Castleman’s Disease

Castleman’s disease is a rare group of disorders where the immune system becomes overactive, leading to enlarged lymph nodes and, in some forms, widespread inflammation that can damage vital organs throughout the body.

Table of contents

• What is Castleman’s Disease?
• Other Names for This Condition
• Types of Castleman’s Disease
• Signs and Symptoms
• Causes and Risk Factors
• How is it Diagnosed?
• Treatment Options
• Outlook and Prognosis

What is Castleman’s Disease?

Castleman’s disease is a group of rare disorders that involve a hyperactive immune system, which means the immune system stays activated when it should settle down^[1]. In a healthy person, the immune system activates to fight germs or illness and then returns to a resting state. But in Castleman’s disease, the immune system remains activated, leading to long-lasting inflammation that can damage organs^[1].

The condition affects lymph nodes, which are small bean-shaped structures that are part of the immune system and help filter germs from the body^[1]. In Castleman’s disease, lymph nodes work overtime, causing an overgrowth of cells that leads to swollen lymph nodes. The lymph nodes don’t just get bigger—Castleman’s disease causes changes in the tissue of affected lymph nodes that can be seen under a microscope^[1].

Castleman’s disease is very rare. In the United States, only about 4,300 to 5,200 new cases are diagnosed each year^[1]. The disease can affect people of any age, gender, or ethnicity^[4]. Whether Castleman’s disease should be considered an autoimmune disease, cancer, or infectious disease is currently unknown^[4].

Other Names for This Condition

angiofollicular lymph node hyperplasia, angiomatous lymphoid, angiofollicular ganglionic hyperplasia, Castleman tumour, giant benign lymphoma, giant lymph node hyperplasia, hamartoma of the lymphatics

Types of Castleman’s Disease

There are two main types of Castleman’s disease, and they are quite different from each other^[2]. The type you have depends on the number and location of enlarged lymph nodes in your body.

Unicentric Castleman Disease (UCD)

Unicentric Castleman disease causes enlargement of one lymph node or a single group of lymph nodes in one region of your body^[1]. This is the most common form, making up about 3 in 4 cases of Castleman’s disease^[1]. The affected lymph node is usually in the chest or neck, but it can occur in other areas of the body as well^[2]. People with this type usually don’t have symptoms beyond the enlarged lymph node itself^[1].

Multicentric Castleman Disease (MCD)

Multicentric Castleman disease involves multiple regions of enlarged lymph nodes throughout the body, along with inflammatory symptoms and problems with organ function^[2]. This form is more likely to cause noticeable symptoms and can be life-threatening^[1].

There are three subtypes of multicentric Castleman disease:

• HHV-8-associated MCD: This type is linked to infection with human herpes virus type 8 (HHV-8)^[2]. You’re more likely to have this type if you’re HIV positive or have a weakened immune system^[1].
• Idiopathic MCD (iMCD): The most common form of MCD is idiopathic, which means its causes are unknown^[1]. There is no evidence of HHV-8 or any other cancer or infectious disease in these patients^[4].
• POEMS-associated MCD: This type is linked to a rare blood disorder called POEMS syndrome, which damages nerves and affects other parts of the body^[2].

Idiopathic MCD has three additional subtypes^[1]:

• iMCD associated with TAFRO: TAFRO syndrome sometimes accompanies iMCD. TAFRO gets its name from its associated signs and symptoms: thrombocytopenia (low platelets), anasarca (swelling from fluid build-up), fever, renal (kidney) dysfunction, and organomegaly (enlarged spleen or liver).
• iMCD with idiopathic plasmacytic lymphadenopathy (iMCD-IPL): This subtype may cause high platelets, and white blood cells may make too many antibodies.
• iMCD, not otherwise specified (iMCD-NOS): This has unknown causes and isn’t associated with TAFRO.

Sometimes people may have 2-3 enlarged lymph nodes and mild symptoms that do not meet the diagnostic criteria for MCD. These people may have the recently described subtype called oligocentric Castleman disease, which is rare^[2].

Signs and Symptoms

Symptoms of Castleman’s disease vary greatly depending on the type you have^[1].

Unicentric Castleman Disease Symptoms

You likely won’t have symptoms with unicentric Castleman disease^[1]. Enlarged lymph nodes may be the only sign. Sometimes, symptoms occur when an enlarged lymph node creates pressure on a nearby organ^[1].

Multicentric Castleman Disease Symptoms

MCD is more likely to cause noticeable symptoms^[1]. In addition to enlarged lymph nodes in multiple regions of the body, signs and symptoms include:

• Fever
• Fatigue (may be a sign of anemia, which is a low red blood cell count)
• Night sweats
• Nausea and vomiting
• Unexplained weight loss
• Swelling in your feet, ankles, or abdomen
• Enlarged spleen (splenomegaly) or liver (hepatomegaly)
• Numbness in your hands and feet (peripheral neuropathy)

Causes and Risk Factors

While the causes of unicentric Castleman disease are unknown, an HHV-8 infection is associated with multicentric Castleman disease^[1]. Scientists believe the condition results from impaired control of the immune system that causes excessive proliferation of certain immune cells in lymphoid organs^[3].

In multicentric Castleman disease, particularly the HHV-8-associated type, the causative factors include human herpesvirus-8, which causes disruption of inflammatory mediators like CD20 and interleukin-6 (IL-6), a protein that signals inflammation^[3]. In Castleman’s disease patients, inflammatory cells become hyperactivated and produce excess inflammatory messengers, particularly interleukin-6, that lead to flu-like symptoms, lymph node enlargement, and dysfunction of vital organs^[14].

Scientists are researching potential causes of unicentric Castleman disease and idiopathic MCD. These include infections other than HHV-8, gene mutations, and autoimmune responses^[1].

There aren’t any known risk factors for unicentric Castleman disease or idiopathic MCD^[1]. However, you’re at increased risk for HHV-8-associated MCD if you’re HIV positive or have a suppressed immune system for another cause^[4].

How is it Diagnosed?

After reviewing your medical history and doing a detailed physical exam, your healthcare professional may recommend several tests^[8].

It is absolutely important to emphasize that diagnosis with Castleman’s disease requires a lymph node biopsy with Castleman disease features identified by a pathologist under the microscope^[14]. During a biopsy, a tissue sample from an enlarged lymph node is removed and examined in a laboratory^[8]. This test is essential to diagnose Castleman’s disease and rule out related disorders, such as lymphoma.

Other diagnostic tests may include^[8]:

• Blood and urine tests: These help rule out other infections or diseases and can find anemia and changes in blood proteins that can be typical of Castleman’s disease.
• Imaging tests: These tests can find enlarged lymph nodes or an enlarged liver or spleen. A CT scan of the neck, chest, abdomen, and pelvis may be used. A positron emission tomography scan (PET scan) may be used to diagnose Castleman’s disease and can also show whether a treatment is working.

Your physician must rule out other diseases before a Castleman’s disease diagnosis is made, as lymph node features found in Castleman’s disease can also be seen in other diseases including cancers and autoimmune diseases^[14].

Treatment Options

Treatment varies depending on the subtype of Castleman’s disease^[10]. The symptoms, causes, and treatments vary greatly for each subtype.

Unicentric Castleman Disease Treatment

Surgery to remove the affected lymph node is the usual treatment for unicentric Castleman disease^[8]. If the lymph node is in the chest or abdomen, major surgery may be needed. Surgery to remove the enlarged lymph node usually cures unicentric Castleman disease^[8]. However, the disease sometimes comes back.

If surgery is not possible, you may need medicines typically used for multicentric Castleman disease^[1]. If medicines don’t work, radiation therapy may be an option^[1]. Radiation therapy with 30-45 Gy can result in complete and partial remission rates^[12].

Multicentric Castleman Disease Treatment

HHV-8-associated MCD: Rituximab is recommended as first-line therapy for HHV-8-associated MCD^[10]. It is highly effective, but occasionally antivirals and cytotoxic chemotherapies are needed. Rituximab targets and eliminates B cells, a special type of immune cell^[10]. For patients with concomitant HIV infection and a low CD4 count and higher HIV load, antiretroviral therapy should be included with the rituximab^[12].

Idiopathic MCD (iMCD): First-line treatment for idiopathic multicentric Castleman disease is anti-IL-6 therapy with siltuximab (or tocilizumab, if siltuximab is not available)^[10]. Siltuximab (Sylvant) is the only FDA-approved treatment for iMCD, and patients who responded to siltuximab tend to have long-term responses^[10]. This drug targets a specific protein (interleukin-6) that plays an important role in the disease^[10]. Anti-IL-6 treatment is continued until progression of disease in order to maintain the response and prevent an early relapse^[12].

Single-agent and combination chemotherapy yields symptomatic relief and a partial response in many patients^[12]. However, symptoms recur when treatment is stopped, necessitating intermittent maintenance therapy, often lifelong.

Your medical team will discuss the options and treatment approach depending on your specific diagnosis and situation^[10].

Outlook and Prognosis

The outlook for Castleman’s disease varies greatly depending on the type you have.

People with unicentric Castleman disease usually do well once the affected lymph node is removed, and life expectancy is usually not changed^[10]. Even in patients whose lesions cannot be completely resected, outcomes remain favorable, and partially resected masses may remain stable and asymptomatic for many years^[12]. There are no reported cases of unicentric Castleman disease transforming into multicentric Castleman disease^[10].

Multicentric Castleman disease is more serious and can be life-threatening^[1]. The historical 5-year overall survival rate for MCD has been 55% to 77%^[13]. However, with the introduction of biological agents in the form of monoclonal antibodies against specific pathogenic processes of the disease, survival rates have improved significantly^[11].

Treatment involves customizing the right therapies based on your unique diagnosis^[1]. There’s still a lot that doctors are learning about this condition, and consultation with the Castleman Disease Collaborative Network is strongly recommended to ensure that patients have timely access to clinicians experienced in the treatment of Castleman’s disease^[13].