Introduction

Castleman disease (CD) is a rare lymphoproliferative disorder that affects lymph nodes found in any area of the body, such as the neck, chest, abdomen and pelvis. The lymph nodes enlarge and can mimic benign and malignant malformations. Castleman disease (CD) has distinct subtypes which depend on clinical and histological manifestations. Clinically, it manifests as unicentric (UCD), which is more frequent and multicentric (MCD), which occurs at a lower frequency.^1,2

Aetiology of Castleman disease (CD)

The cause of Castleman disease (CD) has not been specified, as there is limited evidence. However, some data have suggested it may be due to impaired immunoregulation, which leads to an increased proliferation of B lymphocytes and plasma cells in lymphoid organs. These conditions can also be a result of chronic low-grade inflammation, lymphoid-hamartomatous hyperplasia, viral infections, abnormal modulation of cytokines, and angiogenesis.^1,2 

Additionally, there is an association of Castleman disease (CD) with HIV, which means immunodeficiency is a factor. Specifically in MCD, human herpesvirus (HHV)-8 is a causative factor, and nearly all HIV-associated cases are HHV-8 positive. In non-HIV Castleman disease (CD), about 40% to 50% of the cases are HHV-8 positive. That being said, the remaining cases are idiopathic.^1,2

Unicentric Castleman disease (UCD)

Definition

In unicentric Castleman disease, the condition is localised or unifocal, that is, there is a single enlarged lymph node region. This lymph node is normally in the chest, abdomen, pelvis or neck regions, but it is possible in other body areas.^1,2

Clinical presentation

Notably, most unicentric Castleman disease (UCD) patients are often asymptomatic, and the enlarged lymph node is typically found during a physical examination. This subtype is also slow-developing and non-malignant, with a painless mass which can lead to symptoms as the surrounding areas are compressed. Patients may complain of pain and discomfort, and other symptoms are weight loss, night sweats and low to high-grade fevers. The severity of symptoms increases with the size of the mass.^1,2,3

Diagnosis

Laboratory tests

Testing of blood and urine samples in unicentric Castleman disease (UCD) usually produces normal results^.3

Imaging methods 

This is the most critical aspect of diagnosing unicentric Castleman disease (UCD) following clinical examination and review of patient reports. Methods include ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), and also hybrid methods such as positron emission tomography with computed tomography (PET/CT) or magnetic resonance imaging (PET/MRI). These can be used for the detection or localisation of lymph nodes and possibly for biopsy planning.^1,2,3

Lymph node biopsy

Biopsy results, although not always fully conclusive, are helpful and aid in differentiating Castleman disease from other conditions causing lymphadenopathies.^2,3

Treatment and prognosis

The management of unicentric Castleman disease (UCD) normally involves the complete surgical resection of the tumour / enlarged lymph node. If the lymph node is in the abdomen or the best, then major surgery would be required. Prognosis is good as surgery is known to cure UCD, but relapse is possible. If surgery is not possible, partial resection is suggested, followed by adjuvant radiotherapy or chemotherapy.^1,2,3

The common chemotherapy regimen consists of anti-interleukin 6 (siltuximab) or anti-CD20 (rituximab). The use of radiotherapy is considered carefully based on where the mass is, as its side effects on the surrounding organs can be harmful. In some cases, a watch-and-wait approach is a viable option, and decisions must be made by a multidisciplinary team.^2,3

Multicentric Castleman disease (MCD)

Definition

Multicentric Castleman disease (MCD) involves multiple enlarged lymph nodes, that is, two or more, in different bodily regions.^2,4

Clinical presentation

In multicentric Castleman disease (MCD), it is characterised by a proinflammatory response which causes symptoms like: ^2,4 

• Fever
• Night sweats
• Weight loss
• Malaise
• Generalized lymphadenopathy
• Hepatosplenomegaly
• Polyclonal hypergammaglobulinemia
• Deep vein thrombosis
• Anaemia
• Thrombocytopenia
• Pleural effusion or anasarca
• Angiogenesis
• Multiple organ failure and death (in extreme cases)

Multicentric Castleman disease (MCD) has been categorised into three separate subtypes, which are:^2,4 

1. HHV-8-associated MCD – associated with human herpes virus type 8 (HHV-8), and human immunodeficiency virus (HIV)
2. Idiopathic MCD – the cause in this type is unknown and is called HHV-8-negative MCD. The most serious form of this type of MCD is known as idiopathic multicentric Castleman disease with TAFRO syndrome (iMCD-TAFRO)
3. POEMS-associated MCD – associated with another condition called POEMS syndrome, which damages nerves and other parts of the body

Diagnosis

The diagnosis of multicentric Castleman disease (MCD) is based on clinical signs of systemic inflammation, serological tests, and typical pathological features.^2,4

Lab tests

Testing of blood samples usually showcases elevated C-reactive protein (CRP), anaemia (haemoglobin < 12 g/dL), immunoglobulin A, and immunoglobulin G and hypoalbuminemia. It may also be necessary to conduct serology tests for HIV and HHV-8 and look for HHV-8 DNA in peripheral blood.^2,4

Differential diagnosis

As multicentric Castleman disease (MCD) has similar clinical presentations to infectious diseases, autoimmune diseases, lymphoma and other solid tumour conditions. Some of these diseases include:^2,4

• Systemic lupus erythematosus
• Multiple myeloma
• Active Epstein-Barr virus (EBV) infection
• Juvenile idiopathic arthritis 
• Toxoplasmosis

Treatment and prognosis

Currently, the therapeutic options for multicentric Castleman disease (MCD) include:^2,4

• Glucocorticoids
• Surgery
• Cytotoxic chemotherapy 
• Anti-CD20 monoclonal antibody (rituximab) – for HHV-9 related cases
• Anti-IL-6-targeted monoclonal antibodies (siltuximab and tocilizumab)

Recurrence is common and highly reported in patients with multicentric Castleman disease (MCD) with HIV and HHV-8 infection. In these cases, immunomodulatory drugs (rituximab) are recommended with or without adjuvant chemotherapy.⁴

For POEMS-associated MCD, the aim is to eliminate monoclonal plasma cellsand the commonly used treatment regimens are high-dose melphalan and dexamethasone or cyclical cyclophosphamide every three weeks with glucocorticoids. Positive outcomes have also been obtained from autologous stem cell transplantation has shown promising outcomes.⁴

Regarding the treatment of nonsevere idiopathic MCD, siltuximab 11 mg/kg every 3 weeks is strongly recommended. Sometimes patients do not respond to anti-IL-6 therapy and, as such, have limited therapeutic options. Patients with severe iMCD normally experience a higher mortality rate and require critical care, as the overstimulated immune system leads to a fatal cytokine or chemokine storm. Cytotoxic chemotherapy is recommended for patients who show signs of deterioration or no response after one week of anti-IL-6-targeted therapy, and results are usually promising (78% overall response rate).⁴

In milder cases of idiopathic MCD, low-dose glucocorticoids (prednisolone) are used as an adjunctive treatment, while for more severe symptoms, higher doses of prednisolone are suggested.⁴

Notably, idiopathic multicentric Castleman disease with TAFRO syndrome (iMCD-TAFRO) shows the poorest response even with siltuximab or tocilizumab. Additionally, not all CD cases respond to therapy and are cured.

Summary

Castleman disease (CD) is a rare disorder characterised by abnormal growth of lymph node tissue, which can occur anywhere in the body. It is broadly classified into two clinical forms: unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD). UCD is more common and typically involves a single enlarged lymph node region, usually in the chest, abdomen, neck, or pelvis. It is often asymptomatic and discovered incidentally, though larger masses can cause local pain or compress nearby structures. Diagnosis relies heavily on imaging and biopsy, and treatment is usually curative with complete surgical removal of the affected lymph node. When surgery is not feasible, partial resection with radiotherapy or chemotherapy may be used, but the prognosis remains excellent overall.

In contrast, MCD involves multiple lymph node regions and is a systemic disease driven by chronic inflammation and immune system dysregulation. It is strongly linked to viral infections such as human herpesvirus 8 (HHV-8) and is more common in people with HIV. MCD presents with pronounced systemic symptoms like fever, night sweats, weight loss, widespread lymphadenopathy, anaemia, and, in severe cases, multi-organ failure. Diagnosis combines clinical features, laboratory markers of inflammation, and biopsy, but it must be differentiated from infections, autoimmune diseases, and malignancies like lymphoma. Treatment of MCD is more complex and may include immunotherapy with anti–IL-6 monoclonal antibodies (like siltuximab or tocilizumab), rituximab for HHV-8–associated cases, chemotherapy, and corticosteroids. Outcomes for MCD vary widely; the disease can be recurrent, and certain forms, especially idiopathic MCD with TAFRO syndrome, are associated with a high risk of treatment resistance and significant mortality. Accurate diagnosis and early intervention are essential for both forms, but while UCD is typically curable with surgery alone, MCD requires long-term multidisciplinary management.