Correlation of BRAF V600E mutation with cardiac involvement assessed by heart imaging in a monocentric series of 205 patients with Erdheim-Chester disease.

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7019 Background: Erdheim–Chester disease (ECD), an inflammatory myeloid neoplasm, is an histiocytosis associated with multisystem infiltration. Cardiovascular involvement in ECD is under-diagnosed and associated with poor outcome. The targetable BRAF V600E mutation is present in up to 70% of all ECD. Methods: Retrospective study of 205 patients (pts) with ECD who had cardiac imaging (195 MRI, 10 CT when MRI was contraindicated). We identified the types of lesions (infiltration, tumor, and effusion), localization (pericardial, myocardial, valvular) and consequences on cardiac function (coronary stenosis, atrial wall dyskinesia, diastolic and systolic functions). Results: 141 (68.8%) pts were male. 30 (14.6%) had mixed histiocytosis (mainly ECD + langerhans cell histiocytosis). BRAF mutation ( BRAFm) was found in 112 (54.6%) cases, while 59 pts (28.8%) were Wild Type (WT) and 34 pts (7.6%) had unknown BRAF status. Among the 205 cardiac imaging, 101 (49.3%) were abnormal. Cardiac involvement was found in 93 pts (49%). Among these, 72 had an impairment of the right ventricular atrioventricular sulcus (74%), 65 of the right atrium (RA) enclosure (69%). Alteration of Tricuspid Annular Plane Systolic Excursion was found in 15% and correlated with the size of the tumor. Pericardial involvement (effusion, thickening or contrast enhancement) was found in 59 pts (29%). Among BRAFm pts, 75 (67%) had a heart abnormality while 37 (33%) had normal imaging; Among WT pts 14 (23.7%) showed heart abnormality, whereas 45 (76.3%) had normal imaging (RR 2.8 (CI: 1.8-4.5); p = 1.8*10 ⁻⁷ ). A RA tumor was present in 51 (45.5%) BRAFm but only 6 (10.2%) WT pts respectively (RR 4.5 (CI : 2.0-9.8); p = 7*10 ⁻⁶ ). BRAFm was also associated with aortic infiltration (RR 1.76 (CI: 1.2–2.5)) and pericardial involvement (RR 2.12 (CI: 1.1–3.9), p = 0.0017). Conclusions: Cardiac infiltration is frequent in ECD (49.3%), especially RA tumor. BRAFm is associated with RA, aortic and pericardial involvements.

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... Patients with ECD with the BRAF mutation are more likely to have right atrial pseudotumors, cardiac and aortic infiltrations, and pericardial and central nervous system (CNS) involvement. [24][25][26] The proliferation rate as judged by Ki67 staining is low. It is not surprising that a subset of patients have both LCH and ECD, with ECD following or coincident with the LCH diagnosis, given the common origin of these myeloid dendritic cell disorders. ...
Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are caused by mutations of the MAPK pathway, most often BRAFV600E, in myeloid dendritic cells that lead to some overlapping and other unique presentations of the two diseases. LCH occurs in both children and adults, but ECD is primarily found in the latter. The challenges in diagnosing these conditions relates to the rarity of the conditions and that they mimic diseases that are more widely understood, such as certain rashes; bone, lung, and renal diseases; and other malignancies. The histopathology of LCH is definitive, but not so for ECD. Treatment with BRAF and MEK inhibitors has become one of the important advances in the care of these patients.
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 ECD patients, mainly the BRAFV600E activating mutation in 57-70% 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 ECD patients, 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 the CT-scan (63%), the "coated aorta" (40%), the right atrium pseudo-tumoral infiltration (36%). Central nervous system (CNS) involvement is a strong prognostic factor and independent predictor of death. Interferon-alpha seems to be the best initial treatment for ECD. Since 2012, more than 200 patients worldwide with multi-system 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 side-effects and as yet unknown long-term consequences.
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