Pathology of Interstitial Lung Disease

Question 1

In interstitial lung diseases, what typically happens to the lung compliance, FVC, and FEV1:FVC ratio?

Answer 1

Restrictive pattern:

Reduced lung compliance
Reduced FVC
Normal FEV1:FVC ratio

Question 2

What can be seen generally in pathology in all interstitial lung diseases?

Answer 2

1. Chronic inflammatory infiltrate
2. Cyst formation from coalescence of alveoli
3. Interstitial fibrosis
4. Honeycomb lung

Question 3

What is honeycomb lung?

Answer 3

End stage scarred lung

• > dilated airspaces from destroyed lung alternating with fibrous scars
• > septae are extremely thick with poor gas exchange due to fibrosis of interstitium

Question 4

What are the two names for the most common ILD and what is the prognosis?

Answer 4

Usual Interstitial Pneumonitis (UIP) or Idiopathic Pulmonary Fibrosis (IPF)

Prognosis: Poor - 3 year median survival

Question 5

What are the common risk factors for UIP?

Answer 5

Smoking, wood dust inhalation, and therapy with EGFR TKI’s (mutations for fibrosis develop)

Question 6

What is the common pathology of UIP?

Answer 6

Subpleural and bibasilar accentuation of tissue damage (extensive fibrosis)
->heterogeneity of tissue damage with “fibroblastic foci” - extensive fibroblast proliferation with ECM

Question 7

What must not be present to make a UIP diagnosis?

Answer 7

Pertinent negative findings:
i.e. granulomas, Langerhans cells, asbestos bodies

-> thinks which would rule out idiopathic fibrosis

Question 8

What is the inciting stimulus which begins fibrosis in UIP?

Answer 8

Damage to respiratory epithelium / basement membrane

• > activation of inflammation and coagulation pathways
• > eventual release of growth factors and TGF-beta, with tissue remodelling

Question 9

What processes are responsible for an increase in fibroblasts in UIP?

Answer 9

1. Transformation of pneumocytes into myofibroblasts (Epithelial-Mesenchymal-Transition)
2. Migration from bone marrow
3. Proliferation of native fibroblasts

Question 10

What is DIP and how does it epidemiologically and prognostically differ from UIP?

Answer 10

DIP - Desquamating Interstitial Pneumonitis

Epidemiologically - happens in 40s and 50s vs 60s and 70s with UIP.

DIP is very associated with smoking and is made better by cessations - 90-100% survival

Question 11

What is seen in the pathology of DIP?

Answer 11

Large numbers of alveolar macrophages in the alveoli

Interstitium is filled with lymphocytes, fibrosis is only mild and rarely progresses to honeycomb

Question 12

What is the pathogenesis of DIP?

Answer 12

Similar to UIP, except more reliant on smoking as a stimulus for fibrosis and more reversible

Question 13

What is NSIP and what are its two subtypes? Which has worse prognosis?

Answer 13

Nonspecific Interstitial Pneumonia -
Second most common interstitial lung disease, it is an IP that does not fit into any of the other histological categories

Subtypes:
Cellular - (closer to DIP)
Fibrotic - Worse prognosis (closer to UIP)

Question 14

What does the pathology of NSIP look like / how does it differ from DIP / UIP?

Answer 14

Main difference is that the fibrosis and tissue damage is uniform across the lung rather than pleural or basilar (as in UIP), and there are no alveolar macrophage aggregates in alveoli (as in DIP)

Question 15

What tends to aggregate in the cellular form of NSIP?

Answer 15

Lymphocytes tend to accumulate in the alveolar septae

Question 16

How is diagnosis of hypersensitivity pneumonitis (HP) confirmed typically?

Answer 16

Clinical and CT findings will suggest the diagnosis

Lymphocytosis on bronchoalveolar lavage suggests it

Positive inhalation challenge / serum antibodies to allergen are near diagnostic

Biopsy is rarely required, only when clinical diagnosis cannot be reached

Question 17

How are the tissue findings of subacute vs chronic phases of HP related?

Answer 17

Acute - may be no changes

Subacute - typical tissue findings

Chronic - subacute findings coexisting with fibrosis and restrictive lung pattern of disease

Question 18

What are the classical tissue findings of HP?

Answer 18

Interstitial lymphocytes (like cellular NSIP) - worse in peribronchiolar areas like asthma

Mild interstitial fibrosis

Interstitial poorly formed non-necrotizing granulomas or single giant cells (from T4 hypersensitivity, as in Bosch’s lacture)

Question 19

Why is it difficult to diagnose ILDs and what other things must be ruled out?

Answer 19

Because they have overlapping symptoms and pathologies with inter-observer disagreement

Must rule out toxic agents, infectious etiology, and co-morbid conditions w/ pulmonary manifestations

Question 20

What is the role of the radiologist vs pathologist in diagnosis of Idiopathic Pulmonary Fibrosis?

Answer 20

Radiologist - sees CT scan, which is best to get the big picture of the lung

Pathologist - Can only confirm probable UIP, or definitely see features INCOMPATIBLE with UIP via pathology -> pathology can only rule out, but cannot make diagnosis

Question 21

Sarcoidosis is a systemic disease. Where is it most commonly involved in the lung? What pattern does this make?

Answer 21

Mediastinal / hilar lymph nodes and lymph vessels (lymphangitic pattern) - makes sense because immune-mediated

Bilateral hilar lymphadenopathy causes “butterfly” pattern

Question 22

What is the pathology of sarcoidosis? How can you diagnose based on this?

Answer 22

Noncaseating micro-granulomas with diffuse interstitial involvement and fibrosis

Focal necrosis of tissue may still be present, but rarer

Diagnosis can NOT be made on pathology alone

Question 23

What levels are found to be elevated in diagnosis of sarcoidosis with bronchoalveolar lavage? What lab tests will be elevated?

Answer 23

Elevated CD4+:CD8+ T cell ratio (more CD4 cells due to activation of granulomas)

Noncaseating granulomas of sarcoidosis also elevated blood calcium (increased vitamin D levels due to 1-alpha-hydroxylase activity of macrophages) and elevated ACE (made in granuloma)

Question 24

How are Langerhans cells identified pathologically?

Answer 24

Langerhans cells with grooved, irregular nuclei and cytoplasmic inclusions called “Birbeck granules” -> an endosomal inclusion.

Question 25

How are Langerhans cell histiocytoses identified histochemically?

Answer 25

CD1a surface antigen - identifies Langerhans cells

Question 26

What is the isolated pulmonary version of Langerhans cell histiocytosis called? How does it generally vary from the other forms?

Answer 26

PLCH - Pulmonary Langerhans Cell Histiocytosis / Eosinophilic granuloma (EG)

other forms include multisystem involvement, or unisystem multifocal involvement (bone)

Question 27

What is the development of Eosinophilic Granuloma / PLCH associated with? Who tends to get it?

Answer 27

Usually young adults

Strong association with smoking
-> relieved by cessation of smoking

Question 28

Where in the lungs does PLCH tend to occur and what cell types are often present?

Answer 28

Usually in the upper lobes, especially around bronchioles making a stellate appearance

Langerhans cells are usually, but not always, associated with EOSINOPHILS (eosinophilic granuloma), plasma cells, neutrophils and lymphocytes

Question 29

What is pathognomonic of PLCH and is it a neoplasm?

Answer 29

Collection of CD1a positive Langerhans cells

There is inflammation and fibrosis, so it is unclear whether the process is reactive or neoplastic.