What is a granuloma?

What is a Granuloma?

A granuloma is an organized collection of activated macrophages that forms in response to persistent particulate stimuli (infectious or non-infectious) that individual macrophages cannot eradicate. 1

Structure and Formation

Granulomas have a characteristic structure consisting of:

• Central core: Composed of activated macrophages that have transformed into epithelioid cells, often with multinucleated giant cells
• Peripheral rim: Typically surrounded by lymphocytes (predominantly T-cells)
• Optional features: May include necrosis, fibrosis, or other specialized cells depending on etiology

The formation process follows a stepwise program:

1. Initial macrophage activation in response to persistent antigen
2. Transformation of macrophages into epithelioid cells
3. Recruitment of additional immune cells (primarily lymphocytes)
4. Organization into a structured aggregate
5. Development of characteristic morphological changes

Types of Granulomas

Granulomas can be classified based on their morphological appearance:

1. Epithelioid granulomas: Most common type, composed of transformed macrophages with epithelioid appearance

   • Example: Sarcoidosis, tuberculosis

2. Necrotizing granulomas: Contain central necrosis

   • Example: Tuberculosis, fungal infections

3. Non-necrotizing granulomas: Lack central necrosis

   • Example: Sarcoidosis

4. Suppurative granulomas: Contain neutrophils and pus formation

   • Example: Cat scratch disease, certain fungal infections

5. Foreign body granulomas: Form in response to inert foreign material

   • Example: Suture material, gauze fibers 2

Common Causes of Granulomas

Infectious Causes:

• Mycobacterial infections (tuberculosis, atypical mycobacteria)
• Fungal infections (histoplasmosis, cryptococcosis)
• Parasitic infections
• Bacterial infections (brucellosis)

Non-Infectious Causes:

• Sarcoidosis: Characterized by non-necrotizing granulomas in multiple organs 3
• Inflammatory bowel disease: Particularly Crohn's disease 3
• Hypersensitivity pneumonitis: Features poorly formed granulomas in lung tissue 3
• Foreign body reactions: Response to inert materials like sutures or gauze 2
• Vasculitis: Granulomatosis with polyangiitis (formerly Wegener's)
• Drug reactions
• Berylliosis

Histopathological Features

The microscopic appearance of granulomas varies by etiology:

• Tuberculosis granulomas: Typically show caseous (cheese-like) necrosis with surrounding epithelioid cells and Langhans giant cells 3

• Sarcoidosis granulomas: Non-necrotizing "naked" granulomas with minimal surrounding inflammation 3

• Hypersensitivity pneumonitis granulomas: Small, poorly formed granulomas comprising loose clusters of epithelioid and multinucleated cells that tend to be most prevalent in the peribronchiolar interstitium 3

• Crohn's disease granulomas: Non-caseating epithelioid granulomas, often with one other feature of focal inflammation or architectural abnormalities 3

Pathophysiology

Granulomas represent an immune containment strategy when individual macrophages cannot destroy a persistent stimulus. Key mediators involved in granuloma formation include:

• Cytokines: IL-2, interferon-gamma, TNF-alpha
• Vitamin D metabolites: 1,25(OH)₂D₃
• Interleukins: IL-1 4

The granuloma serves to:

1. Isolate the offending agent
2. Concentrate immune cells to enhance elimination
3. Prevent dissemination of the agent
4. Minimize damage to surrounding tissue

Clinical Significance

Granulomas can be both protective and pathological:

• Protective: Contain and eliminate infectious agents
• Pathological: Cause tissue damage and organ dysfunction

The presence of granulomas narrows the differential diagnosis and guides clinical management. Their identification in tissue samples should prompt a search for the underlying cause through additional testing such as special stains for microorganisms, serological tests, or clinical correlation 5.

Important Considerations

• The site of occurrence in the body often provides clues to etiology
• Clinical context is crucial for interpretation (immunocompromised status, geographic location)
• Some granulomas may have mixed or overlapping features
• Granulomas may be incidental findings or the primary pathology

Understanding granulomas is essential for diagnosing and managing numerous conditions across multiple medical specialties, from infectious diseases to autoimmune disorders.