What is Castleman’s Disease

Castleman’s Disease (CD) is a rare disorder that was first identified by Dr Benjamin Castleman back in the 1950’s.^1,2 It has been studied ever since, but doctors and scientists still don’t know what exactly causes the disease,³ it is thought that an impaired immune system contributes to its development.¹ This is because CD causes excessive production of a type of white blood cells known as lymphocytes.¹ Lymphocytes help our bodies to fight infection, and they travel around the body in the lymphatic system.^4,5 They pass through small, bean-shaped tissues found throughout the body known as lymph nodes, which help to filter lymphocytes into the blood when germs and bugs (like bacteria, viruses and fungi) are detected.⁵ When the body produces too many lymphocytes, the lymph nodes can become enlarged.³ This has allowed doctors to group the condition into two different types (Unicentric CD or Multicentric CD), depending on how many lymph nodes are enlarged.^3,6 Multicentric CD can then be further grouped into more specific subtypes.^3,6 CD affects people of any age or gender, but it is usually diagnosed in middle age.^3,6

The different types of Castleman’s Disease

Unicentric CD

Unicentric Castleman’s Disease (UCD) usually consists of one enlarged lymph node, or multiple enlarged lymph nodes that are found only in one location.⁷ They are usually slow growing and are commonly found around the chest, abdomen or pelvis.⁷ Tissue samples analysed under a microscope are more likely to have ‘hyaline-vascular’ features. This means that the cells look smooth, pale and glassy, nearby blood vessels grow more than normal, the lymph node has more lymphocytes than usual and the lymph node is wrapped in fibrous outer layer.^7,8,9 

Multicentric CD

In Multicentric Castleman’s Disease (MCD), two or more enlarged lymph nodes are found at multiple locations around the body.¹⁰ Tissue samples analysed under the microscope are more likely to look ‘plasmacytic’.¹⁰ This means that they have lots of antibody producing cells, known as plasma cells, located inside of them.¹⁰ This can be a sign of excessive lymphocyte production.¹¹ Once MCD is diagnosed, it must be categorized into one of its subtypes to help doctors to understand the way that the disease will advance and to help doctors to make decisions about which treatment options are the best for your condition.¹⁰ These subtypes include POEMS associated MCD, Human Herpesvirus-8 (HHV-8) Associated MCD, and Idiopathic MCD.^3,10

POEMS Associated MCD

In these cases, MCD occurs at the same time as POEMS syndrome, because the cells that cause POEMs (known as monoclonal plasma cells) may also cause MCD.³

Human Herpesvirus-8 Associated MCD

This form of MCD occurs in people who have been infected with a virus known as human herpesvirus type 8 (HHV-8).³  It also sometimes occurs in people who have been infected with both HHV-8 and human immunodeficiency virus (HIV).³ 

Idiopathic MCD

Idiopathic MCD (iMCD) looks like HHV-8 MCD, but after lab tests have been done, there is no evidence of HHV-8 infection.³ The most serious form of iMCD is MCD-TAFRO, which is a condition named after its symptoms.¹²

Symptoms of Castleman’s Disease

Castleman’s Disease usually does not have any defined symptoms. People often go to the doctors with symptoms that can occur in several different diseases, like swollen lymph nodes, pain and discomfort, unexplained weight loss, night sweats and high temperature. After they are examined and lab tests have been done, a doctor may discover that they are suffering from CD.^7,10  

Testing and diagnosis of Castleman’s Disease

If Castleman’s Disease is suspected, a doctor will perform lots of tests to:

1. Confirm that you definitely have CD and not a different disease with similar symptoms
2. Determine which type of CD you have 

This includes physical examinations and lab based examinations of tissue samples.^1,6 

Imaging tests

CT scans or PET-CT scans are used to take detailed and informative pictures of the inside of your body.^13,14,15 For diagnosing CD, they are usually used to image the chest, abdomen and pelvis so that doctors can identify if any lymph nodes are enlarged, where they are and how many there are.³ CT scans use X-ray beams aimed at the body to produce signals that can be processed and put together by a computer to create a 3D image showing your skeleton, organs and tissues.^13,14 PET-CT scans use a small amount of radioactive tracking liquid that is injected into a vein in your arm to simultaneously take an image and monitor functions inside of your body.¹⁵ This allows doctors to spot abnormalities.¹⁵

Laboratory tests

Laboratory tests use small blood (and sometimes saliva) samples taken from someone with suspected CD to look for abnormalities that may be related to disease. These tests may include:

• Full Blood Count (FBC) - This is a common test used to determine the size and quantity of all the blood cells circulating around your body¹⁶
• Erythrocyte Sedimentation Rate (ESR) - This test measures the amount of inflammation in the body by measuring how quickly your red blood cells (erythrocytes) fall (sedimentation) to the bottom of a tube of blood¹⁷
• C-Reactive Protein (CRP) - CRP is a protein that is produced by the liver if tissue is injured or when there is inflammation. High amounts of CRP can tell doctors that there is inflammation in the body, however it can not tell them where the inflammation is located¹⁸ 
• Direct Antiglobulin Test - This test looks for antibodies that attack red blood cells. It is often used to diagnose a form of anemia known as autoimmune hemolytic anemia¹⁹
• Liver Function Tests - This test uses a range of biological markers to look at how well the liver is working and also to look for potential liver damage²⁰
• Creatinine Levels - This test is used to find out how well your kidneys are working. Creatinine is a waste product of muscle contraction that comes from the breakdown of a compound known as creatine, which is used to provide the energy that allows your muscles to contract. Creatinine is processed by the kidneys so this test measures how much creatinine is in your blood or urine. This value can then be used to calculate how well your kidneys are filtering out small molecules from your blood²¹ 
• Serum protein electrophoresis with immunofixation - This test separates out the proteins found in a sample of blood or urine using an electrical current so that an expert can identify which types of proteins are present in the sample. They can then look for abnormalities that can help doctors make a diagnosis. This test is often used to look for multiple myeloma, so it may be used to rule out a multiple myeloma diagnosis²²
• Serology test for HIV - Serological testing for HIV looks for biological markers of HIV in your sample. This can tell doctors if you have been infected with HIV which can inform a diagnosis of HHV-8 MCD with HIV²³ 
• Urine Sample - This test analyses a sample of your urine to look for any physical, chemical or microscopic abnormalities^3,24
• LANA-1 Immunohistochemistry for HHV-8³ - LANA-1 is a protein that is associated with HHV-8 infections.²⁵ Immunohistochemistry is a lab test that uses antibodies to trap specific proteins to see if they are present in your sample.^25,26 If LANA-1 can be found in your sample, it suggests to a doctor that you have had a HHV-8 infection which may contribute to a HHV-8 MCD diagnosis^3,25 
• PCR for HHV-8 - A polymerase chain reaction (PCR) is a test that is used to look for genetic material such as DNA. If HHV-8 DNA can be found in your sample, it suggests to a doctor that you have had a HHV-8 infection which may contribute to a HHV-8 MCD diagnosis^3,25

Lymph Node biopsy

A biopsy is a test used to analyse a small sample of tissue or cells that has been removed from your body. They are usually performed using local or general anesthetic by a professional who will use a needle to take a sample of your lymph node.²⁷ Biopsies allow doctors to analyse enlarged lymph nodes under a microscope to look for characteristic features of the different types of CD. This includes hyaline-vascular features in UCD and plasmacytic features in MCD.³ 

Summary

• Castleman’s Disease (CD) is a rare disorder that can be grouped into at least 4 different subtypes
• It causes the excessive production of lymphocytes in the body which enter lymph nodes and cause them to become enlarged
• CD often shares common symptoms with other diseases, so it can be hard to identify
• If a doctor suspects Castleman’s Disease, they will order an array of tests to confirm their diagnosis and to group the disease into its subtype
• Common tests can include imaging tests, laboratory tests and lymph node biopsies