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Kirk D. Jones, MDUCSF Dept of Pathology

kirk.jones@ucsf.edu

Pathology Approachto ILD Disclosure Statement

Relevant financial relationships with a commercial interest:Boeringer Ingleheim, speaker

I don’t need you.

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Overview

• Normal lung

• Patterns of fibrosis

• A little on granulomas

Normal Lung

• The lung is divided into numerous lobular units that have a characteristic appearance.

• Arteries run with airways.

• Veins present in interlobular septa.

• Lymphatics in bronchovascular bundles, interlobular septa, and pleura.

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Thinking about Fibrosis

• Usually in patients with chronic or insidious disease.

• Often observed on CT scan as reticulation (possibly with traction bronchiectasis or honeycombing) or nodules (when bronchiolocentric)

Pattern of Fibrosis• The distribution of the fibrosis will often correla te with the

nature of the injury.

• Bronchiolocentric fibrosis – tends to occur in disea ses with inhalation injury (HP, RB, fume) or bronchiola r inflammation (CTD)

• NSIP – tends to occur in diseases with diffuse alveo lar inflammation (autoimmune CTD, drug reaction, HP)

• UIP – odd peripheral distribution pattern. Possibly related to aberrent sensecence with most distal cells eithe r more predisposed to stretch injury, or least likely to b e replenished.

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Bronchiolocentric Fibrosis

• Look for lace-like central regions (fireworks) of peribronchiolar metaplasia

• Think about inhaled diseases (HP, RB, fume inhalation injury) and diseases with small airway inflammation (aCTD)

Nonspecific Interstitial Pneumonia (NSIP)

• Diffuse alveolar septal thickening by either inflammation (cellular NSIP) or fibrosis (NSIP-fibrosis)

• Can be variable, but should show fibrous thickening of the alveolar septa in peribronchiolar, subpleural, and midzones of the lobule.

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Dusty Cobweb Fibrosis

Term by Kevin Leslie

NSIP Pattern

• Look for variable but diffuse alveolar septal thickening (dusty cobweb) by fibrosis or inflammation

• Look for additional clues to help decide the differential (lymphoid aggregates, granulomas, pleuritis, vessel thickening).

If my pathologist tells me the biopsy shows NSIP,

then my job has only just begun.

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Clues for DAD

• A compatible clinical history

• Diffuse alveolar septal thickening or effacement by collapse, edema, and alveolar filling

• Hyaline membranes

• Distal airway squamous metaplasia

UIP Pattern• Fibrosis beginning at the periphery of the lobule

• Temporal and spatial heterogeneity

• Temporal (“HORN”)

• Honeycombing, old (dense collagen) fibrosis, recent (fibroblast foci) fibrosis, and normal

• Spatial – worse subpleural, paraseptal, and basilar

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The “Tip Test”

• Since UIP shows peripheral lobular accentuation of fibrosis, the very tip of the surgical biopsy is often obliterated by fibrosis (often with overlying fatty metaplasia of the pleura)

• NSIP tends to show normal alveolar architecture (with thickened septa) at the tip of the biopsy.

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UIP Pattern

• When there is pure temporal heterogeneity, the diagnosis is almost certain

• Use the “Tip Test”

• Rare cases of HP, CTD may show UIP pattern

• Look for central scarring and granulomas in HP

• Look for increased lymphoid aggregates and lack of normal (NSIP instead) in CTD

OP or FF?• Organizing Pneumonia

– Rounded (usually)– Air on most sides– Location - airspace– Polypoid– Branching

• Fibroblastic Foci– Crescentic (frequently)– Collagen on one side– Location - interstitium– Sessile– Not branched

Organizing Pneumonia

• Clinically acute or subacute presentation.

• Patchy opacifications on CT.

• Pathology findings will mirror CT findings with filling of alveolar spaces.

Organizing Pneumonia

• The appearance of this disorder looks like something got messed up (a pneumonia of some sort) and is now being cleaned up (organizing)

• The body’s method of cleaning up is via granulation tissue (fibroblasts and small vessels with some inflammatory cells).

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Organizing Pneumonia

BronchioleAlveolar duct Alveoli

BOOP

Granulation tissue polyp

Bronchiolitis obliterans

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Organizing Pneumonia

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Acute Fibrinous Organizing Pneumonia

• Polypoid plugs of fibrin (pink slightly granular to fibrillar material) often with flattened cells a t the periphery

• Can look very similar to eosinophilic pneumonia, so make sure you look for eosinophils when you see AFOP

Clues for OP

• Correlates with CT and clinical

• Rounded branching plugs (Nordy)

• Blue with spindly cells (OP)

• Pink with few cells (AFOP)

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Granulomas

• Finding granulomas on a biopsy can help make several diagnoses, so it is important to recognize what they look like

• Rounded aggregates of histiocytes (tissue macrophages) often with multinucleate giant cells

Granuloma – Soft Findings• Tightly packed cells, rounded, coalescing, present

along lymphatic routes, lymphocytes exclude the interior = sarcoidosis

• Tightly packed, rounded, singletons, random or bronchiolocentric, lymphocytes in interior = MAC, hot-tub lung

• Loose, formed of only a few macrophages and giant cells, may show intracytoplasmic cholesterol clefts , bronchiolocentric often = HP

• Associated with neutrophils, big floppy giant cells = aspiration

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Sarcoidosis?

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Hot-tub lung (M. avium)

Hypersensitivity 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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Aspiration Venous injection of crushed tablets

Illustrative Case

• 62-year-old man with severe pulmonary fibrosis

• Prior biopsy with UIP pattern

• Now undergoing bilateral lung transplant

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Pathologic Pattern

• Usual interstitial fibrosis

• Marked fibrosis with honeycombing

• Patchy involvement of lung

• Fibroblast foci present

• ?Features suggesting alternate diagnosis?

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Pathologic Diagnosis

• Interstitial fibrosis, UIP pattern, with bronchiolocentric fibrosis and chronic inflammation, and poorly formed granulomas.

• Most consistent with chronic hypersensitivity pneumonia.

Final Diagnosis

• Familial Interstitial Fibrosis

• Telomerase mutation (TERT gene)

• With superimposed hypersensitivity pneumonia

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Take Away Message• I still think that it is good that we are each in o ur

respective career – and that the best way to make a diagnosis is through multidisciplinary discussion.

• However, the longer I do this, the more value I fin d in knowing at least some of what the other team members do.

• It is my hope that I have effectively communicated a bit about how pathologists look at slides for these few patterns of injury: DAD, OP, fibrosis (UIP, NSI P, bronchiolocentric), and granulomatous disease.