Medicine:Erdheim–Chester disease

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Erdheim–Chester disease
Other namesErdheim–Chester syndrome or Polyostotic sclerosing histiocytosis
Histopathology slide of Erdheim-Chester disease
SpecialtyHematology-Oncology
SymptomsLong bone pain, muscle pain, joint pain, diabetes insipidus, exophthalmos, abdominal pain
Usual onsetAdults aged 40-60
Differential diagnosisLangerhans' cell histiocytosis, Rosai-Dorfman disease, Takayasu arteritis, granulomatosis with polyangiitis, chronic recurrent multifocal osteomyelitis, neurosarcoidosis
PrognosisAsymptomatic to multisystemic, life-threatening forms
FrequencyUnknown. Approximately 1500 cases (<20 pediatric) have ever been reported

Erdheim–Chester disease (ECD) is an extremely rare disease classified as a non-Langerhans-cell histiocytic neoplasm. In 2016, the World Health Organization (WHO) defined ECD as a slow-growing blood cancer that may originate in the bone marrow or precursor cells.[1] Typical onset occurs in middle aged individuals, although pediatric cases have been documented. The exact cause of ECD remains unknown, though it is believed to be linked to an exaggerated TH1 immune response.[2] The disease involves an infiltration of lipid-laden macrophages, multi-nucleated giant cells, an inflammatory infiltrate of lymphocytes and histiocytes in the bone marrow, and a generalized sclerosis of the long bones.[3]

Signs and symptoms

Erdheim-Chester disease can range from having no symptoms to being fatal, depending on how severe the disease is. It can cause symptoms like bone pain, heart problems, neurological issues, exophthalmos, and constitutional changes in health.[4]

Bone pain is the most common symptom, usually affecting the long bones. The pain is typically mild but constant, occurring close to the joints. Most people with ECD have involvement of the long bones similarly on both sides of the body. More than half of cases also involve other organs, such as the heart, eyes, pituitary gland, brain, and kidneys.[5]

The cardiovascular system is the second most affected organ, involved in more than half of reported cases. While periarterial infiltration caused by ECD usually has minimal impact, it can cause increased blood pressure if it affects the renal arteries, which is often treated with subsequent stenting. Other complications include pericardial infiltration causing tamponade, right-sided myocardial infiltration, valve issues requiring replacement, and peri-coronary infiltration, which can lead to fatal heart attacks.[6][7]

Orbital involvement is also common in ECD, with approximately 25% of patients developing bilateral and symmetrical exophthalmos as the disease progresses.[4] The mass effect from retro-orbital lesions can lead to thickening and twisting of the optic nerves. The lesions may also affect the lacrimal glands, orbital muscles, and retro-orbital fat. Additionally, yellowish periorbital cutaneous xanthomas may develop.[2]

Central diabetes insipidus is the most prevalent central nervous system manifestation in ECD. This results from hypothalamic or pituitary infiltration and can also lead to other hormonal disruptions, such as hyperprolactinemia or gonadotropin deficiency.[2][8]

Renal involvement is seen in approximately 11% of ECD cases, often presenting as obstructive uropathy due to retroperitoneal fibrosis or renal histiocytic infiltration. Symptoms can include abdominal pain, trouble urinating, and kidney problems like swelling or reduced kidney function, which may require dialysis.[6]

Diagnosis

Diagnosis can often be challenging due to several factors, including unclear biopsy findings, the rarity of ECD cases, and the need to distinguish it from Langerhans cell histiocytosis. For these reasons, ECD is often diagnosed based on a combination of clinical symptoms, histology, imaging features, and the presence of mutations in the MAPK/ERK and PI3K/AKT pathways.[9]

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.[8]

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.[10] Video-assisted thoracoscopic surgery may be used for diagnostic confirmation and also for therapeutic relief of recurrent pericardial fluid drainage.[11]

Histology

A definitive diagnosis of ECD is made when CD68-positive, CD1a-negative histiocytes are identified in a biopsy specimen.[2] ECD is marked by the buildup of foamy histiocytes and occasional Touton giant cells in a fibrous tissue background. Tissue samples show xanthomatous or xanthogranulomatous infiltration by lipid-laden histiocytes.[8] Lymphoplasmacytic infiltrates may be present but are usually sparse. The histiocytes in ECD typically show similar markers to reactive histiocytes, except when the BRAF V600E mutation is found. Classic signs, like foamy histiocytes, may not always be visible and could instead show general inflammation and fibrosis.[9]

Immunohistochemical staining (IHC) can assist in diagnosing and classifying ECD versus other histiocytic neoplasms such as LCH. Using BRAF V600E-specific antibodies in IHC testing provides high accuracy for diagnosing the former.[9] 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.[8] More sensitive methods like pyrosequencing or digital droplet polymerase chain reaction may be helpful if aforementioned methods return with inconclusive results.

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.[12][13]
  • Cobimetinib, an oral inhibitor of MEK1 and MEK2, was approved in November 2022.[14]

Other treatment options include:

As there is no definitive cure, treatment should also focus on extending life and enhancing quality of life. Psychological support is important, as effective physical treatment often leads to a chronic condition, which may involve various challenges, deficits, and secondary complications.[17]

Prognosis

Erdheim–Chester disease was previously associated with high mortality rates.[18] 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.[12][16][19][20] In 2019, the Mayo Clinic released guidelines for diagnosing and treating the disease, emphasizing the importance of genetic testing. Recent research findings on the disease's genomic structure, especially mutations in the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway, have enabled the use of targeted therapies for most patients.[9]

Epidemiology

Approximately 1500 cases had been reported in the literature as of 2020.[21] ECD affects predominantly adults, with a mean age of 53 years.[8] Cases in children are very rare, with fewer than 20 reported as of 2022. No variations in clinical presentation, imaging, histopathology, or treatment response based on gender or race have been observed.[4]

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.[22]

ECD was previously considered an inflammatory condition. However, current literature supports its clonal origin, which emerged with the discovery of recurrent activating mutations in the MAPK/ERK pathway in over 90% of patients. This led to its inclusion in the 2016 World Health Organization classification of hematopoietic and lymphoid tumors.[23]

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.[24][25] ECD families and patients are also supported by the Histiocytosis Association, Inc.[25][26]

Media

In the TV show House, season 2 episode 17, "All In", the initial and final diagnosis of a 6-year-old boy who presents with bloody diarrhea and ataxia is Erdheim–Chester disease.[27]

References

  1. ↑ "Erdheim-Chester Disease Declared a Histiocytic Neoplasm". 18 May 2016. http://erdheim-chester.org/wp-content/uploads/2015/05/ECD-Declared-a-Histiocytic-Neoplasm_FINAL1.pdf. 
  2. ↑ 2.0 2.1 2.2 2.3 Mazor, Roei D.; Manevich-Mazor, Mirra; Shoenfeld, Yehuda (2013-09-08). "Erdheim-Chester Disease: a comprehensive review of the literature". Orphanet Journal of Rare Diseases 8: 137. doi:10.1186/1750-1172-8-137. ISSN 1750-1172. PMID 24011030. 
  3. ↑ "Erdheim–Chester disease". Medical Subject Headings. United States National Library of Medicine. 8 July 2008. https://meshb.nlm.nih.gov/record/ui?ui=D031249. 
  4. ↑ 4.0 4.1 4.2 Kanakis, Menelaos; Petrou, Petros; Lourida, Giota; Georgalas, Ilias (2022-03-01). "Erdheim-Chester disease: a comprehensive review from the ophthalmologic perspective". Survey of Ophthalmology 67 (2): 388–410. doi:10.1016/j.survophthal.2021.05.013. ISSN 0039-6257. PMID 34081930. https://www.sciencedirect.com/science/article/abs/pii/S0039625721001375. 
  5. ↑ "Erdheim-Chester Disease" (in en-us). Histiocytosis Association. https://www.histio.org/page.aspx?pid=403. 
  6. ↑ 6.0 6.1 Abdelfattah, Ahmed Maher; Arnaout, Karim; Tabbara, Imad A. (2014-07-01). "Erdheim-Chester Disease: A Comprehensive Review" (in en). Anticancer Research 34 (7): 3257–3261. ISSN 0250-7005. PMID 24982329. https://ar.iiarjournals.org/content/34/7/3257.long. 
  7. ↑ "[Recurrent pericardial effusion as first manifestation of Erdheim-Chester disease]" (in de). Deutsche Medizinische Wochenschrift 136 (39): 1952–1956. September 2011. doi:10.1055/s-0031-1286368. PMID 21935854. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 "Erdheim-Chester disease. Clinical and radiologic characteristics of 59 cases". Medicine 75 (3): 157–169. May 1996. doi:10.1097/00005792-199605000-00005. PMID 8965684. 
  9. ↑ 9.0 9.1 9.2 9.3 "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. doi:10.1016/j.mayocp.2019.02.023. PMID 31472931. 
  10. ↑ "Cerebral Erdheim-Chester disease: case report and review of the literature". Neuroradiology 45 (4): 241–245. April 2003. doi:10.1007/s00234-003-0950-z. PMID 12687308. 
  11. ↑ "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. doi:10.1016/j.ijscr.2011.12.001. PMID 22288060. 
  12. ↑ 12.0 12.1 "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. doi:10.1182/blood-2012-07-446286. PMID 23258922. 
  13. ↑ "FDA Approves First Treatment for Erdheim-Chester Disease". Pharmacy Practice News. 6 November 2017. http://www.pharmacypracticenews.com/FDA-Approvals/Article/11-17/FDA-Approves-First-Treatment-for-Erdheim-Chester-Disease/45182/. 
  14. ↑ "FDA Approves Cobimetinib for Histiocytic Neoplasms" (in en). 2 November 2022. https://www.onclive.com/view/fda-approves-cobimetinib-for-histiocytic-neoplasms. 
  15. ↑ "Erdheim Chester Disease". M. D. Anderson Cancer Center. http://www.mdanderson.org/patient-and-cancer-information/cancer-information/cancer-types/eye-cancer/index.html. 
  16. ↑ 16.0 16.1 "Sustained, complete response to pexidartinib in a patient with CSF1R-mutated Erdheim-Chester disease". American Journal of Hematology 97 (3): 293–302. March 2022. doi:10.1002/ajh.26441. PMID 34978715. 
  17. ↑ Mazor, Roei D (2013). "Erdheim-Chester Disease: a comprehensive review of the literature" (in English). Orphanet Journal of Rare Diseases (BMC) 8 (137): 7–10. doi:10.1186/1750-1172-8-137. PMID 4011030. 
  18. ↑ "Treatment of Erdheim-Chester disease with cladribine: a rational approach". The British Journal of Ophthalmology 88 (6): 844–847. June 2004. doi:10.1136/bjo.2003.035584. PMID 15148234. 
  19. ↑ "Vemurafenib in the Treatment of Erdheim Chester Disease: A Systematic Review". Cureus 14 (6). June 2022. doi:10.7759/cureus.25935. PMID 35844342. 
  20. ↑ The ASCO Post Staff (2 November 2022). "FDA Approves Oral MEK Inhibitor Cobimetinib for Histiocytic Neoplasms". The ASCO Post. https://ascopost.com/news/november-2022/fda-approves-oral-mek-inhibitor-cobimetinib-for-histiocytic-neoplasms/. 
  21. ↑ Haroche, Julien; Cohen-Aubart, Fleur; Amoura, Zahir (2020-04-16). "Erdheim-Chester disease". Blood 135 (16): 1311–1318. doi:10.1182/blood.2019002766. ISSN 0006-4971. PMID 32107533. https://ashpublications.org/blood/article/135/16/1311/452578/Erdheim-Chester-disease. 
  22. ↑ "Über Lipoidgranulomatose". Virchows Archiv für Pathologische Anatomie und Physiologie und für Klinische Medizin 279 (2): 561–602. 1930. doi:10.1007/BF01942684. 
  23. ↑ Goyal, Gaurav; Young, Jason R.; Koster, Matthew J.; Tobin, W. Oliver; Vassallo, Robert; Ryu, Jay H.; Davidge-Pitts, Caroline J.; Hurtado, Maria D. et al. (2019-10-01). "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" (in English). Mayo Clinic Proceedings 94 (10): 2054–2071. doi:10.1016/j.mayocp.2019.02.023. ISSN 0025-6196. PMID 31472931. https://www.mayoclinicproceedings.org/article/S0025-6196(19)30273-3/fulltext. 
  24. ↑ "Erdheim–Chester Disease". ECD Global Alliance. http://www.erdheim-chester.org. 
  25. ↑ 25.0 25.1 "Erdheim Chester disease" (in en-US). http://rarediseases.org/rare-diseases/erdheim-chester-disease/#supporting-organizations. 
  26. ↑ "What Do I Do Now? - Erdheim-Chester Disease". Histiocytosis Association. http://www.histio.org/page.aspx?pid=592#Creatingasupportnetwork. 
  27. ↑ "Internet Movie Database". https://www.imdb.com/title/tt0774235/?ref_=ttep_ep17. 

Further reading

  • "Rationale and efficacy of interleukin-1 targeting in Erdheim-Chester disease". Blood 116 (20): 4070–4076. November 2010. doi:10.1182/blood-2010-04-279240. PMID 20724540. 
  • "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. doi:10.1002/art.24848. PMID 19790052. 
  • "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. doi:10.1002/art.27672. PMID 20662053. 
  • "Treatment of refractory Erdheim-Chester disease with double autologous hematopoietic stem-cell transplantation". Annals of Internal Medicine 135 (9): 844–845. November 2001. doi:10.7326/0003-4819-135-9-200111060-00027. PMID 11694122. 
  • "Successful treatment of Erdheim-Chester disease, a non-Langerhans-cell histiocytosis, with interferon-alpha". Blood 106 (9): 2992–2994. November 2005. doi:10.1182/blood-2005-06-2238. PMID 16020507. 
  • "Erdheim-Chester disease: CT findings of thoracic involvement". European Radiology 20 (11): 2579–2587. November 2010. doi:10.1007/s00330-010-1830-7. PMID 20563815. 
  • "Erdheim-Chester disease: case report with unique postmortem magnetic resonance imaging, high-resolution radiography, and pathologic correlation". Clinical Imaging 33 (2): 150–153. 2009. doi:10.1016/j.clinimag.2008.09.009. PMID 19237062. 
  • "Cerebral, facial, and orbital involvement in Erdheim-Chester disease: CT and MR imaging findings". Radiology 255 (2): 586–594. May 2010. doi:10.1148/radiol.10090320. PMID 20413768. 
  • "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. doi:10.1097/01.md.0000145368.17934.91. PMID 15525849. 
  • "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. doi:10.1161/CIRCULATIONAHA.108.825075. PMID 19564564. 
  • "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. doi:10.1002/art.22165. PMID 17009306. 
  • "Imatinib mesylate for platelet-derived growth factor receptor-beta-positive Erdheim-Chester histiocytosis". Blood 111 (11): 5413–5415. June 2008. doi:10.1182/blood-2008-03-148304. PMID 18502845. 
  • "Response of histiocytoses to imatinib mesylate: fire to ashes". Journal of Clinical Oncology 28 (31): e633–e636. November 2010. doi:10.1200/JCO.2010.29.9073. PMID 20733125. 
  • "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. doi:10.1007/s00415-006-0160-9. PMID 17063320. 
  • "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. PMID 12747282. 
  • "Erdheim-Chester disease with predominant mesenteric localization: lack of efficacy of interferon alpha". Joint Bone Spine 76 (3): 315–317. May 2009. doi:10.1016/j.jbspin.2008.09.013. PMID 19119043. 
Classification

Template:Histiocytosis



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