What is castleman's disease?

Castleman disease (CD) is a rare inflammatory disorder in which the lymph nodes and tissue of the body become swollen. Lymph nodes are organs in the body that are the site of immune system reactions. This is where our white blood cells come together and fight against bacteria and viruses that enter the body.

In a healthy person, white blood cells are activated when the body detects a foreign invader (such as bacteria, viruses, or parasites). Once these invaders have been killed, the white blood cell activity reduces. However, in CD, the immune system remains active, and this causes lifelong complications such as inflammation and swelling in your organs.¹

Castleman's disease: systemic effects and key symptoms

The demonstrated figure shows the various symptoms caused by CD due to overactivated white blood cells cause an overgrowth of cells, such as:²

• Swollen lymph nodes in the neck and under the arms
• Enlarged liver (hepatomegaly)
• Enlarged spleen (splenomegaly)
• Swollen ankles and feet

Non-specific symptoms can occur due to the immune system overworking itself. They can include but not limited to:

• Fatigue
• Fever
• Weight loss
• Anaemia

Types of castleman's disease

There are two types of Castleman disease: unicentric (UCD) and multicentric (MCD). UCD causes the enlargement of one or more lymph nodes in one area of the body; this is the most common type of CD.³

On the other hand, MCD causes lymph node enlargement in multiple areas of the body and is classified into three types. 

• Idiopathic MCD: the most common form, and its cause is unknown
• HHV-8-associated MCD: occurs as a result of human herpesvirus-8 and is more common in those suffering from HIV and immunocompromising diseases
• POEMS-associated MCD: is caused by a rare blood disorder called POEMS that occurs alongside MCD

What is a biomarker?

A biomarker is a biological molecule that can help detect the presence of certain diseases and disorders in the body. These could be proteins or hormones found in the tissues, blood, and urine, which can indicate if you have a disease, the severity and stage of the disease, and how well you are responding to treatment.

Biomarkers are an important factor in diagnosing Castleman disease, because the symptoms of CD are mostly nonspecific and can be confused with other illnesses. By measuring the biomarkers in the lab, doctors can spot active inflammation, track the severity of the disease, and monitor the response to treatments.⁴

Biomarkers of castleman's disease 

Blood tests help to diagnose Castleman disease, as the blood can contain many biomarkers that suggest a patient could have CD. This is often the first step in diagnosis.

C-reactive protein

C-reactive protein (CRP) is an inflammatory marker in the body that is produced by the liver. In CD, CRP is usually at high levels due to all of the inflammation that occurs at the lymph nodes. Therefore, detecting elevated CRP by blood tests helps to identify an active disease at early stages or flare-ups.⁵

Low red blood cell count (anaemia)

Anaemia means that the blood has fewer red blood cells (RBC) in the body. This decreases the body’s ability to carry oxygen to and from different tissues in the body. This is common in CD, and it again shows signs of chronic inflammation that comes with CD.⁶

Hypoalbuminemia

Albumin is an essential protein produced in the liver that is key for transporting various substances (like vitamins and hormones) in the bloodstream. It also helps maintain water balance and pressure. Hypoalbuminemia means low albumin levels in the blood, and this is a marker of CD. This is because inflammation that occurs in CD causes the liver to produce less albumin and more CRP, signalling an inflammatory overload. Hypoalbuminemia is common in severe and active cases of MCD.

High platelet count (thrombocytosis)

Platelets (also known as thrombocytes) are cell fragments in the blood that help to stop bleeding by forming blood clots. They bind together when they detect broken blood vessels or skin barriers and form a plug in the wound to prevent bleeding out. An elevated platelet count is often observed in cases of CD as the platelets respond quickly to inflammation. In cases of UCD, thrombocytosis helps to identify which region of the body is affected by CD.⁷

Benefits of blood testing

Blood tests do not confirm or diagnose Castleman disease alone; however, they give doctors an idea as to what is causing the symptoms. Blood tests help to identify the levels of biomarkers in the blood, which can indicate high inflammation in the body. This can support a suspected diagnosis and rule out CD from other illnesses. With other methods such as imaging and biopsies, blood testing is a crucial part of diagnosing CD.

Cytokine markers in castleman's disease

Cytokines are small proteins that are secreted by cells of the immune system to help guide the immune response and trigger symptoms such as inflammation. In CD, especially MCD, disorders in cytokine activity are common and often cause the main inflammatory symptoms of CD. Cytokines can be measured in the blood. They can help to identify inflammation and investigate CD activity to give an accurate diagnosis and treatment.

Interleukin 6 (IL-6)

Interleukin-6 is a pro-inflammatory cytokine. It is often released by white blood cells in response to bacteria and viruses. IL-6 helps to cause acute inflammation whilst the body fights against infection, and so it is a key marker of CD.

IL-6 promotes the general CD symptoms, and it also stimulates the production of CRP. It is found in high levels of MCD (especially idiopathic MCD). High levels of IL-6 mean that there is significant inflammation occurring in the body, a key sign of CD. Therefore, IL-6 expression is an important cytokine marker in diagnosing CD.⁸

Vascular endothelial growth factor (VEGF)

Vascular endothelial growth factor (VEGF) is a chemical that is responsible for the formation of new blood vessels and cell migration. VEGF also plays a key role in increasing the permeability 

(ability to allow liquids to pass through) of the blood vessels. In CD, high levels of VEGF can lead to fluid build-up and swelling (oedema) in various regions of the body and at specific organs such as the liver and spleen. High VEGF levels are often seen in cases of POEMS-associated CD and idiopathic MCD, as these involve systemic inflammation in various regions of the body.⁹

Cytokine markers identification

Cytokine markers are not usually identified in regular blood tests. They are often detected using laboratory techniques that can identify very low amounts of these markers. A sample of the blood is often extracted from the vein, and this is processed in the lab to separate blood plasma (liquid in the blood), as this will contain the cytokine markers of interest.

A range of chemical tests can be applied to the blood plasma sample. For example, the enzyme-linked immunosorbent assay (ELISA) is a common method for detecting cytokine markers. This method utilises antibodies (immune proteins that respond and bind to foreign cells known as antigens). 

The antibodies used are similar in shape to cytokines such as IL-6. A solution containing these IL-6 antibodies is placed in the blood sample, and if a colour change occurs, this signals that the cytokine is present. The intensity of the colour change determines how much of the cytokine is there. A strong colour change would signal high levels of IL-6 and, therefore, high levels of inflammation.

ELISA and other lab methods are used in hospitals and research laboratories to provide an accurate and specific detection. However, these methods are less used as cytokine testing is expensive and requires specialised staff and complex equipment. In Castleman disease, the levels of cytokines can also fluctuate, and so the timing of the test is crucial and so it is only used if Castleman disease is highly suspected.¹⁰

Summary

Castleman's disease is a rare inflammatory disease that occurs in the lymph nodes of the body. Castleman's disease is distinguished into two types: unicentric and multicentric. Unicentric Castleman disease typically affects a group of lymph nodes in one region of the body, such as in the chest. UCD is often asymptomatic and is curable with surgery if the inflamed mass can be removed safely. Multicentric Castleman disease typically affects multiple regions of the body and is the more serious type with severe inflammatory symptoms. This form is not curable with surgery and needs drug treatments such as chemotherapy, immunotherapy and steroids. Blood tests can help to find biomarkers which indicate the possibility of Castleman disease. These include: anaemia, hypoalbuminemia, low platelet counts and high C-reactive protein counts. Blood tests help to aid diagnosis, monitor disease activity and assess the responses to different treatments. Cytokines can also be used to help in diagnosing CD. Cytokines are chemicals released by immune cells which often stimulate inflammation. Cytokines such as IL-6 and VEGF can be used to detect MCD, as their levels and activity are often elevated to produce more inflammation at the lymph nodes.

FAQs

What is castleman's disease?

It is a rare condition in which the lymph nodes grow too much as white blood cells are overactivated. This causes swelling and inflammation at the lymph nodes, internal organs, hands and feet. 

How is castleman's disease contracted?

Castleman's disease is rare and seems to result from genetic mutations and immunocompromising diseases such as HIV. Having human herpes virus-8 makes you susceptible to HHV-8 multicentric Castleman disease. There is no known case of contracting a CD from another person.

Can castleman's disease be treated?

Yes. If it is a unicentric CD, the affected area can be removed via surgery. For a more systemic and widespread disease such as multicentric CD, surgery is not effective, and the use of medications that block inflammatory cytokines is used instead. 

What are the current drugs prescribed for treatment?

Siltuximab and tocilizumab are used for MCD as they block IL-6 from causing inflammation and swelling in the lymph nodes. They are administered by IV or injection, usually weekly at the hospital.

What happens without treatment?

The disease can worsen, causing serious complications such as organ damage and failure.