Histiocytic disorders are a group of rare disorders characterised by the abnormal accumulation of histiocytes, a type of immune cell often found in tissues that regulates immune functions. There are three primary types of histiocytes, including monocytes (plays a role in inflammatory and anti-inflammatory responses during an immune response), macrophages (responsible for ingesting and eliminating foreign substances during an immune reaction), and dendritic cells (initiate and regulate the adaptive immune response).  

Histiocytic disorders are broadly classified into five different groups: L group, C group, M group, R group, and H group. The L group, or Langerhans group, are classified as diseases involving Langerhans cells (an immune cell responsible for initiating an immune response when coming into contact with a foreign material), such as Langerhans cell histiocytosis (LCH). The C group, also known as cutaneous and mucocutaneous non-Langerhans cell histiocytosis, are classified as non-Langerhans cell histiocytic disorders that are localised to the skin or mucosal surfaces, such as the mouth, nose, and gastrointestinal system. The M group, also known as malignant histiocytic disorders, are classified by the presence of malignant (or cancerous) cells within the tumour(s). The R group, also known as Rosai-Dorfman disease and miscellaneous non-cutaneous non-Langerhans cell histiocytosis or sinus histiocytosis, are classified as non-Langerhans histiocytic disorders that often involve lymph nodes. The H group, also known as hemophagocytic lymphocytosis and macrophage activation syndrome, is composed entirely of hemophagocytic lymphohistiocytosis, a rare and aggressive disease caused by the overactivation of the immune system.

This page will focus on Erdheim-Chester disease (ECD), a common subtype of L group histiocytic disorder. It is defined as a is a rare cancer-like disorder that causes an abnormal increase in a type of white blood cell (WBC) called histiocytes, which play a significant role in many vital immune functions. It is most commonly found as lesions on the long bones of the legs, however it can also develop in the cardiovascular system, central nervous system (CNS), and other organs within the body. ECD often affects many systems within the body.

ECD is slightly more common in men, and is generally diagnosed between the ages of 50 and 60. However, anyone can develop this disease.

Treatment 

Each patient with ECD will present with a unique disease behaviour, with varying locations, and symptoms. As such, there is no one treatment method that will work for everyone, and there is no standard staging system for this disease.  Instead of staging and grading, your doctor will recommend a treatment plan based on the following factors:  

• Cancer location.
• Whether or not the cancer has metastasised. 
• Your age. 
• General health. 
• Your treatment preferences. 

Your doctor may recommend genetic testing, which analyses your tumour DNA and can help determine which treatment has the greatest chance of success. Your doctor will discuss the most appropriate course of treatment for you.

Treatment options for patients with ECD may include:

• Watch and wait (may be an option for some asymptomatic patients).
• Corticosteroids.
• Chemotherapy.
• Radiation therapy.
• Immunotherapy.
• Targeted therapy.
• Surgery to remove as much of the tumour as possible.
• Clinical trials.
• Palliative care.

For more information on the treatment options, please refer to the Rare Cancers Australia treatment options page. 

Risk factors 

Because of how rare ECD is, there has been limited research done into the risk factors of this disease. However, a genetic mutation in the BRAF gene (a protein involved in the sending of chemical signals between cells and cell growth) has been identified in a significant portion of people with this disease.

Early symptoms 

The symptoms of ECD will vary depending on the location(s) of the disease.

General Symptoms of ECD

General symptoms of ECD may include:

• Weight loss.
• Fever.
• Fatigue.
• Muscle and/or joint aches.
• General feeling of discomfort.
• Weakness.

ECD affecting bones

Most patients with ECD will experience some changes in the bones.  In addition to the general symptoms listed above, patients with ECD in the bones may experience some of the following symptoms:

• Osteosclerosis (abnormal hardening of the bone).
• Bone pain in affected area.
• Bone lesions.

ECD affecting the Cardiovascular System

In addition to the general symptoms listed above, patients with ECD in the cardiovascular system (such as the heart, pericardium (tissue layer that covers the heart), and aorta (the largest artery in the body)) may experience some of the following symptoms:

• Heart valve abnormalities.
• Heart rhythm abnormalities.
• Heart conduction defects.
• Periaortic fibrosis (inflammation of the aorta).
• Pericardial thickening/effusion (abnormal fluid build-up in the pericardium).
• Myocardial infarctions (heart attacks).
• Cardiomyopathy (a disease of the heart that causes a loss of ability to pump blood effectively).

ECD affecting the CNS

In addition to the general symptoms listed above, patients with ECD in the CNS (including the dura (connective tissue surrounding the brain and spinal cord), pituitary gland (one of the primary endocrine glands of the body), other regions of the brain and/or spinal cord) may also experience some of the following symptoms:

• Diabetes insipidus (a disorder causing a fluid imbalance in the body – caused by too little anti-diuretic hormone (ADH) secretion)).
• Excess urination (polyuria).
• Excessive thirst (polydipsia).
• Impaired muscle coordination.
• Difficulties walking.
• Slurred speech.
• Involuntary, rapid eye movements.
• Hormone imbalances.
• Loss of libido.
• Headache.
• Seizures.
• Changes in behaviour.
• Difficulty concentrating.
• Spinal cord compression.

ECD affecting Retro-orbital Tissues

In addition to the general symptoms listed above, patients with ECD in retro-orbital tissues (the tissues behind the eyes) may also experience some of the following symptoms:

• Pain behind the eyes.
• Exophthalmos (protrusion of one or both eyes out of the eye socket(s)).
• Blindness.

ECD affecting the Skin

In addition to the general symptoms listed above, patients with ECD in the skin may also experience some of the following symptoms:

• Yellow plaques under the skin (most commonly on the eyelids).
• Reddish-brown nodules on the skin.

ECD affecting the Lungs

In addition to the general symptoms listed above, patients with ECD in the lungs may also experience some of the following symptoms:

• Pulmonary fibrosis (progressive scarring and thickening of lung tissue).
• Dry cough.
• Difficulties breathing.
• Decreased breathing output.

ECD affecting the Retroperitoneum 

In addition to the general symptoms listed above, patients with ECD in the retroperitoneum (space behind the abdomen containing many vital organs, such as the kidneys, adrenal glands, rectum, and pancreas) may also experience some of the following symptoms:

• Ureteral obstruction (blockage of ureters – the tubes that carry urine from the kidneys to the bladder).
• Abdominal swelling.
• Impaired kidney function.
• Renal failure (in extreme cases).

Not everyone with the symptoms above will have cancer, but see your general practitioner (GP) if you are concerned. 

Diagnosis/diagnosing 

If your doctor suspects you have ECD, they will order a variety of tests to confirm the diagnosis and refer you to a specialist for treatment.

Physical examination

Your doctor will collect your overall medical history, as well as your current symptoms. Following this, they may examine your body to check for any abnormalities.

Neurological exam

A neurological examination assesses sensory and motor functions, and can generally be done in your GPs office. The doctor may check your vision, hearing, balance, coordination, strength and reflexes, depending on the signs and symptoms you have described. Any problem that is detected in this exam can help determine which portion of the CNS needs further investigation.

Urine & blood tests

Urine and blood tests are used to assess overall health and detect any abnormalities. Some of these tests may include:

• General blood test to assess overall health.
• Full blood count, which measure the levels of red blood cells, white blood cells and platelets.
• Liver function test.
• Blood chemistry and/or blood hormone studies, which analyse the levels of certain hormones and other substances in the blood.
• Genetic testing to check for any abnormalities, specifically with the BRAF, MAP2K1, RAS and ARAF genes.
• Water deprivation test, which analyses urine output on little water. 
• Urinalysis, which analyses the colour of your urine and its contents (e.g., sugar, protein, red and/or white blood cells etc.). 

Imaging tests

The doctor will take images of your body using magnetic resonance imaging (MRI), a computed tomography scan (CT scan), ultrasound, bone scan and/or positron emission tomography (PET scan), depending on where it is suspected the cancer is. The doctor may also look at other parts of the body and look for signs of metastasis. 

Pulmonary function test (PLT)

A pulmonary function test, or lung function test, determines how well your lungs are working. This test measures the amount of air the lungs can hold, as well as airflow in and out of the lungs, how much oxygen is used and how much carbon dioxide is exhaled.

Exploratory procedures 

You may require an exploratory procedure may be required if the imaging scans were inconclusive, or if there were any abnormalities detected in your blood/urine tests. 

Bone marrow aspiration

This process involves inserting the needle into the hipbone (or the breastbone in some cases) to remove samples of solid and liquid bone marrow. These samples will then be analysed for abnormalities.

Endoscopy

An endoscopy is a day procedure that is often performed to examine the tracts of the digestive system. To look for LCH, the doctor will place a long, thin tube with a light and a camera attached (endoscope) into your mouth or nose to check for any abnormalities.

Bronchoscopy

A bronchoscopy is a day procedure that examines the trachea and lungs. A long, thin tube with a light and camera attached (bronchoscope) is inserted through the mouth or nose and into trachea and lungs to check for any abnormalities.

Biopsy 

Once the location(s) of the cancer has been identified, the doctor will perform a biopsy to remove a section of tissue using a needle. The tissue sample will then be analysed for cancer cells. This can be done by a fine needle aspiration (FNA) or a core needle biopsy (CNB). 

Prognosis (Certain factors affect the prognosis and treatment options) 

While it is not possible to predict the exact course of the disease, your doctor may be able to give you a general idea based on the rate and depth of tumour growth, susceptibility to treatment, age, overall fitness, and medical history. Generally, early-stage ECD has a better prognosis and survival rates. However, if the cancer is advanced and has spread, the prognosis may not be as good and there may be a higher risk of cancer recurrence. It is very important to discuss your individual circumstances with your doctor to better understand your prognosis. 

References 

• National Organisation for Rare Disorders
• Radiopaedia
• UpToDate

^{Some references are to overseas websites. There may be references to drugs and clinical trials that are not available here in Australia.}