Castleman disease

by Jason Wasserman MD PhD FRCPC and David Li MD
June 2, 2025

Castleman disease is a rare condition that affects the lymph nodes and the immune system. It involves abnormal growth and inflammation of lymph nodes, leading to various health issues depending on the subtype and extent of involvement. There are different types of Castleman disease, each with distinct characteristics, causes, and clinical outcomes.

What are the types of Castleman disease?

Castleman disease is classified into several types based on two primary factors: whether the disease affects a single lymph node (unicentric) or multiple lymph nodes throughout the body (multicentric), and whether it is associated with infection by the human herpesvirus-8 (HHV-8).

Unicentric Castleman disease (UCD)

Unicentric Castleman disease involves only a single lymph node or one localized area. It usually does not spread throughout the body. Symptoms typically relate to the specific area affected, and surgical removal of the lymph node usually resolves the disease.

Multicentric Castleman disease (MCD)

Multicentric Castleman disease affects multiple lymph nodes throughout the body and is characterized by systemic symptoms, including fever, fatigue, weight loss, and swelling. MCD is further divided into two important subtypes: HHV8-associated multicentric Castleman disease and idiopathic multicentric Castleman disease.

HHV8-associated multicentric Castleman disease

As its name suggests, HHV8-associated multicentric Castlemen disease is directly associated with infection by human herpesvirus-8 (HHV-8). Approximately 80% of patients with this subtype also have HIV/AIDS. Symptoms are typically severe and aggressive, including significant enlargement of lymph nodes, systemic inflammation, and potential progression to lymphoma or other cancers.

Idiopathic multicentric Castleman disease (iMCD)

Idiopathic multicentric Castleman disease occurs without any known association with HHV8 or HIV. It involves widespread lymph node enlargement and systemic inflammation due to uncontrolled cytokine production.

iMCD has two subtypes:

  • iMCD-TAFRO subtype: Characterized by low platelet count (thrombocytopenia), generalized swelling (anasarca), fever, kidney dysfunction, organ enlargement, and bone marrow abnormalities.
  • iMCD-NOS subtype: Diagnosed when criteria for the TAFRO subtype are not fully met, but generalized symptoms and inflammation are present.

What are the symptoms of Castleman disease?

Symptoms of Castleman disease vary depending on the subtype and may include:

  • Enlarged lymph nodes, noticeable in the neck, armpit, chest, or abdomen
  • Fever
  • Fatigue
  • Weight loss
  • Night sweats
  • Loss of appetite
  • Skin rash
  • Swelling or fluid buildup (edema or anasarca)
  • Shortness of breath (if lymph nodes in the chest are involved)

What causes Castleman disease?

The exact cause of Castleman disease varies by subtype:

  • Unicentric Castleman disease: Its cause remains unclear, but abnormal immune system regulation is suspected.
  • HHV8-associated multicentric Castleman disease: Directly caused by the HHV8 virus, typically affecting individuals with weakened immune systems, particularly those with HIV/AIDS.
  • Idiopathic multicentric Castleman disease: The cause is unknown, but it involves abnormal immune activation leading to excessive inflammation and cytokine release.

How is Castleman disease diagnosed?

Castleman disease is typically diagnosed through a series of steps. Initially, your doctor may perform a biopsy of an affected lymph node. These biopsy sample is then examined under a microscope by a pathologist. Blood tests are conducted to measure inflammatory markers and cytokine levels, indicating the severity of systemic inflammation. Imaging studies, such as CT or PET scans, help determine the extent of lymph node and other organ involvement.

What other tests may be performed to confirm the diagnosis?

Additional tests to confirm the diagnosis include immunohistochemistry (IHC) on lymph node tissue to detect HHV-8 infection, which is crucial for differentiating HHV-8-associated MCD from other subtypes. Blood tests measuring inflammatory markers (CRP, ESR) and cytokine levels (particularly IL-6) help assess inflammation severity. Viral load tests for HHV8 and HIV may also be conducted. Bone marrow biopsies can show characteristic changes, especially in iMCD, aiding subtype classification.

What does Castleman disease look like under the microscope?

Castleman disease primarily affects lymph nodes, which are small structures found throughout the body that play a crucial role in fighting infections. Under the microscope, lymph nodes affected by Castleman disease exhibit an abnormal arrangement of cells, which can vary depending on the subtype. In all forms, there is some degree of distortion or disruption of the normal lymph node structure, particularly affecting small round structures called follicles. Follicles are clusters of immune cells, mostly lymphocytes, which normally help the body respond to infection. The area between these follicles, known as the interfollicular region, can also show increased inflammation, abnormal blood vessels, or fibrosis (scarring).

Microscopic features of idiopathic multicentric Castleman disease (iMCD)

Idiopathic multicentric Castleman disease (iMCD) exhibits a range of microscopic features.

Pathologists look for five key microscopic features when making the diagnosis of iMCD:

  1. The number of regressed germinal centers.
  2. Increased visibility of special immune cells called follicular dendritic cells.
  3. An increased number of small blood vessels.
  4. The number of enlarged or hyperplastic follicles.
  5. An increased number of plasma cells (antibody-producing cells).

In addition, there are two subtypes of iMCD, each with slightly different microscopic patterns:

  • iMCD-TAFRO: Typically shows smaller or atrophic (shrunken) follicles with fewer plasma cells in the interfollicular areas but many prominent small blood vessels called high endothelial venules. Bone marrow samples often show an increase in the number of megakaryocytes (cells that produce platelets), clustering of these cells, and increased reticulin fibrosis (scarring).

  • iMCD-NOS: Usually has more plasma cells between follicles (interfollicular plasmacytosis) and fewer shrunken follicles. Bone marrow may show an increase in plasma cells and megakaryocytes.

In contrast to unicentric Castleman disease, the cells known as follicular dendritic cells rarely appear abnormal in iMCD. Also, small channels within the lymph node (sinuses) are usually open and less obstructed, and blood vessels penetrating into follicles tend to be less thickened and scarred.

Microscopic features of HHV8-associated multicentric Castleman disease

HHV8-associated multicentric Castleman disease (HHV8-MCD) shares some microscopic features with iMCD but also has distinctive characteristics due to infection with the HHV8 virus. The most important feature is the presence of infected cells known as plasmablasts. These plasmablasts are medium to large immune cells characterized by one or two small, visible nucleoli (tiny dots within the cell nucleus) and slightly purple-blue (amphophilic) cytoplasm. Plasmablasts are found mostly around the follicles (mantle zones) but can also appear within follicles or between follicles.

The plasmablasts sometimes cluster together in groups called plasmablastic aggregates. They contain HHV8, which pathologists detect using immunohistochemistry. These cells typically express another protein called IgM lambda (a specific type of antibody). However, unlike cancer cells, they do not originate from a single clone but rather from multiple different cells (polyclonal).

Other plasma cells, located around the follicles (interfollicular), are usually numerous and normal-looking, but typically do not produce the IgM antibody type. Small areas of Kaposi sarcoma, a cancerous condition also caused by HHV8, may be present as well.

Microscopic features of unicentric Castleman disease (UCD)

In unicentric Castleman disease (UCD), the microscopic features depend on the specific subtype present, either hyaline vascular (HV-UCD) or mixed/plasmacytic.

Hyaline vascular subtype (HV-UCD)

  • Follicles are more numerous and larger than normal but contain fewer immune cells in their centers (germinal centers). These germinal centers are replaced by increased follicular dendritic cells and thickened blood vessels described as hyalinized (scarred and glassy-looking). Pathologists call these distinctive follicle patterns “lollipop lesions” because they resemble lollipops under the microscope.
  • The rings of immune cells surrounding these germinal centers (mantle zones) often look layered, resembling an onion-skin pattern.
  • Occasionally, two or more small germinal centers occur within a single follicle, a phenomenon known as twinning.
  • Between follicles (interfollicular areas), there are many small lymphocytes, fewer activated, larger immune cells, clusters of special immune cells called plasmacytoid dendritic cells, and increased scar-like fibrosis.
  • The lymph node capsule (outer layer) often thickens and forms fibrous bands, and lymph node channels (sinuses) become compressed or blocked.

Mixed/plasmacytic subtype

  • The lymph node architecture usually remains relatively normal, but the areas between follicles (interfollicular areas) contain numerous plasma cells, which are grouped together and produce antibodies.
  • Follicles can vary greatly in size and appearance, from large and active to smaller, regressed, or inactive.
  • Some follicles might show similar changes seen in HV-UCD, but these are typically less developed and less striking.

Each of these microscopic patterns helps pathologists distinguish between the different forms of Castleman disease and guide appropriate treatment.

What is the prognosis for Castleman disease?

The prognosis for a person diagnosed with Castleman disease varies by subtype:

  • Unicentric Castleman disease: Typically has an excellent prognosis after surgical removal.
  • HHV8-associated multicentric Castleman disease: Prognosis depends heavily on managing underlying HHV8 and HIV infections and the patient’s response to antiviral and immunosuppressive therapies. Outcomes vary, with some patients achieving stable disease control while others may experience aggressive disease progression.
  • Idiopathic multicentric Castleman disease: Prognosis varies greatly depending on severity, organ involvement, and treatment response. Some patients achieve good symptom control with medications targeting inflammation, while others require ongoing management and monitoring due to recurrent or persistent symptoms.

Questions for your doctor

  • Which type of Castleman disease do I have?
  • What additional tests should I undergo?
  • What treatments are specifically recommended for my subtype?
  • How frequently should I have follow-up appointments?
  • What symptoms require immediate medical attention?
  • Are lifestyle or dietary changes recommended to help manage symptoms?
  • What side effects or risks might I encounter with treatment?
  • Could Castleman disease return after treatment?
  • Should my family members be screened or monitored for Castleman disease?
  • Are there clinical trials or new treatments available for my condition?
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