RESPIRATORY SYSTEM

Dr. Sharmila Dudani

. Prof (Path)
STRUCTURE

Bronchus- Have cartilage and submucosal glands

Bronchioles- No cartilage and submucosal glands.

Terminal Bronchiole - < 2 mm in diameter

Acinus – Respiratory bronchiole, Alveolar duct,

Alveolar sac, alveolus
Histology Pharynx, epiglottis,vocal cords lined by
Stratified squamous epithelium

Respy Tract- Pseudostratified

Ciliated columnar epithelium with
mucus secreting goblet cells.
Submucosal glands seen in trachea /
bronchi.

Alveoli lined by continous, plate like

flattened Type I pneumocytes
And rounded Type II pneumocytes
Type II pneumocytes secrete
surfactant and main cell in repair if
injury to Type I pneumocytes
CHRONIC OBSTRUCTIVE
PULMONARY DISEASES ( COPD)
✹ Partial ,complete obstruction at any level

Increase in resistance

Limitation of airflow

❖ Emphysema, Chronic Bronchitis, Bronchial

asthma, Bronchiectasis
✹ Forced Vital Capacity ( FVC)
➢ Volume of air that can be forcibly be exhaled from
lung after full deepest inspiration.

✹ Total Lung Capacity (TLC)

➢ Amt. of air exhaled after maximum inspiration +
residual volume

✹ Forced Expiratory Volume in 1 sec. (FEV1)

➢ FEV1 is volume of air blown out in 1 sec after full
inspiration.
Measure of small airway resistance.
 COPD
✹ Total Lung capacity (TLC) –normal
✹ Forced Vital capacity( FVC) –normal
Decreased expiratory flow rate
✹ Forced Expirat vol. at 1 sec(FEV1)- Decreased

✹ FEV1
------------- Decreased ( < 0.7 indicative of air
FVC way obstruction)
 EMPHYSEMA
✹ Abnormal permanent dilatation of the air spaces
distal to terminal bronchiole
✹ Destruction of their walls
✹ No obvious fibrosis

✹ Subtle ( functionally imp

small airway fibrosis presnt.
EMPHYSEMA - TYPES

➢ Centriacinar >95% cases

➢ Panacinar ( Pan lobular)

➢ Paraseptal (Distal acinar)

➢ Irregular
 CENTRIACINAR EMPHYSEMA
✹ Respiratory bronchiole affected
✹ Distal alveoli spared
✹ Emphysematous & normal airspaces in same
acinus + lobule
✹ Apical segments
of upper lobes
✹ In heavy smokers
PANACINAR EMPHYSEMA
✹ Acini enlarged from respiratory bronchiole to
terminal alveoli
✹ “Pan” : entire acinus; NOT entire lung
✹ Lower zones & anterior margins
✹ Assoc. with alpha-1
Antitrypsin deficiency
PARASEPTAL (DISTAL ACINAR)
✹ Distal part of acinus involved
✹ Adjacent to pleura, along lobular CT septa,
margins of lobules
✹ Adjoining fibrosis/ atelectasis
✹ Severe in upper half of lungs
IRREGULAR EMPHYSEMA
✹ Acinus irregularly involved
✹ Assoc. with scarring
✹ Common
✹ May be asymptomatic
OTHER TYPES OF EMPHYSEMA
✹ Bullous emphysema
✹ Interstitial emphysema
✹ Senile emphysema
✹ Compensatory hyperinflation (emphysema)
✹ Obstructive emphysema
 EMPHYSEMA- ETIOPATHOGENESIS
✹ Protease-Antiprotease Imbalance
Proteases- Elastase,Collagenase,Trypsin,Proteinase3
Cathepsin G
Released from neutrophils, macrophages
Cause Alveolar wall destruction- tissue damage

Antiproteases- α1 antitrypsin, Secretory Leukocyte

Protease inhibitor,α1 macroglobulin
Inhibitor of proteases
Protective
PROTEASES ANTIPROTEASES
Destructive Protective
Elastase ( Neutrophils mainly ) α 1 antitrypsin. Synthesized in liver.
Present in serum, interstitial fluid.
Macrophages, mast cells, pancreas, Secretory leukoprotease inhibitor in
bacteria. bronchial mucus.
Collagenase,Trypsin,Proteinase3 α 1 macroglobulin in serum.
Cathepsin G.
✹ Elastase α 1 antitrypsin
✹ Proteinase3
✹ Cathepsin G

Reactive Oxygen species

✹ Emphysema results from the destructive
effects of high protease activity in subjects
with low antiprotease levels.

✹ Pts’ with a congenital deficiency of

α 1 antitrypsin have increased tendency to
develop emphysema.
✹ Oxidant –Antioxidant Imbalance

✹ Oxidants- ROS. Present in smoke / activated PMNs

✹ Depletes antioxidants.
✹ Inactivates antiproteases.

✹ Antioxidants-Superoxide dismutase, glutathione.

✹ Present in lung.
✹ Neutralize ROS.
✹ Toxic injury and inflammation
✹ Cigarette smoke damages respiratory epithelium
✹ Damag.epithelium / macroph release LTB4, IL-8.TNF
etc.
✹ Inflammation and destruction of lung parenchyma.

✹ Infection : leads to exacerberation of existing disease.

No initiating role
 Smoke contains
Nicotine and ROS which
recruit neutrophils to
alveolar space.

Neutrophils activated to
Release elastase which
Causes tissue damage.

Neutrophil elastase
inhibited by ά1 antitrypsin.

ROS inactivate
antiproteases leading to a
functional deficiency.

Smoke increases
macrophage elastase, not
inhibited by α1 AT
 GROSS
✹ Panacinar-Voluminous lungs-overlapping heart
✹ Centriacinar-More severe in Upper 2/3 of lung.
✹ Large apical bullae (irregular /distal acinar)
Microscopy
✹ Thinning and destruction of alveolar walls
✹ Abnormally large airspaces
✹ Loss of attachment of alveoli to small airways

Advanced disease-
alveolar cap.diminished.

Broken septae, floating into alveolar

spaces, permanent enlargement of
airspaces

? Focal centriacinar fibrosis.

Why obstruction ?
Loss of attachment between alveoli and outer wall of
small airways

✹ Loss of elastic recoil

✹ Loss of radial traction / tethering

Collapse of respiratory bronchioles during expiration.

Limitation of airflow during expiration

No mechanical obst seen, but functional obst present.
CLINICAL FEATURES
✹ Symptoms when >1/3rd lung damaged
✹ Dyspnea
✹ Cough; wheezing
✹ Weight loss
✹ Barrel chested; hunched

✹ Prominent dyspnea , adequate oxygenation

✹ PINK PUFFERS
 EMPHYSEMA : CAUSES OF DEATH

➢ Respiratory acidosis ; coma

➢ Right heart failure ( Cor pulmonale)

➢ Massive collapse of lung (pneumothorax)

CHRONIC BRONCHITIS
✹ Persistent cough + production of sputum for
atleast 3 months in a year for atleast 2
consecutive years with no identifiable cause.

✹ Common in smokers’, people living in

polluted environments.
 ETIOPATHOGENESIS
✹ Chronic Irritation
➢ Tobacco smoke ( 90%)
➢ Grain, Cotton, Silica Dust / Air Pollutants- SO2,NO2

➢ Hypersecretion of mucus in large airways. (T+B)

❑ Enlargement of submucosal glands.
❑ Increase in goblet cells in small airways  airway obst.

➢ Smoking causes production of abn,.dry mucus due to

acquired CFTR dysfunction.
ETIOPATHOGENESIS
➢ Inflammation foll.inhalation of chronic irritants
❑ Acute / chronic inflammatry cells present.
❑ Later fibrosis ensues involv. small airways

➢ Infection
➢ Secondary role. Responsible for acute exacerbations.
Role of Smoking in Chronic Bronchitis
INTERFERES WITH CILIARY
ACTION OF RESP. EPITHELIUM

DIRECT DAMAGE TO EPITHELIUM

INHIBITS BRONCHIAL /
ALVEOLAR LEUKOCYTES TO
CLEAR INFECTION.

CHEMOATTRACTANT FOR
NEUTROPHILS. PROTEASES
RELEASED STIMULATE MUCUS
HYPERSECRETION.

ACQD CFTR DYSFUNCTION 

ABN, DRY MUCUS

Chronic Bronchitis 4-10x common in smokers

CHRONIC BRONCHITIS

HYPERSECRETION OF MUCUS IN LARGE

AIRWAYS

HYPERTROPHY OF SUBMUCOSAL GLANDS IN

TRACHEA AND BRONCHI

INCREASED NUMBER OF GOBLET CELLS

IN SMALL BRONCHI AND BRONCHIOLES

INCREASED MUCUS PRODUCTION

AIRWAY OBSTRUCTION

BRONCHIAL MUCOSA INFLAMMATION

BRONCHIAL SMOOTH MUSCLE

HYPERREACTIVITY-BRONCHOSPASM
Morphology
✹ Swelling edema of mucus membrane
✹ Excessive mucopurulent secretions.May form
casts filling bronchi / bronchioles.
✹ Squamous metaplasia of lining epithelium
✹ Lymphocytic inflammation
✹ Enlargement of mucus secreting glands of trachea/
bronchi
✹ Reid index: ratio of thickness of mucus glands to wall
thickness .(Normal: 0.4)
✹ Mucus hypersecretion- large airway d.
✹ Airflow obstruction-small airway d.

✹ Narrowing of bronchioles: goblet cell metaplasia,

mucus plugging, inflammation, fibrosis: chronic
bronchiolitis
✹ Severe cases : Bronchiolitis obliterans: fibrosis;
obliteration of lumen
Clinical Features
✹ Persistent productive cough
✹ Dyspnea on exertion
✹ Large edematous person
✹ Gradually hypercapnea, hypoxemia , mild
cyanosis:
✹ Edema + Cyanosis
✹ Blue bloaters

✹ Death from
➢ Cor pulmonale
➢ Intercurrent infections
Euler Liljestrand
mechanism wherein
pulm.arteries constrict and
systemic arteries dilate in
presence of hypoxia.
 EMPHYSEMA CHRONIC BRONCHITIS

Age 50-75 years 40-45 years

Dyspnoea Severe and early Mild and late

Cough Late. scant sputum Early. Copious sputum

Infections Uncommon Common

Respy Insufficiency Terminal Repeated

Cor pulmonale Terminal Common

Xray Voluminous lung-small Normal lung

heart

Appearance PINK PUFFER BLUE BLOATER

BRONCHIAL ASTHMA
✹ Chronic inflammatory disorder of airways
✹ Characterised by increased airway responsiveness to
a variety of stimuli.

✹ Variable, episodic bronchoconstriction, airflow

limitation, inflammation of bronchial wall, and
increased mucus secretion.
CLASSIFICATION

ATOPIC / EXTRINSIC

• IgE and TH2 mediated

response to environ. Ags

NON-ATOPIC / INTRINSIC

• Triggered by non- immune

stimuli-drugs, viral infections
ATOPIC ASTHMA

✹ Usually begins in childhood.

✹ Positive family history present.
✹ Triggered by environmental Ags- dusts,pollen, animal
dander, foods.
✹ Serum IgE levels high.
✹ Other associated allergies-urticaria,allergic rhinitis,
eczema.

➢ Allergen sensitisation and immune activation present.

➢ Skin test with offending allergen is positive
NON-ATOPIC ASTHMA
✹ Triggered by
➢ viral infections of respiratory tract ( rhinovirus,
parainfluenzae )
➢ air pollutants (SO2,NO2, ozone)
➢ Inhaled irritants (fumes, resins,chemical dusts,
gases)
✹ Positive family history uncommon.
✹ Serum IgE levels normal.

✹ Skin test is negative.

OTHER TYPES OF ASTHMA

✹ Drug induced Asthma

➢ Aspirin inhibits cyclooxygenase pathway in AA
metabolism. Decreased PGE2.

✹ Occupational asthma
➢ Due to fumes, chemicals, epoxy resins,
formaldehyde, plastics
 ETIOPATHOGENESIS
✹ Genetic predisposition to Type I hypersensitivity
✹ Exaggerated TH2 response against environmental
antigens.
1L-4 stimulates B cells  IgE
1L-5 activates eosinophils
TH2
IL-13 stimulates mucus secretion+
IgE production from B cells
Pathogenesis
IgE mediated hypersensitivity
Triggered by env.ags
Initial sensitization to Ags -
Stimulate inductn of TH2 cells
IL13
Secrete cytokines-
IL-4,IL-5 and IL-13

Stim. B cells to produce IgE

IgE coats mast cells
(sp.receptor)
Subsequent exposure to Ag
Acute and Late phase
response
Activation of mast cells
✹ When mast cell bound
with IgE re exposed to sp. Ag
✹ Cross linking of adj. IgE abs
✹ Activation of signals for
degranulation . Discharge of
primary mediators.
Primary mediators
✹ Biogenic amines- Histamine
(intense s.m.cont., incr.vasc.permeability, secretions. )

✹ Enzymes – Neutral proteases, Acid hydrolases

( tisssue damage)

✹ Proteoglycans- Heparin, chondroitin sulfate

Early Phase Response ( Immediate )
✹ Within 5-30 minutes. Subsides in 60 mins.
✹ Bronchoconstriction ( smooth muscle spasm)
✹ Increased mucus prodn( glandular secretn)
✹ Vascular leakage( edema)
✹ Variable vasodilatation
Late Phase Response ( Delayed )
✹ Within 2-24 hours. Lasts for days.
✹ Infiltration of tissues with eosinophils, neutrophils,
monocytes, basophils
✹ Tissue destruction

✹ Secondary mediators
✹ Leukotriene C4, D4, E4
✹ Prostaglandin D2
✹ Cytokines- TNF,IL-1,IL-3,
IL-4,IL-5,IL-6.GM-CSF.
✹ PAF
Activation of mast cells
Activation of phospholipase A2
✹ Acts on memb. Phospholipids
to release arachidonic acid.
➢ Leukotrienes
➢ Prostaglandins
✹ PAF
✹ Cytokines- TNF,IL-1,IL-3,IL-4,
IL-5,IL-6,GM-CSF
Role of Eosinophils
✹ Recruited by eotaxin

✹ Produce Major basic protein and eosinophil

cationic protein – toxic to epithelial cells

✹ Activate mast cells

 Immediate Phase

1.Re exposure of IgE coated mast

cells to Ag -Causes release of
mediators
Mediators open intercellular tight
junctions
Increase penetration of Ag to more
submucosal Mast cells

Direct stimulation of vagal nerve 

Bronchoconstriction
Edema ( vascular permeability )
 Late Phase

Release of mast cell cytokines

cause Influx of eosinophils,
neutrophils,basophils, Lymphocytes.

Eosinophils release Major basic

protein and eosinophil cationic
protein which damages the
epithelium.
 Genetics of Asthma
✹ Chromosome 5q (encodes cytokines IL-3,4,5,9,13)

✹ ADAM-33 (expresed by lung fibroblasts, bronchial

smooth muscle )Polymorphism accelerate proliferation of
bronchial smooth muscle and fibroblasts.

✹ β adrenergic receptor gene ( Down regulation to β

–agonist stimulation.

✹ Upregulation of chitinases ( contributes to TH2

inflammation)
Morphology Gross
➢Overinflated

➢Bronchi/ bronchioles
obstructed : thick,
tenacious mucus plugs

Microscopically

➢Mucus plugs: whorls of

shed epithelium:
Curschmann’s spirals

➢ eosinophils

➢Charcot leyden crystals

(eosinophil membrane
protein)
AIRWAY REMODELLING

1.Thickening of wall
2.Sub- basement membrane fibrosis
3.inceased vascularity, inflammation
4.Hypertrophy/hyperplasia of smooth
5.Increased size of submucosal
glands
6. Accumulation of mucus in lumen
7. Increased number of goblet cells
Clinical Features

✹ Breathlessness, chest tightness, wheezing,

cough
✹ Status Asthmaticus
✹ Sputum:
➢ eosinophils
➢ Curschmann’s spirals
➢ Charcot Leyden crystals
BRONCHIECTASIS
✹ Permanent dilatation of bronchi and
bronchioles caused by destruction of muscle
and elastic tissue.

✹ Results from/ associated with chronic

necrotizing infections
 ETIOPATHOGENESIS
✹ Bronchial Obstruction
➢ Foreign body / Tumour / Impacted mucus

✹ Post Infectious -Necrotiz.Pneumonias

➢ Bacteria-Mycob.TB/staph aureus/H.influen/Pseudomonas /
Klebsiella sp.
➢ Viruses – Adenovirus / HIV / Influenza
➢ Fungi - Aspergillus
✹ Congenital
➢ Cystic fibrosis- Defect in chloride ion transport in mucus
accumn of thick,viscid mucus which obstructs airways.
➢ primary ciliary dyskinesia – AR. Absence / short. of
arms of cilia retention of secr./ recurrent infections
➢ Kartagner syndromes- bronchiectasis, situs inversus,
sinusitis.

✹ Others
➢ RA/ SLE / IBD
RUCT
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Morphology
❖ Bilateral lower lobes; Vertical air passages
❖ Most severe in distal bronchi/ bronchioles
❖ Airway dilation to 4 X normal
❖ Dilated bronchi upto pleural surfaces
❖ C/S : cysts; mucopurulent secretions
✹Types of Bronchial dilatation
➢ Cylindrical – long tube like enlargements

➢ Fusiform/ Varicose - irregular dilatation

➢ Saccular/Cystic – sharp, sac like distensions

 Microscopy
Acute
Dense inflammation within
walls of bronchi / bronchioles.
Ulceration of lining epithelium
Squamous metaplasia
Lung abcess

Chronic
Fibrosis of wall bronchi/
bronchioles
Peribronchiolar fibrosis
Obliteration of lumen
Clinical Features
✹ Severe, persistent cough
✹ Foul smelling sputum; hemoptysis
✹ Dyspnea; orthopnea; cyanosis
✹ Fever; clubbing

Complications
✹ Cor pulmonale; brain abscess; amyloidosis
✹ SAHI

YA

GALAT
✹ Centriacinar emphysema is common in
patients’ with A1 anti trypsin deficiency.

✹ Centriacinar emhysema is seen in smokers.

A1 antitrypsin deficiency is associated with
pan acinar emphysema.
✹ In obstructive lung disease FEV1 is < 0.7

✹ FEV1 < 0.7

FVC
✹ Pink Puffers suffer from frequent respiratory
infections.

✹ Blue bloaters have repeated respiratory

infections.
 ATELECTASIS ( COLLAPSE)
✹ Loss of lung volume .

➢ Congenital
✹ incomplete expansion of the lungs (neonatal atelectasis)

➢ Acquired
✹ collapse of previously inflated lung
RESORPTION COMPRESSIO CONTRACTIO
• Obstruction N N
prevents air • Associated • Due to local
reaching with or
distal accumulatio generalized
airways. Air n of fluid/ air fibrotic
present gets / blood in changes in
resorbed. pleural lung / pleura
• Eg Obst. of cavity hamper
bronchus by causing expansion
mucus plug. mechanical
collapse of
adj.lung.
Obstructive Restrictive
✹ Increased resistance ✹ Decreased
to airflow expansion of lung;
decreased total lung
capacity
✹ Partial/ complete
obstruction: trachea to
respiratory ✹ Chest wall disorders-
bronchioles polio, obesity, pleural
disease,
kyphoscoliosis
✹ Emphysema, chronic
bronchitis,
bronchiectasis, ✹ Acute/ chronic
asthma interstitial/ infiltrative
diseases eg ARDS,
pneumoconiosis
✹ FeV1: FVC reduced
✹ FeV1 : FVC normal
CHRONIC INTERSTITIAL,RESTRICTIVE
DISEASES
✹ Reduced expansion of lung parenchyma.
✹ Lungs are stiff,-more pressure / effort required
to expand lungs
✹ Increased effort of breathing – dyspneA
CHRONIC INTERSTITIAL,RESTRICTIVE
DISEASES
✹ Diffuse, chronic involvement of the pulmonary
interstitium by inflammation and fibrosis

✹ Heterogenous group
✹ Unknown cause
 Alveolar septa
-Endothelium
-Basement membrane
- Interstitium
-Alveolar epithelium

Damage to alveolar epithelium +

Interstitial vasculature produces
Abnormalities in ventilation-
perfusion ratio -->hypoxia

Progression
Respiratory failure
Pulmonary Hypertension
Cor Pulmonale
✹ Chest X-ray –Bilateral infiltrative lesions (small
nodules, irregular lines, ground glass shadows)
✹ Advanced stage-diffuse interstitial fibrosis
End stage lung- Honey comb lung

Irregular air spaces between bands of dense fibrous connective tissue.

 CATEGORIES OF CHRONIC
INTERSTITIAL LUNG DISEASE
Fibrosing- IPF / NSIP / Cryptogenic org.pneumonia/
Pneumoconiosis / Drug reactions /radiation
pneumonitis

Granulomatous- Sarcoidosis / Hypersensitivity

pneumonitis
SmokingRelated-Desquamative interstitial pneumonia

Eosinophilic

Others -Pulmonary alveolar proteinosis,LCH

 IDIOPATHIC PULMONARY FIBROSIS
Progressive pulmonary fibrosis Respy failure
Cause unknown
Rec alveolar epithelial injury aberrant repair

✹ Genetic predisposition present

✹ M>F
➢ Genetic factors
Mutations in TERT / TERC gene
Mutations in SPA gene
Mutations in MUC5B gene
➢ Age : Older individuals. Rare before 50 years
➢ Environmental factors
Smoking
exposure to environmental irritants / toxins
 Repeated cycles of epithelial
Injury.
Injured Type 1 pneumocytes

Secrete profibrogenic factors like

TGF-β

TGF -B
Epithelial cells express
mesenchymal proteins.
Acquire features of
myofibroblasts.

Favours deposition of collagen/

ECM molecules.
IDIOPATHIC PULMONARY FIBROSIS
✹ Intrinsic abnormality of tissue repair following
epithelial injury
✹ Exuberant fibroblastic/ myofibroblastic
proliferation
✹ Favors deposition of collagen /ECM
molecules.
Gross - IPF
✹ Retraction scars along interlobular septa
✹ Lower lobe involved
✹ Subpleural regions
c/s- Fibrosis ( Firm, whitish areas )
Microscopy – IPF(Usual Interstitial Pneumonia )
✹ Patchy interstitial fibrosis
✹ Fibrosis of different ages

EARLY LESIONS LATE LESIONS

Exuberant fibroblastic More collagenous. Less
proliferation ( Fibroblastic cellular.
foci )

✹ Coexistence of both early and late lesions.

( Temporal heterogeneity)
✹ Destruction of alveolar architecture due to
dense fibrosis.
✹ Moderate inflammation in fibrotic areas
✹ Formation of cystic spaces lined by Type II
pneumocytes
✹ Pulmonary artery hypertensive changes seen.

Histologic changes labelled as usual

Interstitial pneumonia ( UIP )
Clinical Features
✹ 40-70 years
✹ Gradual onset of increasing dyspnoea
✹ Dry cough
✹ Hypoxaemia,
✹ Cyanosis
✹ Survival – 3 years
ADULT RESPIRATORY DISTRESS
SYNDROME ( ARDS )
✹ Clinical syndrome caused by diffuse alveolar
capillary damage.

✹ Syn. Shock lung / Diffuse alveolar damage /

acute lung injury (ALI)/ non cardiogenic
pulmonary edema
 ARDS – CLINICAL FEATURES
✹ Rapid onset of
➢ Severe respiratory distress
➢ Cyanosis
➢ Severe arterial hypoxaemia which is refractory
to O2 therapy.
➢ Diffuse bilateral infiltrates on Xray- chest

✹ May progress to multisystem organ failure.

CAUSES of ARDS
ARDS -CAUSES
INFECTIO
N CHEMICAL
INJURY HEMATOLOGI
Acetylsalicyli C
INFECTION PHYSICAL c acid / CONDITIONS
SEPSIS INJURY Barbiturate / DIC
DIFF.PULM.IN HEAD INJURY methadone Multiple
FECTION NEAR overdose transfusions
Viral / DROWNING INHALED OTHERS
Mycoplasmal FRACTURES IRRITANTS Pancreatitis
/ miliary TB / WITH FAT O2 Toxicity Uremia
Pneumocysti EMBOLISM Smoke Drugs
s BURNS Irritant gases
GASTRIC
ASPIRATION
ARDS- ETIOPATHOGENESIS
✹ Diffuse damage to alveolar capillary
membrane
✹ Initial injury either to capillary endothelium or
alveolar epithelium or both.

✹ Neutrophils play an important role in

pathogenesis
Damage to alveolar capillary membrane

✹ Alveolar macrophages secrete cytokines

✹
✹ Activation of endothelium

✹ Increased expression of adhesion molecules,

procoagulant proteins, chemokines.

✹ Adhesion and extravasation of neutrophils into

alveolar space
✹ Neutrophils release inflammatory mediators

✹ ROS, proteases, cytokines, (MIF)

✹ Recruitment of leukocytes

✹ Further endothelial injury

✹ Leaky pulmonary capillaries

✹ Interstitial / intra alveolar edema

Organisation of edema fluid + necrotic epithelial

cells ( Hyaline membranes)

✹ Alveolar gas exchange compromised.

Macrophages release IL-1,IL-8
TNF

Neutrophils into alveolar

space.

Oxidants, Leukotrienes,
Proteases, PAF.

local tissue damage, accumn

of edema fluid, damage to
Type I + Type II pneumocytes.

Surfactant loss, hyaline

Membrane formation( fibrin
rich edema fluid + necrotic
epithelial cells.

Release of PDGF and TGF β

Fibrosis of alveolar walla

✹ Lung injury in ARDS is due to an

✹ imbalance between proinflammatory and anti

inflammatory mediators.
ADULT RESPIRATORY DISTRESS
SYNDROME : MORPHOLOGY

✹ Acute Stage:
❖ Gross: heavy,airless, red, boggy
MICROSCOPY
❑ Acute stage :
✹ Congestion, necrosis of epithelial cells
✹ Interstitial / Intra alveolar edema
✹ Inflammation, PMNs in capillaries
✹ Fibrin deposition
✹ Alveolar walls : waxy, hyaline membranes
( fibrin rich edema fluid+ necrotic epithelial cells)
❑ Organizing stage

➢ Type II epithelial cells proliferate

➢ Granulation tissue response in alveolar wall.

➢ Resolve Fibrous scarring of

alveolar septae
 Diagnosis
✹ Diffuse bilateral infiltrates on Xray chest
✹ PAO2 : FiO2 < 300 mmHg ( ALI) <200 (ARDS)
✹ No evidence of CCF
✹ Underlying cause is present
 PNEUMOCONIOSIS
✹ Non neoplastic lung reaction to inhaled dusts
➢ Mineral dusts
➢ Organic/ inorganic particulates
➢ Chemical fumes/ vapours

➢ Earlier known as Occupational Lung diseases

well defined occupational exposure to sp.agents
❖ CWP- coal dust
❖ Silicosis – silica particles
❖ Berrylosis- berryllium
❖ Asbestosis- asbestos fibres
❖ Bagassosis – Bagasse
PATHOGENESIS
Depends on
❖ Amount of dust retained in airways
❖ Size, shape, buoyancy of particles
❖ Particle solubility/ physicochemical properties
❖ If inflammasome activated, more intense response
❖ Other irritants eg cigarette smoking

✹ Most dangerous: 1-5µ particle size

✹ Genetic variation in susceptibility
COAL WORKERS PNEUMOCONIOSIS
✹ Asymptomatic anthracosis

✹ Simple coal worker’s pneumoconiosis

✹ Progressive massive fibrosis

OR
Complicated coal workers pneumoconiosis
 Particles reach alveoli,
Pathogenesis Engulfed by alveolar macrophages
transported to respiratory bronchioles
expelled via action of ciliated epithelium.

Some enter interstitium taken up by

lymphatics.
When macrophages die, they release
inorganic material to surrounding tissue l
reactive fibrosis around the foreign
particle.
Reaction starts at level of small
bronchioles, extends to alveoli  loss of
elasticity  Emphysematous dilatation of
acini
particles reaching alveoli are small <
2mm.
Larger ones 2-10 mm deposit in bronchi
and bronchioles, removed by ciliary action.
ANTHRACOSIS
✹ Coal miners / Urban dwellers / Smokers
✹ Upper lobes affected
✹
✹ Macrophages ( containing carbon particles )
accumulate under pleura, around blood vessels and
interstitium of lungs.
✹ Asymptomatic
SIMPLE CWP

➢ Coal macules: 1-2mm

Aggregation of Carbon laden macrophages

➢ Coal nodules : > 2mm

Carbon laden macrophages + collagen fibres
Esp. in upper lobes, around respiratory bronchiole.
Dilatation of adj.alveoli –centrilobular emphysema.
COMPLICATED CWP ( PMF)
✹ Many years foll. simple CWP
✹ Multiple intensely black scars 2 – 10cm

✹ Microscopy
➢ Dense collagen

➢ Pigment in alveolar/
➢ interstitial macrophages
➢ Necrotic centre

✹
 Clinical Features
✹ Benign disease
✹ Mild impairement in lung function

✹ 10% of pts’ develop PMF

✹ PMF- pulmonary dysfn / pulm.HT, Cor pulmonale.
✹ Use of domestic coal – risk of lung cancer
SILICOSIS
✹ Caused by inhalation of crystalline silicon dioxide
✹ Most prevalent occupational disease.

▪ Foundry workers / Sandblasting /Hardrock mining /

Stone cutting / demolishing of concrete structures

▪ Seen after years of exposure as a slowly progressing,

nodular, fibrosing pneumoconiosis
 Cystalline (Quartz, Crystobalite, Tridymite)
✹ Silica:
Amorphous

✹ Silica particles engulfed by macrophages

✹ Activate inflammasome

Release of IL-1 and IL-18

Activation of fibroblasts

Collagen deposition
Pathogenesis
Crystalline form of silica ( Quartz) more
fibrogenic
After inhalation,silica particles ingested by
macrophages

Activation and release of mediators

OFR, ,IL-1, IL-18 Fibrogenic cytokines

Deposition of collagen

Steady recruitment of macrophages,

lymphocytes to alveoli and interstitium

Formation of silicotic nodule.

GROSS
✹ Early Stages
➢ Tiny, discrete, pale to blackened nodules
➢ Upper zones
✹ Later stages
➢ Hard, collagenous scars
➢ Central softening/ cavitation
➢ Fibrotic lesions in L.N / pleura
➢ Eggshell calcification in LN
➢ PMF
Microscopy
✹ Nodular lesions
➢ Concentric layers of
hyalinised collagen
➢ Dense capsule of
condensed collagen.
➢ silica laden macrophages

Polarised microscopy:
➢ Birefringent silica
particles.
Clinical Features
✹ Pulm.Function usually normal
✹ Dyspnea late in the disease.

✹ Associated with increased susceptibility to TB

✹ 2X increased risk of developing lung cancer
ASBESTOS
✹ Crystalline, hydrated silicates; form fibers

➢ Mining, milling & fabrication

➢ Installation/ removal of insulation

➢ Fibrous / Pleural plaque

➢ Pleural effusion
➢ Interstitial fibrosis( Asbestosis)
➢ Lung carcinoma
➢ Mesothelioma
PATHOGENESIS
❖ 2 types : Both fibrogenic
❖ Serpentine : curly & flexible
➢ Chrysotiles

❖ Amphibole: straight, stiff, brittle.

➢ Crocidolite /Amosite/Tremolite/Anthophyllite/
Actinolyte
➢ Associated with mesothelioma
Pathogenesis
✹ Chrysotiles (serpentine : curly / flexible)
more soluble; impacted in upper airways

✹ Crocidolite (Amphiboles:straight /stiff / brittle)

align in airstream; Penetrate deeper. Reach
interstitium.

➢ Length>8 µ; thickness<0.5 µ more injurious

 Straight,stiff and brittle amphiboles align
Pathogenesis
themselves In airstream and are delivered
deeper in the lungs

penetrate epithelial cells, reach interstitium

Longer(> 8um)and thinner(<0.5um) fibres
more Injurious

Asbestos fibres ingested by macrophages

activation of inflammasome

Release of inflammatory,fibrogenic mediators

Generalised pulmonary inflammation And

diffuse interstitial fibrosis

The fibers phagocytized by the macrophages

are coated with hemosiderin, ferritin and
glycoprotein to form the asbestos bodies
✹ Tumour initiator & promoter. Carcinogenic effects
mediated by OFR which localise in distal lung.

✹ Asbestos exposure alone : 5X risk of lung CA

✹ Carcinogens in tobacco adsorbed on asbestos
fiber
✹ Smoking + asbestos exposure -55X increased
risk of Lung CA.
Gross

✹ Begins subpleurally in lower lobes( contrast CWP

and silicosis )
✹ Middle / Upper lobe affected in advanced
disease .

✹ “Honeycomb Lung”
Microscopy
✹ Diffuse pulmonary interstitial fibrosis
✹ Presence of asbestos bodies --golden brown
fusiform / beaded rods with a translucent
centre.
✹ Asbestos body --Asbestos fibre coated with
iron cont. protein (ferritin + glycoprotein)
✹ Diffuse interstitial fibrosis

✹ Starts around respiratory bronchioles.

✹ Involves adjacent alveoli. Distorts the

architecture

✹ Trapping; narrowing of pulmonary arteries 

Pulm.HT and cor pulmonale
Pleural plaque
❖ On anterior/ posterolateral parietal pleura/
domes of diaphragm

❖ Well circumscribed plaques of dense collagen

❖ Visceral pleural fibrosis

❖ Pleural effusion-serous/
bloody
Clinical Features
✹ Dyspnea
✹ Productive cough
✹ Respiratory failure/ cor pulmonale

✹ Risk of
➢ Carcinoma: 5 times higher
➢ Mesothelioma: 1000 times
 PLEURAL TUMOURS-MESOTHELIOMA
✹ From visceral/ parietal pleura (mesothelial cells)
✹ Asbestos exposure in 50%

✹ Latent period : 25- 45years

✹ Smoking: risk not increased
MESOTHELIOMA- ETIOPATHOGENESIS
✹ Asbestos not metabolised, fibres remain for
life.
✹ Localise near the mesothelial layer

Generate ROS

DNA damage ( oncogenic mutations )

✹ Deletions in chromosome 1p,3p,6q,9p,22q
seen in 60-80% of mesotheliomas

✹ Presence of SV40 viral DNA sequence in

60% -80% . ( SV40 –potent carcinogen. Inactivates
RB and p53. )
✹ Preceded by plaque
✹ Lung ensheathed by yellow white, firm or
soft ,gelatinous grayish pink tumour
✹ Obliterates pleural space

✹ Direct invasion of thoracic structures/

subpleural lung may be seen
✹ Mesothelial cells are biphasic -
✹ epithelium lining cells + mesenchymal
stromal cells

Microscopy :
❖ 3 patterns
➢ Epithelioid ( 60%)
➢ Sarcomatoid ( 20%)
➢ Mixed ( 20%)
Clinical Features
✹ Dyspnea, Chest pain
✹ Recurrent pleural effusions.
✹ Direct lung / hilar lymph node invasion
✹ Prognosis poor
✹ Death within 1 year.
SARCOIDOSIS
✹ Systemic, granulomatous disease of unknown
cause

✹ Noncaseating granulomas in many organs.

✹ Bilateral hilar lymphadenopathy / lung

involvement : 90%
✹ Involvement of skin / eye : 25 %
✹ F>M
ETIOPATHOGENESIS
❑ Disordered immune regulation
❑ Exaggerated cellular immune response
skewed in direction of CD4 + TH1 cells

❑ Accumulation of activated TH1 cells in

affected organs
❑ Release of mediators Activate monocytes
❑ Formation of granuloma
✹ CD4+ T cells increased (CD4 / CD8 ratio range from
5:1 to 15:1)
✹ Increased levels of TH1 cytokines – IL-2 and IFN-γ
✹ Increased levels cytokines –IL-8,TNF,MIP1α

✹ Polyclonal hypergammagloulinemia due to TH cell

dysfunction
✹ Anergy to common skin test antigens such as
Candida or tuberculosis ( PPD)
❑ Genetic predisposition
▪ HLA A1 and HLA B8

❑ Environmental factors
▪ Mycobacterium, Propionibacterium, Rickettsia
GROSS
✹ Normal
➢ Advanced cases-
✹ Small nodules/ 1-2cm consolidations which do
not cavitate.
✹ No caseation necrosis seen.
MICROSCOPY
➢ Noncaseating granulomas
➢ Granulomas composed of epithelioid cells
➢ Langhan’s/ foreign body giant cells.

➢ Granulomas replaced by fibrous scars in chronic cases.

➢ Giant cells may contain :
➢ Stellate inclusions: Asteroid bodies
Laminated concretions: calcium + protein:
Schaumann bodies seen within giant cells

Not pathognomic.

Residual bodies
LUNG INVOLVEMENT
✹ Seen in 90% of patients’.
✹ Granulomas seen primarily along lymphatics,
blood vessels, and bronchi
✹ Alveolar involvement less.
✹ Advanced cases show fibrosis / hyalinisation
✹ “Honey comb lung”
LYMPH NODE INVOLVEMENT
✹ Seen in 75-90 % of pts’
✹ Mainly Hilar and paratracheal
✹ Peripheral lymphadenopathy in 35%
✹ Nodes are non-tender, rubbery, firm texture
non-matted
 CUTANEOUS MANIFESTATIONS
✹ Seen in 35-50% pts’.
➢ Discrete subcut nodules-erythema nodosum
➢ Elevated erythematous plaques
➢ Reddened, scaly flat lesions

LUPUS PERNIO
Ocular Involvement
✹ Iritis / Iridocyclitis
✹ Corneal opacity / Glaucoma
✹ Total loss of vision
✹ Inflammation of lacrimal glands
✹ Mikulicz Syndrome - Bilateral sarcoidosis of
parotid, submaxillary, sublingual gland and
uveal involvement.
Other organ involvement
✹ Liver / Spleen
✹ Bone marrow
✹ Muscle
CLINICAL FEATURES
✹ Insidious onset of respiratory abnormalities.
( dyspnea, cough, chest pain, hemoptysis)

✹ Fever, fatigue, weight loss.

✹ Erythema nodosum/ arthralgia -20-30%

✹ Others – Ocular / skin etc

✹ Disturbances in calcium metabolism
-hypercalciuria, hypercalcemia, rarely
nephrocalcinosis due to increased formation of
calcitrol by alveolar macrophages

✹ Serum ACE levels increased

✹ BAL fluid – Increased CD4 : CD8 ratio ( N- 2:1)

PROGNOSIS
✹ 65-70% pts- complete recovery
✹ 20% - permanent loss of lung function/ visual
impairement
✹ 10-15 %- pulmonary fibrosis / CNS / cardiac
complications
SARCOIDOSIS AT A GLANCE
PULMONARY HYPERTENSION

Low resistance circulation

✹

Pulm. BP : 8-20 mm.Hg

 PULMONARY HYPERTENSION
✹ Mean PAP > 25 mm.Hg at rest /
>30 mmHg. after exercise
✹

✹ Types
➢ Primary
➢ Secondary
 PULM.HT – WHO GROUPS
✹ I : Pulm HT – diverse gp impact. small muscular
arteries
➢ Idiopathic,Autoimmune disorders Systemic sclerosis, SLE, HIV
✹ II: Pulm. HT secondary to left heart disease
➢ MS, VSD
✹ III: Pulm.HT due to lung parenchymal disease
➢ Interstitial lung disease, COPD, Obstructive sleep apnoea
✹ IV: Pulm HT due to recurrent thromboembolism
➢ Recurrent pulmonary emboli
✹ V : Pulm HT of multifactorial basis- Unclear glycogen storage diseases,
sarcoidosis
Pulmonary vascular resistance increased

Increased pulmonary blood pressure

Gp IV

Gp III

GP II
 SECONDARY PULM.HT- PATHOGENESIS
❑ Endothelial dysfunction (mechanical injury due to
increased blood flow.
❑ Fibrin (recurrent thromboembolism )

❑ Reduced vasodilators: NO, PGI2-> platelet adh

❑ Increased vasoconstrictors: endothelin
❑ GFs/ cytokines( PDGF, VEGF) – proliferation of
smooth muscle, productn of ECM
PRIMARY PULM. HT- PATHOGENESIS
✹ Inherited : mutation in bone morphogenetic
protein receptor type 2 (BMPR2); normally
inhibits proliferation
 Normally BMPR2 is inhibitory.
When Mutated leads to vascular
endothelial + smooth muscle
proliferation via the TGF-B pathway.

TGF-B Modifier genes- That control vascular

tone
Egs genes for endothelin, prostacyclin
Synthase, ACE

Environmental factors – unknown.

Proliferation of endothelial,smooth
muscle and intimal cells along with
concentric laminar intimal fibrosis.
 MORPHOLOGY
✹ Entire vascular bed affected
✹ Main elastic arteries: atheromas
✹ Small arteries+ arterioles (40-300µ) : medial
hypertrophy + intimal fibrosis narrowed
lumen
✹ Advanced cases
✹ Plexogenic pulmonary arteriopathy( Plexiform
lesion )
Tuft of capillary formations in lumina of dilated
thin walled small arteries
CLINICAL FEATURES-PRIMARY PULM HT

✹ Primary: women; 20- 40 yrs

✹ Dyspnea / Fatigue / Chest pain

✹ Respiratory distress; death from Cor

pulmonale
DIFFUSE PULM. HEMORRHAGIC SYND
✹ Immune mediated diseases

✹ Goodpasture synd
✹ Idiopathic pulmonary hemosiderosis
✹ Vasculitis associated hemorrhage-Wegener
granulomatosis, SLE
GOODPASTURE SYNDROME
✹ Autoimmune disease

✹ Destruction of BM in glomeruli, alveoli

✹ Autoantibodies against alpha3 chain of

collagen IV

➢ Proliferative
RPGN
➢ Necrotising H’gic interstitial pneumonitis
✹ Gross:heavy,areas of red brown consolidation
✹ Microscopy: Focal necrosis of alveolar walls
✹ Intra alveolar hemorrhages; hemosiderin laden
macrophages

✹ Later stage :Fibrous thickening of septae

✹ Hypertrophy of type II pneumocytes
✹ IF : linear deposits of IgG/ IgA/ IgM along BM
of septal wall

✹ Kidneys:
➢ focal proliferative glomerulonephritis
➢ crescentic glomerulonephritis
IDIOPATHIC PULM. HEMOSIDEROSIS
✹ Rare
✹ Intermittent diffuse alveolar hemorrhage.
✹ Cause – Unknown
✹ No anti basement membrane antibodies
✹ Seen mainly in children.
PNEUMONIA
✹ Infection of the lung parenchyma

✹ Acute and fulminant / chronic

✹ May involve alveoli / interstitium

✹ Can be caused by bacteria/ viruses /

mycoplasma / fungi.
✹ Histological spectrum:
➢ Bacterial- Fibrinopurulent alveolar exudate

➢ Viral- Mononuclear interstitial infiltrate

➢ Chronic- Granulomatous inflammn ± cavitn

✹ Systemic resistance of host is lowered
➢ DM, HIV, chronic diseases, cancer, immunosuppressive
therapy

✹ Impaired pulm. local defense mechanisms

➢ Loss of cough reflex – coma, anesthesia,n-m disor.
➢ Injury to mucociliary apparatus-smoking, immotile cilia
synd.
➢ Accumulation of secretions – cystic fibrosis,bronchial
obst.
➢ Interference of phagocytic action of alveolar
macrophages- alcohol,smoking.
➢
PNEUMONIA synd.

Streptococcus pneumoniae Mycoplasma,Chlamydia,RSV,

H.influenzae,Staph aureus Parainfluenza,Influenza Aand B
Klebsiella Coronavirus PNEUMONIA
HOSPITAL
IN
ACQD
COMMUNITY IMMUNOCOM
COMMUNITY PNEUMONIA
ACQD PROMISED
ACQD VIRAL
BACTERIAL HOST
PNEUMONIA
PNEUMONIA

Klebsiella, E.coli, Pseudomonas Cytomegalovirus,Pneumocystis

Staph aureus ( penicillin resistant ) jiroveci, atypical mycobacteria,
Invasive
aspergillosis,candidiasis
Other clinical Pneumonia settings/ syndromes
✹ Healthcare associated pneumonia
✹ Aspiration pneumonia
✹ Chronic pneumonia
✹ Necrotizing Pneumonia / lung abscess
PNEUMONIA -Pathogenesis
✹ Inhalation of microbes

✹ Aspiration of organisms from naso/

oropharynx

✹ Hematogenous spread from distant focus

BACTERIAL PNEUMONIA

✹ Alveoli filled with inflammatory exudate,

causing consolidation (solidification ) of lung

✹2 patterns depending on anatomic distribution

➢ Bronchopneumonia
➢ Lobar pneumonia
ACUTE BACTERIAL PNEUMONIA

✹ Bronchopneumonia
➢ Patchy areas of consolidation
➢ >1 lobe

✹ Lobar pneumonia
➢ Complete consolidation
➢ Part/ all of 1 lobe
➢ Strep pneumoniae >90%
✹ Predisposing conditions for Pneumonias
➢ Altered consciousness

➢ Depressed cough reflex

➢ Impaired function of alveolar macrophages

➢ Impaired mucociliary action

➢ Leucocyte dysfunction
MORPHOLOGY OF LOBAR PNEUMONIA
✹ Stage of congestion

✹ Red hepatisation

✹ Grey hepatisation

✹ Resolution

❖ Whole/ part of a lobe involved

✹ Stage of Congestion:

✹ Gross : Lobe- Red,Heavy,boggy

Dilated, congested capillaries in septa. Edema
fluid, bacteria, few PMNs in alveoli
✹ Stage of Red Hepatization:
✹ Gross :Liver like consistency. Red,firm,airless.
Alveoli filled with RBCs, PMN, Fibrin
✹ Stage of Gray Hepatization:
✹ Gross : Lung is Dry,gray,firm.
Alveoli show RBCs, PMNs, Fibrin (RBCs are
disintegrated)
 ✹ Stage of Resolution :
Alveolar exudate digested: semifluid debris
resorbed / expectorated / organised.

Few disintegrating neutrophils seen

Macrophages remove cellular debris
Proteolytic enzymes have lysed fibrin.
Bronchopneumonia
✹ Patchy areas of consolidation
✹ Involves > 1 lobe
✹ Usually bilateral / basal
Gross
✹ Patchy areas of consolidation- slightly
elevated, dry granular, poorly demarcated
margins. Large intervening areas of lung
normal
Microscopy
✹ Focal suppurative exudate fills bronchi /
bronchioles and adjacent alveolar spaces.
CLINICAL FEATURES
✹ Abrupt onset of high fever
✹ Chills
✹ Productive Cough

✹ Usually respond within 72 hours to antibiotic

therapy.
PNEUMONIA-COMPLICATIONS
✹ Abscess formation – tissue destruction /
necrosis

✹ Empyema- spread of infection to the pleural

cavity

✹ Bacteremic dissemination – abscesses seen in

brain, kidneys, spleen, joints, heart valves. Meningitis,
suppurative arthritis
HOSPITAL ACQD PNEUMONIAS
✹ Defined as pulmonary infection acquired in
the course of hospital stay.

✹Predisposing factors
➢ Pts’ with chronic diseases
➢ Prolonged antibiotic therapy
➢ Immunosuppression
➢ Increased use of invasive procedures- IV
catheters, intubations, mechanical ventilators,
✹Organisms implicated
➢ Pseudomonas
➢ Staph aureus ( penicillin resistant)

✹ Serious complication since most organisms

are resistant to antibiotics.
HEALTHCARE ASSOCIATED PNEUMONIA
✹ Risk Factors include
✓ Hospitalization for min.2 days in recent past
✓ Attending hospital / hemodialysis centre
✓ Presentation from nursing home / hospice
facility
✓ IV antibiotic therapy
✓ Chemotherapy
✹ Methicillin resistant S.aureus
✹ P.aeruginosa

✹ Associated with higher mortality

ASPIRATION PNEUMONIA
✹ Seen in markedly debilitated pts’ who aspirate
gastric contents while unconscious.
✹ Have abnormal gag / swallowing reflex

✹ Chemical + Bacterial pneumonia

✹ Usually necrotizing, fulminant course leading
to death.
CHRONIC PNEUMONIAS
✹ Mycobacterium TB
✹ Fungi – Histoplasmosis,
Blastomycosis,
Coccidiodomycosis

➢ All associated with presence of granulomas

LUNG ABSCESS
✹ Local suppurative process in lung.
✹ Necrosis of lung tissue resulting in formation
of one or more large cavities.

✹ Organisms implicated
➢ Streptococcus, Staph aureus, G –ve bacilli
➢ Bacteroides, fusobacterium, Peptococcus,
Peptostreptococcus
Predisposing Conditions
✹ Aspiration of infective material -carious teeth /
infected sinuses / tonsils
Likely during oral surgery, anesthesia, coma,
debiltated pts’

✹ Aspiration of gastric contents

✹ Following necrotizing bacterial pneumonia

✹ Bronchial obstruction- Bronchogenic CA
obstructing a bronchus / bronchiole

✹ Septic embolism- septic thrombophlebitis/ infective

endocarditis involv. Rt side.

✹ Hematogenous spread of bacteria

Gross
✹ Variable in size. Range from few mms to 6
cms.
✹ May affect any part of lung
✹ Single (aspiration) / Multiple (pneumonia /
bronchiectasis / septic emboli )
✹ Exudate in an abscess cavity may be partially
drained in case of communication with air
passage.
Microscopy

✹ Areas of suppuration with complete

destruction of underlying lung parenchyma
CLINICAL FEATURES
✹ Cough
✹ Fever
✹ Copious amts of purulent sputum
✹ Chest pain / weight loss
✹ Clubbing of fingers
✹ Mortality – 10%
 LUNG TUMOURS
✹ 95% of tumours are carcinomas

✹ 5% Miscellaneous (bronchial carcinoids,

fibrosarcoma, leiomyomas, lymphomas, )

✹ Poor prognosis. 5YSR-16%

General Features
✹ Men :
✹ Incidence and mortality rates have been decreasing
( decreased rates of smoking)

✹ Women:
✹ death due to lung cancer > breast cancer
✹ Peak incidence- 50-60 years
✹ 50% of pts’ have mets at time of diagnosis.
✹ Dismal prognosis
✹ Overall 5YSR- 16%
WOMEN AND LUNG CANCER
✹ Women more prone to carcinogenic effects of
tobacco.

✹ 1.5 times more likely to develop lung cancer than

men with same smoking habits

✹ Decreasing incidence / deaths in men; continued

increase in women
LUNG CANCER IN NON SMOKERS
✹ 25 % lung cancers occur in Non – smokers.
✹ More common in women – Adenocarcinoma
✹ EGFR , Kras mutation present.
 LUNG CARCINOMA

Small cell (SCLC) Non small cell(NSCLC)

Squamous cell CA, Adenocarcinoma
Large cell CA.
Metastasized at Dx
Best Rx by chemotherapy Best Rxed by surgery(respond
+/- radiotherapy poorly to chemotherapy)
RB,p53 gene mutation freq p16/CDKN2A inactivated.
KRAS/EGFR mutat.- AdenoCA
✹ Adenocarcinoma – 50%
✹ Squamous cell carcinoma – 20%
✹ Small cell carcinoma – 15%
✹ Larg cell carcinoma -2%

✹ Others – 13%
LUNG TUMOURS - ETIOLOGY
✹ Tobacco smoke :
➢ 90% of lung carcinomas occur in smokers
➢ Smokers -10X risk compared to non-smokers
➢ Heavy smokers- 60 X risk
➢ Women have higher susceptibility to tobacco carcinogens
➢ Passive smokers 1.3X risk
➢ Strongly associated with
Squamous cell CA and SCLC.

All smokers do not develop lung cancer.

LUNG CANCER - ETIOLOGY
✹ Industrial hazards
➢ High dose ionizing radiation
➢ Uranium ( 4x increased risk. Uranium + smoking 10x risk.)
➢ Asbestos ( 5x increased risk . Asbestos + smoking 55x risk.)

✹ Air pollution
➢ Exposure to Radon. ( Uranium miners, subway,tunnel
workers,
SQUAMOUS CELL CARCINOMA
✹ More common in men
✹ Associated with smoking

✹ Arise near hilus of lung (central)

✹ Origin from 1st / 2nd / 3rd order bronchi.

✹ Associated with precursor lesions(squamous

metaplasia / dysplasia / carcinoma in situ)
✹ Metastasis late.
✹ Benign bronchial epithelium

✹ Stepwise accumulation of genetic abnormalities

✹ Neoplastic epithelium

✹ Well characterised preneoplastic lesions antedate

development of squamous cell
carcinomas .Usually present for years.
PRECURSOR LESIONS
Benign bronchial epithelium

Squamous metaplasia

Squamous dysplasia

CIS in situ

Invasive carcinoma
GROSS
✹ Arise from bronchi (1st/2nd/3rd ) Near hilus
✹ Intrabronchial fungating mass causing
obstruction.
✹ Tumour-gray-white / firm to hard
✹ Areas of h’ge / necrosis seen in large tumours.
 Grows as a cauliflower like intraparenchymal
mass can infiltrate peribronchial tissue.
✹ Spread to tracheal/bronchial / mediastinal
lymph nodes
✹ Can even extend to pleura / pericardium.
Histology
✹ Nests of polygonal cells with pink cytoplasm
distinct cell borders. e/o keratinisaton and intercellular
bridges seen.
✹ Nuclei hyperchromatic
✹ Whorls of keratinised cells – keratin pearls
✹ Metaplasia/ dysplasia/ CIS in adjoining epithelium
✹ SCC positive for p63 and p40
SQUAMOUS CELL CARCINOMA

✹ Chromosomal deletions
✹ 3p
✹ 9p ( site of CDKN2A gene)
✹ 17 p ( p53 gene)
ADENOCARCINOMA LUNG
✹ Most common in women
✹ Seen in non-smokers

✹ More peripherally located

✹ Arise in relation to peripheral lung scars (scar
carcinoma)

✹ KRAS / EGFR oncogene mutations

✹ Grow slowly, form smaller masses
✹ Metastasize at an early stage.
Gross
✹ Poorly circumscribed grey-yellow masses at lung
periphery .
✹ May cause retraction of overlying pleura.
✹ Cavitation unusual
✹ Multiple tumour masses may coalesce together.
 Adenocarcinoma-Precursor Lesions

Atypical Adenomatous Hyperplasia

Dysplastic epithelium lining

Alveoli walls which are mildly
Fibrotic.

Small precursor lesion <5 mm.

 Adenocarcinoma- Precursor Lesions
Adenocarcinoma in situ.
✹ Dysplastic cells growing along pre existing alveolar septae.
✹ More dysplasia seen compared
to AAH

✹ Earlier known – broncho

alveolar carcinoma
❖ 2 subtypes
❖ Mucinous
❖ Non mucinous
➢ Larger < 3 cm in size.
Adenocarcinoma

shows glandular differentiation or mucin production

✹ Histologic patterns :
✹ Acinar – glandular
✹ Lepidic
✹ Papillary
✹ Micropapillary
✹ Solid

✹ Microinvasive adenocarcinomas( <3 cms) associated with

peripheral lepidic growth patterns have better prognosis
What is lepidic growth pattern
✹ Tumour cells “crawl “ or grow as a monolayer on top
of alveolar septae, which serves as a scaffold
( lepidic growth- butterflies on a fence)
✹ No destruction of alveolar architecture.
✹ Mucinous : tall columnar cells, cytoplasmic/ intra
alveolar mucin

✹ Nonmucinous : columnar, peg shaped/ cuboidal cells

Mucinous adenocarcinoma forms

Satellite tumours ( multiple nodules) or
Entire lobe can be consolidated,
SMALL CELL CARCINOMA
✹ Highly aggressive
✹ Metastasize widely

✹ Strong relationship to cigarette smoking

✹ Mutation in p53 and RB gene frequent.
✹ No precursor lesions identified

✹ Derived from neuroendocrine cells of lung

✹ Ectopic hormone production - common
GROSS
✹ Pale gray central or peripheral masses
✹ Early extension to lung parenchyma
✹ Early involvement of hilar / mediastinal lymph
nodes.
 SMALL CELL CARCINOMA
✹ Small cells (round/oval/spindle shaped), scant
cytoplasm, ill defined cell borders,finely granular
chromatin ( salt and pepper)
✹ Absent nucleoli
✹ Mitotic figures / necrosis seen.
✹ Fragile tumour cells- show fragmentation /
crush artefact in biopsy specimens

✹ Nuclear molding prominent.

Round / oval tumour cells

Nuclear molding prominent
Cells smaller than 3xlympho
Cyte
Mitotic count is high
Small cell carcinoma
✹ EM – dense core neurosecretory granules
✹ IHC - Positive for neuroendocrine markers-
chromogranin, synaptophysin, and CD57.

BAL – SMALL CELL CARCINOMA

SHOWING NUCLEAR MOLDING
 LARGE CELL CARCINOMA
✹ Undifferentiated malignant tumour
✹ No glandular / squamous differentiation
✹ Pleomorphic cells have large nuclei, moderate
amount of cytoplasm, and prominent nucleoli.
Clinical Features
✹ 5th- 6th decade
✹ Cough
✹ Weight loss
✹ Chest pain
✹ Dyspnea
✹ Pleural effusion
PATHOLOGY CLINICAL FEATURE

Esophageal invasion Dysphagia

Rec.laryngeal nerve invasion Hoarseness

Obst. of airway Pneumonia, atelectasis

Pleural involvement Pleural effusion

Pericardial –’’--- Pericarditis /Tamponade

SVC compression- SVC syndrome

Sympathetic ganglia invasion Horner syndrome(Enophthalmos /

Ptosis / Miosis /Anhidrosis
Phrenic nerve involvement Paralysis of diaphragm
Spread and Metastasis
✹ Direct extension
➢ Pleura / Pericardium
➢ Hilar / bronchial / mediastinal lymph nodes.
➢ Diaphragm
✹ Metastasis
➢ Adrenals( 50%)
➢ Liver
➢ Brain
➢ Bone
PARANEOPLASTIC SYNDROME
 PARANEOPLASTIC SYNDROME
✹ Seen in 3-10% of lung cancer patients’
SYNDROME UNDERLYING CANCER MECHANISM
CUSHING SYND. SMALL CELL CA-LUNG ACTH
INAPP.ADH SECRETION SMALL CELLCA- LUNG ADH
HYPERCALCEMIA SQUAMOUS CELL CA PTHRP
ACANTHOSIS NIGRICANS BRONCHOGENIC CA EGF

HYPERTROPHIC BRONCHOGENIC CA ?
OSTEOARTPHY/CLUBBING
VENOUS THROMBOSIS BRONCHOGENIC CA TR PR.
GYANECOMASTIA BRONCHOGENIC GONADOTRP

MYASTHENIC SYND. BRONCHOGENIC CA AUTOAb.

Metastatic Tumours
✹ Most common site for metastasis
✹ Multiple discrete nodules scattered in both
lungs throughout all lobes (esp. in periphery)
✹ Spread via blood / lymphatics / contiguity

CA- Breast, GIT, Kidney

Pancreas,prostate
Melanomas
Sarcomas,Melanomas
Choriocarcinomas
 DISEASES OF PLEURA ( EMPYEMA)
✹ Collection of pus in pleural cavity(purulent exudate)

✹ Bacteria / fungi seed pleural space thro’

✹ hematogenous/ lymphatic / contiguity

✹ Gross :
✹ Variable volume of pus(50-1000ml)
✹ May be localised ( small vol.)
✹ Yellow-green pus
 Outcome

Resolve Organisation of exudate

Dense fibrous adhesions

Obliteration of pleural sp
 PLEURAL TUMOURS-MESOTHELIOMA
✹ From visceral/ parietal pleura (mesothelial cells)
✹ Asbestos exposure in 50%

✹ Latent period : 25- 45years

✹ Smoking: risk not increased
MESOTHELIOMA- ETIOPATHOGENESIS
✹ Asbestos not metabolised, fibres remain for
life.
✹ Localise near the mesothelial layer

Generate ROS

DNA damage ( oncogenic mutations )

✹ Deletions in chromosome 1p,3p,6q,9p,22q
seen in 60-80% of mesotheliomas

✹ Presence of SV40 viral DNA sequence in

60% -80% . ( SV40 –potent carcinogen. Inactivates
RB and p53. )
✹ Preceded by plaque
✹ Lung ensheathed by yellow white, firm or
soft ,gelatinous grayish pink tumour
✹ Obliterates pleural space

✹ Direct invasion of thoracic structures/

subpleural lung may be seen
✹ Mesothelial cells are biphasic -
✹ epithelium lining cells + mesenchymal
stromal cells

Microscopy :
❖ 3 patterns
➢ Epithelioid ( 60%)
➢ Sarcomatoid ( 20%)
➢ Mixed ( 20%)
Clinical Features
✹ Dyspnea, Chest pain
✹ Recurrent pleural effusions.
✹ Direct lung / hilar lymph node invasion
✹ Prognosis poor
✹ Death within 1 year.
THANK YOU
a.Identify the lesion.
Adenocarcinoma in situ

b.What is this pattern of

growth known as?
Lepidic growth
(Butterflies on a fence)
a.Identify the lesion.
Small cell lung cancer in
BAL

b. Which microscopic
feature is highlighted
here?
Nuclear molding
✹ A 64-year-old male presented with chest pain and
hemoptysis. He had lost more than 3 kg of weight in the
last four weeks, and complained of feeling "run down and
having no energy." He had smoked heavily since
adolescence.
✹ Physical examination revealed a cachectic, nervous man
with decreased breath sounds on the right side of the
chest.

✹ An x-ray demonstrated a large, right upper lobe mass with

central cavitation.
✹ CT scans indicated that the mediastinal nodes were
enlarged. Sputum cytology revealed a moderate number
of metaplastic and dysplastic and rare malignant cells.

✹ Bronchoscopy revealed several thickened white areas,

which were biopsied, and a large, polypoid mass
obstructing the right upper lobe bronchus.
✹ Mediastinoscopy was performed, and an enlarged node
was biopsied. He received radiation therapy to the chest,
but his condition deteriorated, and he died four months
later. An autopsy was performed.
a. What is the likely
diagnosis?
Squamous cell CA
a. What is the common
location of this lesion?
b. Central /large bronchi

c. What is this microscopic

finding called?
d. Squamous pearl / eddie/
keratin pearl in well
differentiated
squamous cell carcinoma
a. Identify.
Laminated concretions:
calcium + protein:
Schaumann bodies

a. Name the disease

process in which this is
seen.
b. Sarcoidosis
a. Identify.
b. Asbestos body

bDescribe the morphological

appearance.
Golden brown, fusiform, beaded
rods, translucent centers
a. Identify the lesion.
b. Silicotic nodule

c. What is the inciting

agent?
d. Inhalation of crystalline
silicon dioxide.
Foundry workers
▪ Sandblasting
▪ Hardrock mining
▪ Stone cutting
a. Describe the
microscopic finding
seen in the
photograph
b. submucous gland
hyperplasia

c. What is the likely

diagnosis?
d. Chronic bronchitis
This was the appearance of the
lung at autopsy of a 65 year / F

Likely diagnosis is

Squamous cell CA- lung

Adenocarcinoma of lung

Mesothelioma

Metastatic tumour