Castleman disease is a rare group of disorders that causes an overactive immune system, leading to enlarged lymph nodes and tissue changes that can affect many parts of the body. While some forms involve a single area and may cause few symptoms, others affect multiple regions and can become life-threatening without proper treatment.
Understanding Castleman Disease
Castleman disease describes a collection of rare conditions that involve the immune system behaving in ways it shouldn’t. In a healthy person, the immune system springs into action when germs or other threats enter the body, fighting them off and then settling back down once the danger has passed. However, in someone with Castleman disease, the immune system doesn’t calm down. Instead, it remains in an activated state, creating ongoing inflammation that can harm organs and other body systems over time.[1]
This constant immune activation causes lymph nodes to work far harder than they should. Lymph nodes are small, bean-shaped structures scattered throughout the body that act as filtering stations for the immune system. They trap germs and immune cells that are fighting infections. In Castleman disease, an overgrowth of cells occurs within these lymph nodes, causing them to become swollen and enlarged. But the changes go beyond just size—the tissue inside the affected lymph nodes undergoes specific structural changes that can only be seen under a microscope after a biopsy.[1]
The disease was first identified in 1954 by Dr. Benjamin Castleman, who noticed unusual features in a surgically removed mass from the chest. Over the following years, similar cases were reported, confirming the existence of this new disease entity. Today, medical professionals recognize that Castleman disease is not a single condition but rather a spectrum of related disorders that share some common features but differ significantly in their causes, symptoms, severity, and how they should be treated.[11]
Types of Castleman Disease
Castleman disease is divided into two main categories based on how many lymph nodes are involved and where they are located in the body. Understanding which type a person has is crucial because treatment approaches and outcomes vary considerably between them.[1]
Unicentric Castleman disease (UCD) is the more common form, accounting for about three out of every four cases. In UCD, only one lymph node or a single group of lymph nodes in one region of the body becomes enlarged. The affected area is most often in the chest or abdomen, though it can occur anywhere in the body. Most people with UCD experience few or no symptoms at all. Sometimes, if an enlarged lymph node happens to press against a nearby organ, it might cause discomfort or other symptoms related to that pressure. This form of the disease typically has a favorable outlook, especially when the affected lymph node can be surgically removed.[1]
Multicentric Castleman disease (MCD) is less common but tends to be more serious. In MCD, lymph nodes in multiple regions throughout the body become enlarged. Unlike UCD, people with MCD usually experience noticeable symptoms and can develop problems with vital organs such as the liver, kidneys, and bone marrow. This form of the disease causes an inflammatory syndrome—a constellation of symptoms that result from excessive production of inflammatory proteins called cytokines, particularly interleukin-6 (IL-6), which plays a central role in driving the disease process.[1]
MCD is further divided into three distinct subtypes based on their underlying causes. HHV-8-associated MCD occurs when a person is infected with human herpesvirus-8 (HHV-8). This virus is particularly problematic in people who are HIV-positive or have weakened immune systems for other reasons. The uncontrolled viral infection triggers excessive cytokine production and leads to the characteristic features of MCD. Nearly all cases of MCD in HIV-positive individuals are associated with HHV-8 infection.[1]
POEMS-associated MCD occurs alongside POEMS syndrome, a rare blood disorder. POEMS is an acronym that stands for polyneuropathy (nerve damage), organomegaly (enlarged organs), endocrinopathy (hormone problems), monoclonal plasma cell disorder (abnormal blood cells), and skin changes. In some people with POEMS syndrome, cancerous cells produce excessive amounts of cytokines that can trigger MCD features.[1]
Idiopathic multicentric Castleman disease (iMCD) is the most common subtype of MCD. The term “idiopathic” means that the cause is unknown—these cases are not linked to HHV-8 infection, POEMS syndrome, or any other identifiable trigger. Despite this uncertainty, researchers have learned that excessive IL-6 production plays a critical role in driving symptoms and organ damage. iMCD itself has three recognized subtypes based on the specific features present. iMCD-TAFRO is the most severe form, named after its characteristic symptoms: thrombocytopenia (low platelet counts), anasarca (widespread fluid accumulation and swelling), fever, renal dysfunction (kidney problems), and organomegaly (enlarged liver or spleen). iMCD-IPL (idiopathic plasmacytic lymphadenopathy) tends to follow a milder course and may involve high platelet counts and excessive antibody production. Finally, iMCD-NOS (not otherwise specified) includes cases that don’t fit neatly into either of the other two categories.[1]
How Common Is Castleman Disease
Castleman disease is extremely rare. In the United States, only about 4,300 to 5,200 new cases are diagnosed each year. To put this in perspective, this number is far smaller than common cancers or chronic diseases that affect millions of people. The rarity of the condition means that many doctors may go their entire careers without seeing a single case, which can sometimes lead to delays in diagnosis or confusion with other conditions.[1]
Studies examining the epidemiology of the disease have provided some insight into who is affected. For unicentric Castleman disease, the incidence has been estimated at approximately 16 cases per million people per year, and it can affect individuals of any age. The disease does not appear to have a strong preference for any particular sex or racial group.[3]
For multicentric Castleman disease, the patterns are somewhat different depending on the subtype. HHV-8-associated MCD is more commonly seen in HIV-positive men, reflecting the role of immune suppression and viral infection in this form of the disease. Idiopathic MCD, meanwhile, has an estimated incidence of about 5 cases per million people per year. Research examining MCD cases in the United States between 2000 and 2009 found that about 61% of patients were male, with a mean age of 53 years, and approximately 68% were white—though the disease can affect people of all backgrounds.[3]
Among the different pathological patterns seen in Castleman disease, the hyaline-vascular variant is much more common than the plasma-cell type, comprising about 91% of total cases. However, these pathological classifications are separate from the clinical classification into UCD and MCD, and understanding both aspects helps guide treatment decisions.[3]
What Causes Castleman Disease
The causes of Castleman disease remain one of the biggest mysteries in medicine, and researchers continue working to unravel what triggers these conditions. What is known is that the disease involves fundamental problems with how the immune system is regulated. Instead of activating appropriately to fight threats and then returning to a resting state, the immune system in Castleman disease stays switched on, leading to chronic inflammation and the characteristic features of the disease.[1]
For unicentric Castleman disease, the causes remain completely unknown. Scientists suspect that factors such as chronic low-grade inflammation, abnormal lymphoid tissue development, viral infections, or problems with cytokine regulation might play a role, but no definitive trigger has been identified. There are also no known gene mutations that directly cause UCD.[1]
The picture is clearer for HHV-8-associated multicentric Castleman disease. This form is caused by uncontrolled infection with human herpesvirus-8, a virus that most people can harbor without any problems. However, in individuals with weakened immune systems—particularly those who are HIV-positive or immunocompromised for other reasons—HHV-8 can proliferate and produce viral proteins that mimic human interleukin-6. This viral IL-6 drives excessive inflammation and triggers the cascade of problems seen in MCD. The association with HIV is so strong that almost all cases of MCD in HIV-positive individuals are HHV-8-positive, compared to only about 40 to 50% of MCD cases in people without HIV infection.[3]
For idiopathic multicentric Castleman disease, by definition, the cause remains a mystery. The term “idiopathic” specifically indicates that no infectious agent, genetic cause, or other trigger has been found. Nevertheless, research has shown that these patients have dysregulated production of inflammatory cytokines, particularly IL-6, which appears to be central to the disease process. Scientists are actively investigating whether subtle immune system abnormalities, genetic factors not yet identified, or environmental triggers might be responsible.[1]
Current theories about the root causes of Castleman disease include impaired immune regulation that allows B lymphocytes and plasma cells—types of immune cells—to proliferate excessively in lymphoid tissues. This could result from various factors including chronic inflammation, abnormal tissue development resembling a benign growth disorder, viral infections beyond HHV-8, problems with cytokine signaling pathways, or abnormalities in the formation of blood vessels that supply lymph nodes.[3]
Risk Factors for Castleman Disease
One of the most puzzling aspects of Castleman disease is that there are no clearly established risk factors for developing UCD or idiopathic MCD. Unlike many diseases where doctors can identify certain behaviors, exposures, or characteristics that increase risk, these forms of Castleman disease seem to strike randomly. No particular lifestyle factors, environmental exposures, dietary habits, or genetic predispositions have been definitively linked to increased risk. The disease can develop in children, young adults, middle-aged individuals, or elderly people. It affects both men and women, and occurs across all racial and ethnic groups.[1]
For HHV-8-associated multicentric Castleman disease, however, certain risk factors are well-established. The most significant is being HIV-positive. People living with HIV who also become infected with HHV-8 are at substantially increased risk of developing this form of MCD. This is because HIV weakens the immune system’s ability to keep HHV-8 infection under control. Additionally, anyone who is immunocompromised for other reasons—such as those taking immune-suppressing medications after organ transplantation—also faces increased risk if they harbor HHV-8 infection.[1]
The strong association between HIV, HHV-8, and this subtype of MCD has important implications. It means that people with HIV should be aware of Castleman disease as a possible complication, and healthcare providers caring for HIV-positive patients need to maintain vigilance for symptoms that might indicate MCD. However, it’s important to emphasize that the vast majority of people with HIV never develop Castleman disease, even if they have been exposed to HHV-8.[3]
Recognizing the Symptoms
The symptoms of Castleman disease vary dramatically depending on which type a person has. This variation can sometimes make diagnosis challenging, as the disease can present very differently from one patient to another.[1]
People with unicentric Castleman disease often have no symptoms at all. The enlarged lymph node may be discovered incidentally during imaging tests performed for other reasons, or a person might notice a painless lump or mass in an area such as the neck, armpit, or groin. In some cases, if the enlarged lymph node happens to be located in the chest or abdomen where it can press against nearby structures, symptoms might develop from that pressure. For example, an enlarged lymph node in the chest might press on airways and cause cough or difficulty breathing, or one in the abdomen might cause abdominal discomfort or a feeling of fullness.[1]
Multicentric Castleman disease presents a very different picture. Because MCD involves widespread immune activation and inflammatory cytokine overproduction, people with this form typically experience noticeable systemic symptoms—meaning symptoms that affect the whole body rather than just one area. Enlarged lymph nodes in multiple regions are a hallmark feature, often visible or palpable in the neck, armpits, and groin.[1]
Fever is common in MCD and may come and go or persist over time. Many patients describe experiencing night sweats so severe that they wake up drenched, requiring changes of clothing or bed linens. Profound fatigue is another frequent complaint—not just ordinary tiredness, but an exhausting, overwhelming fatigue that doesn’t improve with rest and can make daily activities extremely difficult. This fatigue often results from anemia (low red blood cell counts) that commonly accompanies MCD.[1]
Weight loss can occur without any intentional changes to diet or activity level. Some people lose appetite entirely, while others experience persistent nausea and vomiting that make eating difficult. Fluid retention leading to swelling is another characteristic feature. This swelling, called edema, typically appears in the feet, ankles, and legs, but in severe cases can become widespread, involving the abdomen and other areas. When extensive fluid accumulation occurs throughout the body, it’s called anasarca, which is particularly characteristic of the iMCD-TAFRO subtype.[1]
Internal organ enlargement is common in MCD. The spleen and liver often become enlarged, a condition doctors call splenomegaly and hepatomegaly. An enlarged spleen might cause discomfort or fullness in the upper left side of the abdomen, while liver enlargement can cause similar feelings on the right side. Some people experience numbness, tingling, or other unusual sensations in their hands and feet—a condition called peripheral neuropathy that occurs when the inflammatory process affects nerves.[1]
The iMCD-TAFRO subtype deserves special mention because it can be particularly severe and life-threatening. In addition to the symptoms described above, people with this form often have very low platelet counts, making them vulnerable to bleeding problems. Kidney dysfunction can develop rapidly, and the combination of severe symptoms can constitute a medical emergency requiring immediate, aggressive treatment.[1]
Can Castleman Disease Be Prevented
Unfortunately, there are no known prevention strategies for unicentric Castleman disease or idiopathic multicentric Castleman disease. Because the causes of these conditions remain unknown and no risk factors have been identified, there are no specific lifestyle changes, medications, supplements, or screening programs that can prevent them from developing. This is frustrating for both patients and doctors, but it reflects the current state of understanding about these mysterious disorders.[1]
For HHV-8-associated multicentric Castleman disease, the picture is somewhat different. Since this form is triggered by HHV-8 infection in the context of immune suppression, maintaining a healthy immune system becomes important. For people living with HIV, the most important preventive measure is consistent use of antiretroviral therapy (ART). These medications keep HIV under control, preserve immune function, and reduce the risk of opportunistic infections including those caused by HHV-8. Maintaining good adherence to ART regimens and achieving an undetectable viral load provides the best protection against HIV-related complications, including HHV-8-associated MCD.[8]
Beyond HIV management, there are no vaccines or specific preventive measures for HHV-8 infection itself. The virus is relatively common in the general population, particularly in certain geographic regions and populations, and most people who are infected never develop any problems. Research into vaccines or antiviral strategies to prevent HHV-8-related diseases is ongoing but has not yet produced clinically available options.[3]
What is achievable, however, is early detection and prompt treatment when symptoms do appear. Because Castleman disease is rare and can present with vague symptoms that mimic many other conditions, awareness among both patients and healthcare providers is crucial. People who experience persistent fever, night sweats, unexplained weight loss, or other concerning symptoms should seek medical evaluation. Early diagnosis and treatment can prevent complications and improve outcomes, particularly in the aggressive forms of the disease.[1]
How the Disease Affects the Body
Understanding what happens in the body during Castleman disease helps explain why the symptoms occur and why treatment approaches are designed the way they are. At the core of the disease process is a fundamental disruption in immune system regulation, leading to a cascade of problems that affect multiple organ systems.[1]
In a healthy immune system, lymph nodes serve as command centers where immune cells gather, communicate, and coordinate responses to threats. When an infection occurs, immune cells become activated, multiply, and produce signaling molecules called cytokines that orchestrate the immune response. Once the threat is eliminated, this activity winds down, cytokine levels drop, and the system returns to a surveillance state. In Castleman disease, this normal regulatory process breaks down.[4]
The cells within affected lymph nodes—particularly B lymphocytes and plasma cells—begin multiplying excessively. This proliferation leads to the physical enlargement of the lymph nodes. But more importantly, these activated cells continue producing inflammatory cytokines at abnormally high levels. In particular, interleukin-6 plays a central role in driving the disease process in many cases of MCD. IL-6 is a powerful inflammatory mediator that affects many different cell types and organ systems throughout the body.[4]
The excessive production of IL-6 and other cytokines creates what is essentially a chronic inflammatory state—sometimes referred to as a “cytokine storm” in severe cases. This persistent inflammation has wide-ranging effects. It stimulates the bone marrow to produce more immune cells and inflammatory proteins, but paradoxically can also suppress the production of red blood cells, leading to anemia. This explains the profound fatigue many patients experience. The inflammatory signals also cause blood vessels to become leaky, allowing fluid to escape from the bloodstream into surrounding tissues, resulting in the edema and fluid accumulation characteristic of the disease.[13]
Organs throughout the body respond to the chronic inflammatory environment. The liver may enlarge as it works to produce acute-phase proteins—substances released during inflammation. The spleen enlarges as it filters the increased number of immune cells and inflammatory proteins from the blood. The kidneys can be affected by the inflammatory mediators or by the proteins produced in excessive amounts, leading to kidney dysfunction. In severe cases, multiple organ systems can fail simultaneously, creating a life-threatening situation.[1]
The blood itself undergoes changes. In addition to anemia, the chronic inflammation affects platelet production. In iMCD-TAFRO, platelet counts drop dangerously low, creating bleeding risks. In other subtypes, platelet counts might actually increase. White blood cell counts often rise, and antibody levels may be elevated as plasma cells produce excessive immunoglobulins. Blood protein levels become abnormal, with certain proteins increasing dramatically while others drop.[1]
In HHV-8-associated disease, an additional layer of complexity exists. The virus infects certain cells within lymph nodes and produces viral proteins that mimic human IL-6. This viral IL-6 acts on the same receptors as human IL-6, driving inflammation and cell proliferation. The virus also produces other proteins that help infected cells avoid detection and destruction by the immune system, allowing the infection to persist and continue driving the disease process.[3]
The nerve damage that sometimes occurs—peripheral neuropathy—likely results from multiple factors including the direct effects of inflammatory cytokines on nerve cells, damage to small blood vessels that supply nerves, or in POEMS-associated cases, from the abnormal proteins produced by malignant plasma cells. This can cause numbness, tingling, burning sensations, or weakness in the hands and feet.[1]
The microscopic changes within lymph nodes are distinctive enough to help pathologists recognize Castleman disease. These include abnormalities in the architecture of the lymph node, changes in blood vessel patterns, and characteristic appearances of the cellular components. However, these changes alone aren’t specific to Castleman disease, which is why careful evaluation to exclude other conditions is essential before making the diagnosis.[13]
