How can Rosai‑Dorfman disease be differentiated from the hyaline‑vascular variant of Castleman disease?

Differentiating Rosai-Dorfman Disease from Hyaline-Vascular Castleman Disease

The key to distinguishing these two entities lies in identifying S100-positive histiocytes with emperipolesis in RDD versus abnormal germinal centers with hyaline-vascular transformation and follicular dendritic cell proliferation in Castleman disease, combined with their distinct immunophenotypic profiles. 1, 2

Histopathologic Features

Rosai-Dorfman Disease

• Large histiocytes with pale "watery-clear" cytoplasm, round hypochromatic nuclei, and prominent nucleoli 1
• Emperipolesis (intact leukocytes trafficking through histiocyte cytoplasm) - highly characteristic but not required for diagnosis, as it can be focal 1
• Sinus expansion by histiocytes in nodal disease 1
• Lymphoplasmacytic background with plasma cells in medullary cords and around venules 1

Hyaline-Vascular Castleman Disease

• Abnormal germinal centers with hyaline-vascular transformation 2
• Multiple germinal centers within a single reactive lymphoid follicle 2
• Follicular dendritic cell proliferation - this is fundamentally a disorder of follicular dendritic cells, not histiocytes 2
• Onion-skin layering of mantle zone lymphocytes
• Prominent interfollicular vascularization

Immunohistochemistry Algorithm

For RDD, confirm:

• S100: Positive (cytoplasmic AND nuclear) - this is critical 1, 3
• CD68: Positive 1
• CD163: Variable positive 1
• OCT2: Positive 3
• Cyclin D1: Positive 3
• CD1a/CD207: Negative (distinguishes from Langerhans cell histiocytosis) 1

For Hyaline-Vascular Castleman Disease:

• CD21/CD23: Highlights expanded follicular dendritic cell networks
• S100: Negative in the characteristic cells
• Focus on follicular architecture rather than histiocytic proliferation

Clinical Context Matters

RDD typically presents with:

• Bilateral massive cervical lymphadenopathy (most common) 1
• Extranodal involvement in 43% of cases 1
• Constitutional symptoms (fevers, night sweats, weight loss) 1
• Can involve skin (10%), CNS (5%), sinuses (11%) 1

Hyaline-Vascular Castleman Disease presents with:

• Unicentric disease in most cases 2
• Solitary enlarged lymph node, often asymptomatic 4
• Mediastinal location common
• Minimal systemic symptoms 4

Critical Pitfalls to Avoid

Emperipolesis is not pathognomonic - it can occur focally in Erdheim-Chester disease, juvenile xanthogranuloma, and malignant histiocytoses 1. Do not rely on this feature alone.

Extranodal RDD is challenging - these lesions have more fibrosis, fewer histiocytes, and less emperipolesis, requiring immunostains to highlight residual RDD histiocytes 1

RDD can coexist with lymphomas - always evaluate for superimposed pathology, as RDD histology may represent a minor reactive process in the setting of primary malignancy 1

Diagnostic Algorithm

1. Examine architecture: Sinus expansion with histiocytes → consider RDD; Abnormal follicles with hyaline vessels → consider Castleman
2. Identify the key cell: Large pale histiocytes → RDD; Follicular dendritic cells → Castleman
3. Run immunostains: S100+/CD68+/OCT2+ → RDD; CD21+/CD23+ expanded networks → Castleman
4. Look for emperipolesis: Supportive of RDD if present, but absence doesn't exclude it
5. Correlate clinically: Massive bilateral cervical nodes with extranodal disease → RDD; Solitary node, minimal symptoms → Castleman

Additional Considerations

Evaluate IgG4/IgG ratio in all RDD cases, as some extranodal forms show increased IgG4+ plasma cells 1. Consider MAPK/ERK pathway mutation testing (NRAS, KRAS, MAP2K1) in RDD, as 30-50% harbor these mutations, indicating a clonal neoplastic process 3, 5.