Castleman's disease: symptoms, forms, diagnosis and treatment

Castleman disease is a rare group of lymphoproliferative disorders in which lymph nodes enlarge and develop characteristic changes under a microscope. Today, it is considered not as a single disease, but rather as a spectrum of conditions with different biology, different clinical courses, and different treatments. The main modern dichotomy lies between a localized form, in which a single lymph node or anatomical region is affected, and a multicentric form, in which the lesion affects multiple regions and is accompanied by systemic inflammation. [1]

Localized Castleman disease, also known as unicentric, often behaves as a localized lesion and is often treated surgically. Multicentric Castleman disease, in contrast, is potentially life-threatening because it is associated with hyperproduction of proinflammatory cytokines, multiple organ damage, and the risk of severe exacerbations. Within the multicentric form, a virus-associated variant associated with human herpesvirus type 8, a variant associated with POEMS syndrome, and idiopathic multicentric Castleman disease are distinguished, where the exact cause is unknown. [2]

This disease is important for clinical practice for three reasons. First, it can mimic lymphoma, autoimmune diseases, infections, and inflammatory syndromes. Second, a diagnosis cannot be made without a lymph node biopsy. Third, modern treatment approaches have already significantly diverged from older approaches: for the idiopathic multicentric form, interleukin 6 blockade is considered first-line therapy, rather than "non-specific chemotherapy with everything." [3]

Table 1. What you need to understand about Castleman disease at the very beginning

Question	Short answer
What is this?	A rare lymphoproliferative disorder
Is it cancer or not?	Not a classic cancer, but a severe immune-inflammatory and lymphoid disease
Main forms	Unicentric and multicentric
How are they different?	Localization of the process and the presence of systemic inflammation
Why is the diagnosis difficult?	The disease is similar to lymphoma, infections and autoimmune conditions.
What is critical for diagnosis?	Lymph node biopsy and exclusion of similar diseases

Code according to ICD 10 and ICD 11

There's an important nuance to the coding of Castleman disease. In international clinical practice, the code D47.Z2 from the International Classification of Diseases, Clinical Modification 10, is widely used, where it directly designates Castleman disease. The introduction of this code in 2016 significantly improved epidemiological research and analysis of real-world clinical practice. [4]

However, the basic international version of the International Classification of Diseases, 10th revision, of the World Health Organization does not have a specific category specifically for Castleman disease. Therefore, when describing the disease internationally, it is important to clearly clarify that the specific code D47.Z2 refers specifically to the clinical modification. For the International Classification of Diseases, 11th revision, Castleman disease is included in the category 4B2Y - Other specified disorders involving the immune system, where localized and multicentric Castleman disease are explicitly listed among the synonyms. [5]

Table 2. Castleman disease coding

Classification	Code	Comment
International Classification of Diseases, Clinical Modification 10	D47.Z2	Castleman's disease
International Classification of Diseases, 10th revision of the World Health Organization	there is no separate narrow section	Clinical clarification is usually required.
International Classification of Diseases, 11th revision	4B2Y	Other specified disorders involving the immune system
International Classification of Diseases, 11th revision	4B2Y	Includes localized and multicentric Castleman disease

Epidemiology

Castleman disease is a rare disorder. According to the Castleman Disease Collaborative Network, approximately 4,300–5,200 new cases are diagnosed annually in the United States. Older estimates suggested approximately 4,000–6,000 new cases per year and an overall incidence of 21–25 cases per million person-years, but these estimates were made before the advent of more precise criteria and a separate code. [6]

For the idiopathic multicentric form, estimates are even lower. In American real-world analyses, its annual incidence was estimated at approximately 3.1-3.4 cases per million, and its prevalence at approximately 6.9-9.7 cases per million. For Japan, publications cite a rate of approximately 2.4 cases per million for the idiopathic multicentric form. [7]

Based on case composition, the unicentric form is more common than the multicentric form. Educational and review sources typically indicate that the localized form accounts for the majority of cases. However, the multicentric form is clinically much more severe and is more often seen in large, specialized centers, which is why its prevalence may appear higher in some series. [8]

Table 3. Epidemiological landmarks

Indicator	Grade
New cases of Castleman disease in the United States per year	4300-5200
An earlier estimate of new cases in the US	4000-6000
Overall incidence of Castleman disease	21-25 per 1 million person-years
Incidence of idiopathic multicentric form	3.1-3.4 per 1 million per year
Prevalence of idiopathic multicentric form	6.9-9.7 per 1 million
What is more common?	Unicentric form

Reasons

The exact cause of unicentric Castleman disease remains unknown. It is generally considered a localized abnormal proliferation of lymphoid tissue with characteristic histology. Most cases are considered sporadic, with no familial transmission and no known universal trigger. [9]

In multicentric disease, the causes depend on the subtype. In the form associated with human herpesvirus type 8, the virus itself plays a key role, triggering hypercytokinemia, including through the viral analogue of interleukin 6. This is why this form is especially important in patients with immunodeficiency and human immunodeficiency virus infection. [10]

In idiopathic multicentric Castleman disease, the exact underlying cause is unknown, but it is currently considered a cytokine-mediated disorder. Recent reviews from 2025 emphasize that dysregulation of interleukin 6 and other proinflammatory signaling pathways plays a leading role. Some patients also exhibit other molecular abnormalities, including pathological activation of the PI3K, AKT, and mTOR signaling cascades. [11]

Table 4. Causes by subtype

Subtype	What is known about the cause?
Unicentric form	The exact cause is unknown.
Virus-associated multicentric form	Associated with human herpes virus type 8
Idiopathic multicentric form	The exact cause is unknown, but hypercytokinemia plays a leading role.
Form associated with POEMS syndrome	Treated as a separate associated category

Risk factors

No generally accepted household or hereditary risk factors have been identified for the unicentric form. The disease typically occurs sporadically in individuals without a family history. Therefore, in practical medicine, the localized form is more often diagnosed not by risk factors but by the incidental discovery of an enlarged lymph node or mass in the mediastinum, neck, abdomen, or retroperitoneum. [12]

For the virus-associated multicentric form, the most important risk factor is immunodeficiency, especially in the presence of the human immunodeficiency virus. This form often has an aggressive course and is accompanied by more pronounced systemic symptoms. [13]

For the idiopathic multicentric form, predisposing immune and inflammatory mechanisms are more often discussed than classical risk factors. However, reliable factors suitable for routine prevention, such as diet or lifestyle, have not yet been identified. This is one of the differences between Castleman disease and more common oncological and cardiovascular diseases. [14]

Table 5. What can be considered risk factors

Factor	For which option is it important?
Immunodeficiency	For virus-associated multicentric form
Human immunodeficiency virus	For virus-associated multicentric form
Human herpes virus type 8	For virus-associated multicentric form
Clear household risk factors	For most forms not established
Hereditary transmission	Usually not typical

Pathogenesis

Castleman disease is caused by abnormal activation of the lymph node and immune system. All forms are characterized by specific histopathological changes, but the clinical presentation depends on whether the process is limited to a single node or has become systemic. The unicentric form most often corresponds to localized lymphoid hyperplasia, while the multicentric form is associated with the circulation of proinflammatory cytokines and systemic organ damage. [15]

In the idiopathic multicentric form, interleukin 6 was long considered the key mediator, and its blockade became the basis of modern therapy. However, new data show that the pathogenesis is not limited to a single cytokine. Studies from 2025 described the involvement of stromal cells, disrupted signaling networks, and the complex immune microenvironment of the lymph node. [16]

Histologically, hypervascular, plasma cell, and mixed patterns have traditionally been described. However, the current position is that histological subtype helps in tissue characterization, but should not, by itself, automatically determine treatment, particularly in the idiopathic multicentric form. This is an important update compared to previous practice. [17]

Table 6. Pathogenesis

Link	What's happening
Lymphoid activation	The lymph nodes enlarge and become rebuilt
Hypercytokinemia	Fever, weakness, inflammation, and organ damage occur.
Interleukin 6	One of the key mediators, especially in the idiopathic multicentric form
Stromal and immune dysregulation	Supports chronic course
Organ dysfunction	Occurs in the systemic form of the disease

Symptoms

Unicentric Castleman disease often presents asymptomatically. It is often discovered incidentally during a CT scan, X-ray, or examination for a space-occupying lesion. If symptoms do occur, they are typically related to pressure from the enlarged node on adjacent structures, such as cough, shortness of breath, chest pain, or a feeling of fullness in the abdomen, depending on the location. [18]

Multicentric Castleman disease presents differently. It is characterized by multiple enlarged lymph nodes, fever, sweating, weight loss, severe weakness, edema, fluid in the cavities, enlargement of the liver and spleen, anemia, and laboratory evidence of inflammation. A 2024 systematic review found that in the idiopathic multicentric form, anemia occurred in approximately 89.4% of patients, hypoalbuminemia in approximately 60.8%, and elevated C-reactive protein in approximately 92.4%. [19]

For the virus-associated multicentric form, systemic symptoms are often even more pronounced. In the same analysis, fever was observed in approximately 96.2% of patients, splenomegaly in 89.2%, and hepatomegaly in 74.1%. In the idiopathic multicentric form, renal dysfunction and the TAFRO variant with thrombocytopenia, anasarca, fever, reticulin fibrosis, renal failure, and organomegaly were described more frequently than in the virus-associated form. [20]

Table 7. How Castleman disease usually manifests itself

Symptom	Unicentric form	Multicentric form
Enlarged lymph node	Often	Almost always
Fever	Rarely	Often
Weight loss	Rarely	Often
Anemia	Less often	Very often
Enlargement of the liver and spleen	Rarely	Often
Edema and effusions	Rarely	Possible
Pain or pressure symptoms	Possible	Possible

Classification, forms and stages

The primary division of Castleman's disease is unicentric and multicentric. Unicentric disease involves a single lymph node. Multicentric disease involves multiple nodes with systemic inflammation. This division remains fundamental and practically determines prognosis and treatment. [21]

The multicentric form is further divided into three broad categories: virus-associated, POEMS syndrome-associated, and idiopathic. Within the idiopathic form, clinical subtypes are distinguished, including TAFRO. A recent review in 2025 emphasizes that TAFRO is not simply a set of symptoms, but a validated clinical subtype of idiopathic multicentric Castleman disease. [22]

Histologically, hypervascular, plasma cell, and mixed patterns are described. However, these are not "stages" but morphological variants. There is no classical oncological staging for Castleman disease, as there is for lymphomas or solid tumors. In clinical practice, it is more important to assess the localization, severity of systemic inflammation, and degree of organ dysfunction. [23]

Table 8. Modern classification

Classification level	Options
By prevalence	Unicentric, multicentric
Multicentric form	Virus-associated, associated with POEMS syndrome, idiopathic
Idiopathic multicentric form	Including the TAFRO subtype
By histology	Hypervascular, plasma cell, mixed

Complications and consequences

With the unicentric form, the main problems are usually related to localized pressure on adjacent organs and tissues. However, with complete removal of the affected node, outcomes are usually good, and the disease is often considered cured. In a systematic review cited in recent publications, overall survival after surgical treatment of the unicentric form reached approximately 95.3%. [24]

The multicentric form is more dangerous. Without adequate therapy, it can lead to a severe inflammatory response, multiple organ failure, renal dysfunction, effusions, severe anemia, and death. A 2024 systematic review indicates that the 5-year mortality rate for the idiopathic multicentric form in published series was approximately 23%-49%. [25]

Furthermore, multicentric Castleman disease can be associated with progression to non-Hodgkin's lymphoma and other severe immune complications. Therefore, the disease requires not only initial therapy but also long-term monitoring. [26]

Table 9. Main complications

Complication	For which form is it especially characteristic?
Compression of adjacent structures	For unicentric
Anemia	Mainly for multi-center
Hypoalbuminemia and edema	For multicenter
Renal dysfunction	For idiopathic multicentric
Effusions and anasarca	For multicenter, especially TAFRO
Multiple organ failure	For heavy multi-center
Transformation to lymphoma	Possible with multicenter

When to see a doctor

You should consult a doctor if you experience persistent lymph node enlargement, especially if it doesn't resolve within several weeks and is accompanied by weakness, fever, night sweats, or weight loss. These symptoms don't automatically indicate Castleman disease, but they do require ruling out lymphoma, infection, autoimmune conditions, and other serious conditions. [27]

Urgent evaluation is especially important when enlarged lymph nodes are combined with edema, shortness of breath, decreased urine output, severe weakness, rapid weight loss, abdominal distension, or signs of effusion. For the multicentric form, delay is dangerous, as a severe exacerbation can develop into a cytokine storm with organ damage. [28]

Table 10. Symptoms requiring prompt assessment

Symptom	How urgent is it?
An enlarged lymph node that won't go away	Coming soon
Fever and night sweats	Coming soon
Weight loss	Coming soon
Edema, fluid in the abdomen, shortness of breath	Urgently
Weakness with anemia and inflammatory tests	Urgently
Rapid deterioration of general condition	Urgently

Diagnostics

The main principle of diagnosing Castleman disease is that a lymph node biopsy is essential for diagnosis. The Mayo Clinic explicitly states that a biopsy is necessary to confirm Castleman disease and rule out lymphoma and related conditions. Fine-needle aspiration cytology alone is not sufficient; a complete tissue sample is needed so that the pathologist can evaluate the node's architecture. [29]

Following morphological confirmation, subtype differentiation begins. It is necessary to determine whether the process is localized or multicentric, and whether there is evidence of human herpesvirus type 8, human immunodeficiency virus, POEMS syndrome, autoimmune disease, infection, IgG4-related disease, or lymphoma. The 2017 international criteria for the idiopathic multicentric form require a combination of characteristic histology, multizonal lymph node enlargement, additional clinical and laboratory criteria, and the mandatory exclusion of a number of similar conditions. [30]

Laboratory diagnostics typically include a complete blood count, C-reactive protein, erythrocyte sedimentation rate, albumin, immunoglobulins, renal function, liver function tests, and urine. The Mayo Clinic emphasizes that blood and urine tests can help identify anemia and typical protein abnormalities. Computed tomography (CT) of the neck, chest, abdomen, and pelvis, as well as positron emission tomography (PET) scans, are used for staging and assessing the prevalence of the disease. [31]

Table 11. Step-by-step diagnostics

Step	What are they doing?	For what
1	Lymph node biopsy	Confirm characteristic histology
2	Computed tomography	Understand whether the process is local or multicentric
3	Blood and urine tests	Assess inflammation, anemia, albumin, organs
4	Tests for human immunodeficiency virus and human herpes virus type 8	Specify subtype
5	Exclusion of POEMS syndrome and similar diseases	Don't make a mistake with the diagnosis
6	Severity assessment	Choose a treatment strategy

Differential diagnosis

Castleman disease is one of those diagnoses often made after other causes have been excluded. It is particularly difficult to distinguish from lymphomas, autoimmune diseases, severe infections, IgG4-related disease, macrophage activation syndrome, and other cytokine syndromes. Therefore, modern criteria for the idiopathic multicentric form are built around the mandatory exclusion of competing diagnoses. [32]

Morphologically, "Castelman-like" changes in the lymph node can also be observed in other conditions. The 2017 international criteria explicitly state that such histology can be observed in four broad contexts: diseases other than multicentric Castleman disease, the form associated with POEMS syndrome, the idiopathic form, and the form associated with human herpesvirus type 8. Thus, a microscopic image alone without a clinical context is insufficient. [33]

Table 12. What most often has to be excluded

Disease	Why does it look like this?
Lymphoma	Enlarged lymph nodes, systemic symptoms
Infections	Fever, inflammation, lymphadenopathy
Autoimmune diseases	Systemic inflammation, cytopenias, organomegaly
IgG4-related disease	Similar lymphoid and plasma cell picture
POEMS syndrome	May be accompanied by multicentric Castleman disease
Virus-associated form	Requires separate confirmation for HHV-8
Macrophage activation syndrome and other hyperinflammatory conditions	Similar severe systemic picture

Treatment

For unicentric Castleman disease, the primary treatment is complete surgical removal of the affected lymph node or nodular cluster. This is the primary and best option, as surgery results in a permanent cure in most cases. Mayo Clinic and international guidelines for the unicentric form consider surgical resection to be the first-line standard. [34]

If the unicentric form is technically inoperable, treatment depends on symptoms. If the disease is asymptomatic, observation is sometimes possible. For symptomatic, inoperable forms, medical approaches are used, which are partly similar to the treatment of the multicentric form, and if there is no effect, radiation therapy is considered. This is an important point: not all localized forms automatically require immediate surgery at any cost if intervention is dangerous. [35]

Treatment of multicentric Castleman disease begins with accurate subtype determination. For the virus-associated form, rituximab is usually considered the standard, with antiviral drugs and chemotherapy added if necessary. The Mayo Clinic recommends this approach for the HHV8-positive multicentric form. [36]

In idiopathic multicentric Castleman disease, interleukin-6 blockade is considered first-line therapy. The 2018 international consensus guidelines recommend siltuximab as the preferred first-line agent for mild cases. If siltuximab is unavailable or not approved, tocilizumab is considered an acceptable alternative. In patients with a response, treatment is typically continued indefinitely, as discontinuation may be followed by relapse. [37]

Glucocorticosteroids are used as adjunctive therapy but should not replace full-fledged targeted therapy where available. They help reduce inflammation more quickly, especially in cases of severe symptoms, but sustained disease control with steroids alone is usually poorer. This is why current guidelines consider them an adjunct rather than a mainstay of long-term therapy. [38]

In severe idiopathic multicentric forms, where life is at risk, the approach is more aggressive. Consensus guidelines recommend siltuximab in combination with high-dose steroids, and if there is no rapid response within 1 week, consider combination chemotherapy. A 2018 publication cites R-CHOP, R-VDT-PACE, or combinations with etoposide, cyclophosphamide, and rituximab as examples. [39]

If interleukin 6 blockade fails, second- or third-line therapy is considered. These include rituximab-containing regimens, immunomodulators, and immunosuppressants, including thalidomide, cyclosporine A, anakinra, bortezomib, and sirolimus. Recent reviews from 2025 further highlight interest in mTOR-targeted treatment in refractory patients. However, this is an area of individualized decisions, where the opinion of an expert center is particularly important. [40]

Real-world clinical practice confirms the value of current guidelines. A 2025 review and studies in recent years have shown that treatment according to consensus algorithms for the idiopathic multicentric form is associated with better outcomes. This is an important shift from the era when patients often received heterogeneous, non-specific therapy without a single standard. [41]

New treatment trends are now associated not so much with a complete revision of standards as with a deeper molecular understanding of the disease. In 2025, data on spatial and single-cell mapping of lymph nodes became available, better revealing the role of stromal cells and cytokine pathways. In practical terms, this means that a more personalized approach can be expected in the coming years, especially for refractory forms of idiopathic multicentric Castleman disease. [42]

Table 13. Treatment by forms

Form of the disease	The basic approach
Unicentric, operable	Complete surgical resection
Unicentric, inoperable, asymptomatic	Observation
Unicentric, inoperable, symptomatic	Drug treatment, sometimes radiation therapy
Multicentric, HHV-8-associated	Rituximab, antiviral drugs and chemotherapy if necessary
Idiopathic multicentric, mild	Siltuximab 1 line
Idiopathic multicentric, severe	Siltuximab plus high-dose steroids, with rapid escalation to chemotherapy if unresponsive
Refractory idiopathic multicentric	Rituximab-containing regimens, sirolimus, and other 2nd- and 3rd-line drugs

Prevention

There is currently no specific prevention for unicentric and idiopathic multicentric Castleman disease. There are no proven dietary, vaccination, or lifestyle measures that reliably prevent these forms of the disease. This is because their exact underlying causes have not yet been fully established. [43]

For the virus-associated form, prevention and control of immunodeficiency-related conditions are more important, especially high-quality treatment of the human immunodeficiency virus. However, even here, the focus is more on reducing the risk of severe disease and virus-mediated lymphoproliferation than on guaranteed prevention of Castleman disease itself. [44]

In practice, the main preventative principle is early recognition. This means avoiding months and years of wandering between diagnoses of "unclear inflammatory disease," "autoimmune condition," or "suspected lymphoma" without a full biopsy and expert evaluation. For rare diseases, reducing the diagnostic delay is often the most realistic way to prevent severe outcomes. [45]

Table 14. What can actually be done

Approach	Practical benefits
Early biopsy of an enlarged node	Helps not to miss a diagnosis
Treatment of human immunodeficiency virus and control of immunodeficiency	Particularly important for the HHV-8-related form
Postoperative observation for the unicentric form	Helps to detect rare relapses in time
Treatment according to modern consensus algorithms	Improves outcomes in multicenter setting

Forecast

The prognosis depends primarily on the form of the disease. In the unicentric form, it is usually good, especially if the affected node is completely removed. In published series, surgery remains a highly effective method, and overall survival after treatment is very high. [46]

In the multicentric form, the prognosis is more serious and is determined by the subtype, severity of systemic inflammation, organ dysfunction, and response to therapy. Historically, survival was significantly worse, but modern targeted approaches have improved outcomes, particularly in patients with the idiopathic multicentric form who receive siltuximab and treatment according to guidelines. [47]

The key practical conclusion is this: for Castleman disease, the prognosis is determined not so much by the fancy name of the histological subtype, but by the timeliness of recognition, the correctness of subtyping, and access to the right treatment. For rare diseases, this is especially important. [48]

Table 15. What influences the forecast

Factor	Usually associated with
Unicentric form	The best forecast
Complete surgical resection	A very favorable outcome
Multicentric form	A more serious forecast
Severe organ dysfunction	Higher risk of death
Response to interleukin 6 blockade	Best long-term disease control
Diagnostic delay	Worst outcomes

Frequently asked questions

Is Castleman disease cancer?
No, it's not a classic cancer, but it's not just a "harmless swollen lymph node." It's a rare lymphoproliferative disorder that, when multicentric, can be very serious. [49]

Can a blood test be used to diagnose the condition?
No. Blood tests can show inflammation, anemia, and organ damage, but a lymph node biopsy is required for diagnosis. [50]

Is only one lymph node always enlarged?
No. This is typical only for the unicentric form. In the multicentric form, several areas of the lymph nodes are enlarged. [51]

What is currently considered the primary treatment for the idiopathic multicentric form?
For mild forms, siltuximab is first-line therapy. For severe forms, siltuximab plus high-dose steroids with rapid escalation of treatment if response is insufficient. [52]

Can the disease return after surgery?
With the unicentric form, this is rare, but possible, so observation is necessary after surgery. [53]

What is TAFRO?
It is a clinical subtype of idiopathic multicentric Castleman disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal failure, and organomegaly.[54]

Key points from experts

David C. Fajgenbaum, MD, MBA, and MS, is an associate professor of medicine at the University of Pennsylvania, founder of the Center for Cytokine Storm Treatment and Laboratory, and co-founder and president of the Castleman Disease Collaborative Network. His major contributions include the development of international diagnostic criteria for idiopathic multicentric Castleman disease and the advancement of the concept of the disease as a cytokine-mediated syndrome requiring accurate subtyping and targeted therapy. [55]

Frits van Rhee, Doctor of Medicine, Doctor of Philosophy, Member of the Royal College of Physicians, Professor of Medicine and Director of Developmental and Translational Medicine, UAMS Myeloma Institute. His work formed the basis for international treatment guidelines for both unicentric and idiopathic multicentric forms. The practical conclusion of his approach: localized forms require surgery, while idiopathic multicentric forms should be treated with interleukin 6 blockade, taking into account the severity of the disease. [56]

Amy Chadburn, MD, a hematopathologist at Weill Cornell Medicine, is important because Castleman disease cannot be properly treated without accurate morphology. The practical implications of this thesis are simple: clinical and laboratory examinations are important, but definitive differentiation of subtypes and exclusion of mimics require an experienced pathologist. [57]