Castleman Disease in Children
Castleman Disease in Children
Castleman Disease (CD), also known as angiofollicular lymph node hyperplasia or giant lymph node hyperplasia, is a rare lymphoproliferative disorder first described by Benjamin Castleman in 1956. While it can affect individuals of any age, its occurrence in children is particularly challenging due to its rarity and the potential for misdiagnosis. Pediatric Castleman Disease requires special consideration in terms of diagnosis, treatment, and long-term management.
Pathophysiology
The pathophysiology of Castleman Disease in children is complex and not fully understood. Key factors include:
- Cytokine dysregulation: Overproduction of interleukin-6 (IL-6) plays a central role in the pathogenesis, leading to lymphoproliferation and systemic symptoms.
- Human Herpesvirus 8 (HHV-8): Associated with some cases of multicentric CD, particularly in immunocompromised patients. HHV-8 produces a viral IL-6 homolog that contributes to disease progression.
- PDGFRB gene fusions: Recently identified in some pediatric cases of unicentric CD, suggesting a potential role of growth factor signaling in disease development.
- Immune dysregulation: Abnormal immune responses, potentially triggered by viral infections or autoimmune processes, may contribute to disease pathogenesis.
Classification
Castleman Disease is classified based on histopathological features and clinical presentation:
Histopathological Variants:
- Hyaline vascular type: Most common in children, characterized by small hyaline vascular follicles and interfollicular capillary proliferation.
- Plasma cell type: Less common, features large follicles with intervening sheets of plasma cells.
- Mixed type: Exhibits features of both hyaline vascular and plasma cell types.
Clinical Subtypes:
- Unicentric Castleman Disease (UCD):
- Involves a single lymph node or localized region of lymph nodes
- More common in children and young adults
- Usually asymptomatic or presents with local mass effect
- Multicentric Castleman Disease (MCD):
- Involves multiple lymph node regions or organs
- Less common in children
- Associated with systemic symptoms and can be further classified as:
- HHV-8-associated MCD
- POEMS-associated MCD
- Idiopathic MCD (iMCD)
Clinical Features
The clinical presentation of Castleman Disease in children varies depending on the subtype:
Unicentric Castleman Disease (UCD):
- Usually asymptomatic or minimally symptomatic
- Presents as a solitary, enlarged lymph node or localized mass
- Common sites: neck, chest, abdomen, or retroperitoneum
- Occasionally causes local compression symptoms (e.g., cough, abdominal pain)
Multicentric Castleman Disease (MCD):
- Systemic symptoms: fever, night sweats, fatigue, weight loss
- Generalized lymphadenopathy
- Hepatosplenomegaly
- Anemia, thrombocytopenia
- Elevated inflammatory markers (ESR, CRP)
- Hypergammaglobulinemia
- Skin manifestations: rash, purpura
- Fluid retention: peripheral edema, pleural effusions, ascites
In children, UCD is more common and tends to have a better prognosis compared to MCD. However, MCD can be particularly aggressive in pediatric patients and may be associated with severe complications if left untreated.
Diagnosis
Diagnosing Castleman Disease in children can be challenging due to its rarity and overlap with other conditions. A comprehensive diagnostic approach includes:
- Clinical evaluation: Thorough history and physical examination
- Laboratory studies:
- Complete blood count (CBC)
- Inflammatory markers (ESR, CRP)
- Serum protein electrophoresis
- IL-6 levels
- HHV-8 testing (for suspected MCD)
- HIV testing (due to association with HHV-8-positive MCD)
- Imaging studies:
- CT or MRI to assess the extent of disease and guide biopsy
- PET-CT may be useful in evaluating disease activity and response to treatment
- Histopathological examination:
- Excisional lymph node biopsy is the gold standard
- Core needle biopsy may be considered if excisional biopsy is not feasible
- Immunohistochemistry to characterize cell populations and exclude other lymphoproliferative disorders
- Molecular studies:
- Testing for PDGFRB gene fusions in cases of UCD
- Next-generation sequencing to exclude other lymphoproliferative disorders
Differential diagnosis includes lymphoma, autoimmune lymphoproliferative syndrome (ALPS), IgG4-related disease, and other causes of lymphadenopathy in children.
Treatment
Treatment strategies for Castleman Disease in children depend on the subtype and extent of disease:
Unicentric Castleman Disease (UCD):
- Surgical excision: Complete resection is curative in most cases
- Radiation therapy: May be considered for unresectable lesions or as adjuvant therapy
- Observation: In select cases where immediate intervention is not necessary
Multicentric Castleman Disease (MCD):
- Anti-IL-6 therapy:
- Siltuximab: FDA-approved for iMCD in adults, used off-label in children
- Tocilizumab: Alternative anti-IL-6 receptor antibody
- Rituximab: Particularly effective in HHV-8-associated MCD
- Combination chemotherapy: For severe or refractory cases
- R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
- CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)
- Corticosteroids: Used for symptomatic relief and as part of combination therapy
- Antiviral therapy: Ganciclovir or valganciclovir for HHV-8-associated MCD
- Immunomodulators: Thalidomide or lenalidomide in select cases
- Targeted therapies: JAK inhibitors (e.g., ruxolitinib) or mTOR inhibitors (e.g., sirolimus) in refractory cases
Treatment of pediatric Castleman Disease often requires a multidisciplinary approach involving pediatric hematology-oncology, surgery, and radiation oncology. Long-term follow-up is essential due to the risk of recurrence and potential treatment-related complications.
Prognosis
The prognosis of Castleman Disease in children varies depending on the subtype and extent of disease:
- Unicentric Castleman Disease (UCD):
- Excellent prognosis with complete surgical resection
- 5-year overall survival rate >90%
- Low risk of recurrence after complete excision
- Multicentric Castleman Disease (MCD):
- Generally poorer prognosis compared to UCD
- Prognosis has improved with the advent of targeted therapies
- 5-year overall survival rates vary widely (65-90%) depending on disease severity and treatment response
- HHV-8-associated MCD may have a more aggressive course, particularly in immunocompromised patients
Long-term complications and considerations include:
- Risk of recurrence, particularly in MCD
- Potential for development of secondary malignancies
- Treatment-related toxicities, especially with prolonged use of immunosuppressive or cytotoxic therapies
- Impact on growth and development in pediatric patients
- Need for long-term follow-up and monitoring
Castleman Disease in Children
- What is another name for Castleman Disease?
Answer: Giant lymph node hyperplasia or angiofollicular lymph node hyperplasia - Who first described Castleman Disease?
Answer: Dr. Benjamin Castleman - What are the two main clinical types of Castleman Disease?
Answer: Unicentric (localized) and Multicentric - Which type of Castleman Disease is more common in children?
Answer: Unicentric (localized) Castleman Disease - What are the three main histological variants of Castleman Disease?
Answer: Hyaline vascular, plasma cell, and mixed type - Which histological variant is most common in pediatric Castleman Disease?
Answer: Hyaline vascular type - What is the most common site of involvement in unicentric Castleman Disease in children?
Answer: Mediastinum - Is Castleman Disease considered a neoplastic or reactive condition?
Answer: Generally considered a lymphoproliferative disorder, with some debate about its nature - What virus is associated with some cases of multicentric Castleman Disease?
Answer: Human Herpesvirus 8 (HHV-8) - Is HHV-8 commonly associated with unicentric Castleman Disease in children?
Answer: No, it's rarely associated with unicentric disease - What cytokine plays a key role in the pathogenesis of Castleman Disease?
Answer: Interleukin-6 (IL-6) - What are the typical symptoms of unicentric Castleman Disease in children?
Answer: Often asymptomatic, may present with a painless mass - What are common systemic symptoms in multicentric Castleman Disease?
Answer: Fever, night sweats, weight loss, fatigue - What is the first-line treatment for unicentric Castleman Disease in children?
Answer: Surgical excision - Is chemotherapy typically used for unicentric Castleman Disease in children?
Answer: No, it's rarely needed for unicentric disease - What is the role of rituximab in treating Castleman Disease?
Answer: It's used in some cases of multicentric Castleman Disease, especially HHV-8 associated cases - Can Castleman Disease transform into lymphoma?
Answer: Yes, particularly in multicentric cases - What is the prognosis for children with unicentric Castleman Disease after complete surgical excision?
Answer: Excellent, with very low recurrence rates - Is anemia a common finding in Castleman Disease?
Answer: Yes, particularly in multicentric disease - What imaging modality is typically used for initial evaluation of suspected Castleman Disease?
Answer: CT scan or MRI - Can PET-CT be useful in evaluating Castleman Disease?
Answer: Yes, particularly for assessing disease extent in multicentric cases - What is POEMS syndrome and how is it related to Castleman Disease?
Answer: POEMS is a rare paraneoplastic syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) that can be associated with Castleman Disease - Is thrombocytosis or thrombocytopenia more common in Castleman Disease?
Answer: Thrombocytosis is more common - What is the typical age of onset for unicentric Castleman Disease in children?
Answer: It can occur at any age, but often presents in adolescence - Can Castleman Disease affect the spleen?
Answer: Yes, particularly in multicentric disease - What is the role of anti-IL-6 therapy in Castleman Disease?
Answer: It's used in some cases of multicentric Castleman Disease, particularly those refractory to other treatments - Is multicentric Castleman Disease associated with HIV infection?
Answer: Yes, HIV-positive individuals are at higher risk for multicentric Castleman Disease - What is the typical serum IL-6 level in active Castleman Disease?
Answer: Elevated - Can Castleman Disease present with nephrotic syndrome?
Answer: Yes, it's a rare presentation but has been reported - What is the role of corticosteroids in treating Castleman Disease?
Answer: They can be used for symptomatic relief, particularly in multicentric disease
