Definition/General
Introduction:
Splenic sarcoidosis represents splenic involvement in sarcoidosis, a multisystem granulomatous disease of unknown etiology
It is characterized by non-necrotizing epithelioid granulomas in the spleen
Splenic involvement occurs in 50-60% of sarcoidosis patients but is often asymptomatic
The diagnosis requires exclusion of other granulomatous diseases and correlation with clinical findings.
Origin:
Part of systemic sarcoidosis affecting multiple organs
Unknown etiology: Likely interaction between environmental triggers and genetic susceptibility
Abnormal immune response: Excessive T-helper 1 (Th1) cell activation
Granuloma formation: Activated macrophages transform into epithelioid cells
No infectious agent: Extensive search for causative organisms negative.
Classification:
By extent: Isolated splenic involvement (rare)
Multisystem disease with splenic involvement (common)
By activity: Active disease
Chronic/fibrotic disease
By pattern: Nodular pattern
Diffuse infiltrative pattern
By associated features: With splenomegaly
With hypersplenism.
Epidemiology:
Age distribution: Bimodal - young adults (20-40 years) and older adults (>50 years)
Gender: Female slight predominance (1.3:1)
Race: Higher incidence in African Americans and Northern Europeans
Geographic distribution: More common in temperate climates
Splenic involvement: Detected in 50-60% of sarcoidosis patients at autopsy.
Clinical Features
Presentation:
Asymptomatic in majority (60-70%) of splenic involvement cases
Splenomegaly (30-40% of patients): Usually mild to moderate
Left upper quadrant discomfort if significant splenomegaly
Hypersplenism (rare): Cytopenia due to sequestration
Systemic symptoms related to other organ involvement.
Symptoms:
Splenic symptoms: Usually minimal or absent
Left upper quadrant fullness or discomfort
Systemic manifestations: Fatigue, fever, weight loss
Dyspnea (lung involvement)
Organ-specific symptoms: Skin lesions, joint pain, ocular symptoms
Constitutional symptoms: Night sweats, malaise.
Risk Factors:
Genetic factors: HLA associations (HLA-DRB1, HLA-DQB1)
Family history of sarcoidosis
Environmental exposures: Dust, molds, infectious agents (possible triggers)
Geographic factors: Certain geographic clusters
Age and gender: Young to middle-aged adults, female predominance.
Screening:
Multisystem evaluation: Chest imaging, pulmonary function tests
Laboratory studies: Serum ACE levels, calcium levels
Imaging studies: CT chest and abdomen
Tissue diagnosis: Biopsy of accessible lesions
Exclusion of infections: Tuberculosis, fungal infections.
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Gross Description
Appearance:
Multiple small nodules: 2-4 mm gray-white nodules scattered throughout splenic parenchyma
Well-demarcated lesions: Discrete nodules with sharp borders
No central necrosis: Unlike tuberculous granulomas
Uniform appearance: Similar-sized nodules throughout spleen
Firm consistency: Granulomas firmer than surrounding tissue.
Characteristics:
Small granulomas: Typically <5 mm in diameter
Gray-white color: Characteristic appearance
No calcification: In active disease (may calcify in chronic cases)
No cavitation: Solid nodules without central breakdown
Preservation of splenic architecture: Between granulomas.
Size Location:
Random distribution: Throughout red and white pulp
Multiple lesions: Rarely solitary
Size uniformity: Most granulomas similar in size
No specific anatomic predilection
Associated splenomegaly: Mild to moderate enlargement (300-600g).
Multifocality:
Multifocal involvement: >95% of cases have multiple granulomas
Bilateral distribution: Both splenic lobes involved
Associated organ involvement: Lungs (90%), lymph nodes (75%), liver (50%)
Systemic pattern: Part of multisystem disease
No dominant mass: Multiple small lesions pattern.
Microscopic Description
Histological Features:
Non-necrotizing epithelioid granulomas: Hallmark feature distinguishing from TB
Epithelioid cells: Abundant with vesicular nuclei and eosinophilic cytoplasm
Multinucleated giant cells: Langhans-type or foreign body-type
Lymphocytic cuff: Surrounding granulomas
Absence of caseous necrosis: Key distinguishing feature.
Cellular Characteristics:
Epithelioid cells: Elongated activated macrophages with abundant cytoplasm
Giant cells: May contain inclusions (Schaumann bodies, asteroid bodies)
Lymphocytes: Predominantly T-cells at periphery
Plasma cells: Few, usually at granuloma periphery
Neutrophils: Typically absent unless complicated.
Architectural Patterns:
Well-circumscribed granulomas: Organized collections of epithelioid cells
Compact arrangement: Tightly packed epithelioid cells
Central giant cells: Often present in center of granuloma
Peripheral lymphocytes: Surrounding inflammatory cells
Minimal fibrosis: In active disease (increases in chronic disease).
Grading Criteria:
Active sarcoidosis: Well-formed granulomas with abundant epithelioid cells
Chronic sarcoidosis: Increased fibrosis around granulomas
Inactive sarcoidosis: Fibrotic nodules with few viable epithelioid cells
Progressive disease: Increasing number and size of granulomas.
Immunohistochemistry
Positive Markers:
CD68: Strongly positive in epithelioid cells and giant cells
Lysozyme: Positive in epithelioid cells
CD3: Positive in surrounding T-lymphocytes
ACE (Angiotensin Converting Enzyme): May be positive in epithelioid cells.
Negative Markers:
Acid-fast stains: Negative for mycobacteria (crucial for differential diagnosis)
Fungal stains: GMS, PAS negative
Cytokeratins: Negative in epithelioid cells
S-100: Usually negative
CD1a: Negative (excludes Langerhans cell histiocytosis).
Diagnostic Utility:
Confirmation of macrophage origin: CD68+ epithelioid cells
Exclusion of infections: Negative organism stains crucial
T-cell response assessment: CD3+ lymphocytes
Differentiation from other granulomatous diseases: Combined with morphology and clinical features.
Molecular Subtypes:
Classical sarcoid granulomas: Non-necrotizing, CD68+, organism-negative
Fibrotic variant: Extensive fibrosis with residual epithelioid cells
Giant cell variant: Prominent multinucleated giant cells
Schaumann body variant: Giant cells containing laminated inclusions.
Molecular/Genetic
Genetic Mutations:
HLA associations: HLA-DRB1*1101, HLA-DQB1*0602 in some populations
ANXA11 gene: Associated with chronic sarcoidosis
FAM177B gene: Familial sarcoidosis association
BTNL2 gene: Immune regulation gene variants
TNF-α gene: Polymorphisms affecting disease susceptibility.
Molecular Markers:
Elevated ACE levels: In serum and tissue (60-70% of active cases)
Hypercalcemia: Due to extrarenal 1α-hydroxylase activity
Cytokine expression: IL-2, IFN-γ, TNF-α in granulomas
Chemokine expression: CCL2, CCL5 for macrophage recruitment.
Prognostic Significance:
Spontaneous remission: Occurs in 60-70% of cases within 2 years
Chronic progressive disease: 20-30% develop chronic disease
Organ dysfunction: Depends on extent and location of involvement
Mortality: Overall low (<5%), higher with cardiac/CNS involvement
Splenic involvement: Usually benign course.
Therapeutic Targets:
Corticosteroids: First-line therapy for symptomatic disease
Immunosuppressive agents: Methotrexate, azathioprine for steroid-sparing
TNF-α inhibitors: Infliximab for refractory cases
Hydroxychloroquine: For skin and joint involvement
Observation: For asymptomatic disease.
Differential Diagnosis
Similar Entities:
Tuberculous granulomas: Necrotizing granulomas with AFB
Fungal infections: Histoplasma, Cryptococcus with organisms
Hypersensitivity reactions: Drug-induced granulomas
Primary immunodeficiencies: Chronic granulomatous disease
Malignancy-associated granulomas: Hodgkin lymphoma, carcinomas.
Distinguishing Features:
Sarcoidosis vs TB: Non-necrotizing vs necrotizing
Negative vs positive AFB
Sarcoidosis vs fungi: Negative vs positive fungal stains
Clinical correlation: Multisystem involvement, elevated ACE
Response to treatment: Steroid responsiveness
Geographic factors: TB more common in endemic areas.
Diagnostic Challenges:
Exclusion of infections: Requires multiple stains and cultures
Clinical correlation: Essential for diagnosis
Tissue adequacy: Multiple samples may be needed
Atypical presentations: In immunocompromised patients
Overlap syndromes: Sarcoidosis with concurrent infections.
Rare Variants:
Necrotizing sarcoidosis: Rare variant with central necrosis
Hyalinizing granulomas: Extensive hyalinization and fibrosis
Sarcoidal reactions: To malignancy or infections
Cardiac sarcoidosis: With splenic involvement
Neurosarcoidosis: CNS involvement with splenic 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
[Biopsy/splenectomy] specimen with clinical history of [multisystem disease] and [splenomegaly]
Gross Description
Multiple gray-white nodules measuring [size range] distributed throughout splenic parenchyma
Microscopic Findings
Non-necrotizing epithelioid granulomas with [giant cells] and [lymphocytic infiltrate]
Special Stains
AFB stain: negative. GMS stain: negative. PAS stain: negative
Laboratory Correlation
Serum ACE: [elevated/normal]. Serum calcium: [elevated/normal]
Diagnosis
Splenic sarcoidosis with non-necrotizing granulomatous inflammation
Systemic Disease
Part of multisystem sarcoidosis with [pulmonary/lymph node/other] involvement
Recommendations
Clinical correlation with [chest imaging/PFTs] and consider [systemic therapy] if symptomatic