What Is Castleman Disease? Symptoms and Treatment

Overview

Castleman disease (Castleman Disease – CD) is an excessive enlargement of the lymph nodes that occurs regardless of age or sex.

It was first described in 1956 by Dr. Benjamin Castleman and is a rare disease. Castleman disease is not a type of cancer; instead, it is called a "lymphoproliferative disorder". This refers to an abnormal overgrowth of cells of the lymphatic system, as occurs in lymphomas (lymph node cancers).

Even though CD is not officially a cancer, one form of this disease (multicentric Castleman disease) behaves like lymphoma. In fact, many people with this disease eventually develop lymphomas. Like lymphoma, CD is often treated with chemotherapy or radiotherapy. It is therefore included in cancer guidelines.

Castleman disease (CD) is a group of three immune system disorders that share a similar appearance of the lymph nodes under the microscope but have different symptoms, causes and treatments.

The three main subtypes of CD are:

1. Unicentric Castleman disease (UCD)
2. HHV-8-associated multicentric Castleman disease (HHV-8+ MCD)
3. HHV-8-negative / idiopathic multicentric Castleman disease (iMCD)

Lymph nodes and the cells within them (lymphocytes) are an integral part of our immune system that helps us fight invading organisms. For unknown reasons, these lymph nodes undergo certain changes that result in the overproduction of lymphocytes and other inflammatory compounds.

Subtypes

The two main subtypes are Unicentric Castleman disease (UCD) and Multicentric Castleman disease (MCD). As the name suggests, enlarged lymph nodes in UCD occur in only one region of the body. The single enlarged lymph node is usually located in the chest or abdomen. UCD has milder symptoms and rarely affects organs. Multicentric types are characterized by lymph node enlargement in many regions of the body, and symptoms tend to be more severe than in UCD.

Multicentric Castleman disease affects multiple lymph nodes in the body. The multicentric subtype can also be divided into two categories: HHV-8-positive Multicentric Castleman disease and idiopathic Multicentric Castleman disease. HHV-8 is a common virus that does not cause disease in the vast majority of individuals. Unfortunately, however, a small proportion of people with this virus, particularly those with a suppressed immune system, may develop a form of MCD. Although the association with the virus is known, it remains unclear why the disease develops in a few patients who have this virus.

The other category is idiopathic Multicentric Castleman disease (iMCD). Idiopathic refers to the fact that we do not know the causative agent. We know that these individuals are HHV-8-negative and therefore have a different origin for their disease. iMCD also has important differences in symptoms, disease course and treatment compared with the HHV-8-associated type. In addition, some iMCD patients may develop a particular subform coded by the acronym TAFRO, characterized by Thrombocytopenia (a low platelet count), Anasarca (ascites, swelling), Fever or elevated c-reactive protein (an inflammatory marker), Reticulin fibrosis (assessed in a bone marrow biopsy) and Organomegaly (hepatomegaly / splenomegaly).

- Related topic: Medical Oncologist Dr. David Fajgenbaum Describes How He Overcame Castleman Disease

The most important cancer meeting worldwide, the ASCO Congress, had its opening address in 2020 delivered by a 35-year-old doctor: Medical Oncologist Dr. David Fajgenbaum.

Incidence

There are 6500-7700 new cases annually in the United States. CD is a rare disease. For comparison, it is enough to note that approximately 220,000 new lung cancer diagnoses and 22 million diabetes diagnoses are made each year.

Causes

The causes of UCD and idiopathic MCD cases are not yet known. There are no known risk factors; there is no evidence of any food, lifestyle or environmental exposure associated with these diseases. There is no known case of someone contracting Castleman disease directly from another person.

The HHV-8-positive MCD subtype is known to be associated with HHV-8 virus infection occurring at the same time as some form of immunosuppression (such as HIV or genetic causes). It is not understood why only a few patients with HHV-8 + infection and immunosuppression develop Castleman disease. Although the HHV-8 virus is contagious, the vast majority of HHV-8 + patients do not develop Castleman disease.

Symptoms

The clinical spectrum of disease severity is very broad. It can range from gradually enlarging lymph nodes with mild symptoms to the onset of sudden, intense symptoms that may cause life-threatening organ dysfunction. The symptoms of Castleman disease often overlap with those of more common diseases. It therefore cannot be diagnosed from symptoms alone. A diagnosis of Castleman disease can be made only through a lymph node biopsy showing features of Castleman disease. Common symptoms include, among others:

• Flu-like symptoms / signs: fever, night sweats, loss of appetite, nausea and vomiting
• Unintentional weight loss
• Weakness and fatigue
• Enlarged liver or spleen
• Peripheral neuropathy (numbness in the hands and feet)
• Cherry hemangiomas (also known as senile hemangiomas), a skin rash
• Edema (swelling), ascites (fluid accumulation in the abdomen) and / or other signs of fluid overload
• Impaired kidney function

Many people with unicentric Castleman disease have no signs or symptoms. The enlarged lymph node may be detected during a physical examination or an imaging test performed for another reason.

Enlarged lymph nodes associated with multicentric Castleman disease are most commonly found in the neck, collarbone, armpit and groin regions.

Although the above features are mostly seen in the multicentric subtype, they can also be seen in some patients with the unicentric subtype.

When Should You See a Doctor?

If you notice an enlarged lymph node at the side of your neck or in your armpit, collarbone or groin region, you can consult your doctor. You can also seek help from your doctor if you experience a persistent feeling of fullness in your chest or abdomen, fever, fatigue or unexplained weight loss.

Risk Factors

Castleman disease can affect people of any age. However, the average age of people diagnosed with unicentric Castleman disease is 35. Most people with the multicentric form are in their 50s and 60s. The multicentric form is also slightly more common in men than in women. People infected with the virus called human herpesvirus 8 (HHV-8) have a higher risk of developing multicentric Castleman disease.

Complications

People with unicentric Castleman disease generally do well after the affected lymph node is removed. Multicentric Castleman disease, however, can lead to life-threatening infections or organ failure. Patients with HIV / AIDS may also generally face the worst outcomes.

Having either unicentric or multicentric Castleman disease can also increase the risk of lymphoma.

How Is It Diagnosed?

Castleman disease (CD) can be difficult to diagnose because it is both a rare disease and a mimic of many other diseases. Patients may have the same symptoms as some types of cancer and some autoimmune diseases. Because of the complexity of the disease, doctors must rule out many other diseases before suspecting CD.

Diagnostic Tests

• Blood and urine tests to rule out other infections or diseases. These tests can sometimes reveal anemia and abnormalities in blood proteins typically seen in Castleman disease.
• Imaging tests are requested to detect enlarged lymph nodes, liver or spleen. A CT (Computed Tomography) scan or MRI (Magnetic Resonance Imaging) of your neck, chest, abdomen and pelvis may be used. Positron emission tomography (PET) scans may also be used to diagnose Castleman disease and assess whether treatment is effective.
• A lymph node biopsy is used to distinguish Castleman disease from other disorders of lymphatic tissue, such as lymphoma. A tissue sample is taken from an enlarged lymph node and examined in a laboratory.
• A lymph node biopsy is needed for a definitive diagnosis of CD because disease-specific changes are seen in the lymph nodes under the microscope. The biopsy is important to avoid a misdiagnosis.

Treatment

The treatment method varies according to the subtype of the disease. Unicentric Castleman disease (UCD): Surgery is considered by experts to be the first-line treatment for almost all UCD cases. If the enlarged lymph node or nodes are completely removed and previous clinical / laboratory abnormalities return to normal, the UCD patient is considered cured. Sometimes it is not possible to remove the enlarged lymph node(s) completely. In such cases, treatments frequently used for MCD may sometimes be needed. No case of UCD transforming into MCD has been reported. The medical team assesses surgical options and risks depending on the location of the enlarged lymph nodes.

HHV-8-associated Multicentric Castleman disease (HHV-8-associated MCD): Rituximab is highly effective in treating HHV-8-associated MCD. This drug is specific to B cells, a particular type of immune cell. This is seen as an advantage of Rituximab because conventional chemotherapy drugs are not specific and therefore cause different side effects. The degree of immunosuppression is also milder than with conventional chemotherapy drugs.

HHV-8-negative / idiopathic Multicentric Castleman disease (iMCD): Several specific therapies, such as siltuximab and tocilizumab, are considered first-line treatments. These drugs target a specific compound (interleukin-6) that is highly involved in inflammation. Unlike conventional chemotherapy, anti-IL6 treatment is more specific, so side effects are milder. The degree of immunosuppression will depend on whether other drugs are used at the same time. For reasons that are still unknown, Rituximab works more successfully in iMCD patients than in patients with HHV-8-associated MCD.

Unfortunately, however, anti-IL6 treatment is not effective in all patients. Sometimes, if a patient does not improve with anti-IL-6 treatment, rituximab or chemotherapy regimens used for blood cancers are used.

A new clinical trial with sirolimus for iMCD patients who do not improve with siltuximab or tocilizumab began in the United States in 2019.

The treatment methods for Multicentric Castleman disease are as follows:

• Immunotherapy: Drugs such as siltuximab (Sylvant) or rituximab (Rituxan) may prevent a protein that is overproduced in people with multicentric Castleman disease from having an effect.
• Chemotherapy: These drugs may slow the overgrowth of lymphatic cells. Your doctor may recommend chemotherapy if the disease does not respond to immunotherapy or if you have organ failure.
• Corticosteroids: Drugs such as prednisone may help control inflammation.
• Antiviral drugs: These drugs may block HHV-8 or HIV activity if you have it.

Patient Outcomes

• UCD (unicentric Castleman disease): Average survival after a UCD diagnosis is more than 10 years, and life expectancy generally does not change with UCD.
• MCD (multicentric Castleman disease): The 5-year overall survival rate is 65% according to a 2012 literature review. Survival rates are thought to have increased substantially at present because of new breakthroughs in treatment (such as anti-IL6 therapy). Research is ongoing worldwide to obtain new data.