ANTICANCER RESEARCH 34: 3257-3262 (2014)

Review Erdheim-Chester Disease: A Comprehensive Review

AHMED MAHER ABDELFATTAH2, KARIM ARNAOUT1 and IMAD A. TABBARA1

1Division of Hematology and Oncology, Department of , George Washington University Medical Center, Washington, DC, U.S.A.; 2Faculty of Medicine, University of Alexandria, Alexandria, Egypt

Abstract. Erdheim-Chester disease is a rare form of non- identified, none are pathognomonic or diagnostic of ECD. Langerhans' cell characterized by multi-system Stoppacciaro et al. demonstrated that a cytokine and infiltration by xanthogranulomas composed of foamy chemokine network similar to that described in Langerhans' surrounded by fibrosis. Approximately 400 cases cell histiocytosis exists in ECD lesions (2). Secretion of have been reported in the literature, and the recent increase interleukin (IL)-6 and cysteine x cysteine (CXC) chemokine in the number of cases is likely due to the increased ligand 8/IL-8 (CXCL8/IL8) plays a major role in recruitment awareness of its associated morbidity and mortality. The and activation of histiocytes and inflammatory cells (3). This etiology of this disease remains unknown, the clinical course process is regulated by tumor necrosis factor, which is also is variable and treatment is still not well-established. The expressed in ECD lesions and which activates other objective of this review is to describe the pathogenesis, downstream inflammatory factors, further worsening tissue clinical manifestations, and diagnosis of this rare disorder, damage. In addition, chemokines expressed by ECD and to review its prognosis and treatment. Erdheim-Chester histiocytes are thought to attract inflammatory cells including disease (ECD) is a rare form of non-Langerhans’ cell T helper-1 (Th1)-type T-lymphocytes expressing chemokine histiocytosis. It was first described in 1930. Approximately receptors, which, in turn, drive activation and chemokine 400 cases have been reported in the literature. production by histiocytes (2, 4).

Erdheim-Chester disease (ECD) is a rare form of non- Clinical Presentation Langerhans’ cell histiocytosis characterized by multisystem infiltration by Cluster of Differentiation 68 (CD68) positive Patients with ECD have a variable clinical course, ranging foamy histiocytes surrounded by fibrosis (1). It was first from asymptomatic to fatal, depending on the extent and described in 1930. Fewer than 500 cases have been reported distribution of the disease (Table I). Bone pain represents the in the literature. most common symptom and usually involves the lower limbs. Typical radiological findings, including symmetric Etiology and Pathogenesis diaphyseal osteosclerosis, or symmetric uptake seen in the long bones of the extremities using bone scintigraphy, are The etiology and pathogenesis of ECD are poorly-understood. almost pathognomonic of the disease. Bone involvement is The clonal nature of this disease is still controversial. the first manifestation of ECD in half of all patients. It also Although occasional clonal cytogenetic aberrations have been becomes symptomatic in about 50% of patients over the course of the disease (5). The second most common involved organ is the cardiovascular system which is affected in 77% of the cases. Correspondence to: Imad A. Tabbara, MD, Professor of Medicine, Periarterial infiltration usually has little clinical significance Director Blood & Marrow Transplant Program, Division of except in the case of renovascular infiltration, which may Hematology and Oncology, Department of Medicine, George cause systemic hypertension, usually corrected by renal artery Washington University Medical Center, 2150 Pennsylvania Avenue, stenting (6). Pericardial infiltration causing tamponade, NW, Washington, DC 20037, U.S.A. Tel: +1 2027412478, Fax: +1 2027412487, e-mail: [email protected] predominantly right sided myocardial infiltration, valvular involvement occasionally requiring valve replacement and Key Words: Erdheim-Chester disease, Langerhans’ cell histiocytosis, peri-coronary artery infiltration that may cause potentially review. fatal myocardial infarction have been reported (6-12).

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Table I. Organ involvement in Erdheim-Chester disease (ECD) Table II. Differential diagnosis of Erdheim-Chester disease (ECD) and Langerhans’ cell histiocytosis (LCH). Organ involved Frequency Marker ECD LCH Skeletal 96% Cardiovascular 77% S-100 protein − + CNS 51% Group 1 CD1a glycoproteins − + Orbital 27% CD68 + − Urologic 11% Birbeck granules − + Pulmonary 43-53% Endocrine Rare Retroperitoneal 29-59%

insufficiency that may require hemodialysis (25-27). Retroperitoneal involvement leading to peri-renal or ureteral obstruction and causing renal impairment has been reported Brain involvement occurs in 51% of the cases and is in 29-59% of patients with ECD (20, 28, 29). thought to be the only major predictor of worse prognosis in patients with ECD (13). In a comprehensive neurological Diagnosis series of patients with ECD, Lachenal et al. reported that cerebellar (41%) and pyramidal (45%) manifestations were The diagnosis of ECD is often challenging because of the the the most frequent (14). Other neurological symptoms rarity of the disease and its multi-organ involvement. Tissue include seizures, headache, psychiatric manifestations and biopsy, preferably of an osteosclerotic bone lesion if paroxysmal dystonia. Recently published case reports possible, is crucial for diagnosis. Histopathological mention that ECD might present as an intramedullary spinal examination usually shows foamy S-100-negative and cluster cord lesion (14-18). of differentiation 68 (CD68)-positive histiocytes as the Pulmonary involvement is also common. Arnaud et al. principal cells, surrounded by fibrosis and inflammatory reported that 53% of patients have some degree of lung cells, such as lymphocytes, plasma cells, and Touton-type parenchymal infiltration and 41% have pleural infiltration giant cells (30). CD68-positive and CD1a-negative (19). In another cohort of 53 patients, Arnaud et al. showed immunohistological staining helps to differentiate it from similar results, with 43% of their cases having lung Langerhans' histiocytosis (20, 24) (Table II). A combination infiltration (13). However, both studies concluded that of clinical assessment, pathological examination and pulmonary involvement was not a predictor of worse immunohistochemical staining is used to differentiate ECD prognosis for ECD, contrary to what has been reported in from the other rare types of non-Langerhans’ histiocytosis as earlier studies. shown in Table III (31). Orbital involvement, which is often bilateral and manifests Laboratory workup includes complete blood count, as exopthalmos due to retro-orbital infiltration, is found in chemistries, and urine electrolytes if is 27% of ECD patients (20). Occasionally it may be resistant suspected. Imaging studies include magnetic resonance to treatment, requiring surgical debulking (21, 22). imaging (MRI) of the brain, a computed tomographic (CT) Xanthelasmas of the eyelids or the periorbital spaces were scan or an MRI of the entire aorta, a cardiac MRI, a CT scan also reported in 18% of the patients (20). of the chest, abdomen, and pelvis, and a transthoracic Diabetes insipidus is a characteristic endocrine echocardiography. An MRI of the spinal cord is only manifestation of ECD. It is secondary to hypothalamic or necessary if the patient has signs or symptoms of spinal cord pituitary infiltration, which may lead to other endocrinal involvement. abnormalities such as hyperprolactinemia or gonadotropin No clear staging, prognostic, or scoring system for insufficiency (20, 23). Haroche et al. reported in 2007 seven ECD has been established. It is suggested that 18F- cases of ECD with involvement of the adrenals. Diagnosis fluorodeoxyglucose positron-emission tomography (PET was established radiologically except for one case which was scan) and C-reactive protein elevation may predict disease confirmed via biopsy. However, only one case had activity (32, 33). A retrospective study of 31 patients with symptomatic adrenal insufficiency (24). Renal involvement ECD showed a variable sensitivity of PET scanning among is reportedly present in about 11% of ECD cases. Renal the different organs studied. However, in one study, its disease consists of obstructive uropathy due to specificity remained helpful in the assessment of CNS retroperitoneal fibrosis or renal histiocytic infiltration. involvement, as well as in the earlier detection of treatment Symptoms commonly include abdominal pain, dysuria and response as compared to brain MRI, and in the assessment possible development of hydronephrosis and renal of the cardiovascular system (32).

3258 Abdelfattah et al: Erdheim-Chester Disease: A Comprehensive Review

Table III. Differential diagnosis of Erdheim-Chester disease and other types of non-Langerhans’ cell histiocytosis based on immunohistochemical staining.

Disease (ref) CD68 CD1a S100 Factor XIIIa Other markers

Erdheim-Chester disease (44) + − − + Birbeck granules absent Benign cephalic histiocytosis (45-47) + − − + Positive reaction for /leucocyte, HAM56 Generalised eruptive histiocytosis (48) + − − −/+ No reaction for CD34; positive reaction for MAC387, CD14, CD36 Indeterminate cell histiocytosis (49, 50) + + + − No reaction for CD3, CD4, CD8, CD20, CD36, CD79a (51, 52) + − − + Progressive nodular histiocytosis (53) + − − Necrobiotic xanthogranuloma (54) + − − Giant cell reticulohistocytosis (55) + May show May show Variable positivity for CD31, CD43, CD45; no focal reactivity focal reactivity reaction for CD3, CD20, CD30, HMB45, keratins Multicentric reticulohistocytosis (56) + − No reaction for α1-antitrypsin Rosai–Dorfman disease (57) + − + disseminatum (51, 58) + − − + Kikuchi disease (59) + Positive reaction for CD8, CD4, KiM1P monoclonal antibody, Ki67 antigen; no reaction for CD15, CD30

Treatment showed persistent bone uptake on follow-up PET assessment at four months, despite normalization of C-reactive protein Various therapies for ECD have been reported. Interferon- level and lack of clinical symptoms (41). This study provides alpha was shown to improve survival and is currently the an exciting mean of targeted approach in treating ECD, which standard first-line treatment for patients with ECD (34). Its should be studied further as a single agent or in combination mechanism of action remains unclear. The dose used is 3-9 with other treatment modalities. MIU three times a week. Pegylated interferon-alpha (135- 200 μg once a week) has also been used. Higher doses are Prognosis indicated for progressive disease unresponsive to lower doses, and in cases of CNS or cardiovascular involvement Prognosis of patients with ECD is variable and depends on (13). However, interferon therapy can be associated with its extent and distribution. A 2011 multi-center observational severe side-effects including severe asthenia, myalgia, cohort of 58 patients showed 1-year and 5-year survival rates pruritis and thrombopenia, which may require cessation of of 96% and 68%, respectively. CNS involvement and therapy (35). Other treatment options include recombinant treatment with interferon-α and/or Pegylated interferon-α human interleukin-1 receptor antagonist, , tyrosine were found to be major predictors of survival in these kinase inhibitors, and autologous hematopoietic stem cell patients. Other causes of mortality included pulmonary transplantation (20, 28, 36-39). Corticosteroids, , infection, myocardial infarction, gastrointestinal hemorrhage, vincristine, cyclosphosphamide, doxorubicin, cyclosporine metabolic abnormalities and multisystem organ failure due and radiotherapy have also been used (20, 29, 40). to various causes (13). V-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E gain-of-function mutations have been reported in 54% Future Directions of cases of ECD. Vemurafenib, an inhibitor of mutant BRAF that has shown some efficacy against melanoma and hairy-cell With the significant progress in identifying molecular associated with the BRAF V600E mutation, was used aberrations and mutational abnormalities in a variety of in the treatment of three patients with refractory ECD carrying disorders, efforts should be dedicated to establishing the BRAF V600E mutation. The patients in the study improved molecular defects in ECD. The documented presence of clinically within a few days, with normalization of C-reactive BRAF mutation in 54% of patients with ECD suggests a protein value and substantial regression of lesions on PET scan. common pathological pathway with other disorders such as MRI studies showed that perivascular sheathing regressed, and melanoma and hairy cell leukemia. Drugs that have been heart infiltration improved markedly one to two months after shown to be effective in melanoma such as vemurafenib, IL2, treatment. However, all patients developed a rash, requiring and ipilimumab, as well as drugs that are curative in hairy dose reduction of vemurafenib (41, 42). Furthermore, among cell leukemia, such as pentostatin, cladribine, and rituximab, patients with ECD treated with vemurafenib, one patient need to be studied in patients with ECD.

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Conflicts of Interest Chester disease: a multicenter survival analysis of 53 patients. Blood 117(10): 2778-2782, 2011 The Authors report no conflicts of interest. The authors alone are 14 Lachenal F, Cotton F, Desmurs-Clavel H, Haroche J, Taillia H, responsible for the content and writing of this article. Magy N, Hamidou M, Salvatierra J, Piette JC, Vital-Durand D and Rousset H: Neurological manifestations and neuroradiological References presentation of Erdheim-Chester disease: report of 6 cases and systematic review of the literature. J Neurol 253(10): 1267-1277, 1 Chester W: Über Lipoid granulomatose. Virchows Arch Pathol 2006. Anat 279: 561-602, 1930. 15 Baldacci F, Lucetti C, Vergallo A, Borelli P, Tessa C, Viacava P 2 Stoppacciaro A, Ferrarini M, Salmaggi C, Colarossi C, Praderio L, and Bonuccelli U: Paroxysmal exertion-induced dystonia Tresoldi M, Angelo A, Beretta AA and Sabbadini MG: Immuno- secondary to Erdheim-Chester disease. Clin Neurol Neurosurg histochemical evidence of a cytokine and chemokine network in 115(7): 1105-1106, 2013. three patients with Erdheim-Chester disease: implications for 16 Takeuchi T, Sato M, Sonomura T and Itakura T: Erdheim- pathogenesis. Arthritis Rheum 54(12): 4018-4022, 2006. Chester disease associated with intramedullary spinal cord 3 Dagna L, Girlanda S, Langheim S, Rizzo N, Bozzolo EP, lesion. Br J Radiol 85: e62-64, 2012. Sabbadini MG and Ferrarini M: Erdheim-Chester disease: report 17 Tzoulis C, Gjerde IO, Søfteland E, Neckelmann G, Strøm E, on a case and new insights on its immunopathogenesis. Vintermyr OK, Sviland L and Biermann M: Erdheim-Chester Rheumatology 49(6): 1203-1206, 2010. disease presenting with an intramedullary spinal cord lesion. J 4 Dagna L, Corti A, Langheim S, Guglielmi B, De Cobelli F, Neurol 259(10): 2240-2242, 2012. Doglioni C, Fragasso G, Sabbadini MG and Ferrarini M: Tumor 18 Shanmugam SV, Kolappan M, Garg M, Rennie WJ, Furness P necrosis factor α as a master regulator of inflammation in and Rajabally YA: A rare cause of late-onset cerebellar ataxia: Erdheim-Chester disease: rationale for the treatment of patients Erdheim-Chester disease. Cerebellum 12(4): 593-595, 2013. with infliximab. J Clin Oncol 30(28): e286-290, 2012. 19 Arnaud L, Pierre I, Beigelman-Aubry C, Capron F, Brun AL, 5 Cavalli G, Guglielmi B, Berti A, Campochiaro C, Sabbadini MG Rigolet A, Girerd X, Weber N, Piette JC, Grenier PA, Amoura Z and Dagna L: The multifaceted clinical presentations and and Haroche J: Pulmonary involvement in Erdheim-Chester manifestations of Erdheim-Chester disease: comprehensive disease: a single-center study of thirty-four patients and a review review of the literature and of 10 new cases. Ann Rheum Dis of the literature. Arthritis Rheum 62(11): 3504-3512, 2010. 72(10): 1691-1695, 2013. 20 Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, Wechsler J, 6 Haroche J, Amoura Z, Dion E, Wechsler B, Costedoat- Brun B, Remy M, Wallaert B, Petit H, Grimaldi A, Wechsler B and Chalumeau N, Cacoub P, Isnard R, Généreau T, Wechsler J, Godeau P: Erdheim-Chester disease. Clinical and radiologic chara- Weber N, Graef C, Cluzel P, Grenier P and Piette JC: cteristics of 59 cases. Medicine (Baltimore) 75(3): 157-169, 1996. Cardiovascular involvement, an overlooked feature of Erdheim- 21 Alper MG, Zimmerman LE and Piana FG: Orbital manifestations Chester disease: report of 6 new cases and a literature review. of Erdheim-Chester disease. Trans Am Ophthalmol Soc 81: 64-85, Medicine (Baltimore) 83(6): 371-392, 2004. 1983. 7 Gupta A, Kelly B and Mcguigan JE: Erdheim-Chester disease 22 Sheidow TG, Nicolle DA and Heathcote JG: Erdheim–Chester with prominent pericardial involvement: clinical, radiologic, and disease: two cases of orbital involvement. Eye (Lond) 14: 606- histologic findings. Am J Med Sci 324(2): 96-100, 2002. 612, 2000. 8 Chen MT, Wang SM, Lin SY, Ting IW, Liu JH, Kuo HL and 23 Khamseh ME, Mollanai S, Hashemi F, Rezaizadeh A and Azizi Huang CC: Pericardial effusion as a crucial presentation of F: Erdheim-Chester syndrome, presenting as hypogonadotropic Erdheim-Chester disease in a hemodialysis patient: an hypogonadism and diabetes insipidus. J Endocrinol Invest 25(8): overlooked diagnosis. Clin Nephrol 78(1): 81-84, 2012. 727-729, 2002. 9 George OK and Subhendu MS: Recurrent and rapidly occurring 24 Haroche J, Amoura Z, Touraine P, Seilhean D, Graef C, Birmelé B, pericardial tamponade in Erdheim Chester disease: Indian Heart Wechsler B, Cluzel P, Grenier PA and Piette JC: Bilateral adrenal J 64(1): 103-5, 2012. infiltration in Erdheim-Chester disease. Report of seven cases and 10 Kenn W, Stäbler A, Zachoval R, Zietz C, Raum W and literature review. J Clin Endocrinol Metab 92(6): 2007-12, 2007. Wittenberg G: Erdheim-Chester disease: a case report and 25 Droupy S, Attias D, Eschwege P, Hammoudi Y, Benoit G, Jardin literature overview. Eur Radiol 9(1): 153-158, 1999. A: Bilateral hydronephrosis in a patient with Erdheim-Chester 11 Fink MG, Levinson DJ, Brown NL, Sreekanth S and Sobel GW: disease. J Urol 162(6): 2084-2085, 1999. Erdheim-Chester disease. Case report with autopsy findings. 26 Sanchez JE, Mora C, Macia M and Navarro JF: Erdheim-Chester Arch Pathol Lab Med 115(6): 619-623, 1991 disease as cause of end-stage renal failure: a case report and review 12 Loeffler AG and Memoli VA: Myocardial involvement in of the literature. Int Urol Nephrol 42(4): 1107-1112, 2010. Erdheim-Chester disease. Arch Pathol Lab Med 128(6): 682-685, 27 Tsukamoto M, Akahane M and Nangaku M: Image of Erdheim- 2004. Chester disease requiring hemodialysis. Clin Exp Nephrol 16(5): 13 Arnaud L, Hervier B, Néel A, Hamidou MA, Kahn JE, Wechsler 811-812, 2012. B, Pérez-Pastor G, Blomberg B, Fuzibet JG, Dubourguet F, 28 Pan A, Doyle T, Schlup M, Lubcke R and Schultz M: Unusual Marinho A, Magnette C, Noel V, Pavic M, Casper J, Beucher manifestation of Erdheim-Chester disease. BMC Gastroenterol AB, Costedoat-Chalumeau N, Aaron L, Salvatierra J, Graux C, 11: 77, 2011. Cacoub P, Delcey V, Dechant C, Bindi P, Herbaut C, Graziani 29 Mascalchi M, Nencini P, Nistri M, Sarti C and Santoni R: G, Amoura Z and Haroche J: CNS involvement and treatment Failure of radiation therapy for brain involvement in Erdheim with interferon-α are independent prognostic factors in Erdheim- Chester disease. J Neurooncol 59(2): 169-172, 2002.

3260 Abdelfattah et al: Erdheim-Chester Disease: A Comprehensive Review

30 Dickson BC, Pethe V, Chung CT, Howarth DJ, Bilbao JM, 44 Weitzman S and Jaffe R: Uncommon histiocytic disorders: the Fornasier VL, Streutker CJ, Sugar LM and Bapat B: Systemic non-Langerhans cell histiocytoses. Pediatr Blood Cancer 45(3): Erdheim-Chester disease. Virchows Arch 452(2): 221-7, 2008. 256-64, 2005. 31 Cerio R, Griffiths CE, Cooper KD, Nickoloff BJ and Headington 45 Jeong JS, Jang EJ, Lee JY, Suh KS and Yoon TY: A case of benign JT: Characterization of factor XIIIa positive dermal dendritic cephalic histiocytosis. Korean J Dermatol 46: 1292-1295, 2008. cells in normal and inflamed skin. Br J Dermatol 121(4): 421- 46 Gianotti R, Alessi E and Caputo R: Benign cephalic histiocytosis: 431, 1989. A distinct entity or a part of a wide spectrum of histiocytic 32 Arnaud L, Malek Z, Archambaud F, Kas A, Toledano D, Drier proliferative disorders of children? A histopathological study. Am A, Zeitoun D, Cluzel P, Grenier PA, Chiras J, Piette JC, Amoura J Dermatopathol 15(4): 315-319, 1993. Z and Haroche J: 18F-fluorodeoxyglucose-positron emission 47 Azulay-abulafia L, Benez MD, Abreu Cde S, Miranda CV and tomography scanning is more useful in followup than in the Alves Mde F: Case for diagnosis. Benign cephalic histiocytosis. initial assessment of patients with Erdheim-Chester disease. An Bras Dermatol 86(6): 1222-1225, 2011. Arthritis Rheum 60(10): 3128-3138, 2009. 48 Marzano AV, Facchetti M and Caputo R: Guess what? 33 Haroche J, Amoura Z, Wechsler B, Veyssier-belot C, Charlotte Generalized eruptive histiocytosis (). Eur J F, Piette JC: Erdheim-Chester disease. Presse Med 36(11 Pt 2): Dermatol 12(2): 205-206, 2002. 1663-1668, 2007. 49 Ratzinger G, Burgdorf WHC, Metze D, Zeiger BG and Zelger 34 Haroche J, Amoura Z, Trad SG, Wechsler B, Cluzel P, Grenier PA B: Indeterminate cell histiocytosis: Fact or fiction? Journal of and Piette JC: Variability in the efficacy of interferon-alpha in Cutaneous Pathology 32(8): 552-560, 2005. Erdheim-Chester disease by patient and site of involvement: results 50 Ventura F, Pereira T, Da luz duarte M, Marques H, Pardal F and in eight patients. Arthritis Rheum 54(10): 3330-3336, 2006. Brito C: Indeterminate cell histiocytosis in association with acute 35 Hervier B, Arnaud L, Charlotte F, Wechsler B, Piette JC, . Dermatol Res Pract 2010: 569345, 2010. Amoura Z and Haroche J: Treatment of Erdheim-Chester disease 51 Zelger BW, Sidoroff A, Orchard G and Cerio R: Non- with long-term high-dose interferon-α. Semin Arthritis Rheum Langerhans’ cell histiocytoses. A new unifying concept. Am J 41(6): 907-913, 2012. Dermatopathol 18: 490-504, 1996. 36 Serratrice J, Granel B, De Roux C, Pellissier JF, Swiader L, 52 Strehl JD, Stachel KD, Hartmann A and Agaimy A: Juvenile Bartoli JM, Disdier P and Weiller PJ: "Coated aorta": a new sign xanthogranuloma developing after treatment of Langerhans cell of Erdheim-Chester disease. J Rheumatol 27(6): 1550-1553, histiocytosis: case report and literature review. Int J Clin Exp 2002. Pathol 5(7): 720-725, 2012. 37 McIntosh RS, Stevens SE, Gregson RHS, Sokal M, AP Haynes and 53 Chuang F, Chern E and Wu W: Progressive nodular histiocytosis: Powell RJ: Treatment of Erdheim-Chester disease with cladribine: a rare type of xanthogranuloma. Dermatologica Sinica 29(3): 98- a rational approach. Br J Ophthalmol 88(6): 844-847, 2004. 100, 2011. 38 Boissel N, Wechsler B and Leblond V: Treatment of refractory 54 Kadakia S, Nadkarni N, Sonavane S, Ghate S: Spectacular skin Erdheim-Chester disease with double autologous hematopoietic nodules: cutaneous necrobiotic xanthogranuloma without stem-cell transplantation. Ann Intern Med 135(9): 844-845, 2001. paraproteinemia. Indian J Dermatol 57(5): 396-398, 2012. 39 Gaspar N, Boudou P, Haroche J, Wechsler B, Van Den Neste E, 55 Miettinen M and Fetsch JF: (solitary Hoang-Xuan K, Amoura Z, Guillevin R, Savatovski J, Azar N, epithelioid histiocytoma): a clinicopathologic and immunohisto- Piette JC and Leblond V: High-dose chemotherapy followed by chemical study of 44 cases. Am J Surg Pathol 30(4): 521-528, autologous hematopoietic stem cell transplantation for adult 2006. histiocytic disorders with central nervous system involvement. 56 Luz FB, Gaspar AP, Ramos-e-Silva M, Carvalho da Fonseca E, Haematologica 91: 1121-1125, 2006. Villar EG, Cordovil Pires AR and Kalil-Gaspar N: Immuno- 40 Matsui K, Nagata Y and Hiraoka M: Radiotherapy for Erdheim- histochemical profile of multicentric reticulo-histiocytosis. Chester disease. Int J Clin Oncol 12(3): 238-241, 2007. Skinmed 4(2): 71-77, 2005. 41 Haroche J, Cohen-Aubart F, Emile JF, Arnaud L, Maksud P, 57 Becker MR, Gaiser T, Middel P and Rompel R: Charlotte F, Cluzel P, Drier A, Hervier B, Benameur N, Besnard Clinicopathologic challenge. Destombes–Rosai–Dorfman disease S, Donadieu J and Amoura Z: Dramatic efficacy of vemurafenib (DRDD) (sinus histiocytosis with massive lymphadenopathy). in both multisystemic and refractory Erdheim-Chester disease Int J Dermatol 47(2): 125-127, 2008. and Langerhans cell histiocytosis harboring the BRAF V600E 58 Zelger B, Cerio R, Orchard G, Fritsch P and Wilson-jones E: mutation. Blood 121(9): 1495-1500, 2013. Histologic and immunohistochemical study comparing xanthoma 42 Haroche J, Charlotte F, Arnaud L, von Deimling A, Hélias- disseminatum and histiocytosis X. Arch Dermatol 128(9): 1207- Rodzewicz Z, Hervier B, Cohen-Aubart F, Launay D, Lesot A, 1212, 1992. Mokhtari K, Canioni D, Galmiche L,Rose C, Schmalzing M, 59 Silva AF, Focaccia R, Oliveira AC, Sementilli A and Reis GF: Croockewit S, Kambouchner M, Copin MC, Fraitag S, Sahm F, Kikuchi-Fujimoto disease: an unusual association with acute Brousse N, Amoura Z, Donadieu J and Emile JF: High renal failure. Braz J Infect Dis 14(6): 621-627, 2010. prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood 120(13): 2700-2703, 2012. 43 Brun AL, Touitou-Gottenberg D, Haroche J, Toledano D, Cluzel P, Beigelman-Aubry C, Piette JC, Amoura Z and Grenier PA: Received March 31, 2014 Erdheim-Chester disease: CT findings of thoracic involvement. Revised May 28, 2014 Eur Radiol 20(11): 2579-2587, 2010. Accepted May 29, 2014

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