Introduction

The lymphatic or lymphoid system makes up part of the immune system in the body to help protect us from infection. It is made up of lymph nodes, lymphatic tissues, lymphoid organs, vessels and a fluid that flows from the vessels back to the heart which is called lymph. Moreover, once the plasma, which carries oxygen and nutrients throughout the body, starts to collect additional waste products and return to the bloodstream, some extra fluid is left behind. This extra fluid, named lymph rather than plasma, is carried through lymphatic vessels to the subclavian veins which are in the upper chest region and the cycle restarts.

Like other systems in the body, the lymphatic system can face issues, which includes swelling of the lymph nodes as one of the most important. There are many lymph nodes in the upper section of the body, especially in the head, neck, chin and armpits. Swelling often occurs due to the body’s natural response to an infection; however, it is also possible to have a specific type of blood cancer called lymphoma. It is important that diagnosis of swollen lymph nodes is done correctly and accurately. This is because lymph nodes can swell for a range of reasons which include common infections to more severe and life-threatening illnesses such as cancer.

Castleman's Disease consists of several rare lymphoproliferative disorders that are distinguished by swollen and enlarged lymph nodes. These are split into two main types depending on if there is one singular enlarged lymph node, which would be Unicentric Castleman Disease (UCD), while Multicentric Castleman Disease (MCD) occurs when there are several regions of enlarged lymph nodes.

Why do lymph nodes swell?

Lymph nodes, which are small constituents of the lymphatic system, have an important job in fighting off infection in the body by acting as filters of potentially harmful substances in the body. When lymph nodes enlarge and become swollen, this is identified by a range of symptoms such as:

• Physical pain and visual swelling mostly in the neck, underarms and groin; however, this can occur in other parts of the body
• Fever and night sweats
• Runny nose, continuous cough and sore throat
• In some rare cases such as lymphoma or otherwise known as cancer of the lymphatic system, there could be very firm lymph nodes that don’t budge when pushed

In most cases, swelling of lymph nodes is caused by an infection, either viral or bacterial. This could be a minor upper respiratory infection, such as a normal cold or flu, but also conditions such as sinusitis, strep throat and skin infections. The swelling means that the body is fighting the infection and in the majority of cases, the infection is stopped. There is an increase of blood cells congregating at the lymph nodes, which causes the swelling observed. 

Cancers such as lymphoma and leukemia can also cause swelling of lymph nodes. However, mostly lymph node swellings aren’t a sign to be concerned as the swelling goes down when the infection has been dealt with. Swelling does become an issue when the enlargement happens due to an unidentified reason, for example, when the individual does not exhibit any symptoms of cold, flu or any other form of infection. This could signify a more dangerous illness such as cancer, which would require imaging scans and further blood tests.

Castleman disease

Castleman Disease as stated above is a group of lymphoproliferative diseases that are identified by enlarged lymph nodes, mostly in the neck and chest region but can occur in different parts of the body. They are categorized into two types: Unicentric Castleman Disease (UCD) and Multicentric Castleman Disease (MCD).¹ The difference between the two is the number of enlarged lymph nodes present. Unicentric means that there is only a single swollen lymph node, while multicentric refers to multiple lymph nodes. There are not a lot of identifiable symptoms in UCD apart from swelling during a physical exam, which is why MCD exhibits more signs and symptoms.

Multicentric Castleman Disease is split further into three subcategories. The first category are cases which are associated with human immunodeficiency virus (HIV) and human herpes virus type 8 (HHV-8), This occurs when HHV-8 infects a particular form of white blood cells called B cells, which produce antibodies, and thus is predominantly found in individuals with HIV which have a deficient immune system function as part of the disease.² It is accompanied by symptoms such as fatigue, fever, night sweats, weight loss and of course swelling of the lymph nodes.

The second type of MCD is POEMS-associated (named after its main symptoms: olyneuropathy, or nerve damage; organomegaly, or organ enlargement; endocrinopathy, or hormone issues; M protein, involving abnormal antibodies in the blood, and skin changes). This form is accompanied by POEMS syndrome, which is a rare hematological disorder that happens due to a certain type of pro-inflammatory proteins called cytokines being overproduced. The symptoms that individuals might experience are nerve damage and weakness in the limbs, enlargement of lymph nodes and organs, changes in hormone production, and changes to the skin such as hyperpigmentation and fatigue.³

Idiopathic MCD is the third and most common type. In this form, the individual’s cause is unknown. There are similar symptoms to other forms of MCD, such as fever, fatigue, weight loss, lymph node enlargement and inflammation of tissues and organs. As we will explore later, a lot of symptoms in Castleman’s Disease “mimic” other diseases.

Castleman's disease mimicking other diseases 

As Castleman's Disease can affect multiple body systems and presents various symptoms common to other illnesses, it can often be mistaken for similar diseases. One of the main diseases that is mimicked is Lymphoma, which is cancer of the Lymphatic System. Both diseases show up as enlarged lymph nodes during imaging scans, which can cause a potential misdiagnosis of Castleman disease as lymphoma. There can also be a significant overproduction of Interleukin-6 (IL-6), which is a cytokine found in the body.⁴ 

Castleman Disease can also mimic autoimmune diseases such as Systemic Lupus Erythematosus (SLE), which is when the immune system attacks the healthy organs, tissues and cells by mistake. Similar to before, here both diseases show enlarged lymph nodes, and the individual can experience fevers, fatigue and weight loss. In a specific case report, a 46-year-old Chinese man was admitted to hospital due to having a fever and fatigue. The diagnosis after analysis of the test results suggested SLE was present; however, the results of a kidney biopsy showed a negative result for immunofluorescence patterns that are normally present during lupus, which lead to the conclusion that it was Castleman Disease and not SLE.⁵

Diagnosis

There are several tests that can be performed to identify and diagnose Castleman's Disease. The quickest and normally first test would be a physical and visual check of the area by a medical professional to identify any swelling and enlargement of the lymph nodes. If this is accompanied by the presence of fever, fatigue and night sweats, that would be taken into consideration along with a family history of immunocompromising conditions such as HIV. After that, blood and urine samples may be taken to make sure that there is not another type of infection present that may have similar symptoms. A CT scan may also be taken to get a closer look at the enlarged lymph nodes.

A lymph node biopsy is taken to fully determine if the illness is Castleman Disease, which consists of a sample of tissue from the enlarged lymph node being taken and examined under a microscope.

The biopsy is crucial as it helps to determine Castleman Disease due to the distinct characteristics of CD, and its potential misdiagnosis through the methods previously mentioned.⁶

Summary

Castleman's Disease is difficult to diagnose due to the many similarities in symptoms compared to other diseases; symptoms include: enlarged lymph nodes, fever, fatigue, night sweats and overproduction of cytokines. 

Surgical removal of the swollen lymph nodes is the current treatment option for Unicentric Castleman Disease as the single lymph node can be separated. For Multicentric Castleman Disease, a mix of corticosteroids, chemotherapy and other medications may be needed if the disease is particularly difficult to cure.

Early diagnosis is crucial in Castleman Disease. The sooner it is identified, the more treatment options can be provided, and less impact will take place on healthy cells and tissues of the individual. Research is still ongoing for safer and less intrusive treatments to cure Castleman Disease, but more time is needed to ensure a safe treatment procedure and close monitoring to prevent the disease from returning.