5/24/2018 Disclosures Granulomatous Lung Disease • I have nothing to disclose. • I may mention Tomales Farmstead Creamery Kirk D. Jones, MD UCSF Dept of Pathology kirk.jones@ucsf.edu Talk Overview Definition • Some terminology • "A granuloma is a compact (organized) • Solitary granulomas collection of mature mononuclear – Pink dead wipeout phagocytes (macrophages and/or epithelioid – Blue dead wipeout cells) which may or may not be accompanied – Dead with ghosts by accessory features such as necrosis or the • Diffuse lung disease with granulomas infiltration of other inflammatory – Sarcoidal leukocytes" – Small granulomas with some inflammation – Small granulomas with lots of inflammation Adams DO. The granulomatous inflammatory response. Am J Pathol 1976: 84: 163-192. Yale Rosen’s granuloma website: http://granuloma.homestead.com/ 1
5/24/2018 To cheese or not to cheese Solitary Pink Dead Wipeout • Caseating • Nodules with pink central necrosis (without – Term used to describe the feta-like consistency of visible structures underneath) are almost several necrotic infections and tumors always of infectious origin • Necrotizing – Mycobacteria • Tuberculosis – Term used to describe the microscopic • MAC (in COPD patients) appearance of necrosis in granulomas – Fungus • Histoplasma Don’t call it caseating as a microscopic • Coccidioides diagnosis! • Cryptococcus When infectious, the dominant necrotic nodule often shows satellite non-necrotizing (“sarcoidal”) granulomas 2
5/24/2018 Stains for Granulomas • Look for micro-organisms (Tuberculosis, Histoplasma) in • Your favorite AFB (Kinyoun, Fite, etc) the necrosis • Do stains on two blocks if you – How long to look at? What power? are concerned for infection • GMS – stains nearly all fungi. • If there is only one nodule, and you are thinking GPA, you • PAS-D – looks pretty, but misses might think again histoplasma and pneumocystis • Mucicarmine – positive in cryptococcus. • Immunohistochemical stains – Pneumocystis Ulbright TM, Katzenstein AL. Am J Surg Pathol. 1980 Feb; 4(1): 13-28. PMID: 7361992. 3
5/24/2018 Cryptococcus Coccidioides 4
5/24/2018 Some Small Fungi Fungus Shape Size (µm) Features Blastomyces Round 8-15 Broad-based budding Basophilic nucleoplasm Neutrophils Candida Round to oval 2-5 Single bud (bowling pin) Usually Gram-positive Coccidioides Spherule with 60 Variable size, can swell up Endospores 1-2 Thin rim of inflammation Eosinophils Cryptococcus Round to oval 2-20 Marked variablilty in size Mucoid capsule (mucicarmine) Retraction / shrinking Histoplasma Round 2-4 Small. Use 20x lens. Hides in the necrosis Talaromyces Oval 3-7 Divides by fission (gel-capsule) Pneumocystis Round 4-7 Froth and dot Deflated ball Small granulomas rarely Talaromyces marneffei 5
5/24/2018 • Pathologists are pretty good at classifying fungi into broad groups morphologically • Degeneration leading to swollen septa and variable yeast forms may cause difficulties • Thinking that septation means Aspergillus only may cause problems • Give a differential after favored diagnosis KJ10-114: Aspergillus fumigatus Sangoi AR, et al. Am J Clin Pathol. 2009 Mar; 131(3): 364-75. PMID: 19228642. 6
5/24/2018 Nodular amyloid with low-grade lymphoma Blue dead wipeout (aka ) • Necrosis with moderate amount of nuclear debris • Infection – Particularly in patients with low level immunosuppression – Do your stains • Granulomatosis with polyangiitis • Rheumatoid nodule 7
5/24/2018 Histologic features of GPA • Histiocyte rich mixed inflammation • No well-formed granulomas, instead some singleton hyperchromatic giant cells • Geographic necrosis • Neutrophilic micro-abscesses • Vasculitis 8
5/24/2018 GPA – Points to Consider Rheumatoid nodule • GPA usually shows multiple lesions and is • Rare to not have the history of rheumatoid frequently bilateral arthritis • GPA only rarely shows well-formed • Often biopsied to rule out infection, but “sarcoidal” granulomas often see coexisting with cutaneous rheumatoid nodules • GPA often involves sinuses and kidneys, and • Often crosses the pleura will frequently show cytoplasmic Anti- Neutrophil-Cytoplasmic Antibodies (ANCA) – usually to proteinase-3 (PR3). 9
5/24/2018 Pink and Dead with Ghosts • Occasionally, the central portion of the necrotic nodule shows coagulative or ischemic-type necrosis. • Often these are not granulomas, but rather necrotic nodules from vascular abnormalities. Pink and Dead with Ghosts • Infection – Less common in mycobacterial disease – Occasionally in fungal (Coccidioides and Histoplasma) • Venous infarct • Parasite • Lymphomatoid granulomatosis 10
5/24/2018 Granuloma versus Venous Infarct Causes of Venous Infarcts • Granuloma • Venous infarct – Central liquefactive or – Central coagulative • Sclerosing mediastinitis coagulative necrosis necrosis • Pulmonary venous ablation (for a-fib) • Pulmonary veno-occlusive disease • Tumor (rare) – Peripheral histiocytic – Peripheral granulation reaction, often with tissue-like fibrosis giant cells 11
5/24/2018 Dirofilaria (dog heartworm) • Humans are dead-end host • Worm ends up in lung vessel and shows a mixed infarct-inflammatory reaction 12
5/24/2018 Lymphomatoid granulomatosis (lymphoma) Lymphomatoid Granulomatosis Solitary Necrotizing • Pink and dead • Nodule with mixed T and B lymphocytes and – Infection histiocytes – Occasional mimics such as amyloidoma • Ranges from possibly reactive (grade 1) to • Blue and dead Epstein-Barr virus (EBV)-associated B cell – Infection lymphomas (grade 2 and 3) – Granulomatosis with polyangiitis, rheum nodule • As the number of large B-cells and EBER-positive • Pink and dead with ghosts cells increases, the more likely that this – Infection represents a lymphoma – Lymphomatoid granulomatosis • Grade 3 LYG should be diagnosed as diffuse large – Venous infarct B-cell lymphoma – Dirofilaria 13
5/24/2018 Diffuse Lung Disease with Granulomas Sarcoidal Granulomas • Non-necrotizing granulomas • Sarcoidal granulomas • Follow lymphatic routes • Small granulomas with mild inflammation – Bronchovascular bundles – Subpleural region • Small granulomas with a lot of inflammation – Interlobular septa • Sarcoidosis • Metal-related sarcoid-like reaction – Chronic beryllium disease of the lung • Drug reaction – Alpha-interferon – HAART 14
5/24/2018 Small granulomas with some H.P. - Micro chronic inflammation • “Triad of four things” • Hypersensitivity pneumonia – 1a: Interstitial chronic inflammation • Drug reaction – 1b: Bronchiolocentric inflammation – Methotrexate – 2: Poorly formed granulomas – Sirolimus (and other mTOR inhibitors) – 3: Foci of organizing pneumonia • Hot-tub lung 15
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5/24/2018 Courtesy of Rick Webb, MD Hypersensitivity Pneumonia • Cases we have observed: – Feathers: Pets, Farm animal, Duvet, Pillow, Jacket. – Molds: Work freezer, Man-Cave, Sleep number mattress, Hay, Orchid bark – Mycobacteria: Indoor spa, shower – Machine oil – ? Central valley: Almond dust? 17
5/24/2018 Everolimus toxicity Granulomatous Drug Toxicity • Best described in methotrexate and mTOR inhibitors • Look for additional features that suggest immune activation (lymphs and eos around venules) • May see airspace granulomas • Get your stains – suggest culture of BAL 18
5/24/2018 Small granulomas with a lot of Hot-tub Lung chronic inflammation • Hypersensitivity reaction to Mycobacterium • Hypersensitivity pneumonia within inhaled mist from indoor spas or hot • Drug reaction showers – Methotrexate • Unusual to see on AFB staining (usually only if – Sirolimus (and other mTOR inhibitors) necrosis present). May take several weeks to • Hot-tub lung grow out of BAL cultures • Usually treated similar to HP 19
5/24/2018 A lot of chronic inflammation with small granulomas • Granulomatous lymphocytic interstitial lung disease (GLILD) – LIP (or follicular bronchiolitis) with small non- necrotizing granulomas • Autoimmune connective tissue disease – Sjogren syndrome • LIP (or follicular bronchiolitis) with small non- necrotizing granulomas KJ11-67: GLILD V-39: GLILD – with evidence of B-cell clonality 20
5/24/2018 Prior core showed B-cell lymphoma – GLILD? 21
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