Introduction

Castleman disease (CD) is a rare, heterogeneous lymphoproliferative disorder that primarily affects lymph nodes and surrounding tissues. While it is more commonly reported in adults, pediatric cases, though uncommon, are clinically significant and often underrecognized. CD can present as either unicentric, involving a single lymph node region, or multicentric, affecting multiple nodal areas with systemic symptoms.

In children, persistent lymphadenopathy is frequently attributed to infections or malignancies, making Castleman disease an unlikely consideration. However, delayed diagnosis can lead to serious complications, particularly in multicentric CD, which is associated with systemic inflammation and potential organ dysfunction. Recognizing this rare entity is crucial for pediatricians and specialists to ensure timely intervention and improved outcomes.

Classification of castleman's disease

Castleman's disease is classified into two main clinical types:

• Unicentric Castleman Disease (UCD): Involves a single lymph node or a single region of lymph nodes. It is the most common form and typically presents without systemic symptoms. Surgical excision is often curative
• Multicentric Castleman Disease (MCD) affects multiple lymph node regions and is associated with systemic symptoms such as fever, weight loss, and fatigue. MCD is further subdivided into:
  
  • HHV-8–associated MCD: Linked to human herpesvirus eight infection, more common in immunocompromised patients.
  • Idiopathic MCD (iMCD): Occurs without detectable HHV-8 infection; exact cause remains unknown²

Clinical presentation in children

The clinical presentation of Castleman disease in children varies depending on whether the disease is unicentric (UCD) or multicentric (MCD).

Unicentric Castleman Disease (UCD)

• Symptoms: Most children with UCD are asymptomatic, and the condition is often discovered incidentally during imaging or evaluation of a painless lymph node enlargement
  Physical Findings: A solitary, firm, non-tender lymph node mass is the most common finding. The mediastinum is the most frequent location, followed by the abdomen and neck
• Systemic Symptoms: Rare in UCD but may include mild fatigue or low-grade fever in some cases
  

Multicentric Castleman Disease (MCD)

• Symptoms:
  Children with MCD often present with systemic inflammatory features, such as:
  • Persistent fever
  • Night sweats
  • Fatigue and weight loss
    
• Physical Findings:
  • Generalized lymphadenopathy involving multiple regions
  • Hepatosplenomegaly is common
    
• Laboratory abnormalities:
  • Anemia
  • Elevated inflammatory markers (ESR, CRP)
  • Hypoalbuminemia
  • Occasionally elevated IL-6 levels.
    
• Imaging:
  CT or MRI typically reveals multiple enlarged lymph nodes in the thoracic, abdominal, or pelvic regions³

Pathogenesis and associated conditions

Role of interleukin-6 (IL-6)

IL-6, a pro-inflammatory cytokine, plays a central role in the pathogenesis of CD, particularly in Multicentric Castleman Disease (MCD). Overproduction of IL-6 leads to:

• B-cell proliferation
• Increased acute-phase reactants
• Systemic inflammatory symptoms such as fever, fatigue, and weight loss

Viral associations

• Human Herpesvirus-8 (HHV-8): Strongly linked to MCD, especially in immunocompromised patients, though rarely seen in children. HHV-8 encodes viral IL-6, amplifying the inflammatory cascade
• HIV Infection: Increases the risk of HHV-8–associated MCD in adults; scarce in pediatric CD but still relevant in immunocompromised children

Idiopathic cases

Many pediatric cases are idiopathic, with no clear viral association. The disease mechanism in these cases may involve genetic susceptibility and abnormal immune regulation.

Diagnostic approach

Diagnosing Castleman disease (CD) in children is challenging due to its rarity and nonspecific clinical presentation. The process involves a combination of clinical assessment, imaging, and histopathological confirmation.[4]

Clinical evaluation

• Persistent or unexplained lymphadenopathy should raise suspicion, particularly when associated with systemic symptoms such as fever, weight loss, or hepatosplenomegaly.
• A thorough history and physical examination help differentiate CD from more common causes such as infections or lymphoma.⁵

Laboratory investigations

• Complete Blood Count (CBC): May show anemia and thrombocytosis in MCD
• Inflammatory Markers: Elevated ESR and CRP are common in MCD
• Serum Protein Electrophoresis: This test may reveal polyclonal hypergammaglobulinemia
• Cytokine Profile: Increased IL-6 levels in MCD cases

Imaging studies

• Ultrasound or CT Scan: Useful for identifying lymph node enlargement and ruling out other masses
• MRI or PET Scan: Provides additional information on disease extent and activity

Histopathology (Gold standard)

• Excisional Lymph Node Biopsy is essential for definitive diagnosis
• Histological patterns include:
  
  • Hyaline vascular type: Small hyalinized follicles with prominent vascularity
  • Plasma cell type: Dense sheets of plasma cells with interfollicular hyperplasia
  • Mixed type: Features of both patterns⁶

Management strategies

Treatment of Castleman disease in children depends on the clinical subtype, unicentric (UCD) or multicentric (MCD), as well as the severity of symptoms and associated conditions.

Unicentric Castleman Disease (UCD)

• Surgical Excision:
  • Complete surgical removal of the affected lymph node or mass is the first-line treatment and is usually curative
  • Postoperative prognosis is excellent, with minimal risk of recurrence
    
• Non-Resectable UCD:
  • Radiation therapy may be considered if surgery is not feasible due to anatomical location or surgical risks

Multicentric Castleman Disease (MCD)

Management of MCD is more complex due to systemic involvement and risk of organ dysfunction.⁷

• Immunotherapy:
  • Anti–IL-6 Agents:
    • Siltuximab (anti–IL-6 monoclonal antibody) or Tocilizumab (anti–IL-6 receptor antibody) are mainstays for idiopathic MCD (iMCD)
  • These agents help reduce systemic inflammation, improve laboratory abnormalities, and control lymph node enlargement
    
• Corticosteroids:
  • Used for symptom control or as bridging therapy while waiting for immunotherapy to take effect
    
• Chemotherapy:
  • Reserved for severe or refractory cases, or when associated with other hematologic conditions
    
• Antiviral Therapy:
  • For HHV-8–associated cases (rare in children), antiviral agents may be combined with immunomodulators

Supportive care

• Management of Complications:
  • Address anemia, malnutrition, and organ dysfunction
    
• Regular Monitoring:
  • Long-term follow-up with imaging and laboratory evaluations to detect relapse or transformation⁸

Prognosis and follow-up

The prognosis of Castleman disease in children largely depends on the clinical subtype and timely initiation of appropriate therapy.

Unicentric Castleman Disease (UCD)

• Prognosis:
  • Excellent outcomes following complete surgical excision, with near-100% survival rates reported in pediatric cases
  • Recurrence is infrequent but may occur in cases of incomplete resection
    
• Follow-up:
  • Periodic clinical evaluation and imaging (every 6–12 months initially) to rule out local recurrence or new lymphadenopathy

Multicentric Castleman Disease (MCD)

• Prognosis:
  • More variable and generally less favorable compared to UCD due to systemic involvement
  • Prognosis depends on the response to immunotherapy, the presence of associated infections (such as HHV-8), and complications, including organ failure
    
• Follow-up:
  • Requires long-term monitoring with:
    • Physical exams for lymphadenopathy and organomegaly
    • Laboratory tests (CBC, inflammatory markers, IL-6 levels if applicable)
    • Imaging to assess disease activity
  • Regular multidisciplinary care involving specialists in hematology, infectious disease, and immunology is often necessary

Long-term considerations

• Risk of Malignancy:
  • Although rare, some patients with MCD may develop lymphoma over time, necessitating vigilant surveillance
    
• Quality of Life:
  • Ongoing management of chronic symptoms and treatment side effects is essential for optimizing pediatric patient outcomes⁹

Summary

Castleman disease in children, though rare, remains an important differential diagnosis for persistent or unexplained lymphadenopathy. Its clinical presentation can mimic more common pediatric conditions, often leading to diagnostic delays. Unicentric Castleman disease generally carries an excellent prognosis with surgical excision, while multicentric disease requires systemic therapy and close monitoring due to its more aggressive course and potential complications.¹⁰

Early recognition, timely histopathological confirmation, and a multidisciplinary approach to management are crucial for improving outcomes. Increased awareness among pediatricians and specialists, along with more research and reporting of pediatric cases, will help enhance understanding and optimize care for this rare but significant condition.