Frequently Asked Questions about Erdheim-Chester disease (ECD)

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General information about histiocytoses

1 - What does histiocytosis mean?

Histiocytoses are defined as histiocytic disorders due to an abnormal accumulation of histiocytes. They include a wide variety of conditions that affect both children and adults.

2 - What is a a histiocyte?

A histiocyte is one kind of white blood cell which belongs to the immune system. There are histiocytes in many parts of the body, especially in the bone-marrow, blood, skin, liver, lungs, lymphatic glands and spleen. Their functions are associated to the immune response like the destruction of foreign bodies and infection defence.

3 - Are all histiocytic disorders the same?

No, histiocytic disorders are very heterogeneous and their treatment is different. Diagnosis can be difficult, especially in the rarest forms.

4 - What is the basis for the classification of histiocytic disorders?

The diseases are divided in Langerhans cell histiocytoses, non-Langerhans cell histiocytoses, and malignant histiocytoses.

In Langerhans cell histiocytosis, there are different forms, some of which are localized (e.g. isolated bone, isolated skin, or isolated lung disease). Other Langerhans cell histiocytoses are multi-systemic forms which affect several organs and/or organ systems.

Non-Langerhans cell histiocytoses can be divided into the following different groups:
• Histiocytoses of exogenous origin
• Infectious histiocytoses
• Hemophagocytic histiocytoses
• Hereditary histiocytoses
• Sporadic histiocytoses

"Histiocytic disorders" are generally defined by their constitutive cell, on the basis of pathological criteria (tissue examination) but require also the correct clinical context.

There have been many difficulties to classify this group of diseases. Since 1987, the Histiocyte Society has proposed the classification according to the relationship to normal histiocyte subsets. The revision done in 1997 took into account the biologic behaviour. The disorders are now divided in two broad groups, those of varying biological behaviour and those that are truly malignant. Within each category the disorders are subclassified according to their affiliation with different cell types.

5 - How can I find a patient association for histiocytic disorders?

If you are suffering from a histiocytic disorder, you will find a list of all patient associations worldwide known by our team in our web portal.
Links:
[1] Histio International
[2] Histio in countries

General information about Erdheim-Chester disease (ECD)

1 - Why is the disease called ECD?

The disease was first described in the medical literature in 1930 by the Austrian pathologist Jakob Erdheim, and the American pathologist William Chester (“lipoid granulomatosis”). It is therefore called Erdheim-Chester disease (ECD).

2 - What is ECD?

ECD is an extremely rare disorder that can affect many different systems or organs in the body. It is characterized by excessive production and/or accumulation of histiocytes and is considered to be a sporadic non-Langerhans cell histiocytosis.

3 - What causes ECD?

So far, it’s precise cause is unknown. (See also “Research”)

4 - How common is ECD?

ECD is an extremely rare disorder. There have been approximately 500 published cases of ECD in the world since the first description in 1930. Most published articles on ECD are anecdotal in nature. As it is so rare and not discussed in the common textbooks of medicine so far, many doctors have never heard of it. It is also considered difficult to diagnose. For these reasons the disease is under-diagnosed and may not be quite as rare as thought. Nevertheless there has been much progress in the general knowledge of the disease in the past 10 years.

5 - At what age does ECD usually occur?

ECD usually affects adults, although there are childhood cases documented (about 10 known cases worldwide). The average age at onset is 53 years of age in the largest monocentric series reported in 2011, with a strong male predilection (about 75%).

6 - Is the course of ECD the same in all patients?

No. The behaviour of the disease varies between patients. The clinical course is mainly depending on the extent and distribution of the disease. It reaches from asymptomatic bone lesions to multisystemic life-threatening forms.

7 - Can ECD be inherited?

No familial cases of ECD have been described so far.

8 - Is ECD contagious?

ECD has not been found to be contagious.

9 - What kind of disease is ECD?

ECD is not currently categorized as a cancer, infection, auto-immune, or a storage disorder disease. It is described as a rare multi-system, non-Langerhans cell histiocytosis of unknown origin. Nevertheless, the recent finding of certain mutations (BRAFV600E) in half of the patients raises the question whether these cases are clonal, which means cancer-like (see also “Research”).

Diagnosis of Erdheim-Chester disease (ECD)

1 - How is ECD diagnosed?

It is often difficult to diagnose ECD. As some diseases can exhibit symptoms that closely resemble ECD, only a doctor can provide a correct diagnosis. ECD is diagnosed through imaging studies and the histologic proof of the affected tissue - called biopsy - is mandatory. (This can be peri-renal fat, bone, sinus etc.) Different additional tests might be necessary to determine the extent of the disease.

The diagnostic criteria which have been defined are:
1. Typical histologic findings:
Infiltration with foamy histiocytes nested among polymorphic granuloma and fibrosis or xanthogranulomatosis with CD68+ and CD1a- immunohistochemical staining
2. Typical skeletal findings:
• X-rays showing bilateral and symmetric cortical osteosclerosis of the diaphyseal and metaphyseal regions in the long bones and/or
• Symmetric and abnormally increased labelling of the distal ends of the long bones of the lower limbs, and sometimes the upper limbs, on 99Tc bone scintigraphy.

2 - How can I be sure that the diagnosis of ECD is correct?

A correct diagnosis relies upon findings of a biopsy of the affected tissue along with imaging studies. The tissue samples should be reviewed by a trained pathologist and imaging by a radiologist who have knowledge of ECD.

3 - What additional tests may be needed to know the disease extent?

Additional tests may be blood studies and imaging (x-rays), echocardiogram, computed tomography (CT), magnetic resonance (MRI), bone scintigraphy, positrone emission (PET scan). These tests are needed to assess the extent of the disease. The particular tests performed for an individual patient may depend on the particular symptoms and physical signs experienced. It is important to make a systematic study of the organs possibly affected: skeleton, lungs, heart, central nervous system, kidneys, eyes, pituitary, skin, teeth.

4 - What diseases can mimick ECD and can be confused with it (differential diagnosis)?

The symptoms and signs of ECD can very closely resemble to many other diseases, among which mainly the following must be considered while trying to reach a diagnosis:
• Takayasu arteritis (mainly due to certain imaging aspects)
• Retroperitoneal fibrosis
• Rosai Dorfman disease, another non-Langerhans cell histiocytosis
• Langerhans cell histiocytosis
This list in not exhaustive. The diagnosis of ECD relies on the presence of a strong clinico-radiologic and pathologic context which must be evaluated by a physician with detailed knowledge about the diagnostic criteria.

5 - Why does it take so long to diagnose ECD?

Diagnosis of ECD is sometimes a difficult issue for physicians due to several aspects:
1. The symptoms can vary depending on the organ(s) involved.
2. ECD is a very rare disease. It may present with symptoms similar to those in a more common disease, making a final diagnosis difficult.

Possible symptoms and signs of Erdheim-Chester disease (ECD)

1 - What are the first symptoms of ECD?

The first symptoms of ECD are extremely variable. Diabetes insipidus (15% of the patients) and bone pain (13%) are perhaps the most common first symptoms. Other possible first symptoms are exophthalmos, seizures, sinusitis, fever, etc.

2 - Which organs and/or organ systems may be affected by ECD?

ECD may affect bone (= rheumatologic involvement), pituitary (= diabetes insipidus), central nervous system, heart, kidneys, eyes, skin and lungs. Ca. 98% of the patients show extra-osseous involvement.

3 - Which symptoms and signs can occur when ECD affects bone?

In 95-100% of cases of ECD, there is bone involvement seen in bone scintigraphy (or X-ray, PET-CT, MRI), but only 50% of the patients have bone pain in the long bones of the legs and arms on both sides (bilateral). Bone pain usually affects the lower limbs and less frequently the upper limbs. It is important to note some patients never have bone pain. The intensity of bone pain is variable, ranging between mild and very intense.

4 - Which findings can be observed in blood samples?

There might be the following findings in a blood test:
• increased C-reactive protein found in the majority of patients implying an inflammatory condition occurring somewhere within the body
• a low number of red blood cells (moderate anemia due to the systemic inflammatory response), and/or
• high creatinine level indicating a dysfunction of the kidneys (hydronephrosis).

5 - What symptoms and signs can be observed when ECD affects the pituitary?

If ECD involves the pituitary, excessive urination and extreme thirst (up to 7 litres a day) can occur. Reduction of fluid intake doesn’t have any effect on the excretion of urine. This condition is called diabetes insipidus.

6 - What are possible symptoms and signs when ECD affects the central nervous system (CNS)?

Many patients with ECD show abnormalities in CNS imaging, but approximately half of them do not show any neurological symptoms. Possible neurological symptoms are: balance issues; difficulty walking (ataxia); slurred speech (dysarthria); involuntary rapid eye movements (nystagmus), and swallowing difficulties. More rarely, seizures, headaches and psychiatric or cognitive impairment are observed.
CNS involvement is a major prognostic factor of ECD.

7 - Which symptoms and signs can occur when ECD affects the kidneys?

If ECD involves the kidney(s), lower back, flank or abdominal pain might occur, often associated with kidney issues (retroperitoneal fibrosis). Kidney function can be reduced causing high creatinine level in blood tests (due to hydronephrosis) and high blood pressure (hypertension due to infiltration and sheathing of renal arteries).

8 - Which symptoms and signs can be observed when ECD affects the eyes?

If ECD involves the eyes, there can be a bulging of the eye called exophthalmos. Vision difficulties might occur. These may include bilateral fluttering in the peripheral vision, double vision, reduced vision or other vision disturbances.

9 - What symptoms and signs can occur when ECD affects the skin?

If ECD involves the skin, there may be sore or bump under the skin called xanthomas. A rash might occur. One typical finding of skin involvement in ECD is xanthelasma which are often in the periorbital space.

10 - What are possible symptoms and signs when ECD affects the lungs?

It is not yet known how many ECD patients have lung involvement. Lung involvement is not a major prognostic factor. As it is often asymptomatic, a high resolution chest CT scan should be performed. Possible, but rare respiratory symptoms are a persistent dry cough and chronic shortness of breath called dyspnea and crackles.

11 - Which symptoms and signs can be observed when ECD affects the immune system?

There is usually no involvement of the immune system in ECD, although some treatments may increase susceptibility to infections.

12 - Which symptoms and signs can occur when ECD affects the heart and the vascular system?

Cardiovascular involvement in ECD is known since the first descriptions of the disease but was for a very long time under-recognized.
Cardiovascular issues are the following:
• Diffuse periaortic fibrosis (also known as "coated aorta") which implies there is abnormal, thickened dense tissue surrounding the aorta, the great artery coming from the left ventricle of the heart.
• Pericardial infiltration with pericardial effusion which means there is excess of fluid in the pericardium, the sac which contains the heart and the base of the major arteries and veins attached to the heart. It may be responsible for tamponade.
• Myocardial infiltration which means there is abnormal tissue growth within the actual heart muscle.
• Atrial pseudotumour which means there is an enlargement in the upper chambers of the heart that appears to look like a tumor.
• Aortic and mitral valve disease which means that the aortic and mitral valves do not function properly in keeping the blood flowing properly through the heart.
• There has also been numerous cases of myocardial infarctions due to ECD (pericoronary infiltration).
Some of the above can be documented by echocardiogram, but may also require more sophisticated imaging studies such as heart MRI and vascular aortic CT.

13 - What are possible symptoms and signs when ECD affects teeth and jaw bones?

ECD has been reported in the medical literature to cause degeneration of bone tissue, including those of the upper and/or lower jaw. Evidence of ECD has also been reported in the tissue that surrounds and supports the teeth. In addition, some patients experience difficulty with tooth enamel "chipping off" or tooth "erosion". Dental examinations are needed to identify any of these issues. These symptoms can also be found in Langerhans cell histiocytosis.

14 - Which other symptoms and signs can occur with ECD?

General symptoms (which are totally unspecific) are: weight loss; fever; night sweats; muscle and joint aches; feeling of discomfort, weakness, and fatigue (malaise); flu-like symptoms that linger or continue to return.

Therapy of Erdheim-Chester disease (ECD)

1 - What is the prognosis of ECD?

The prognosis is variable and depends mainly on the extent and distribution of the disease. It reaches from asymptomatic bone lesions to multisystemic life-theatening forms. Scientific literature, mainly published before the year 2000, often reports a very poor prognosis but treatment has improved since. Due to this, mortality has considerably decreased. It is important to know there are patients who are living high quality lives with ECD for decades.

2 - Is there a standard treatment for ECD?

No, there is no standard treatment for ECD. The rarity of this disease has prevented any clinical trials of treatments. As a result, all treatments for ECD are considered ‘off-label’. Off-label use of medications is very common. Off-label use is the practice of prescribing medication approved for treatment of one disorder, for the treatment of another disorder. While it is legal for a physician to independently decide to prescribe medication off-label, it is illegal for the manufacturer of the medication to promote off-label uses to prescribers. Nevetheless, treatment is now better standardised and the outcome has considerably improved.

3 - What is the optimal treatment of ECD?

Because of the heterogeneous clinical features and the rarity of the disease, few clinical studies have been conducted to improve treatment of patients with ECD. Nevertheless a clinical study published in 2011 on 53 patients by Arnaud et al has shown that immunotherapy with Interferon alpha (IFN alpha) has considerably improved the survival of patients. It should therefore be chosen as first-line treatment, provided the drug is well tolerated by the patient and there is a good response. IFN alpha is sometimes poorly tolerated on a long term basis due to side effects such as fatigue and depression. It is targeted to have an influence on the immune system.
In addition, sypmptomatic treatment like double-pigtail ureteral stents and renal artery stenting may be necessary.
To date, there is no "cure" for ECD. The discovery of BRAFV600E mutations might change the therapeutic approaches in the near future. (See also “Research”)

4 - Which other treatments are available for ECD?

Double autologous hematopoietic stem cell transplantation has been reported as an efficacious treatment in cases of refractory ECD.

In 2013, a study of Haroche et al has reported efficacy of treatment with vemurafenib, a newly approved BRAF inhibitor, in patients with severe multisystemic and refractory ECD carrying the BRAFV600E mutation. It should therefore be considered for these patients, particularly when the disease is life-threatening. Nevertheless such treatments can be associated with severe cutaneous side-effects such as skin tumours and long term evaluation of their tolerance should be carefully analysed.

Surgical debulking is an operative removal of a mass which has formed as a result of ECD. It can be chosen as an option on a case-by-case basis either for other treatments to work more effectively and/or for symptoms to be reduced in order to improve the quality of the patient’s life.

Many patients need therapy with antibiotics as a result of an increased tendency to suffer from infections due to the fact that some of the other treatments can reduce or even compromise the patient’s immune system. There are various methods to help keeping infections under control, from case-to-case targeted antibiotic treatment to long-term therapy with antibiotics to treat patients with chronic infections. There are differing opinions on the benefits versus risks of the long-term approach.

The following other treatment options which have been reported in medical literature are no longer recommended:
• Treatment with systemic corticosteroids (such as prednisone) should be avoided except as an acute treatment to get through for a major exophthalmos for instance.
• Vinblastine (which is efficacious in Langerhans cell histiocytosis) is not effective in ECD. There are case reports on other chemotherapy medications used in the treatment of ECD, like cyclophosphamide, mycophenolate mofetil, cladribine, vincristine, doxorubicin and etoposide. Their efficacy is uncertain and there is a lack of follow-up and therefore no long-term knowledge.
• A few reports of efficacy of cladribine have been reported in ECD, by analogy with Langerhans cell histiocytosis (LCH).
• Some patients have been treated with inhibitor therapy:
- Anakinra works to block interleukin 1, a protein in the body found to exist at higher levels within the cells of ECD lesions. It seems to be efficacious on mild forms of ECD but there is no proven efficacy on involvement of the central nervous system nor cardiovascular involvements.
- Imatinib, a drug blocking the action of the abnormal protein that signals cancer cells to multiply, has been used to treat some patients with ECD. It did not seem efficacious on involvement of the central nervous system, on cardiovascular infiltration, on exophthalmos, bone pain or diabetes insipidus.

5 - How can the efficacy of treatments for ECD be evaluated?

The efficacy of treatments is difficult to evaluate and the disease can be relentless in its course. PET-CT is nevertheless an important tool to assess the clinical efficacy of treatments, along with other imaging modalities, physical assessment, and CRP values.

Research about Erdheim-Chester disease (ECD)

1 - What approaches are made to detect what causes ECD?

Recent studies have shown the following: Stoppacciaro et al. described an immunohistochemical study of three patients showing that histiocyte recruitment and accumulation in the lesions is regulated by a complex network of cytokines and chemokines. Dagna et al. studied both spontaneous and stimulated cytokine production by mononuclear cells in biopsy fragments from a single patient; they report the production of tumor necrosis factor alpha after stimulation, and spontaneous secretion of IL-6 and IL-8, IL-8 being a chemoattractant for polymorphonuclear cells and monocytes. Aouba et al. reported evidence in two patients that targeting the IL-1 pathway might be beneficial. Arnaud et al. assayed serum samples from 37 ECD patients for 23 cytokines: they found substantial and systemic immune activation, mainly involving IFN alpha, IL-1/IL1-RA, IL-6, IL-12, and MCP-1. This further confirms that ECD is associated with systemic immune Th-1-oriented perturbation, and provides clues for choosing better targeted therapeutic agents.
The recent finding of BRAFV600E mutations in more than 50% of ECD cases clearly adds further complexity to the pathophysiology of this disorder: it also provides evidence of clonal proliferation (associated with the BRAFV600E mutation) and of both non-clonal accumulation of histiocytes within the affected tissues (as a consequence of systemic chemokines and pro-inflammatory cytokines in the circulation).

2 - What consequences might these new discoveries have?

The classification of histiocytic disorders might be revised in the near future with new discoveries such as BRAF mutations found in about 50% of cases of ECD and Langerhans cell histiocytosis (LCH) but not in other histiocytoses.

If you have any further questions please do not hesitate to contact the Histio Net team.