Granulomatous Lung Disease I have nothing to disclose. I may - - PowerPoint PPT Presentation

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Kirk D. Jones, MD UCSF Dept of Pathology kirk.jones@ucsf.edu

Granulomatous Lung Disease

Disclosures

• I have nothing to disclose.
• I may mention Tomales Farmstead Creamery

Talk Overview

• Some terminology
• Solitary granulomas

– Pink dead wipeout – Blue dead wipeout – Dead with ghosts

• Diffuse lung disease with granulomas

– Sarcoidal – Small granulomas with some inflammation – Small granulomas with lots of inflammation

Definition

• "A granuloma is a compact (organized)

collection of mature mononuclear phagocytes (macrophages and/or epithelioid cells) which may or may not be accompanied by accessory features such as necrosis or the infiltration of other inflammatory leukocytes"

Adams DO. The granulomatous inflammatory response. Am J Pathol 1976: 84: 163-192. Yale Rosen’s granuloma website: http://granuloma.homestead.com/

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To cheese or not to cheese

• Caseating

– Term used to describe the feta-like consistency of several necrotic infections and tumors

• Necrotizing

– Term used to describe the microscopic appearance of necrosis in granulomas

Don’t call it caseating as a microscopic diagnosis!

Solitary Pink Dead Wipeout

• Nodules with pink central necrosis (without

visible structures underneath) are almost always of infectious origin

– Mycobacteria

• Tuberculosis
• MAC (in COPD patients)

– Fungus

• Histoplasma
• Coccidioides
• Cryptococcus

When infectious, the dominant necrotic nodule often shows satellite non-necrotizing (“sarcoidal”) granulomas

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• Look for micro-organisms

(Tuberculosis, Histoplasma) in the necrosis

• Do stains on two blocks if you

are concerned for infection

• If there is only one nodule, and

you are thinking GPA, you might think again

Ulbright TM, Katzenstein AL. Am J Surg Pathol. 1980 Feb; 4(1): 13-28. PMID: 7361992.

Stains for Granulomas

• Your favorite AFB (Kinyoun, Fite, etc)

– How long to look at? What power?

• GMS – stains nearly all fungi.
• PAS-D – looks pretty, but misses

histoplasma and pneumocystis

• Mucicarmine – positive in cryptococcus.
• Immunohistochemical stains

– Pneumocystis

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Cryptococcus Coccidioides

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Talaromyces marneffei

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 Endospores 60 1-2 Variable size, can swell up 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 Deflated ball 4-7 Froth and dot Small granulomas rarely

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KJ10-114: Aspergillus fumigatus

Sangoi AR, et al. Am J Clin Pathol. 2009 Mar; 131(3): 364-75. PMID: 19228642.

• 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

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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

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Histologic features of GPA

• Histiocyte rich mixed inflammation
• No well-formed granulomas, instead some

singleton hyperchromatic giant cells

• Geographic necrosis
• Neutrophilic micro-abscesses
• Vasculitis

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GPA – Points to Consider

• GPA usually shows multiple lesions and is

frequently bilateral

• GPA only rarely shows well-formed

“sarcoidal” granulomas

• GPA often involves sinuses and kidneys, and

will frequently show cytoplasmic Anti- Neutrophil-Cytoplasmic Antibodies (ANCA) – usually to proteinase-3 (PR3).

Rheumatoid nodule

• Rare to not have the history of rheumatoid

arthritis

• Often biopsied to rule out infection, but
• ften see coexisting with cutaneous

rheumatoid nodules

• Often crosses the pleura

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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

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Granuloma versus Venous Infarct

• Granuloma

– Central liquefactive or coagulative necrosis – Peripheral histiocytic reaction, often with giant cells

• Venous infarct

– Central coagulative necrosis – Peripheral granulation tissue-like fibrosis

Causes of Venous Infarcts

• Sclerosing mediastinitis
• Pulmonary venous ablation (for a-fib)
• Pulmonary veno-occlusive disease
• Tumor (rare)

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Dirofilaria (dog heartworm)

• Humans are dead-end host
• Worm ends up in lung vessel and shows a

mixed infarct-inflammatory reaction

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Lymphomatoid granulomatosis (lymphoma)

Lymphomatoid Granulomatosis

• Nodule with mixed T and B lymphocytes and

histiocytes

• Ranges from possibly reactive (grade 1) to

Epstein-Barr virus (EBV)-associated B cell lymphomas (grade 2 and 3)

• As the number of large B-cells and EBER-positive

cells increases, the more likely that this represents a lymphoma

• Grade 3 LYG should be diagnosed as diffuse large

B-cell lymphoma

Solitary Necrotizing

• Pink and dead

– Infection – Occasional mimics such as amyloidoma

• Blue and dead

– Infection – Granulomatosis with polyangiitis, rheum nodule

• Pink and dead with ghosts

– Infection – Lymphomatoid granulomatosis – Venous infarct – Dirofilaria

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Diffuse Lung Disease with Granulomas

• Sarcoidal granulomas
• Small granulomas with mild inflammation
• Small granulomas with a lot of inflammation

Sarcoidal Granulomas

• Non-necrotizing granulomas
• Follow lymphatic routes

– Bronchovascular bundles – Subpleural region – Interlobular septa

• Sarcoidosis
• Metal-related sarcoid-like reaction

– Chronic beryllium disease of the lung

• Drug reaction

– Alpha-interferon – HAART

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Small granulomas with some chronic inflammation

• Hypersensitivity pneumonia
• Drug reaction

– Methotrexate – Sirolimus (and other mTOR inhibitors)

• Hot-tub lung

H.P. - Micro

• “Triad of four things”

– 1a: Interstitial chronic inflammation – 1b: Bronchiolocentric inflammation – 2: Poorly formed granulomas – 3: Foci of organizing pneumonia

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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?

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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

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Hot-tub Lung

• Hypersensitivity reaction to Mycobacterium

within inhaled mist from indoor spas or hot showers

• Unusual to see on AFB staining (usually only if

necrosis present). May take several weeks to grow out of BAL cultures

• Usually treated similar to HP

Small granulomas with a lot of chronic inflammation

• Hypersensitivity pneumonia
• Drug reaction

– Methotrexate – Sirolimus (and other mTOR inhibitors)

• Hot-tub lung

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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

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Prior core showed B-cell lymphoma – GLILD?

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Lymphocytic interstitial pneumonia (LIP)

• r

Follicular Bronchiolitis with granulomas

• Seeing dense inflammation with small granulomas

should generate the differential of:

– GLILD

• Hypogammaglobulinemia/Common variable immunodeficiency

– Autoimmune connective tissue disease

• Sjogren syndrome

– Lymphoma – Less likely the entities covered for mild inflammation such as HP

Distribution Appearance Associated inflammation Hypersensitivity pneumonia Random Bronchiolocentric Poorly formed Diffuse mild to moderate +/- OP Hot-tub Lung Random Bronchiolocentric Loosely formed with lymphocytes Air-space Patchy mild interstitial chronic inflammation Often with OP Drug reaction Random Poorly formed Occasional air-space Diffuse mild to moderate +/- OP GLILD Random Rare Poorly formed Dense lymphoid inflammation Rule out lymphoma Sjogren syndrome Random Rare Poorly formed Dense lymphoid (LIP) Follicular bronchiolitis Sarcoidosis “Lymphangitic” Well-formed Lymphocyte-poor Sparse It is important to remember that there are tremendous overlaps in the diffuse granulomatous diseases. This should help generate a differential diagnosis with a hierarchy of possibilities.

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Aspiration Venous injection of crushed tablets

Take home message

• Solitary granulomas are often infectious, but

it is important to rule out mimics by evaluating the appearance closely

• Histologic features of diffuse interstitial lung

disease with granulomas allow for sub- classification based on distribution and character of granulomas, and presence of associated inflammation