Definition/General
Introduction:
Rosai-Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy (SHML), is a benign histiocytic disorder characterized by painless lymphadenopathy
First described by Rosai and Dorfman in 1969
The hallmark feature is emperipolesis - the presence of intact lymphocytes within histiocyte cytoplasm
It can present as nodal or extranodal disease.
Origin:
Etiology remains unclear but likely represents an abnormal immune response to unknown stimulus
Viral infections (EBV, HHV-6) suggested as potential triggers
Immune dysregulation leads to histiocyte activation and proliferation
Genetic factors may play a role given familial cases
Environmental triggers possible but not identified
Autoimmune component suggested by association with autoimmune diseases.
Classification:
Classified by anatomical distribution: Classical nodal form (massive lymphadenopathy with systemic features)
Extranodal form (skin, CNS, bone, other organs)
Mixed form (both nodal and extranodal involvement)
Histological variants: Classical histiocytes with emperipolesis
Xanthogranulomatous variant
Fibrosclerotic variant.
Epidemiology:
Bimodal age distribution: peak in children/young adults and elderly
Slight male predominance (M:F = 1.4:1)
More common in African and Caribbean populations
Familial clustering reported in some cases
Association with immune dysfunction
Extranodal disease more common in adults
Cutaneous involvement in 10% of cases.
Clinical Features
Presentation:
Massive, painless cervical lymphadenopathy (classical presentation in 90%)
Bilateral neck involvement common (75% of cases)
Fever (70% of cases)
Weight loss and night sweats
Hepatosplenomegaly (25% of cases)
Skin lesions (papules, nodules)
Ocular involvement (orbital masses)
Upper respiratory symptoms.
Symptoms:
Constitutional symptoms: fever, malaise, weight loss
Respiratory symptoms due to mediastinal involvement
Neurological symptoms (CNS involvement)
Skin rash and nodules
Arthralgia and myalgia
Anemia symptoms (fatigue, weakness)
Recurrent infections (immune dysfunction)
No specific B-symptoms like lymphoma.
Risk Factors:
African or Caribbean ancestry (genetic predisposition)
Immune dysfunction or immunodeficiency states
Autoimmune disease association (SLE, rheumatoid arthritis)
Family history (rare familial cases)
Previous viral infections (possible trigger)
Young age (bimodal distribution)
Male gender (slight predominance).
Screening:
Complete blood count (anemia, leukocytosis)
Inflammatory markers (elevated ESR, CRP)
Immunoglobulin levels (hypergammaglobulinemia)
Autoimmune markers when indicated
Imaging studies: CT, MRI for extent assessment
Fine needle aspiration may suggest diagnosis
Excisional biopsy required for definitive diagnosis.
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Gross Description
Appearance:
Markedly enlarged lymph nodes with smooth, intact capsule
Cut surface shows gray-white to tan coloration
Soft to firm consistency
Prominent sinusoidal pattern may be visible
No necrosis or caseation typically
Fibrotic areas in chronic cases
Capsular thickening common
Hemorrhagic areas occasionally present.
Characteristics:
Massive enlargement (up to 10-15 cm possible)
Multinodular appearance in some cases
Homogeneous cut surface without significant variegation
Prominent vascularity
Fibrotic bands in longstanding disease
No calcification typically
Capsular adherence to surrounding tissues may occur.
Size Location:
Cervical lymph nodes most commonly affected (>90%)
Bilateral cervical involvement typical
Mediastinal lymphadenopathy in 25% of cases
Axillary and inguinal involvement less common
Retroperitoneal lymphadenopathy may occur
Size ranges from 2-15 cm in greatest dimension
Multiple lymph node groups involved simultaneously.
Multifocality:
Bilateral cervical involvement in majority of cases
Generalized lymphadenopathy common
Extranodal involvement (skin, CNS, bone, orbit)
Hepatosplenomegaly in 25% of cases
Progressive involvement over time
Skip lesions possible in extranodal disease
Spontaneous regression may occur.
Microscopic Description
Histological Features:
Massive sinus dilatation filled with large histiocytes
Emperipolesis - intact lymphocytes within histiocyte cytoplasm (pathognomonic)
Large histiocytes with abundant eosinophilic cytoplasm and vesicular nuclei
Preserved lymphoid follicles compressed by expanded sinuses
Plasma cell infiltration in interfollicular areas
Fibrosis in chronic cases.
Cellular Characteristics:
Characteristic histiocytes with large, round to oval nuclei and prominent nucleoli
Abundant, pale eosinophilic cytoplasm
Emperipolesis of lymphocytes, plasma cells, and occasionally neutrophils
S-100 positive histiocytes
CD68 positive but variable intensity
Plasma cells with Russell bodies
No significant atypia or mitotic activity.
Architectural Patterns:
Sinus histiocytosis pattern with marked sinus expansion
Preserved nodal architecture with compressed follicles
Interfollicular plasma cell infiltration
Capsular and pericapsular fibrosis
Subcapsular sinus expansion prominent
Medullary sinus involvement
Paracortical preservation with reactive changes.
Grading Criteria:
No standard grading system for Rosai-Dorfman disease
Activity assessment based on histiocyte proliferation
Emperipolesis quantification (should be readily identifiable)
Fibrosis extent indicates chronicity
Plasma cell infiltration degree
Sinus expansion assessment
No malignant potential grading as condition is benign.
Immunohistochemistry
Positive Markers:
S-100 protein strongly positive in characteristic histiocytes (diagnostic marker)
CD68 positive but may be weak or focal
CD163 positive in macrophages
Lysozyme positive in histiocytes
α1-antitrypsin positive
CD138 highlights plasma cells
IgG and IgA positive in plasma cells.
Negative Markers:
CD1a negative (excludes Langerhans cell histiocytosis)
Langerin negative
CD30 negative (excludes lymphoma)
ALK-1 negative
CD21 and CD23 may highlight compressed follicular dendritic cells
Melanoma markers negative
CD34 negative in histiocytes.
Diagnostic Utility:
S-100 positivity in histiocytes is diagnostic hallmark
CD68 expression confirms histiocytic nature but may be weak
Negative CD1a and Langerin exclude Langerhans cell histiocytosis
Polyclonal plasma cells demonstrated by light chain staining
Ki-67 shows low proliferation index
EBV/EBER usually negative.
Molecular Subtypes:
No molecular subtypes recognized for Rosai-Dorfman disease
Polyclonal histiocyte population
No clonal gene rearrangements
Cytokine expression studies show inflammatory profile
KRAS mutations reported in some extranodal cases
MAP2K1 mutations in subset of cases
No consistent chromosomal abnormalities.
Molecular/Genetic
Genetic Mutations:
KRAS mutations identified in some cases (particularly extranodal)
MAP2K1 mutations reported in subset of patients
ARAF mutations rarely detected
SLC29A3 mutations in familial cases with H syndrome
No consistent chromosomal abnormalities
Familial clustering suggests genetic component
HLA associations reported in some studies.
Molecular Markers:
Elevated inflammatory cytokines (IL-6, TNF-α)
Increased immunoglobulin production
Complement activation markers
S-100 protein overexpression in histiocytes
Histiocyte activation markers
Apoptosis resistance markers
Growth factor expression (PDGF, VEGF).
Prognostic Significance:
Benign condition with no malignant potential
Variable clinical course: self-limiting to chronic progressive
Spontaneous remission in 20-50% of cases
Extranodal disease may have different behavior
CNS involvement more serious complications
Overall prognosis excellent
Mortality rare and usually related to complications
Recurrence possible but uncommon.
Therapeutic Targets:
Observation for asymptomatic, stable disease
Corticosteroids for symptomatic disease
Surgical excision for localized, symptomatic lesions
Radiation therapy for refractory cases
Chemotherapy rarely needed (alkylating agents)
Rituximab reported in refractory cases
Targeted therapy (MEK inhibitors) for MAP2K1 mutated cases.
Differential Diagnosis
Similar Entities:
Langerhans cell histiocytosis (CD1a/Langerin positive)
Histiocytic sarcoma (malignant histiocytes)
Hodgkin lymphoma (Reed-Sternberg cells)
Metastatic carcinoma (sinus involvement)
Infectious lymphadenitis (specific organisms)
Storage diseases (Gaucher, Niemann-Pick)
Hemophagocytic lymphohistiocytosis.
Distinguishing Features:
Rosai-Dorfman: S-100+ histiocytes with emperipolesis, benign morphology
LCH: CD1a/Langerin positive, coffee-bean nuclei, no emperipolesis
Histiocytic sarcoma: malignant cytology, high mitotic rate, no emperipolesis
Hodgkin lymphoma: Reed-Sternberg cells, CD30+, CD15+
Metastatic carcinoma: epithelial markers positive, cytokeratin+
Storage disease: specific enzyme deficiency, different morphology.
Diagnostic Challenges:
Extranodal presentations may lack classical features
Early stages may have minimal emperipolesis
Fibrotic phases may obscure diagnostic features
Mixed inflammatory infiltrates can be confusing
Rare malignant transformation reported
Immunohistochemistry essential for diagnosis
Clinical correlation required for extranodal disease.
Rare Variants:
Cutaneous-only disease (without lymphadenopathy)
CNS variant (intracranial masses)
Orbital variant (periorbital involvement)
Bone variant (osteolytic lesions)
Familial variant (genetic predisposition)
Fibrosclerotic variant (extensive fibrosis)
Xanthogranulomatous variant (foamy histiocytes)
Malignant transformation (extremely 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
Lymph node biopsy from [cervical/axillary/other] region, measuring [X.X] cm in greatest dimension
Diagnosis
Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy)
Classification
Pattern: [classical nodal form/extranodal involvement], activity: [active/chronic/fibrosclerotic]
Histological Features
Shows [massive sinus dilatation] with [large histiocytes displaying emperipolesis] and [preserved lymphoid architecture]
Size and Pattern
Size: [X.X] cm, sinus involvement: [extensive/focal], emperipolesis: [readily identified/prominent]
Cellular Composition
Contains [large histiocytes with emperipolesis/plasma cell infiltrate/preserved follicular architecture] without malignant features
Special Studies
IHC: S-100 [strongly positive in histiocytes], CD68 [positive], CD1a [negative], Langerin [negative]
Additional: CD138 [plasma cells], lysozyme [positive], Ki-67 [low proliferation]
Molecular: [if performed] KRAS/MAP2K1 mutation analysis [when indicated]
Final Diagnosis
Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy), consistent with benign histiocytic disorder