B) RESPIRATORY SYSTEM

1) Pulmonary Tuberculosis
Causative Mycobacterium tuberculosis (AFB)
Agent
MOT Respiratory droplets, Inhalation
Virulence - Glycolipid lipoarabinomannan (inhibit intracellular [Ca2+] increase  impaired
factor phagosome-lysosome fusion )

Pathogenesis
 MTb enters macrophages by endocytosis mediated by several macrophage
receptos.
 Mannose receptors > lipoarabinomannan (glycolipid of bacterial cell)
< 3/52, not
sensitized

 Complement receptors > Opsonized bacteria

 Acute inflammatory response of neutrophils and naive macrophage
 Survival and replication of MTb intracellularly (inside macrophage) by
blocking phagolysosome formation.
 Release of new MTb from rupture macrophage causing bacteriemia

Type IV Hypersensitivity (Delayed)

Antigen presenting cells that encounter MTb produce IL-12, leading to

differentiation of TH 1 cells.
 TH 1 cells produce IFN-γ
 IFN-γ cause:

> 3/52,

Stimulate formation of phagolysosome in infected macrophage,

thereby killing the MTb inside
 Increase production of Nitric Oxide to kill MTb
 Maturation of macrophage > epitheliod histiocytes > Giant cells of
Langhan’s
 Activated macrophage produce TNF, recruiting more monocytes
 Chronic inflammation leads to formation of granulomas with caseous
necrosis.

85
 Survival of MTb intracellularly in
acute inflammatory cells

Antigen presenting cells produce IL-

12
Type IV Delayed Hypersensitivity

Maturatoin of TH 1 cells

TH 1 cells produce IFN-γ

Maturation of macrophage into epitheliod

cells > Langhan’s giant cells

Chronic inflammation with formation of

granuloma and caseous necrosis

Summary of TB pathogenesis:
Inoculation  Phagocytosis of MTB by naïve alveolar macrophage  Intracellular survival
of MTB  Intracellular replication  rupturing of macrophage and releasing of bacillary
contents  repetition of cycle as new release bacilli are phagocytized

(3 weeks later)= Type IV (Delayed) Hypersensitivity

MTB antigen enters draining LN  antigen-displaying cells produce IL-12  differentiation

of T-helper (TH 1) cells  production of IFN-ϒ  macrophage differentiate into “epitheliod
histiocytes”  fusion of histiocytes into giant cells of Langhan’s  formation of granuloma
and center caseous necrosis  stimulation of MTB killing and confinement of infection

86
Histopathology

Granulomas : Small nodular collection of modified macrophages (epitheliod cells &

Langerhan’
Giant cells) surrounded by lymphocytes and plasma cells with central
necrosis (caseous)

87
Diagnostic Distinguish Sx: LOW, Night sweat, Night fever, Whitish sputum  Haemoptysis
features
Mantoux Test:
- Subcutaneous injection of PPD
- +ve if skin induration > 10mm after 48 hours
- +ve if blister formation regardless of size
- -ve if induration < 10mm (possible BCG vaccination, weakened immune system)

Sputum Culture:
- Lowenstein-Jensen agar
- AFB in serpentine cord
Clinical
manifestation 1 ° TB Clinical Manifestation:

 Resemble acute bacterial pneumonia

 Lower & Middle lobe consolidation
 Hilar adenopathy
 Pleural effusion
 Rarely cavitation
 Grey white inflammation with granuloma and caseous necrosis leading to
Ghon focus (Lung parenchyma) or Ghon complex (Lung parenchyma + Hilar
LN)
 Ghon Complex undergo fibrosis and calcified to form Ranke Complex

2 ° TB Clinical Manifestation:

 Classically involve apex of lung

 Cavitation occur readily
 Malaise, anorexia, weight loss
 Low grade and remittent (night) fever
 Night Sweat
 Sputum: Mucoid> Purulent> Hemoptysis
 Pleuritic pain
 Sharply circumscribed lesion (peripheral fibrosis

Miliary TB Clinical Manifestation:

 MTb drain into lymphatics > Venous blood > Back to lung
 Spread, small individual lesion
 If into systemic arterial blood > systemic manifestation, e.g. liver, spleen,
bone marrow, kidneys, adrenals, vertebrae (Pott’s disease, hutch back) etc.

88
 Signs & Symptoms:
- LOW
- Night fever & Sweat
- Hemoptysis
- IncreaseVocal fremitus and vocal resonance  consolidation of lung parenchyma 
fibrosis  caseous necrosis granulomas  TB
Clinical
Progression
Primary Infection
(previously Unexposed)

Primary TB
Controlled?

Scarred Miliary TB
lession (Liver and
Spleen
involvement)
Halted,
Dormant MTb
in granuloma

Reinfection /
Reactivation
(Lowered
immune)
Secondary
TB

Scarred
lession

89
Management - Isoniazid
- Rifampin
- Pyrazinamide
- Ethambutol/ Streptomycin

First-line drugs Classes of drugs Mode of action Adverse effects

Isoniazid Antimycobacterial (Bactericidal)  Peripheral
 Drug of choice in (mycolic acid inhibit synthesis neuropathy
preventive therapy synthesis inhibitor) of mycolic acid (alleviated with
 Primary drug for pyridoxine
active TB [vitamin B6]
replenishment)
Rifampin Antimycobacterials Inhibit DNA-  Red Urine
 Treatment of active (RNA polymerase dependent RNA  Elevated liver
TB inhibitor) polymerase function test
activity in  Rash
bacterial cells by  Epigastric
binding to β distress
subunit to block
RNA transcription
Pyrazinamide Antimycobacterials Bacteriostatic/  Hepatotoxicity
(Pyrazine analog of bactericidal  Malaise
Nicotinamide) against M.  Arthralgia
tuberculosis  Myalgia
Ethambutol Antimycobacterials (Bacteriostatic)  Hyperuricaemia
(arabinosyl diffuse in actively  Abdominal pain
transferase growing tubercle  Anorexia
inhibitor) bacilli and impair  Confusion
cell metabolism
 Optic neuritis
by inhibiting
synthesis of > 1  Peripheral
metabolites neuritis
(arabinogalactan),  Febrile
causing increased  Headache
permeability of  Malaise
cell wall  Pruritis
Streptomycin Aminoglycoside Interfere with  Hypotension
normal bacterial  Neurotoxicity
protein synthesis  Drug fever
by binding to the  Ototoxicity
30S ribosomal  Nephrotoxicity
subunits  Arthralgia
 Skin rash
Prevention BCG Vaccine:
- Intradermal injection within 1st 15 D of life
- Protection for 15 years

90
 2) Pneumonia
Description - Infection of lung parenchyma causing inflammation to one or both lungs
Causative agent Most common causative agent is STREPTOCOCCUS PNEUMONIA

Other possible causes:

Community-Acquired Typical P. Community-Acquired Atypical P.

- Strep. pneumoniae - Mycoplasma pneumoniae
- Haemphilus influenzae - Chlamydia pneumonia
- Staph. aureus - Legionella sp.
- Klebsiella pneumoniae
Nosocomial P. Chronic P.
- Klebsiella spp - Nocardia
- E.coli
- Pseudomonas aeruginosa
- MRSA
- Acinetobacter spp.
- Pneumonia jiroveci (AIDs)

Possible Causative Agent for Children:

a) 0-4 W: Group B Streptococcal, GN enterics, Listeria monocytogens
b) 4-12 W: C. trachomatis, GN enterics, Listeria, Viral (RSV, respiratory syncytial virus/
parainfluenza), Bordetella pertussis
c) 3 M – 4 Y: Viral, S. pneumonia, H. influenza, M. catarrhalis, Group A Strep, Mycoplasma
d) >5 Y: Mycoplasma (5-15 Y), C. pneumonia, S. pneumonia, Viral

Types Lobar Pneumoniae:

- Involvement of distinct region of lungs (lobes)
- Exudate formed due to infection clot in alveoli  consolidation
- Consolidation spread until limited by anatomical barrier (lungs segment/ lobes)

Bronchopneumoniae:
- Involvement of small airway initially
- More diffuse patchy consolidation
- May spread throughout the lung

Interstitial Pneumoniae: (Viral)

- Invasion of lung interstitium
- Characteristic of viral pneumonia

Lung Abscess: (Necrotizing Pneumoniae)

- Cavitation & destruction of lung parenchyme

CXR Pattern Possible Causative Agent

Lobar S. pneumonia, Klebsiella, Haemophilus influenza, GN
Patchy Atypical, viral, Legionella
Interstitial Viral, PCP, Legionella
Cavitary (Lung abscess) Anaerobes, Klebsiella, TB, S. aureus, Fungi
Large effusion Staph. Anaerobes, Klebsiella

91
Risk factors Impaired Defence of Respiratory Tract
- Antecedent viral respi tract disease
- Impaired mucous secretion / cilia action (disease e.g. cystic fibrosis, smoking)
- Immunocompromised (children and elderly at highest risk of meningitis  strep. pneu cause
meningitis)
- Cool months
- Old age (Lung changes: Low recoil & compliance, Low functional alveoli, Low PO2,
immunocompromised)

For Nosocomial setting:

- Mechanical ventilation, tracheostomy
- Prolonged hospital stay
- Comatose/ stroke (aspiration impaired cough reflex)

Clinical Signs & Symptoms:

Manifestation - Fever
- Chills
- Flu-like symptom

Atypical Pneumonia: Milder Sx, non-productive cough, no focal infiltration on CXR, extrapulmonary
manifestation
A) Streptococcus Pneumoniae
Morphology - G +ve diplococci / short chain
- Group B α-haemolytic
- Bile soluble, Optocihn sensitive
- Encapsulated
- Cell wall has teichnoic acid rich in phosphorylcholine ( C polysaccharide)
- Phosphorylcholine - regulatory role in cell wall hydrolysis

Route of 1. Endogenous spread from the colonized nasopharynx or oropharynx to distal site (lung, sinuses,
infection ear, blood, meninges)
2. Person-to-person spread through infectious droplets is rare.
3. Colonization is highest in young children and their contact

92
Virulent factors Virulent Factors Description
Surface protein - Ability to colonize oropharynx
adhesion - Binding to epithelial cell
Pneumolysin - Cytotoxin, bind cholesterol in the host cell membrane and creates
pores. destroy ciliated epithelial cells and phagocytic cell
- Spread into normal sterile tissue.
- Degrade haemoglobin and producing green product. Thus, colony
appears α-hemolysis on blood agar if incubated aerobically. β-
hemolysis if grown anaerobically.
Teichnoic acid - Required for the activity of an autolytic enzyme, amidase.
- Stimulate local inflammatory response
Technoic acid, - Stimulate local inflammatory response → alternative complement
peptidoglycan pathway
fragments,
pneumolysin
Polysaccharide - Evade phagocytic killing
capsule
Pneumococcal - Release cell wall components
autolysin (amidase)
IgA protease - Prevents IgA traps bacteria in mucus

Hydrogen peroxide - Tissue damage caused by reactive oxygen intermediates

Phosphorylcholine - Bind to receptor in endothelial cell surface for platelet-activating

factor → can enter cell → protected from phagocytosis → pass to
sequestered area (blood) → spread
Pathogenesis Colonization and Migration
- surface protein adhesion
- secrete IgA protease
- pneumolysin

Tissue destruction
- Teichnoic acid
- peptidoglycan fragment
- amidase
- pneumolysin
- hydrogen peroxidase
- phosphorylcholine

Phagocytic survivial
- capsular polysaccharide

** explain according to the sequence and the action of the virulent factors

93
 Inhalation of Aspiration of Haematogenous
aerosolized material normal URT flora seeding (less common)

Access to lower
respiratory tract
Red Hepatitization:
- Engorgement of
capilarries
Attachment to respiratory
- Flow of RBC from
epithelium (Adhesin)
capillaries into
alveolar space

Replication & Colonization

Grey Hepatitization:
- Dead & dying Inflammatory Response
neutrophils
- Degenerating RBC Exudate & inflammatory cells

Alveoli fill with fluid & pus  consolidation

Breathing difficulty Resolve (Antibiotics)

94
Clinical 3 classic features:
Manifestation - Abrupt onset accompanied by single rigor
- Rusty-colored sputum (bloody)
- Pleuritic chest pain

Signs and Symptoms:

- Fever & chills
- Flu-like symptoms 1 – 3 days before onset

Presentation Pathophysiology
Severe shaking ↑Temp. set point → sensation of cold → chills
chills
High grade fever Infection → IL (thermoregulator) ↑ prostaglandins(PGE2)→↑ temp. set
point

Productive cough Adherence to alveolar macrophages → exposure of cell wall components

→ attract neutrophils → release inflammatory mediators → accm. of
fibrinous exudates, RBC and bacteria → mucus → obstruction → stim.
cough centre in medulla.

Haemoptysis Infection → macrophage → mediators → complement activation → ↑

(blood sputum)/ permeability → bacteria+exudates+blood+neutrophils
Rusty sputum
Dypsnea ↑ ventilation perfusion (V/Q mismatch) → ↓alveolar ventilation → ↑CO2
→ stim. respiratory centre in medulla oblongata → ↑respiratory work →
respi muscle fatigue

Chest pain Pleural rub

(pleurisy)/tightnes
SOB Bronchoconstriction

Tachypneic Gasping for more O2 due to V/D mismatch , ↓O2 perfusion →

compensatory mechanism

Lung consolidation Organism → inflam response → vasodilate → ↑vascular permeability →

transudate → exudate → edema

Complication:
- Bacteremia  valvular heart disease
- Extra pulmonary manifestation: Meningitis, Otitis media and sinusitis

95
Examination Examination Result Explaination
Vital signs - Tachypnea ↑respiratory rate → ↑HR → more O2
- Fever circulate
- Normal BP
- Normal HR
Percussion - Dullness on side of Inflammation, pus, exudates, abscess
abscess/ effusion

Auscultation - Crackles (inspire) - Bronchoconstriction

- Wheeze (expire)
- Pleural rub
Chest X-ray - Lobar / interstitial pattern
depends on infecting agent
Other - V/Q mismatch
- Intrapulmonary shunting
- Fibrous blood neutrophils exudate →
fibrin on the pleural and lung surface →
rough pleural surface rub together
Inflammation  purulent exudate formation
 dense area (liquid)
blood → alveoli but oxygen does not enter
the blood. So, no O2 blood →pulmonary
artery →pulmonary vein → heart → tissue
→ hypoxia.

Investigation Laboratory Diagnosis Result

Microscopy & Staining - Pneumococcal pneumoniea / meningitis
- Gram +Ve diplococci
- Gram stain consistent confirmed with quellung (swelling)
reaction.
Antigen detection - 70% sensitivity
Pneumococcal C - Positive
polysaccharide (in urine)
Nucleic Acid-Based test & PCR
essay
Culture - Sputum specimen
Sheep blood agar - Green pigments

Catalase test - Negative

- No bubbles

Optochin sensitivity - Susceptible

Bile Solubility test - Colonies dissolved within few minutes

- (negative result for other α-hemolytic strep)

96
Treatment Drug MOA
Penicilin - Cell wall synthesis inhibitor

Vancomycin + - Inhibits synthesis of bacterial cell wall phospholipid

Ceftriaxone - Cell wall inhibitor + resistant to β-lactames
Prevention Vaccine:
- 23-valent pneumococcal polysaccharide vaccine, PPSV-23 (> 2 y/o)
- 13-valent conjugated pneumococcal vaccine, PCV-13 (infant < 2y/o)

Recommendation:
- All children < 2 yr old
- Adult at risk for disease

Others:
- Haemophilus influezae vaccine (HiB)

97
 3) Obstructive Lung Disease
Clinical Term Anatomi Pathology Changes Aetiology Signs & Symptoms
cal Site
Chronic Bronchus Mucous gland hyperplasia & Tobacco smoke, air Cough, sputum
bronchitis hypersecretion pollutant
Asthma Smooth muscle hyperplasia, Immunological/ Episodic wheezing,
excess mucous, inflammation undefined cough, dyspnoea
Bronchiectasis Airway dilation & scarring Persistence severe Cough, Copious
infection &/or sputum
obstruction
Emphysema Acinus Airspace enlargement, wall Tobacco smoke Cough, dyspnea
destruction
A) Asthma (Acute onset, reversible)
Definition An chronic inflammatory airway disease associated with increase airway responsiveness to
variety of stimuli causing:
- Bronchial hypersensitivity
- Episodic reversible bronchospasm
- Increase mucous secretion
- Oedema
- Cellular infiltration (neutrophil, eosinophil, mast cells)
Status asthmaticus: rare, state of unremitting attacks, fatal
Aetiology Bronchospasm trigger by:
- Respiratory infections (esp. viral)
- Environmental irritants (smokes, fumes)
- Cold air
- Stress
- Exercise
- Drug (aspirin)
Classification Atopic Asthma : (Allergen sensitization)
- Classic type I Hypersensitivity (IgE mediated)
- Begins in childhood
- Trigger by environmental allergens (dust, pollens, fur)
- +ve family history
- Diagnose with skin test/ serum radioallergosorben test (RAST) to identify to
allergen
Non-Atopic Asthma: (No Allergen sensitization)
- Due to hyperirritability of bronchial tree
- Viral infection (e.g. rhinovirus, parainfluenza virus)  Viral-induced inflammation
 affected respiratory mucosa  lowers threshold of subepithelial vagal receptors
to irritants
- No evidence of allergen (-ve skin test & RAST)
- Weak family history
Drug Induced Asthma:
- Aspirin  inhibition of cyclooxygenase pathway with sparing of lipoxygenase
pathway  increase leukotrienes (bronchoconstrictors)

98
Pathogenesis
Allergens (Type I Hypersensitivity)

Initial sensitization

Induction of TH2 which produce

IL-4 IL-5 IL-13

B cells Local recruit Mucus

of secretion
eosinophil
Ig E coating
Major basic Bronchoconstriction
protein
Mast cells “sensitized”

Allergen re- Epithelial damage Viral infections

exposure
Release of granule
contents and Decrease threshold of Inflammation
subepithelial vagus nerve
cytokines
(PSN stimulation=
constriction) Mucous
secretion

Granules content (Early phase/ immediate hypersensitivity):

- Bronchoconstriction
- Increase mucus production
- Vasodilation & increase vessel permeability

Cytokines released (Late phase):

- Inflammation
- Recruitment of leukocytes, e.g. eosinophils, neutrophils,
more T cels

Major cytokines involved:

- Leukotrienes
- Acetylcholine
- Histamine
- Prostaglandin D

99
Clinical Signs & Symptoms: (Acute onset, short duration, <hours)
Manifestation - Episodic wheezing(expiratory) & coughing
- Shortness of breath
- Chest tightness
- Productive/ Non-productive cough
- Findings of air trapping (Pectus cavinatum, barrel chest, resonance percussion,
reduce tactile and vocal fremitus)

Status asthmaticus: persist for days or weeks  severe cyanosis and death
Diagnosis FBC:
- Eosinophilia

Lung Function Test: (Spirometry)

- FVC, FEV1, FEV1/FVC ratio
- FRC (Functional residual capacity)

Bronchodilator Challenge Test:

- Symptom relieved (Increase FEV1/FVC ratio) after bronchodilator administration

Sputum:
- Eosinophil (Curschmann spirals / Charcot-Leyden crystal)

Histopathology
- Hypertrophy and hyperplasia of Smooth Muscle Cells & Subepithelial Mucus Gland
- Epithelial injury
- Increase airway vascularity
- Deposition of subepithelial collagen

100
Management
β2 agonist (Salbutamol)
Short term
Anticholinergic
Reliever
Methylxantine

Sodium chromoglycate
Anti-
asthmatic Long term Corticosteriods
Prevention
Leukotriene Receptor Antagonist

Long term Long acting β2 agonist

Controller (Salmeterol, inhaled)

101
 Bronchodilators
β2 agonist Salbutamol (short duration, fast acting)
Salmeterol (long duration, slow acting)

MOA:
- Sympathetic effect (bronchodilation)
- Reduce mediator release from mast cell
- Increase mucociliary function
Methylxanthines Caffeine-like stimulation

MOA:
- Sympathetic like effect
Anti-muscuranic Ipratropium Bromide

MOA:
- Inhibition of Parasympathetic (inhibit bronchoconstriction and
mucus secretion)

Anti-inflammatory Agent (for long term only)

Corticosteriods Permissive action for bronshodilation

Side effect:
- Impaired immunity
- Gastric bleeding
Leukotriene Side effect:
synthesis inhibitors - Hepatotoxic
(e.g. Zileuton)
Leucotriene Longer onset
receptor antagonist Useful for aspirin induced asthma
(e.g. Monteleukast)
Mast cells stabilizer Side effect:
(e.g. Cromolyn - Dry mouth
sodium) - Bitter taste
Omalizumab New drug
Inhibit Ig E sensitization of mast cells

Overall MOA of Bronchodilator drug:

Adenyl
Β2 Agonist
Cyclase

cAMP
Bronchodilation
Phosphodiesterase

AMP Methyxanthine

102
Overall MOA of Immuno-modulatory drug: - Prednisolone
- Dextamethasone
Phospholipid In cell membrane - Hydrocortisone
Steriod - Budesonide
Phospholipase A2 Enzyme (inhale)
- Beclomethasone
Arachidonic Acid
(inhale
NSAIDs Zileuton

Cyclooxygenase Lipoxygenase
(COX) enzyme enzyme Ig E

Omalizumab

Prostagladins Leukotriene
Sensitized
mast cells
Montelukast

Leucotriene receptor
of mast cells

Chromolyn sodium

Mast cells
degranulation

103
 B) Chronic Bronchitis (COPD, Irreversible)
Definition Persistent cough with sputum production for at least 3 months in at least 2 consecutive
year
Risk Factor - Smoking
- Recurrent bronchial infection may cause progression of the disease.
Pathogenesis

Cigarette, pollutants, irritants causes:

a) Hypersecretion of bronchial mucous glands  hypertrophy and hyperplasia of mucous
glands  increase mucous production  bronchial obstruction  chronic obstructive
bronchitis
b) Toxic radiate to epithelial lining the bronchial wall  squamous metaplasia
with/without cilia  abnormal ciliary action  trapping of particles and irritants 
*increase susceptibility to bacterial infection (H.Influenza, pneumococci, Streptococcal
viridans) inflammation  progressive obstruction of smooth muscle of bronchial wall 
replaced by collagen (healing by fibrosis)  permanent obstruction

Chronic cough causes by increase mucus accumulation in the bronchial tree due to:
- Impaired ciliary movement
- Mucous gland (goblet cells) hypertrophy and hyperplasia (Hypersecretion)
- Inhibition of alveolar macrophage

* Fever, purulent sputum  chronic mucopurulent bronchitis (sputum containing pus)

104
Clinical “Blue Bloater”
Manifestation
Signs and Symptoms
Smoking  persistent irritation of bronchial mucosal hypersecretion of bronchial mucus
gland hypertrophy of the mucous gland and increased number of goblet cells 
increase mucus production causes:

Clinical Features:
- Less dyspnoea and respiratory drive (retain CO2  cyanosis  blue bloaters)
- Obese
- Cor pulmonale with associated oedema

Pathophysiology Signs and Symptoms

Inflammation excessive mucous production, epithelial Productive cough
damage  stimulation of the receptor of airways  afferent
(vagus nerve)  medullar cough center efferent
(glossopharyngeal)  stimulation of laryngeal, intercostal
muscle, diaphragm  deep inspiration and closure of glottis 
contraction of abdominal muscle  pushes diaphragm 
increased intrathoracic pressure  glottis open suddenly 
expulsion of mucous and other desquamated cell 
Increase inspiratory pressure  rapid air entry into distal Crepitation
airways  abrupt opening of alveoli and bronchi containing
secretions in the regions of the lung deflated to residual
volume 
Airway obstructed by mucus  reduction of peripheral airway Wheezing ronchi
calibre  prolonged turbulent airflow during expiration 
Airway obstructed by mucus  air trapping during expiration Barrel chest, Decrease
hyperinflated lung  Chest expansion and
Hyperresonant on
percussion
Airway obstructed by mucus  ventilation-perfusion (V/Q) Dyspnoae (Hypoxiaa
mismatch decrease alveolar ventilation hypoxia hyperpnoea) 
hypercapnoea stimulate respiratory centerincrease Flapping Tremor and
respiratory work against airway  respiratory muscle Cyanosis
fatigue
Superficial mucosal nflammation  rupture of the superficial Haemoptysis
blood vessels

* Might co-exist with emphysema

Complication
- Asthma
- Bronchiectasis
- Cystic fibrosis
- Tuberculosis
- Sinusitis
- Cor pulmonale (hypoxia-induced pulmonary vascular spasm)

105
Diagnosis Physical Examination:
- Inspection: cyanosis (Blue bloaters)
- Oedema: from right ventricular failure
- Palpation: hyperinflated chest with reduced expansion
- Percussion: increased resonance
- Breath sounds: reduced with end-expiratory high or low-pitched wheezes and early
inspiratory crackles

Lab Investigation:
- Chest X-ray.
- Sputum culture
- Pulmonary function test blow into a device called a spirometer, which measures
how much air your lungs can hold and how quickly you can get air out of your
lungs.
- Reduce FEV1 and decrease FVC  FEV1/ FVC ratio decrease
Pathology Gross:
a) Mucosal lining of the larger airways is hyperemic and swollen by edema fluid,
often covered by a layer of mucinous or mucopurulent secretions.
Histologic:
a) Trachea and larger bronchi: enlargement of the mucus-secreting glands.
b) Magnitude of the increase in size is assessed by the ration of the thickness of the
submucosal gland layer to that of the bronchial wall (Reid index 0.4).
c) Inflammatory cells, largely mononuclear but sometimes admixed with neutrophils,
are frequently present in variably density in the bronchial mucosa.
d) Goblet cell metaplasia, mucous plugging, inflammation, and fibrosis

Histologic changes in chronic bronchitis:

- Oedematous & hypermic mucosa
- Epithelium squamous metaplasia
- Goblet cells hyperplasia & metaplasia
- Mucus gland hypertrophy
- Smooth muscle hyperplasia
- Inflammation  wall fibrosis

106
Management To relieve symptoms and ease breathing.
a) Medication (O2 inhaler) to prevent Cor pulmonale ( not 100% O2 as patient
depends on hypoxic drive due to chronic hypoxia)

In most cases, acute bronchitis requires only self-care treatments such as:
a) Getting more rest
b) Taking over-the-counter pain medications
c) Drinking fluids
d) Breathing in warm, moist air

107
 C) Emphysema (COPD, irreversible)
Description o Permanent enlargement of the airspaces distal to the terminal bronchioles
accompanied by destruction of their walls
o Restricted to the acinus
Risk Factor o Smoking
o α1-antitrypsin deficiency (inherited).
o Age between the ages of 40 and 60.
o Occupational exposure to fumes or dust.
o Exposure to indoor and outdoor pollution.
Types Centriacinar:
- Consequences of smoking
- Dilatation initially affects the respiratory bronchioles

Panacinar:
- Mainly due to α-antitrypsin deficiency (anti elastase deficiency)
- Initial distention of the peripheral structures (alveolus and alveolar duct) which
later extend to the respiratory bronchioles

108
Pathogenesis Cigarette smoking, recurrent infection  inflammation, irradiation, increase neutrophil
neutrophil produce elastase and other proteases  overcome inhibition by α1-
antitrypsin (in normal person) α1-antitrypsin deficiency Centriacinar emphysema
(destruction of bronchioles only) or Panacinar emphysema (destruction of bronchioles,
alveolar duct and alveoli)DYSPNOEA

Chronic smoker / Genetic defect  imbalance of Elastase and α1-antitrypsin 

Destruction of elastic connective tissue of the lung  Permanent dilatation of the air
spaces distal to the terminal bronchioles, accompanied by destruction to inner wall and
without obvious fibrosis.

“Protease-antiprotease” and “oxidant-antioxidant” imbalance  tissue damage

α-antitrypsin (antiprotease) deficiency can be caused by inflammation (smoking) or

congenital.

109
Clinical “Pink Puffer”
Manifestation
Signs and Symptoms:
Smoking  increase pulmonary alveolar neutrophils and macrophages  release
elastase unopposed elastase activity (due to inherited α1-antitrypsin deficiency or
inhibition of α1-antitrypsinby oxidants and oxygen free radicals)elastase tissue
destruction  abnormal dilatation of air spaces distal to terminal bronchioles,
characterized by destruction of the wall without obvious fibrosis 

Pathophysiology Signs and Symptoms

Ventilation-perfusion (V/Q) mismatch  hypoxia Dyspnoae (Hypoxiaa
hypercapnoea stimulate respiratory center hyperpnoea) 
Flapping Tremor
and Cyanosis

Loss of alveolar elasticity  collapse alveolar on expiration  Pursed Lips (pink

pursed lip on expiration  increase airway resistance  increase puffer)
bronchial pressure  to prevent airway collapse
Loss of stability of air spaces  collapse on expiration  rapid air Creptitation
entry into distal airways  abrupt opening of alveoli and small
bronchi containing secretions in the regions of the lung deflated
to residual volume 
Decrease lung elastic recoil  increase total lung capacity Barrel chest,
trapping of air hyperinflated lung Decrease Chest
expansion and
Hyperresonant on
percussion

Clinical Features:
- Prominent dyspnoea (differ from chronic bronchitis, less prominent cyanosis)
- Weight loss
- Sitting forward with attempt to squeeze air out during expiration

Complication:
- Collapsed lung (pneumothorax)
- Heart problems: can increase the pressure in the arteries that connect the heart
and lungs corpulmonale (a section of the heart expands and weakens).
- Giant bullae (large holes in the lungs): develop empty spaces in the lungs called
bullae, can be as large as half the lung reducing the amount of space available
for the lung to expand / infected collapsed lung (pneumothorax).

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Diagnosis Physical Examination:
- Pursed-lip breathing: expiration through partly closed lips increases the end-
expiratory pressure and keeps airways open, helping to minimize air trapping.

Lab investigation:
- X-ray: Lungs are overinflated with low, flat hemidiaphragms. Level of
hemidiaphragms is well below the anterior aspects of the 6th ribs. There is
increased translucency of both upper zones with loss of the vascular markings due
to bulla formation. Increased in translucency is not due to overexposure.
Prominent hila due to enlarged central pulmonary arteries. In contrast, the smaller
peripheral pulmonary arteries decreased in size and number. This is due to actual
destruction, displacement around bullae and decreased perfusion through
emphysematous areas.
- Computerized tomography (CT)
- Blood tests (ABG relatively normal)
- Pulmonary function tests (Reduce FEV1 and decrease FVC, Reduce FEV1/ FVC ratio)
Pathology Gross:
- Panacinar emphysema: pale, voluminous lungs
- Centriacinar emphysema: lungs are deeper pink and less voluminous, upper 2
thirds more severe

Histology:
- Destruction of alveolar walls without fibrosis enlarged airspaces.
- Alveolar loss, number of alveolar capillaries reduced.
- Terminal and respiratory bronchioles may be deformed loss of septa that help
tether these structures in the parenchyma.
- Loss of elastic tissue in the surrounding alveolar septa, radial traction on the small
airways is reduced tend to collapse during expiration.
- Bronchiolar inflammation and submucosal fibrosis are present in advanced disease.

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 Autopsy reveals bollae (large, dilated airspaces that bulge out from beneath the pleura)
Management Emphysema can't be cured, but treatments can help relieve symptoms and slow the
progression of the disease.

o Bronchodilators (tremor, tachycardia, hypokalaemia)

a) β2agonist (inhaled): stimulate β2 adrenergic receptors increasing cyclic
adenosine monophosphate (cAMP) bronchodilation. E.g. Salbutarol, Salmeterol.
b) Anticholinergic agents: block M2 and M3 cholinergic receptors. E.g. ipratropium
bromide
c) Phosphodiesterase inhibitors (oral): increase intracellular cAMPbronchodilation.
E.g. Theophylline
o Anti-inlflammatory therapy:
a) Inhaled steroids: corticosteroid drugs relieve shortness of breath. (decrease in
mucus production  infection)
o Antibiotics: for with Streptococcus pneumonia (lung infection), Haemophilia influenza
(kids). E.g. Amoxicillin, Cephalosporin
o Mucolytic agents: reduce sputum viscosity and improve secretion clearance.
o Pharmacologic attempts to increase endogenous production of α1-antitrypsin by the
liver (ie, danazol, tamoxifen) or administration of purified α1-antitrypsin by periodic
intravenous infusion or by inhalation.
o Vaccination
o Oxygen therapy (To prevent Cor pulmonale)
o Surgery
a) Lung volume reduction: removal of small wedges of damaged lung tissue to
decrease hyperinflation. This improves airflow by increasing the elastic recoil of
the remaining lung and the mechanical efficiency of the respiratory muscles to
generate expiratory pressures.
b) Lung transplant
c) Bullectomy: removal of these bullae may result in expansion of compressed lungs
and improvement of lung function.

112
 D) Bronchiectasis (COPD, irreversible)
Description - “-Ectasis” = dilatation
- Permanent abnormal dilatation of bronchi and bronchioles caused by destruction
of the muscle and elastic supporting tissue due to/ associated with chronic
necrotizing infection.
- Not a disease, but a consequences of other prolonged lung disease
Pathogenesis Malignancy,
TB,
Pneumonia Cystic fibrosis,
foreign bodies

Infection Obstruction
Infection can cause
obstruction &
Inflammation obstruction can cause
infection also. They are
interrelated and cause
Destruction occur together, both
of wall acting as predisposing
Increase mucous
production factor for each other
Necrotizing and qorsing the
wall situation

Permanent dilation &

Copious purulent sputum

Mucous stasis

Recurrent
infection

Predisposing All lung disease that can cause chronic inflammation :

factor - Bronchial obstruction (tumor, foreign body, mucous impaction)
- Congenital (Cystic fibrosis, immune defiency  recurrent infection, immotile cilia –
Kartagener’s syndrome)
- Necrotizing pneumonia (S. aureus, klebsiella spp.)
- Chronic infection (TB, aspergillosis, sacardiosis_
Clinical Clinical Features:
Manifestation - Cough
- Fever
- Copious foul smelling purulent sputum
- Dyspnoae
- Cyanosis

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Complication - Haemorrhage
- Lung abscess
- Septic emboli
- Secondary amyloidosis
- Respiratory failure
- Cor pulmonale
Pathology Macroscopic:
- Dilated airway, maybe cystic

Microscopic:

- Active chronic inflammation

- Desquamation of epithelium
- Squamous metaplasia
- Fibrosis & scarring

- Dilated bronchus with necrotizing inflammation with destruction (mucosa and wall
no clearly seen)
Complication - Haemorrhage
- Lung abscess
- Septic emboli
- Secondary amyloidosis
- Respiratory failure
- Cor pulmonale
Management To cure underlying condition & improve symptoms(symptomatic) & reduce complication
- Antibiotics
- Physiotherapy
- Bronchodilator
- Dietary & oxygen supplement

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 Chronic Bronchitis Emphysema
- Less hypoxic drive - More hypoxic drive
- Less dyspnoea - More dyspnoea
- More cyanotic - Less cyanotic
- ABG relatively abnormal - ABG relatively normal
- Obese - LOW
- No wheezing - “Pink Puffer”
- “Blue Bloater”

Physical Examination:

Hyperinflatted lung.:
- Barrel shaped chest
- Increase AP diameter
- Decrease supra-sternal notch (Tracheal tug)
- Increase resonance on percussion
- Decrease tactile & vocal fremitus

Use of Accessary muscle:

- Subcostal/ intercostal/ suprasternal recession

Complication:

Signs of heart failure (Elevated JVP, Oedema)

- Right ventricular failure  decrease stroke volume  high volume of blood in right ventricle
after systole Starling’s law of heart not applied (because of failing myocardium lead to
depression of ventricular function)  high venous pressure to right atrium  backflow of
blood through superior vena cava JVP ELEVATED
- Decrease in oxygen supply  right ventricle hypoxia  decrease force of right ventricle
contraction  decrease emptying of right ventricle  increase right ventricle end-diastolic
pressure and volume increase volume and pressure in great veins  increase volume in
distensible organs (hepatomegaly, splenomegaly)  increase pressure of capillary line
PERIPHERAL OEDEMA

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Pathogenesis:

Lab investigations:

1) Lung ability to Exchange Oxygen and Carbon Dioxide

a) Arterial Blood Gas: to determine the amount of oxygen and carbon dioxide in the blood (its
saturation). Low oxygen (hypoxia) and high carbon dioxide (hypercapnia) levels often
indicate chronic bronchitis, but not always emphysema.
b) Pulse Oximetry Test.: measuring oxygen in the blood is called pulse oximetry, which involves
placing a probe on the finger or ear lobe. The probe emits two different lights, and the
amount of each light the blood absorbs is related to how much oxygen the red blood cells
carry. This test measures only oxygen in the blood, however, and not carbon dioxide.
c) Carbon Monoxide Diffusing Capacity: determines how effectively gases are exchanged
between the blood and airways in the lungs. Patients should not eat or exercise before the
test, and they should not have smoked for 24 hours.

116
 2) Imaging Tests
a) Chest X-Rays.:
i. Abnormally large amounts of air spaces in the lung.
ii. A flattened diaphragm.
iii. A smaller heart; if heart failure is present, however, the heart becomes enlarged and
there may not be signs of overinflated lungs.
iv. Exaggerated lung inflation in upper areas.
v. Larger amounts of air in the lower lungs in patients with A1AD-related emphysema.
Chest x-rays are rarely useful for diagnosing chronic bronchitis, although they sometimes
show mild scarring and thickened airway walls.
b) Computed Tomography. Computed tomography (CT) scans: determine the size of the air
pockets (bullae) in the lungs.

Principles of Management:

Smoking cessation

Drugs Therapy:
- Bronchodilators
- Steriods
- Antibiotics
- Mucolytics

O2 Therapy:
- Gives slowly in case of Chronic Bronchitis (Hypoxic drive)

Nutritional Support

Surgery:
- Giant bullectomy
- Lung volume reduction surgery (LVRS)
- Lung transplant

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 D) Restrictive Lung - Fibrosis
Aetiology Chest wall disorder: (Extrapulmonary)
- Neuromuscular diseases (e.g. poliomyelitis, severe obesity, pleural disease,
Kyphoscoliosis)
- Myasthenia gravis
- Obese

Chronic interstitial and infiltrative disease: (Pulmonary)

- Pneumoconioses
- Interstitial fibrosis of unknown etiology
1) Lung Fibrosis
Pathogenesis Epithelial injury/ activation  inflammatory response  proliferation of fibroblast 
deposition of collagen and ECM (fibrosis)  Reduce lung compliance + increase lung recoil
 difficult to expand
Clinical Characteristic: Small lung volume with rapid expiration
manifestation
Clinical Features:
- Dyspnea
- Tachypnea
- End-inspiratory crackles
- No wheezing/ evidence of airway obstruction
- Eventual cyanosis

Complication:
- Secondary pulmonary hypertension
- Right heart failure (Cor pulmonale)
- Scarring & gross destruction of lung (honey-comb lung)
Diagnosis Lung Function Test:
- Reduce in all lung volume (TLC, IC, VC)
- Increase FEV1/ FVC ratio as decrease in FEV1 < decrease in FVC

Chest X Ray:
- Bilateral infiltrative lesions in form of small nodules, irregular lines or ground-glass
shodows

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 Obstructive Lung Restrictive Lung
- Increase resistance to airflow due to partial or - Reduced expansion of the lung parenchyma due to
complete obstruction at any level chest wall disorder

- Increase total lung capacity due to air trapping - Reduce total lung capacity due to reduce expansion

- Decreased FEV1 - Decrease FEV1

- Increased FRC (TLC) - Decrease FRC (TLC)
FEV1/FVC FEV1/FVC

FEV1, FVC, FEV1, FVC

RV, TLC, FRC RV, TLC, FRC

Large volume with slow expiration Small volume with fast expiration

Asthma Chronic Emphysema Pulmonary

bronchitis fibrosis

FEV1 ↓↓ ↓↓ ↓↓ ↓
VC ↓ ↓ ↓ ↓↓
FEV1/VC ↓ ↓ ↓ →/↑
TLco → →  
Kco → →  →/↓
TLC →/↑ ↑ ↑↑ 
RV →/↑ ↑ ↑↑ 

119
120
 E) Pulmonary Embolism
Definition - Condition in which blood clot(s) or thrombus or multiple thrombi migrate from the
systemic circulation to the pulmonary vasculature
- Blockage of arteries in the lungs by blood clot, fat, air, septic emboli or clumped of
tumour cells
- Most pulmonary thrombi are multiple, with lower lobes (majority) involved
- Pulmonary thromboembolism is a complication of underlying venous thrombosis

Thrombus – a solid mass formed in circulation from constituents of flowing blood

Embolism – A detached intravascular solid, liquid or gaseous mass that is carried by the blood
to a site distant from its point of origin
Aetiology Possible types of Pulmonary Embolism:
- Thromboembolism (DVT) – 80-95%
- Fat embolism (Multiple fracture of long bone/ pelvic)
- Air embolism (iatrogenic)
- Amniotic embolism
- Septic embolism (IE)
- Malignancy (Part of tumour)
- Blood clot disorder (DIVC, sickle cells)
- Blood borne parasite (schistosomiasis)
Risk Factor Endothelial injuries:
- Bacterial endotoxins
- Smoking
- Trauma/ surgery

Alteration in blood flow (Laminar flow):

- Turbulence flow  defective valve
- Stasis  hyperviscosity  Polycythaemia, sickle cell, dehydration
- Venous Stasis  Congestive heart disease/ Pregnancy/ prolonged immobility (bed
rest, post-operation, long journey, etc.)

Hypercoagulability state:
- Smoking
- Oestrogen supplement (OCP)
- Pregnancy (Most common cause in woman < 40 y/o)
- Malignancy
- Thromophilic state (Heparin-induced thrombocytopenia syndrome-HITs, DIVC,
Antiphospholipid antibody syndrome, sickle cell anaemia etc.)
- Genetic
- Obese

Surgery (tissue debris enter blood stream):

- Orthopedic, neurosurgical, gynaecological and urological (30-50%)

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Pathogenesis Pathogenesis of DVT:

Virchow’s Triad:
- Endothelial injury Thrombus Emboli detached &
- Alteration of flow formation flow in blood steam
- Hypercoagulability

Occlusion of Pulmonary arteries

depending on size of emboli

Large Medium Small (60-80%)

Main pulmonary Medium sized Small sized arteries

artery occlusion arteries occlusion occlusion

- Right heart failure - Pulmonary - Clinically silent

- CVS collapse hemorrhage - Multiple emboli
- Saddle emboli (in - Pulmonary over time (50-
pulmonary infarction (rare, 60% obstruction)
bifurcation, alternative  pulmonary
sudden death) bronchial blood hypertension 
supply) Cor pulmonale
- Hypoxic state

Lower limb:
Great (Deep) Sapheneous v.  Popliteal v.  Femoral v.  External Illiac v.  Common Illiac
v.  Inferior vena cava – Rt. Heart  Lung

Upper limb: (associated with central venous catheters)

Basillic v. -> Subclavian v.  Branchiocephalic v.  Superior vena cava  Rt Heart  Lung

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Clinical Clinical spectrum of PE ranging from asymptomatic to haemodynamic collapse, depends on:
Manifestation - Size of embolus
- Duration over which obstruction accumulates
- Humoral mediators (serotonin or thromboxane) released and vascular hypoxic
response cause vasoconstriction of non-embolised lung segment
- State of patient (cardiopulmonary disease)

Signs & Symptoms: (Common)

- Chest pain (Pleuritic)
- Dyspnoea  reduce gas exchange  reduce blood flow  obstruction
- Cough, hemoptysis, syncope
- Tachypnic, Tachycardia

Complication:
- Pleural effusion due to Pul HPT
- Chronic thrombotic pulmonary embolism  Pul HPT  cor pulmonale  right heart
failure
- Haemodynamic disturbance  cardiogenic shock
- Haemodynamic collapse  no blood flow from right heart to lung/ from lung to left
heart  zero cardiac output  sudden death
- Paradoxical embolism: emboli from Rt heart  Lt heart through patent foramen oval
or atrial septal defect  stroke

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 Pathophysiology Signs & Symptoms
Embolic occlusion  increase pulmonary resistance  increase right - Sudden death
ventricle afterload  increase right ventricular pressure  reduced - Syncope
CO  Cor pulmonale  right heart failure - Lung edema

Embolic occlusions  intrapulmonary shunt  redirect of blood - Tachypnea

flow  V/Q ratio mismatch  hypoxic vasoconstriction of non- - Tachycardia
embolic alveolar + regional hypocapnic bronchoconstriction of - Dyspnae
terminal bronchial  increase alveolar dead space  reduce in - Excessive sweating
gaseous exchange  Hypoxic state  sympathetic outflow - Palpitation
- Cyanosis

Embolic occlusion  pulmonary infarction (rare, alternative O2 - Lung edema

source from bronchial arteries and airway)  inflammatory - Pleuritic chest pain
response & mucus secretion - Haemorrhage
- Hemoptysis
- Cough
- Fever
DVT of lower extremities  blood pooling  oedema - Leg swelling & pain

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Diagnosis - Clinical history (previous DVT, risk factors

Non- Confirmatory
C-XR - Plate-like atelectasis
- Pleural effusion
- Elevation of hemidiaphragm
ECG - Signs of right heart strain (T inversion of V1-V4, classic S1Q3T3,
right bundle branch block, QR pattern of L1)
- Sinus tachycardia

S1Q3T3 – S wave in Lead 1, Q wave in Lead III, Inverted T in Lead III

D-dimer - Presence of thrombolic event
- DDx: DIVC, denggi, DVT, PE,
- High negative predictive value, low positive specificity
Arterial Blood Gas - Low PO2
- Low PCO2
Diagnostic
CT Scan (Spiral/ - First-line imaging test of PE
helical CT scan) - Effectively diagnosed large central PE

Pulmonary - “Gold Standard” for PE diagnosis

angiogram - Visualization of intraluminal filling defect and abrupt occlusion
or “cut-off” vessels

125
 Ventilation- - Monitoring of ventilation and perfusion state using radiolabeled
Perfusion Scanning particles
- PE is of high probability if 2 or more segmental perfusion defects
in presence of normal ventilation

Echocardiogram - Unexplained increase right ventricle volume

Venous - Duplex (compression) ultrasonography
ultrasonography - To detect lower extremities DVT
Differential DDX:
Diagnosis - Acute coronary syndrome (Unstable angine, acute MI)
- Pneumonia, bronchitis, asthma, COPD
- Congestive heart failure
- Pericarditis
- Pleurisy
- Primary pulmonary HPT
- Anxiety

Wells Score & Geneva Score

126
Morphology Macroscopic:

(Saddle embolus)

Microscopic:

Management Supportive:
- Respiratory & Haemodynamic support

Medical:
- Fibrinolytic agents (e.g. Urokinase, streptokinase)
- Anticoagulant (Heparin, warfarin, etc)

Surgical:
- Embolactomy
- IVC filter insertion (reserve for patient not tolerant/responsive to anticoagulant drugs)

Primary therapy : Thromolytic agent + Embolectomy

Secondary (Preventive) therapy : Anticoagulant + IVC filter

Prevention:
- Anticoagulant therapy for high risk population/ patient with DVT history
- Gradual compression stockings
- Pneumatic compression
- Physical activity

127
 F) Respiratory Malignancies
Classification Upper respiratory  Nasopharyngeal carcinoma
 Laryngeal carcinoma
Lower respiratory  Squamous cell carcinoma (25-40%)
 Adenocarcinoma (25-40%)
 Small cell carcinoma (20-25%)
 Large cell carcinoma (10-15%)
Clinical Nasopharyngeal  Nasal symptoms: including bleeding, obstruction, and discharge
manifestation carcinoma  Ear symptoms: including infection, deafness, and tinnitus
 Headaches
 Enlargement of cervical lymph nodes
 Related to infection of EBV
 Keratinizing squamous cell carcinoma/ Non-keratinizing
squamous cell carcinoma (undifferentiated, differentiated),
Basaloid squamous cell carcinoma
Laryngeal carcinoma  Dysphonia/aphonia
 Dysphagia, Dyspnea
 Aspiration, Blood-tinged sputum
 Fatigue, weakness, cachexia
 Pain
 Halitosis
 Expectoration of tissue
 Neck mass
 Otalgia
 Squamous cell carcinoma/Adenocarcinoma
Squamous cell  Cough, weight loss, chest pain, dyspnoea
carcinoma  Haemoptysis
Adenocarcinoma  Increased sputum production containing tumour cells.
Small cell carcinoma  Focal emphysema, atelectasis, bronchiectasis, pulmonary
Large cell carcinoma abscess.
 Superior vena cava syndrome
 Pericarditis, pleuritis/ effusion
 Horner’s syndrome (Sympathetic ganglia –Pancoast’s
tumour(Apex of lung-SCC))
 Paraneoplastic syndrome (ADH, ACTH, PTHrP)
 Hoarseness (recurrent laryngeal nerve)
Risk factor Tobacco smoking  Carcinogenic substances such as polycyclic aromatic hydrocarbon
and phenol deriatives
Industrial hazrds  Exposure to radiation, uranium, asbestos
Air pollution  Atmospheric air pollution eg. Radon radioactive gas
Molecular genetics  Genetic predisposition. K-ras in adenocarcinoma, c-myc in
small cell carcinoma. Loss of 3p, p53.

128
Pathogenesis • Multistep process in which gradually accruing sequential genetic & cellular changes
result in formation of an invasive tumour
• Driven by genetic/epigenetic damage caused by chronic exposure to tobacco
carcinogens.
• Oncogenes – activated via point mutation, gene amplification or chromosomal
rearrangements.
• Tumour suppressor gene – inactivated by loss of one parental allele & mutation or
abberant methylation of target tumour suppressor gene in the remaining allele.
Morphology Nasopharyngeal Gross  Close anatomical
carcinoma relationship to
lymphoid tissue
 Can be
proliferative,
ulcerative or
infiltrative

Histology  Composed of
tumour cells
arranged in
compact nests
 Composed of cells
growing in a diffuse
“syncytial” pattern

129
Laryngeal Gross  Supraglottic, glottis
carcinoma and subglottic
lesions
 Large, ulcerated,
fungating lesion
involving vocal cord
and pyriform sinus
 Epithelium changes
from smooth, white
or reddened focal
thicke

Histology  Presence of keratin

pearl
 Anaplasia
 Massive tumor
giant cells and
multiple bizarre
mitotic figures

Squamous cell Gross  Arise from 1st, 2nd,

carcinoma 3rd order bronchi
 Cauliflower like
intraparenchymal
mass
 Irregular warty
excrescences in
lining epithelium
 Invasive (Fungate
into bronchial
lumen or penetrate
bronchial wall to
infiltrate along
peribronchial
tissue)
 Extension to pleura
& lymph nodes

130
 Hisology  Characterised by
presence of
keratinization
and/or intercellular
bridges
 Keratinisation in
form of squamous
pearls or individual
cells with markedly
esosinophilic dense
cytoplasm

Adenocarcinoma Gross  Arise in periphery,

from alveolar septa
or terminal
bronchioles
 Cauliflower like
intraparenchymal
mass
 Irregular warty
excrescences in
lining epithelium
 Invasive (Fungate
into bronchial
lumen or penetrate
bronchial wall to
infiltrate along
peribronchial
tissue)
 Extension to pleura
& lymph nodes
Histology  Well differentiated
 Glandular elements
 Mucin-producing
glands and cells

131
Small cell Gross  Arise in major
carcinoma bronchi or in
periphery of the
lung
 Most malignant
 Metastasize widely
 Derived from
neuroendocrine
cells of the lining
bronchial
epithelium

Histology  Classic “oat cell”:

small blue cell,
round to oval, 2-3X
size of
lymphocytes, scant
cytoplasm, nuclear
moulding
 Spindle or
polygonal small cell
 Dense-core
neurosecretory
granules
Large cell Gross  Arise from 1st, 2nd,
carcinoma 3rd order bronchi
 Cauliflower like
intraparenchymal
mass
 Irregular warty
excrescences in
lining epithelium
 Invasive (Fungate
into bronchial
lumen or penetrate
bronchial wall to
infiltrate along
peribronchial
tissue)
 Extension to pleura
& lymph nodes

132
 Histology  Anaplastic, large,
polygonal cells with
vesicular nuclei
 Giant cell
carcinoma, clear
cell carcinoma,
spindle cell
carcinoma
Staging Tx Primary tumour cannot be assessed, or tumour proved by the presence of
(TNM system) malignant cells in sputum or bronchial wash but not visualized with imaging or
bronchoscopy
T0 No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumor <3 cm without pleural or main stem bronchus involvement
T2 Tumor more than >3 cm or involvement of main stem bronchus 2cm from carina,
visceral pleural involvement, or lobar atelectasis
T3 Tumor of any size with involvement of chest wall including superior sulcus tumors),
diaphragm, mediastinal pleura, pericardium ,main stem bronchus 2 cm from carina
or entire lung atelectasis or obstructive pneumonitis of the entire lung
T4 Tumour of any size with invasion of mediastinum , heart, great vessels, trachea,
pleural effusion
Nx Regional lymph nodes cannot be assessed
N0 No demonstrable metastasis to regional lymph nodes
N1 Ipsilateral hilar or peribronchial nodal involvement
N2 Metastasis to ipsilateral , mediastinal and /or subcarinal lymph nodes
N3 Metastasis to contralateral mediastinal or hilar lymph nodes, ipsilateral or
contralateral scalene, or supraclavicular lymph nodes
M0 No (known) distant metastasis
M1 Distant metastasis present

Stage TNM subset

Stage0 Tis: carcinoma in situ
Stage lA T1 N0 M0
Stage lB T2 N0 M0
Stage llA T1 N1 M0
Stage llB T2 NI M0
T3 N0 M0
Stage lllA T1-3 N2 M0
T3 N1 M0
Stage lllB Any T N3 M0
T3 N2 M0
T4 Any N M0
Stage lV Any T Any N M1

133
Complications Paraneoplastic  ADH secretion (hyponatremia)
and effects syndrome  ACTH secretion (Cushing syndrome)
 Parathormone, parathyroid related peptide, prostaglandins
E, cytokines (Hypercalcemia)
 Calcitonin (Hypocalcemia)
 Gonadotrophins (Gynecomastia)
 Serotonin and bradykinin (Carcinoid syndrome – Flushing,
diarheaa, cardiomyopahy)
Pneumonia, abcess, Due to tumor obstruction of airway
lobar collapse
Lipid pneumonia Tumor obstruction  Accumulation of cellular lipid in foamy
macrophages
Pleural effusion Tumor spread in pleural
Hoarseness Recurrent laryngeal nerve invasion
Dysphagia Esophageal invasion
Diaphragm paralysis Phrenic nerve invasion
Rib destruction Chest wall invasion
SVC syndrome Compression of SVC
Horner syndrome Symphathetic ganglion invasion
Severe pain in Invasion of neural structures around trachea and cervical
distribution of ulnar sympathetic plexus
nerve
Pericarditis and Pericardial involvement
tamponade
Laboratory  LIFE (laser induced fluorescence endoscope) bronchoscopy
investigations  Low-dose spiral computed tomography
 Chest X-ray
 Sputum examination
 Bronchial washing or brushing
 Neuroendocrine markers e.g. neuron specific enolase (NSE), chromogranin
 Tissue biopsy
Management  Chemotherapy
 Radiotherapy
 Thoracic surgery
 Reduce exposure to carcinogens
 Reduce smoking

134