Juvianee Estrada-Veras

Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease

Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis. Recent findings suggest that ECD is a clonal disorder, marked by recurrent BRAFV600E mutations in >50% of patients, in which chronic uncontrolled inflammation is an important mediator of disease pathogenesis. Although ∼500 to 550 cases have been described in the literature to date, increased physician awareness has driven a dramatic increase in ECD diagnoses over the last decade. ECD frequently involves multiple organ systems and has historically lacked effective therapies. Given the protean clinical manifestations and the lack of a consensus-derived approach for the management of ECD, we provide here the first multidisciplinary consensus guidelines for the clinical management of ECD. These recommendations were outlined at the First International Medical Symposium for ECD, comprised of a comprehensive group of international academicians with expertise in the pathophysiology and therapy of ECD. Detailed recommendations on the initial clinical, laboratory, and radiographic assessment of ECD patients are presented in addition to treatment recommendations based on critical appraisal of the literature and clinical experience. These formalized consensus descriptions will hopefully facilitate ongoing and future research efforts in this disorder.

Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms

UNLABELLED Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAF(V600E) mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAF(V600E)-wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAF(V600E)-wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders. SIGNIFICANCE We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders.

The clinical spectrum of Erdheim-Chester disease: an observational cohort study

Erdheim-Chester Disease (ECD) is a rare, potentially fatal, multi-organ myeloid neoplasm occurring mainly in adults. The diagnosis is established by clinical, radiologic, and histologic findings; ECD tumors contain foamy macrophages that are CD68+, CD163+, CD1a-, and frequently S100-. The purpose of this report is to describe the clinical and molecular variability of ECD. Sixty consecutive ECD patients (45 males, 15 females) were prospectively evaluated at the NIH Clinical Center between 2011 and 2015. Comprehensive imaging and laboratory studies were performed, and tissues were examined for BRAF V600E and MAPK pathway mutations. Mean age at first manifestations of ECD was 46 years; a diagnosis was established, on average, 4.2 years after initial presentation. Bone was the most common tissue affected, with osteosclerosis in 95% of patients. Other manifestations observed in one-third to two-thirds of patients include cardiac mass and periaortic involvement, diabetes insipidus, retro-orbital infiltration, retroperitoneal, lung, CNS, skin and xanthelasma, usually in combination. Methods of detection included imaging studies of various modalities. Mutation in BRAF V600E was detected in 51% of 57 biopsies. One patient had an ARAF D228V mutation, and one had an activating ALK fusion. Treatments included interferon alpha, imatinib, anakinra, cladribine, vemurafenib and dabrafenib with trametinib; eleven patients received no therapy. The diagnosis of ECD is elusive because of the rarity and varied presentations of the disorder. Identification of BRAF and other MAPK pathway mutations in biopsies improves ECD diagnosis, allows for development of targeted treatments, and demonstrates that ECD is a neoplastic disorder.

FDG PET images in a patient with Erdheim-Chester disease.

Erdheim-Chester disease is an uncommon non-Langerhans-cell histiocytosis, due to excessive production of histiocytes deposited in various organs and tissues in the human body. FDG PET was performed in a 68-year-old man with documented active Erdheim-Chester disease to evaluate the extent of the disease. The patient was previously treated with high-dose subcutaneous Interferon α2b, 1,000,000 units 3 times a week, but treatment was interrupted approximately 5 weeks before evaluation at the National Institutes of Health because of adverse effects of the medication. FDG PET/CT showed lesions were imaged in brain, heart, mediastinum, abdomen, and skeleton.

Abdominal involvement in Erdheim-Chester disease (ECD): MRI and CT imaging findings and their association with BRAFV600E mutation

ObjectivesTo use magnetic resonance imaging (MRI) and computed tomography (CT) to define abdominal involvement in Erdheim–Chester disease (ECD), and to investigate the association between these findings and the BRAFV600E mutation.MethodsThis prospective study was performed on 61 ECD patients (46 men). The MRI and CT imaging studies were reviewed independently by two experienced radiologists. The association between BRAFV600E mutation and imaging findings was analysed using Fisher’s exact test, and odds ratios with 95% confidence intervals.ResultsPerinephric infiltration was the most common finding (67%), followed by involvement of proximal ureters (61%). In 56% of cases, infiltration extended to the renal sinuses, and in 38% caused hydronephrosis. Adrenal gland infiltration was present in 48% of patients. Infiltration of renal artery (49%) and aorta (43%) were the most common vascular findings, followed by sheathing of celiac, superior mesenteric artery (SMA) or inferior mesenteric artery (IMA) (23%). The BRAFV600E mutation was positive in 53% of patients with interpretable BRAF sequencing. There was a statistically significant association between this mutation and perinephric infiltration (p = 0.003), renal sinus involvement (p < 0.001), infiltration of proximal ureters (p < 0.001), hydronephrosis (p < 0.001), adrenal gland involvement (p < 0.001), periaortic infiltration (p = 0.03), sheathing or stenosis of renal artery (p < 0.001) and sheathing of other aortic branches (p = 0.04).ConclusionsRenal and vascular structures are the most commonly affected abdominal organs in ECD patients. Some of these findings have significant positive association with the BRAFV600E mutation.Key Points• Abdominal imaging plays a crucial role in management of Erdheim–Chester disease.• Significant associations exist between BRAFV600Emutation and several abdominal imaging findings.• Considering several associations, evaluating BRAFV600Emutation status is recommended in ECD patients.

Thoracic involvement in Erdheim-Chester disease: computed tomography imaging findings and their association with the BRAFV600E mutation

ObjectivesTo investigate the computed tomography (CT) thoracic findings in Erdheim-Chester disease (ECD) and evaluate the association of these findings with the BRAFV600E mutation.MethodsThis was a prospective study of patients with ECD (n=61, men=46) who underwent thoracic CT imaging. CT examinations were independently interpreted by two experienced radiologists. Association of imaging findings with BRAFV600E was achieved via the Chi-square or Fisher’s exact test and odds ratios (OR) with 95% confidence intervals (CI), as appropriate.ResultsFifty-five ECD patients (90%) showed pulmonary findings, which included interlobular septal thickening (69%), pulmonary nodules (62%), airway thickening (13%) and ground glass opacities (36%). Pulmonary nodules were classified by the pattern of distribution: subpleural regions (36%), lung parenchyma (13%) and both regions (13%). Pleural and mediastinal involvement were present in 15% and 62% of cases, respectively. The most common mediastinal finding was sheathing of the right coronary artery (34%), followed by sheathing of the thoracic aorta (30%). The BRAFV600E mutation, positive in 31 patients, was associated with the frequency of sheathing of the coronary arteries (p = 0.01).ConclusionsOf the thoracic findings reported in this study, we found a statistically significant positive association between the BRAFV600E mutation and presence of coronary artery sheathing.Key Points• To assess the degree of thoracic involvement in ECD with CT.• BRAFV600Emutation has a high association with right coronary artery sheathing.• BRAFV600Egenetic testing detects patients at high risk of developing RCA sheathing.

Medical genetics and genomic medicine in the Dominican Republic: challenges and opportunities

Medical genetics and genomic medicine in the Dominican Republic: challenges and opportunities.

Clinical and Histopathologic Features of Interstitial Lung Disease in Erdheim–Chester Disease

Limited information is available regarding interstitial lung disease (ILD) in Erdheim–Chester disease (ECD), a rare multisystemic non-Langerhans cell histiocytosis. Sixty-two biopsy-confirmed ECD patients were divided into those with no ILD (19.5%), minimal ILD (32%), mild ILD (29%), and moderate/severe ILD (19.5%), based on computed tomography (CT) findings. Dyspnea affected at least half of the patients with mild or moderate/severe ILD. Diffusion capacity was significantly reduced in ECD patients with minimal ILD. Disease severity was inversely correlated with pulmonary function measurements; no correlation with BRAF V600E mutation status was seen. Reticulations and ground-glass opacities were the predominant findings on CT images. Automated CT scores were significantly higher in patients with moderate/severe ILD, compared to those in other groups. Immunostaining of lung biopsies was consistent with ECD. Histopathology findings included subpleural and septal fibrosis, with areas of interspersed normal lung, diffuse interstitial fibrosis, histiocytes with foamy cytoplasm embedded in fibrosis, lymphoid aggregates, and focal type II alveolar cell hyperplasia. In conclusion, ILD of varying severity may affect a high proportion of ECD patients. Histopathology features of ILD in ECD can mimic interstitial fibrosis patterns observed in idiopathic ILD.

Diabetes insipidus, bone lesions, and new-onset red-brown papules in a 42-year-old man

HistoryA 42-year old Caucasian man was referred to theNationalInstitutes ofHealth(NIH) for evaluation.Hissymptoms began approximately 10 years before re-ferral with pituitary dysfunction that manifested asdiabetes insipidus, secondary hypogonadism, andhyperprolactinemia, treated with desmopressin andtestosterone gel. Eight years later, he began to expe-rience vertigo, dizziness, diplopia, and difficultyfocusingandtracking.Thiswasfollowedbyprogress-ive left-sided weakness, poor coordination, and bal-ancedifficulties.Magneticresonanceimagingwithoutcontrast revealed multiple nonspecific white-matterlesions. Subsequent evaluation failed to identify anunderlyinginfectionorinflammatoryorigin.Systemiccorticosteroid therapy was initiated with minimalimprovement. Corticosteroids were tapered off 2monthslaterandthepatientnotednewasymptomaticskin lesions on his bilateral upper and lower extrem-ities, leading to reinitiation of systemic steroids andintroduction of interferon alfa. He denied fevers,chills, weight loss, or difficulty breathing.Physical examinationThe patient was a well-appearing Caucasian man.Cutaneous examination was notable for approxi-mately twenty 2- to 3-mm, firm, reddish-brown pap-ules scattered on the trunk and extremities, withgreater density on the front of his thighs (Fig 1).Diascopy revealed a yellowishhue. Ophthalmologicexamination was notable for nystagmus, saccadicpursuit,andmilddysmetria.Neurologicexaminationrevealed unsteady tandem gait, abnormal finger-to-nose pointing, and left-sided dysdiadochokinesia.Left arm strength was diminished (4/5). The oralmucosa was unremarkable. No lymphadenopathywas appreciated.HistopathologyA punch skin biopsy specimen of a papule on theleft thigh was obtained, and histology revealed amoderately dense dermal infiltrate of epithelioidhistiocytes characterized by rounded to slightlyelongated nuclei with inconspicuous nucleoli andmoderatetoabundanteosinophiliccytoplasm(Fig2,A). CD68 and CD163 immunochemistry highlightedthe lesional histiocytes (Fig 2, B). Lesional cells alsoshowedstrong,diffusestainingforfactorXIIIa(Fig2,C). CD1a and S100 immunostains were negative.Significant diagnostic studiesRadiographs of the upper and lower extremitiesrevealed sclerotic lesions involving the metaphyseal