Definition/General
Introduction:
Castleman disease is a rare lymphoproliferative disorder characterized by abnormal lymph node proliferation
It was first described by Benjamin Castleman in 1956
The condition involves dysregulated immune response and abnormal cytokine production
It can present as localized (unicentric) or systemic (multicentric) disease.
Origin:
Arises from dysregulated immune system activation involving excessive cytokine production, particularly interleukin-6 (IL-6)
Human herpesvirus-8 (HHV-8) infection plays a role in some cases, especially multicentric disease
The pathogenesis involves abnormal B-cell proliferation and plasma cell differentiation
Vascular endothelial growth factor (VEGF) overproduction leads to characteristic vascular changes.
Classification:
Classified by disease distribution: Unicentric Castleman disease (UCD) - single lymph node region
Multicentric Castleman disease (MCD) - multiple lymph node regions
Histological variants: Hyaline-vascular variant (90% of UCD)
Plasma cell variant (most MCD cases)
Mixed variant (intermediate features)
Plasmablastic variant (HHV-8 positive MCD).
Epidemiology:
Rare disorder with estimated incidence 1-2 cases per 100,000
Unicentric disease more common in young adults (20-40 years)
Multicentric disease peaks in 5th-6th decades
Slight male predominance in unicentric disease
Associated with HIV infection in HHV-8 positive multicentric cases
Higher prevalence in sub-Saharan Africa and Mediterranean regions.
Clinical Features
Presentation:
Unicentric disease: asymptomatic mediastinal mass (60-70%)
Multicentric disease: systemic symptoms with constitutional features
Generalized lymphadenopathy in multicentric cases
Hepatosplenomegaly (40-50% of multicentric cases)
Pleural effusions and ascites
Skin lesions (Kaposi sarcoma-like in HHV-8 positive cases).
Symptoms:
B-symptoms: fever, night sweats, weight loss (multicentric disease)
Fatigue and weakness (anemia-related)
Dyspnea (mediastinal involvement)
Abdominal distension (hepatosplenomegaly, ascites)
Peripheral edema (hypoalbuminemia)
Recurrent infections (immunosuppression)
Neurological symptoms (POEMS syndrome association).
Risk Factors:
HIV infection (HHV-8 positive multicentric disease)
Immunosuppression (organ transplant recipients)
HHV-8 infection (Mediterranean variant multicentric disease)
Autoimmune disorders (increased cytokine production)
POEMS syndrome association (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes)
Geographic factors (higher prevalence in certain regions).
Screening:
CT imaging for mediastinal masses and lymphadenopathy assessment
Laboratory studies: CBC, comprehensive metabolic panel, inflammatory markers
Cytokine levels: elevated IL-6, VEGF
HHV-8 serology and viral load in suspected multicentric disease
Protein electrophoresis (monoclonal gammopathy screening)
HIV testing in appropriate clinical context.
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Gross Description
Appearance:
Unicentric disease: well-circumscribed, encapsulated mass
Hyaline-vascular variant: gray-white, firm consistency with prominent vascularity
Plasma cell variant: softer consistency with hemorrhagic areas
Cut surface shows prominent follicular pattern with intervening fibrosis
Vascular prominence with dilated vessels throughout the parenchyma.
Characteristics:
Size ranges from 2-20 cm in greatest dimension
Multinodular appearance with fibrotic bands
Prominent capsular thickening in longstanding cases
Areas of calcification may be present
No necrosis typically present
Vascular channels visible on cut surface as small holes or slits.
Size Location:
Mediastinal location most common (60-70% of unicentric cases)
Retroperitoneal and mesenteric locations (20-25%)
Peripheral lymph nodes (cervical, axillary, inguinal) less common
Multiple locations in multicentric disease
Size correlation with variant type (hyaline-vascular typically larger).
Multifocality:
Unicentric disease: single lymph node region involvement
Multicentric disease: widespread lymphadenopathy with hepatosplenomegaly
Bilateral involvement common in multicentric cases
Extranodal involvement: bone marrow, liver, spleen, kidneys
Progressive enlargement over time in untreated cases.
Microscopic Description
Histological Features:
Hyaline-vascular variant: small, regressed germinal centers with thick mantle zones
Onion-skin appearance of follicles due to concentric mantle cell layers
Interfollicular vascular proliferation with prominent vessels
Plasma cell variant: large germinal centers with abundant interfollicular plasma cells
Lollipop lesions: vessels penetrating germinal centers.
Cellular Characteristics:
Regressed germinal centers with few centroblasts and centrocytes
Hyalinized blood vessels within and around follicles
Interfollicular plasma cells (abundant in plasma cell variant)
Russell bodies and Dutcher bodies in plasma cells
Eosinophils and immunoblasts in interfollicular areas
Plasmablasts (HHV-8 positive multicentric disease).
Architectural Patterns:
Preserved follicular architecture with altered follicle morphology
Interfollicular expansion with vascular proliferation
Concentric mantle zones (onion-skinning pattern)
Atrophic germinal centers with sclerosis
Prominent high endothelial venules
Fibrotic bands separating lymphoid tissue
Sinus histiocytosis may be present.
Grading Criteria:
No standard grading system for Castleman disease
Classification based on histological variant
Assessment of plasma cell proportion (>5% for plasma cell variant)
Evaluation of HHV-8 positive plasmablasts in multicentric disease
Vascular prominence scoring for hyaline-vascular features
Cytokine production assessment through functional studies.
Immunohistochemistry
Positive Markers:
CD20 highlights B-cell follicles and mantle zones
CD3 shows interfollicular T-cells
CD138 demonstrates plasma cells (abundant in plasma cell variant)
Lambda and kappa light chains show polytypic plasma cells
CD34 highlights prominent vasculature
HHV-8/LANA-1 positive in plasmablasts (multicentric disease)
IL-6 and VEGF expression elevated.
Negative Markers:
CD10 weak or negative in regressed germinal centers
BCL-6 decreased in atrophic germinal centers
Cyclin D1 negative (excludes mantle cell lymphoma)
CD5 negative in B-cells
CD30 negative (may be positive in plasmablasts)
ALK-1 negative
EBV/EBER typically negative (except in some plasmablastic cases).
Diagnostic Utility:
HHV-8/LANA-1 essential for diagnosing HHV-8 positive multicentric disease
CD138 quantification helps classify plasma cell variant
Light chain restriction assessment (polytypic pattern expected)
CD34 staining highlights characteristic vascular pattern
Ki-67 shows low proliferation in germinal centers
IL-6 expression supports pathogenesis understanding.
Molecular Subtypes:
HHV-8 positive multicentric Castleman disease (MCD-HHV8+)
HHV-8 negative multicentric Castleman disease (MCD-HHV8-)
POEMS-associated Castleman disease
Unicentric Castleman disease (typically HHV-8 negative)
Idiopathic multicentric Castleman disease (unknown etiology).
Molecular/Genetic
Genetic Mutations:
No consistent chromosomal abnormalities in unicentric disease
HHV-8 integration in multicentric cases (viral episome maintenance)
IL-6 gene upregulation through various mechanisms
VEGF gene overexpression
p53 mutations rare but may occur in progressive cases
PIK3CA mutations reported in some cases
Clonal B-cell populations may develop in multicentric disease.
Molecular Markers:
HHV-8 viral load elevated in HHV8+ multicentric disease
IL-6 overexpression (key pathogenic mechanism)
VEGF overproduction causing vascular changes
Viral IL-6 (vIL-6) in HHV-8 positive cases
Increased angiogenic factors
Elevated inflammatory cytokines (TNF-α, IL-1β)
Immunoglobulin gene rearrangements (polyclonal in most cases).
Prognostic Significance:
Unicentric disease: excellent prognosis with complete surgical excision
Multicentric disease: variable prognosis depending on subtype
HHV-8 positive MCD: worse prognosis, higher malignancy risk
POEMS-associated: systemic complications affect prognosis
HIV-associated: prognosis depends on immune status
5-year survival: >95% unicentric, 65-75% multicentric.
Therapeutic Targets:
IL-6 receptor antagonists (tocilizumab, siltuximab)
Anti-CD20 therapy (rituximab) for B-cell depletion
Antiviral therapy (ganciclovir, valganciclovir) for HHV-8 positive cases
Chemotherapy (CVP, CHOP) for aggressive multicentric disease
Proteasome inhibitors (bortezomib) in refractory cases
Immunomodulatory agents (lenalidomide, thalidomide).
Differential Diagnosis
Similar Entities:
Reactive follicular hyperplasia (normal germinal centers)
Follicular lymphoma (BCL-2 positive germinal centers)
Mantle cell lymphoma (cyclin D1 positive)
Marginal zone lymphoma (monocytoid B-cells)
Angioimmunoblastic T-cell lymphoma (aberrant T-cells)
Thymoma (mediastinal location overlap)
Inflammatory pseudotumor (reactive process).
Distinguishing Features:
Castleman disease: regressed germinal centers with onion-skinning
Castleman disease: prominent interfollicular vascularity
Castleman disease: HHV-8 positive plasmablasts (MCD)
Reactive hyperplasia: normal germinal center morphology
Follicular lymphoma: BCL-2 positive, monomorphic germinal centers
Mantle cell lymphoma: cyclin D1 positive mantle cells
AITL: aberrant T-cell phenotype, high endothelial venules.
Diagnostic Challenges:
Hyaline-vascular variant vs reactive follicular hyperplasia with sclerosis
Plasma cell variant vs plasmacytoma or reactive plasmacytosis
Mixed variant may show overlapping features
Early multicentric disease may resemble reactive process
HHV-8 negative multicentric disease diagnosis challenging
POEMS association requires clinical correlation.
Rare Variants:
Plasmablastic variant (HHV-8 positive, aggressive behavior)
Sclerosing variant (extensive fibrosis)
Interfollicular plasma cell variant
POEMS-associated variant (polyneuropathy syndrome)
HIV-associated multicentric variant
Pediatric variant (rare, different clinical behavior)
Extranodal variant (lung, retroperitoneum).
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
[Lymph node/mass] biopsy from [location], measuring [X.X] cm in greatest dimension
Diagnosis
Castleman disease, [hyaline-vascular/plasma cell/mixed] variant
Disease Classification
Classification: [Unicentric/Multicentric] Castleman disease, [variant type]
Histological Features
Shows [regressed germinal centers with onion-skin mantle zones/prominent interfollicular plasma cells] and [interfollicular vascular proliferation/sclerosis]
Size and Morphology
Size: [X.X] cm, morphology: [well-circumscribed mass/multinodular/fibrotic]
Vascular Features
Vascular features: [prominent interfollicular vessels/lollipop lesions/sclerotic vessels]
Special Studies
IHC: CD20 [B-cells], CD138 [plasma cells], HHV-8/LANA-1 [positive/negative], light chains [polytypic]
Molecular: HHV-8 viral load [if indicated], cytokine studies [IL-6 levels]
Flow cytometry: [polyclonal B-cell population/no aberrant expression]
Final Diagnosis
Castleman disease, [specific variant], [unicentric/multicentric], HHV-8 [positive/negative]