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Granuloma and Granulomatous Infection of the Lung

DEFINITION AND ETYMOLOGY

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CLASSIFICATION OF GRANULOMAS

A. By Mechanism

B. By Necrosis

C. By Architecture

• Hard (proliferative) granuloma — well-circumscribed, compact epithelioid cells, lymphocyte cuff, few or no AFB
• Soft (exudative) granuloma — loose collection, neutrophils, macrophages, likely to harbour AFB

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HISTOLOGICAL STRUCTURE OF A GRANULOMA

• Caseous necrosis (in TB) — structureless, acellular, eosinophilic material representing permanent tissue destruction
• Low O₂ tension and low pH within the caseum inhibit mycobacterial replication

• Activated macrophages with abundant pale eosinophilic cytoplasm
• Indistinct cell margins — form a continuous sheet resembling stratified squamous epithelium → hence "epithelioid"
• Express MHC class II molecules; function as antigen-presenting cells

• Langhans giant cell: nuclei arranged along the periphery of the cell, forming a horseshoe/rosette — characteristic of TB
• Foreign body giant cell: nuclei irregularly scattered throughout the cytoplasm

• Predominantly CD4+ T cells (Th1) in the centre; CD8+ T cells at periphery
• B cells may also be present

• Surrounding fibrosis (more marked in hard granulomas)
• Reticulin fibres — preserved in sarcoidosis (useful distinguishing feature); lost or reduced in TB

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PATHOGENESIS OF GRANULOMA FORMATION

1. Inhaled antigen (e.g., M. tuberculosis) is phagocytosed by alveolar macrophages via pattern recognition receptors (TLR2, TLR4, TLR9)
2. Macrophage-mycobacterium interaction: Mycobacteria prevent phagolysosome fusion, surviving intracellularly. Infected macrophages present antigen via MHC class II molecules to naïve CD4+ T cells in draining lymph nodes
3. Th1 polarisation: In the absence of IL-4, IL-12 released by macrophages drives differentiation of CD4+ T cells toward the Th1 phenotype. IFN-γ further amplifies IL-12 production — a positive feedback loop
4. Chemokine-mediated recruitment: Activated Th1 cells produce chemokines (MCP-1, MIP-1α, RANTES, IP-10) that recruit circulating monocytes and T cells to the lung parenchyma
5. Macrophage activation: IFN-γ and TNF-α activate recruited macrophages → production of reactive oxygen intermediates (H₂O₂) and reactive nitrogen intermediates (NO via iNOS2) → mycobactericidal activity
6. Granuloma assembly: Activated macrophages differentiate into epithelioid histiocytes; some fuse to form giant cells. CD4+ T cells predominate centrally; CD8+ cells at the periphery
7. Outcome: In immunocompetent hosts → containment, fibrocaseous healing, calcification. In immunocompromised → liquefaction, cavitation, dissemination

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CAUSES OF GRANULOMATOUS LUNG DISEASE

Infectious

Non-infectious

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PULMONARY TUBERCULOSIS — GRANULOMATOUS PATHOLOGY IN DETAIL

A. Exudative (Soft) Granuloma

• Less well-demarcated
• Neutrophils, lymphocytes, macrophages, epithelioid cells in loose arrangement
• Little fibroblastic proliferation
• More likely to harbour AFB
• Seen more in primary disease, serous surfaces, immunosuppressed

B. Proliferative (Hard) Granuloma

• Well-circumscribed with a dense lymphocyte cuff
• Well-aggregated epithelioid histiocytes
• Prominent surrounding fibrosis
• Langhans giant cells more common
• AFB less readily demonstrated

C. Specific Pulmonary Lesions

• Subpleural/lower lobe caseating granuloma at site of entry
• Draining lymph node granulomas + lymphangitis = Ghon complex

1. Nodular lesions (Tuberculomas) — well-defined, <1 cm or >1 cm; central caseation surrounded by concentric fibrosis; rim calcification in healing
2. Fibrocaseous disease — extensive caseation, fibrosis, multiple epithelioid palisades and Langhans cells; typically upper lobe/apical posterior segments
3. Cavitary disease — liquefaction of caseous material + bronchial communication; cavity wall lined by TB granulation tissue; fibrosis; Rasmussen aneurysm from arterial wall erosion → fatal haemoptysis; AFB demonstrable in 88% of cavitary vs 77% non-cavitary lesions
4. Miliary TB — haematogenous dissemination; symmetrical bilateral millet-seed nodules; two types:
   • Hard (cellular) tubercles: compact epithelioid cells + Langhans cells, minimal caseation
   • Soft tubercles: loose granulomas, prominent caseation, many AFB
5. TB bronchopneumonia — acute dissemination via airways; neutrophilic reaction may mimic bacterial pneumonia; AFB stain essential

• Fibrosis → cicatrisation (fibrocaseous → fibrous scar)
• Calcification (weeks to months)
• Ossification (years)
• Dormant bacilli may persist in calcified foci for decades

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DIFFERENCES: TB vs SARCOIDOSIS GRANULOMAS

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GRANULOMATOUS INFECTION: HISTOLOGICAL DIAGNOSIS

Staining Methods for AFB in Tissue

Differential Diagnosis of Pulmonary Granulomas

• Fungal infections (PAS, GMS stains for fungal organisms)
• Sarcoidosis (exclusion diagnosis; noncaseating, naked granulomas)
• Hypersensitivity pneumonitis (loose, ill-formed, bronchiolocentric granulomas + organizing pneumonia pattern)
• GPA (necrotising granulomatous vasculitis; C-ANCA/PR3-ANCA positive)
• Chronic beryllium disease (identical to sarcoidosis; beryllium lymphocyte proliferation test required)
• Foreign body granuloma (polarisable material on polarised light)

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GRANULOMA IN IMMUNOCOMPROMISED HOSTS

• Granulomas become poorly formed and eventually absent ("non-reactive TB")
• Epithelioid cells not well-developed; lymphocyte collar may be absent
• Giant cells rare; karyorrhexis present
• Multibacillary histiocytosis (macrophages stuffed with AFB, minimal inflammation) — characteristic of MAC in AIDS
• Middle and lower zone involvement rather than the classical apical disease
• Cavitation less frequent; sputum smear may be negative
• Antiretroviral therapy restores CMI → more typical granulomatous response returns

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RADIOLOGICAL CORRELATION

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SUMMARY TABLE: CAUSES OF GRANULOMATOUS LUNG INFECTION

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KEY POINTS FOR EXAM

1. Definition: Focal compact collection of mononuclear inflammatory cells, predominantly activated macrophages (epithelioid histiocytes), ± necrosis, ± giant cells, ± lymphocytic cuff
2. TB is the classical example of granulomatous inflammation — caseating, confluent granulomas
3. Langhans giant cell (peripheral nuclear rosette) = TB; Foreign body giant cell (random nuclei) = foreign material
4. Reticulin preserved in sarcoidosis; lost in TB — useful distinguishing histological feature
5. Caseation implies active disease but mycobacteria can survive dormant in calcified foci
6. Cavitation = liquefaction + bronchial communication; highest bacillary load; most infectious stage
7. Th1 axis (IFN-γ, TNF-α, IL-12) is essential for granuloma integrity; defects → disseminated infection
8. TNF-α blockade (biologics for RA) → reactivation TB via granuloma dissolution
9. Non-reactive TB in AIDS: absent granulomas, sheets of AFB-laden macrophages
10. Modified ZN stain remains the workhorse for AFB in tissue (30–40% positivity in histology)

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