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

ABSTRACT: 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.

SUBMITTER: Estrada-Veras JI

PROVIDER: S-EPMC5446206 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Estrada-Veras Juvianee I JI O'Brien Kevin J KJ Boyd Louisa C LC Dave Rahul H RH Durham Benjamin B Xi Liqiang L Malayeri Ashkan A AA Chen Marcus Y MY Gardner Pamela J PJ Alvarado-Enriquez Jhonell R JR Shah Nikeith N Abdel-Wahab Omar O Gochuico Bernadette R BR Raffeld Mark M Jaffe Elaine S ES Gahl William A WA

Blood advances 20170201 6

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 an ...[more]

PMID: 28553668

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Project description:ImportanceWhile cladribine is best known for the treatment of hairy cell leukemia and other lymphoid cancers, it also has activity against myeloid neoplasms, such as Erdheim-Chester disease (ECD).ObjectiveTo assess the efficacy of cladribine (2-chloro-2'-deoxyadenosine) in the treatment of ECD.Design, setting, and participantsThis study was a single-institution retrospective medical record review from January 1, 1998, to April 6, 2016, at a tertiary academic medical center. In all eligible cases, the diagnosis of ECD was made using clinical criteria in conjunction with histopathologic findings.ExposureCladribine therapy in first-line treatment or later.Main outcomes and measuresTwo response criteria were used, clinical and radiological. For clinical response, the following criteria were used: complete response (complete resolution of symptoms attributed to ECD), partial response (partial resolution of symptoms attributed to ECD), stable disease (no change in symptoms attributed to ECD), and progressive disease (worsening of symptoms attributed to ECD). For radiological response, the following categories were used: complete response (complete resolution of proven or suspected lesion due to ECD), partial response (partial resolution of proven or suspected lesion due to ECD), stable disease (no significant change in proven or suspected lesion due to ECD for ≥3 months), and progressive disease (progression or worsening of proven or suspected lesion due to ECD).ResultsA total of 63 adult patients with confirmed ECD were identified. Their median age at diagnosis of ECD was 54 years (age range, 18-80 years), and 67% (42 of 63) were male. Cladribine was the most commonly used chemotherapeutic agent and was administered in 21 of 63 patients (33%). Their median age at the time of cladribine therapy was 62 years (age range, 40-78 years). Cladribine was used as the first-line treatment in 9 patients and as later-line treatment in the remaining 12 patients. The median number of cycles of cladribine administered was 2.5 (range, 1-6). The overall clinical response rate was 52% (9 of 17) (6% [1 of 17] complete response and 46% [8 of 17] partial response), with 18% (3 of 17) stable disease and 30% (5 of 17) progressive disease. Among patients who responded to cladribine therapy, the median duration of clinical response was 9 months (range, 6-129 months), with ongoing response in 2 patients. The overall radiological response rate was 54% (8 of 15) (all partial response), with 26% (4 of 15) stable disease and 20% (2 of 15) progressive disease. Treatment-related adverse effects included 2 infectious complications (pneumonia and central line infection, both requiring hospitalization) and 2 hematologic adverse effects (grade 4 neutropenia and thrombocytopenia, and grade 3 neutropenia, both requiring therapy discontinuation).Conclusions and relevanceCladribine has moderate clinical efficacy in the treatment of ECD and can be considered a treatment option in cases without the BRAF V600E mutation. It is generally well tolerated and may result in a durable response.

Project description:Erdheim-Chester disease is a rare, non-Langerhans cell histiocytosis histologically characterized by multi-systemic proliferation of mature histiocytes in a background of inflammatory stroma. The disease can involve virtually any organ system; most commonly the bones, skin, retroperitoneum, heart, orbit, lung, and brain are affected. Although a histiocytic proliferation is the histological hallmark of the disease, a wide range of morphological appearances have been described as part of case studies or small series. A comprehensive review of histopathological features in clinically and molecularly defined Erdheim-Chester disease has yet to be characterized. To address this issue and help guide clinical practice, we comprehensively analyzed the pathological spectrum of Erdheim-Chester disease in a clinically and molecularly defined cohort. We reviewed 73 biopsies from 42 patients showing involvement by histiocytosis from a variety of organ systems, including bone (16), retroperitoneum (11), skin (19), orbit (6), brain (5), lung (6), cardiac structures (2), epidural soft tissue (3), oral cavity (2), subcutaneous soft tissue (2), and testis (2). In eight patients, one or more bone marrow biopsies were performed due to clinical indication and an accompanying myeloid neoplasm was detected in six of them. Thirty-eight cases were investigated for genetic abnormalities. Somatic mutations involving BRAF (25/38), MAP2K1 (6/38), ARAF (2/38), MAP2K2 (1/38), KRAS (1/38), and NRAS (1/38) genes were detected. One of the cases with a MAP2K1 mutation also harbored a PIK3CA mutation. We have observed marked heterogeneity in histology and immunophenotype, identified site-specific features, overlap with other histiocytic and myeloid disorders and potential diagnostic pitfalls. We hope that broadening the spectrum of recognized pathologic manifestations of Erdheim-Chester disease will help practicing clinicians and pathologists to diagnose Erdheim-Chester disease early in the disease course and manage these patients effectively.

Project description:IntroductionErdheim-Chester disease (ECD) is a rare disease that belongs to the group of Dendritic and histiocytic neoplasms. Only 2000 cases have been reported worldwide. It can present with a wide range of symptoms, making a differential diagnosis especially difficult. The primary and most important diagnostic tool is a biopsy of the affected organ/tissue. Nowadays the analysis of different mutations affecting the BRAF and MAPK pathways makes it possible to use targeted treatments, such as vemurafenib, dabrafenib, or cobimetinib.ObjectiveOur aim is to present the results of three male patients treated in our hematology department.ResultsOur BRAF mutation-positive patient presented with retroperitoneal tissue proliferation and diabetes insipidus. The initial therapy of choice was dabrafenib. After 3 months of treatment, 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) scans showed regression, and after 2 years of treatment, no disease activity was detected. In our second patient, a recurrent febrile state (not explained by other reasons) and diabetes insipidus suggested the diagnosis. A femoral bone biopsy confirmed BRAF-negative ECD. The first-line therapy was interferon-alpha. After 3 months of treatment, no response was observed on 18FDG-PET/CT, and treatment with cobimetinib was started. The control 18FDG-PET/CT imaging was negative. Our third patient was evaluated for dyspnea, and a CT scan showed fibrosis with hilar lymphadenomegaly. A lung biopsy confirmed BRAF-negative ECD. We started treatment with interferon-alpha, but unfortunately, no improvement was observed. Second-line treatment with cobimetinib resulted in a partial metabolic response (PMR) according to control 18FDG-PET/CT.ConclusionsOur results demonstrate that an appropriately chosen treatment can lead to a good therapeutic response, but dose reduction may be necessary due to side effects. With advanced targeted therapeutic treatment options, survival and quality of life are significantly improved.

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

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

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