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      Diverse cutaneous manifestations of Erdheim-Chester disease in a woman with a history of Langerhans cell histiocytosis

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          Abstract

          Introduction Erdheim-Chester disease (ECD) is a rare, systemic, non–Langerhans cell histiocytosis (non-LCH). Diagnosis is based on a combination of specific radiologic, histologic, and clinical findings. Although there have been hundreds of prior reports of ECD, very few cases have described the spectrum of potential cutaneous manifestations.1, 2, 3, 4 Most of these cases describe ECD skin findings as xanthelasmalike lesions surrounding the periorbital area,1, 2 whereas 2 patients were reported to have a red-brown papular eruption affecting the chest and lower extremities.3, 4 We discuss a case of a 45-year-old woman with an extensive childhood history of LCH who then presented more than 20 years later with a new eruption of polymorphous skin lesions distributed over the face, trunk, arms, and legs. These lesions were clinically varied yet histologically all consistent with xanthogranulomas. Upon further workup, the patient was found to have specific radiographic findings pathognomonic for ECD and a BRAF V600E mutation, which has been reported in both LCH and ECD. Our case is unique, in that this patient was affected by both diseases within her lifetime. Identification of the BRAF V600E mutation suggests the possibility of a common origin between LCH and ECD. Case report A 45-year-old woman presented with complaints of a new widespread eruption across her face, arms, and legs. The patient described an occasionally pruritic, nonpainful, papular rash that would erupt sporadically without a known trigger and resolve to leave hyperpigmented macules. A review of systems was noncontributory, including no episodes of fever, chills, night sweats, or weight loss. The patient's medical history was significant for childhood LCH that manifested as eosinophilic granuloma of the cranium, treated at age 3 with surgery, radiation, and vincristine. She also had recurrent disease treated with prednisone and methotrexate between the ages of 9 and 24. The patient had no other chronic medical problems, no allergies, and no relevant family history and was not taking any medications. On physical examination, erythema was noted on her face, arms, chest, and back. Upon closer inspection, the erythema was composed of numerous, pinpoint, pink-to-red papules (Fig 1). In addition, examination found yellow papules coalescing into thin plaques along her bilateral temples and periorbital regions (Fig 1) and scattered 2- to 4-mm red brown papules across her arms and legs. Biopsies performed on the arm, leg, and face, found foamy cells and multinucleated cells in the dermis without 2-toned cytoplasm. Immunohistochemistry found positive CD68 and negative CD1a and S-100 staining, consistent with non-LCH histiocytosis (Fig 2). The patient was subsequently referred to the hematology department for further evaluation of an underlying hematologic malignancy given the xanthogranulomas on histology, but findings from a thorough workup (a complete blood count, comprehensive metabolic panel, lactate dehydrogenase, peripheral blood flow cytometry, serum protein electrophoresis, serum immunofixation electrophoresis, β-2 microglobulin, quantitative immunoglobulins, and serum free light chains) were normal. A positron emission tomography–computerized tomography (PET-CT) scan was performed to evaluate for multiorgan involvement. The PET-CT scan was significant for multifocal 18F flurodeoxyglucose avid sclerotic changes in the sternum, sacrum, and bilateral symmetric uptake in the femoral and tibial bones, and the diagnosis of ECD was made based on these pathognomonic radiologic findings (Fig 3). Given recent findings of the high prevalence of BRAF V600E mutation in ECD patients and potential therapeutic implications,5, 6 the tissue was tested for this mutation and found to be BRAF V600E positive. The patient was then enrolled in an open-label, phase II clinical trial of vemurafenib in patients with BRAF V600E mutation–positive cancers, but her participation was discontinued because of the development of severe myalgias and arthralgias during the trial. Discussion ECD is a rare, non-LCH, neoplasm that is diagnosed by clinical, histologic, and radiologic findings. Previously reported cases of ECD have a slight male predominance, disease onset typically in the fifth to seventh decades of life 1 and bone pain as the most common presenting symptom.2, 3, 4, 7 Patients with ECD have pathognomonic changes of bilateral symmetric sclerosis of the diametaphyseal regions of the long bones on plain radiographs and symmetric technetium Tc 99m labeling of the distal long bones with bone scintigraphy.1, 2, 3, 4, 7 Biopsies (taken typically from bone) show foamy histiocytes without any Birbeck granules with immunohistochemistry positive for CD68 and negative for CD1a and S-100.3, 4, 7 Although our patient did have the characteristic histologic and radiologic findings that established the diagnosis of ECD, the initial cutaneous manifestations of ECD were different from those previously described in the literature. Although ECD has been reported to significantly affect the cardiovascular, pulmonary, renal, and central nervous systems,3, 7 involvement of the skin is relatively uncommon, with approximately 28% of reported cases having any skin manifestations. 1 The most commonly described dermatologic findings in ECD include xanthomalike papules and periorbital xanthelasmalike skin lesions.2, 8 Other reports describe red-brown papular lesions affecting the extremities and trunk.9, 10 Our reported patient with ECD manifested a diverse array of cutaneous manifestations, all with identical histologic findings. Although there is no standardized treatment for ECD, a recent consensus guideline for the diagnosis and treatment of ECD reported interferon-alfa as first-line therapy with the largest amount of supporting evidence.1, 7, 11, 12 Treatment with interferon-alfa was identified as an individual predictor of survival of ECD patients. 1 Another treatment currently being investigated is the use of vemurafenib in ECD patients with a BRAF V600E mutation. 6 Recent studies have shown a high prevalence of the BRAF V600E mutation in up to 54% to 100% of tested ECD patients and 38% to 68% of LCH patients. 5 In addition, no such mutation has been found in any of the other tested histiocytoses, including Rosai-Dorfman disease, juvenile xanthogranuloma, histiocytic sarcoma, xanthoma disseminatum, interdigitating dendritic cell sarcoma, and necrobiotic xanthogranuloma, which suggests a common origin between ECD and LCH. 5 Vemurafenib is a serine/threonine kinase inhibitor that inhibits the RAS-ERK cellular signaling pathway, which is constitutively activated by the BRAF V600E mutation. 6 Although marked response of ECD to vemurafenib has been reported in several cases, the drug is still being studied to determine the safety, optimal duration of therapy, and potential adverse drug reactions. 6 Treatment continues to pose a challenge, as there is no standardized regimen or any modality that has demonstrated disease eradication. However, the discovery of the highly prevalent BRAF V600E is a promising treatment target. Early diagnosis of ECD could potentially limit disease morbidity and mortality by initiating early treatment. Our case is unique to previously reported cases of ECD, as our patient presented initially with a clinical array of cutaneous lesions and pathognomonic radiographic findings. Her history of childhood LCH raises a question of whether there is a common origin linking the 2 histiocytoses, ECD and LCH.

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          High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses.

          Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAF mutations have been observed in Langerhans cell histiocytosis (LCH). We investigated the frequency of BRAF mutations in several types of histiocytoses. Histology from 127 patients with histiocytoses were reviewed. Detection of BRAF(V600) mutations was performed by pyrosequencing of DNA extracted from paraffin embedded samples. Diagnoses of Erdheim-Chester disease (ECD), LCH, Rosai-Dorfman disease, juvenile xanthogranuloma, histiocytic sarcoma, xanthoma disseminatum, interdigitating dendritic cell sarcoma, and necrobiotic xanthogranuloma were performed in 46, 39, 23, 12, 3, 2, 1, and 1 patients, respectively. BRAF status was obtained in 93 cases. BRAF(V600E) mutations were detected in 13 of 24 (54%) ECD, 11 of 29 (38%) LCH, and none of the other histiocytoses. Four patients with ECD died of disease. The high frequency of BRAF(V600E) in LCH and ECD suggests a common origin of these diseases. Treatment with vemurafenib should be investigated in patients with malignant BRAF(V600E) histiocytosis.
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            Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation.

            Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAFV600E gain-of-function mutations have been observed in 57% of cases of Langerhans cell histiocytosis (LCH) and 54% of cases of Erdheim-Chester disease (ECD), but not in other types of histiocytoses. Targeted therapy with an inhibitor of mutated BRAF (vemurafenib) improves survival of patients with melanoma. Here, we report vemurafenib treatment of 3 patients with multisystemic and refractory ECD carrying the BRAFV600E mutation; 2 also had skin or lymph node LCH involvement. The patients were assessed clinically, biologically (CRP values), histologically (skin biopsy), and morphologically (positron emission tomography [PET], computed tomography and magnetic resonance imaging). For all patients, vemurafenib treatment led to substantial and rapid clinical and biologic improvement, and the tumor response was confirmed by PET, computed tomography, and/or magnetic resonance imaging 1 month after treatment initiation. For the first patient treated, the PET response increased between months 1 and 4 of treatment. The treatment remained effective after 4 months of follow-up although persistent disease activity was still observed. Treatment with vemurafenib, a newly approved BRAF inhibitor, should be considered for patients with severe and refractory BRAFV600E histiocytoses, particularly when the disease is life-threatening.
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              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.
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                Author and article information

                Contributors
                Journal
                JAAD Case Rep
                JAAD Case Rep
                JAAD Case Reports
                Elsevier
                2352-5126
                05 March 2016
                March 2016
                05 March 2016
                : 2
                : 2
                : 128-131
                Affiliations
                [a ]Department of Dermatology, Yale School of Medicine, New Haven, Connecticut
                [b ]Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
                [c ]Department of Radiology, Yale School of Medicine, New Haven, Connecticut
                Author notes
                []Correspondence to: Michael Girardi, MD, Department of Dermatology at Yale School of Medicine, PO Box 208059, 333 Cedar St, New Haven, CT 06520-8059.Department of Dermatology at Yale School of MedicinePO Box 208059, 333 Cedar St, New Haven, CT 06520-8059 michael.girardi@ 123456yale.edu
                Article
                S2352-5126(15)00175-7
                10.1016/j.jdcr.2015.10.010
                4810280
                27051852
                © 2015 by the American Academy of Dermatology, Inc. Published by Elsevier, Inc.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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