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.
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 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 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.
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 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:
Symptoms of Castleman disease vary depending on the subtype and may include:
The exact cause of Castleman disease varies by subtype:
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.
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.
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).
Idiopathic multicentric Castleman disease (iMCD) exhibits a range of microscopic features.
Pathologists look for five key microscopic features when making the diagnosis of iMCD:
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.
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.
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)
Mixed/plasmacytic subtype
Each of these microscopic patterns helps pathologists distinguish between the different forms of Castleman disease and guide appropriate treatment.
The prognosis for a person diagnosed with Castleman disease varies by subtype: