Definition/General
Introduction:
Splenic granulomas are organized collections of epithelioid cells representing a specific type of chronic inflammatory response
They form in response to persistent antigens that cannot be eliminated by conventional inflammatory mechanisms
Splenic granulomas can be infectious or non-infectious in origin and may be solitary or multiple
The spleen is commonly involved in systemic granulomatous diseases.
Origin:
Result from activated macrophages (epithelioid cells) attempting to contain persistent stimuli
Infectious causes: Mycobacteria, fungi, parasites
Non-infectious causes: Sarcoidosis, foreign bodies, drugs
Immune response: T-helper cell mediated immunity
Chronic antigenic stimulation leads to organized tissue response.
Classification:
By etiology: Infectious granulomas (mycobacteria, fungi, parasites)
Non-infectious granulomas (sarcoidosis, foreign body, drug-induced)
By morphology: Epithelioid granulomas
Giant cell granulomas
Necrotizing granulomas
By number: Solitary granulomas
Multiple granulomas
By special features: Caseating vs non-caseating.
Epidemiology:
Common finding: Present in 5-10% of spleens at autopsy
Geographic variation: Higher incidence in tuberculosis-endemic areas
Age distribution: Varies by cause - young adults (sarcoidosis) vs any age (infections)
Most common cause: Mycobacterial infections globally
Sarcoidosis: Second most common in developed countries.
Clinical Features
Presentation:
Often asymptomatic (60-70% of cases)
Splenomegaly in systemic granulomatous diseases
Constitutional symptoms: Fever, weight loss, night sweats
Left upper quadrant discomfort in large granulomas
Hypersplenism with cytopenia in extensive involvement.
Symptoms:
Systemic symptoms: Low-grade fever, fatigue, malaise
Weight loss and decreased appetite
Local symptoms: Left upper quadrant pain or fullness
Early satiety if splenomegaly present
Associated symptoms: Depend on underlying cause (cough in TB, skin lesions in sarcoidosis).
Risk Factors:
Infectious exposures: Tuberculosis contact, endemic mycoses, parasitic infections
Immunocompromise: HIV infection, immunosuppressive therapy
Geographic factors: Travel to endemic areas
Occupational exposures: Dust, organic antigens
Genetic predisposition: Family history of sarcoidosis.
Screening:
Systemic evaluation: For underlying granulomatous disease
Imaging studies: CT chest for pulmonary involvement
Laboratory studies: ACE levels, calcium levels
Microbiologic workup: Cultures, special stains for organisms
Biopsy: For tissue diagnosis.
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Gross Description
Appearance:
Small, discrete nodules scattered throughout splenic parenchyma
Gray-white to yellow color
Firm consistency compared to surrounding tissue
Size range: Few millimeters to 1-2 centimeters
Well-demarcated borders from normal splenic tissue.
Characteristics:
Multiple small nodules typical pattern (80-90% of cases)
Caseous centers: May have yellow, cheesy material (TB)
Calcification: In healed granulomas
Confluence: Multiple granulomas may coalesce
No hemorrhage or necrosis unless complicated.
Size Location:
Random distribution: Throughout red and white pulp
Size correlation: Larger granulomas more likely symptomatic
Bilateral involvement: Of splenic lobes
No specific anatomic predilection
Associated findings: May involve hilar lymph nodes.
Multifocality:
Multiple granulomas in 85-90% of cases
Scattered distribution: Random throughout spleen
Associated organ involvement: Liver, lungs, lymph nodes commonly involved
Systemic disease pattern: Part of generalized granulomatous process.
Microscopic Description
Histological Features:
Epithelioid cells: Activated macrophages with abundant eosinophilic cytoplasm
Giant cells: Langhans-type or foreign body-type
Lymphocytes: Surrounding the epithelioid cells
Central necrosis: Caseous necrosis in TB, absent in sarcoidosis
Peripheral fibrosis: In chronic cases.
Cellular Characteristics:
Epithelioid cells: Elongated cells with vesicular nuclei, abundant pink cytoplasm
Multinucleated giant cells: Langhans giant cells with peripherally arranged nuclei
Lymphocytes and plasma cells: At periphery of granuloma
Neutrophils: Usually absent unless secondary infection
Eosinophils: May be present in parasitic infections.
Architectural Patterns:
Well-formed granulomas: Organized structure with central epithelioid cells
Concentric arrangement: Central epithelioid cells, surrounded by lymphocytes
Confluent pattern: Multiple granulomas merging
Necrotizing pattern: Central caseous necrosis
Non-necrotizing pattern: No central necrosis.
Grading Criteria:
Well-formed granulomas: Classic appearance with epithelioid cells and giant cells
Poorly formed granulomas: Loose collections of epithelioid cells
Necrotizing granulomas: With central caseous necrosis
Non-necrotizing granulomas: No central necrosis (sarcoidosis-type).
Immunohistochemistry
Positive Markers:
Macrophage markers: CD68 positive in epithelioid cells and giant cells
Lysozyme: Positive in epithelioid cells
S-100 protein: May be positive in epithelioid cells
CD3: Positive in surrounding T-lymphocytes.
Negative Markers:
Cytokeratins: Negative in epithelioid cells (helps distinguish from carcinoma)
Melanoma markers: Negative (S-100 positive but Melan-A negative)
Lymphoma markers: Negative in epithelioid cells
Specific tumor markers: Negative.
Diagnostic Utility:
Confirmation of granulomatous inflammation: CD68+ epithelioid cells
Exclusion of malignancy: Negative tumor markers
Assessment of T-cell response: CD3+ lymphocytes
Differential diagnosis: From other inflammatory conditions.
Molecular Subtypes:
Infectious granulomas: May have pathogen-specific features
Sarcoidosis granulomas: Characteristic non-necrotizing pattern
Foreign body granulomas: Giant cells containing foreign material
Drug-induced granulomas: Variable patterns.
Molecular/Genetic
Genetic Mutations:
Sarcoidosis susceptibility genes: HLA associations, ANXA11 mutations
Immunodeficiency genes: Predisposing to infections
Cytokine genes: TNF-α, IL-10 polymorphisms
Granuloma formation genes: Interferon-gamma pathway genes.
Molecular Markers:
Cytokine expression: IFN-γ, TNF-α, IL-12 in granuloma formation
Chemokine expression: CCL2, CCL5 for macrophage recruitment
Transcription factors: STAT1, IRF-1 in activated macrophages
Antimicrobial peptides: In infectious granulomas.
Prognostic Significance:
Underlying disease determines prognosis
Infectious granulomas: Good prognosis with appropriate treatment
Sarcoidosis: Variable course, may resolve spontaneously
Extent of involvement: Massive involvement may cause hypersplenism
Response to treatment: Monitoring for resolution.
Therapeutic Targets:
Antimicrobial therapy: For infectious causes (anti-TB drugs)
Immunosuppressive therapy: Corticosteroids for sarcoidosis
TNF-α inhibitors: For refractory sarcoidosis
Splenectomy: Rarely needed for hypersplenism.
Differential Diagnosis
Similar Entities:
Splenic lymphoma: May have epithelioid cell reaction
Metastatic carcinoma: May elicit granulomatous response
Langerhans cell histiocytosis: Histiocytic infiltrate
Hodgkin lymphoma: May have epithelioid cells and Reed-Sternberg cells
Infectious lesions: Abscesses, chronic inflammation.
Distinguishing Features:
Granuloma vs lymphoma: Organized epithelioid cells vs monomorphic lymphoid population
Mixed inflammatory cells vs clonal population
Granuloma vs carcinoma: CD68+ vs cytokeratin+
Infectious vs non-infectious: Organism demonstration vs sterile inflammation.
Diagnostic Challenges:
Determining etiology: Requires clinical correlation and special studies
Sampling adequacy: Multiple samples may be needed
Organism detection: May require multiple stains and cultures
Distinguishing causes: Necrotizing vs non-necrotizing patterns.
Rare Variants:
Epithelioid hemangioma: Vascular granulomatous lesion
Malakoplakia: Histiocytes with Michaelis-Gutmann bodies
Rosai-Dorfman disease: Histiocytes with emperipolesis
Xanthogranulomatous inflammation: Foamy macrophages
Granulomatous hypersensitivity: Drug-induced.
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 [symptoms] and [risk factors]
Gross Description
[Number] discrete granulomas measuring [size range] distributed throughout splenic parenchyma
Microscopic Findings
[Well-formed/poorly formed] granulomas with [epithelioid cells], [giant cells], and [necrosis status]
Special Stains
AFB stain: [positive/negative]. GMS stain: [positive/negative]. PAS stain: [positive/negative]
Granuloma Classification
[Necrotizing/non-necrotizing] granulomas consistent with [infectious/non-infectious] etiology
Diagnosis
Splenic granulomatous inflammation, [necrotizing/non-necrotizing], [probable etiology]
Probable Etiology
[Mycobacterial infection/sarcoidosis/other] based on morphology and clinical correlation
Recommendations
Recommend [cultures/systemic evaluation/ACE levels] and clinical correlation for definitive diagnosis