Definition/General
Introduction:
Castleman disease, also known as angiofollicular lymph node hyperplasia, is a rare lymphoproliferative disorder characterized by abnormal lymph node enlargement
First described by Benjamin Castleman in 1956
It represents a spectrum of disorders with distinctive histopathological features
FNAC shows characteristic patterns that vary depending on the morphological subtype.
Origin:
Etiology involves dysregulated cytokine production, particularly interleukin-6 (IL-6)
HHV-8 (KSHV) association in some cases, especially multicentric variant
Results in abnormal B-cell proliferation and plasma cell differentiation
Angiogenesis and follicular hyperplasia are key features
Immune dysregulation leads to systemic manifestations.
Classification:
Clinical classification: Unicentric Castleman Disease (UCD) - localized, single lymph node region
Multicentric Castleman Disease (MCD) - multiple lymph node regions, systemic symptoms
Histological variants: Hyaline-vascular (HV) variant (90% of UCD)
Plasma cell (PC) variant (most MCD cases)
Mixed variant (rare)
Plasmablastic variant (HHV-8 associated).
Epidemiology:
Rare disorder with unknown exact incidence
Bimodal age distribution: UCD peaks in 3rd-4th decades, MCD in 5th-6th decades
No significant gender predilection overall
HHV-8 positive MCD more common in HIV-positive patients and Mediterranean regions
Idiopathic MCD more common in Japan and other Asian countries.
Clinical Features
Presentation:
Unicentric Disease: Solitary lymph node mass, usually mediastinal or retroperitoneal
Multicentric Disease: Multiple lymph node enlargement, hepatosplenomegaly
Constitutional symptoms in MCD (fever, night sweats, weight loss)
Skin lesions (violaceous papules and nodules in HHV-8 associated)
Fluid accumulation (pleural effusion, ascites).
Symptoms:
Unicentric: Usually asymptomatic or symptoms due to mass effect
Multicentric: Fever (80-90%), night sweats, fatigue, weight loss
Anemia symptoms (weakness, dyspnea)
Bleeding tendency due to thrombocytopenia
Peripheral neuropathy (POEMS syndrome association)
Skin changes and organomegaly.
Risk Factors:
HIV infection (for HHV-8 positive MCD)
HHV-8 infection
Immunosuppression
Autoimmune conditions
Geographic factors (Mediterranean region for HHV-8 positive)
Male gender for HHV-8 positive MCD
Advanced age for idiopathic MCD.
Screening:
No routine screening available
Complete blood count shows anemia, thrombocytopenia
Elevated acute phase reactants (ESR, CRP)
Hypergammaglobulinemia
Elevated IL-6 levels
HHV-8 serology and PCR
CT/PET scan for staging
VEGF levels may be elevated.
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Gross Description
Appearance:
Enlarged lymph nodes (typically 2-15 cm)
Nodes are firm and rubbery
Well-demarcated masses in unicentric disease
Cut surface shows tan to pink coloration
Prominent vascularity characteristic
No necrosis typically
Follicular pattern may be visible grossly.
Characteristics:
FNAC yields variably cellular material depending on subtype
Hyaline-vascular: Moderate cellularity with mixed population
Plasma cell variant: Highly cellular with abundant plasma cells
Hemorrhagic background due to vascularity
Proteinaceous background
May contain hyaline material.
Size Location:
Mediastinal location most common in UCD (70%)
Retroperitoneal, cervical, and axillary locations also occur
Multiple sites in MCD
Size ranges from 2-20 cm
Generalized lymphadenopathy in multicentric disease
Extranodal involvement possible.
Multifocality:
Solitary involvement in unicentric disease (90%)
Multiple lymph node groups in multicentric disease
Bilateral involvement common in MCD
Hepatosplenomegaly in systemic disease
Bone marrow involvement in some cases
Extranodal masses rarely occur.
Microscopic Description
Histological Features:
Hyaline-vascular variant: Small, regressed follicles with thick mantle zones, prominent interfollicular vascularity
Plasma cell variant: Hyperplastic follicles with sheets of interfollicular plasma cells
Mixed variant: Features of both subtypes
Plasmablastic variant: HHV-8 positive plasmablasts in interfollicular areas.
Cellular Characteristics:
Hyaline-vascular: Small lymphocytes, dendritic cells, endothelial cells, scant plasma cells
Plasma cell variant: Abundant mature plasma cells, lymphoplasmacytic cells, Russell bodies
Follicular dendritic cells: Prominent in both variants
Endothelial cells: Plump, reactive appearance
Plasmablasts: Large cells with prominent nucleoli (in HHV-8 positive).
Architectural Patterns:
Preserved nodal architecture with abnormal follicles
Onion-skin mantle zones (hyaline-vascular)
Penetrating vessels in follicle centers
Interfollicular plasmacytosis (plasma cell variant)
Sclerosis may be present
Regressed follicle centers with hyalinization.
Grading Criteria:
No formal grading system for Castleman disease
Classification based on morphological variants
Clinical severity assessment: Asymptomatic vs symptomatic
Extent of disease: Unicentric vs multicentric
HHV-8 status important for classification
Response to treatment varies by subtype.
Immunohistochemistry
Positive Markers:
CD20 positive in B-cells (follicles and interfollicular areas)
CD3 positive in T-cells (mantle zones)
CD21 and CD23 highlight expanded follicular dendritic cell networks
CD138 positive in plasma cells (plasma cell variant)
LANA-1 positive in HHV-8 associated cases
CD68 positive in macrophages.
Negative Markers:
Cytokeratin negative (excludes carcinoma)
CD30 and CD15 negative (excludes Hodgkin lymphoma)
ALK negative (excludes ALCL)
Cyclin D1 negative (excludes mantle cell lymphoma)
Bcl-2 typically negative in follicle centers
CD10 may be negative in regressed follicles.
Diagnostic Utility:
IHC essential for subtype classification
HHV-8 (LANA-1) testing crucial for treatment decisions
Helps exclude lymphoma (especially follicular lymphoma)
CD21/CD23 staining highlights abnormal follicular dendritic cell networks
Plasma cell markers quantify plasma cell component
Useful for differential diagnosis.
Molecular Subtypes:
HHV-8 positive MCD: Associated with immunosuppression, responds to antiviral therapy
HHV-8 negative/Idiopathic MCD: Often associated with autoimmune features
POEMS-associated: Associated with polyneuropathy, organomegaly
iMCD-TAFRO: Thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly.
Molecular/Genetic
Genetic Mutations:
No specific genetic mutations in classic Castleman disease
HHV-8 viral integration in some cases
Somatic mutations rare compared to lymphomas
Clonal evolution may occur in transformation to lymphoma
Chromosomal abnormalities generally absent
p53 mutations rare.
Molecular Markers:
Elevated IL-6 levels (key pathogenic cytokine)
VEGF overexpression
HHV-8 viral load in positive cases
Interferon-gamma pathway activation
JAK-STAT pathway activation
mTOR pathway involvement
Complement activation.
Prognostic Significance:
Unicentric disease: Excellent prognosis after complete excision
HHV-8 positive MCD: Good response to targeted therapy
Idiopathic MCD: Variable course, may be chronic/relapsing
Risk of lymphoma transformation (especially in MCD)
TAFRO syndrome: More aggressive course
POEMS association affects prognosis.
Therapeutic Targets:
IL-6 receptor: Tocilizumab (anti-IL-6 receptor antibody)
IL-6: Siltuximab (anti-IL-6 antibody)
HHV-8: Rituximab, antiretroviral therapy
mTOR pathway: Sirolimus
Proteasome: Bortezomib
Surgical resection for unicentric disease.
Differential Diagnosis
Similar Entities:
Reactive follicular hyperplasia
Follicular lymphoma
Mantle cell lymphoma
Marginal zone lymphoma
Hodgkin lymphoma with reactive features
Rheumatoid arthritis lymphadenopathy
Sjogren syndrome lymphadenopathy
IgG4-related lymphadenopathy.
Distinguishing Features:
Reactive hyperplasia: Normal follicular architecture, no hyaline-vascular features
Follicular lymphoma: Bcl-2 positive follicle centers, back-to-back follicles
Mantle cell lymphoma: Cyclin D1 positive, different morphology
Marginal zone lymphoma: Monocytoid B-cells, different architecture
IgG4-related disease: High IgG4+ plasma cells, sclerosis.
Diagnostic Challenges:
Distinguishing hyaline-vascular variant from reactive hyperplasia
Plasma cell variant from reactive plasmacytosis
Risk of lymphoma development requires follow-up
HHV-8 negative cases challenging to diagnose
Sampling limitations on FNAC
Mixed patterns complicating classification.
Rare Variants:
TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly)
POEMS-associated Castleman disease
Paraneoplastic Castleman disease
Localized cutaneous Castleman disease
Primary effusion lymphoma-associated
Pediatric Castleman disease.
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
Fine needle aspiration cytology of [site] lymph node
Clinical History
Clinical presentation: [unicentric/multicentric]. Associated symptoms: [constitutional symptoms]. Imaging findings: [describe findings]
Adequacy
Adequate for evaluation - cellular smears with adequate lymphoid tissue
Morphological Features
Cellular smears showing [describe follicular component]. Interfollicular component: [plasma cells/mixed population]. Vascular component: [prominent/minimal]. Hyaline material: [present/absent]
Plasma Cell Component
Plasma cells: [abundant/moderate/scanty]. Morphology: [mature/immature/Russell bodies]. Distribution: [interfollicular/diffuse]
Immunocytochemistry
CD20: [result]. CD3: [result]. CD138: [result]. LANA-1 (HHV-8): [positive/negative]. Other markers: [as applicable]
Cytological Diagnosis
Lymphoid hyperplasia, consistent with Castleman disease, [hyaline-vascular/plasma cell/mixed] variant
Recommendations
Histopathological examination recommended for definitive diagnosis and subtyping. Clinical staging workup. IL-6 levels. Oncology consultation for management planning
Comments
The cytological features suggest Castleman disease. Tissue biopsy is essential for definitive diagnosis, variant classification, and treatment planning