Erdheim–Chester disease: A systematic review
Introduction
Erdheim–Chester disease (ECD) is a non-Langerhans-cell form of histiocytosis characterized by xanthomatous infiltration of tissues by CD68-positive, CD1a-/S100-negative foamy histiocytes [1]. It is a rare disorder accounting for up to 600 cases to date, which primarily affects male patients between their 5th and 7th decade of life [2]. Although, according to the WHO classification, ECD is a neoplasm deriving from histiocytes, there is a long standing debate as to whether the disorder is of malignant or polyclonal reactive nature [3]. Clinical manifestations of ECD at presentation are protean and encompass bone pain, diabetes insipidus, neurological and constitutional symptoms, although retroperitoneal, cutaneous, cardiovascular and pulmonary involvement have also been described [4], [5]. Since the clinical picture of ECD arises as a slowly forming mosaic with sequential manifestations, the diagnosis is often challenging. However, X-ray peculiar aspects such as symmetric diaphyseal osteosclerosis or parallel scintigraphy uptake in long bones of both extremities provide a striking signature of the disease and may favor the diagnosis [2].
Recently, the discovery of activating mutations of BRAF in 54% of ECD patients, along with the role of tumor microenvironment in its development, has modified the traditional interpretation of the disease, supporting novel therapeutic potential in adopting the targeted therapy [6], [7], [8]. In particular, the BRAF inhibitor Vemurafenib [9], the anti-TNFα moAb Infliximab [10], and the IL-1R antagonist Anakinra [11] have been used with variable though promising results. However, the 5-year survival occurs in less than 70% of patients [12].
Based on the availability of new drugs, some of which exceeding the blood–brain barrier, optimized treatments for patients with CNS lesions are urgently needed. Here, we report a single case of ECD and systematically revisit all published, reliably diagnosed cases of ECD.
Section snippets
Case report
A 28-year-old man with a 5-year history of diabetes insipidus, vespertine fever, dyspepsia, nausea and vomiting was admitted in 2010 at our Department complaining of paresthesia and weakness of the lower extremities. Physical examination demonstrated mild left hand dysmetria, ataxic gait as well as the presence of bilateral eyelid xanthelasmas and well-defined papules on the thoracic wall. The results of extensive serum laboratory analyses were otherwise unremarkable. The brain MRI documented a
Literature review and methods of analysis
We searched the English-language literature indexed in PubMed using the keyword “Erdheim–Chester disease” and published up to June 2014. Among the described cases, diagnosis of ECD was considered consistent when the criteria proposed by Haroche et al. (Table 1) [2] were fulfilled. Only papers reporting data from individual patients were included for review. Cases with doubtful or not univocal diagnosis as well as repeated reports on the same patients were excluded. In particular, three
Patient population
From the systematic review of the literature, we retrieved 331 manuscripts describing patients with ECD (Table S1). In 448 patients the ECD diagnosis was considered consistent. Median age at diagnosis in the population of patients with neurological involvement was 51.5 years (range, 4–77) and was lower with highly significant difference (p = 0.002) compared to patients without neurological symptoms (54.5 years). Comparison by sex using the Dunn's post-test failed to show any significant
Discussion
During the last decades histiocytoses have been described as a collection of highly heterogeneous clinical manifestations connected only by a common histopathology. Despite its rarity, ECD includes clinically variable disorders that range from asymptomatic bone infiltration to multiorganic diseases and its clinical course is determined by the extent and distribution of the disease [2]. Recently, major genetic and molecular advances including the detection of recurrent BRAFV600E gain-of-function
Conflict of interest statement
The Authors declare no affiliation with industries or organizations with a financial interest, direct or indirect, that may affect the conduct or reporting of the work submitted.
Contributions
MC contributed to the design of the study, acquisition, analysis and interpretation of data, and drafting of the article. VS, FMR and MCL contributed to the acquisition, analysis and interpretation of data. Franca Dicuonzo and GI contributed to acquisition of data. FS contributed to drafting and critical revision of the article. Franco Dammacco designed the study and critically revised the article. All Authors have approved the final article version.
Reviewers
Julien Haroche, M.D, Ph.D, Hôpital Pitié-Salpêtrière, Médecine Interne 2, 47-83 bd de l’Hôpital, F-75013 Paris, France.
Acknowledgments
This work was supported by a grant from the Italian Association for Cancer Research (AIRC, IG11647) and from the Italian Ministry for the University and Research (PRIN 2010). The Authors are grateful to Dr. Giuseppina Zagaria and Dr. Francesca Bisceglia for the editorial assistance in the manuscript preparation.
Dr. Franco Silvestris was born in Bari, Italy in 1949. He was awarded with the M.D. degree in 1974 and with specializations in ‘Clinical Hematology’ and ‘Oncology’ in 1977 and 1980, respectively. Dr. Silvestris spent a four-years period in USA at the University of New Mexico, Albuquerque as Research Associate Professor by 1982 working on research collaborative projects in oncology with the University of Bari. By 1994 he completed a second period of studies over the University of Florida in
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Dr. Franco Silvestris was born in Bari, Italy in 1949. He was awarded with the M.D. degree in 1974 and with specializations in ‘Clinical Hematology’ and ‘Oncology’ in 1977 and 1980, respectively. Dr. Silvestris spent a four-years period in USA at the University of New Mexico, Albuquerque as Research Associate Professor by 1982 working on research collaborative projects in oncology with the University of Bari. By 1994 he completed a second period of studies over the University of Florida in Gainesville (USA) where he obtained a personal award for research in the autoimmunity field. Dr. Silvestris is Professor of ‘Internal Medicine and Oncology’ and Director of the School of Specialization in ‘Oncology’ at the University of Bari. Also, he heads a clinical division of Internal Medicine and Clinical Oncology at the Department of Internal Medicine and Oncology of the University of Bari.
At present, Dr. Silvestris is involved in a number of collaborative researches in oncology and particularly in studies of the pathogenesis of bone metastases in multiple myeloma and malignant lymphomas. In addition, he is also involved in other studies exploring the properties of mesenchymal stem cells in the regenerative medicine in human experimental models. His previous studies include specific fields of autoimmunity, immunodeficiencies and tumor immunology whose results have been widely published.