Definition/General
Introduction:
Rosai-Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy (SHML), is a rare benign histiocytic disorder
First described by Rosai and Dorfman in 1969
Characterized by emperipolesis (engulfment of intact cells by histiocytes)
FNAC shows distinctive large histiocytes with characteristic cytological features.
Origin:
Etiology remains unknown but likely represents an abnormal immune response
Possible infectious triggers include EBV, CMV, and bacterial infections
Results in histiocyte activation and lymph node infiltration
Polyclonal nature suggests reactive process
Self-limited disorder in most cases.
Classification:
Clinical classification: Classic nodal disease (bilateral cervical lymphadenopathy)
Extranodal disease (skin, orbit, respiratory tract, bone)
Mixed nodal and extranodal
Histological pattern: Sinus histiocytosis with characteristic emperipolesis
IgG4-related variant recently described.
Epidemiology:
Rare disorder with unknown exact incidence
Bimodal age distribution: peak in 1st-2nd decades and 5th decade
Male predominance (male:female = 1.4:1)
Higher incidence in African and African-Caribbean populations
Worldwide distribution
Familial cases rarely reported.
Clinical Features
Presentation:
Massive bilateral cervical lymphadenopathy (most common, 90%)
Painless, progressive enlargement
Matted lymph node masses
Extranodal involvement in 40-50% cases
Fever and night sweats common
Skin lesions (nodules, plaques) in 10% cases
Ocular involvement possible.
Symptoms:
Constitutional symptoms: fever (70%), night sweats, weight loss
Local symptoms due to mass effect (respiratory obstruction, dysphagia)
Skin lesions: painless nodules and plaques
Ocular symptoms: proptosis, visual disturbances
Respiratory symptoms: cough, dyspnea (if pulmonary involvement)
Bone pain (if skeletal involvement).
Risk Factors:
African ancestry (higher predisposition)
Young age (peak in childhood and young adults)
Male gender
Immunocompromised states
Previous infections
Autoimmune conditions
Genetic predisposition (rare familial cases).
Screening:
No specific screening available
Complete blood count may show leukocytosis, anemia
Elevated ESR and CRP
Hypergammaglobulinemia (especially IgG)
Elevated LDH
Autoimmune markers (ANA, RF) may be positive
IgG4 levels in suspected IgG4-related variant.
Master Rosai-Dorfman Disease FNAC Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Massively enlarged lymph nodes (typically 3-15 cm)
Nodes are firm and may be matted
Bilateral cervical involvement characteristic
Cut surface shows tan-gray coloration
Prominent sinuses may be visible
No necrosis typically
Thickened capsule common.
Characteristics:
FNAC yields moderately cellular material
Mixed inflammatory population
Large histiocytes are characteristic
Background inflammatory cells
May be hemorrhagic
Proteinaceous background
Engulfed cells within histiocytes visible.
Size Location:
Cervical lymph nodes most commonly affected (90%)
Bilateral involvement typical
Axillary, inguinal, and mediastinal nodes may be involved
Extranodal sites: skin (most common), orbit, respiratory tract
Node size ranges from 2-20 cm
Generalized lymphadenopathy possible.
Multifocality:
Multiple lymph node groups commonly involved
Bilateral cervical involvement characteristic
Contiguous spread pattern
Extranodal involvement in significant number of cases
Regression may occur spontaneously
Waxing and waning course possible.
Microscopic Description
Histological Features:
FNAC shows large histiocytes with abundant pale cytoplasm
Emperipolesis (intact lymphocytes within histiocyte cytoplasm) is pathognomonic
Mixed inflammatory background with lymphocytes, plasma cells
Foamy histiocytes may be present
Giant cells occasionally seen
No significant atypia.
Cellular Characteristics:
Large histiocytes: Abundant pale eosinophilic cytoplasm, vesicular nuclei, small nucleoli
Emperipolesis: Intact lymphocytes and plasma cells within histiocyte cytoplasm
Foamy macrophages: Lipid-laden cytoplasm
Plasma cells: Polyclonal population
Lymphocytes: Small mature type
Neutrophils may be present.
Architectural Patterns:
Sinus expansion with histiocyte infiltration
Preservation of follicular architecture initially
Progressive architectural distortion
Capsular and perinodal extension
Interfollicular histiocyte infiltration
Sclerosis may develop in chronic cases.
Grading Criteria:
No formal grading system for Rosai-Dorfman disease
Assessment based on extent of histiocyte infiltration
Degree of emperipolesis
Background inflammatory pattern
Presence of sclerosis
Extranodal involvement affects clinical management.
Immunohistochemistry
Positive Markers:
S-100 protein strongly positive in histiocytes (characteristic)
CD68 positive in histiocytes
CD163 positive in macrophages
Lysozyme positive
CD1a usually negative (unlike Langerhans cell histiocytosis)
Fascin may be positive
IgG4 positive in subset of cases.
Negative Markers:
Langerin (CD207) negative (key differentiating feature from LCH)
Cytokeratin negative (excludes carcinoma)
CD30 and CD15 negative (excludes Hodgkin lymphoma)
ALK negative (excludes ALCL)
Melanoma markers negative
CD21 and CD23 negative in histiocytes.
Diagnostic Utility:
S-100 positivity is characteristic and diagnostically important
Helps differentiate from other histiocytic disorders
Langerin negativity excludes Langerhans cell histiocytosis
Useful in confirming histiocytic nature
IgG4 staining identifies IgG4-related variant
Essential for differential diagnosis.
Molecular Subtypes:
Rosai-Dorfman disease shows polyclonal inflammatory response
No specific molecular signature identified
Cytokine dysregulation likely involved
IgG4-related variant has distinct features
No clonal gene rearrangements
Reactive immunophenotype.
Molecular/Genetic
Genetic Mutations:
Recent studies identified activating mutations in some cases
KRAS mutations in subset of patients
MAP2K1 mutations
ARAF mutations
PIK3CA mutations
SLC29A3 mutations in familial cases
RAS-MAPK pathway involvement.
Molecular Markers:
No specific molecular markers for routine diagnosis
Polyclonal immunoglobulin pattern
Normal cytogenetics in most cases
Inflammatory cytokine elevation
Complement activation may occur
No viral genome integration demonstrated.
Prognostic Significance:
Generally benign course with spontaneous resolution in many cases
Extranodal disease may have more persistent course
CNS involvement can be problematic
Immunodeficiency-associated cases may have worse prognosis
Malignant transformation extremely rare
Functional impairment depends on location.
Therapeutic Targets:
Conservative management often sufficient
Corticosteroids for symptomatic disease
Methotrexate for refractory cases
Rituximab in selected cases
Surgical excision for localized disease
Radiotherapy rarely used
Targeted therapy for mutation-positive cases (under investigation).
Differential Diagnosis
Similar Entities:
Langerhans cell histiocytosis
Hemophagocytic syndrome
Hodgkin lymphoma with reactive histiocytes
Large cell lymphoma
Metastatic carcinoma
Infectious lymphadenitis
Erdheim-Chester disease
Storage diseases.
Distinguishing Features:
Langerhans cell histiocytosis: Langerin positive, grooved nuclei, Birbeck granules
Hemophagocytic syndrome: Hemophagocytosis, systemic symptoms, cytopenia
Hodgkin lymphoma: Reed-Sternberg cells, CD15/CD30 positive
Large cell lymphoma: Atypical lymphoid cells, monoclonal
Infectious lymphadenitis: Specific organisms, different clinical context.
Diagnostic Challenges:
Distinguishing from other histiocytic disorders
Limited material on FNAC may miss emperipolesis
Reactive histiocytes in other conditions may mimic
Extranodal presentations can be challenging
IgG4-related variant requires special attention
Atypical presentations possible.
Rare Variants:
IgG4-related Rosai-Dorfman disease
Cutaneous-only disease
CNS Rosai-Dorfman disease
Osseous involvement
Immunodeficiency-associated
Familial Rosai-Dorfman disease
Clonal Rosai-Dorfman disease (rare).
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: [bilateral cervical lymphadenopathy]. Duration: [duration]. Associated symptoms: [fever, constitutional symptoms]
Adequacy
Adequate for evaluation - cellular smears with adequate inflammatory cells
Morphological Features
Cellular smears showing numerous large histiocytes with abundant pale eosinophilic cytoplasm. Characteristic emperipolesis with intact lymphocytes and plasma cells within histiocyte cytoplasm. Mixed inflammatory background
Emperipolesis
Present - intact lymphocytes and plasma cells engulfed within histiocyte cytoplasm (pathognomonic feature)
Immunocytochemistry
S-100: Strongly positive in histiocytes. CD68: Positive. Langerin: Negative. CD1a: Negative. Other markers: [as applicable]
Cytological Diagnosis
Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease)
Recommendations
Clinical correlation advised. Multisystem evaluation to assess extent of disease. Conservative management vs treatment based on symptoms. Hematology-oncology consultation
Comments
The presence of large S-100 positive histiocytes with characteristic emperipolesis is diagnostic of Rosai-Dorfman disease. This is generally a benign, self-limiting condition