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Erdheim-Chester disease (EC) is a rare disease that is included in Group L in the 2016 revised classification of Langheransian histiocytoses. This disease may be clinically asymptomatic or manifest as a multi-systemic and life-threatening condition. All organs can be affected but typically there is bone involvement, retroperitoneal fibrosis, pituitary involvement, involvement of large vessels, lung, pleura or central nervous system. We are reporting a 70-year-old patient who, as of 2014, had a pelvic mass with retroperitoneal fibrosis and large vessel vasculitis without a definite diagnosis. Histological and molecular examination of the surgical specimen of the pelvic mass with the discovery of the BRAF V600E mutation provided new elements for the definitive diagnosis of Erdheim-Chester disease. We will describe the clinical, histological and molecular features to be known in EC disease.

Langerhans cell histiocytosis (LCH) is a rare multisystemic disease. LCH is characterized by proliferation of myeloid progenitors with altered differentiation program and similar phenotypic features to epidermal dendritic cells termed Langerhans cell. LCH cells express CD1a+ and langerin and exhibit BRAF V600E mutation in ∼50% of cases. Neurological involvement or neuro-LCH is observed in 5 to 10% of cases. Three subtypes of neuro-LCH are individualized. The tumor type, accounting for 45% of neuro-LCH, affect mainly young adults. Tumor neuro-LCH is characterized by space occupying lesion(s) with contrast enhancement on MRI. Clinical symptoms are due to tumor brain location(s). Pathological examination of tumor neuro-LCH lesions reveals typical features of LCH. Treatment relies on surgical resection with/without chemotherapy. Degenerative neuro-LCH, accounting for 45% of cases, is usually revealed, mostly in children, by: (i) a cerebellar syndrome, (ii) a pyramidal syndrome, (iii) a pseubulbar palsy, and/or (iv) cognitive disorders. On MRI, several signs may coexist: (i) cortex atrophy, (ii) white matter T2 hyperintensities, and (iii) deep gray matter T1 hyperintensities. Pathological analysis of degenerative neuro-LCH lesions have been rarely performed and have never detected CD1a+ histiocytes but unspecific lesions (i.e. gliosis, neuronal loss and/or demyelination). Treatment of degenerative neuro-LCH patients is poorly standardized and poorly efficient. Functional rehabilitation and socio-educational care of these young patients are crucial. The mixed subtype of neuro-LCH combines clinico-radio-pathological characteristics of the first two first forms in the same patient, and represents 10% of neuro-HL. Neuro-HL, therefore, includes three very distinct entities with epidemiological, clinical, radiological and histological specific features requiring specific medical management.

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

International audience; Langerhans cell histiocytosis (LCH) is a rare multisystemic disease. LCH is characterized by proliferation of myeloid progenitors with altered differentiation program and similar phenotypic features to epidermal dendritic cells termed Langerhans cell. LCH cells express CD1a+ and langerin and exhibit BRAF V600E mutation in ∼ 50% of cases. Neurological involvement or neuro-LCH is observed in 5 to 10% of cases. Three subtypes of neuro-LCH are individualized. The tumor type, accounting for 45% of neuro-LCH, affect mainly young adults. Tumor neuro-LCH is characterized by space occupying lesion(s) with contrast enhancement on MRI. Clinical symptoms are due to tumor brain location(s). Pathological examination of tumor neuro-LCH lesions reveals typical features of LCH. Treatment relies on surgical resection with/without chemotherapy. Degenerative neuro-LCH, accounting for 45% of cases, is usually revealed, mostly in children, by: (i) a cerebellar syndrome, (ii) a pyramidal syndrome, (iii) a pseubulbar palsy, and/or (iv) cognitive disorders. On MRI, several signs may coexist: (i) cortex atrophy, (ii) white matter T2 hyperintensities, and (iii) deep gray matter T1 hyperintensities. Pathological analysis of degenerative neuro-LCH lesions have been rarely performed and have never detected CD1a+ histiocytes but unspecific lesions (i.e. gliosis, neuronal loss and/or demyelination). Treatment of degenerative neuro-LCH patients is poorly standardized and poorly efficient. Functional rehabilitation and socio-educational care of these young patients are crucial. The mixed subtype of neuro-LCH combines clinico-radio-pathological characteristics of the first two first forms in the same patient, and represents 10% of neuro-HL. Neuro-HL, therefore, includes three very distinct entities with epidemiological, clinical, radiological and histological specific features requiring specific medical management.; L’histiocytose langerhansienne (HL) est une maladie multisystémique rare. L’HL est correspond à une prolifération de cellules myéloïdes progénitrices au programme de différenciation altéré et au phénotype proche de celui des cellules dendritiques épidermiques, les cellules de Langerhans. Les cellules de l’HL sont caractérisées par l’expression de CD1a et de la langerin et par la présence (∼ 50 %) de mutation du gène BRAF. L’atteinte neurologique ou neuro-HL est observée dans 5 à 10 % des cas. Trois formes de neuro-HL sont individualisées. La forme tumorale, représentant 45 % des neuro-HL, touche l’adulte jeune. Elle se caractérise un ou (des processus) expansif(s) intracrânien(s) prenant le contraste à l’IRM. Les manifestations neurologiques sont en rapport avec la (ou les) localisation(s) lésionnelle(s). L’analyse histologique des lésions neurologiques retrouve les caractéristiques de l’HL. Le traitement repose sur la chirurgie et/ou la chimiothérapie. La forme dégénérative, représentant 45 % des cas, se manifeste, principalement chez l’enfant, par un syndrome cérébello-spasmodique, un syndrome pseudobulbaire et/ou des troubles neuropsychologiques. À l’IRM cérébrale, on observe dans la forme complète : (i) une atrophie corticale, (ii) des hypersignaux T2 de la substance blanche et (iii) des hypersignaux T1 de la substance grise profonde. Les analyses histologiques des lésions cérébrales, bien que rares, n’ont jamais mis en évidence d’histiocytes CD1a+ caractéristiques de la maladie mais des lésions aspécifiques de gliose, de perte neuronale, et/ou de démyélinisation. Le traitement est peu codifié et d’efficacité modeste. La rééducation fonctionnelle et la prise en charge socio-éducative, de ces jeunes patients, sont cruciales. La forme mixte combine les caractéristiques clinicoradiopathologiques des deux premières formes chez le même patient, et représente 10 % des neuro-HL. Les neuro-HL regroupent donc trois entités très distinctes sur le plan épidémiologique, clinique, radiologique et histologique nécessitant des prises en charge spécifiques.

During the last decade, new biotherapies have been developed for the treatment of systemic autoimmune diseases. These new approaches are based on a better understanding of the auto-immune response. Targets of these new treatments are the main steps of the immune response. These new treatments include: B lymphocytes inhibitors, inhibitors of the costimulation between antigen-presenting cells and T lymphocytes, T lymphocytes inhibitors, B and T lymphocytes inhibitors, modulators of the cytokine network, complement system inhibitors, and chemokines and integrins inhibitors. Advances in molecular biology, genetics and immunology have accelerated our understanding of auto-immune diseases, and allow identification of new targets. Development of new biotechnological tools with longer half-lives and increased affinity is an important next step. In spite of these exciting new perspectives, a systematic risk/benefit evaluation of these new treatments appears mandatory because immunity plays a key role in the control of infectious and tumor diseases. Further research is also needed to evaluate the cost/effectiveness ratio of these new therapies.

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 (99)Tc 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.