Erdheim–Chester disease explained

Erdheim–Chester disease
Synonyms:	Erdheim–Chester syndrome or Polyostotic sclerosing histiocytosis

Erdheim–Chester disease (ECD) is an extremely rare disease characterized by the abnormal multiplication of a specific type of white blood cells called histiocytes, or tissue macrophages (technically, this disease is termed a non-Langerhans-cell histiocytosis). It was declared a histiocytic neoplasm by the World Health Organization in 2016.^[1] Onset typically is in middle age, although younger patients have been documented. The disease involves an infiltration of lipid-laden macrophages, multinucleated giant cells, an inflammatory infiltrate of lymphocytes and histiocytes in the bone marrow, and a generalized sclerosis of the long bones.^[2]

Signs and symptoms

Long bone involvement is almost universal in ECD patients and is bilateral and symmetrical in nature. More than 50% of cases have some sort of extraskeletal involvement. This can include kidney, skin, brain and lung involvement, and less frequently retroorbital tissue, pituitary gland and heart involvement is observed.^[3]

Bone pain is the most frequent of all symptoms associated with ECD and mainly affects the lower limbs, knees and ankles. The pain is often described as mild but permanent, and in nature. Exophthalmos occurs in some patients and is usually bilateral, symmetric and painless, and in most cases it occurs several years before the final diagnosis. Recurrent pericardial effusion can be a manifestation,^[4] as can morphological changes in adrenal size and infiltration.^[5]

A review of 59 case studies by Veyssier-Belot et al. in 1996 reported the following symptoms in order of frequency of occurrence:^[6]

• Bone pain
• Retroperitoneal fibrosis
• Diabetes insipidus
• Exophthalmos
• Xanthomas
• Neurological and central nervous system involvement
• Dyspnea caused by interlobular septal and pleural thickening
• Kidney failure
• Hypopituitarism
• Liver failure

Diagnosis

Radiologic osteosclerosis and histology are the main diagnostic features. Diagnosis can often be difficult because of the rareness of ECD as well as the need to differentiate it from LCH. A diagnosis from neurological imaging may not be definitive. The presence of symmetrical cerebellar and pontine signal changes on T2-weighted images seem to be typical of ECD, however, multiple sclerosis and metabolic diseases must also be considered in the differential diagnosis.^[7] ECD is not a common cause of exophthalmos but can be diagnosed by biopsy. However, like all biopsies, this may be inconclusive.^[8] Video-assisted thoracoscopic surgery may be used for diagnostic confirmation and also for therapeutic relief of recurrent pericardial fluid drainage.^[9]

Histology

Histologically, ECD differs from Langerhans cell histiocytosis (LCH) in a number of ways. Unlike LCH, ECD does not stain positive for S-100 proteins or Group 1 CD1a glycoproteins, and electron microscopy of cell cytoplasm does not disclose Birbeck granules. Tissue samples show xanthomatous or xanthogranulomatous infiltration by lipid-laden or foamy histiocytes, and are usually surrounded by fibrosis. Bone biopsy is said to offer the greatest likelihood of reaching a diagnosis. It would appear that approximately half these patients harbor point mutations of the BRAF gene at codon 600 substituting the amino acid glutamine for valine. In some, there is histiocyte proliferation, and on staining, the section is CD68+ and CD1a-.

Treatment

There are two FDA-approved targeted drugs to treat ECD.

• Vemurafenib, an oral agent approved in 2019, targets the BRAF protein. It was approved after showing dramatic efficacy in ECD patients harboring the BRAF V600E mutation.^{[10] [11]}
• Cobimetinib, an oral inhibitor of MEK1 and MEK2, was approved in November 2022.^[12]

Other treatment options include:

• Interferon-α
• High-dose corticosteroid therapy
• Chemotherapy
• Pexidartinib, a drug that targets a mutation in the CSF1R pathway and has shown sustained, complete response in limited use.^[13]
• Radiation therapy
• Surgical debulking
• Ciclosporin

Prognosis

Erdheim–Chester disease was previously associated with high mortality rates.^[14] However, long-term survival is now more promising. Recent studies have reported that some patients receiving targeted therapies showed no disease progression. Targeted therapies using BRAF, MEK and/or other inhibitors have been dramatically efficacious.^{[15] [16]} In 2019, the Mayo Clinic published guidelines for the diagnosis and treatment of the disease, stressing the importance of genetic testing: "Recent insights into their genomic architecture demonstrating mitogen-activated protein kinase/extracellular signal-regulated kinase pathway mutations have now enabled potential treatment with targeted therapies in most patients."^[17]

Epidemiology

Approximately 500 cases had been reported in the literature as of 2014.^[18] ECD affects predominantly adults, with a mean age of 53 years.

History

The first case of ECD was reported by the American pathologist William Chester in 1930, during his visit to the Austrian pathologist Jakob Erdheim in Vienna.^[19]

Society and culture

The Erdheim–Chester Disease Global Alliance is a support and advocacy group with the goal of raising awareness of and promoting research into ECD.^{[20] [21]} ECD families and patients are also supported by the Histiocytosis Association, Inc.^[22]

Media

In the TV show House, season 2 episode 17, "All In", the final diagnosis of a 6-year-old boy who presents with bloody diarrhea and ataxia is Erdheim–Chester disease.^[23]

Further reading

• Aouba A, Georgin-Lavialle S, Pagnoux C, Martin Silva N, Renand A, Galateau-Salle F, Le Toquin S, Bensadoun H, Larousserie F, Silvera S, Provost N, Candon S, Seror R, de Menthon M, Hermine O, Guillevin L, Bienvenu B . 6 . Rationale and efficacy of interleukin-1 targeting in Erdheim-Chester disease . Blood . 116 . 20 . 4070–4076 . November 2010 . 20724540 . 10.1182/blood-2010-04-279240 . free. none .
• Arnaud L, Malek Z, Archambaud F, Kas A, Toledano D, Drier A, Zeitoun D, Cluzel P, Grenier PA, Chiras J, Piette JC, Amoura Z, Haroche J . 6 . 18F-fluorodeoxyglucose-positron emission tomography scanning is more useful in followup than in the initial assessment of patients with Erdheim-Chester disease . Arthritis and Rheumatism . 60 . 10 . 3128–3138 . October 2009 . 19790052 . 10.1002/art.24848 . free. none .
• Arnaud L, Pierre I, Beigelman-Aubry C, Capron F, Brun AL, Rigolet A, Girerd X, Weber N, Piette JC, Grenier PA, Amoura Z, Haroche J . 6 . Pulmonary involvement in Erdheim-Chester disease: a single-center study of thirty-four patients and a review of the literature . Arthritis and Rheumatism . 62 . 11 . 3504–3512 . November 2010 . 20662053 . 10.1002/art.27672 . free . none.
• Boissel N, Wechsler B, Leblond V . Treatment of refractory Erdheim-Chester disease with double autologous hematopoietic stem-cell transplantation . Annals of Internal Medicine . 135 . 9 . 844–845 . November 2001 . 11694122 . 10.7326/0003-4819-135-9-200111060-00027 . none.
• Braiteh F, Boxrud C, Esmaeli B, Kurzrock R . Successful treatment of Erdheim-Chester disease, a non-Langerhans-cell histiocytosis, with interferon-alpha . Blood . 106 . 9 . 2992–2994 . November 2005 . 16020507 . 10.1182/blood-2005-06-2238 . free . none.
• Brun AL, Touitou-Gottenberg D, Haroche J, Toledano D, Cluzel P, Beigelman-Aubry C, Piette JC, Amoura Z, Grenier PA . 6 . Erdheim-Chester disease: CT findings of thoracic involvement . European Radiology . 20 . 11 . 2579–2587 . November 2010 . 20563815 . 10.1007/s00330-010-1830-7 . 5775587 . none.
• de Abreu MR, Castro MO, Chung C, Trudell D, Biswal S, Wesselly M, Resnick D . Erdheim-Chester disease: case report with unique postmortem magnetic resonance imaging, high-resolution radiography, and pathologic correlation . Clinical Imaging . 33 . 2 . 150–153 . 2009 . 19237062 . 10.1016/j.clinimag.2008.09.009 . none.
• Drier A, Haroche J, Savatovsky J, Godenèche G, Dormont D, Chiras J, Amoura Z, Bonneville F . 6 . Cerebral, facial, and orbital involvement in Erdheim-Chester disease: CT and MR imaging findings . Radiology . 255 . 2 . 586–594 . May 2010 . 20413768 . 10.1148/radiol.10090320 . none.
• Haroche J, Amoura Z, Dion E, Wechsler B, Costedoat-Chalumeau N, Cacoub P, Isnard R, Généreau T, Wechsler J, Weber N, Graef C, Cluzel P, Grenier P, Piette JC . 6 . Cardiovascular involvement, an overlooked feature of Erdheim-Chester disease: report of 6 new cases and a literature review . Medicine . 83 . 6 . 371–392 . November 2004 . 15525849 . 10.1097/01.md.0000145368.17934.91 . 1426013 . none.
• Haroche J, Cluzel P, Toledano D, Montalescot G, Touitou D, Grenier PA, Piette JC, Amoura Z . 6 . Images in cardiovascular medicine. Cardiac involvement in Erdheim-Chester disease: magnetic resonance and computed tomographic scan imaging in a monocentric series of 37 patients . Circulation . 119 . 25 . e597–e598 . June 2009 . 19564564 . 10.1161/CIRCULATIONAHA.108.825075 . free . none.
• Haroche J, Amoura Z, Trad SG, Wechsler B, Cluzel P, Grenier PA, Piette JC . Variability in the efficacy of interferon-alpha in Erdheim-Chester disease by patient and site of involvement: results in eight patients . Arthritis and Rheumatism . 54 . 10 . 3330–3336 . October 2006 . 17009306 . 10.1002/art.22165 . none.
• Haroche J, Amoura Z, Charlotte F, Salvatierra J, Wechsler B, Graux C, Brousse N, Piette JC . 6 . Imatinib mesylate for platelet-derived growth factor receptor-beta-positive Erdheim-Chester histiocytosis . Blood . 111 . 11 . 5413–5415 . June 2008 . 18502845 . 10.1182/blood-2008-03-148304 . free . none.
• Janku F, Amin HM, Yang D, Garrido-Laguna I, Trent JC, Kurzrock R . Response of histiocytoses to imatinib mesylate: fire to ashes . Journal of Clinical Oncology . 28 . 31 . e633–e636 . November 2010 . 20733125 . 10.1200/JCO.2010.29.9073 . free . none.
• Lachenal F, Cotton F, Desmurs-Clavel H, Haroche J, Taillia H, Magy N, Hamidou M, Salvatierra J, Piette JC, Vital-Durand D, Rousset H . 6 . Neurological manifestations and neuroradiological presentation of Erdheim-Chester disease: report of 6 cases and systematic review of the literature . Journal of Neurology . 253 . 10 . 1267–1277 . October 2006 . 17063320 . 10.1007/s00415-006-0160-9 . 27976718 . none.
• Mossetti G, Rendina D, Numis FG, Somma P, Postiglione L, Nunziata V . Biochemical markers of bone turnover, serum levels of interleukin-6/interleukin-6 soluble receptor and bisphosphonate treatment in Erdheim-Chester disease . Clinical and Experimental Rheumatology . 21 . 2 . 232–236 . 2003 . 12747282 . none.
• Perlat A, Decaux O, Sébillot M, Grosbois B, Desfourneaux V, Meadeb J . Erdheim-Chester disease with predominant mesenteric localization: lack of efficacy of interferon alpha . Joint Bone Spine . 76 . 3 . 315–317 . May 2009 . 19119043 . 10.1016/j.jbspin.2008.09.013 . none.

Notes and References

1. Web site: Erdheim-Chester Disease Declared a Histiocytic Neoplasm . 2018-07-18 . 18 May 2016 . erdheim-chester.org .
2. Web site: Erdheim–Chester disease . Medical Subject Headings . United States National Library of Medicine . 8 July 2008 . 19 June 2008 .
3. Web site: Erdheim-Chester Disease . Histiocytosis Association . en-us. 2017-12-21.
4. Lutz SZ, Schmalzing M, Vogel-Claussen J, Adam P, May AE . [Recurrent pericardial effusion as first manifestation of Erdheim-Chester disease] . de . Deutsche Medizinische Wochenschrift . 136 . 39 . 1952–1956 . September 2011 . 21935854 . 10.1055/s-0031-1286368 . Recurrent pericardial effusion as first manifestation of Erdheim-Chester disease .
5. Haroche J, Amoura Z, Touraine P, Seilhean D, Graef C, Birmelé B, Wechsler B, Cluzel P, Grenier PA, Piette JC . 6 . Bilateral adrenal infiltration in Erdheim-Chester disease. Report of seven cases and literature review . The Journal of Clinical Endocrinology and Metabolism . 92 . 6 . 2007–2012 . June 2007 . 17405844 . 10.1210/jc.2006-2018 . free .
6. Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, Wechsler J, Brun B, Remy M, Wallaert B, Petit H, Grimaldi A, Wechsler B, Godeau P . 6 . Erdheim-Chester disease. Clinical and radiologic characteristics of 59 cases . Medicine . 75 . 3 . 157–169 . May 1996 . 8965684 . 10.1097/00005792-199605000-00005 . 32150913 . free .
7. Weidauer S, von Stuckrad-Barre S, Dettmann E, Zanella FE, Lanfermann H . Cerebral Erdheim-Chester disease: case report and review of the literature . Neuroradiology . 45 . 4 . 241–245 . April 2003 . 12687308 . 10.1007/s00234-003-0950-z . 9513277 .
8. Web site: Erdheim Chester Disease . M. D. Anderson Cancer Center . 2007-08-26 .
9. Egan A, Sorajja D, Jaroszewski D, Mookadam F . Erdheim-Chester disease: The role of video-assisted thoracoscopic surgery in diagnosing and treating cardiac involvement . International Journal of Surgery Case Reports . 3 . 3 . 107–110 . 2012 . 22288060 . 3267285 . 10.1016/j.ijscr.2011.12.001 .
10. Haroche J, Cohen-Aubart F, Emile JF, Arnaud L, Maksud P, Charlotte F, Cluzel P, Drier A, Hervier B, Benameur N, Besnard S, Donadieu J, Amoura Z . 6 . Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation . Blood . 121 . 9 . 1495–1500 . February 2013 . 23258922 . 10.1182/blood-2012-07-446286 . free .
11. Web site: FDA Approves First Treatment for Erdheim-Chester Disease . Pharmacy Practice News . 6 November 2017 .
12. Web site: Rosa K . 2 November 2022 . FDA Approves Cobimetinib for Histiocytic Neoplasms . 2022-11-19 . OncLive . en.
13. Abeykoon JP, Lasho TL, Dasari S, Rech KL, Ranatunga WK, Manske MK, Tischer A, Ravindran A, Young JR, Tobin WO, Flanagan EP, Nowakowski KE, Ruan GJ, Shah MV, Bennani NN, Vassallo R, Ryu JH, Koster MJ, Davidge-Pitts CJ, Patnaik MM, Wu X, Witzig TE, Goyal G, Go RS . 6 . Sustained, complete response to pexidartinib in a patient with CSF1R-mutated Erdheim-Chester disease . American Journal of Hematology . 97 . 3 . 293–302 . March 2022 . 34978715 . 9536810 . 10.1002/ajh.26441 .
14. Myra C, Sloper L, Tighe PJ, McIntosh RS, Stevens SE, Gregson RH, Sokal M, Haynes AP, Powell RJ . 6 . Treatment of Erdheim-Chester disease with cladribine: a rational approach . The British Journal of Ophthalmology . 88 . 6 . 844–847 . June 2004 . 15148234 . 1772168 . 10.1136/bjo.2003.035584 .
15. Aziz SN, Proano L, Cruz C, Tenemaza MG, Monteros G, Hassen G, Baskar A, Argudo JM, Duenas JB, Fabara SP . 6 . Vemurafenib in the Treatment of Erdheim Chester Disease: A Systematic Review . Cureus . 14 . 6 . e25935 . June 2022 . 35844342 . 10.7759/cureus.25935 . free . 9282605 .
16. Web site: The ASCO Post Staff . 2 November 2022 . FDA Approves Oral MEK Inhibitor Cobimetinib for Histiocytic Neoplasms . The ASCO Post . 2022-11-19 .
17. Goyal G, Young JR, Koster MJ, Tobin WO, Vassallo R, Ryu JH, Davidge-Pitts CJ, Hurtado MD, Ravindran A, Sartori Valinotti JC, Bennani NN, Shah MV, Rech KL, Go RS . 6 . The Mayo Clinic Histiocytosis Working Group Consensus Statement for the Diagnosis and Evaluation of Adult Patients With Histiocytic Neoplasms: Erdheim-Chester Disease, Langerhans Cell Histiocytosis, and Rosai-Dorfman Disease . Mayo Clinic Proceedings . 94 . 10 . 2054–2071 . October 2019 . 31472931 . 10.1016/j.mayocp.2019.02.023 . 201713697 . free .
18. Haroche J, Arnaud L, Cohen-Aubart F, Hervier B, Charlotte F, Emile JF, Amoura Z . Erdheim-Chester disease . Current Rheumatology Reports . 16 . 4 . 412 . April 2014 . 24532298 . 10.1007/s11926-014-0412-0 . free .
19. 10.1007/BF01942684 . Über Lipoidgranulomatose . 1930 . Chester W . 27359311 . Virchows Archiv für Pathologische Anatomie und Physiologie und für Klinische Medizin . 279 . 2 . 561–602.
20. Web site: Erdheim–Chester Disease. ECD Global Alliance. 2009-05-08.
21. Web site: Erdheim Chester disease . NORD (National Organization for Rare Disorders). en-US. 2016-03-01.
22. Web site: What Do I Do Now? - Erdheim-Chester Disease . Histiocytosis Association . 2016-03-01.
23. Web site: Internet Movie Database . IMDB . 27 October 2021.