Pathology of interstitial/restrictive lung diseases

Question 1

These diseases involve what? What are radiographic changes seen in restrictive/interstitial lung diseases?

Answer 1

In general, these diseases involve inflammation and fibrosis of the interstitium, resulting in loss of lung pliability/flexibility. The functional changes are then a decrease in compliance, capacity, and volume.

Radiographic changes are very suggestive of restrictive/interstitial lung disease and include small nodules, irregular lines, or ‘ground-glass’ shadows, and are an important adjunct to any patient presenting with dyspnea, tachypnea, crackles, wheezing or cyanosis.

Question 2

Fibrosis and the lung parenchyma?

Answer 2

A very important concept is how fibrosis distorts the lung parenchyma over time. Like cirrhosis in the liver, increased collagen and connective tissue eventually render the lung tissue largely incapable of adequate function. Keep central the idea that as fibrosis collects in the interstitium, the distance between the capillary lumen and the alveolar space will increase, and will eventually make adequate oxygen diffusion impossible.

Question 3

What do these images show?

Answer 3

Upper image: End stage fibrotic changes - honeycomb lung. Fibrosis has expanded and filled the interstitium, and destroyed airspaces. The airspaces that are left resemble the tiny spaces of honeycomb.

Lower image: Abundant pink fibrosis, which markedly distorts normal histology. Remaining airspaces are irregular in size and shape, and provide very little in the way of actual ventilation. Lymphocytes are also focally clustered in abundance, as inflammation adds to the overall injury.

Question 4

Explain Usual interstitial pneumonia (UIP)/Idiopathic pulmonary fibrosis (IPF)?

Answer 4

This clinicopathologic syndrome is characterized by progressive pulmonary fibrosis and respiratory failure. The clinical entity is named IPF and has the following features:

 Unknown etiology, although genetic susceptibility is suggested

 An exclusion of other causes of lung disease

 Dyspnea on exertion and dry cough are initial symptoms

 Males > females and usually greater than 60 years old; most are smokers

 Radiographic findings (CT) can be characteristic and include bilateral interstitial lines/markings, traction bronchiectasis, or honeycomb change

 Lung biopsy findings can be paired with clinical information to aid in therapeutic management/palliative care

 Median survival after diagnosis is about 3 years and therapy is not curative

Question 5

pathologic features of IPF?

Answer 5

 Patchy interstitial fibrosis, most commonly in the lower lobes and subpleural regions (image right)

 Temporal heterogeneity in that some areas look ‘younger’ or ‘older’ than others

 Fibroblastic foci are the early plugs on connective tissue that get remodeled into permanent fibrosis

 Honeycomb fibrosis (honeycomb lung) will eventually evolve as the changes progress to end stage

Question 6

What does this image show?

Answer 6

Image: low power view of UIP. Note variable thickness of fibrosis involving the interstitium space/alveolar walls.

Question 7

Pathogenesis of UIP?

Answer 7

The pathogenesis of UIP is repeated cycles of epithelial activation and injury by an unknown agent, resulting in abnormal repair and fibrosis.

When the fibrosis is ‘younger,’ we call it a fibroblastic focus, essentially a swath of immature collagen in the interstitium (see arrows at left) with surrounding inflammation.

Temporal heterogeneity can be seen in this image as ‘younger’ fibroblastic foci and inflammation (mostly in the bottom left at arrows), as compared to the ‘older,’ now inflammation-free, more mature pink fibrosis below the pleura (thin arrow).

One theory posits that TGF-β may be an important mediator in UIP because it is fibrogenic, and that defects in TERT genes (which encode for telomerase) allow for senescence of alveolar epithelium.

Question 8

What is non-specific interstitial pneumonia?

Answer 8

This interstitial lung disease is more likely found in female nonsmokers in their sixth decade who present with cough of several months, and in those who lack diagnostic features of other interstitial lung diseases (hence, nonspecific). It is very important to recognize this entity and separate it from UIP, because these patients get better with corticosteroids (and UIP patients may get worse with steroids).

Question 9

What are the two histological appearances of non-specific interstitial pneumonia?

Answer 9

 Fibrosing pattern (left image below) – interstitial fibrosis that appears all the same age (no temporal heterogeneity); no fibroblastic foci or honeycomb change seen either

 Cellular pattern (right image below) – mild to moderate chronic inflammation expands the interstitium, consisting predominately of lymphocytes and a few plasma cells

Question 10

Cryptogenic Organizing pneumonia (COP) is what? histologically?

Answer 10

This is an organizing pneumonia with intra-alveolar fibrosis (not centered in the interstitium) that develops in patients with known viral or bacterial pneumonia, adverse reactions to toxins or drugs, connective tissue diseases affecting the lung, or graft-vs-host disease in bone marrow transplant recipients.
Histologically, plugs of loose organizing, connective tissue are found in alveolar spaces (arrows), while overall architecture and interstitial spaces are relatively preserved.

These plugs of connective tissue (called Masson bodies) can also be present in small airways (at arrow).
This connective tissue is somewhat unusual in that apparently the body can “remove” or resolve it – many patients with COP either recover spontaneously or achieve complete recovery following several months of corticosteroids.

Question 11

what does the image show?

Answer 11

Mason bodies of COP

Question 12

Pulmonary involvement from autoimmune diseases?

Answer 12

Not to be belabored, but not to be excluded, pulmonary involvement by autoimmune disease is a common finding that may mimic many of the interstitial lung diseases to some degree.

SLE – pleural disease (inflammation and/or fibrosis) is very common, as is parenchyma and interstitial infiltrates of inflammatory cells and/or patchy or extensive fibrosis – almost any pathology is possible!! 
Rheumatoid arthritis – rheumatoid nodules, diffuse interstitial fibrosis, chronic pleuritis and/or effusions are common 
Systemic sclerosis (scleroderma) – diffuse interstitial fibrosis (NSIP-like or UIP-like patterns)

Question 13

What is pneumoconiosis? Pathogenesis?

Answer 13

These non-neoplastic lung diseases are induced by inhaled organic or nonorganic particulates, chemical fumes and vapors, usually acquired in a workplace setting.

The pathogenesis involves both the small size of the offending agent (usually between 1-5 µm) which can reach the terminal small airways, and also the reaction of resident pulmonary macrophages:

 IL-1 and TNF released when particles are taken up by macrophages

 Mediator-promoted collagen deposition and fibrosis cause the symptoms of disease

Question 14

Coal workers pneumoconiosis?

Answer 14

Pathology ranges from anthracosis (carbon deposited in lung macrophages and lymphatics) to progressive massive fibrosis. The fibrosis occurs primarily in the upper zones of the lungs, when isolated or first starting, and then progresses…
Image: black anthracotic lungs, involved by (end-stage) progressive massive fibrosis.

Question 15

What is silicosis? describe the images?

Answer 15

Pathology first involves the production of fibrotic silica nodules that eventually coalesce into collagenous scars, more typical in the upper lobes.

Images: Polarized light highlights the whitish silica surrounded by fibrosis and anthracosis. A silicotic scar in the upper lobe (arrow), surrounded by pleural scarring and fibrosis. Other regions of scarring are also present.

Question 16

Asbestos pathology?

Answer 16

1) asbestos bodies are iron-containing proteinaceous material surrounding asbestos fibers – an uncommon finding
2) ferruginous bodies (see image) are same material surrounding other inorganic particles – uncommon, but more common than above
Both of these can help create asbestosis – the lung disease (wheezing, coughing, SOB, chest pain, etc.) due to the interstitial reaction.

3) pleural plaques are dense collagen plaques that develop on the parietal pleural and over the domes of the diaphragm – most common pathologic finding with asbestos exposure. Plaques are not the same as having asbestosis, and aren’t known to increase the risk for asbestos-induced neoplasia. It’s proposed that asbestos fibers reach the pleural space through lymphatics.

Question 17

Hypersensitivity pneumonia is what? what kinds?

Answer 17

This can develop when inhaled, organic antigens cause a predominately interstitial allergic response. These manifest functionally as restrictive lung disease, and numerous syndromes are named according to the exposure:

 Farmer’s lung – spores of actinomycetes in warm, humid hay

 Pigeon breeder’s lung (bird fancier’s disease) – several types of bird-derived material

 Bagassosis – exposure to bagasse (byproduct of sugarcane)

Question 18

What are the two hypersensitivities involved with hypersensitivities pneumonia? what does the image show?

Answer 18

 Type IV reaction with granuloma formation

 Type III reaction with complement and immunoglobulins in vessel walls can also be present

Image: interstitial pneumonitis and granulomas (arrow) are common; UIP-like fibrosis with fibroblastic foci and honeycombing can also be seen uncommonly.

Question 19

Explain Sarcoidosis? Immmune abnormalities?

Answer 19

This is a systemic, autoimmune disease of unknown etiology that causes granulomatous pulmonary changes. Black women in 30-40’s age range are most at risk. Clinical course is unpredictable; patients can have complete remission, but also 20% develop permanent lung dysfunction, and 10-15% die from progressive interstitial fibrosis and cor pulmonale.

Immune abnormalities include:

 Anergy to skin antigens (TB, Candida)

 Polyclonal hypergammaglobulinemia

 Accumulations of CD4+ TH1 cells

 Angiotensin converting enzyme (ACE) levels may be elevated, as ACE is produced by epithelioid macrophages

Question 20

Histologic character of sarcoidosis?

Answer 20

Noncaseating granulomata characterize sarcoidosis, and may occur in any organ of the body. In the lung:
 Diffuse scattered granulomas

 Lymph node involvement causing hilar and mediastinal adenopathy

Question 21

what does the image reveal?

Answer 21

Upper image: Granulomas develop in and around airways and vessels (both are arrowed in image); eventually granulomas can coalesce, incite fibrosis, and expand the interstitium.

Lower image: nodal enlargement (arrow) due to granulomatous inflammation, with surrounding bronchi showing variable bronchiectasis.

Question 22

desquamative interstitial pneumonia is characterized by?

Answer 22

Desquamative Interstitial Pneumonia (DIP)

This is characterized by large collections of macrophages filling the alveolar spaces, originally and incorrectly thought to be desquamated pneumocytes.

 the macrophages contain faint/dusty brown pigment (smokers’ macrophages)

 interstitium remains relatively preserved

Question 23

What are two types of Smoking-Related Interstitial Diseases?

Answer 23

Desquamative Interstitial Pneumonia (DIP)

Respiratory Bronchiolitis-Associated Interstitial Lung Disease (RBILD)

Question 24

Explain Respiratory Bronchiolitis-Associated Interstitial Lung Disease (RBILD)?

Answer 24

The most common pathologic finding in smokers is the presence of peribronchiolar fibrosis with chronic inflammation (particularly lymphocytes), called respiratory bronchiolitis (see image).

The surrounding alveolar spaces likely are normal, and symptoms range from nothing to restrictive-type symptoms.

 Smokers macrophages may be found in and around the bronchioles, adjacent vessels, or otherwise in the peribronchiolar spaces

 DIP areas may be seen in some alveolar spaces

Question 25

Explain Pulmonary Alveolar Proteinosis (PAP)? What is the image? Therapy? Presentation?

Answer 25

This rare disease is defined by defects in granulocyte-macrophage colony stimulating factor (GM-CSF) or macrophage function, resulting in the accumulation of surfactant in the alveolar spaces. Autoimmune, secondary, and congenital forms have all been identified.

 Presentation: cough that is productive of abundant, mucoid/gelatinous material  Secondary findings include infectious pneumonia, progressive dyspnea, cyanosis, and eventual pulmonary failure

 Therapy is pulmonary lavage – essentially, washing out the material from alveolar spaces

image: proteinaceous, eosinophilic surfactant material filling alveolar spaces. Clinically, this degree of alveolar filling, if diffuse, would result in fairly acute, severe symptoms. However, focal or patchy involvement of airspaces is fairly common.