top of page
eduo
visual
Hematology & Immunology
Granulomatous Inflammation: Caseating vs Noncaseating, Causes (TB, Sarcoidosis, Berylliosis, Crohn Disease, Cat-Scratch Disease, Histoplasmosis, Foreign Body), Histologic Features
Core Principle of Granulomatous Inflammation
Granulomas are organized collections of activated macrophages (epithelioid cells) that form when the immune system cannot eliminate a persistent antigen.
This represents a type IV hypersensitivity reaction where T cells activate macrophages via IFN-γ, but the inciting agent resists degradation.
The key distinction is between caseating (central necrosis with cheese-like appearance) and noncaseating (no central necrosis) granulomas.
Board pearl: Granulomas = chronic inflammation with activated macrophages attempting to wall off what they cannot destroy.
Cellular Architecture of Granulomas
Central core: epithelioid macrophages (activated macrophages with abundant pink cytoplasm resembling epithelial cells).
Peripheral rim: lymphocytes (predominantly CD4+ T cells) providing ongoing activation signals.
Multinucleated giant cells: formed by fusion of epithelioid macrophages, including Langhans type (horseshoe nuclei) and foreign body type (scattered nuclei).
Fibroblasts and collagen may surround older granulomas.
Board distinction: Epithelioid cells are the hallmark — without them, it's not a granuloma.
Caseating Granulomas: The TB Paradigm
Caseation = central necrosis with acellular, cheese-like debris visible on H&E staining.
Tuberculosis is the prototypical cause — Mycobacterium tuberculosis lipids (cord factor) induce this specific necrosis pattern.
Other causes: certain fungal infections (histoplasmosis, coccidioidomycosis), some atypical mycobacteria.
The necrotic center appears pink and amorphous on H&E, lacking cellular detail.
Board pearl: Caseating granuloma in lung = TB until proven otherwise; always stain for acid-fast bacilli.
Noncaseating Granulomas: The Sarcoidosis Model
Noncaseating = intact epithelioid cells throughout, no central necrosis.
Sarcoidosis is the classic cause — "naked" granulomas with minimal surrounding lymphocytes.
Other causes: Crohn disease, berylliosis, foreign body reactions, cat-scratch disease (Bartonella), some fungal infections.
These granulomas maintain cellular architecture throughout their structure.
Board clue: Bilateral hilar lymphadenopathy + noncaseating granulomas + elevated ACE = sarcoidosis.
Tuberculosis: Primary and Secondary Patterns
Primary TB: initial infection → Ghon complex (lung lesion + hilar lymph node), usually middle/lower lobes.
Secondary TB: reactivation → apical cavitary lesions with caseating granulomas, hemoptysis, night sweats.
Miliary TB: hematogenous spread → multiple small granulomas throughout organs.
Staining: Ziehl-Neelsen (acid-fast) or auramine-rhodamine (fluorescent) reveals mycobacteria.
Board pearl: Apical cavitary lesion in immigrant/immunocompromised patient = reactivation TB.
Sarcoidosis: Systemic Granulomatous Disease
Unknown etiology causing noncaseating granulomas in multiple organs, most commonly lungs and lymph nodes.
Classic presentation: African American woman with bilateral hilar lymphadenopathy, erythema nodosum, arthritis (Löfgren syndrome).
Elevated ACE (from epithelioid cells), hypercalcemia (1α-hydroxylase in macrophages → calcitriol).
Other manifestations: uveitis, facial nerve palsy, restrictive cardiomyopathy, hepatic granulomas.
Board distinction: Sarcoidosis granulomas contain Schaumann bodies (laminated calcium) and asteroid bodies (stellate inclusions).
Berylliosis: Occupational Granulomatous Disease
Chronic beryllium exposure → sensitization → noncaseating granulomas identical to sarcoidosis.
Occupational history is key: aerospace, electronics, nuclear weapons manufacturing.
Beryllium lymphocyte proliferation test (BeLPT) distinguishes from sarcoidosis.
Progressive dyspnea, restrictive lung disease, hilar lymphadenopathy.
Board pearl: Sarcoidosis-like presentation + occupational exposure = consider berylliosis.
Crohn Disease: Intestinal Granulomas
Transmural inflammation with noncaseating granulomas in 25-50% of cases — helps distinguish from ulcerative colitis.
Skip lesions, cobblestoning, creeping fat, fistulas, strictures.
Granulomas found in bowel wall, mesenteric lymph nodes.
Terminal ileum most commonly affected, but can involve mouth to anus.
Board clue: Young adult with RLQ pain, diarrhea, and intestinal granulomas = Crohn disease.
Cat-Scratch Disease: Bartonella henselae
Tender regional lymphadenopathy following cat scratch/bite, especially in children.
Stellate (star-shaped) necrotizing granulomas with central microabscesses — unique pattern.
Warthin-Starry silver stain reveals small curved bacilli.
Self-limited in immunocompetent hosts; can cause bacillary angiomatosis in HIV.
Board pearl: Child with tender axillary node after kitten scratch + stellate granulomas = Bartonella.
Histoplasmosis: Dimorphic Fungal Granulomas
Histoplasma capsulatum → intracellular yeast in macrophages → granuloma formation.
Mississippi/Ohio River valleys, bat/bird droppings, cave exploration.
Can be caseating (especially in immunocompetent) or noncaseating.
Pulmonary nodules, mediastinal lymphadenopathy, hepatosplenomegaly in disseminated disease.
Board distinction: Small yeast with narrow-based budding inside macrophages on methenamine silver stain.
Foreign Body Granulomas
Response to indigestible exogenous (splinters, sutures, talc) or endogenous (keratin, cholesterol) material.
Foreign body giant cells with scattered nuclei attempt to engulf material.
Polarizable material visible under polarized light microscopy.
Common sites: surgical sites, injection sites, ruptured cysts.
Board clue: Granuloma at surgical site with refractile material under polarized light = suture granuloma.
Giant Cell Types and Associations
Langhans giant cells: peripheral horseshoe arrangement of nuclei — seen in TB, sarcoidosis.
Foreign body giant cells: haphazardly arranged nuclei — seen around foreign material.
Touton giant cells: ring of nuclei with foamy cytoplasm — seen in xanthomas, not typical granulomas.
Warthin-Finkeldey giant cells: multiple nuclei with inclusion bodies — seen in measles.
Board pearl: Nuclear arrangement in giant cells can suggest etiology but is not pathognomonic.
Special Stains for Granuloma Workup
Ziehl-Neelsen/AFB: mycobacteria appear as red/pink rods.
Methenamine silver (GMS): fungi appear black against green background.
PAS: fungi and some bacteria stain magenta.
Warthin-Starry: Bartonella appears as small dark rods.
Polarized light: reveals birefringent foreign material.
Board strategy: Granuloma + special stain finding = specific diagnosis.
Immunologic Basis: Th1 Response
Antigen presentation → Th1 cell activation → IFN-γ release → macrophage activation.
TNF-α from macrophages maintains granuloma structure.
IL-12 from dendritic cells drives Th1 differentiation.
Defects in this pathway (IFN-γ receptor mutations) → disseminated mycobacterial infections.
Board pearl: Anti-TNF therapy can reactivate latent TB by disrupting granuloma integrity.
Granulomatous Disease in Immunodeficiency
CGD (chronic granulomatous disease): defective NADPH oxidase → catalase-positive organism infections → granulomas.
HIV/AIDS: impaired granuloma formation → diffuse disease rather than organized granulomas.
Anti-TNF therapy: granuloma breakdown → TB reactivation.
IFN-γ pathway defects: susceptibility to mycobacterial infections.
Board distinction: Poor granuloma formation in AIDS explains atypical TB presentations.
Hypercalcemia in Granulomatous Disease
Activated macrophages express 1α-hydroxylase → convert 25-OH vitamin D to active 1,25-OH vitamin D.
Not subject to normal PTH/calcium feedback → unregulated calcitriol production.
Most common in sarcoidosis, also seen in TB, histoplasmosis, berylliosis.
Presents with hypercalcemia, hypercalciuria, suppressed PTH.
Board pearl: Hypercalcemia + low PTH + granulomatous disease = extrarenal calcitriol production.
Granulomatous Hepatitis
Sarcoidosis: most common cause in developed countries, typically asymptomatic with elevated alkaline phosphatase.
TB: more common in endemic areas, may have concurrent pulmonary disease.
Drug-induced: allopurinol, sulfonamides, phenytoin.
Primary biliary cholangitis: granulomas around damaged bile ducts.
Board clue: Isolated elevated alkaline phosphatase + hepatic granulomas = consider sarcoidosis.
Diagnostic Approach to Granulomas
History: exposures (travel, occupation, animals), medications, systemic symptoms.
Location: lung (TB, sarcoidosis, fungi), skin (foreign body, infections), liver (sarcoidosis, TB, PBC).
Morphology: caseating (TB, fungi) vs noncaseating (sarcoidosis, Crohn).
Special stains: AFB, GMS, cultures.
Serology: ACE, Histoplasma antigen, Bartonella titers.
Board approach: Location + morphology + clinical context → focused differential.
Board Question Stem Patterns
Apical lung cavity + caseating granulomas + acid-fast bacilli → tuberculosis.
Bilateral hilar adenopathy + noncaseating granulomas + black woman → sarcoidosis.
Terminal ileum inflammation + noncaseating granulomas + skip lesions → Crohn disease.
Tender lymph node + cat exposure + stellate granulomas → cat-scratch disease.
Lung nodules + Ohio River valley + yeast in macrophages → histoplasmosis.
Aerospace worker + sarcoid-like illness + noncaseating granulomas → berylliosis.
Surgical site nodule + polarizable material → foreign body granuloma.
One-Line Recap
Granulomas represent organized macrophage collections attempting to contain persistent antigens, divided into caseating (TB, fungi) with central necrosis and noncaseating (sarcoidosis, Crohn, berylliosis) without necrosis, diagnosed through pattern recognition combining morphology, location, special stains, and clinical context.
bottom of page