Chapter 15

RESPIRATORY SYSTEM
(Refer to Respiratory System, Quick review for MCQs)

Sr. No. TOPIC Page No.

1 COPD 2

Emphysema 2
Chronic bronchitis 6

2 Asthma 7
3 Bronchiectasis 12

4 Pneumoconiosis 14

Coal workers pneumoconiosis 15

Silicosis 16
Asbestosis 17

5 Pneumonia 19
6 Pulmonary tuberculosis 26

7 Lung tumours 34

Squamous cell carcinoma 36

Adenocarcinoma 37
Small cell carcinoma 39
Large cell carcinoma 41

8 Metastatic tumours to lung 41

9 Important questions 42

Revision No. 1 (2019);

Notes: Robbins & Cotran, Pathologic Basis of Diseases, South Asia Edition, 2014.

Page 1 of 42
 CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

Definition
Obstructive lung disease includes emphysema, chronic bronchitis, asthma, bronchiectasis and
small airway disease- bronchiolitis.

Emphysema and chronic bronchitis are grouped under chronic obstructive pulmonary disease
(COPD) since they are characterized by airflow limitation (obstruction) that is not fully
reversible, and the major trigger is cigarette smoking. Majority of the patients have features of
both. Small airways disease (bronchiolitis) is known to contribute to obstruction in emphysema
and chronic bronchitis.

Incidence

• 4th leading cause of morbidity and mortality in US

• Projected to rank 5th worldwide by 2020

EMPHYSEMA
Definition
Emphysema is characterized by abnormal permanent enlargement of the airspaces distal to
terminal bronchiole (acinus), accompanied by destruction of their walls and without obvious
fibrosis.

Clinical features
• Symptoms appear after one third of the lung tissue is damaged.
• Age of presentation: 50-75
• Dyspnea is the first symptom
• Coughing, wheezing and expectoration develop late
• Severe weight loss
• Prolonged expiration: Patients sit forward in a hunched-over position (“tripod”) and
breathe through pursed lips. Their chests are barrel-shaped. They over-ventilate and
remain well oxygenated; therefore, are called “pink puffers”. Impaired expiratory
airflow measured by spirometry is diagnostic.

Classification
Centriacinar and panacinar emphysema are clinically significant, of which centriacinar account
for 95% of cases.

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Type of Segment of Etiology Affected site Gross appearance
emphysema acinus in lung
involved
Centriacinar Central or Smoking Upper lobes, • Less impressive
proximal particularly • Central areas
parts of acini apical show
formed by segments emphysematous
respiratory changes
bronchioles • Voluminous only
in advanced stage
Panacinar Uniformly Alpha-1- • Lower • Produces
enlarged from antitrypsin zones, voluminous
the level of (α1-AT) along the lungs
respiratory deficiency anterior • Lung overlaps
bronchiole to margin the heart and
terminal • Base of hides it
alveoli lung
Distal acinar Distal part • Pleural fibrosis • More Large apical blebs
(Paraseptal) (alveoli) • Scarring severe in and bullae seen
• Atelectasis upper half measuring <0.5 cm
• Spontaneous of lungs to >2.0 cm
pneumothorax • Adjacent
in young adults to pleura,
at the
margins
of lobules
Irregular Acinus is Associated with
irregularly scarring
involved from healed
inflammatory
process

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Pathogenesis
Cigarette smoke is by far the most common cause of emphysema. In a small percentage of
people, emphysema results from genetic disorder: alpha-1-antitrypsin (α1- AT) deficiency.

Pathogenesis of emphysema can be explained by:

1. Protease-antiprotease mechanism
2. Oxidant – antioxidant mechanism

Protease – Antiprotease mechanism:

Smokers:
Nicotine and reactive oxygen species contained in smoke, lodge predominantly at bifurcation
of respiratory bronchioles- centriacinar region
ß
Smoke causes accumulation of neutrophils and macrophages, which secrete proteases
• Neutrophil proteases: neutrophil elastase, matrix metalloproteinases, proteinase 3,
cathepsin G
• Macrophage proteases: macrophage elastase, matrix metalloproteinases
ß
Proteases have the capacity to digest lung tissue
ß
In non-smokers, in any inflammatory condition of lung, the destructive action of proteases, is
checked by antiproteases (inhibitors of proteases); thus, preventing tissue
destruction. Antiproteases include:
• α - anti-trypsin (α - AT) synthesized by liver
1 1

• secretory leukoprotease inhibitor in bronchial mucus

• serum α -macroglobulin
1

ß
But in smokers, anti-proteases are inactivated by reactive oxygen species contained in
smoke. Thus, in smokers, proteases are in excess of antiproteases causing tissue destruction,
and thus emphysema of the centriacinar region.

α -AT deficiency:
1

α1-AT is a protease inhibitor, secreted by hepatocytes.

α -AT deficiency is an autosomal recessive disorder, affecting predominantly the lung and the
1

liver.
1. Lung disorders: Individuals with α1-AT deficiency have low levels of anti-protease α1-
AT throughout the acinus. Under effect of inflammatory process &/ smoking, whole
acinus is digested, leading to panacinar emphysema. It may cause bronchiectasis.
2. Liver disorders: Hepatitis, cirrhosis, hepatocellular carcinoma
3. Others: Cutaneous panniculitis, Arterial aneurysm, Wegener's granulomatosis

• α1-AT (PiMM): normal phenotype present in 90% of the population

• α1-AT deficiency “S” allele (PiSS): associated with slightly reduced α1-AT levels
• α1-AT deficiency “Z” allele (PiZZ): associated with markedly reduced α1-AT levels,
seen in 1-2% of COPD patients. These patients develop symptomatic emphysema at an
earlier age and with greater severity.

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PAS stain: Abnormal PiZZ α1-AT seen as PAS positive diastase resistant globules in the
hepatocytes.

Oxidant-antioxidant imbalance:

Normally lungs contain antioxidants like, superoxide dismutase, glutathione. These minimize
oxidative damage caused by free radicals.

In smokers:
Tobacco-smoke and recruited leukocytes
ß
Release abundant "free radicals”
ß
They destroy antioxidants
ß
Thus, causing oxidative tissue damage.

Morphological appearance
Gross appearance (described in table above)

Microscopic appearance:

• abnormally large alveoli separated by thin septa, with only focal centriacinar fibrosis
• pores of Kohn are so large that septa appear to be floating into alveolar spaces
• changes of pulmonary arterial hypertension are seen

Fate
Development of CCF and pulmonary HT are signs of poor prognosis. Death in most patients
is due to:
1. Coronary artery disease
2. Respiratory failure
3. Right-sided heart failure
4. Massive collapse of the lungs secondary to pneumothorax

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 CHRONIC BRONCHITIS
Definition

Chronic bronchitis per se is defined clinically. It is said to be present in any patient who has
persistent cough with sputum production for at least 3 months in at least 2 consecutive years,
in the absence of any other identifiable cause.

Cause
• COPD is 4 to 10 times more common in habitual smokers
• Common in inhabitants of smog-laden cities
• Places with grains, cotton and silica dust

Clinical features

• Middle age disease (40-45)

• Men are more affected than women
• Persistent cough
• Later dyspnoea on exertion, hypercapnia, hypoxemia and cyanosis develop; the patients
are therefore called “blue bloaters”.

Pathogenesis
1. Mucus hypersecretion: The lung undergoes protective mechanisms when exposed to
chronic irritants such as tobacco smoke, grains, cotton and silica dust. The protective
mechanisms include:
a. release of inflammatory mediators (histamine and IL-13), which cause hypertrophy
of submucosal glands of larger airways (trachea and bronchi).
b. marked increase in goblet cells of small airways (small bronchi and bronchioles)
leading to excessive mucus production.
2. Inflammation: Chronic irritants cause tissue damage, which elicit acute and chronic
inflammatory response. Tissue damage also interferes with ciliary action of the
respiratory epithelium, which prevents clearance of mucus and increases risk of
infection.
3. Infection: Infection does not initiate chronic bronchitis but is significant in maintaining
and/or exacerbating chronic bronchitis.

Morphological appearance
Gross appearance:
• Mucous membranes show hyperemia, swelling and edema
• Bronchi and bronchiolar lumen show mucinous to mucopurulent secretions

Microscopic appearance:
1. Mucus plugging in lumen
2. Goblet cell metaplasia of the epithelium. In longstanding severe cases, there may be
squamous metaplasia/dysplasia.

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 3. Increase in the mucus-secreting glands, which can be assessed by the ratio of the
thickness of the mucous gland layer to the thickness of the wall between the epithelium
and the cartilage, called Reid’s index. The normal Reid index is 0.4. It is increased in
chronic bronchitis.
4. Bronchioles: Bronchiolar lumen is narrowed due to mucus plugging, inflammation and
fibrosis. In severe cases, the lumen is obliterated due to fibrosis, called bronchiolitis
obliterans.

Fate
1. Cor pulmonale and heart failure
2. Chronic bronchitis is an example of squamous metaplasia, in which columnar
epithelium is replaced by squamous epithelium. The metaplastic epithelium may
undergo atypical hyperplasia / dysplasia / cancerous transformation (SCC)
3. Death due to superimposed acute infections

ASTHMA

Definition
Asthma is a chronic disorder of the conducting airways, usually caused by an immunological
reaction, which is marked by episodic bronchoconstriction due to increased airway sensitivity
to a variety of stimuli; inflammation of the bronchial walls and increased mucus secretion.

Clinical features
Classic asthmatic attack: It is triggered by a stimulant. The attack lasts up to several hours. It
is characterized by episodes of wheezing, breathlessness, chest tightness and coughing,
particularly in the night and/or early morning. Raising of copious mucous secretions provides
relief of the respiratory difficulty. Between the attacks, patients are virtually asymptomatic.

Acute severe asthma (previously known as status asthmaticus): in the severe form, the
paroxysms persist for days and even weeks, sometimes causing so severe airflow obstruction
that it can lead to cyanosis and even death.

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Classification
Pathophysiological classification:
1. Extrinsic: initiated by type I hypersensitivity reaction (immediate IgE associated)
induced by exposure to an extrinsic antigen. It occurs in childhood.
2. Intrinsic: initiated by nonimmune mechanisms; like viral infections, cold, stress,
exercise and inhaled industrial pollutants. It occurs in later life.

Simplified classification:
1. Atopic
2. Nonatopic
3. Drug-induced
4. Occupational

ATOPIC ASTHMA

Definition
Atopic asthma is associated with genetic predisposition to type I hypersensitivity; mediated by
IgE. It is characterized by an acute or immediate response and a late-phase reaction.

Acute or immediate response, which occurs within minutes of exposure to allergen and lasts
up to several hours is characterised by chest tightness, dyspnoea, wheezing and coughing
(with or without sputum production).

Acute phase response is followed by a late-phase reaction, which starts 4 to 8 hours later and
may persist for 12 to 24 hours or more.

Salient features
Atopic asthma is the most common type of asthma. It begins in childhood. A positive family
history of atopy is common. It is triggered by environmental antigens like dust, pollen, animal
dander and food, which act in synergy with other environmental factors like viral
infections. The patient shows a positive skin test for allergen.

Pathogenesis
TH2 response, IgE and Inflammation:
Atopic asthma is caused by TH2 and IgE response to an allergen in genetically predisposed
individuals.

TH2 cells in response to allergens secrete cytokines, which have the following effect:

Mediators EFFECT
IL-4 Stimulate production of IgE from B cells, which bind to mast cells
IL-5 Activate eosinophils
IL-13 Stimulate mucus secretion from bronchial submucosal glands and IgE from B cells

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Many mediators are secreted by leucocytes and epithelial cells. Mediators and their effects are
as follows:

Mediators EFFECT
LT C4-E4 Bronchoconstriction, increased vascular permeability, increased
mucus secretion
Acetylcholine Secreted by intrapulmonary parasympathetic nerves cause
smooth muscle constriction
Histamine Potent bronchoconstrictor
PGD2 Bronchoconstriction and vasodilation
Platelet-activating factor Platelet aggregation and release of histamine and serotonin

Other mediators of inflammation include IL-1, IL-6, IL-13, TNF, chemokine eotaxin (CCL11),
neuropeptides, NO, bradykinin, endothelins.

Early phase reaction is dominated by bronchoconstriction, increased mucus production,

vasodilation and increased vascular permeability; while late phase reaction is dominated by
recruitment of eosinophils2, neutrophils and more T cells.

Genetic susceptibility:

Genes Associated with

Polymorphism in IL13 gene Has the strongest and most consistent association with
located on chr 5q asthma
HLA class II Production of IgE against ragweed pollen
Polymorphism in gene Increased proliferation of bronchial smooth muscle and
ADAM33 fibroblasts
b2-adrenergic receptor gene Hyperresponsiveness of airway
IL-4 receptor gene variant Elevated serum IgE level
Increased expression of lung Associated with airway remodeling and decreased
YKL-40 pulmonary function

Environmental factors:

Asthma is a disease of industrialized societies, especially seen in people living in cities. The
two reasons for this are:
1. Increased airborne pollutants due to industries
2. Hygiene hypothesis: Exposure to microbial agents during early development
(pregnancy and childhood) reduces incidence of allergic diseases and some
autoimmune diseases, called hygiene hypothesis. City life limits exposure to microbial
antigens, thus evading the protective effect against asthma.

Viral (rhinovirus type C, respiratory syncytial virus) and bacterial infections do not cause or
trigger asthma but are associated with acute exacerbations of the disease.

Laboratory diagnosis
No single laboratory test can establish a diagnosis of asthma, but a battery of tests provides
supportive evidence in a setting of clinical and radiological findings, for the diagnosis of
asthma.

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Specific tests:

1. Peripheral blood eosinophil count: elevated

2. Serum allergen-specific IgE: elevated
3. Sputum or bronchioalveolar lavage (BAL) examination: Look for eosinophils,
Curschmann’s spirals (whorls of shed epithelium with thick mucus) and Charcot-
leyden crystals (collections of crystalloids made up of eosinophil membrane protein).
Creola bodies are clusters of ciliated columnar bronchial epithelial cells seen in the
sputum of asthmatics.

Curschmann’s spirals Charcot-leyden crystals Creola bodies

4. Skin test for allergens: Patients with atopic asthma react to a wide range of external
allergens. A drop of each allergen solution is distributed on the forearm and a needle
introduced through the drop into the skin surface to a depth of about 1 mm. The
patient's skin at the site of inoculation is assessed after 15-20 minutes for a positive,
wheal-and-flare reaction.

Morphology of lung in a patient of asthma

Gross appearance:
- Lungs are overdistended because of overinflation
- Occlusion of bronchi and bronchioles by thick, tenacious mucous plugs

Microscopic appearance:
- The lumen shows presence of mucous plugs, which contain Curschmann spirals, numerous
eosinophils and Charcot-Leyden crystals.

- Changes in bronchial wall: Structural changes in the bronchial wall in asthmatic is called
“airway remodeling”. These changes, include:
1. Subepithelial deposition of collagen, leading to thickening of basement membrane
of bronchial epithelium
2. Edema and inflammatory infiltrate in the bronchial walls, with a prominence of
eosinophils and mast cells
3. An increase in size of the submucosal glands
4. Hypertrophy of the bronchial wall smooth muscle

Page 10 of 42
 NONATOPIC OR NONREAGINIC ASTHMA

FEATURES ATOPIC NONATOPIC ASTHMA

ASTHMA
Positive family history Common Uncommon
Association with allergens Present Absent but is triggered by respiratory tract
infection, particularly viruses (e.g., rhinovirus,
parainfluenza virus, respiratory syncytial virus).
Smoking, sulphur dioxide, ozone and nitrogen
dioxide may be the contributing factors.
Serum IgE levels or serum Positive Negative
radioallergosorbent tests
(RAST)
Skin test Positive Negative

DRUG-INDUCED ASTHMA

Drug induced asthma is associated with sensitivity to aspirin and other NSAIDs.

Mechanism of action:
Aspirin and other NSAIDs
ß
Inhibit cyclooxygenase pathway of arachidonic acid metabolism
ß
Decrease in PG-E2, which in the normal course inhibit enzymes that produce LT-B4 to -E4
ß
Thus, leading to exacerbation of inflammatory process

OCCUPATIONAL ASTHMA
Some of the occupational stimulants that can cause asthma are:
1. Fumes (epoxy resins, plastics)
2. Organic and chemical dusts (wood, cotton, platinum)

Page 11 of 42
 3. Gases (toluene)
4. Other chemicals (formaldehyde, penicillin products)

BRONCHIECTASIS

Definition
Bronchiectasis is characterized by permanent dilation of bronchi and bronchioles due to
destruction of muscle and elastic tissue, secondary to chronic necrotizing infections. To be
considered bronchiectasis, the dilation should be permanent.

Associated clinical conditions

Bronchiectasis develops secondary to a variety of disorders, which include:

Congenital disorders 1. Cystic fibrosis

2. Primary ciliary dyskinesia
3. Kartagener syndrome
Infections Necrotizing pneumonia
Bronchial obstruction 1. Tumor
2. Foreign bodies
3. Mucus impaction
Other conditions 1. RA
2. SLE
3. IBD
4. COPD
5. Post-transplant

Clinical features
• Fever
• Severe persistent cough, frequent when the patient rises from bed in the morning
• Copious amounts of foul-smelling purulent sputum; sometimes bloody
• Dyspnoea and orthopnoea in severe cases
• Occasionally life-threatening haemoptysis

Aetiology & Pathogenesis

Obstruction and infection, both are necessary for the development of full-fledged lesions.

Obstruction:
Bronchial obstruction
ß
Impairment of normal lung clearing
ß
Pooling of secretions distal to obstruction

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 ß
Infection
ß
Inflammation, necrosis and fibrosis; leading to destruction and dilation of airways

Infection:
Severe infections of the bronchi
ß
Inflammatory response
ß
Followed by necrosis, fibrosis, and dilatation of airways

Pathophysiology of bronchiectasis in cystic fibrosis:

In cystic fibrosis, the patients have defect in ion transport. It leads to increases Na and water
+

reabsorption resulting in thick and viscous mucus.

Added defective mucociliary action leads to airway obstruction by thick viscous secretions.

This leads to a marked susceptibility to bacterial infections, which damage the airways, causing
bronchiectasis.

Pathophysiology of bronchiectasis in primary ciliary dyskinesia:

It is an autosomal recessive disorder, whereby the cilia are either immotile or dysmotile.

In the lung, poorly functioning cilia contribute to the retention of secretions, infection and
destruction of lung parenchyma.

Half of the patients have Kartagener syndrome [characterized by triad of bronchiectasis,

chronic sinusitis and situs inversus1 (major visceral organs are reversed from their normal
positions)].

Morphology
Gross appearance:
• Usually affects lower lobes bilaterally, particularly air passages that are vertical and is
most severe in most distal bronchi and bronchioles.
• Airways may be dilated up to four times the normal size
• Dilations may be long tube-like (cylindrical bronchiectasis) or fusiform or saccular
(saccular bronchiectasis)
• On cut surface, affected bronchi/bronchioles appear cystic and contain mucopurulent
secretions

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Microscopic appearance:
• intense acute and chronic inflammation of the wall of bronchi and bronchioles
• lining respiratory epithelium may be necrosed and may undergo squamous metaplasia
• peribronchiolar fibrosis may be seen
• necrosis of the bronchial/bronchiolar walls may lead to formation of lung abscess

Complications
1. Obstructive ventilatory insufficiency
2. Cor pulmonale
3. Metastatic brain abscesses
4. Amyloidosis

PNEUMOCONIOSIS

Definition
Pneumoconiosis is defined as non-neoplastic lung reaction to inhalation of mineral/organic
dusts and chemical fumes/vapours encountered in the workplace.

Example

Agent Disease
Mineral dust
Coal dust Anthracosis
Caplan syndrome (Rheumatoid arthritis and
pneumoconiosis)
Silica Silicosis
Caplan syndrome
Asbestos Asbestosis
Pleural plaques

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 Caplan syndrome
Mesothelioma
Carcinoma of lung, pharynx, stomach, colon
Organic dust that induce hypersensitivity pneumonitis
Modly hay Farmer’s lung
Bird droppings Bird-breeder’s lung
Organic dust that induce asthma
Red cedar dust Asthma
Chemical fumes and vapors
Sulfur dioxide, ammonia, Bronchitis
insecticides Asthma
ARDS

Pathogenesis
The development of pneumoconiosis depends on:

1. amount of dust in lungs

2. size, shape and buoyancy of the particles: Most dangerous particles are 1-5 µm in
diameter because they can reach the terminal airways and air sacs.
3. particle solubility and physiochemical reactivity: Small particles with high solubility
cause acute lung injury. Large particles that resist dissolution develop fibrosis; e.g.
silicosis.
4. additional effects of other irritants: E.g., concomitant tobacco smoking worsens the
effect in patients of asbestosis.

COAL WORKERS' PNEUMOCONIOSIS (CWP)

Coal workers’ pneumoconiosis (CWP) is lung disease caused by inhalation of coal particles.
The spectrum of disease varies from:
1. asymptomatic anthracosis to
2. simple CWP with little to no pulmonary dysfunction to
3. complicated CWP or progressive massive fibrosis (PMF) with compromised lung
function

Morphology
Anthracosis:

Inhaled carbon pigment is engulfed by alveolar or interstitial macrophages, which accumulate

in connective tissue along the lymphatics of pleura, bronchi or lung hilum.

Simple CWP:

Characterized by coal macules (1 to 2 mm in diameter) and larger coal nodules:

• scattered throughout the lung, more heavily in upper lobes and upper zones of the lower
lobes
• located primarily adjacent to respiratory bronchioles

Page 15 of 42
 • later there is dilation of adjacent alveoli (centrilobular emphysema)
• microscopically they consist of carbon-laden macrophages with delicate network of
collagen fibers

Complicated CWP:

• Characterized by multiple intensely blackened scars of ≥1 cm diameter, sometimes

reaching up to 10 cm in diameter.
• Microscopically the lesions consist of dense collagen and pigment. Central necrosis
may be present.

Fate
• Usually a benign disease
• 10% of complicated CWP may develop pulmonary hypertension, cor pulmonale,
chronic bronchitis, emphysema
• CWP is not associated with increased risk of TB/lung cancer. However, domestic
indoor use of “smoky coal” cooking is associated with increased risk of lung cancer.

SILICOSIS (GRINDER’S DISEASE)

Silicosis is the most prevalent chronic occupational disease in the world. It is the most
fibrogenic dust in pneumoconiosis, causing progressive nodular fibrosis. Workers involved in
sandblasting, hard rock mining, stone cutting, jewellers using chalk moulds, building and road
construction are exposed to silica.

Pathogenesis
• Silica occurs in crystalline and amorphous forms
• Crystalline forms (quartz, crystobalite, tridymite) are more fibrogenic. Quartz is most
commonly implicated in silicosis.
• After inhalation, the particles interact with epithelial cells and macrophages.
• Within macrophages, silica leads to their activation and release of inflammatory
mediators like IL-1, TNF, fibronectin, lipid mediators, oxygen-derived free radicals and
fibrogenic cytokines.

Morphology
Gross appearance:
• Characterized by tiny, barely palpable, discrete pale to blackened nodules in hilar
lymph nodes and upper zones of the lungs.
• Later nodules may coalesce to form hard, collagenous scars.
• Some nodules may undergo central softening and cavitation due to superimposed
tuberculosis or ischemia.
• Hilar lymph node lesions when surrounded by thin sheets of calcification give eggshell
calcification appearance radiologically (calcification surrounding a non-calcified
center).

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Microscopic appearance:
• Light microscopy: central area of whorled collagen surrounded by peripheral zone of
dust-laden macrophages
• Polarized microscopy: nodule reveals the birefringent silica particles

Area of whorled collagen

Fate
• Onset of silicosis is slow and insidious in most (10-30 years) or accelerated (within 10
years of exposure) or rapid (within few weeks/months of exposure).
• Impaired pulmonary function occurs only late when progressive massive fibrosis
supervenes.
• Associated with increased susceptibility to tuberculosis
• Have two-times risk of developing lung cancer

ASBESTOSIS

Workers involved in mining, milling, fabrication, insulation and automobiles are exposed to
asbestos. Following are the asbestos associated diseases:
1. Localized fibrous plaques or diffuse pleural fibrosis
2. Pleural effusions
3. Pulmonary interstitial fibrosis
4. Mesotheliomas
5. Lung carcinoma

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 6. Laryngeal, ovarian, colonic and other extrapulmonary neoplasms. Family members are
also at an increased risk of developing cancer.
7. Systemic autoimmune and cardiovascular diseases

Geometric forms of asbestos

Properties Serpentine (Chrysotiles) Amphibole7

Prevalence Account for 90% asbestos used Less used
in industry
Solubility More soluble, hence easily removed Less soluble
Shape Curled and flexible; thus, get Straight and stiff; thus, reach deeper,
impacted in the upper airways and may penetrate epithelial cells and
removed by mucociliary action reach the interstitium
Pathogenicity Less pathogenic. Not associated with More pathogenic, particularly
mesothelioma associated with mesothelioma

Pathogenesis
Fibrosis:

Asbestos fibers penetrate alveolar and interstitial macrophages

ß
Activated macrophages release chemotactic factors and fibrogenic mediators
ß
Leads to interstitial pulmonary inflammation and interstitial fibrosis

Carcinogenesis:

Asbestos can also act as a tumor initiator and promoter

ß
Asbestos fibers localize in the distal lung, close to the mesothelial layers
ß
They generate reactive free radicals causing lung carcinoma
ß
Toxic chemicals (e.g. tobacco) adsorbed on asbestos fibers increase the carcinogenicity of
fibers. Exposure to asbestos alone has 5-fold increased risk of lung cancer, while asbestos
and smoking together have 55-fold increased risk. Concomitant smoking however does not
increase the risk of mesothelioma.

Morphology
Pleural involvement:

• Pleural plaques: are the most common and earliest manifestation of asbestosis. consists
of well-circumscribed plaques of dense collagen, seen on anterior and posterolateral
aspects of the parietal pleura and domes of the diaphragm, which are often calcified.
• Pleural effusion: usually serous but may be bloody

Page 18 of 42
Lung disease:

• Diffuse pulmonary interstitial fibrosis:

o begins in the lower lobes and subpleurally
o scarring may trap and narrow pulmonary vessels causing pulmonary
hypertension and cor pulmonale
• Asbestos bodies and Ferruginous bodies are seen in the areas of interstitial fibrosis, not
in pleural plaques:
o Asbestos bodies: are golden brown, fusiform or beaded rods with a translucent
center. The bodies consist of asbestos fibers coated with iron-protein complex;
the iron being derived from phagocyte ferritin.
o Ferruginous bodies: are composed of other inorganic particulates coated with
similar iron-protein complexes

Tumor:
• Asbestosis is associated with 5-fold increased risk of lung carcinoma and 1000-fold
increased risk of mesothelioma.

Asbestos bodies Pleural mesothelioma

Fate

• Disease may remain static

• Progress to respiratory failure
• Cor pulmonale
• Death
• Carcinogenic

PNEUMONIA

Definition

Pneumonia is defined as any infection of the lung parenchyma.

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Classification

Pneumonia can arise in seven distinct clinical settings, called "pneumonia syndromes”:
1. Community-Acquired Bacterial Pneumonia
2. Community-Acquired Viral Pneumonia
3. Health Care-Associated Pneumonia
4. Hospital-acquired Pneumonia
5. Aspiration Pneumonia
6. Lung Abscess
7. Chronic pneumonia
8. Pneumonia in Immunocompromised Host

COMMUNITY-ACQUIRED BACTERIAL (ACUTE) PNEUMONIA

Definition

Community-acquired bacterial pneumonia refers to bacterial lung infection in otherwise

healthy individual, that is acquired from the normal environment.

Clinical features

Characterized by abrupt onset of high fever, shaking chills, cough with mucopurulent
sputum; some may have hemoptysis and pleuritic pain.

Causative organisms

Organism Pneumonia
Streptococcus pneumonia Most common cause of community acquired acute
(pneumococcus)1 pneumonia.
Haemophilus influenzae - H. Influenza, type b (encapsulated variant) is the most
virulent type. Because of its use in H. influenza vaccine, the
incidence of pneumonia due to H. influenza b serotype has
declined.
- H. influenza pneumonia following viral infection in
children, is associated with high mortality.
Staphylococcus aureus - Important cause of secondary bacterial pneumonia
following viral infection.
- IV drug abusers are at a higher risk
- Associated with high incidence of complications such as
lung abscess and empyema
Klebsiella pneumoniae - Most common cause of gram-negative bacterial
pneumonia.
- More commonly affects chronic alcoholics.
- Characterized by thick mucoid secretion, often blood-

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 tinged
Pseudomonas More commonly, a hospital-acquired infection
Mycoplasma pneumoniae More common in children and young adults living in closed
communities (schools, military camps, prisons)

Morphology

Acute pneumonia is characterized by consolidation, literally meaning solidification. Bacterial

invasion of the lung parenchyma leads to filling of the otherwise empty air-filled spaces
(bronchiole, alveoli) with an inflammatory exudate, called consolidation. There are two
morphological patterns of consolidation:
1. Lobular bronchopneumonia
2. Lobar pneumonia

Bronchopneumonia

Definition: Bronchopneumonia is characterized by patchy consolidation of lung in the

peribronchiolar tissue.

Morphology:
Gross appearance:
- patchy consolidation confined to one lobe, more often multilobar and bilateral
- consolidates are more common in the basal regions of lower lobes
- lesions are slightly elevated, dry, granular, firm, gray-red to yellow and poorly
delimited

Microscopic appearance: neutrophil-rich exudate that fills the bronchi, bronchioles and
adjacent alveolar spaces

Lobar pneumonia

Definition: Lobar pneumonia is characterized by consolidation of a large portion of a lobe or

of an entire lobe of lung.

Stages of lobar pneumonia:

Stage Gross appearance Microscopic appearance
(within alveolar spaces)
I Stage of Lung is heavy, boggy, and red. - vascular engorgement
congestion - intra-alveolar fluid with few red
(1-2 days) cells, neutrophils and numerous
bacteria
II Stage of red Lobe appears red, firm & airless; - massive exudation of red cells and
hepatization with a liver-like consistency, neutrophils
(2-4 days) hence called hepatization. - few fibrin strands

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 III Stage of gray Affected area of lung is firm, - disintegration of red cells and
hepatization airless, grayish brown, with dry neutrophils
(4-8 days) surface. - Macrophages begin to appear
- fibrin strands are dense and
numerous
IV Stage of Granular, semifluid, debris in - macrophages are numerous with
resolution alveolar spaces engulfed debris
(1-3 weeks) - fragmented strands of fibrin

Complications:

1. Abscess, particularly common with type 3 pneumonia or Klebsiella infection

2. Empyema
3. Metastatic abscesses to the heart valves (endocarditis), pericardium, brain
(meningitis), kidneys, spleen, or joints (suppurative arthritis).

COMMUNITY-ACQUIRED VIRAL (ATYPICAL) PNEUMONIA

Definition

It is an inflammatory disease of alveolar septa and pulmonary interstitium. It differs from

typical pneumonia in the following ways:

VARIABLE TYPICAL (Air space) ATYPICAL (Interstitial)

Etiology S. pneumonia M. pneumoniae
H. Influenza Viral:
1. Influenza A and B (adults)
2. Respiratory syncytial virus
3. Adenovirus
4. Rhinovirus
5. Rubeola virus
6. Varicella virus
Onset Abrupt Gradual
Constitutional symptoms Few (High-grade fever) Prominent (low-grade fever,
myalgia, fatigue, N/V,
diarrhea)
Local symptoms Present (pleuritic chest pain, Few (dyspnea, dry cough)
productive cough)
WBC count Raised Moderate elevation
Lung biopsy findings Alveolar exudate present Alveolar exudate absent4,
interstitial inflammation
Predominant cell type- Predominant cell type-
neutrophils lymphocytes

Page 22 of 42
Influenza virus

Influenza A virus infect humans, pigs, horses and birds causing pandemic and epidemics.

Structure:

Proteins haemagglutinin (subtypes H1-H3) and neuraminidase (N1, N2) are components of
lipid bilayer envelope.

Haemagglutinin serves to attach the virus to the target cell and release viral RNA into cell
cytoplasm. Neuraminidase helps to release newly formed virions budding from the infected
cell.

The viral genome consists of eight single-stranded RNAs packed into helices by nucleoprotein,
which determine type A, B or C.

Antigenic drift and shift:

Antigenic drift: Epidemics of influenza are caused by mutations that alter antigenic epitopes of
haemagglutinin and neuraminidase proteins. Usually these new strains bear resemblance to the
prior strains, hence some members are resistant to infection.

Antigenic shift: Pandemics occur when haemagglutinin and neuraminidase are replaced by
animal influenza viruses. In this case, all individuals are susceptible to new influenza virus
infection. The 1918 swine flu (HIN1) influenza pandemic killed 20-40 million people world-
wide. H1N1 2009 pandemic affected young, while old had immunity from the previous
pandemic. June 2011 was H5N1 avian virus pandemic, which is less efficient and caused 325
deaths across 15 countries.

Morphology of atypical pneumonia

Gross appearance: lung involvement may be patchy or involve whole lobes bilaterally or
unilaterally. Affected area is red-blue and congested.

Microscopic appearance: Characteristically it has interstitial nature of the inflammatory

reaction, localized within the walls of the alveoli. Alveolar septa are widened, edematous and

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show presence of mononuclear inflammation (lymphocytes, macrophages, plasma cells); in
acute cases, neutrophils.

The alveoli are usually free from exudate, but many patients may have intra-alveolar
proteinaceous material and a cellular exudate.

Complications:

1. Adult respiratory distress syndrome

2. Secondary bacterial pneumonia caused by Staphylococcus aureus can be life-
threatening
3. Epidemics and pandemics are associated with significant morbidity and mortality

HEALTH CARE-ASSOCIATED PNEUMONIAS

Most common organisms isolated from health care workers suffering from pneumonia are:
1. Methicillin-resistant staphylococcus aureus
2. Pseudomonas

HOSPITAL-ACQUIRED PNEUMONIA
Defined as pulmonary infections acquired in the course of a hospital stay.

Common in patients with:

1. Severe underlying disease
2. Immunosuppression
3. Prolonged antibiotic therapy
4. Invasive devices e.g. intravascular catheters
5. Patients on ventilators

Causative organisms:
1. Gram positive bacteria: S. aureus, S. pneumonia
2. Gram negative bacteria: Enterobacteria, Pseudomonas

ASPIRATION PNEUMONIA

Introduction

Aspiration pneumonia occurs in markedly debilitated patients, those who aspirate gastric
contents either while unconscious or during repeated vomiting. The resultant pneumonia is
partly chemical, the gastric acid and partly bacterial (from the oral flora). Typically, more than
one organism is cultured, more commonly aerobes than anaerobes.

Clinical course

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This type of pneumonia is often necrotizing. Pursues a fulminant clinical course and is a
frequent cause of death. In those who survive, lung abscess formation is a common
complication.

LUNG ABSCESS

Definition

“Pulmonary abscess" describes a local suppurative process within the lung, characterized by
necrosis of lung tissue.

Associated clinical settings

1. Aspiration of infective material

2. Oropharyngeal or dental surgical procedures
3. Antecedent primary lung infection
4. Septic embolism from thrombophlebitis or from vegetations of infective bacterial
endocarditis
5. Primary or secondary lung malignancy

Gross appearance

- Size: few millimeters to 5 to 6 cm

- Site: any part of the lung and may be single or multiple
- Lung abscess due to aspiration are more common on the right (because of the more
vertical right main bronchus) and are most often single in the lower lobe5.
- Abscesses from primary lung infection are usually multiple and basal.
- Abscess from septic emboli are multiple and can affect any part of lung.

Microscopic appearance

Suppurative destruction of the lung parenchyma with central area of cavitation.

CHRONIC PNEUMONIA

Definition

It is a localized lesion in immunocompromised patient. The reaction is typically granulomatous

caused by bacteria (M. tuberculosis) or fungi (histoplasmosis, blastomycoccis,
Coccidioidomycosis).

Histoplasmosis

Histoplasma capsulatum infection is acquired by inhalation of dust particles from soil,

contaminated with bird/bat droppings containing microconidia, the infectious form of the
fungus. The target of infection are the macrophages.

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Clinical presentation:

1. Self-limited primary lung disease, producing coin-like lesions on X-ray chest

2. Chronic progressive secondary lung disease: localized to lung apices
3. Extension to extrapulmonary sites: mediastinum, adrenal, liver or meninges
4. Widely disseminated disease seen in immunocompromised patients

Morphology:
Gross appearance:
- Caseating granuloma with cavity
- Effectively treated lesions undergoing fibrosis and concentric calcification giving the
classical ‘tree-bark appearance’.

Microscopic appearance:
- Caseating granuloma
- 3-5 µm thin-walled yeast forms seen within the macrophages
- In fulminant disseminated histoplasmosis, granulomas are not seen. There is presence
of collections of macrophages infected with fungal yeast throughout the body.

Tree-bark appearance Histoplasma yeast forms

PNEUMONIA IN IMMUNOCOMPROMISED HOST

Causative organisms

1. Bacteria: Pseudomonas, Mycobacterium

2. Virus: CMV, Herpes
3. Fungus: Candida, Aspergillosis, Cryptococcus neoformans, Pneumocystis jiroveci
(carinii)

PULMONARY TUBERCULOSIS

CAUSATIVE ORGANISM

Causative organism
• Pathogenic strains of mycobacterium:
Mycobacterium tuberculosis
M. bovis

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 M. avium
M. murine
Cold-blooded vertebrate strain

M. tuberculosis is pathogenic for humans. M. bovis is usually pathogenic for animals.

Human infection by M. bovis occurs through consumption of un-pasteurized milk, leading
to oropharyngeal and intestinal tuberculosis. The most common site of intestinal
tuberculosis is terminal ileum and caecum. M. avium-intracellulare infection is seen in
patients of AIDS.

• Atypical mycobacterium

Properties
• M. TB are obligate aerobes, grow well in tissues with a high oxygen content
• Habitat: intracellular pathogens infecting the macrophages
• Slow-growing organisms, with a generation time of 12 - 18 hours

PATHOGENESIS

Entry into macrophage:

When an individual is first exposed to M. tuberculosis bacilli, the bacilli get coated or
opsonized with complement factors C2a and C3b.
ß
Macrophages identify these opsonized bacilli.
ß
Opsonized bacilli enter macrophages by endocytosis mediated by macrophage receptors,
mannose binding lectin and CR3.

Replication in macrophages:
Once inside the macrophage, M. tuberculosis replicates within the phagosome by blocking
fusion of the phagosome and lysosome. This is facilitated by inhibiting Ca2+ signals and
blocking the required proteins.
ß
Thus, early in infection, tuberculosis bacilli replicate unchecked.

TH1 response:
Later, about 3 weeks after infection, the mycobacterial antigens drain to the lymph nodes,
where they bind to antigen presenting cells- the dendritic cells through Toll-like receptor 2
(TLR2).

ß
This leads to production of IL12 by dendritic cells.

ß
In the presence of IL-12, CD4+ T cells get differentiated into TH1 cells.

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TH1 cells produce IFN-γ, which activate macrophages enabling them to become bactericidal:
1. IFN-γ stimulates formation of phagolysosome in infected macrophages, exposing the
bacteria to an inhospitable acidic environment.
2. IFN-γ also stimulates expression of inducible nitric oxide synthase (iNOS), which
produces NO. NO in turn produces reactive nitrogen intermediates and other free
radicals causing oxidative injury to mycobacterium.
3. IFN-γ mobilizes antimicrobial peptides (defensins) against the bacteria.
4. It stimulates autophagy, which destroys damaged organelles and intracellular M. TB.

In addition, NKT cells also recognize M. TB antigens that bind to CD1 on dendritic/T cells.
These NKT cells also secrete IFN-γ.

Granulomatous inflammation and tissue damage:

The macrophages activated by IFN-γ undergo structural changes, resembling epithelium-like

cells, called "epithelioid cells".

Epithelioid cells in time aggregate into tight clusters.

Some of these epithelioid cells fuse to form multinucleated giant cells, called ‘Langhan’s giant
cells’.

Activated macrophages secrete several growth factors:

1. TNF and chemokines which recruit more monocytes
2. PDGF which stimulate fibroblast proliferation

Some of the TH1 cells enter the circulation and remain in the memory pool of T cells for long
periods.

On reactivation or re-exposure of the bacilli in a previously sensitized host, the memory TH1
cells identify the opsonized bacilli and host not only a rapid defensive reaction but at the same
time cause increased tissue necrosis.

Host susceptibility to disease: People with genetic deficiency of IL-12 and IFN-γ pathways ar
vulnerable to severe mycobacterial infections.

MORPHOLOGY

Primary pulmonary tuberculosis

Definition
Primary tuberculosis is the form of infection that develops in a previously unexposed, and
therefore unsensitized, person.

Route of infection

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In primary tuberculosis, the source of infection is exogenous. Individuals acquire TB through
person-to-person transmission of airborne droplets of organisms from an active host. Thus,
tuberculosis flourishes wherever there is poverty and crowding, chronic debilitating illness
and in patients of AIDS. DM, Hodgkin’s lymphoma, pneumoconiosis particularly silicosis,
chronic renal failure, malnutrition, alcoholism and immunosuppression4 increase the risk of
infection.

Signs and symptoms

In most people, primary tuberculosis is asymptomatic, although it may cause fever and pleural
effusion.

Gross appearance
Distal airspaces of lower part of upper lobe or upper part of lower lobe5, usually close to the
pleura, show presence of 1- to 1.5 cm area of grey-white consolidation, called ‘Ghon
focus’. Centre of Ghon focus undergoes caseous necrosis. Tubercle bacilli now get access to
lymphatics and drain to regional hilar nodes. This combination of parenchymal lung lesion,
draining lymphatics and hilar nodal involvement is called ‘Ghon complex’.

Rarely, hematogenous spread of primary TB can lead to a lesion in the apex of upper lobe,
which heals with scarring called ‘Simon’s focus’.

Microscopic appearance
The mass of epithelioid cells with scattered Langhan’s giant cells, rimmed by a zone of
lymphocytes, plasma cells and fibroblasts; form a granuloma. This is a ‘hard tubercle’.

Later the centre of the granuloma undergoes necrosis. The necrotic material is cheesy white
due to the high lipid content of the bacillary cell wall, called ‘caseous necrosis’. The granuloma
is now called ‘soft tubercle’, which is the hallmark of tuberculosis.

Immunocompromised hosts do not form granulomas. Their macrophages contain many AFB.

Page 29 of 42
Fate of primary tuberculosis
In 95% cases, the Ghon complex heals forming a tiny, fibrocalcific nodule, called Ranke
complex.

5% of newly infected individuals develop progressive disease, called progressive primary

tuberculosis.

Progressive primary and primary miliary tuberculosis

It is characterized by middle and lower lobe consolidation, hilar adenopathy, and pleural
effusion.

If untreated lymphohematogenous dissemination may result in the development of tuberculous

meningitis and primary miliary tuberculosis.

Secondary/Reactivation/Post-primary pulmonary tuberculosis

Definition
Secondary tuberculosis arises in a previously sensitized host.

Source of infection

Endogenous: Viable organisms remain dormant in the healed Ghon complex for
decades. When the person's immune defences are lowered, the infection gets reactivated,
leading to endogenous infection.

Exogenous: Individual is exposed to a large inoculum of infection with virulent bacilli.

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Gross appearance
Focus in lung: Classically the lesion is localized to the apex and posterior segments of upper
lobes of one or both lungs called Puhl’s lesion. Infraclavicular lesion is called Assman’s focus.
High oxygen tension in the apices promotes growth of the bacteria. The apical pulmonary
lesion is <2 cm in diameter, within 1 to 2 cm of the apical pleura. The lesion is sharply
circumscribed, firm, grey-white with yellow areas of central caseation and peripheral fibrosis.

The central caseous necrosis leads to cavitation and thus dissemination of mycobacteria along
the airways and the sputum coughed out by the patient contains bacilli; thus, the patient is an
active source of infection.

Regional nodes: Because of pre-existing hypersensitivity, there is marked tissue response

(fibrosis) that walls off the focus of infection. As a result, regional lymph nodes are less
prominently involved early in secondary tuberculosis than they are in primary tuberculosis.

Progressive secondary tuberculosis

In unfavourable cases (elderly, immunosuppressed) the apical lesion enlarges with expansion
of the area of caseation. Erosion into a bronchus evacuates the caseous centre, creating a
ragged, irregular cavity lined by caseous material and poorly walled off by fibrous tissue.

With adequate treatment, the process is arrested and apical irregular cavitatory lesion heals by
fibrosis, distorting the pulmonary architecture.

Page 31 of 42
 Secondary miliary tuberculosis

If the treatment is inadequate or if host defences are impaired, infection spreads through
airways, lymphatic channels, and vascular system.

Dissemination through the lymphatics, leads to drainage of the organisms into:

lymphatic ducts
ß
venous return
ß
right side of the heart
ß
pulmonary arteries.

Dissemination through pulmonary arteries leads to microscopic or small, visible (2-mm) foci
of yellow-white consolidation scattered through the lung parenchyma. These lesions are called
"miliary" since these foci resemble millet seeds.

Miliary lesions may expand and coalesce to yield almost total consolidation of large regions or
even whole lobes of the lung - tuberculous pneumonia.

Pleural cavity is invariably involved - tuberculous empyema.

If the bacilli seed pulmonary venous return to the heart; the organisms disseminate through the
systemic arterial system, leading to systemic miliary tuberculosis. Almost every organ in the
body can be seeded; most favoured sites are liver, bone marrow, spleen, adrenals, meninges,
kidneys, fallopian tubes, and epididymis.

Congenital tuberculosis

The most common site of congenital tuberculosis is liver.

LABORATORY DIAGNOSIS
1. Hemogram: Lymphocytosis

2. Elevated ESR due to increase in plasma fibrinogen, Ig and other acute phase reactants
which cause RBC aggregation.

3. Mantoux test:

Principle: Tuberculin (Mantoux) test is based on the principle of delayed (cell-mediated)

hypersensitivity to M. tuberculosis antigens. It does not differentiate between infection and
disease.

Procedure: 0.1 ml of 5 Tuberculin units Purified protein derivative (PPD) of M.

tuberculosis is injected intradermally in the flexor aspect of forearm.

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 Reading: Measure visible and palpable induration perpendicular to the long axis of forearm
in millimeters, after 48 to 72 hours of inoculation. Erythema (redness) should not be
measured.

Interpretation:
1. 5 mm or more is positive in:
a. HIV-positive person,
b. Recent contact with a patient of TB,
c. Persons with nodular or fibrotic changes on chest x-ray consistent with old
healed TB,
d. Patients with organ transplants and other immunosuppressed patients.

2. 10 mm or more is positive in:

a. Recent arrivals (< 5 years) from high-prevalence countries,
b. Injection drug users,
c. Residents and employees of high-risk congregate settings (e.g., prisons, nursing
homes, hospitals...),
d. Mycobacteriology laboratory personnel,
e. Persons with in high risk group (diabetes, chronic malabsorption syndrome,
end-stage renal disease…),
f. Children and adolescents exposed to adults in high-risk categories.

3. 15 mm or more is positive in:

a. Persons with no known risk factors for TB.

False negative reaction:

1. Certain viral infections
2. Sarcoidosis
3. Malnutrition
4. Hodgkin disease
5. Immunosuppression
6. Overwhelming active tuberculous disease
False-positive reactions:
1. Atypical mycobacteria
2. Prior BCG may result in a false-positive result for many years afterwards

4. Ziehl-Neelsen acid-fast stain:

Specimen: Sputum, bronchioalveolar lavage, tissue
Result: Mycobacteria are acid-fast bacilli. Sputum smears are negative in 80% cases of miliary
tuberculosis.
Auramine Rhodamine stain is more sensitive for M. TB than ZN stain.

5. Culture:
- Material: sputum of patients
- Conventional cultures required up to 10 weeks
- Löwenstein-Jensen (LJ) medium culture is reported within 2 weeks
- Cultures also allow testing of drug susceptibility

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6. BACTEC:
Principle: BACTEC is an automated system for detecting early growth of mycobacteria by a
radiometric method. Sputum or other homogenates are decontaminated and added to vials
containing Middlebrook 7H12 medium, an antibiotic mixture (to avoid the growth of other
organisms) and 14C-labelled palmitic acid.

If mycobacterial growth occurs, 14C palmitic acid is utilized and 14CO2 is produced. The
air space above the medium in each bottle is sampled automatically by the BACTEC machine
at fixed intervals and the amount of radioactive gas is estimated and recorded.

Result: Growth of mycobacteria may be detected within 5-7 days, but positive results
require further testing to distinguish between tubercle bacilli and other mycobacteria.

7. PCR/Line probe assay/GeneXpert:

Advantages of PCR amplification of M. tuberculosis DNA:
a. Gives rapid diagnosis
b. High sensitivity, can detect as few as 10 organisms, as compared to more than 10,000
organisms required for smear-positivity

8. Tissue diagnosis:
Microscopic appearance: Characterized by epithelioid cell granulomas with or without
central caseation:
• Caseous necrosis is structureless eosinophilic granular material with nuclear debris.
• Epithelioid cells are modified macrophages with elongated vesicular nuclei & pale
eosinophilic cytoplasm; resembling epithelial cells.
• Langhan’s giant cells are formed by fusion of epithelioid cells, the nuclei are arranged :
o Peripherally in form of horseshoe
o Peripherally in ring form
o Foreign body type with centrally placed nuclei
o Clustered at two poles

LUNG TUMORS

Paraneoplastic syndrome

Lung cancers are associated with a number of paraneoplastic syndromes. However, clinically
significant syndromes caused by these ectopic hormones are seen in only 1-10% of lung cancer
patients.

1. Antidiuretic hormone (ADH) inducing hyponatremia

2. Adrenocorticotropic hormone (ACTH) producing Cushing syndrome
3. Parathormone causing hypercalcemia
4. Calcitonin causing hypocalcaemia
5. Gonadotropins causing gynecomastia
6. Serotonin and bradykinin causing carcinoid syndrome

Tumors that produce ACTH and ADH are predominantly small cell carcinoma. Hypercalcemia
is mostly seen in squamous cell carcinoma of lung.

Page 34 of 42
Etiology and Pathogenesis
1. Tobacco smoking:
- 80% of lung carcinomas occur in active smokers or those who stopped smoking
recently.
- Cessation of smoking reduces the risk but does not bring to baseline.
- There is 60-fold increased risk of lung cancer in an individual who smoked 2 packs
a day for 20 years, as compared to non-smoker.
- Lung cancers develop in only 11% of heavy smokers. This is because of mutagenic
effect of carcinogens in smoke being modified by genetic variations. E.g.
individuals with specific P-450 polymorphisms, which convert procarcinogens into
carcinogens are associated with increased risk. Individuals with more numerous
breakages in peripheral blood lymphocytes after exposure to tobacco-related
carcinogens are at 10-fold increased risk.
- Women have higher susceptibility to tobacco carcinogens than men.
- Passive smoking increases risk to twice as compared to non-smokers.
- Secondhand smoke or environmental tobacco smoke is also associated with
increased risk of cancer.
- Smoking pipes and cigars is associated with modest risk.
- Smokeless tobacco spare lungs but cause oral cancer and can lead to nicotine
addiction.

2. Industrial Hazards:
a. Ionizing radiation: High-dose ionizing radiation is carcinogenic; e.g. increased
incidence of lung cancer among Hiroshima and Nagasaki atomic bomb blasts
survivors.
b. Uranium: Increased risk of lung cancer 4 times higher than the general population
among non-smoking uranium miners and 10 times higher amongst smoking
miners.
c. Asbestos exposure: Asbestos non-smoking workers have 5 times greater risk of
developing lung cancer while asbestos smoking workers have 55 times greater risk.
The latent period for development of lung cancer is 10 to 30 years.

3. Air Pollution: Radioactive Radon gas comes from the natural breakdown of uranium in
soil, rock and water and gets into the air we breathe. Low-level indoor exposure of
radon in the homes in areas where soil is rich in uranium leads to increased incidence
of lung tumours.

4. Lung cancer in Never Smokers: 25% lung cancers occur in never smokers; more
common in women and most are adenocarcinoma. They show EGFR mutations.

5. Precursor lesions include:

a. Squamous dysplasia and carcinoma in situ

b. Atypical adenomatous hyperplasia
c. Adenocarcinoma in situ
d. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

Page 35 of 42
Classification of lung cancer
1. Adenocarcinoma (38%)
2. Squamous cell carcinoma (20%)
3. Small cell carcinoma (14%)
4. Large cell carcinoma (3%)
5. Others (25%): adenosquamous, carcinoma with sarcomatoid elements, carcinoid
tumor

For practical and therapeutic purposes, the various histologic types of lung cancer can be short
listed into two groups:

1. Small cell carcinomas: frequently metastasize and have high initial response to
chemotherapy
2. Non-small cell carcinomas: less often metastatic and less responsive to chemotherapy

SQUAMOUS CELL CARCINOMA

Aetiology: Squamous cell carcinomas are closely associated with history of smoking.

Sex: M:F= 6.6-15:1. However, this difference is declining due to changing smoking habits in
women.

Age of presentation: 50s-70s

Gross appearance:

1. Hilar type: 50% arise in the hilum of lung; grow as cauliflower-like exophytic mass or
as infiltrative growth.

2. Peripheral type: occurs as tumor with central or subpleural fibrosis. Both the types
develop as nodular mass, with well-defined borders. Central necrosis leading to
cavitation is common.

Page 36 of 42
Microscopic appearance: Classified into:

1. Well-differentiated squamous cell carcinoma (infrequent in lung): characterized by the

presence of squamous pearls, single cell keratinization and intercellular bridges
2. Moderately-differentiated: characterized by single cell keratinization and intercellular
bridges
3. Poorly-differentiated

Another characteristic feature is intraepithelial dysplasia of the surrounding uninvolved

bronchial mucosa. This feature is not seen in adenocarcinoma and small cell carcinoma
because these tumors grow beneath the epithelium.

Genetic work up:

Oncogenes: EGFR is over-expressed in 80% of the cases.

Tumor suppressor genes:

1. loss of p53
2. Loss of CDKN2A gene (65% cases)
3. Loss of RB gene (15% cases)
Immunohistochemistry: Positive for low- and high- molecular weight keratin

Metastasis: occurs late in the course of disease

Prognosis: Overall prognosis of lung cancer is poor, with 5-year survival rate of only 16%.
Squamous cell carcinoma is however, the most curable of all lung cancer.

ADENOCARCINOMA
Aetiology: Adenocarcinoma is the most common type of lung cancer in non-smokers.
However, the incidence of adenocarcinoma in smokers has increased significantly in the last
two decades because of the change in cigarette types used today; cigarettes with filter tips,
lower tar and nicotine. The smoke of these cigarettes is inhaled more deeply reaching the
peripheral airways and cells.

Peripheral airways (alveoli) are composed of:

Cell type Pneumocyte Alveolar surface Function

Squamous cells Type-I Cover 95% Gaseous exchange
Cuboidal (Clara) Type-II Cover 5% Secrete alveolar surfactant
cells

Type-I and type-II pneumocytes develop into squamous cell carcinoma and adenocarcinoma
respectively.

Sex: Adenocarcinoma as compared to squamous cell carcinoma is more common in women.

Page 37 of 42
Age of presentation: Average age of presentation is lower than squamous cell carcinoma of
lung

Gross appearance:

- peripherally located, commonly associated with pleural fibrosis and retraction; hence
called “scar cancer”
- 72% peripheral tumours with pleural fibrosis are adenocarcinoma, while 18%
squamous
- may massively spread into pleural space, leading to pleural carcinomatosis
- smaller in size
- cavitation is rare

Scar cancer

Microscopic appearance:

Growth pattern:

- Acinar
- Papillary
- Solid
- Mixed pattern

At the periphery of the tumor, they grow in “lepidic” pattern, in which tumor cells crawl along
normal alveolar septa.

Genetic work-up:

- K-RAS mutation is seen in 30% of smokers and 5% of non-smokers

- EGFR, ALKM ROS, MET, RET mutations

Immunohistochemistry:

Adenocarcinoma are positive for

- Low molecular weight cytokeratin (CK): Primary pulmonary adenocarcinoma are

CK7+ / CK20-. Metastatic adenocarcinoma to lung are CK7- / CK20+.

Page 38 of 42
 - Thyroid transcription factor-1 (TTF-1)
- EMA
- CEA
- Berep-4

Metastasis: Adenocarcinoma of lung grows slowly at the primary site but tend to metastasize
widely and earlier. Often metastasis presents as the first manifestation of an underlying occult
pulmonary lesion. Favoured sites for metastasis:

- Adrenals (> 50%)

- liver (30% to 50%)
- brain (20%)
- bone (20%)

Chemotherapeutic agents are targeted against EGFR.

SMALL CELL CARCINOMA

Aetiology: Small cell carcinomas have strongest relationship to cigarette smoking; only about
1% occur in non-smokers.

Sex: M:F = 4:1

Gross appearance:

- Occur both in central and peripheral location

- Central tumor arising in the main bronchus spreads subepithelially, along its long axis,
not destroying the bronchial epithelium. Therefore, the gross appearance is of a nodular,
smooth and glistening lesion in the bronchus.
- Peripheral tumor presents as solid nodular mass with well-defined borders
- Cut surface is fleshy (medullary)

Nodular central tumor Nodular peripheral tumor

Page 39 of 42
Microscopic appearance:

Growth pattern:

- diffuse growth of small cells

- Occasionally tumor cells from rosettes, trabeculae and nests

Cytological features: The tumor cells are:

- small, smaller than small resting lymphocytes

- round, oval, and spindle-shaped
- with scant cytoplasm
- ill-defined cell borders
- nuclear molding is prominent
- hyperchromatic finely granular nuclear chromatin (“salt and pepper” pattern)
- absent or inconspicuous nucleoli

Mitotic activity: high

Secondary features:

- May show extensive areas of coagulative necrosis

- Tumor cell necrosis leads to basophilic staining of vascular walls due to nuclear DNA
(Azzopardi effect).

Electron microscopy: shows presence of dense-core neurosecretory granules

IHC: Positive for neuroendocrine markers:

- chromogranin
- synaptophysin
- Leu-7

Genetic workup:

- Rb gene mutation (in 100% cases)

- TP53 mutation (75-90%)

Prognosis: It is the most aggressive of lung tumors, metastasizing early and widely, to regional
lymph nodes and distant organs. The tumor is sensitive to radiotherapy and chemotherapy.
Even with treatment, mean survival rate is only 1 year.

Page 40 of 42
 LARGE CELL CARCINOMA
Introduction: Large cell carcinoma is an undifferentiated tumor, a diagnosis by exclusion.

Gross appearance:

- More frequently a peripheral tumor

- Spheric tumor with well-defined borders
- Cut surface is bulging, homogenous fleshy (sarcomatous-like)
- Anthrocotic pigments are not seen due to compressive growth

Microscopic appearance:

Pattern of growth: solid nests of polygonal cells

Cytological features:

- large cells
- vesicular nuclei
- prominent nucleoli
- moderate cytoplasm

METASTATIC TUMORS

Introduction
Lung is the most common site of metastatic neoplasms. Both carcinomas and sarcomas arising
anywhere in the body may spread to the lungs via the blood or lymphatics or by direct
continuity. The primary is most commonly from:
1. Colorectal carcinoma
2. Renal carcinoma
3. Uterine cervical cancer
4. Salivary gland tumor
5. Stomach
6. Breast

Growth of contiguous tumours occurs by direct spreading, most often with oesophageal
carcinomas and mediastinal lymphomas.

Gross appearance
Present as multiple discrete nodules (cannonball lesions) scattered throughout all lobes. These
lesions tend to occur in the periphery of the lung rather than in the central locations. Other
patterns include:
• solitary nodule
• endobronchial growth
• pleural nodule
• foci of lepidic growth similar to bronchioloalveolar carcinoma

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Microscopic appearance
Histologically, they express features characteristic to their primary site.

IMPORTANT QUESTIONS

SHORT NOTES:
1. Emphysema- definition, types and etiology
2. Etiopathology of bronchogenic carcinoma
3. Etiopathology of bronchiectasis
4. Localized bronchiectasis
5. Bronchopneumonia
6. Enumerate various types of pneumoconiosis. Write a note on silicosis.

SHORT ANSWERS:
(Note: Answers only to those questions not addressed in the text or written scattered are given here.
In some answers are given in detail to cover relative topics.)

1. Lesions caused by asbestosis

2. Mention the types of emphysema
3. Name two common hereditary conditions associated with bronchiectasis.
4. Two lung lesions predisposing to bronchiectasis
5. Name two conditions caused by α-1 anti-trypsin deficiency.
Ans. 1. Pulmonary emphysema
2. Cirrhosis
3. Cutaneous panniculitis
4. Arterial aneurysm
5. Bronchiectasis
6. Wegener's granulomatosis
6. Give two important complications of bacterial pneumonia.
7. Name two conditions affecting small airways.
8. Mention the stages and complications of lobar pneumonia
9. Differences between lobar and bronchopneumonia
10. Complications of bronchiectasis
11. Aetiology of bronchogenic carcinoma
12. Spread of bronchogenic carcinoma
13. Paraneoplastic syndromes of oat cell carcinoma of lung
Ans. 1. Antidiuretic hormone (ADH) inducing hyponatremia
2. Adrenocorticotropic hormone (ACTH) producing Cushing syndrome
14. Name neuroendocrine tumours of lung
Ans. Small cell carcinoma, large cell neuroendocrine carcinoma, carcinoid tumor

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