Table 3.
Key Infectious and Noninfectious Differential Diagnoses for Granulomatous Lesions within Commonly Biopsied Sites
| Granulomatous Lesion within These Sites: |
Testing and Clinical Pearls | |||||
|---|---|---|---|---|---|---|
| Lung | Lymph Node | Skin | Liver | Bone Marrow | ||
| Infectious etiologies | ||||||
| Bacteria | ||||||
| Tuberculosis* | X | X | X | X | X | Culture is diagnostic gold standard; IFN-γ release assay used for screening, and preferable to tuberculin skin testing due to anergy |
| Nontuberculous mycobacteria (MAC and M. kansasii)* | X | X | X | X | X | Culture is the gold standard |
| Aspiration pneumonia* | X | Culture | ||||
| Brucella | X | X | X | X | Serum agglutination and ELISA; livestock exposure history | |
| Tropheryma whippelii | X | X | Periodic acid–Schiff stain; immunohistochemistry testing; diarrhea, weight loss, and joint pains | |||
| Mycobacterium leprae | X | Culture is the gold standard, but can be difficult; histology; PCR | ||||
| Francisella tularensis | X | X | Serologic assay, then repeat in 2 wk; rabbit exposure | |||
| Bartonella henselae | X | X | Titers >1:256; cat exposure | |||
| Coxiella burnetii | X | X | Serology; PCR; livestock exposure | |||
| Fungi | ||||||
| Aspergillus* | X | X | X | Culture; Aspergillus IgG; histology | ||
| Histoplasma* | X | X | X | X | Culture; urine histoplasma antigen | |
| Blastomyces* | X | X | Culture; histology; blasto Ag is nonspecific | |||
| Coccidioides* | X | X | Serologic tests using EIA for IgM and IgG; then confirmatory immunodiffusion | |||
| Cryptococcus | X | X | X | X | Cryptococcal serum antigen | |
| Pneumocystis | X | Histology; screen with β-d-glucan assay | ||||
| Viruses | ||||||
| Herpes zoster | X | X | Granulomas may occasionally be found | |||
| Parasitic | ||||||
| Toxoplasma gondii | X | X | X | Toxoplasma serologic assay IgM and IgG | ||
| Schistosomiasis | X | X | X | Serology and microscopic visualization of eggs in stool or urine | ||
| Leishmaniasis | X | X | Histology and PCR for Leishmania | |||
| Echinococcosis | X | X | EIA; ultrasound imaging | |||
| Enterobius | X | X | Pinworm paddle test, then microscopy | |||
| Dirofilaria | X | Histology; eosinophilia | ||||
| Noninfectious etiologies | ||||||
| Malignancy | ||||||
| Lymphoma* | X | X | X | X | X | Clonal cell population; rarely can have elevated serum ACE |
| Sarcoid-like reaction to tumor* | X | X | X | X | X | PET useful for selecting biopsy site but not diagnostic; biopsy must be performed to diagnose |
| Lymphomatoid granulomatosis | X | Atypical clonal EBV-positive B cells; multiple pulmonary nodules with lymphocytic transmural angiitis and granulomas noted sometimes in skin | ||||
| Germ cell tumor | X | Serum α fetoprotein, human chorionic gonadotropin, lactate dehydrogenase | ||||
| Autoimmune or immune dysfunction | ||||||
| ANCA-associated vasculitides (GPA, MPA, and EGPA) | X | X | MPO or PR3 ANCA+, renal disease, necrotizing vasculitis; eosinophilic infiltration if EGPA | |||
| GLILD associated with CVID | X | X | Nonnecrotizing granulomas, LIP, and follicular bronchiolitis on lung biopsy; hypogammaglobulinemia and recurrent infections | |||
| Rheumatoid nodules | X | Multiple subpleural nodules in patient with anti-CCP antibodies, arthralgias; necrotizing granulomas | ||||
| Langerhans cell histiocytosis | X | X | X | X | X | Young smoker; multiple bizarre-shaped upper lung zone cysts and/or nodules; Langerhans cell stain CD1a and S100 positive; eosinophilic granulomas most common |
| IgG4-related disease | X | X | X | X | X | Elevated serum IgG4; elevated tissue IgG4+ plasma cell count and IgG4:IgG ratio; granulomas rare; differential diagnosis with multicentric Castleman disease |
| Inflammatory bowel disease | X | X | X | GI symptoms; granulomatous bronchiolitis | ||
| Primary biliary cholangitis | X | Cholestasis; antimitochondrial antibodies; portal based, poorly formed granulomas with bile duct destruction | ||||
| Primary sclerosing cholangitis | X | Cholestasis; P-ANCA+; ulcerative colitis associated; biliary strictures present, granulomas rare and not associated with bile duct destruction | ||||
| Autoimmune hepatitis | Abnormal liver function tests and autoantibodies (e.g., anti–smooth muscle); syncytial multinucleated giant cells are rare in adults but may be observed in children or adolescents | |||||
| Exposures | ||||||
| Hypersensitivity pneumonitis* | X | X | Organic exposure, small poorly formed interstitial granulomas in interstitium, prominent lymphocytic infiltrates, chronic inflammatory infiltrates accentuated around bronchioles | |||
| Hot tub lung syndrome (MAC exposure with hypersensitivity features) | X | X | Aerosolized water exposure, MAC cultured from sputum, lung or hot tub, large well-formed granulomas in bronchiole lumens | |||
| Pneumoconiosis (such as beryllium, titanium, aluminum, zirconium, cobalt, and others) | X | X | X | Inorganic exposure history | ||
| Drug-induced granulomatous disease (including but not limited to IFN, checkpoint inhibitor, anti-TNF, and/or biologic therapies)* | X | X | X | X | X | Usually nonnecrotizing granulomas. Drug exposure history essential. Seewww.pneumotox.com for full list |
| Foreign body granulomatosis (such as talc aspirated or injected, tattoo ink)* | X | X | X | Serum ACE elevated in many patients; particles found on biopsy; perivascular granulomas | ||
| Steatosis (lipogranulomas) | X | Central lipid vacuole; ingestion of mineral oil or hepatic steatosis | ||||
| Idiopathic | ||||||
| Sarcoidosis | X | X | X | X | X | Multisystemic; well formed, usually nonnecrotic granulomas |
| Necrotizing sarcoid granulomatosis | X | X | Granulomatous pneumonitis with necrosis and vasculitis; multiple necrotic lung nodules | |||
| Histiocytic necrotizing lymphadenitis (Kikuchi’s disease) | X | Cervical lymphadenopathy and low-grade fever. Granulomas are not found, although necrotic areas with histiocytes are present | ||||
| GLUS | X | X | X | X | Lacks progressive lung parenchymal disease, elevated serum calcium, 1,25-dihydroxyvitamin D, and ACE | |
| Bronchocentric granulomatosis | X | Associated with asthma and Aspergillus infection in 50%. Necrotizing granulomas exclusively in bronchi and bronchioles | ||||
Definition of abbreviations: ACE = angiotensin-converting enzyme; Ag = antigen; EIA = enzyme-linked immunoassays; ANCA = antineutrophil cytoplasmic antibody; CCP = cyclic citrullinated peptide; CVID = common variable immune deficiency; EBV = Epstein-Barr virus; EGPA = eosinophilic GPA; GI = gastrointestinal; GLILD = granulomatous–lymphocytic interstitial lung disease; GLUS = granulomatous lesions of unknown significance syndrome; GPA = granulomatosis with polyangiitis; LIP = lymphocytic interstitial pneumonia; MAC = Mycobacterium avium complex; M. kansasii = Mycobacterium kansasii; MPA = microscopic polyangiitis; MPO = myeloperoxidase; p-ANCA = perinuclear ANCA; PR3 = PR3-ANCA; PET = positron emission tomography; TNF = tumor necrosis factor.
*
More commonly found alternative diagnoses for granulomatous disease in U.S. populations. The differential diagnosis should be prioritized on the basis of the individual’s clinical history and presentation.