HOME

TheInfoList



OR:

Erdheim–Chester disease (ECD) is an extremely
rare disease A rare disease is any disease that affects a small percentage of the population. In some parts of the world, the term orphan disease describes a rare disease whose rarity results in little or no funding or research for treatments, without financi ...
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. 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. The disease involves an infiltration of
lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
-laden macrophages, multi-nucleated
giant cell A giant cell (also known as a multinucleated giant cell, or multinucleate giant cell) is a mass formed by the union of several distinct cells (usually histiocytes), often forming a granuloma. Although there is typically a focus on the patholog ...
s, an inflammatory infiltrate of
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...
s and histiocytes in the
bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
, and a generalized sclerosis of the
long bone The long bones are those that are longer than they are wide. They are one of five types of bones: long, short, flat, irregular and sesamoid. Long bones, especially the femur and tibia, are subjected to most of the load during daily activities ...
s.


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. 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. 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. Orbital involvement is also common in ECD, with approximately 25% of patients developing bilateral and symmetrical exophthalmos as the disease progresses. 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. 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. 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.


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 LCH. 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. Bone
biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, an interventional radiologist, or an interventional cardiology, interventional cardiologist. The process involves the extraction of sampling (medicine), sample ...
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. A diagnosis from neurological imaging may not be definitive. The presence of symmetrical
cerebellar The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or e ...
and pontine signal changes on T2-weighted images seem to be typical of ECD, however,
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
and metabolic diseases must also be considered in the
differential diagnosis In healthcare, a differential diagnosis (DDx) is a method of analysis that distinguishes a particular disease or condition from others that present with similar clinical features. Differential diagnostic procedures are used by clinicians to di ...
. Video-assisted thoracoscopic surgery may be used for diagnostic confirmation and also for therapeutic relief of recurrent pericardial fluid drainage.


Histology

A definitive diagnosis of ECD is made when CD68-positive, CD1a-negative histiocytes are identified in a biopsy specimen. ECD is marked by the buildup of foamy histiocytes and occasional Touton giant cells in a fibrous tissue background. Tissue samples show
xanthoma A xanthoma (pl. xanthomas or xanthomata) (condition: xanthomatosis) is a deposition of yellowish cholesterol-rich material that can appear anywhere in the body in various disease states. They are cutaneous manifestations of lipidosis in which lip ...
tous or xanthogranulomatous infiltration by lipid-laden histiocytes. 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. 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. Unlike LCH, ECD does not stain positive for S-100 proteins or Group 1 CD1a
glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
s, and
electron microscopy An electron microscope is a microscope that uses a beam of electrons as a source of illumination. It uses electron optics that are analogous to the glass lenses of an optical light microscope to control the electron beam, for instance focusing i ...
of cell
cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
does not disclose Birbeck granules. 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 Vemurafenib ( INN), sold under the brand name Zelboraf, is a medication used for the treatment of late-stage melanoma.; It is an inhibitor of the B-Raf enzyme and was developed by Plexxikon. Mechanism of action Vemurafenib causes programm ...
, 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. * Cobimetinib, an oral inhibitor of MEK1 and MEK2, was approved in November 2022. Other treatment options include: *
Interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten ...
* High-dose
corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invo ...
therapy *
Chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
* Pexidartinib, a drug that targets a mutation in the CSF1R pathway and has shown sustained, complete response in limited use. *
Radiation therapy Radiation therapy or radiotherapy (RT, RTx, or XRT) is a therapy, treatment using ionizing radiation, generally provided as part of treatment of cancer, cancer therapy to either kill or control the growth of malignancy, malignant cell (biology), ...
* Surgical debulking *
Ciclosporin Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken Oral administration, orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephr ...
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.


Prognosis

Erdheim–Chester disease was previously associated with high mortality rates. 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. 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.


Epidemiology

Approximately 1500 cases had been reported in the literature as of 2020. ECD affects predominantly adults, with a mean age of 53 years. 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.


History

The first case of ECD was reported by the American pathologist William Chester in 1930, during his visit to the
Austria Austria, formally the Republic of Austria, is a landlocked country in Central Europe, lying in the Eastern Alps. It is a federation of nine Federal states of Austria, states, of which the capital Vienna is the List of largest cities in Aust ...
n pathologist Jakob Erdheim in
Vienna Vienna ( ; ; ) is the capital city, capital, List of largest cities in Austria, most populous city, and one of Federal states of Austria, nine federal states of Austria. It is Austria's primate city, with just over two million inhabitants. ...
. 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.


Society and culture

Th
Erdheim–Chester Disease Global Alliance
is a support and advocacy group with the goal of raising
awareness In philosophy and psychology, awareness is the perception or knowledge of something. The concept is often synonymous with consciousness. However, one can be aware of something without being explicitly conscious of it, such as in the case of bli ...
of and promoting research into ECD. ECD families and patients are also supported by the Histiocytosis Association, Inc.


Media

In the TV show ''
House A house is a single-unit residential building. It may range in complexity from a rudimentary hut to a complex structure of wood, masonry, concrete or other material, outfitted with plumbing, electrical, and heating, ventilation, and air c ...
'', season 2 episode 17, " All In", the initial and final diagnosis of a 6-year-old boy who presents with bloody diarrhea and
ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
is Erdheim–Chester disease.


References


Further reading

* * * * * * * * * * * * * * * *


External links

* {{DEFAULTSORT:Erdheim-Chester disease Rare diseases Histiocytosis Skeletal disorders Syndromes affecting blood Diseases named after discoverers