Pulmonary Diseases

Non-neoplastic Lung Pathology

Parts 1 and 2
Fadi W. Abdul-Karim MD MEd
Professor of Pathology- Emeritus
Case Western Reserve Univ and Cleveland Clinic Learner School of Medicine
University of Balamand

Pathologic Basis of Disease – 10th Edition- Chapters 15

Non-neoplastic Lung Pathology
• A. Obstructive Lung Diseases.
• Emphysema
• Chronic Bronchitis
• Asthma
• Bronchiectasis

• B. Chronic Diffuse Interstitial ( Restrictive) Lung Diseases

A. Obstructive Lung Diseases.
A. Obstructive Lung Diseases
• Common obstructive lung diseases include:
1. Emphysema
2. Chronic bronchitis.
3. Asthma.
4. Bronchiectasis.

• Emphysema and Chronic Bronchitis= Chronic Obstructive Pulmonary

Disease (COPD): - majority have features of both and share major trigger—
cigarette smoking.
• Asthma (reversible bronchospasm): Some patients also develop an irreversible
component. Conversely, some patients with COPD have a reversible component-
COPD/asthma.
 Obstructive Lung Diseases
Recognizing that there is
overlap between various forms
of COPD, it is still useful to
discuss each individually in
order to highlight the
pathophysiologic basis of
different causes of airflow
obstruction.

Small-airway disease, a variant of chronic bronchiolitis, can contribute to obstruction both in emphysema and chronic bronchitis.
COPD
• Major public health problem. 4 th leading cause of morbidity and
mortality in the USA.

• 35-50% of heavy smokers develop COPD; 80% of COPD is due to

smoking.

• Other risk factors:

• Environmental and occupational pollutants.
• Airway hyperresponsiveness.
• Genetic polymorphisms.
1. Emphysema

• Irreversible enlargement of airspaces distal to terminal bronchiole

accompanied by destruction of their walls without obvious fibrosis.

• Small airway disease/fibrosis (distinct from chronic bronchitis) has

recently been to shown to be present in patients with emphysema; it
is a significant contributor to airflow obstruction.
Emphysema: Variants
• Centriacinar (Centrilobular) emphysema 95% of
sig. cases :
• Central or proximal parts of acini, formed by respiratory
bronchioles are affected, distal alveoli spared
• Upper lobes/Apical segments more severe
• Heavy smokers
• Panacinar (Panlobular) emphysema:
• Acini uniformly enlarged from respiratory bronchiole to
terminal alveoli
• Lower zones, bases more severe
• Alpha-1-antitrypsin deficiency
• Distal acinar (Paraseptal) emphysema:
• Distal acinus more involved, adjacent to pleura, along
lobular septa and margins of lobule
• Upper half of lungs
• Young adults: Spontaneous pneumothorax
• Irregular emphysema (Airspace enlargement with
fibrosis):
• Scarring, usually clinically insignificant
Centriacinar (Centrilobular)
Emphysema

Most common form of emphysema.

Most common emphysema found in
smokers.
Associated with symptomatic COPD
Can be seen in coal workers’
pneumoconiosis.
Most severe in the upper zones of
the lung.
 Panacinar Emphysema

Most common form in familial

emphysema associated with alpha-1-
antitrypsin abnormalities
 May be seen more commonly in
intravenous drug abusers
 More severe in lower zones of the
lung
Emphysema: Pathogenesis
 Emphysema: Morphology
• Voluminous lungs, often overlapping the heart and hiding it when
the anterior chest wall is removed.
• The upper two thirds of the lungs are more severely affected.
• Large apical blebs or bullae are more characteristic of irregular
emphysema secondary to scarring and of distal acinar
emphysema.
• Large alveoli can easily be seen on the cut surface of fixed lungs.
• Abnormally large alveoli are separated by thin septa with only
focal centriacinar fibrosis. Septa appear to be floating or protrude
blindly into alveolar spaces with a club shaped end.
• Prolonged vasoconstriction leads to changes of pulmonary
arterial hypertension. As alveolar walls are destroyed, there is a
decrease in the capillary bed area.
Emphysematous Blebs/Bulla(e)

A single site of
destruction larger than
2 cm in an
emphysematous lung,
usually subpleural
2. Chronic Bronchitis
• Clinically as persistent cough with sputum production for at least 3
months in at least 2 consecutive years, in the absence of any other
identifiable cause.

• One end of the spectrum of COPD, with emphysema being the other.
Most patients lie somewhere in between, having features of both.

• May lead to cor pulmonale and heart failure, or cause atypical

metaplasia and dysplasia of the respiratory epithelium- soil for
cancerous transformation.
 Chronic Bronchitis: Pathogenesis

• Common in habitual smokers (90% of patients are smokers) and

inhabitants of smog-laden cities, and dust from grain, cotton, and
silica.
• Mucus hypersecretion.
• Inflammation: Acute and chronic inflammatory responses involving
neutrophils, lymphocytes, and macrophages. Affects also ciliary
motility.
• Long-standing inflammation and accompanying fibrosis involving
small airways can also lead to chronic airway obstruction.
• Infection: Acute exacerbations.
Chronic Bronchitis: Morphology

Bronchial epithelium may exhibit squamous

metaplasia and dysplasia
Chronic Bronchitis: Clinical Features
• Persistent cough productive of sparse sputum.

• Hypercapnia, hypoxemia, and mild cyanosis (“blue bloaters”).

• Many patients with COPD have both Emphysema and Chronic

Bronchitis

• Cor pulmonale and cardiac failure.

• Death may also result from further impairment of respiratory

function due to superimposed acute infections.
COPD: Emphysema and Chronic Bronchitis
3. Asthma

Chronic disorder of the conducting airways, usually caused by an immunological reaction,

which is marked by episodic bronchoconstriction due to increased airway sensitivity to a
variety of stimuli; inflammation of the bronchial walls; and increased mucus secretion.

Genetic Susceptibility: Multigenic and often associated with other allergic disorders: Allergic
rhinitis (hay fever) and eczema.

Environmental Factors: Disease of industrialized societies where the majority of people live
in cities
Asthma

Atopic (evidence of
allergen sensitization and
immune activation, often
in a patient with allergic
rhinitis or eczema)

or non-atopic (no
evidence of allergen
sensitization).
 Asthma
Pathology:
Eosinophils
Thickened basement
membrane
Increased size of submucosal
glands
Increased airway goblet cells
Mucus plugging
Hypertrophy of bronchial wall
smooth muscle
 Pathology of Asthma: Cytology (Sputum/BAL)
► Mucus plugging
(Curschmann’s spirals)
► Crystals (Charcot-
Leyden)
► Desquamated epithelial cells
(Creola bodies) arise from
bronchial hyperplasia and
can easily be misdiagnosed
as a carcinoma. Have
cilia,on the surface
#adenocarcinoma

► Mucous plugs
Figure 15.10 (A and B) Comparison of a normal airway and an airway involved by asthma. The asthmatic airway is marked by accumulation of mucus in the bronchial lumen secondary to an
increase in the number of mucus-secreting goblet cells in the mucosa and hypertrophy of submucosal glands; intense chronic inflammation due to recruitment of eosinophils, macrophages,
and other inflammatory cells; thickened basement membrane; and hypertrophy and hyperplasia of smooth muscle cells. (C) Inhaled allergens (antigen) elicit a Th2-dominated response
favoring IgE production and eosinophil recruitment. (D) On re-exposure to antigen, the immediate reaction is triggered by antigen-induced cross-linking of IgE bound to Fc receptors on mast
cells. These cells release preformed mediators that directly and via neuronal reflexes induce bronchospasm, increased vascular permeability, mucus production, and recruitment of leukocytes.
(E) Leukocytes recruited to the site of reaction (neutrophils, eosinophils, and basophils; lymphocytes and monocytes) release additional mediators that initiate the late phase reaction. Several
factors released from eosinophils (e.g., major basic protein, eosinophil cationic protein) also cause damage to the epithelium. IL-5, Interleukin-5.
4. Bronchiectasis
• Permanent dilatation of bronchi and bronchioles
due to destruction of muscle and elastic tissue in
their walls, resulting from or associated with
chronic infections.

• Obstruction and infection are needed, either one

may come first

• Clinical presentation: Cough, Copious sputum-

purulent

• Numerous conditions can lead to Bronchiectasis

 Bronchiectasis: Underlying conditions
• Congenital/hereditary conditions: Cystic fibrosis, intralobar sequestration of the
lung, immunodeficiency states, and primary ciliary dyskinesia, Kartagener syndromes*

• Infections: Necrotizing pneumonia caused by bacteria, viruses, or fungi (Allergic

bronchopulmonary Aspergillosis)- single severe episode or recurrent infections

• Bronchial obstruction: Tumor, foreign bodies, mucus impaction-

localized/segmental

• Rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease,

COPD, post transplantation (chronic lung rejection, chronic GVH after BM
transplant.).

• ¼ to 1/2 of cases are idiopathic, lacking the aforementioned associations.

*Situs inversus, bronchiectasis, sinusitis, male infertility (due to sperm dysmotility)

Bronchiectasis
Localized Diffuse
A. Summary: Obstructive Lung Diseases
KEY CONCEPTS COPD
Most common in long-standing tobacco smokers (typically >40 pack-years); air pollutants also
contribute.
• Underlying pulmonary pathology usually includes both chronic bronchitis and emphysema.
• Often fatal due to development of heart failure or of respiratory failure due to superimposed
infection.
Emphysema
• In COPD, usually follows a centroacinar distribution characterized by permanent enlargement of
airspaces distal to terminal bronchioles.
• Particularly severe in patients with α1-antitrypsin deficiency, in which a panacinar pattern of
emphysematous change may be seen.
• Tissue destruction is caused by elastases and oxidants released from inflammatory cells,
particularly neutrophils, which are responding to cellular injury caused by tobacco smoke and
pollutants.
Chronic Bronchitis
• Defined as persistent productive cough for at least 3 consecutive months in at least 2 consecutive
years.
• Dominant pathologic features are mucus hypersecretion due to enlargement of mucus-secreting
glands and chronic inflammation associated with bronchiolar wall fibrosis
KEY CONCEPTS ASTHMA
• Asthma is characterized by reversible bronchoconstriction caused by airway
hyperresponsiveness to a variety of stimuli.
• Atopic asthma is caused by aTh2 and IgE-mediated immunologic reaction to
environmental allergens and is characterized by acute-phase (immediate) and
late-phase reactions. The Th2 cytokines IL-4, IL-5, and IL-13 are important
mediators.
• Triggers for non-atopic asthma are less clear but include viral infections and
inhaled air pollutants, which can also trigger atopic asthma.
• Eosinophils are key inflammatory cells in atopic asthma; other inflammatory
cells implicated in its pathogenesis include mast cells, neutrophils, and T
lymphocytes.
• Airway remodeling (sub–basement membrane fibrosis, hypertrophy of
bronchial glands, and smooth muscle hyperplasia) adds an irreversible
component to the obstructive disease.
Non-neoplastic Lung Pathology
• A. Obstructive Lung Diseases.
• Emphysema
• Chronic Bronchitis
• Asthma
• Bronchiectasis

• B. Chronic Diffuse Interstitial ( Restrictive) Lung Diseases

B. Chronic Diffuse Interstitial
(Restrictive) Lung Diseases
B. CHRONIC DIFFUSE INTERSTITIAL
(RESTRICTIVE) DISEASES
• Two general categories:
• (2) Chest wall disorders (e.g., neuromuscular diseases such as
poliomyelitis, severe obesity, pleural diseases, and kyphoscoliosis)-
not discussed here.

• (1) Chronic interstitial and infiltrative diseases, such as interstitial

fibrosis of unknown etiology and pneumoconiosis.
• Heterogeneous group of disorders characterized predominantly by
inflammation and fibrosis of the lung interstitium associated with pulmonary
function studies indicative of restrictive lung disease.
Diffuse Interstitial (Restrictive) Diseases- ILD
• ILD is a broad term that includes a large number of unrelated lung
diseases that involve the lungs diffusely.
• To clinicians, the term ILD includes all diseases that involve the lungs
diffusely and is often used synonymously with “diffuse lung disease.”
• To pathologists, ILD is restricted to diseases that predominantly affect the
interstitium.

• Categorized based on histology and clinical features

• Most ILDs are acute and self-limited (best example: atypical pneumonia)
• Some ILDs are chronic and progressive
• Acute and chronic ILDs can cause restrictive pulmonary function change
Chronic Diffuse Interstitial (Restrictive) Diseases
• Symptoms: Dyspnea, tachypnea, end-inspiratory crackles, and eventual
cyanosis, without wheezing evidence of airway obstruction: reductions
in diffusion capacity, lung volume, and lung compliance.
• Chest radiographs show bilateral lesions that take the form of small
nodules, irregular lines, or ground-glass shadows.
• Eventually, secondary pulmonary hypertension and right-sided heart
failure associated with cor pulmonale may result.
• The entities can often be distinguished in the early stages,
the advanced forms are hard to differentiate: All result in
scarring and destruction of the lung- End-stage lung or
Honeycomb lung.
Chronic Diffuse Interstitial (Restrictive) Diseases
About 200 entities in which the lung is altered by interstitial
inflammation, granulomatous inflammation, or fibrosis.

These disorders account for about 15-20% of noninfectious

diseases seen by pulmonary physicians.

Classified together because of similar clinical, radiologic,

physiologic, and pathologic features.

Many are of unknown cause and pathogenesis/some have

an intra-alveolar as well as an interstitial component.
Include environmental or drug exposures, collagen vascular
diseases, sarcoid, other

Pneumoconiosis 20%
Sarcoidosis 20%
Idiopathic pulmonary fibrosis 20%
Connective tissue disease associated 10%
Others 30%
1. Usual Interstitial Pneumonia (UIP)/Idiopathic Pulmonary Fibrosis Idiopathic (IPF) Pathogenesis

metal fumes, wood dust, farming,

hairdressing, stone-polishing Persistent exposure to the
injurious stimulus
>50 years ↓
Macrophages +/-
Neutrophils
↓
Acute alveolitis
↓
Chronic alveolitis
↓
Progressive fibrosis

Proposed pathogenic mechanisms in idiopathic pulmonary fibrosis. Environmental factors that are potentially injurious to alveolar epithelium interact with genetic
or aging-related factors that place epithelium at risk, creating a persistent epithelial injury. Factors secreted from injured/activated epithelium, possibly augmented
by factors released from innate and adaptive immune cells responding to “danger” signals produced by damaged epithelium, activate interstitial fibroblasts. There
is some evidence that these activated fibroblasts exhibit signaling abnormalities that lead to increased signaling through the PI3K/AKT pathway. The activated
fibroblasts synthesize and deposit collagen, leading to interstitial fibrosis and eventual respiratory failure.
Characteristic involvement both lower lobes
The histologic pattern of fibrosis is referred to as
usual interstitial pneumonia (UIP), which can
often be diagnosed based on its characteristic
appearance in CT scans and must be
distinguished from IPF based on other clinical,
laboratory, and histological features
Usual Interstitial Pneumonia (UIP)/Idiopathic Pulmonary Fibrosis
Idiopathic (IPF)
UIP Pathology
•Patchwork Pattern
•Scarring
•Honeycomb
Change
•Fibroblastic Foci
 UIP: Honeycomb (Lt-Evident; Rt-Microscopic)

Radiologists identify UIP on High Resolution CT scan only when honeycomb is identified
In 50% of cases honeycomb is present microscopically and not seen on CT scan- Microscopic
honeycomb pattern
Usual Interstitial Pneumonia (UIP)/Idiopathic
Pulmonary Fibrosis Idiopathic (IPF): Clinical Course
Most patients are 55 to 75 years old at presentation.

Insidious onset of dyspnea on exertion and dry cough.

Hypoxemia, cyanosis, and clubbing occur late in the

course. The progression in an individual patient is
unpredictable.

Usually there is a gradual deterioration in pulmonary

status despite medical treatment with
immunosuppressive drugs such as steroids,
cyclophosphamide, or azathioprine. 60% mortality in 5
years
UIP
• No effective treatment
• Does not effectively respond to
corticosteroids or Nintedanib/
Pirfenidone
• Lung transplant
• Prognosis poor: Progressive
dyspnea and death- Median
survival 3-4 years
IPF Bronchiectasis
Chronic Diffuse Interstitial (Restrictive) Diseases
 2. Nonspecific Interstitial Pneumonia
Nonspecific interstitial pneumonia is most often
associated with connective tissue disease but may
also be idiopathic.

Dyspnea and cough of several months’ duration.

More likely to be female nonsmokers in their sixth

decade of life.

High-resolution computed tomography are bilateral,

symmetric, predominantly lower lobe reticular
opacities..

UIP is patchy with involved areas alternating with normal lung and gross area of honey combing. NSIP is diffuse
with uniform fibrosis throughout and minimal microscopic or absent honey combing.
Very Important To Recognize:
UIP had a median survival of 78 months compared with 178 months for NSIP (much better prognosis)
NSIP
• UIP is a pathologic ( Pathologic
criteria) /or radiographic
diagnosis ( Honeycomb)

• IPF is a clinical diagnosis

• NSIP has a better prognosis than

(UIP/IPF). But, any UIP/IPF
features in a NSIP=UIP/IPF
Chronic Diffuse Interstitial (Restrictive) Diseases
3. Histologic pattern: Organizing Pneumonia (OP)
Clin-Radiol-Path Dx: Cryptogenic Organizing Pneumonia
• COP is the preferred term, also synonymous with idiopathic
Bronchiolitis obliterans organizing pneumonia BOOP. Unknown
etiology

• Symptoms:
• Around 55 years old- Cough and dyspnea and have patchy subpleural or
peribronchial areas of airspace consolidation radiographically.
• Flu-like illness < 2 months in 3/4, in many it is acute (1 to 2 weeks).
• Patchy subpleural or peribronchial areas of airspace consolidation

• Steroids Rx leads to complete recovery in 2/3. Response is rapid usually

days to weeks.
Cryptogenic Organizing
Pneumonia
• Characterized by the presence of
polypoid plugs of loose organizing
connective tissue (Masson bodies). The
connective tissue is all of the same age,
and the underlying lung architecture is
normal. There is no interstitial fibrosis or
honeycomb lung.
• A dx of exclusion since this histologic
pattern is most frequently associated
with infections, collagen vascular
diseases, inhalation injuries,
hypersensitivity pneumonitis, lung
irradiation-
• The clinician should rule out any of the
conditions with known etiology before
diagnosis BOOP
Chronic Diffuse Interstitial (Restrictive) Diseases

Pneumoconioses 20%
Sarcoidosis 20%
Idiopathic interstitial
pneumonias 20%
Collagen vascular diseases
10%
Others 30%
4. Pulmonary Involvement in Connective Tissue
Diseases/Autoimmune Diseases
Rheumatoid Arthritis (RA) Systemic Lupus Erythematous (SLE)
• Airway: Constrictive bronchiolitis, • Airway: Usually does not produce airway
follicular bronchiolitis, bronchiectasis, disease
bronchogenic granulomatosis.

• Alveoli/interstitium: alveolar • Alveoli/interstitium: alveolar

hemorrhage, UIP, NSIP, Diffuse alveolar hemorrhage, UIP, NSIP, “acute lupus
damage (DAD), OP, Lymphocytic pneumonitis” DAD, OP, LIP,, vasculitis,
Interstitial Pneumonia (LIP), rheumatoid pulmonary hypertension (PHT).
nodules, vasculitis, pulmonary
Hypertension (PHT).

• Pleura: pleuritis, effusion, fibrosis • Pleura: pleuritis, effusion, fibrosis.

Also progressive systemic sclerosis (scleroderma), and dermatomyositis-polymyositis, can involve the lung at some
point in their course.
Chronic Diffuse Interstitial (Restrictive) Diseases

Pneumoconioses 20%
Sarcoidosis 20%
Idiopathic interstitial
pneumonias 20%
Collagen vascular diseases
10%
Others 30%
KEY CONCEPTS CHRONIC INTERSTITIAL LUNG
DISEASES
• Diffuse interstitial fibrosis of the lung gives rise to restrictive lung diseases
characterized by reduced lung compliance and reduced FVC. The ratio of
FEV1 to FVC is normal.
• Idiopathic pulmonary fibrosis is prototypic of restrictive lung diseases. It is
characterized by patchy interstitial fibrosis, fibroblastic foci, and formation of
cystic spaces (honeycomb lung). This histologic pattern is known as usual
interstitial fibrosis.
• The cause of idiopathic pulmonary fibrosis is unknown, but genetic
analyses point to roles for senescence of alveolar epithelium (due to
telomere shortening), altered mucin production, and abnormal signaling in
alveolar fibroblasts. Injury to alveolar epithelial cells sets in motion events
that lead to increased local production of fibrogenic cytokines, such as TGF-β
5. Pneumoconiosis
Nonneoplastic lung reaction to inhalation of mineral dusts encountered in the workplace, now Pneumoconiosis is a lung
disease that is due to chronic inhalation of certain mineral or organic dusts encountered in the workplace.
Now includes diseases induced by organic as well as inorganic particulates and chemical fumes and vapors.
 1. Anthracosis
Coal Worker
Pneumoconiosis
(CWP)
2. Simple CWP:
Black Macules
Centrilobular
Emphysema

3. Complicated CWP:
Black Nodules
(anthracosilicotic)
with Plum. Fibrosis
,TB, COPD in smokers

Figure 15.17 Progressive massive fibrosis in a coal

worker. A large. amount of black pigment is
associated with dense interstitial fibrosis
 Bonding between silica par cles & membranes → cell destruc on. Macrophages
Silicosis ingest particles & secrete fibrogenic cytokines. Progressive massive fibrosis

Includes sandblasting, rock mining, stone cutting, ceramic

work, polishing & sharpening metals.

The most prevalent chronic occupational disease in the world

 Silicosis is a common lung disease caused by inhalation
of proinflammatory crystalline silicon dioxide (silica)

Figure 15.18 Advanced silicosis. Scarring has

contracted the upper lobe into a small dark
mass (arrow). Note the dense pleural thickening Figure 15.19 Several coalescent collagenous silicotic nodules.
 Asbestosis: Clinical Course
• Very similar to those caused by other diffuse interstitial lung
diseases.
• Rarely appear fewer than 10 years after first exposure and are more
common after 20 to 30 years.
• Dyspnea , and cough associated with production of sputum, when
present, is likely to be due to smoking rather than asbestosis.
• Radiography: Irregular linear densities, particularly in both lower
lobes. With advancement of the pneumoconiosis, a honeycomb
pattern develops.

• The disease may remain static or progress to respiratory failure,

cor pulmonale, and death. Pleural plaques are usually
asymptomatic and are detected on radiographs as circumscribed
densities. Asbestosis complicated by lung or pleural cancer
(adenocarcinoma mesothelioma)- poor prognosis.
Asbestos-Related Diseases
• Localized fibrous plaques or, rarely, diffuse pleural fibrosis
• Pleural effusions, recurrent
• Parenchymal interstitial fibrosis (asbestosis)
• Lung carcinoma
• Mesothelioma
• Laryngeal, ovarian, and perhaps other extrapulmonary neoplasms,
including colon carcinoma
• Increased risks for systemic autoimmune diseases and cardiovascular
disease also have been proposed
Smaller asbestos fibers are engulfed by alveolar
macrophages which are activated to release inflammatory
mediators including fibrogenic cytokines. Bronchogenic Carcinoma: Commonest malignant
Larger fibers may enter the interstitium directly. Free complication Chrysolites and amphiboles
asbestos fibers are also fibrogenic.
Asbestos body/Ferruginous body (Fe coating)

Mesothelioma
Pleural Plaques
Amphiboles
KEY CONCEPTS: Pneumoconioses
■ Encompass a group of chronic fibrosing diseases of the lung resulting
from exposure to organic and inorganic particulates, most commonly
mineral dust.

■ Pulmonary alveolar macrophages play a central role in the

pathogenesis of lung injury by promoting inflammation and producing
reactive oxygen species and fibrogenic cytokines.
 KEY CONCEPTS: Pneumoconioses
■ Asbestos fibers come in two forms; the stiff
amphiboles have a greater fibrogenic and carcinogenic
potential than the serpentine chrysotiles.
■ Asbestos exposure is linked with six disease processes:
(1) parenchymal interstitial fibrosis (asbestosis); (2)
localized pleural plaques (asymptomatic) or rarely diffuse
pleural fibrosis; (3) recurrent pleural effusions; (4) lung
cancer; (5) malignant pleural and peritoneal
mesotheliomas; and (6) laryngeal cancer.
■ Cigarette smoking increases the risk of lung cancer in
the setting of asbestos exposure; even family members
of workers exposed to asbestos are at increased risk for
cancer and mesothelioma.
KEY CONCEPTS: Pneumoconioses
■ Silicosis is the most common pneumoconiosis in the world, and crystalline
silica (e.g., quartz) is the usual culprit. The lung disease is progressive even
after exposure stops.
■ The manifestations of silicosis can range from asymptomatic silicotic
nodules to large areas of dense fibrosis; persons with silicosis also have an
increased susceptibility to tuberculosis. There is two-fold increased risk of
lung cancer.
■ Coal dust-induced disease varies from asymptomatic anthracosis to simple
coal workers’ pneumoconiosis (coal macules or nodules, and centrilobular
emphysema), to progressive massive fibrosis (PMF), manifested by increasing
pulmonary dysfunction, pulmonary hypertension, and cor pulmonale.
Chronic Diffuse Interstitial (Restrictive) Diseases

Pneumoconioses 20%
Sarcoidosis 20%
Idiopathic interstitial
pneumonias 20%
Collagen vascular diseases
10%
Others 30%
6 and 7
Complications of Therapies
• Drug-Induced Lung Diseases:
• Cause interstitial fibrosis, bronchiolitis obliterans, and eosinophilic pneumonia.
• Cancer therapy (e.g., bleomycin) cause pulmonary damage and fibrosis .
• Amiodarone (cardiac arrhythmias), causes significant pneumonitis in 5% to 15% of patients.
• Cough induced by ace inhibitors is very common.
• Illicit intravenous: Lung infections and particulate matter causes granulomas and fibrosis occur.
• Radiation-Induced Lung Diseases.
• Radiation pneumonitis involves the lung within the radiation port
• Acute radiation pneumonitis (lymphocytic alveolitis or hypersensitivity pneumonitis) occurs 1
to 6 months after irradiation in 3% to 44% of patients, depending on dose and age. It is manifest
by fever, dyspnea out of proportion to the volume of lung irradiated, pleural effusion, and
infiltrates that usually correspond to an area of previous irradiation. With steroid therapy, these
symptoms may resolve completely in some patients, while in others there is progression to
chronic radiation pneumonitis (pulmonary fibrosis).
Chronic Diffuse Interstitial (Restrictive) Diseases

Pneumoconioses 20%
Sarcoidosis 20%
Idiopathic interstitial
pneumonias 20%
Collagen vascular diseases
10%
Others 30%
8. Hypersensitivity Pneumonitis
• Spectrum of immunologically mediated, predominantly, lung disorders
caused by intense, prolonged exposure to inhaled of organic dust
containing antigens made up of the spores of thermophilic bacteria,
fungi, animal proteins, or bacterial products.

• Affected individuals have an abnormal sensitivity or heightened

reactivity to the causative antigen (in contrast to asthma), leads to
pathologic changes that involve the “interstitial wall” -“extrinsic
allergic alveolitis”.

• Progression to serious chronic fibrotic disease can be prevented by

removal of the environmental agent.
Hypersensitivity Pneumonitis
• Numerous syndromes are described:
• Farmer’s lung results from exposure to dusts
generated from humid, warm, newly
harvested hay that permits the rapid
proliferation of the spores of thermophilic
actinomycetes.
• Pigeon breeder’s lung (bird fancier’s disease)
is provoked by proteins from serum, excreta,
or feathers of birds.
• Humidifier or air-conditioner lung is caused
by thermophilic bacteria in heated water
reservoirs.
• Pet birds and moldy basements are easily
missed unless asked about specifically
Chronic Diffuse Interstitial (Restrictive) Diseases

Pneumoconioses 20%
Sarcoidosis 20%
Idiopathic interstitial
pneumonias 20%
Collagen vascular diseases
10%
Others 30%
 9. Histologic pattern: Desquamative Interstitial Pneumonia
(DIP)
Clin-Radiol-Path Dx: same
• Almost exclusively in smokers

• Insidious onset (weeks to months)

• Accumulation of macrophages in
airspaces without fibrosis

• Patients who do not improve may

respond to corticosteroids or
cytotoxic drugs. Prognosis is good,
with about 70% survival at 10 years.
 Histologic pattern: Respiratory Bronchiolitis (RB)
Clin-Radiol-Path Dx: Respiratory Bronchiolitis Interstitial Lung Disease (RB-ILD)
• A mild form of interstitial lung disease, related to DIP.
• Rare, mild inflammatory pulmonary disorder that
occurs almost exclusively in current or former heavy
smokers, usually between the third and sixth decades,
most likely with no gender predilection.
• Nearly all patients with respiratory bronchiolitis
asymptomatic
• Respiratory bronchiolitis interstitial lung disease
patients often symptomatic
• 90% dyspnea; 50% cough
• Pulmonary function tests: obstructive or restrictive >
normal > mixed patterns

• The course of RB-ILD is heterogeneous. Some patients

respond favorably to corticosteroids and/or smoking
cessation, but often there is no functional
improvement and the disease progresses despite
smoking cessation and treatment.
Pigmented macrophages accumulate in respiratory
bronchioles and adjacent alveolar spaces. Alveolar
parenchyma between bronchioles relatively normal
Respiratory Bronchiolitis Interstitial Lung Disease is now referred to as SRIF
Acute Respiratory Distress Syndrome (ARDS- Clinical)
= Diffuse Alveolar Damage ( Histology)
Damage to pulmonary capillary endothelium and
alveolar epithelium causes edema to enter pulmonary
alveoli.
This edema will result in hypoxia when oxygen cannot
cross edema into alveolar capillaries.
Clin-Radiol-Path Dx: Acute Respiratory Distress Syndrome- ARDS
Histologic pattern: Diffuse Alveolar Damage- DAD

DAD, acute exudative phase DAD, organizing phase

Prominent hyaline membranes. Core biopsy with masses of fibrin
Interstitial edema and inflammation. within alveoli.
Alveolus contains edema fluid few Fibroblasts within the fibrin and
inflammatory cells & RBCs. immature fibrous
connective tissue in some alveoli
reflect organization
The overall rate of death in the hospital
of approximately 40 %. Many
ARDS recover most of their lung
function within several months to two
years, but others may have breathing
problems shortness of breath and
fatigue and may need supplemental
oxygen for the rest of their lives.
These are Extra Detailed slides on Interstitial
Fibrosis Slides for Future Referral During the
Clinical Years- An update only if there is
additional interest in the topic
 Usual interstitial pneumonia (UIP): a clinically
significant pathologic diagnosis
• A pathologic or radiologic diagnosis of UIP is required for the clinical/multidisciplinary
diagnosis of idiopathic pulmonary fibrosis (IPF) but it has also been described in several
other clinical settings.
1. UIP is a pathologic diagnosis and is better conceptualized as a “pattern” than as
a specific clinical entity.
2. Pathology IS the gold standard for UIP.
3. “Soft” histologic features can raise the possibility of certain etiologies UIP, but
the final determination of etiology comes from the multidisciplinary team.
With few exceptions, there are no findings pathognomonic for any etiology in UIP.
4. UIP does not imply IPF
5. When HRCT suggests a non-UIP diagnosis such as NSIP and histology shows
UIP, histology has been shown to predict prognosis in multiple studies. In other
settings, the radiologic impression based on HRCT is often proven to be incorrect
by the histologic findings.

Modern Pathology; https://doi.org/10.1038/s41379-022-01053-3

Usual interstitial pneumonia (UIP)
• The pathologic correlate of the clinically defined entity idiopathic pulmonary
fibrosis (IPF).
• A pathologic or radiologic diagnosis of UIP is required for a clinical diagnosis of
IPF.
• The clinical diagnosis of IPF is made after a multidisciplinary discussion between
pulmonologists, radiologists and pathologists.
• The pathologic features of UIP can occur in a wide variety of clinical settings,
including various forms of connective tissue disease (CTD), familial interstitial
lung disease, asbestos exposure, fibrotic hypersensitivity pneumonitis.
• Most cases of UIP in lung biopsies are diagnosed in patients without an obvious
underlying cause (IPF). In each of these settings, a pathologic diagnosis of UIP
connotes a poor prognosis and a lack of response to immunomodulators when
compared to other histologic tissue reactions such as non-specific interstitial
pneumonia (NSIP) or organizing pneumonia.
Usual interstitial pneumonia (UIP): Pathology
• 1. Interstitial fibrosis in a patchwork pattern. This means that scarred lung with
significant architectural distortion and/or honeycombing is abruptly juxtaposed to
non-fibrotic lung. In UIP, fibrosis is always present in subpleural and paraseptal
lung parenchyma, but also commonly extends deeper into the lobule and
frequently involves peribronchiolar parenchyma. In advanced cases, the lobules
are entirely obliterated.
• 2. Scarring. This is fibrosis that distorts lung architecture (“architectural
distortion”) and is the most essential feature of the diagnosis .
• 3. Honeycomb change. This process also distorts lung architecture. It is
characterized by clusters of dilated, mucin-filled epithelium-lined airspaces in a
fibrotic background . Honeycomb change may be visible grossly and on high
resolution chest tomography (HRCT) or “microscopic honeycomb change”
• 4. Fibroblast foci. These are dome-shaped (convex on one side) collections of
fibroblasts within the interstitium. They are common in UIP but are not specific.
 Fig. 3 Honeycomb change in UIP. Explanted
Fig. 1 Pathologic features of UIP. Explant pneumonectomy in a
Fig. 2 Pathologic features of UIP. Same patient/case as lung from a 70-year-old man with a clinical
68-year-old man with a clinical diagnosis of IPF. A Pre-
Fig. 1. A Scarring distorts lung architecture (arrows). B diagnosis of IPF. A This section shows
transplant chest CT was read as “fibrotic interstitial lung
This image shows the difference between interstitial architectural distortion with extensive
disease with UIP imaging pattern”, with a comment that “the
fibrosis without architectural distortion (arrows) and honeycomb change, manifesting as clusters of
presence of significant air trapping makes the CT inconsistent
scarring (arrowheads). Scarring is the most essential dilated, mucin-filled airspaces (short arrows).
with UIP per the ATS criteria…”. Note honeycomb change in No normal lung architecture is identified.
feature for the diagnosis of UIP
the left lower lobe (arrow). Surgical lung biopsy 9 years prior Compare honeycomb change (short arrows)
to this CT was consistent with UIP. The patient was treated with dilated airways (traction bronchiolectasis,
with Pirfenidone. B Honeycomb change in the left upper lobe long arrows). Note that honeycombing
(arrow). C Explanted lung shows UIP with interstitial fibrosis in surrounds several airways. B Honeycomb
a patchwork pattern. Fibrosis with architectural distortion change at high magnification. Dilated bronchus
(scarring, short arrows) is juxtaposed to normal lung is at top. The honeycombed areas are filled
(arrowheads). Note extensive fibrosis around airways causing with mucin (short arrows) and are lined by
traction bronchiolectasis (long arrow). respiratory-type epithelium (arrowheads)
Fig. 5 Fibroblast foci in UIP (arrows). Note that these collections of fibroblasts (A–C) are
located within the interstitium, with a layer of epithelial cells covering their luminal
surface.
DOES UIP IMPLY IPF?
• No. UIP is a pathologic diagnosis, while IPF is a clinical (multidisciplinary)
diagnosis. While a multidisciplinary diagnosis of IPF does require a pathologic (or
radiologic) diagnosis of UIP, not all cases of pathologic UIP will be acceptable to a
multidisciplinary group as IPF.
• This is analogous to DAD, which is a pathologic diagnosis, while ARDS is a clinical
diagnosis. Many cases of pathologic DAD meet clinical criteria for ARDS, but some
do not.
• Similarly, some cases with a pathologic diagnosis of organizing pneumonia are
eventually deemed idiopathic by the clinical team and given the clinical label of
“cryptogenic organizing pneumonia” (COP). However, some cases of pathologic
organizing pneumonia are attributed to specific etiologies by multidisciplinary
teams, including infection, vaping, drug toxicity, CTD. Should we start labeling
some cases as “organizing pneumonia of COP” based on histologic findings
because some clinicians feel that a pathologic diagnosis of organizing pneumonia
represents COP?
DOES UIP IMPLY IPF?
• There are situations in which the treating physician may decide that -
despite a pathologic diagnosis of UIP - the clinical setting does not fit
with IPF. The clinical judgment as to whether a given case of UIP
represents IPF or not, takes into account many factors including the
patient’s demographics, history, exposures, tempo of disease,
radiologic findings, serologies, extrapulmonary clinical manifestations
and other factors.
DOES UIP IMPLY IPF?

• UIP is and always has been a clinically significant pathologic diagnosis that
connotes a poor prognosis, irreversibility, and poor response to
corticosteroids and other immunomodulators. In contrast, IPF, as defined
by the ATS/ERS guidelines, is a clinical diagnosis that requires
multidisciplinary input and assimilation of all available clinical, imaging and
laboratory data. By ATS/ERS definition, the diagnosis of IPF requires a
pathologic or radiologic diagnosis of UIP.

• However, IPF is not a pathologic diagnosis. Disagreements between expert

pulmonary pathologists regarding UIP revolve around the specificity of
histologic findings for indicating an etiology of UIP, and in how pathologic
findings should be worded in pathology reports