compatible clinico-radiological setting, the diagnosis of Erdheim-Chester disease (ECD) involves the analysis of histiocytes in tissue biopsies: they are typically foamy and CD68+ CD1a, whereas in Langerhans cell histiocytosis (LCH) they are CD68+ CD1a+. Overlap forms of histiocytoses are frequent. Technetium bone scintigraphy showing nearly constant tracer uptake by the long bones is highly suggestive of ECD and a ‘hairy kidney’ appearance on abdominal CT scan is observed in more than half ECD cases. CNS involvement is a strong prognostic factor and an independent predictor of death in cases of ECD. Optimal initial therapy for ECD appears to be administration of IFN-α (and/or pegylated IFN-α) and prolonged treatment significantly improves survival; however, tolerance may be poor. Best alternative therapies are anakinra, mainly effective for mild forms of the disease, infliximab, and sirolimus. Cases of ECD present with strong systemic immune activation, involving IFN-α, IL-1/IL1-RA, IL-6, IL-12, and MCP-1, consistent with the systemic immune Th-1-oriented disturbance associated with the disease. Between 57 and 75 % of ECD patients carry the BRAF^V600E mutation, an activating mutation of the proto-oncogene BRAF. More than 50 cases harboring BRAF mutation and with severe multisystemic and refractory ECD (sometimes associated with LCH) have been treated worldwide with vemurafenib, a BRAF inhibitor that proved to be very beneficial. Other recurrent mutations of the MAPK (NRAS, MAP2K1) and PIK3 pathways (PIK3CA) have been found among ECD patients. As recurrent mutations in the MAPK pathway are found in ECD and LCH on a background of chronic inflammation, we believe that both conditions should be redefined as an inflammatory myeloid neoplasia.

View all citing articles on Scopus

View full text

Mise au pointMaladie d'Erdheim-ChesterErdheim-Chester disease

Key points

Points essentiels

Section snippets

Diagnostic positif

Manifestations cliniques

Marqueurs biologiques

Diagnostics différentiels

Traitement

Pronostic

Conclusion

Blood

Am J Med

J Urol

Erdheim-Chester disease. Clinical and radiologic characteristics of 59 cases

Medicine (Baltimore)

Cardiovascular involvement, an overlooked feature of Erdheim-Chester disease: report of 6 new cases and a literature review

Medicine (Baltimore)

Erdheim-Chester disease: a form of xanthogranulomatosis

Ann Dermatol Venereol

Über lipoidgranulomatose

Virchows Arch Pathol Anat.

Erdheim-Chester disease: clinical and pathologic spectrum of four cases from the Arkadi M. Rywlin slide seminars

Adv Anat Pathol

Bone involvement in Erdheim-Chester disease: imaging findings including periostitis and partial epiphyseal involvement

Radiology

“Coated aorta”: a new sign of Erdheim-Chester disease

J Rheumatol

Mise au point
Maladie d'Erdheim-ChesterErdheim-Chester disease