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PA3.3 | Chronic & Granulomatous Inflammation — SDL Guide (Part 3)

Granuloma Formation Mechanism

Four-panel medical diagram showing how persistent antigen drives macrophage-T cell cytokine signaling, granuloma architecture, and anti-TNF-related TB reactivation. — **Panel A:** Poorly digestible antigen, macrophage phagocytosis, MHC II antigen presentation, CD4+ T cell, IL-12, Th1 polarisation, IFN-gamma, activated macrophage, epithelioid histiocyte, multinucleated giant cell, peripheral lymphocytes, fibroblast collagen rim. **Panel B:** Central persistent antigen or caseous necrotic center, epithelioid histiocytes, Langhans-type multinucleated giant cell, peripheral lymphocyte cuff, outer fibrous collagen rim. **Panel C:** Macrophage, IL-12, CD4+ Th1 cell, IFN-gamma, macrophage activation, TNF-alpha, granuloma maintenance loop. **Panel D:** Intact latent TB granuloma, TNF-alpha blockade, anti-TNF biologic infliximab or adalimumab, disrupted granuloma, released dormant bacilli, latent TB reactivation.

Granulomas form when the immune system cannot eliminate an antigen — instead, it attempts to contain or wall it off.

Step-by-step sequence:

Macrophages engulf the poorly digestible agent (mycobacterium, fungal cell wall, foreign particle).
Macrophages present antigen to CD4+ T cells via MHC II.
Th1 polarisation: IL-12 (from macrophages) + antigen → Th1 CD4+ cells → secrete IFN-γ.
IFN-γ activates macrophages → epithelioid transformation.
Activated macrophages secrete TNF-α — critical for granuloma maintenance (TNF-α blockade with anti-TNF biologics reactivates latent TB by disrupting this step).
Epithelioid histiocytes fuse → multinucleate giant cells.
Lymphocytes accumulate at periphery, sustaining IFN-γ production.
Over weeks–months, fibroblasts deposit collagen → fibrous rim (walling-off).

Clinical implication: Patients on anti-TNF therapy (infliximab, adalimumab for rheumatoid arthritis/Crohn) must be screened for latent TB before treatment — TNF-α blockade can dissolve pre-existing granulomas and reactivate dormant bacilli.

Caseating vs Non-Caseating Granulomas

The presence or absence of central necrosis is the single most important distinguishing feature at histology.

Caseating (necrotising) granulomas:
• Central zone of coagulative necrosis with a cheese-like (caseous) gross appearance — pale, crumbling, dry
• Microscopically: amorphous eosinophilic debris, no surviving cell outlines (unlike liquefactive necrosis)
• Caused by: TB (most common), histoplasmosis, coccidioidomycosis, blastomycosis, occasionally cat-scratch disease
• Mechanism: Th1-mediated delayed hypersensitivity (Type IV) + direct cytotoxic killing → necrosis of macrophages and adjacent tissue

Non-caseating (non-necrotising) granulomas:
• No central necrosis — epithelioid histiocytes fill the granuloma to its centre
• Histologically "cleaner" — well-circumscribed aggregate with no debris
• Caused by: sarcoidosis (tight, "naked" granulomas), Crohn disease, foreign-body reactions, leprosy (tuberculoid type), berylliosis

Practical rule: Find acid-fast bacilli (Ziehl-Neelsen stain) or fungal elements (Grocott methenamine silver) in any caseating granuloma before labelling it sarcoidosis — sarcoidosis is a diagnosis of exclusion.

A split medical diagram compares caseating granulomas with central necrosis against non-caseating granulomas without necrosis and shows the diagnostic rule to exclude infection before diagnosing sarcoidosis. — **Panel A:** Caseating granuloma with central amorphous eosinophilic necrosis, caseous debris, epithelioid histiocytes, Langhans-type giant cells, lymphocyte rim, Ziehl-Neelsen acid-fast bacilli, and Grocott methenamine silver fungal elements.. **Panel B:** Non-caseating sarcoid-type naked granuloma with epithelioid histiocytes filling the centre, no central necrosis, no caseous debris, and sparse peripheral lymphocytes.. **Panel C:** Diagnostic flow showing central necrosis as the key histologic discriminator and prompting exclusion of TB or fungal infection before diagnosing sarcoidosis..

SELF-CHECK

A 28-year-old woman has bilateral hilar lymphadenopathy and erythema nodosum. Lymph node biopsy shows tight clusters of epithelioid histiocytes WITHOUT central necrosis. AFB and fungal stains are negative. Which pattern best describes this granuloma?

A. Caseating granuloma — consistent with active TB

B. Non-caseating granuloma — consistent with sarcoidosis

C. Foreign-body granuloma — likely suture reaction

D. Suppurative granuloma — consistent with cat-scratch disease

Reveal Answer

Answer: B. Non-caseating granuloma — consistent with sarcoidosis

Tight non-caseating granulomas in bilateral hilar nodes with negative AFB/fungal stains in a young woman are the hallmark of sarcoidosis. TB (caseating) and cat-scratch disease (suppurative centre, Bartonella) have distinct patterns. Foreign-body granulomas require identifiable foreign material.

Classic Causes of Granulomatous Inflammation

Infographic comparing tuberculosis, tuberculoid leprosy, fungal infection, sarcoidosis, and foreign body reaction as classic causes of granulomatous inflammation. — **Panel A:** Core granuloma patterns showing caseating granuloma, non-caseating granuloma, central caseous necrosis, epithelioid macrophages, Langhans giant cell, and lymphocyte rim. **Panel B:** Mycobacterium tuberculosis with caseating granuloma, acid-fast bacilli on Ziehl-Neelsen stain, and Langhans giant cells. **Panel C:** Tuberculoid leprosy with non-caseating granulomas tracking peripheral nerves and AFB in nerve or skin tissue. **Panel D:** Fungal granulomatous inflammation with often-caseating necrosis, GMS/PAS-positive yeast forms, and geography clues for Histoplasma, Coccidioides, and Blastomyces. **Panel E:** Sarcoidosis with naked tight non-caseating granulomas, Schaumann bodies, asteroid bodies, and negative special stains. **Panel F:** Foreign body granuloma with foreign body giant cells and birefringent material under polarized light.

A structured differential for granulomas is a core clinical skill. Learn the distinguishing histological or microbiological clue for each:

Cause	Caseating?	Distinguishing feature
Mycobacterium tuberculosis	Yes	AFB on ZN stain; Langhans giant cells
M. leprae (tuberculoid leprosy)	No	AFB in nerves/skin; granulomas track nerves
Fungal (Histoplasma, Coccidioides, Blastomyces)	Yes (often)	GMS/PAS stain — yeast forms; geography (Ohio valley, SW USA)
Sarcoidosis	No	Naked tight granulomas; Schaumann bodies, asteroid bodies; all stains negative
Foreign body	No	Birefringent material under polarised light; FBGCs
Crohn disease	No	Transmural inflammation; non-caseating micro-granulomas
Syphilis (T. pallidum)	No (gumma = coagulative)	Gumma (rubbery, not caseous); plasma cell rich; VDRL/TPHA positive
Cat-scratch disease (Bartonella)	No	Suppurative (stellate) centre; Warthin-Starry silver stain

Memory framework: TB-FLOSS-C — TB, fungal, Leprosy, sarcOidosiS, Syphilis, Crohn, cat-scratch.

In India, prioritise TB and leprosy in your differential before considering sarcoidosis.

CLINICAL PEARL

The anti-TNF trap in clinical practice:

Before starting any biologic that blocks TNF-α (infliximab, adalimumab, etanercept) — used in rheumatoid arthritis, Crohn disease, psoriasis, ankylosing spondylitis — you must screen the patient for latent tuberculosis (tuberculin skin test or IGRA + chest X-ray).

Why? TNF-α is essential for granuloma integrity. Its blockade causes "granuloma dissolution" — previously walled-off dormant mycobacteria are released into the circulation. The resulting reactivation TB can be miliary (disseminated), rapidly fatal, and is notoriously difficult to diagnose in immunosuppressed patients.

In high-burden countries like India, this screening is non-negotiable before every biologic prescription.