What is castleman disease?

Castleman disease (CD) is a rare lymphoproliferative disorder. This is a type of inflammatory disease in which the lymph nodes of the body become swollen and often enlarged. This causes symptoms such as:

• Swollen lymph nodes, ankles and feet
• Enlarged liver
• Enlarged spleen
• Numbness in the feet and hands
• Unintentional weight loss
• Nausea or vomiting
• Fatigue¹

These symptoms occur when the white blood cells of the immune system are keeps on overworking. In the lymph nodes, white blood cells help to fight off infections caused by bacteria and viruses. They typically stop working once the infection has cleared. However, in CD, white blood cells continue to activate without infection, and this causes an overgrowth of cells in the lymph node, contributing to inflammation and enlargement.¹

Types of castleman disease

Castleman disease is divided into two types. Unicentric Castleman disease (UCD) causes inflammation in various lymph nodes in one section of the body (e.g., the chest). Multicentric Castleman disease (MCD) causes inflammation in the lymph nodes at various sections of the body.² MCD is much harder to treat and often has various factors that causes the disease, and so it is divided into three subtypes:

• Idiopathic MCD
• Human herpesvirus 8-associated MCD
• Plasma cell type MCD²

Classifying CD is very important for the diagnosis of the disease and to determine what has caused it. Classification also helps to develop treatment plans that are suitable for the symptoms and locations of the inflammation as well as providing a prognosis as each type of CD is different. This article will explore the different types of CD, what causes them and how they can be treated.

Unicentric castleman disease

Unicentric CD is a localised and mild form where a single lymph node or multiple in one region are affected. This causes little to no symptoms, sometimes including mild symptoms such as localised pain and discomfort due to the swollen mass. 

Hyaline vascular type UCD

Hyaline vascular type UCD is the most common histological subtype (approximately 90% of cases). This is observed as abnormal lymph node structure, involving small follicles and prominent blood vessels.³

These features of hyaline vascular UCD highly organise the lymph node, however the lymph node still does not function effectively. The germinal center is the location in which white blood cells known as B-cells should mature, and form proteins known as antibodies which then fight infection. However, B-cells in the affected lymph nodes are shrunken and fibrotic. Hyaline vascular UCD therefore presents an abnormal immune architecture rather than an overactive immune system. This causes the majority of the patients to face a localised infection and either have no symptoms or mild inflammatory symptoms at the affected lymph nodes.³

Multicentric castleman disease

Multicentric Castleman disease (MCD) is the systemic and progressive form, causing inflammation in various regions of the body and displaying a wide range of symptoms. MCD usually occur as a result of other underlying diseases and so it is categorised into three subtypes.

Idiopathic MCD

Idiopathic MCD (iMCD) occurs for unknown reasons. However, it is proposed that iMCD can occur as a result of underlying autoimmune diseases or unidentified viral infections.⁴

The symptoms of iMCD are often expressed due to increased levels of cytokines within the blood. Cytokines are chemicals that are released from cells of the immune system in order to activate inflammation. Increased production of interleukin-6 (IL-6) cytokine often causes high levels of inflammation in iMCD, as well as weight loss, tiredness and swollen lymph nodes.⁴

Plasma cell type

Plasma cell type occurs in multicentric CD. Plasma cells are a type of white blood cells which releases antibodies to fight against infection. In plasma cell type MCD, large clusters or sheets of plasma cells develop where they should not grow. The germinal center of the lymph node is often enlarged and contains high amounts of plasma cells. This causes the immune system to become overactivated.⁵

The areas surrounding the germinal centres have high plasma cell counts and can cause inflammation as the immune system activity spreads throughout the lymph node. More blood vessels can develop and feed the growing inflamed lymph nodes, causing symptoms such as fever, tiredness and even low red blood cell count (anaemia).⁵

Plasma cell type MCD can be treated with anti-IL-6 drugs such as siltuximab as well as steroids and chemotherapy for more serious cases.

Human herpesvirus 8-associated MCD

Human herpesvirus 8 (HHV-8) is a virus from the herpes family, however it does not cause cold sores as seen in herpes simplex virus 1. HHV-8 is contracted through bodily fluids (mainly saliva) and often through sexual contact, blood and organ transplants.⁶

HHV-8 can cause Castleman disease as it can infect the lymph nodes and trigger immune activation at extreme levels. HHV-8 infects B-cell white blood cells primarily, and creates proteins that are similar to IL-6 cytokines in humans. This causes powerful inflammation and overworks the immune system to combat this, causing symptoms such as:

• Fever
• Fatigue
• Swollen lymph nodes
• Organ problems ⁶

HHV-8-associated MCD also increases the amount of plasma cells in the lymph node (as seen in plasma cell type MCD) and creates abnormal blood vessels in the node. HHV-8-associated MCD has a high risk level in those with an already compromised immune system. This can be due to underlying diseases such as HIV/AIDS and those who are recovering from immunosuppressive surgeries such as organ transplantation. However, the general healthy population are less susceptible to this type of MCD.⁶

Clinical relevance

Classifying Castleman disease into its subtypes is crucial for the differentiation of the disease and pinpointing the exact causes. This helps to provide an accurate prognosis for the patient. In unicentric CD, the prognosis is good after successful surgical removal of the inflamed mass. However, symptoms may take longer to relieve in hyaline vascular type. On the other hand, multicentric CD is more complex and requires ongoing treatment and monitoring as it has systemic effects.⁷

Treatment methods

Treatment strategies of Castleman disease vary. With localised UCD, the most common form of treatment is surgical excision of the affected node, which often cures the disease. However, if surgery is not possible, radiotherapy is used. Where there are symptoms (which is unlikely), anti-inflammatory drugs such as corticosteroids are used.⁷

Plasma cell type CD treatment depends on the type of CD it appears in. The first form of treatment for plasma cell type UCD is surgical removal of the lymph node (curative) or radiotherapy alongside short-term corticosteroids for any symptoms.⁷ Plasma type MCD requires tocilizumab (an IL-6 receptor blocker) which prevents the inflammatory activity of IL-6. If this fails, immunosuppressants can also be used.⁵

HHV-8-associated MCD requires antiviral therapy and HIV targeting drugs if the patient is HIV positive. If not, the first line of therapy is rituximab, an anti-inflammatory antibody which targets white blood cells that have been infected by HHV-8.⁶

Idiopathic MCD has unclear causes and so treatment is focused on targeting and reducing immune system activity. This can be achieved through anti-IL-6 therapy, using drugs such as siltuximab or tocilizumab. Steroids also help to reduce inflammation and immunotherapy is used in severe cases to deactivate immune cells.⁴

Summary

Castleman disease refers to a group of rare inflammatory disorders which occur within the lymph nodes and organs. They involve the abnormal growth of cells in the lymph node tissue. The disease is classified into two main forms: unicentric (affecting a single lymph node) and multicentric (affecting multiple lymph nodes in multiple areas). Multicentric CD includes subtypes which are based on what causes the disease, such as: human herpesvirus-8-associated MCD and idiopathic MCD (in which the cause is unknown). Differentiating between these diseases is key for diagnosis, including: imaging of lymph node mass, blood tests and lymph node biopsy. These also help to identify histological subtypes such as hyaline and plasma cell CD. Accurate classification is therefore central to effective diagnosis, treatment and understanding of Castleman disease. 

FAQs

How can castleman disease be diagnosed?

Diagnosis involves a combination of clinical evaluation, lymph node biopsies and lab testing. CT or MRI scans can help to identify enlarged lymph nodes or swelling of organs and differentiate between CD subtypes.

How can blood tests help to diagnose castleman’s disease?

Blood tests can pick up on low red blood cell counts (anaemia), low platelet counts (thrombocytopenia) and low albumin levels (hypoalbuminemia) which can be caused by the increased inflammation in CD. 

Can castleman disease be cancerous?

Castleman disease is not a type of cancer. However, patients with multicentric CD are more susceptible to developing lymphoma and so regular monitoring and treatment is necessary.

Why is accurate classification of castleman disease important?

Accurate classification can help determine prognosis, guide treatment plans and improve patient outcomes because each subtype has a different clinical presentation and treatment approach.