The Respiratory System Normal Structure Of Lungs
Anatomy The normal adult right lung weighs 375 to 550 gm (average 450 gm) and is divided by two fissures into three lobes—the upper, middle, and lower lobes.
Table of Contents
- The weight of the normal adult left lung is 325 to 450 gm (average 400 gm) and has one fissure dividing it into two lobes the upper and lower lobes, while the middle lobe is represented by the lingula.
- The airways of the lungs arise from the trachea by its division into right and left main bronchi which continue to divide and subdivide further, eventually terminating into the alveolar sacs.
- The right main bronchus is more vertical so aspirated foreign material tends to pass down to the right lung rather than to the left.
Read And Learn More: Systemic Pathology Notes
- The trachea, major bronchi, and their branchings possess cartilage, smooth muscle, and mucous glands in their walls, while the bronchioles have smooth muscle but lack cartilage as well as mucous glands.
- Between the tracheal bifurcation and the smallest bronchi, about 8 divisions take place.
- The bronchioles so formed further undergo 3 to 4 divisions leading to the terminal bronchioles which are less than 2 mm in diameter. The part of the lung tissue distal to a terminal bronchiole is called an acinus.
A cluster of about 5 acini supplied by terminal bronchioles and enclosed by visible fibrous septa is termed the pulmonary lobule. An acinus consists of 3 parts
- Several (usually 3 to 5 generations) respiratory bronchioles originate from a terminal bronchiole.
- Each respiratory bronchiole divides into several alveolar ducts.
- Each alveolar duct opens into many alveolar sacs (alveoli) which are blind ends of the respiratory passages.
The lungs have a double blood supply of oxygenated blood from the bronchial arteries and venous blood from the pulmonary arteries, and there is a mixing of the blood to some extent.
In case of blockage of one side of the circulation, the supply from the other can maintain the vitality of pulmonary parenchyma.
The bronchial veins drain the blood supplied by the bronchial arteries.
The lungs have abundant intercommunicating lymphatics on the surface which drain into the subpleural plexus.
Hilar and tracheobronchial lymph nodes receive the lymph and drain into the thoracic duct.
Histology: The Bronchi And Their Subdivisions Up To bronchioles are lined by pseudostratified columnar ciliated epithelial cells, also called the respiratory epithelium.
These cells are admixed with mucus-secreting goblet cells which decrease in number as the bronchioles are approached.
The mucosa of the bronchi contains numerous submucosal mucous glands and neuroendocrine cells which are bronchial counterparts of the argentaffin cells of the alimentary tract.
The structure of bronchioles differs from that of bronchi and their subdivisions as well as from alveoli.
They are lined by a single layer of pseudostratified columnar ciliated epithelium but no mucus cells and hence, unlike the bronchi, contain no mucus secretion on the surface.
They contain some nonciliated Clara cells which secrete protein rich in lysozyme and immunoglobulins but unlike the alveoli contain no surfactant.
The alveolar walls or alveolar septa are the sites of exchange between the blood and air and have the following microscopic features:
1. The capillary endothelium lines the anastomosing capillaries in the alveolar walls.
2. The capillary endothelium and the alveolar lining epithelial cells are separated by the capillary basement membrane and some interstitial tissue.
The interstitial tissue consists of a scanty amount of collagen, fibroblasts, fine elastic fibers, smooth muscle cells, a few mast cells, and mononuclear cells.
3. The alveolar epithelium consists of 2 types of cells: type I or membranous pneumocytes are the most numerous covering about 95% of the alveolar surface, while type II or granular pneumocytes project into the alveoli and are covered by microvilli.
Type II pneumocytes are essentially reserve cells that undergo compensatory hyperplasia when type I pneumocytes are injured and are also the source of pulmonary surfactants rich in lecithin.
The main functions of coating surfactant are to lower the surface tension of the alveolar lining cells and in maintaining the stability of the alveoli.
4. The alveolar macrophages belonging to the mononuclear-phagocyte system are present either free in the alveolar spaces or attached to the alveolar cells.
5. The pores of Kohn are the sites of alveolar connections between the adjacent alveoli and allow the passage of bacteria and exudate.
The primary functions of the lungs are oxygenation of the blood and removal of carbon dioxide.
The respiratory tract is particularly exposed to infection as well as to the hazards of inhalation of pollutants from inhaled air and cigarette smoke. There exists a natural mechanism of filtering and clearing such pollutants through the respiratory epithelium, tracheobronchial lymphatics, and alveolar macrophages.
Normal Structure Of Lungs:
- The average weight of a normal adult right lung is 450 gm and has three lobes, while the average weight of a normal adult left lung is 400 gm and has two lobes.
- The right main bronchus is more vertical.
- Between the tracheal bifurcation and the smallest bronchi, about 8 divisions take place and bronchioles are formed, which further undergo 3 to 4 divisions leading to the terminal bronchioles.
- Bronchioles are lined by a single layer of pseudostratified columnar ciliated epithelium.
- Alveolar walls or alveolar septa are the sites of exchange between blood and air.
- Alveolar wall has the capillary endothelium, capillary basement membrane and some interstitial tissue, and the alveolar epithelium which consists of 2 types of cells: type I or membranous pneumocytes and type II or granular pneumocytes.
Congenital Anomalies
A number of congenital anomalies (e.g. agenesis, hypoplasia, heterotopic tissue, vascular anomalies, tracheal and bronchial anomalies, congenital pulmonary overinflation or lobar emphysema,
congenital cysts and bronchopulmonary sequestration) and certain neonatal-acquired lung diseases (respiratory distress syndrome or hyaline membrane disease,
bronchopulmonary dysplasia, meconium aspiration syndrome, persistent fetal circulation, atelectasis, collapse, and bronchiolitis) have been described.
Some of the important conditions from the point of view of morphology are discussed here.
Congenital Cysts:
Developmental defects may involve any component of the lung parenchyma.
- A single large cyst in the lung occupying almost a lobe is called a pneumatocele.
- Multiple small cysts are more common and give a sponge-like appearance to the lung.
- Multiple cysts may also be present in cases of Marfan syndrome.
- The cysts are thin-walled and dilated and generally lined by flattened ciliated epithelium overlying a thin layer of supportive connective tissue.
- These cysts may contain air or may get infected and become abscesses.
- A bronchial or bronchogenic cyst is attached to the trachea and is communicating with it. It is due to a deficiency of bronchial cartilage, elastic tissue, and muscle.
- The congenital cystic adenomatoid malformation is a rare diffuse hamartoma containing cystic cavities. It appears as a large mass in one lobe and compresses the rest of the lung.
- Cysts may rupture into bronchi producing hemoptysis, or into the pleural cavity producing pneumothorax.
Bronchopulmonary Sequestration: Sequestration is the presence of lobes or segments of lung tissue which are not connected to the airway system.
The blood supply of the sequestered area is not from the pulmonary arteries but from the aorta or its branches. Sequestration may be intralobar or extralobar.
Intralobar sequestration is the sequestered bronchopulmonary mass within the pleural covering of the affected lung.
Extralobar sequestration is the sequestered mass of lung tissue lying outside the pleural investing layer such as in the base of the left lung or below the diaphragm.
Extrasolar sequestration is predominantly seen in infants and children and is often associated with other congenital malformations.
Bronchopulmonary Dysplasia: Bronchopulmonary dysplasia occurs as a complication in infants treated for neonatal ARDS with oxygen and assisted ventilation.
The toxicity of oxygen and barotrauma from the high pressure of oxygen give rise to the subacute or chronic fibrosing condition of the lungs termed bronchopulmonary dysplasia.
The condition is clinically characterized by the persistence of respiratory distress for up to 3 to 6 months.
Microscopically, there is an organization of hyaline membranes resulting in fibrous thickening of the alveolar walls, bronchiolitis, peribronchial fibrosis, and the development of emphysema due to alveolar dilatation. Many bronchioles show squamous metaplasia
Atelectasis And Collapse:
Atelectasis in the newborn or primary atelectasis is defined as the incomplete expansion of a lung or part of a lung, while pulmonary collapse or secondary atelectasis is the term used for the reduction in lung size of a previously expanded and well-aerated lung.
Obviously, the former occurs in newborns whereas the latter may occur at any age.
Atelectasis: Stillborn infants have total atelectasis, while newborn infants with weak respiratory action develop the incomplete expansion of the lungs and clinical atelectasis.
The common causes are prematurity, cerebral birth injury, CNS malformations, and intrauterine hypoxia. Grossly, the lungs are small, dark blue, fleshy, and non-crepitant.
Microscopically, the alveolar spaces in the affected area are small and airless with thick interalveolar septa. The alveolar spaces may contain proteinaceous fluid with a few epithelial squames and meconium.
Scattered aerated areas of the lung are hyperinflated causing interstitial emphysema and pneumothorax.
Collapse: Pulmonary collapse or secondary atelectasis in children and adults may occur from various causes such as compression, obstruction, contraction, and lack of pulmonary surfactant.
Accordingly, collapse may be of the following types:
1. Compressive collapse: Pressure from outside causes compressive collapse e.g. by massive pleural effusion, haemothorax, pneumothorax, intrathoracic tumor, high diaphragm, and spinal deformities.
Compressive collapse involves subpleural regions and affects the lower lobes more than the central areas.
2. Obstructive/absorptive collapse: Obstruction of a bronchus or many bronchioles causes absorption of oxygen in the affected alveoli followed by collapse e.g. by viscid mucus secretions in bronchial asthma, chronic bronchitis, bronchiectasis, bronchial tumors and aspiration of foreign bodies.
Obstructive collapse is generally less severe than compressive collapse and is patchy.
3. Contraction collapse: This type occurs due to localized fibrosis in the lung causing contraction followed by collapse.
Congenital Anomalies:
- Developmental deficiency of alveolar parenchyma, bronchial or bronchiolar cartilage, elastic tissue, and muscle results in congenital cystic disease of the lungs. There may be single, multiple pulmonary cysts, bronchogenic cysts, or adenomatoid cystic hamartoma.
- Sequestration is the presence of lobes or segments of lung tissue which are not connected to the airway system.
- Atelectasis or primary atelectasis is defined as the incomplete expansion of a lung or part of a lung, while pulmonary collapse or secondary atelectasis is the reduction in lung size of a previously expanded and well-aerated lung.
Respiratory Distress Syndrome
Respiratory distress syndrome (RDS) is a severe, at times life-threatening, progressive respiratory insufficiency that involves pulmonary tissues diffusely i.e. involvement of the alveolar epithelium, alveolar lumina, and interstitial tissue.
It is clinically characterized by severe rapidly developing dyspnoea and hypoxemia.
Acute respiratory distress syndrome (ARDS) exists in 2 forms:
- Neonatal RDS, and
- Adult ARDS.
Both have the common morphological feature of the formation of the hyaline membranes in the alveoli and hence is also termed hyaline membrane disease (HMD).
The two forms of RDS have different clinical settings, responses to treatment and consequences, etiology, and pathogenesis but have similar morphology, and hence are discussed together below.
Clinical Features And Consequences:
These are as under:
Neonatal RDS: occurring in newborn infants begins with dyspnoea within a few hours after birth with tachypnoea, hypoxia, and cyanosis; in severe cases, death may occur within a few hours.
Adult ARDS is known by various synonyms such as shock-lung syndrome, diffuse alveolar damage (DAD), acute lung injury, traumatic wet lungs, and post-traumatic respiratory insufficiency.
The condition was first recognized in adults during World War II in survivors of non-thoracic injuries with shock.
Adult ARDS: also presents clinically with sudden and severe respiratory distress, tachypnoea, tachycardia, cyanosis, and severe hypoxemia.
Etiology:
The etiology of two forms of ARDS is distinctive:
Neonatal RDS: is primarily initiated by hypoxia, either shortly before birth or immediately afterward. It occurs in the following clinical settings:
- Preterm infants
- Infants born to diabetic mothers
- Delivery by cesarean section
- Infants born to mothers with previous premature infants
- Excessive sedation of the mother causes depression in the respiration of the infant
- Birth asphyxia from various causes such as coils of umbilical cord around the neck
- Male preponderance (1.5 to 2 times) over female babies due to early maturation of female lungs
- Finally, many cases of neonatal ARDS remain idiopathic.
- Adult ARDS may occur from the following causes:
1. Direct lung injury:
- Diffuse pulmonary infections, chiefly viral pneumonia
- Oxygen toxicity
- Inhalation of toxins and irritants e.g. smoke, war gases, nitrogen dioxide, metal fumes etc.
- Aspiration of gastric contents
- Near drowning
2. Indirect lung injury:
- Shock due to sepsis, trauma, burns
- Narcotic overdose
- Pancreatitis
- Drugs e.g. salicylates, colchicines
- Fat embolism
- Radiation
- Multiple transfusions
Pathogenesis:
In both neonatal RDS and adult ARDS, there is damage to the alveolocapillary wall triggered by the etiologic factors listed above, but the final pathologic consequence of the formation of a hyaline membrane is similar.
However, how it occurs is different in neonates than in adults.
The sequence of events in the pathogenesis of both neonatal RDS and adult ARDS is schematically illustrated.
Neonatal RDS Entry of air into alveoli is essential for the formation of hyaline membrane i.e. stillborn infants do not develop HMD.
- The basic defect in neonatal RDS is a deficiency of pulmonary surfactant, normally synthesized by type II alveolar cells.
- The production of surfactant is normally increased shortly before birth but in prematurity and in neonatal hypoxia from any of the foregoing causes, its synthesis is decreased.
- The main function of alveolar surfactant is the lowering of alveolar surface tension, its deficiency leads to increased alveolar surface tension which in turn causes atelectasis.
- Atelectasis of the lungs results in hypoventilation, pulmonary hypoperfusion, and ischaemic damage to capillary endothelium.
This results in ischaemic necrosis of the alveolocapillary wall, exudation of plasma proteins including fibrinogen into the alveoli, and eventually formation of a hyaline membrane on the alveolar surface containing largely fibrin.
Adult ARDS: The mechanism of acute injury by etiologic agents listed earlier depends upon the imbalance between pro-inflammatory and anti-inflammatory cytokines:
- Activated pulmonary macrophages release proinflammatory cytokines such as IL8, IL1, and tumor necrosis factor (TNF), while macrophage inhibitory factor (MIF) helps to sustain inflammation in the alveoli.
- The number of neutrophils in the alveoli is increased in acute injury. Neutrophils on activation release products that cause active tissue injury e.g. proteases, platelet-activating factors, oxidants, and leukotrienes.
- Besides the role of cytokines in acute injury, a few fibrogenic cytokines such as transforming growth factor-α (TGF-α) and platelet-derived growth factor (PDGF) play a role in the repair process by stimulating the proliferation of fibroblasts and collagen.
In either case, injury to the capillary endothelium leads to increased vascular permeability while injured pneumocytes, especially type 1, undergo necrosis.
The net effect of injury to both the capillary endothelium and the alveolar epithelium is interstitial and intra-alveolar edema, congestion, fibrin deposition, and formation of hyaline membranes.
As a result of coating the alveoli with hyaline membranes, there is a loss of surfactant causing collapse resulting in ‘stiff lung’.
There is an attempt at the regeneration of alveolar cells by the proliferation of type II alveolar cells so as to increase the secretion of surfactant.
Morphologic Features:
Grossly, the lungs are normal in size. They are characteristically stiff, congested, heavy, and airless so that they sink in water.
Microscopically, the important features are as follows:
- There is the presence of collapsed alveoli (atelectasis) alternating with dilated alveoli.
- Necrosis of alveolar epithelial cells and formation of characteristic eosinophilic hyaline membranes lining the respiratory bronchioles, alveolar ducts, and proximal alveoli.
- The membrane is largely composed of fibrin admixed with cell debris derived from necrotic alveolar cells.
- Interstitial and intra-alveolar edema, congestion, and intra-alveolar hemorrhages.
- Changes in bronchopneumonia may supervene.
- With time, the compensatory proliferation of pneumocytes into the alveolar lumen may be seen as tufts of the alveolar epithelium.
- In the organizing stage, there is interstitial fibrosis obliterating alveolar spaces.
Consequences:
Neonatal RDS and adult ARDS may have the following consequences:
1. Death: The mortality rate in neonatal RDS is high (20 to 30%) and is still higher in babies under 1 kg of body weight.
The stiff lung in adult ARDS fails to respond to oxygen therapy and is an acutely serious and severe respiratory problem that may be fatal.
2. Resolution: Milder cases of neonatal RDS recover with adequate oxygen therapy by ventilator assist methods in a few days, while in adult ARDS control of the trigger which initiated it may result in resolution.
The hyaline membrane is liquefied by the neutrophils and macrophages and thus absorbed. The cell debris in the alveolar lumina is cleared by the macrophages and restored to the normal aeration of the alveoli.
3. Other sequelae: Besides the two extremes—death and recovery, other long-term sequelae of RDS are as under:
- In some cases of neonatal RDS who recover may develop bronchopulmonary dysplasia later on.
- In both neonatal and adult ARDS, there may be the development of desquamative interstitial pneumonia (DIP) due to pneumocyte proliferation supervened with inflammation.
- Patients of adult ARDS who survive acute episodes may develop widespread interstitial fibrosis later and progress to diffuse fibrosing alveolitis (Hamman-Rich syndrome).
Respiratory Distress Syndrome:
- Respiratory distress syndrome (RDS) is a severe form of progressive respiratory insufficiency which involves pulmonary tissues diffusely and exists as neonatal RDS and
adult acute RDS (or diffuse alveolar damage). - Clinically, RDS is characterized by severe and rapidly developing dyspnoea and hypoxemia.
- Neonatal RDS is primarily initiated by hypoxia, while adult ARDS is caused by either direct or indirect lung injury.
- In either case, RDS is characterized by the formation of a hyaline membrane in the alveolar wall.
- In neonatal RDS, mortality is high, while the milder case may have a resolution.
- In adult ARDS, patients who survive may develop diffuse fibrosing alveolitis.
Pulmonary Vascular Disease
Pulmonary vasculature has peculiar characteristics compared with the systemic circulation. The pressure in the pulmonary arteries is much lower than in the systemic arteries.
The pulmonary arterial system is thinner than the systemic arterial system; they are thin elastic vessels that can be easily distinguished from thick-walled bronchial arteries supplying the large airways and the pleura.
General diseases of vascular origin occurring in the lungs such as pulmonary edema, pulmonary congestion, pulmonary embolism, and pulmonary infarction, have all been already.
The other important disease of the pulmonary alveocapillary wall, ARDS, has already been discussed above. Here, an account of pulmonary hypertension is given.
Pulmonary Hypertension:
Normally, the pulmonary arterial circulation is a high-flow and low-pressure system with much lower blood pressure than systemic blood pressure; it does not exceed 30/15 mmHg even during exercise (normally, blood pressure in the pulmonary veins is between 3 and 8 mmHg).
Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure of >25 mmHg. It is a rare disease and clinically characterized by features of dyspnoea, chest pain, and syncope.
Classification:
Conventionally, PH has been classified into primary (idiopathic) and secondary; the latter being more common. Primary or idiopathic PH is an uncommon condition of unknown cause.
The diagnosis can be established only after a thorough search for the known causes of secondary PH.
However, this classification has now been replaced with the WHO classification based on causes and pathogenesis and has categorized PH into 5 groups, each with a different set of causes:
Group 1: Pulmonary arterial hypertension (PAH): This group includes all causes that lead to structural narrowing of pulmonary arteries.
Its subtypes are:
- idiopathic PAH
- Heritable PAH
- Drug and toxin-induced PAH
- Association with systemic diseases e.g. connective tissue diseases, HIV infection, portal hypertension
- Pulmonary venous-occlusive disease
- Congenital heart disease
- PH of newborn
Group 2: Pulmonary hypertension due to left heart disease: In this group pulmonary arteries are initially normal but there is pathology in the left heart, resulting in passive elevation of pressure in the pulmonary arteries.
This group includes:
- Left ventricular dysfunction (systolic, diastolic)
- Valvular heart disease
- Left heart congenital/acquired inflow/outflow obstructions
Group 3: Pulmonary hypertension due to lung disease: This is a large and diverse group in which the primary pathology is within the lungs or control of lung function.
These are:
- Chronic obstructive pulmonary disease (COPD), most importantly chronic bronchitis and emphysema
- Interstitial lung diseases (ILDs), lead to inflammation and scarring in the lung parenchyma
- Sleep-disordered breathing
- Alveolar hypoventilation
- Chronic exposure to high altitude
- Developmental lung diseases
Group 4: Chronic thromboembolic pulmonary hypertension: In this group are included conditions in which either the blood clots are formed within the lung or they enter the lung from
elsewhere and block the flow of blood through pulmonary arteries.
Group 5: Pulmonary hypertension with unclear and multifactorial mechanisms: These are a Few rare disorders in which the mechanism of pulmonary hypertension is poorly understood.
These are:
- Certain haematologic disorders e.g. chronic hemolytic anemias, myeloproliferative disorders, and splenectomy.
- Systemic disorders with lung involvement e.g. sarcoidosis, Langerhans cell histiocytosis (LCH), vasculitis.
- Metabolic disorders e.g. glycogen storage diseases, Gaucher’s disease, thyroid disorders.
- Others (unclassified) e.g. tumor obstructing pulmonary arteries, chronic renal failure, fibrosis of the mediastinum
Pathogenesis:
Pathogenesis of long-standing PH involves the following sequential mechanism: Vasoconstriction→ Intimal smooth muscle cell proliferation → In situ thrombosis → Inflammation → Fibrous thickening of pulmonary vasculature → Vascular occlusion.
The exact stimulus for these changes is still unclear.
However, molecular studies in cases of idiopathic PH have revealed a mutation in bone morphogenetic protein receptor type 2 (BMPR2) and certain other modifier genes which are downregulated in these patients, that stimulate the proliferation of endothelial cells and vascular smooth muscle cells.
Morphologic Features:
Irrespective of the type of PH, chronic cases invariably lead to cor pulmonale.
The pathologic changes are confined to the right side of the heart and pulmonary arterial tree in the lungs. There is hypertrophy of the right ventricle and dilatation of the right atrium.
The vascular changes are similar in primary and secondary types and involve the entire arterial tree from the main pulmonary arteries down to the arterioles.
These changes are as under:
1. Arterioles and small pulmonary arteries: These branches show the most conspicuous changes.
These are as follows:
- Medial hypertrophy.
- Thickening and reduplication of elastic laminae.
- Plexiform pulmonary arteriopathy in which there is an intraluminal tuft of capillary formation in dilated thin-walled arterial branches.
- These lesions are not so marked in secondary pulmonary hypertension.
2. Medium-sized pulmonary arteries:
- Medial hypertrophy, which is not so marked in secondary pulmonary hypertension.
- Concentric intimal thickening.
- Adventitial fibrosis.
- Thickening and reduplication of elastic laminae.
3. Large pulmonary arteries:
- Atheromatous deposits.
Pulmonary Hypertension:
- Pulmonary hypertension (PH) is elevated systolic blood pressure in the pulmonary arterial circulation >25 mmHg.
- It may be primary (idiopathic) or secondary; the latter is common. Based on causes and mechanisms, the WHO has classified PH into 5 groups:
- Pulmonary Arterial Hypertension,
- PH Due To Left Heart Disease,
- PH Due To Lung Diseases,
- Chronic Thromboembolic Ph, And
- Ph With Unclear/Multifactorial Mechanisms.
- The mechanism of PH involves intimal smooth muscle cell proliferation, in situ thrombosis, inflammation, fibrous thickening, and vascular occlusion.
- Morphologic changes in the pulmonary arterial branches are intimal thickening and medial hypertrophy.
Pulmonary Infections
Acute and chronic pulmonary infections are common at all ages and are a frequent cause of death.
They are generally caused by a wide variety of microorganisms such as bacteria, viruses, fungi, and mycoplasma.
Important and common examples of acute pulmonary infectious diseases discussed here are cases of pneumonia, fungal infections, and lung abscesses, while pulmonary tuberculosis, is generally regarded as an example of chronic lung infection.
Pneumonias:
Pneumonia is defined as an acute infection of the lung parenchyma, excluding the terminal bronchioles, by one or more co-pathogens.
This definition excludes bronchiolitis which is invariably caused by viral agents.
The terms ‘pneumonia’ and ‘pneumonitis’ are often used synonymously for inflammation of the lungs, while ‘consolidation’ (meaning solidification) is the term used for the gross and radiologic appearance of the lungs in pneumonia.
Pathogenesis:
The microorganisms gain entry into the lungs by one of the following four routes:
- Inhalation of the microbes present in the air.
- Aspiration of organisms from the nasopharynx or oropharynx.
- Hematogenous spread from a distant focus of infection.
- Direct spread from an adjoining site of infection.
The normal lung is free of bacteria because of the presence of a number of lung defense mechanisms at different levels such as nasopharyngeal filtering action, mucociliary action of the lower respiratory airways, the presence of phagocytosing alveolar macrophages, and immunoglobulins.
Failure of these defense mechanisms and the presence of certain predisposing factors result in pneumonia.
These conditions are as under:
1. Altered consciousness: The oropharyngeal contents may be aspirated in states causing unconsciousness e.g. in coma, cranial trauma, seizures, cerebrovascular accidents, drug overdose, alcoholism, etc.
2. Depressed cough and glottic reflexes: Depression of effective cough may allow aspiration of gastric contents e.g. in old age, pain from trauma or thoracoabdominal surgery, neuromuscular disease, weakness due to malnutrition, kyphoscoliosis, severe obstructive pulmonary diseases, endotracheal intubation, and tracheostomy.
3. Impaired mucociliary transport: The normal protection offered by mucus-covered ciliated epithelium in the airways from the larynx to the terminal bronchioles is impaired or destroyed in many conditions favoring passage of bacteria into the lung parenchyma.
These conditions are cigarette smoking, viral respiratory infections, immotile cilia syndrome, inhalation of hot or corrosive gases, and old age.
4. Impaired alveolar macrophage function: Pneumonias may occur when alveolar macrophage function is impaired e.g. by cigarette smoke, hypoxia, starvation, anemia, pulmonary edema, and viral respiratory infections.
5. Endobronchial obstruction: Effective clearance mechanism is interfered in endobronchial obstruction from tumors, foreign bodies, cystic fibrosis, and chronic bronchitis.
6. Immunocompromised states: Disorders of lymphocytes including congenital and acquired immunodeficiencies (e.g. AIDS, debility, senility, immunosuppressive therapy, uncontrolled diabetes mellitus) and granulocyte abnormalities may predispose to pneumonia.
Classification:
Over the last few decades, different approaches have been followed by various international groups for classifying pneumonia due to the following observations about the course of the disease
Although by definition, pneumonias are caused by microbial agents, identification of etiologic agents in individuals is often not possible in about half the cases.
In the absence of an identifiable etiologic agent, many patients with pneumonia, thus, may empirically receive antibiotic therapy.
High-risk groups of patients have been identified who develop pneumonia such as Hospitalised patients, or admitted in low-care setups, on ventilators for a long duration, or aged individuals, etc, who are vulnerable to developing multidrug-resistant (MDR) pathogens.
The following three approaches for the classification of pneumonia have been often described:
1. Anatomic Classification: On the basis of the anatomic region of the lung parenchyma involved, cases of pneumonia are traditionally classified into 3 main types
- Lobar pneumonia
- Bronchopneumonia (or lobular pneumonia)
- Interstitial pneumonia
2. Etiologic Classification Based On Etiologic Agent, Pneumonias Are Classified As Under:
- Bacterial pneumonia
- Viral pneumonia
- Mycoplasmal pneumonia
- Fungal pneumonia
- Pneumonia from non-infectious etiology
3. Clinical Classification: Based on the clinical settings in which the infection occurred, pneumonia are classified into the following groups; each group is caused by one or more specific etiologic agents
- Community-acquired pneumonia (CAP)
- Healthcare-associated pneumonia (HCAP)
- Hospital-acquired pneumonia (HAP)
- Ventilator-associated pneumonia (VAP)
- Pneumonia in the immunocompromised host (fungal pneumonia)
Miscellaneous pneumonia (aspiration pneumonia, hypostatic pneumonia, lipid pneumonia, necrotizing pneumonia, chronic pneumonia)
Since the clinical classification of pneumonia combines clinical settings as well as the etiologic agent, it is widely followed and is discussed below.
1. Community-Acquired Pneumonia:
Community-acquired pneumonia (CAP) is defined as an acute infection of the lung parenchyma in a patient who has been not hospitalized or admitted in a long-term care facility for ≥14 days preceding presentation.
Etiologic agents in CAP include bacteria (most commonly), while viruses, fungi, and protozoa may cause CAP alone or as co-pathogens with bacteria. In 10-15% of cases, CAP is polymicrobial in etiology.
1. Community-Acquired Pneumonia (Cap)
1. Typical bacterial pathogens:
Streptococcus pneumoniae (most common), Haemophilus influenzae, Staphylococcus aureus, Klebsiella pneumonia, Pseudomonas aeruginosa and Moraxella catarrhalis
2. Atypical bacterial pathogens:
Mycoplasma pneumoniae, Chlamydia pneumonia, and Legionella species.
3. Viruses:
Respiratory syncytial virus (RSV) (most common), influenza and parainfluenza viruses, adenoviruses, human metapneumoviruses, coronaviruses, and cytomegaloviruses (CMV).
2. Healthcare-associated pneumonia (HCAP)
3. Hospital-acquired pneumonia (HAP)
4. Ventilator-associated pneumonia (VAP)
5. Pneumonia in the immunocompromised host (fungal pneumonia)
- Pneumocystis pneumonia
- Other fungal infections (aspergillosis, mucormycosis, candidiasis, cryptococcosis, coccidioidomycosis, blastomycosis)
6. Miscellaneous pneumonia
- Aspiration pneumonia
- Hypostatic pneumonia
- Lipid pneumonia
- Necrotizing pneumonia
- Chronic pneumonia
1. Community-Acquired Bacterial Pneumonia:
Bacterial infection of the lung parenchyma is the most common cause of CAP or consolidation of one or both lungs.
Etiology: Etiologic agents for bacterial pneumonia can be divided into typical and atypical:
Typical bacterial pathogens: in CAP are those which are frequently implicated.
These are Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Klebsiella pneumonia, Pseudomonas aeruginosa, and Moraxella catarrhalis.
Atypical bacterial pathogens: include Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella species.
Atypical organisms cannot be generally cultured or identified on Gram’s stain. Based on the etiologic agent, the following common types of bacterial pneumonia are described:
1. Pneumococcal pneumonia: Approximately 30-60% of cases of CAP are caused by Streptococcus pneumoniae, a lancet-shaped diplococcus. Out of various types, type 3 S. pneumonia causes a particularly virulent form of bacterial pneumonia.
2. Staphylococcal pneumonia: Staphylococcus aureus causes pneumonia by hematogenous spread of infection from another focus or after viral infections. It also includes strains of methicillin-resistant Staphylococcus aureus (MRSA).
3. Moraxella pneumonia: Moraxella catarrhalis is one of the common organisms identified in bacterial pneumonia in children (etiologic agent in otitis media) and in the elderly (etiologic agent in COPD).
4. Pneumonia by gram-negative aerobic bacteria: Other causes of bacterial pneumonia are gram-negative organisms like Haemophilus influenza, Klebsiella pneumonia (Friedlander’s
bacillus), Pseudomonas aeruginosa and Moraxella catarrhalis. H. influenzae commonly causes pneumonia in children below 3 years of age after a preceding viral infection.
5. Legionella pneumonia: Legionnaire’s disease is an epidemic illness caused by gram-negative bacilli, Legionella pneumophila that thrives in aquatic environments.
The epidemic occurs in the summer months by the spread of organisms through contaminated drinking water or in airconditioning cooling towers.
Morphologically, two types of acute bacterial CAP are distinguished—lobar pneumonia and broncho-(lobular-) pneumonia, each with distinct morphologic changes.
Another type distinguished by some workers separately is confluent pneumonia which combines the features Of both lobar and bronchopneumonia and involves larger (confluent) areas in both lungs irregularly, while others consider this as a variant of bronchopneumonia.
Lobar Pneumonia:
Lobar pneumonia is an acute bacterial infection of a part of a lobe, the entire lobe, or even two lobes of one or both lungs. The lower lobes are affected most commonly.
Morphologic Features:
Laennec’s original description divides lobar pneumonia into 4 sequential pathologic phases: stage of congestion (initial phase), red hepatization (early consolidation), grey hepatization (late consolidation), and resolution.
However, these classic stages seen in untreated cases are found much less often nowadays due to the early institution of antibiotic therapy and improved medical care.
The sequence of pathologic changes described below represents the inflammatory response of the lungs in bacterial infection.
1. Stage Of Congestion: Initial Phase The initial phase represents the early acute inflammatory response to bacterial infection that lasts for 1 to 2 days.
Grossly, the affected lobe is enlarged, heavy, dark red, and congested. The cut surface exudes blood-stained frothy fluid.
Histologically, typical features of the acute inflammatory response to the organisms are seen.
These are as under:
- Dilatation and congestion of the capillaries in the alveolar walls.
- Pale eosinophilic edema fluid in the airspaces.
- A few red cells and neutrophils in the intra-alveolar fluid.
- Numerous bacteria are demonstrated in the alveolar fluid by Gram’s staining.
2. Red Hepatisation: Early Consolidation This phase lasts for 2 to 4 days.
The term hepatization in pneumonia refers to the liver-like consistency of the affected lobe on the cut section.
Grossly, the affected lobe is red, firm, and consolidated. The cut surface of the involved lobe is airless, red-pink, dry, granular, and has liver-like consistency.
The stage of red hepatization is accompanied by serofibrinous pleurisy.
Histologically, the following features are observed:
- The edema fluid of the preceding stage is replaced by strands of fibrin.
- There is marked cellular exudate of neutrophils and extravasation of red cells.
- Many neutrophils show ingested bacteria.
- The alveolar septa are less prominent than in the first stage due to cellular exudation.
3. Grey Hepatisation: Late Consolidation This phase lasts for 4 to 8 days.
Grossly, the affected lobe is firm and heavy. The cut surface is dry, granular, and grey in appearance with liver-like consistency. The change in color from red to grey begins at the hilum and spreads toward the periphery. Fibrinous pleurisy is prominent.
Histologically, the following changes are present:
- The fibrin strands are dense and more numerous.
- The cellular exudate of neutrophils is reduced due to the disintegration of many inflammatory cells as evidenced by their pyknotic nuclei.
- The red cells are also fewer. The macrophages begin to appear in the exudate.
- The cellular exudate is often separated from the septal walls by a thin clear space.
- The organisms are less numerous and appear as degenerated forms.
4. Resolution: This stage begins on the 8th to the 9th day if no chemotherapy is administered and is completed in 1 to 3 weeks.
However, antibiotic therapy induces resolution on about 3rd day. Resolution proceeds in a progressive manner.
Grossly, the previously solid fibrinous constituent is liquefied by enzymatic action, eventually restoring the normal aeration in the affected lobe.
The process of softening begins centrally and spreads to the periphery. The cut surface is grey-red or dirty brown and frothy, yellow, creamy fluid can be expressed on pressing.
The pleural reaction may also show resolution but may undergo organization leading to fibrous obliteration of the pleural cavity.
Histologically, the following features are noted:
Macrophages are the predominant cells in the alveolar spaces, while neutrophils diminish in number. Many of the macrophages contain engulfed neutrophils and debris.
Granular and fragmented strands of fibrin in the alveolar spaces are seen due to progressive enzymatic digestion. Alveolar capillaries are engorged.
There is the progressive removal of fluid content as well as cellular exudate from the airspaces, partly by expectoration but mainly by lymphatics, resulting in the restoration of normal
lung parenchyma with aeration.
Complications:
With the early institution of antibiotics, serious complications of lobar pneumonia are uncommon.
However, they may develop in neglected cases and in patients with impaired immunologic defense.
These are as under:
1. Organisation: In about 3% of cases, resolution of the exudate does not occur but instead it undergoes organization.
There is ingrowth of fibroblasts from the alveolar septa resulting in fibrosis, tough, airless leathery lung tissue. This type of post-pneumonic fibrosis is called carnification.
2. Pleural effusion: About 5% of treated cases of lobar pneumonia develop inflammation of the pleura with effusion.
The pleural effusion usually resolves but sometimes may undergo organization with fibrous adhesions between the visceral and parietal pleura.
3. Empyema: Less than 1% of treated cases of lobar pneumonia develop encysted pus in the pleural cavity termed empyema.
4. Lung abscess: A rare complication of lobar pneumonia is the formation of a lung abscess, especially when there is a secondary infection by other organisms.
5. Metastatic infection: Occasionally, infection in the lungs and pleural cavity in lobar pneumonia may extend into the pericardium and the heart causing purulent pericarditis, bacterial endocarditis, and myocarditis.
Other forms of metastatic infection encountered rarely in lobar pneumonia are otitis media, mastoiditis, meningitis, brain abscess, and purulent arthritis.
Clinical Features: Classically, the onset of lobar pneumonia is sudden. The major symptoms are: shaking chills, fever, malaise with pleuritic chest pain, dyspnoea, and cough with expectoration which may be mucoid, purulent, or even bloody.
The common physical findings are fever, tachycardia, tachypnoea, and sometimes cyanosis if the patient is severely hypoxaemic. There is generally a marked neutrophilic leucocytosis. Blood cultures are positive in about 30% of cases.
Chest radiograph may reveal consolidation. The culture of the organisms in the sputum and antibiotic sensitivity is the most significant investigations for an institution of specific antibiotics.
The response to antibiotics is usually rapid with clinical improvement in 48 to 72 hours after the initiation of antibiotics.
Bronchopneumonia:
Bronchopneumonia or lobular pneumonia is an infection of the terminal bronchioles that extends into the surrounding alveoli resulting in patchy consolidation of the lung.
The condition is particularly frequent at the extremes of life (i.e. in infancy and old age), as a terminal event in chronic debilitating diseases, and as a secondary infection following viral respiratory infections such as influenza, measles, etc.
Morphologic Features:
Grossly, bronchopneumonia is identified by patchy areas of red or grey consolidation affecting one or more lobes, frequently found bilaterally and more often involving the lower zones of the lungs due to the gravitation of the secretions.
On the cut surface, these patchy consolidated lesions are dry, granular, firm, red or grey in color, 3 to 4 cm in diameter, slightly elevated over the surface, and are often centered around a bronchiole.These patchy areas are best picked up by passing the fingertips on the cut surface.
Histologically, the following features are observed:
- Bronchi and bronchioles contain acute inflammatory exudate.
- Peribronchiolar alveolar parenchyma is congested and contains neutrophilic infiltrate.
- Alveolar septa are thickened due to congested capillaries and leucocytic infiltration.
- Less involved alveoli contain edema fluid.
Complications: The complications of lobar pneumonia may occur in bronchopneumonia as well.
However, complete resolution of bronchopneumonia is uncommon.
There is generally some degree of destruction of the bronchioles resulting in foci of bronchiolar fibrosis that may eventually cause bronchiectasis.
Clinical Features:
The patients of bronchopneumonia are generally infants or elderly individuals. There may be a history of preceding bedridden illness, chronic debility, aspiration of gastric contents, or upper respiratory infection.
For the initial 2 to 3 days, there are features of acute bronchitis but subsequently signs and symptoms similar to those of lobar pneumonia appear.
Blood examination usually shows a neutrophilic leucocytosis. Chest radiograph shows mottled, focal opacities in both lungs, chiefly in the lower zones. Salient contrasting features of bacterial lobar and bronchopneumonia are summarised.
2. Community-Acquired Viral Pneumonia:
Community-acquired viral pneumonia is also called interstitial pneumonitis due to the interstitial location of the inflammation, and primary atypical pneumonia is due to the atypical feature of an absence of alveolar exudate which is commonly present in bacterial pneumonia.
Interstitial pneumonitis may occur in all ages. Most of the cases are mild and transient; exceptionally they may be severe and fulminant.
Etiology:
Common viral causative agents in viral CAP are respiratory syncytial virus (RSV) (most commonly), influenza and parainfluenza viruses, adenoviruses, and human metapneumoviruses.
Severe acute respiratory syndrome (SARS) is caused by a newer respiratory coronavirus that affected several regions of the world as an epidemic.
Cytomegalovirus (CMV) is an important etiologic agent in viral pneumonia in immunosuppressed patients.
Infections of the upper respiratory tract with viruses are quite common.
In most cases, the infection remains confined to the upper respiratory tract presenting as the common cold. Occasionally, it may extend lower down to involve the interstitium of the lungs.
The circumstances favoring such an extension of infection are malnutrition, chronic debilitating diseases, and alcoholism.
Morphologic Features:
Irrespective of the etiologic agent, the pathologic changes are similar in all cases.
Grossly, depending upon the severity of the infection, the involvement may be patchy to massive and widespread consolidation of one or both lungs.
The lungs are heavy, congested, and sub crepitant. The sectioned surface of the lung exudes a small amount of frothy or bloody fluid. The pleural reaction is usually infrequent and mild.
Histologically, the hallmark of viral types of pneumonia is the interstitial nature of the inflammatory reaction.
The microscopic features are as under:
Interstitial inflammation: There is a widening of alveolar walls due to congestion, edema, and mononuclear inflammatory infiltrate comprised of lymphocytes, macrophages and some
plasma cells.
Alveolar changes In severe cases, the alveolar lumina may contain edema fluid, fibrin, scanty inflammatory exudate, and coating of alveolar walls by a pink, hyaline membrane similar to the one seen in respiratory distress syndrome.
Alveolar changes: are prominent if bacterial infection supervenes.
Reactive changes: The lining epithelial cells of the bronchioles and alveoli proliferate in the presence of viruses and may form multinucleate giant cells and syncytia in the bronchiolar and alveolar walls.
Occasionally, viral inclusions (intranuclear and/or intracytoplasmic) are found, especially in pneumonitis caused by CMV.
Complications: The major complication of interstitial pneumonitis is superimposed bacterial infection and its complications.
Most cases of interstitial pneumonitis recover completely. In more severe cases, there may be interstitial fibrosis and permanent damage.
Clinical Features:
The majority of cases of interstitial pneumonia initially have upper respiratory symptoms with fever, headache, and muscle aches.
A few days later, a dry, hacking, non-productive cough with retrosternal burning appears due to tracheitis and bronchitis.
Blood film shows characteristic neutrophilic leucocytosis. Chest radiographs may show patchy or diffuse consolidation.
Cold agglutinin titers in the serum are elevated in almost half the cases of mycoplasmal pneumonia, 20% of cases of adenovirus infection but absent in other forms of viral pneumonia. Isolation of the etiologic agent, otherwise, is difficult.
2. Healthcare-Associated Pneumonia:
Healthcare-associated pneumonia (HCAP) is defined as pneumonia occurring in patients who had extensive healthcare contact in the following ways
- Hospitalization or in an acute care facility for 2 or more days within the prior 90 days
- Intravenous antibiotic therapy or wound care in the preceding 3 months
- Hemodialysis in the previous 30 days
- Residence in a nursing home or long-term care facility
- Family members having MDR infection Common etiologic agents in HCAP are MRSA, Pseudomonas aeruginosa, Acinetobacter species, and MDR Enterobacteriaceae.
3. Hospital-Acquired Pneumonia:
Hospital-acquired pneumonia (HAP), also called nosocomial pneumonia, is an infection acquired during a hospital stay for ≥48 hours in a non-intubated patient.
These patients have a higher frequency of non-MDR infection and have better underlying host immunity than VAP.
Conditions predisposing to HAP are as under:
- Severe debility
- Immunosuppression
- Prolonged antibiotic therapy
- Long-term in situ intravenous catheter
Common pathogens in HAP are Staph. aureus, Streptococcus pneumonia, Pseudomonas aeruginosa and enterobacteriaceae.
4. Ventilator-Associated Pneumonia
Ventilator-associated pneumonia (VAP) is a variant of HAP in ICU patients who have been intubated by endotracheal tube for ≥48 hours.
Cases of VAP can be better diagnosed from the culture of the pathogen in the sputum than HAP patients.
Common etiologic agents are Streptococcus pneumonia, Pseudomonas aeruginosa, and MRSA. Less often, fungi and viruses may be involved in VAP, especially in immunocompromised patients.
5. Pneumonia In Immunocompromised Host (Fungal Pneumonias)
Fungal infections of the lung are more common than tuberculosis in the US.
These infections in healthy individuals are rarely serious but in immunosuppressed individuals may prove fatal.
General aspects of mycotic infections are covered. Here, some common examples of fungal infections of the lung causing fungal pneumonia are briefly given.
Pneumocystis Pneumonia:
Pneumocystis is an opportunistic fungal infection of the lungs.
The original species P. carinii infects rats while P. jirovecii causes pneumonia by inhalation of the organisms in neonates and immunosuppressed people.
Almost 100% of cases of HIV/AIDS develop an opportunistic infection during the course of the disease, most commonly Pneumocystis pneumonia (PCP).
The common etiologic types of cases of pneumonia are associated with HIV infection due to profound immunosuppression.
Other immunosuppressed groups are patients on chemotherapy for organ transplants and tumors, malnutrition, agammaglobulinemia, etc.
Morphologic Features:
Grossly, the affected parts of the lung are consolidated, dry, and grey.
Microscopically, the features are as under:
- Interstitial pneumonitis with thickening and mononuclear infiltration of the alveolar walls.
- Alveolar lumina contain pink frothy fluid having the organisms.
- By Grocott’s methenamine-silver (GMS) stain, the characteristic oval or crescentic cysts, about 5 µm in diameter and surrounded by numerous tiny black dot-like organism of P. jirovecii is demonstrable in the frothy fluid.
- No significant inflammatory exudate is seen in the airspaces.
Clinical Features:
There is rapid onset of dyspnoea, tachycardia, cyanosis, and nonproductive cough. If untreated, it causes death in one or two weeks. Chest radiograph shows diffuse alveolar and interstitial infiltrate.
1. Fungal
- Pneumocystis pneumonia (PCP)
- Coccidioidomycosis
- Invasive aspergillosis
- Invasive candidiasis
2. Viral
- Cytomegalovirus
- Idiopathic interstitial pneumonia
3. Bacterial
- Streptococcus pneumoniae
- Haemophilus influenza
- Staphylococcus aureus
- Pseudomonas aeruginosa
- Mycobacterium tuberculosis
- Mycobacterium avium-intracellulare
Other Fungal Infections of the Lung:
1. Aspergillosis: Aspergillosis is the most common fungal infection of the lung caused by Aspergillus fumigatus which grows best in cool, wet climates.
The infection may result in allergic bronchopulmonary aspergillosis, aspergilloma, and necrotizing bronchitis.
Immunocompromised persons develop more serious manifestations of Aspergillus infection, especially in leukemic patients on cytotoxic drug therapy and HIV/AIDS.
Extensive hematogenous spread of aspergillus infection may result in widespread changes in lung tissue due to arterial occlusion, thrombosis, and infarction.
Grossly, pulmonary aspergillosis may occur within pre-existing pulmonary cavities or in bronchiectasis as a fungal ball.
Microscopically, the fungus may appear as a tangled mass within the cavity.
The organisms are identified by their characteristic morphology—thin septate hyphae with dichotomous branching at acute angles which stain positive for fungal stains such as PAS and silver impregnation technique.
The wall of the cavity shows chronic inflammatory cells
2. Mucormycosis: Mucormycosis or phycomycosis is caused by Mucor and Rhizopus.
The infection in the lung occurs in a similar way as in aspergillosis. Pulmonary lesions are especially common in patients with diabetic ketoacidosis.
Mucor is distinguished by its broad, nonparallel, non septate hyphae which branch at an obtuse angle.
Mucormycosis: is more often angioinvasive, and disseminates; hence it is more destructive than aspergillosis.
3. Candidiasis: Candidiasis or moniliasis caused by Candida albicans is a normal commensal in the oral cavity, gut, and vagina but attains pathologic form in an immunocompromised host.
Angioinvasive growth of the organism may occur in the airways.
4. Histoplasmosis: It is caused by an oval organism, Histoplasma capsulatum, by inhalation of infected dust or bird droppings.
The condition may remain asymptomatic or may produce lesions similar to the Ghon complex.
5. Cryptococcosis: It is caused by Cryptococcus neoformans which is round yeast having a halo around it due to shrinkage in tissue sections.
The infection occurs from infection inhalation of pigeon droppings. The lesions in the body may range from a small parenchymal granuloma in the lung to cryptococcal meningitis.
6. Coccidioidomycosis: Coccidioidomycosis is caused by Coccidioides immitis which are spherical spores.
The infection in human beings is acquired by close contact with infected dogs. The lesions consist of peripheral parenchymal granuloma in the lung.
7. Blastomycosis: It is an uncommon condition caused by Blastomyces dermatitidis.
The lesions result from the inhalation of spores in the ground. Pathological features may present as Ghon’s complex-like lesion, as a pneumonic consolidation, and as multiple skin nodules.
6. Miscellaneous Pneumonia:
A few other clinical settings or a non-infectious etiology may produce pneumonia.
1. Aspiration Pneumonia: Aspiration or inhalation pneumonia results from the inhalation of different agents into the lungs.
These substances include food, gastric contents, foreign body, and infected material from the oral cavity.
A number of factors predispose to inhalation pneumonia which includes: unconsciousness, drunkenness, neurological disorders affecting swallowing, drowning, necrotic oropharyngeal tumors, in premature infants, and congenital tracheo-oesophageal fistula.
Some patients die immediately from asphyxiation or laryngospasm without developing pneumonia.
Morphologic Features:
Pathologic changes vary depending upon the aspirated particulate matter but in general right lung is affected more often due to the direct path from the main bronchus
1. Aspiration of a small amount of sterile foreign matter such as acidic gastric contents produces chemical pneumonitis.
It is characterized by hemorrhagic pulmonary edema with the presence of particles in the bronchioles.
Patients rapidly develop cyanosis, dyspnoea, shock, and bloody sputum and are often likely to die of cardiac failure.
If the patient survives the acute episode, a secondary bacterial infection is likely to occur.
2. Non-sterile aspirate: causes widespread bronchopneumonia with multiple areas of necrosis and suppuration.
A granulomatous reaction with foreign body giant cells may surround the aspirated vegetable matter.
2. Hypostatic Pneumonia:
Hypostatic pneumonia is the term used for the collection of edema fluid and secretions in the dependent parts of the lungs in severely debilitated, bedridden patients.
The accumulated fluid in the basal zone and posterior part of the lungs get infected by bacteria from the upper respiratory tract and sets in bacterial pneumonia.
Hypostatic pneumonia is a common terminal event in old, feeble, comatose patients.
3. Lipid Pneumonia: Another variety of non-infective pneumonia is lipid pneumonia which is of 2 types exogenous and endogenous.
1. Exogenous lipid pneumonia: This is caused by the aspiration of a variety of oily materials.
These are inhalation of oily nasal drops, regurgitation of oily medicines from the stomach (e.g. liquid paraffin), and administration of oily vitamin preparation to reluctant children or to debilitated old patients.
2. Endogenous lipid pneumonia: Endogenous origin of lipids causing pneumonic consolidation is more common.
The sources of origin are tissue breakdown following obstruction to airways e.g. obstruction by bronchogenic cancer, tuberculosis, and bronchiectasis.
Morphologic Features:
Grossly, exogenous lipid pneumonia affects the right lung more frequently due to the direct path from the main bronchus.
Quite often, the lesions are bilateral. The affected part of the lungs is consolidated. The Cut surface is characteristically ‘golden yellow’.
Microscopically, the features are as under:
- Lipid is finely dispersed in the cytoplasm of macrophages forming foamy macrophages within the alveolar spaces.
- There may be the formation of cholesterol clefts due to the liberation of cholesterol and other lipids.
- Formation of granulomas with foreign body giant cells may be seen around the large lipid droplets.
4. Necrotising Pneumonia:
Necrotizing pneumonia is a condition in which there is a fulminant infection of the lungs with aerobic gram-negative bacteria such as Pseudomonas aeruginosa and has a high mortality.
It occurs particularly in low-birth infants or in the elderly with debility, The condition is characterized by extensive confluent bronchopneumonia with coagulative necrosis.
5. Chronic Pneumonia: Chronic pneumonia is the term used for organizing pneumonia from various etiologies or a microbial infection that incites chronic inflammation.
These examples include infection with mycobacteria causing granulomatous inflammation (e.g. tuberculosis) and certain fungal infections discussed above.
In organizing pneumonia, the alveoli show ingrowth of granulation tissue organizing the inflammatory exudates and fibrin. Eventually, the alveolar spaces are replaced with fibrous scars.
Lung Abscess:
A lung abscess is a localized area of necrosis of lung tissue with suppuration. It is of 2 types:
- Primary lung abscess that develops in an otherwise normal lung. The commonest cause is aspiration of infected material.
- Secondary lung abscess that develops as a complication of some other disease of the lung or from another site.
Etiopathogenesis:
Microorganisms commonly isolated from the lungs in lung abscesses are streptococci, staphylococci, and various gram-negative organisms.
These are introduced into the lungs from one of the following mechanisms:
1. Aspiration of infected foreign material: A number of foreign materials such as food, decaying teeth, gastric contents, severely infected gingivae and teeth, and necrotic tissue from lesions in the mouth, upper respiratory tract, or nasopharynx may be aspirated.
This occurs particularly in favorable circumstances such as during sleep, unconsciousness, anesthesia, general debility, and acute alcoholism.
2. Preceding bacterial infection: Preceding bronchopneumonia in a debilitated patient may develop into a lung abscess.
Other infective conditions like tuberculosis, bronchiectasis, and mycotic infections may occasionally result in the formation of lung abscesses.
3. Bronchial obstruction: An abscess may form distal to an obstructed bronchus such as from a bronchial tumor or from an impacted foreign body.
4. Septic embolism: Infected emboli originating from pyemia,
thrombophlebitis or vegetative bacterial endocarditis may be disseminated in the venous circulation and reach the right side of the heart from where they are lodged in the lung and result in multiple abscesses.
5. Miscellaneous: Rarely lung abscesses may occur from the following causes:
- Infection in pulmonary infarcts.
- Amoebic abscesses due to infection with Entamoeba histolytica.
- Trauma to the lungs.
- Direct extension from a suppurative focus in the mediastinum, esophagus, subphrenic area, or spine.
Morphologic Features:
- Abscesses due to aspiration are more likely to be in the right lung due to more vertical main bronchus and are frequently single.
- They are commonly located in the lower part of the right upper lobe or apex of the right lower lobe.
- Abscesses developing from preceding pneumonia and septic or pyaemic abscesses are often multiple and scattered throughout the lung.
- Grossly, abscesses may be of variable size from a few millimeters to large cavities, 5 to 6 cm in diameter.
- The cavity often contains exudate. An acute lung abscess is initially surrounded by acute pneumonia and has a poorly defined ragged wall.
- With the passage of time, the abscess becomes chronic and develops a fibrous wall.
Histologically, a characteristic feature is the destruction of lung parenchyma with suppurative exudate in the lung cavity.
The cavity is initially surrounded by acute inflammation in the wall but later there is replacement by chronic inflammatory cell infiltrate composed of lymphocytes, plasma cells, and macrophages.
In more chronic cases, there is considerable fibroblastic proliferation forming a fibro collagenic wall.
Clinical Features:
The clinical manifestations are fever, malaise, loss of weight, cough, purulent expectoration, and hemoptysis in half the cases.
Clubbing of the fingers and toes appears in about 20% of patients. Secondary amyloidosis may occur in chronic long-standing cases.
Pulmonary Infections:
- Pulmonary tuberculosis is the most common lung infection.
- Pneumonia or consolidation is acute inflammation of the lung parenchyma excluding the terminal bronchioles.
- Pneumonias occur in settings of altered consciousness, impaired immunity, endobronchial obstruction, etc.
- Pneumonia is classified in various ways: on anatomic location, on etiology, and on clinical settings.
- The most widely accepted is a clinical classification of pneumonia.
- The largest group under this is community-acquired pneumonias (CAP) which may be bacterial pneumonias (lobar and bronchopneumonia) and viral (interstitial) pneumonias.
- Bacterial CAP is commonly caused by pneumococci, staphylococci, streptococci and gram-negative organisms. Morphologically, lobar pneumonia passes through stages of congestion, red and grey hepatization, and resolution
- Bronchopneumonia is a patchy area of consolidation around terminal bronchioles.
- Viral CAP is characterized by the widening of alveolar septa, interstitial inflammation, and multinucleate giant cells in the alveoli. Other pneumonias are healthcare-associated pneumonias and related pneumonias (hospital-acquired and ventilator-associated).
- Pneumonias in immunocompromised hosts are various fungal infections of the lung, notably Pneumocystis; others are aspergillosis, mucormycosis, candidiasis, etc. CMV is an opportunistic viral infection that occurs frequently in HIV infection.
- Miscellaneous pneumonias include those due to different clinical settings or due to noninfectious etiology e.g. aspiration, hypostatic, lipid, necrotising, and chronic pneumonias.
- Lung abscesses may be primary or secondary. They are variable in size and may form cavities.
Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) or chronic obstructive airway disease (COAD) is a group of clinicopathological conditions characterized by airflow limitation due to chronic, partial, or complete,
obstruction to the airflow at any level from the trachea to the smallest airways that is not fully reversible; in other words, these are diffuse lung diseases.
Smoking is one etiologic factor that is a common denominator in all forms of COPD; in fact, chronic smoker cough may be considered pre-COPD. The following entities are included in COPD
- Chronic bronchitis
- Emphysema
- Bronchial asthma
- Bronchiectasis
- Small airways disease (bronchiolitis) Chronic bronchitis and emphysema are quite common and often occur together. Contrasting features of all five conditions included in COPD.
Chronic Bronchitis:
Chronic bronchitis is a common condition defined clinically as persistent cough with expectoration on most days for at least three months of the year for two or more consecutive
years.
The cough is caused by oversecretion of mucus. In spite of its name, chronic inflammation of the bronchi is not a prominent feature.
The condition is more common in middle-aged males than females; approximately 20% of adult men and 5% of adult women have chronic bronchitis, but only a minority of them develop serious disabling COPD or cor pulmonale.
Quite frequently, chronic bronchitis is associated with emphysema.
Etiopathogenesis:
Two most important etiologic factors responsible for majority of cases of chronic bronchitis are: cigarette smoking and atmospheric pollution.
Other contributory factors are occupation, infection, familial and genetic factors.
1. Smoking: Most commonly identified factor implicated in the causation of chronic bronchitis and in emphysema is heavy smoking.
Heavy cigarette smokers have 4 to 10 times higher proneness to develop chronic bronchitis.
Prolonged cigarette smoking appears to act on the lungs in a number of ways:
- It impairs ciliary movement.
- It inhibits the function of alveolar macrophages.
- It leads to hypertrophy and hyperplasia of mucus-secreting glands.
- It causes considerable obstruction of small airways.
- It stimulates the vagus and causes bronchoconstriction.
2. Atmospheric pollution: The incidence of chronic bronchitis is higher in industrialised urban areas where air is polluted.
Some of the atmospheric pollutants which increase the risk of developing chronic bronchitis are sulfur dioxide, nitrogen dioxide, particulate dust and toxic
fumes.
3. Occupation: Workers engaged in certain occupations such as in cotton mills (byssinosis), plastic factories, etc.
are exposed to various organic or inorganic dusts which contribute to disabling chronic bronchitis in such individuals.
4. Infection: Bacterial, viral, and mycoplasmal infections do not initiate chronic bronchitis but usually occur secondary to bronchitis.
Cigarette smoke, however, predisposes to infection responsible for acute exacerbation in chronic bronchitis.
5. Familial and genetic factors: There appears to be a poorly-defined familial tendency and genetic predisposition to develop disabling chronic bronchitis.
However, it is more likely that nonsmoker family members who remain in the air-pollution of home are significantly exposed to smoke (passive smoking) and hence have increased blood levels of carbon monoxide.
Microscopically, just as there is clinical definition, there is histologic definition of chronic bronchitis:
- There is increased Reid index; Reid index is the ratio between thickness of the submucosal mucus glands (i.e. hypertrophy and hyperplasia) in the cartilage-containing large airways to that of the total bronchial wall, as measured from the basement membrane to the cartilage. An increase in thickness can be quantitatively assessed by a micrometer lens or by morphometry.
- Bronchial epithelium may show squamous metaplasia and dysplasia.
- There is little chronic inflammatory cell infiltrate.
- Non-cartilage containing small airways show goblet cell hyperplasia and intraluminal and peribronchial fibrosis.
Clinical Features:
There is considerable overlap of clinical features of chronic bronchitis and pulmonary emphysema (discussed below) as quite often the two coexist.
Some important features of ‘predominant bronchitis’ are as under:
- Persistent cough with copious expectoration of long duration; initially beginning in a heavy smoker with ‘morning catarrh’ or ‘throat clearing’ which worsens in winter.
- Recurrent respiratory infections are common.
- Dyspnoea is generally not prominent at rest but is more on exertion.
- Patients are called ‘blue bloaters’ due to cyanosis and edema.
- Features of right heart failure (cor pulmonale) are common.
- Chest X-ray shows an enlarged heart with prominent vessels.
Emphysema:
The WHO has defined pulmonary emphysema as a combination of permanent dilatation of airspaces distal to the terminal bronchioles and the destruction of the walls of dilated airspaces.
Thus, emphysema is defined morphologically, while chronic bronchitis is defined clinically.
Since the two conditions coexist frequently and show considerable overlap in their clinical features, it is usual to label patients as having ‘predominant emphysema’ and ‘predominant bronchitis’.
Classification:
As mentioned in the beginning of this chapter, a lobule is composed of about 5 acini distal to a terminal bronchiole and that an acinus consists of 3 to 5 generations of respiratory bronchioles and a variable number of alveolar ducts and alveolar sacs.
As per WHO definition of pulmonary emphysema, it is classified according to the portion of the acinus involved, into 5 types: centriacinar, panacinar (panlobular), para-septal (distal acinar), irregular (para-cicatricial) and mixed (unclassified) emphysema.
A number of other conditions to which the term ‘emphysema’ is loosely applied are, in fact, examples of ‘overinflation’. A classification based on these principles is outlined.
Etiopathogenesis:
The commonest form of COPD is the combination of chronic bronchitis and pulmonary emphysema.
Chronic bronchitis, however, does not always lead to emphysema, nor all cases of emphysema have changes of chronic bronchitis.
The association of the two conditions is principally linked to the common etiologic factors—most importantly tobacco smoke and air pollutants.
Other less significant contributory factors are occupational exposure, infection and somewhat poorly-understood familial and genetic influences.
All these factors have already been discussed above.
However, pthogenesis of the most significant event in emphysema, the destruction of the alveolar walls, is not linked to bronchial changes but is closely related to deficiency of serum α-1-antitrypsin (α1-protease inhibitor) commonly termed protease-antiprotease hypothesis.
Protease-antiprotease hypothesis α-1-antitrypsin (α-1-AT), also called α1-protease inhibitor (α-1-Pi), is a glycoprotein that forms the normal constituent of the α1-globulin fraction of the plasma proteins on serum electrophoresis.
The single gene locus that codes for α-1-AT is located on the long arm of chromosome 15.
It is normally synthesised in the liver and is distributed in the circulating blood, tissue fluids and macrophages.
The normal function of α1-AT is to inhibit proteases and hence its name α1-protease inhibitor. The proteases (mainly elastases) are derived from neutrophils.
Neutrophil elastase has the capability of digesting lung parenchyma but is inhibited from doing so by anti-elastase effect of α1-AT.
1. True Emphysema
Centriacinar (centrilobular) emphysema
- Panacinar (pan lobular) emphysema
- Paraseptal (distal acinar) emphysema
- Irregular (para-cicatricial) emphysema
- Mixed (unclassified) emphysema
2. Overinflation
- Compensatory overinflation (compensatory emphysema)
- Senile hyperinflation (ageing lung, senile emphysema)
- Obstructive overinflation (infantile lobar emphysema)
- Unilateral translucent lung (unilateral emphysema)
- Interstitial emphysema (surgical emphysema)
There are several known alleles of α1-AT which have an autosomal codominant inheritance pattern and are classified as normal (PiMM), deficient (PiZZ), null type (Pi null null) having no detectable level, and dysfunctional (PiSS) type having about half the normal level.
- The most common abnormal phenotype in classic α1-AT deficiency is homozygous state PiZZ resulting from a single amino acid substitution Glu→ Lys which causes spontaneous
polymerisation of a1-AT and inhibits its release from the liver. The remaining material of a1-AT in the liver causes hepatic cirrhosis. - Clinically significant deficiency is also associated with homozygous Pi null null and heterozygous Pi null Z.
- Heterozygote pattern of PiMZ has intermediate levels which is not sufficient to produce clinical deficiency, but heterozygote individuals who smoke heavily have higher risk of developing emphysema.
The α1-AT deficiency develops in adults and causes pulmonary emphysema in smokers as well as in non-smokers, though smokers become symptomatic about 15 years earlier than nonsmokers.
The other organ showing effects of α1-AT deficiency is the liver which may develop obstructive jaundice early in infancy, and cirrhosis and hepatoma late in adulthood.
The mechanism of alveolar wall destruction in emphysema by elastolytic action is based on the imbalance between proteases (chiefly elastase) and anti-proteases (chiefly anti-elastase):
- By decreased anti-elastase activity i.e. deficiency of α-1 antitrypsin.
- By increased activity of elastase i.e. increased neutrophilic infiltration in the lungs causing
excessive elaboration of neutrophil elastase.
There are enough evidence to suggest that smoking promotes emphysema by both decreasing the amount of anti-elastase as well as by increasing the elastolytic protease in the
lungs.
These are as under:
Oxidant in cigarette smoke has inhibitory influence on αα-1-antitrypsin, thus lowering the level of anti-elastase activity.
Smokers have up to ten times more phagocytes and neutrophils in their lungs than nonsmokers; thus they have very high elastase activity.
Morphologic Features:
Emphysema can be diagnosed with certainty only by gross and histologic examination of sections of whole lung.
The lungs should be perfused with formalin under pressure in inflated state to grade the severity of emphysema with naked eye.
Grossly, the lungs are voluminous, pale with little blood. The edges of the lungs are rounded. Mild cases show dilatation of airspaces visible with hand lens.
Advanced cases show subpleural bullae and blebs bulging outwards from the surface of the lungs with rib markings between them.
The bullae are air-filled cyst-like or bubble-like structures, larger than 1 cm in diameter.
They are formed by the rupture of adjacent airspaces while blebs are the result of rupture of alveoli directly into the subpleural interstitial tissue and are the common cause of spontaneous pneumothorax.
Microscopically, depending upon the type of emphysema, there is dilatation of airspaces and destruction of septal walls of part of acinus involved i.e. respiratory bronchioles, alveolar ducts and alveolar sacs.
Changes of bronchitis may be present. Bullae and blebs when present show fibrosis and chronic inflammation of the walls.
Clinical Features:
Cases of ‘predominant emphysema’ develop clinical features after about one-third of the pulmonary parenchyma is damaged which occurs most severely in panacinar emphysema.
The age at the time of diagnosis is often a decade later (about 60 years) than the age for predominant bronchitis (about 50 years).
Though there is considerable overlap between the clinical features of chronic bronchitis and emphysema, the following features generally characterize ‘predominant emphysema’:
- There is a long history of slowly increasing severe exertional dyspnoea.
- The patient is quite distressed by the obvious use of accessory muscles for respiration.
- The chest is barrel-shaped and hyper-resonant.
- Cough occurs late after dyspnoea starts and is associated with scanty mucoid sputum.
- Recurrent respiratory infections are not frequent.
- Patients are called ‘pink puffers’ as they remain well-oxygenated and have tachypnoea.
- Weight loss is common.
- Features of right heart failure (cor pulmonale) and hypercapnic respiratory failure are the usual terminal events.
- Chest X-ray shows a small heart with hyperinflated lungs.
- After these general comments about morphologic and clinical features of emphysema, the specific pathologic changes in individual types of ‘emphysema’ and ‘overinflation’.
Specific Types of Emphysema
1. Centriacinar (Centrilobular) Emphysema: Centriacinar or centrilobular emphysema is one of the common types.
It is characterized by initial involvement of respiratory bronchioles i.e. the central or proximal part of the acinus.
This is the type of emphysema that usually coexists with chronic bronchitis and occurs predominantly in smokers and in coal miners’ pneumoconiosis.
Grossly, the lesions are more common and more severe in the upper lobes of the lungs.
The characteristic appearance is obvious in the cut surface of the lung.
It shows distended airspaces in the center of the lobules surrounded by a rim of normal lung parenchyma in the same lobule.
The lobules are separated from each other by fine fibrous tissue septa.
A large amount of black pigment is often present in the walls of emphysematous spaces.
In more severe cases, the distal part of acini is also involved and the appearance may closely resemble panacinarc emphysema.
Microscopically, there is distension and destruction of the respiratory bronchiole in the center of lobules, surrounded peripherally by normal uninvolved alveoli.
The terminal bronchioles supplying the acini show chronic inflammation and are narrowed.
2. Panacinar (Panlobular) Emphysema: Panacinar or panlobular emphysema is the other common type. In this type, all portions of the acinus are affected but not of the entire lung.
Panacinar emphysema is most often associated with α1-antitrypsin deficiency in middle-aged smokers and is the one that produces the most characteristic anatomical changes in the lung in emphysema.
Grossly, in contrast, to centriacinar emphysema, panacinar emphysema involves the lower zone of the lungs more frequently and more severely than the upper zone.
The involvement may be confined to a few lobules or maybe more widespread affecting a lobe or part of a lobe of the lung.
The lungs are enlarged and over-inflate. Microscopically, usually, all the alveoli within a lobule are affected to the same degree.
All portions of acini are distended—respiratory bronchioles, alveolar ducts, and alveoli, are all dilated and their walls stretched and thin.
Ruptured alveolar walls and spurs of broken septa are seen between the adjacent alveoli. The capillaries are stretched and thinned. Special stains show loss of elastic tissue. Inflammatory changes are usually absent.
3. Paraseptal (Distal Acinar) Emphysema: This type of emphysema involves the distal part of the acinus while the proximal part is normal.
Paraseptal or distal acinar emphysema is localized along the pleura and along the per lobular septa. The involvement is seen adjacent to the areas of fibrosis and atelectasis and involves the upper part of the lungs more severely than the lower.
This form of emphysema is seldom associated with COPD but is the common cause of spontaneous pneumothorax in young adults.
Grossly, the subpleural portion of the lung shows air-filled cysts, 0.5 to 2 cm in diameter.
4. Irregular (Para-Cicatricial) Emphysema: This is the most common form of emphysema, seen surrounding scars from any cause.
The involvement is irregular as regards the portion of acinus involved as well as within the lung as a whole. During life, irregular emphysema is often asymptomatic and may be only an incidental autopsy finding.
5. Mixed (Unclassified) Emphysema: Quite often, the same lung may show more than one type of emphysema.
It is usually due to more severe involvement resulting in loss of clear-cut distinction between one type of emphysema and the other.
Thus, the lungs of an elderly smoker at autopsy may show a continuation of centriacinar emphysema in the upper lobes, panacinar in the lower lobes, and para septal emphysema in the subpleural region.
6. Interstitial Emphysema (Surgical Emphysema): Entry of air into the connective tissue framework of the lung is called interstitial or surgical emphysema.
Though not a true emphysema, it is described here due to its name. The usual sources of entry of air into the stroma of the lung are rupture of alveoli or of larger airways.
The causes are as under:
Violent coughing with bronchiolar obstruction e.g. in children with whooping cough, bronchitis, in patients with obstruction to the airways by foreign bodies, blood clots, and exposure to irritant gases.
- Rupture of the esophagus, trauma to the lung, or major bronchus and trachea.
- Entry of air through a surgical incision.
- Fractured rib puncturing the lung parenchyma.
- Sudden change in atmospheric pressure e.g. in decompression sickness.
- The condition may affect patients of all ages.
On rupture of alveoli, the leaked air enters the fibrous connective tissue of the alveolar walls from where it extends into the fibrous septa of the lung, into the mediastinum, the pleura, and even the subcutaneous tissues.
Escape of air into the pleural cavity may cause pneumothorax. Collection of small quantities of air is generally harmless and is resorbed.
However, extensive accumulation of air in surgical emphysema may produce impaired blood flow in the lungs. Pneumo-mediastinum may produce symptoms resembling myocardial infarction.
Histologically, the alveoli are distended but the septal walls are not damaged; therefore it is not true emphysema.
There are clear spaces of leaked-out the air in connective tissue septa.
Bronchial Asthma:
Asthma is a disease of the airways that is characterized by increased responsiveness of the tracheobronchial tree to a variety of stimuli resulting in widespread spasmodic narrowing of the air passages which may be relieved spontaneously or by therapy.
Asthma is an episodic disease manifested clinically by paroxysms of dyspnoea, cough, and wheezing. However, a severe and unremitting form of the disease termed status asthmaticus may prove fatal.
Bronchial asthma is common and prevalent worldwide; in the United States about 4% of the population is reported to suffer from this disease.
It occurs at all ages but nearly 50% of cases develop it before the age of 10 years.
In adults, both sexes are affected equally but in children, there is a 2:1 male-female ratio.
Classification And Pathogenesis:
Based on the stimuli initiating bronchial asthma, two broad etiologic types are traditionally described: extrinsic (allergic, atopic) and intrinsic (idiosyncratic, non-atopic) asthma.
A third type is a mixed pattern in which the features do not fit clearly into either of the two main types. The contrasting features of the two main types are summed.
1. Extrinsic (atopic, allergic) asthma: This is the most common type of asthma. It usually begins in childhood or in early adult life.
Most patients of this type of asthma have personal and/or family history of preceding allergic diseases such as rhinitis, urticaria, or infantile eczema.
Hypersensitivity to various extrinsic antigenic substances or ‘allergens’ is usually present in these cases. Most of these allergens cause ill effects by inhalation e.g. house dust, pollens, animal danders, molds, etc.
Occupational asthma stimulated by fumes, gases, and organic and chemical dusts is a variant of extrinsic asthma.
There is an increased level of IgE in the serum and a positive skin test with the specific offending inhaled antigen representing an IgE-mediated type I hypersensitivity reaction which includes an ‘acute immediate response’ and a ‘late phase reaction’:
Acute immediate response is initiated by IgE-sensitised mast cells (tissue counterparts of circulating basophils) on the mucosal surface.
Mast cells on degranulation release mediators like histamine, leukotrienes, prostaglandins, platelet-activating factor, and chemotactic factors for eosinophils and neutrophils.
The net effects of these mediators are bronchoconstriction, edema, mucus hypersecretion, and accumulation of eosinophils and neutrophils.
Late-phase reaction follows the acute immediate response and is responsible for the prolonged manifestations of asthma.
It is caused by the excessive mobilization of blood leucocytes that include basophils besides eosinophils and neutrophils.
These result in the further release of mediators which accentuate the above-mentioned effects.
In addition, inflammatory injury is caused by neutrophils and by the major basic protein (MBP) of eosinophils.
2. Intrinsic (idiosyncratic, non-atopic) asthma: This type of asthma develops later in adult life with a negative personal or family history of allergy, negative skin test, and normal serum levels of IgE.
Most of these patients develop typical symptom-complex after an upper respiratory tract infection by viruses.
Associated nasal polyps and chronic bronchitis are commonly present.
It is hypothesized that upper and lower airways both show similar airways hyperresponsiveness and are a manifestation of the same underlying allergic-inflammatory process.
Thus, allergic rhinitis is frequently associated with bronchial asthma, and vice versa (i.e. a pan-airways disease).
There are no recognizable allergens but about 10% of patients become hypersensitive to drugs, most notably to small doses of aspirin (aspirin-sensitive asthma).
3. Mixed type: Many patients do not clearly fit into either of the above two categories and have mixed features of both.
Those patients who develop asthma in early life have a strong allergic component, while those who develop the disease late tend to be non-allergic.
Either type of asthma can be precipitated by cold, exercise, and emotional stress.
Morphologic Features:
The pathologic changes are similar in both major types of asthma.
The pathologic material examined is generally autopsy of lungs in patients dying of status asthmaticus but the changes are expected to be similar in non-fatal cases.
Grossly, the lungs are overdistended due to over-inflation. The cut surface shows characteristic occlusion of the bronchi and bronchioles by viscid mucus plugs.
Microscopically, the following changes are observed:
- The mucus plugs contain normal or degenerated respiratory epithelium forming twisted strips called Curschmann’s spirals.
- sputum usually contains numerous eosinophils and diamond-shaped crystals derived from eosinophils called Charcot-Leyden crystals.
- The bronchial wall shows thickened basement membrane of the bronchial epithelium, submucosal edema, and inflammatory infiltrate consisting of lymphocytes and plasma cells with a prominence of eosinophils. There is hypertrophy of submucosal glands as well as of the bronchial smooth muscle.
- Changes of bronchitis and emphysema may supervene, especially in intrinsic asthma.
Clinical Features: Asthmatic patients suffer from episodes of acute exacerbations interspersed with symptom-free periods.
Characteristic clinical features are paroxysms of dyspnoea, cough, and wheezing.
Most attacks typically last for a few minutes to hours. When attacks occur continuously, it may result in a more serious condition called status asthmaticus.
The clinical diagnosis is supported by a demonstration of circulation eosinophilia and a sputum demonstration of Curschmann’s spirals and Charcot-Leyden crystals. Long-standing chronic cases may develop cor pulmonale.
Bronchiectasis:
Bronchiectasis is defined as abnormal and irreversible dilatation of the bronchi and bronchioles (greater than 2 mm in diameter) developing secondary to inflammatory weakening of the bronchial walls.
The most characteristic clinical manifestation of bronchiectasis is a persistent cough with expectoration of copious amounts of foul-smelling, purulent sputum. Post-infectious cases commonly develop in childhood and in early adult life.
Etiopathogenesis:
The origin of the inflammatory destructive process of bronchial walls is nearly always a result of two basic mechanisms: endobronchial obstruction and infection.
Endobronchial obstruction by a foreign body, neoplastic growth, or enlarged lymph nodes causes resorption of air distal to the obstruction with consequent atelectasis and retention of secretions.
Infection may be secondary to local obstruction and impaired systemic defense mechanism promoting bacterial growth, or infection may be a primary event i.e. bronchiectasis developing in suppurative necrotizing pneumonia.
These 2 mechanisms—endobronchial obstruction and infection, are seen in a number of clinical settings as under:
1. Hereditary and congenital factors: Several hereditary and congenital factors may result secondarily in diffuse bronchiectasis
Congenital bronchiectasis is caused by a developmental defect of the bronchial system.
Cystic fibrosis, a generalized defect of exocrine gland secretions, results in obstruction, infection, and bronchiectasis. primary immunodeficiencies are often associated with a high incidence of bronchiectasis.
Immotile cilia syndrome that includes Kartagener’s syndrome (bronchiectasis, situs inversus, and sinusitis) is characterized by ultrastructural changes in the microtubules causing immotility of cilia of the respiratory tract epithelium, sperms, and other cells. Males with this syndrome are often infertile.
Atopic bronchial asthma patients have often a positive family history of allergic diseases and may rarely develop diffuse bronchiectasis.
2. Obstruction: Post-obstructive bronchiectasis, unlike the congenital-hereditary forms, is of the localized variety, usually confined to one part of the bronchial system.
The causes of endobronchial obstruction include foreign bodies, endobronchial tumours, compression by enlarged hilar lymph nodes and post-inflammatory scarring (e.g. in healed tuberculosis) all of which favour the development of post-obstructive bronchiectasis.
3. As a secondary complication: Necrotising pneumonias such as in staphylococcal suppurative pneumonia and tuberculosis may develop bronchiectasis as a complication.
Morphologic Features: The disease characteristically affects distal bronchi and bronchioles beyond the segmental bronchi.
Grossly, the lungs may be involved diffusely or segmentally. Bilateral involvement of lower lobes occurs most frequently. More vertical air passages of the left lower lobe are more often involved than the right. The pleura is usually fibrotic and thickened with adhesions to the chest wall.
The dilated airways, depending upon their gross or bronchographic appearance, have been sub-classified into the following different types:
- Cylindrical: the most common type characterised by tube-like bronchial dilatation.
- Fusiform: having spindle-shaped bronchial dilatation.
- Saccular: having rounded sac-like bronchial distension.
- Varicose: having irregular bronchial enlargements.
The cut surface of the affected lobes, generally the lower zones, shows a characteristic honeycombed appearance. The bronchi are extensively dilated nearly to the pleura, their walls are thickened and the lumina are filled with mucus or mucopus. The intervening lung parenchyma is reduced and fibrotic.
Microscopically, fully-developed cases show the following histologic features
The bronchial epithelium may be normal, ulcerated or may show squamous metaplasia.
The bronchial wall shows infiltration by acute and chronic inflammatory cells and destruction of normal muscle and elastic tissue with replacement by fibrosis. The intervening lung parenchyma shows fibrosis, while the surrounding lung tissue shows changes in interstitial pneumonia.
The pleura in the affected area is adherent and shows bands of fibrous tissue between the bronchus and the pleura.
Clinical Features:
The clinical manifestations of bronchiectasis typically consist of chronic cough with foul-smelling sputum production, hemoptysis and recurrent pneumonia.
Sinusitis is a common accompaniment of diffuse bronchiectasis.
Late complications occurring in cases uncontrolled for years include the development of clubbing of the fingers, metastatic abscesses (often to the brain), amyloidosis and cor pulmonale.
Small Airways Disease:
Bronchiolitis and bronchiolitis are obliterans are inflammatory conditions affecting the small airways occurring predominantly in the older paediatric age group and in quite elderly persons.
A number of etiologic factors have been stated to cause this condition.
These include viral infection (frequently adenovirus and respiratory syncytial virus), bacterial infection, fungal infection, inhalation of toxic gases (e.g. in silo-fillers’ disease) and aspiration of gastric contents.
Microscopically, the lumina of affected bronchioles are narrow and occluded by fibrous plugs.
The bronchiolar walls are inflamed and are infiltrated by lymphocytes and plasma cells.
There are changes in interstitial pneumonitis and fibrosis in the alveoli around the affected bronchioles.
Chronic Obstructive Pulmonary Disease:
- Chronic obstructive pulmonary disease (COPD) is a group of pathological conditions having chronic, partial or complete, obstruction to the airflow at any level from the trachea to the smallest airways, causing limitation in airflow.
- Smoking is one etiologic factor which is a common denominator for all COPD.
- The most common types of COPD are chronic bronchitis and emphysema; quite often both coexist.
- The two most important etiologic factors responsible for chronic bronchitis and emphysema are cigarette smoking and atmospheric pollution.
- Chronic bronchitis is defined clinically as a persistent cough with expectoration on most days for at least three months of the year for two or more consecutive years.
- Emphysema is defined by morphologic features of permanent dilatation of airspaces distal to terminal bronchioles.
- Emphysema is linked to a deficiency of serum α-1-antitrypsin, commonly termed proteaseantiprotease hypothesis.
- In asthma, there is a widespread narrowing of the air passage causing bronchospasm Asthma may be due to allergy (extrinsic) or may occur following viral infection
(intrinsic). - Bronchiectasis is abnormal and irreversible dilatation of the bronchi and bronchioles (greater than 2 mm in diameter).
- Bronchiolitis and bronchiolitis obliterans are small airway inflammatory conditions occurring predominantly in older paediatric patients.
Chronic Restrictive Lung Disease
Chronic restrictive pulmonary disease is another large group of diffuse lung disease that is characterised by reduced expansion of lung parenchyma with decreased total lung capacity.
Major clinical manifestations of restrictive lung diseases are exertional dyspnoea, non-persistent productive cough, tachypnoea, cyanosis and sometimes haemoptysis but no wheezing so characteristic of COPD.
Features distinguishing this group of diseases from the foregoing COPD.
Classification:
Restrictive lung disease includes 2 groups of disorders:
1. Restriction due to chest wall disorder It includes the following conditions:
- Kyphoscoliosis
- Poliomyelitis
- Severe obesity
- Pleural diseases.
As a group, these conditions cause restriction to the expansion of lungs due to alterations in the chest wall, pleura and neuromuscular apparatus, but are primarily not lung parenchymal diseases.
Restriction due to interstitial and infiltrative diseases Commonly called interstitial lung diseases (ILDs), these are diseases characterised by non-infectious diffuse parenchymal involvement of the lung (i.e. the alveolar lumina and alveolar epithelium, capillary basement
membrane, the intervening space, perivascular tissue and lymphatic tissue).
Diffuse lung parenchymal involvement may be primary, or it may be involved secondarily as a part of some other multi-organ disease process.
The term ‘infiltrative’ is used here to denote the radiologic appearance of lungs in chest radiographs which show characteristic diffuse interstitial ground-glass opacities.
The ILDs consist of more than 200 heterogeneous conditions which have common clinical, radiologic, and functional manifestations but diverse pathological features.
As a group, ILDs have high mortality and morbidity. Depending upon the underlying pathologic findings.
ILDs have been broadly classified into the following 4 groups:
Conditions with predominant fibrosis (following non-specific inflammation i.e. alveolitis, interstitial inflammation, and fibrosis).
Conditions with predominant granulomatous inflammation Immunologic lung diseases Smoking-related ILDs
Classification of interstitial lung diseases (ILDs).
Pathogenesis:
The exact pathogenesis of ILDs from injury to pulmonary fibrosis is not known.
However, it can be explained on an immune basis as under:
Schematic evolution of interstitial lung disease (ILD).
In response to various exogenous and endogenous stimuli, there is a local inflammatory reaction in the alveoli in the form of lymphocytes (both B and T) and macrophages.
Various stimulating agents may be specks of dust, fumes, smoke, radiation, drugs, viral infections, genetic predisposition, autoimmune conditions and other diseases.
Activated macrophages stimulate the recruitment of neutrophils and also produce fibrogenic and chemotactic cytokines.
Neutrophils liberate proteases and oxidants which injure the type I pneumocytes resulting in initial microscopic alveolitis, while cytokines cause subsequent proliferation of type II pneumocytes and fibrosis.
The result is inflammatory destruction of the pulmonary parenchyma followed by fibrosis.
Eventually, there is widespread destruction of alveolar capillary walls resulting in the end-stage lung or ‘honeycomb lung’.
Important and common examples of ILDs are discussed here.
1. With Predominant Fibrosis
- Pneumoconiosis with inorganic minerals: coal, asbestos, fumes, gases
- Connective tissue disease-associated ILDs
- Idiopathic pulmonary fibrosis (usual interstitial pneumonia)
- Cryptogenic organising pneumonia (bronchiolitis obliterans organising pneumonia i.e. BOOP)
- Nonspecific interstitial pneumonia
- Therapy related-ILD (radiation, antibiotics, chemotherapy)
- Residual effects of ARDS
2. With a Predominant Granulomatous Reaction
- Sarcoidosis
- Pneumoconiosis with inorganic dust: silica, beryllium
- Granulomatous vasculitis
- Wegener’s granulomatosis
3. Immunologic Lung Diseases (Eosinophilic Pneumonias)
- Hypersensitivity pneumonitis: with organic specks of dust
- Pulmonary infiltrates with eosinophilia (PIE)
- Pulmonary haemorrhage syndromes (Goodpasture syndrome)
- Pulmonary alveolar proteinosis
4. Smoking-Associated ILDs
- Desquamative interstitial pneumonia (DIP)
- Respiratory bronchiolitis-associated ILD
- Pulmonary Langerhans cell histiocytosis (eosinophilic granuloma of the lung)
Pneumoconioses:
Pneumoconiosis is the term used for lung diseases caused by inhalation of dust, mostly at work (pneumo= lung; coins = dust in Greek).
These diseases are, therefore, also called ‘dust diseases or ‘occupational lung diseases’.
The type of lung disease varies according to the nature of inhaled dust.
some dust is inert and causes no reaction and no damage at all, while others cause immunologic damage and predispose to tuberculosis or to neoplasia.
The factors which determine the extent of damage caused by inhaled dust are as under:
- Size and shape of the particles,
- Their solubility and physicochemical composition,
- The amount of dust retained in the lungs,
- The additional effect of other irritants such as tobacco smoke, and
- Host factors such as the efficiency of the clearance mechanism and the immune status of the host.
In general, most of the inhaled dust particles larger than 5 µm reach the terminal airways where they are ingested by alveolar macrophages.
Most of these too are eliminated by expectoration but the remaining accumulate in alveolar tissue.
Of particular interest are the particles smaller than 1 µm which are deposited in the alveoli most efficiently.
Most of the dust-laden macrophages accumulated in the alveoli die leaving the dust, around which fibrous tissue
is formed.
Some macrophages enter the lymphatics and reach regional lymph nodes.
The tissue response to inhaled dust may be one of the following three types:
- Fibrous nodules e.g. in coal workers’ pneumoconiosis and silicosis.
- Lnterstitial fibrosis e.g. in asbestosis.
- Hypersensitivity reaction e.g. in berylliosis.
A comprehensive list of various types of occupational lung diseases caused by inorganic (mineral) dust and organic dust is presented in The more common examples of pneumoconioses are described here.
Coal-Workers’ Pneumoconiosis:
This is the commonest form of pneumoconiosis and is defined as the lung disease resulting from inhalation of coal dust particles, especially in coal miners engaged in handling soft bituminous coal for a number of years, often 20 to 30 years.
It exists in 2 forms—a milder form of the disease called simple coal workers’ pneumoconiosis and an advanced form termed progressive massive fibrosis (complicated coal miners’ pneumoconiosis).
Anthracosis, on the other hand, is not a lung disease in the true sense but is the common, benign and asymptomatic accumulation of carbon dust in the lungs of most urban dwellers due to atmospheric pollution and cigarette smoke
(anthracite refers to coal).
Anthracite pigment is deposited in the macrophages in the alveoli and around the respiratory bronchioles and into the draining lymph nodes but does not produce any respiratory difficulty or radiologic changes.
Pathogenesis: Anthracosis, simple coal worker’s pneumoconiosis and progressive massive fibrosis are different stages in the evolution of fully-developed coal worker’s pneumoconiosis.
However, progressive massive fibrosis develops in a small proportion of cases (2-8%) of simple coal workers’ pneumoconiosis.
A number of predisposing factors have been implicated in this transformation as follows:
- Older age of the miners.
- The severity of coal dust burden engulfed by macrophages.
- Prolonged exposure (20 to 30 years) to coal dust.
- Concomitant tuberculosis.
- An additional role of silica dust.
Activation of alveolar macrophage plays the most significant role in the pathogenesis of progressive massive fibrosis by the release of various mediators Free radicals which are reactive oxygen species which damage the lung parenchyma.
- Chemotactic factors for various leucocytes (leukotrienes, TNF, IL-8 and IL-6) result in infiltration into pulmonary tissues by these inflammatory cells which on activation cause further damage.
- Fibrogenic cytokines such as IL-1, TNF and platelet-derived growth factor (PDGF) which stimulate healing by fibrosis due to the proliferation of fibroblasts at the damaged tissue site.
Morphologic Features: In life, the pathologic changes in lungs in coal workers’ pneumoconiosis are graded by radiologic appearance according to the size and extent of opacities.
The pathologic findings at autopsy of lungs in the major forms of coal worker’s pneumoconiosis are considered below under 3 headings simple coal worker’s pneumoconiosis, progressive massive fibrosis and rheumatoid pneumoconiosis (Caplan’s syndrome).
Simple Coal-Workers’ Pneumoconiosis: Grossly, the lung parenchyma shows small, black focal lesions, measuring less than 5 mm in diameter and evenly distributed throughout the lung but have a tendency to be more numerous in the upper lobes.
These are termed coal macules, and if palpable are called nodules. The airspaces around coal macules are dilated with little destruction of alveolar walls.
Though some workers have called it centrilobular emphysema of coal miners, others prefer not to consider it emphysema because there is no significant destruction of alveolar walls.
Similar blackish pigmentations are found on the pleural surface and in the regional lymph nodes.
Histologically, the following features are seen:
- Coal macules are composed of aggregates of dust-laden macrophages.
- These are present in the alveoli and in the bronchiolar and alveolar walls.
- There is some increase in the network of reticulin and collagen in the coal macules.
- Respiratory bronchioles and alveoli surrounding the macules are distended without significant destruction of the alveolar walls.
Progressive Massive Fibrosis: Grossly, besides the coal macules and nodules of simple pneumoconiosis, there are larger, hard, black scattered areas measuring more than 2 cm in diameter and sometimes massive.
They are usually bilateral and located more often in the upper parts of the lungs posteriorly.
Sometimes, these masses break down centrally due to ischaemic necrosis or due to tuberculosis forming cavities filled with black semifluid resembling Indian ink.
The pleura and the regional lymph nodes are also blackened and fibrotic.
Histologically, the following features are present:
The fibrous lesions are composed almost entirely of dense collagen and carbon pigment.
The wall of respiratory bronchioles and pulmonary vessels included in the massive scars are thickened and their lumina is obliterated.
There is scanty inflammatory infiltration of lymphocytes and plasma cells around the areas of massive scars.
The alveoli surrounding the scars are markedly dilated. Progressive massive fibrosis probably has an immunological pathogenetic basis as described above.
Rheumatoid Pneumoconiosis (Caplan’S Syndrome): The development of rheumatoid arthritis in a few cases of coal worker’s pneumoconiosis, silicosis, or asbestosis is termed rheumatoid pneumoconiosis or Caplan’s syndrome.
Grossly, the lungs have rounded, firm nodules with central necrosis, cavitation or calcification.
Histologically, the lung lesions are modified rheumatoid nodules with a central zone of dust-laden fibrinoid necrosis enclosed by palisading fibroblasts and mononuclear cells.
The lung lesions in Caplan’s syndrome have an immunological basis for their origin as evidenced by the detection of rheumatoid factor and antinuclear antibodies.
Clinical Features: Simple coal workers’ pneumoconiosis is the mild form of the disease characterized by chronic cough with black expectoration.
The radiological findings of nodularities in the lungs appear after working for several years in coal mines.
Progressive massive fibrosis is, however, a serious disabling condition manifested by progressive dyspnoea and chronic cough with jet-black sputum.
Recurrent bacterial infections may produce purulent sputum.
More advanced cases develop pulmonary hypertension and right ventricular hypertrophy (cor pulmonale).
The radiological appearance may suggest tuberculosis or cancer.
Tuberculosis and rheumatoid arthritis are more common in coal miners than in the general population.
Coalworkers have an increased risk of developing carcinomas of the stomach, probably due to swallowing coal dust containing carcinogens.
But bronchogenic carcinoma does not appear to be more common in coal miners than in other groups.
Silicosis:
- Historically, silicosis used to be called ‘knife grinders’ lung.
- Silicosis is caused by prolonged inhalation of silicon dioxide, commonly called silica.
- Silica constitutes about one-fourth of Earth’s crust.
Therefore, the number of occupations engaged in siliceous rocks or sand and products manufactured from them are at increased risk.
These include miners (e.g. of granite, sandstone, slate, coal, gold, tin and copper), quarry workers, tunnellers, sandblasters, grinders, ceramic
workers, foundry workers and those involved in the manufacture of abrasives containing silica.
Peculiar to India is the occupational exposure to pencil, slate and agate-grinding industry carrying high risk of silicosis (agate = very hard stone containing silica).
According to an Indian Council of Medical Research report, it is estimated that about 3 million workers in India are at a high potential risk of silica exposure employed in a variety of occupations including construction workers.
An infrequent acute form of silicosis called accelerated silicosis produces irregular fibrosis adjoining the alveoli which is filled with lipo proteinaceous exudate and resembles alveolar proteinosis.
However, if not specified, silicosis refers to the common chronic form of the disease characterised by the formation of small collagenous silicotic nodules.
Pathogenesis: Silicosis appears after prolonged exposure to silica dust, often a few decades.
Besides, it depends upon a number of other factors such as total dose, duration of exposure, the type of silica inhaled and individual host factors.
The mechanisms involved in the formation of silicotic nodules are not clearly understood. The following sequence of events has been proposed and schematically illustrated, B:
Silica particles between 0.5 to 5 µm in size on reaching the alveoli are taken by the macrophages which undergo necrosis.
New macrophages engulf the debris and thus a repetitive cycle of phagocytosis and necrosis is set up.
Some silica-laden macrophages are carried to the respiratory bronchioles, alveoli and interstitial tissue.
Some of the silica dust is transported to the subpleural and interlobar lymphatics and into the regional lymph nodes.
The cellular aggregates containing silica become associated with lymphocytes, plasma cells, mast cells and fibroblasts.
Silica dust is fibrogenic. Crystalline form, particularly quartz, is more fibrogenic than a noncrystalline form of silica.
Simultaneously, there is the activation of T and B lymphocytes. This results in increased serum levels of immunoglobulins (IgG and IgM), antinuclear antibodies, rheumatoid factor and circulating immune complexes as well as the proliferation of T cells.
As noted above, silica is cytotoxic and kills the macrophages which engulf it.
The released silica dust activates viable macrophages leading to the secretion of macrophage-derived growth factors such as interleukin-1 that favour fibroblast proliferation and collagen synthesis.
Morphologic Features: Grossly, the chronic silicotic lung is studded with well-circumscribed, hard, fibrotic nodules, 1 to 5 mm in diameter.
They are scattered throughout the lung parenchyma but are initially more often located in the upper zones of the lungs.
These nodular lesions frequently have simultaneous deposition of coal dust and may develop calcification.
The pleura is grossly thickened and adherent to the chest wall.
There may be similar fibrotic nodules on the pleura and within the regional lymph nodes.
The nodular lesions are detectable as egg-shell shadows in chest X-rays.
The lesions may undergo ischemic necrosis and develop cavitation, or be complicated by tuberculosis and rheumatoid pneumoconiosis.
Histologically, the following features are observed:
The silicotic nodules are located in the region of respiratory bronchioles, adjacent alveoli, pulmonary arteries, the pleura and the regional lymph nodes.
The silicotic nodules consist of central hyalinised material with scanty cellularity and some
amount of dust.
The hyalinised centre is surrounded by concentric laminations of collagen which is further enclosed by more cellular connective tissue, dust-filled macrophages and a few lymphocytes and plasma cells. Some of these nodules may have calcium deposits.
The collagenous nodules have cleft-like spaces between the lamellae of collagen which when examined polariscopically may demonstrate numerous birefringent particles of silica.
A severe and progressive form of the disease may result in the coalescence of adjacent nodules and cause complicated silicosis similar to the progressive massive fibrosis of coal workers’ pneumoconiosis.
The intervening lung parenchyma may show hyperinflation or emphysema.
When cavitation is present, it may be due to ischaemic necrosis in the nodules or may reveal changes of tuberculosis or rheumatoid pneumoconiosis (Caplan’s syndrome)
Clinical Features: The functional effects of silicosis develop slowly and insidiously.
The main presenting complaint is dyspnoea. In time, the patient may develop features of the obstructive or restrictive pattern of disease.
Other complications such as pulmonary tuberculosis, rheumatoid arthritis (Caplan’s syndrome) and cor pulmonale may occur. The chest radiograph initially shows fine nodularity, while later there are larger and coalescent nodules. Silicosis does not carry an increased risk of developing bronchogenic carcinoma.
Asbestos Disease: Asbestos as a mineral is known to mankind for more than 4000 years but its harmful effects have come to light during the last few decades. Asbestos is a Greek word meaning ‘unquenchable’.
In general, if coal is a lot of dust and little fibrosis, asbestos is little dust and a lot of fibrosis. Prolonged exposure for a number of years to asbestos dust produces three types of severe
diseases such asbestosis of the lungs, non-neoplastic pleural disease and tumours (lung cancer and mesothelioma).
In nature, asbestos exists as long thin fibrils which are fire-resistant and can be spun into yarns and fabrics suitable for thermal and electrical insulation and have applications in various industries.
Particularly at risk are workers engaged in mining, construction, and ship repair and those exposed to fabrication and manufacture of a number of products from asbestos such as asbestos pipes, tiles, roof sheets, textiles, insulating boards, sewer and water conduits, brake lining, clutch castings, cement and floor tiles etc.
There are two major geometric forms of asbestos:
Serpentine consists of curly and flexible fibres. It includes the most common chemical form chrysotile (white asbestos) comprising more than 90% of commercially used asbestos.
Amphibole consists of straight, stiff and rigid fibres. It includes the less common chemical forms crocidolite (blue asbestos), amosite (brown asbestos), tremolite, anthophyllite and actinolite.
However, the group of amphibole, though less common, is more important since it is associated with the induction of malignant pleural tumours, particularly in association with crocidolite.
In view of the long-term harmful effects of asbestos exposure, it has been mostly replaced with synthetic mineral fibres such as fibreglass in developed countries since 1975 but it continues to be used in developing countries of the world.
Pathogenesis: Overexposure to asbestos for more than a decade may produce asbestosis of the lung, pleural lesions and certain tumours.
How asbestos causes all these lesions is not clearly understood but the following mechanisms have been suggested
1. The inhaled asbestos fibres are phagocytosed by alveolar macrophages from where they reach the interstitium. Some of the engulfed dust is transported via lymphatics to the pleura and regional lymph nodes.
2. The asbestos-laden macrophages release chemo-attractants for neutrophils and for more macrophages, thus inciting cellular reactions around them.
3. Asbestos fibres are coated with glycoprotein and endogenous haemosiderin to produce characteristic beaded or dumbbell-shaped asbestos bodies.
4. All types of asbestos are fibrogenic and result in interstitial fibrosis.
Fibroblastic proliferation may occur via macrophage-derived growth factors such as interleukin-1.
Alternatively, fibrosis may occur as a reparative response to tissue injury by lysosomal enzymes released from
macrophages and neutrophils or by toxic free radicals.
5. A few immunological abnormalities such as antinuclear antibodies and rheumatoid factor have been found in cases of asbestosis but their role in the genesis of the disease is not clear.
6. Asbestos fibres are carcinogenic, the most carcinogenic being crocidolite.
There is a high incidence of bronchogenic carcinoma in asbestosis which is explained on the basis of the role of asbestos fibres as tumour promoters or by causing cell death of the airways so that it is exposed to the carcinogenic effect of cigarette smoke.
The development of pleural mesothelioma in these cases are probably by carrying of asbestos fibres via lymphatics to the pleura.
Morphologic Features: As stated already, over-exposure to asbestos is associated with 3 asbestos-related diseases asbestosis, pleural disease and certain tumours.
1. Asbestosis: The gross pulmonary fibrosis caused by asbestos exposure and histologic demonstration of asbestos bodies on asbestos fibres is termed asbestosis.
Grossly, the affected lungs are small and firm with cartilage-like thickening of the pleura.
The sectioned surface shows variable degrees of pulmonary fibrosis, especially in the subpleural areas and in the bases of the lungs. The advanced cases may show cystic changes.
Histologically, the following changes are observed:
There is non-specific interstitial fibrosis.
There is a presence of characteristic asbestos bodies in the involved areas. These are asbestos fibres coated with glycoprotein and haemosiderin and appear beaded or dumbbell-shaped.
The coating stains positively for the Prussian blue reaction. There may be changes of emphysema in the pulmonary parenchyma between the areas of interstitial fibrosis.
The involvement of hilar lymph nodes in asbestosis is not as significant as in silicosis.
2. Non-Neoplastic Pleural Disease: Asbestos exposure may produce the following non-neoplastic pleural lesions
Pleural effusion develops in about 5% of asbestos workers and is usually a serious type. Pleural effusion is generally accompanied by subpleural asbestosis.
Visceral pleural fibrosis Quite often, asbestosis is associated with dense fibrous thickening of the visceral pleura encasing the lung.
Pleural plaques Fibrocalcific pleural plaques are the most common lesions associated with asbestos exposure.
Grossly, the lesions appear as circumscribed, flat, small (up to 1 cm in diameter), firm or hard, bilateral nodules.
They are seen more often on the posterolateral part of the parietal pleura and on the pleural surface of the diaphragm.
Microscopically, they consist of hyalinised collagenous tissue which may be calcified so that they are visible on chest X-ray.
Asbestos bodies are generally not found within the plaques.
3. Tumours: Asbestos exposure predisposes to a number of cancers, most importantly lung cancer (page 520) and mesothelioma.
A few others are carcinomas of the oesophagus, stomach, colon, kidneys and larynx and various lymphoid malignancies.
1. Bronchogenic carcinoma: is the most common malignancy in asbestos workers.
Its incidence is 5 times higher in non-smoker asbestos workers than the non-smoker general population and 10 times higher in smoker asbestos workers than other smokers.
2. Mesothelioma: is an uncommon tumour of the pleura and peritoneum in which association with asbestos exposure is present in 30 to 80% of cases.
The exposure need not be heavy because mesothelioma may also develop in people living near asbestos plants or in family members of asbestos workers.
Clinical Features: Asbestosis is a slow and insidious illness. The patient may remain asymptomatic for a number of years in spite of radiological evidence of calcific pleural plaques and parenchymatous changes.
However, the onset of interstitial fibrosis brings about dyspnoea with a dry or productive cough. More advanced cases show the development of Caplan’s syndrome, pulmonary hypertension, cor pulmonale, and various forms of cancers.
Berylliosis: Berylliosis is caused by heavy exposure to dust or fumes of metallic beryllium or its salts.
Beryllium was used in the past in fluorescent tubes and light bulbs but currently, it is principally
used in nuclear and aerospace industries, and in the manufacture of electrical and electronic
equipment two forms of pulmonary berylliosis are recognized—acute and chronic.
Acute Berylliosis: Acute berylliosis occurs in individuals who are unusually sensitive to it and are heavily exposed to it for 2 to 4 weeks.
The pulmonary reaction is in the form of an exudative chemical pneumonitis in which the alveoli are filled with protein-rich fluid with the formation of a hyaline membrane.
The patient develops sudden dyspnoea, hyperpnoea and substernal pain. Most patients recover completely.
Chronic Berylliosis: Chronic berylliosis develops in individuals who are sensitized to it for a number of years, often after a delay of 20 or more years. The disease is a cell-mediated hypersensitivity reaction in which the metal beryllium acts as a hapten.
The condition is characterized by the development of non-caseating epithelioid granulomas like those of sarcoidosis.
These granulomas are diffusely scattered throughout the lung parenchyma.
The granulomas have giant cells which frequently contain 3 types of inclusions:
- Birefringent crystals.
- Concentrically-laminated haematoxyphilic, Schaumann or conchoid bodies.
- Acidophilic stellate-shaped asteroid bodies.
These inclusions are described in giant cells of granulomas in sarcoidosis too.
Similar sarcoid-like granulomas can occur in other organs such as in the liver, kidneys, spleen or lymph nodes in chronic berylliosis.
ILDs Associated With Connective Tissue Diseases:
A number of connective tissue diseases or collagen diseases may result in chronic interstitial fibrosis and the destruction of blood vessels.
These diseases but the lung involvement in important forms of collagen diseases are briefly considered here.
1. Scleroderma (Progressive Systemic Sclerosis): The lungs are involved in 80% of cases of scleroderma. Interstitial pulmonary fibrosis is the most common form of pulmonary involvement.
The disease usually involves the lower lobes and subpleural regions of the lungs and may lead to honeycombing of the lung.
There is an increased risk of development of cancer of the lung in pulmonary fibrosis in scleroderma.
2. Rheumatoid Arthritis: Pulmonary involvement in rheumatoid arthritis may result in pleural effusion, interstitial pneumonitis, necrobiotic nodules and rheumatoid pneumoconiosis. The parenchymatous lesions in rheumatoid arthritis are most commonly seen in the lower lobe. Necrobiotic nodules are the most specific manifestations of rheumatoid disease and closely resemble the subcutaneous nodules commonly found in rheumatoid arthritis.
3. Systemic Lupus Erythematosus: Patients with systemic lupus erythematosus (SLE) commonly develop some form of lung disease during the course. The most common manifestation of SLE is pleurisy with a small amount of pleural effusion that may contain LE cells.
Other pulmonary lesions in SLE are interstitial pneumonitis, pulmonary haemorrhage and vasculitis.
4. Sjogren’s Syndrome: Patients with Sjogren’s syndrome often have rheumatoid arthritis and associated pulmonary changes.
Involvement of the bronchial mucous gland by a process similar to that in the salivary glands can lead to inadequate bronchial clearance and repeated infections.
5. Dermatomyositis And Polymyositis: Interstitial pneumonitis and interstitial fibrosis commonly accompany dermatomyositis and polymyositis.
6. Wegener’S Granulomatosis: Wegener’s granulomatosis is a necroinflammatory lesion having 4 components—granulomas of the upper respiratory tract, granulomas of the lungs,
systemic vasculitis and focal necrotizing glomerulonephritis.
A localized or limited form of the disease occurs in the lungs without the involvement of other organs. Pulmonary involvement is in the form of single or multiple granulomas.
Microscopically, these granulomas have foci of fibrinoid necrosis and intense infiltration of lymphocytes, plasma cells and macrophages with scattered multinucleate giant cells. Besides necrotizing granulomas, there is associated vasculitis.
ILDs Of Unknown Cause With Predominant Fibrosis:
Besides pneumoconioses and connective tissue diseases, two other common conditions associated with predominant interstitial alveolitis, inflammation, and fibrosis of unknown cause are idiopathic pulmonary fibrosis (or usual interstitial pneumonia) and cryptogenic organizing
pneumonia (or bronchiolitis obliterans organizing pneumonia i.e. BOOP).
Idiopathic Pulmonary Fibrosis:
Idiopathic pulmonary fibrosis is the most common form of diffuse interstitial pneumonia and has a bad prognosis compared with other forms of lung fibrosis.
Although diffuse interstitial fibrosis can occur as a result of a number of pathologic entities such as pneumoconiosis, hypersensitivity pneumonitis, and collagen-vascular disease but in half the cases, no apparent cause or underlying disease is identified for diffuse interstitial fibrosis.
Such cases are included under the entity idiopathic pulmonary fibrosis in the United States and cryptogenic fibrosing alveolitis in Great Britain.
Pathogenesis: The pathogenesis of idiopathic pulmonary fibrosis is unknown and the condition is diagnosed by excluding all known causes of interstitial fibrosis.
However, a few pieces of evidence point toward immunologic mechanism:
High levels of autoantibodies such as rheumatoid factor and antinuclear antibodies. Elevated titers of circulating immune complexes.
Immunofluorescent demonstration of the deposits of immunoglobulins and complement on the alveolar walls in biopsy specimens.
Morphologic Features: Lung involvement in idiopathic pulmonary fibrosis is often bilateral and widespread.
Grossly, the lungs are firm and heavier with reduced volume. Honeycombing (i.e. enlarged, thick-walled airspaces) develops in parts of the lung, particularly in the subpleural region.
Histologically, the changes vary according to the stage of the disease.
In the early stage, there is a widening of the alveolar septa by edema and cellular infiltration by mononuclear inflammatory cells. The alveolar lining cells may show hyperplasia in places and are flattened in other places.
There is often the formation of hyaline membranes. The alveolar spaces contain exudate consisting of macrophages, lymphocytes, and neutrophils.
Many of the macrophages contain lamellar bodies derived from the surfactant of the necrotic alveolar lining epithelial cells.
In the advanced stage, there is an organization of the alveolar exudate and replacement fibrosis in the alveoli as well as in the interstitial septal wall with a variable amount of inflammation.
Eventually, there are small cystic areas (honeycomb lung) with alternating areas of fibrosis containing thick-walled and narrowed vessels. This stage is often referred to as usual interstitial pneumonia.
Clinical Features: Middle-aged males are affected more frequently.
The usual features are of respiratory difficulty beginning with dry cough and slowly progressing dyspnoea. More advanced cases may develop clubbing of fingers and cor pulmonale.
A rapidly progressive form of idiopathic pulmonary fibrosis with death within 6 weeks to 6 months is termed HammanRich syndrome.
Cryptogenic Organising Pneumonia:
Cryptogenic organizing pneumonia, also known as bronchiolitis obliterans organizing pneumonia (BOOP), is a disease of unknown etiology.
The condition is characterized by the presence of Masson bodies composed of loose fibrous tissue and capillaries; these structures are seen replacing alveolar lumina, alveolar ducts and bronchioles.
The distinction of this condition from organizing bacterial pneumonia is the absence of organizing inflammatory exudates which are present in the late stages of healing in pneumonia.
ILDs Associated With Immunologic Lung Diseases:
Hypersensitivity (Allergic) Pneumonitis: Hypersensitivity pneumonitis is a group of immunologically-mediated ILDs occurring in workers inhaling a variety of organic (biologic) antigenic materials.
The condition may have an acute onset due to isolated exposure or may be chronic due to repeated low-dose exposure.
Etiopathogenesis: A list of important organic (biologic) dusts which may be inhaled to produce hypersensitivity pneumonitis is already The immunologic mechanisms underlying hypersensitivity pneumonitis from any of these causes appear to be either type III immune-complex disease or type IV delayed-hypersensitivity reaction.
Farmer’s lung: is the classic example resulting from exposure to thermophilic actinomycetes generated by humid and warm mouldy hay.
Bagassosis: occurs in individuals engaged in the manufacture of paper and cardboard from sugarcane bagasse.
Spores of thermophilic actinomycetes grow rapidly in mouldy sugarcane bagasse which is inhaled.
Byssinosis: is an occupational lung disease occurring in workers exposed to fibres of cotton, flex and hemp for a number of years.
The role of immunologic mechanisms in byssinosis is not as clear as exposure to other organic dust.
4. Bird-breeders’ (Bird-fanciers’) lung: occurs in pigeon breeders, parrot breeders, chicken farmers and bird-fanciers who are exposed to bird-droppings and danders from their feathers.
5. Mushroom workers’ lung: is found in mushroom cultivators exposed to mushroom compost dust.
6. Malt workers’ lung: is seen in distillery and brewery workers who are exposed to mouldy barley and malt dust.
7. Maple-bark disease: occurs in those involved in stripping of maple bark and inhaling mouldy maple bark (the maple tree is grown in the northern hemisphere for timber and its leaf is the national emblem of Canada).
8. Silo-fillers’ disease: occurs in individuals who enter the silo (silo is an airtight store-house of fodder for farm animals) in which toxic fumes of nitric oxide and nitrogen dioxide are formed due to fermentation of silage. The condition is generally rapidly fatal; less often it may lead to ILD.
Morphologic Features: The pathologic changes primarily involve the alveoli in contrast to bronchiolar involvement in asthma. The changes vary depending on whether the biopsy is examined in the early stage or in the late stage.
In the early stage, the alveolar walls are diffusely infiltrated with lymphocytes, plasma cells
and macrophages. A proportion of cases show granulomas consisting of histiocytes and giant cells of foreign body or Langhans’ type.
In chronic cases, the lungs show interstitial fibrosis with some inflammatory infiltrate. Honeycombing of the lung may be present.
Clinical Features: The clinical features vary according to the stage.
In acute cases, there is generally a sudden attack of fever, myalgia, dyspnoea, cough and leucocytosis.
In more chronic cases, there are signs of slowly progressive respiratory failure, dyspnoea and cyanosis as seen in other interstitial lung diseases.
Pulmonary Infiltrates With Eosinophilia:
Pulmonary eosinophilia, eosinophilic pneumonia or pulmonary infiltration with eosinophilia (PIE) syndrome are a group of immunologically-mediated lung diseases characterised by a combination of 2 features
- Infiltration of the lungs in chest radiographs.
- Elevated eosinophil count in the peripheral blood.
Etiopathogenesis Pie: syndrome has a number of diverse causes and pathogenesis.
These are as under:
1. Loeffler’s syndrome: is characterised by eosinophilia in the blood and typical wandering radiologic shadows, appearing in some part of the lung for a few days, and then disappearing to appear again somewhere else in the lung.
The condition is generally self-limiting and mild, associated with a slight fever and a few respiratory symptoms. The aetiology is unknown.
2. Tropical pulmonary eosinophilia: is caused by the passage of larvae of worms through the lungs e.g. in filariasis, ascariasis, strongyloidosis, toxocariasis and ancylostomiasis.
3. Secondary chronic pulmonary eosinophilia: occurs secondary to adverse drug reactions; infection with fungi, bacteria, and helminths; allergic bronchopulmonary aspergillosis and in association with asthma.
4. Idiopathic chronic eosinophilic pneumonia: is characterised by prominent focal areas of consolidation of the lung. The condition is clinically diagnosed by excluding other known causes of pulmonary eosinophilia.
5. Hypereosinophilic syndrome: the occurrence of eosinophilia of over 1500/µl for more than 6 months without any identifiable cause and without eosinophilic infiltrates in the lungs and other organs.
Morphologic Features: The lesions in the lungs are similar in all cases of hypersensitivity pneumonitis.
Grossly, the lungs usually show patchy consolidation.
Microscopically, there is thickening of the alveolar walls by oedema and exudate, chiefly of eosinophils, and some lymphocytes and plasma cells. The alveolar lumina also contain eosinophils. Occasionally, small granulomas may be present.
Goodpasture Syndrome:
Goodpasture syndrome or pulmonary haemorrhage syndrome is a combination of necrotising haemorrhagic interstitial pneumonitis and rapidly progressive glomerulonephritis. The renal lesions of Goodpasture syndrome.
Etiopathogenesis: The condition results from immunologic damage (type II hypersensitivity reaction) produced by anti-basement membrane antibodies formed against antigens common to the glomerular and pulmonary basement membranes.
The trigger for the initiation of this autoimmune response is not clear; it could be a viral infection, exposure to hydrocarbons and smoking.
Morphologic Features: Grossly, the lungs are heavy with red-brown areas of consolidation.
Microscopically, the features vary according to the stage of the disease:
- In the acute stage, there are focal areas of haemorrhages in the alveoli and focal necrosis in the alveolar walls.
- In more chronic cases, there is an organisation of the haemorrhage leading to interstitial fibrosis and filling of alveoli with haemosiderin-laden macrophages.
Clinical Features: The condition occurs commonly in 2nd or 3rd decades of life with preponderance in males. The pulmonary manifestations generally precede renal disease.
Most cases present with haemoptysis accompanied by dyspnoea, fatigue, weakness and anaemia.
Renal manifestations soon appear which include haematuria, proteinuria, uraemia and progressive renal failure.
Pulmonary Alveolar Proteinosis:
Pulmonary alveolar proteinosis is a rare chronic disease in which the distal airspaces of the lungs are filled with granular, PAS-positive, eosinophilic material with abundant lipids in it. The condition can occur at any age from infancy to old age.
Etiopathogenesis: The aetiology and pathogenesis of alveolar proteinosis are unknown.
A number of possibilities have been suggested:
- Since the alveolar material is a combination of lipid and protein, it is not simply an overproduction of surfactant.
- Alveolar proteinosis may have an occupational aetiology as seen in patients heavily exposed to silica.
- It may have an etiologic association with hematologic malignancies.
- There may be a defective alveolar clearance of debris.
Morphologic Features:
Grossly, usually, both lungs are involved, particularly the lower lobes.
The lungs are heavier with areas of consolidation. Sectioned surface exudes abundant turbid fluid.
Histologically, the hallmark of the condition is the presence of homogeneous, granular, eosinophilic material which stains brightly with PAS.
Often, the material contains cholesterol clefts. There is no significant inflammatory infiltrate in the affected alveoli.
Biochemically, the material consists of serum proteins of low molecular weight, cholesterol and phospholipids similar to surfactants.
Electron microscopy reveals that the material consists of necrotic alveolar macrophages and desquamated alveolar epithelial cells.
Clinical Features: The condition is manifested clinically by dyspnoea, cough, chest pain, pyrexia, fatigue and loss of weight. Chest X-ray shows confluent areas of consolidation.
Occasionally, alveolar proteinosis may recover spontaneously but more often it is a fatal condition.
ILDs Associated With Smoking
The long-term consequence of smoking is associated with the following two groups of non-neoplastic conditions that manifest with respiratory insufficiency:
Smoking-related COPD: These are chronic bronchitis and emphysema, which frequently coexist as discussed already.
Smoking-related ILDs: These are chronic restrictive pulmonary diseases due to desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis-associated ILD.
Most forms of smoking-related ILDs have already been discussed A few others are described here.
Desquamative Interstitial Pneumonia (Dip): It is an uncommon condition occurring exclusively in smokers in the 4th to 5th decades of life and is more common in males.
Most patients present with dyspnoea and cough. Chest X-ray shows peculiar diffuse hazy opacities which characterise all ILDs.
DIP was earlier thought to represent a forerunner lesion in the sequence of development of idiopathic pulmonary fibrosis.
However, DIP has minimal fibrosis and has a far better prognosis for cessation of smoking compared to idiopathic pulmonary fibrosis.
Microscopically, the features are as under:
- Hallmark finding is collections of a large number of intra-alveolar macrophages having abundant cytoplasm and containing brown-black pigment and are termed as smokers macrophages.
- These pigment-laden cells were initially thought to be desquamated pneumocytes, and hence the misnomer DIP.
- The intervening septa contain a few lymphocytes, plasma cells and an occasional eosinophil.
- Late cases show mild interstitial fibrosis.
Respiratory Bronchiolitis-Associated Ild: Respiratory bronchiolitis is a far more common lesion in chronic smokers than DIP and is considered a milder form of DIP having a similar clinical presentation.
Respiratory bronchiolitis-associated ILD is the term used for advanced cases which develop impaired pulmonary function and radiologic features. The condition resolves following cessation of smoking.
Microscopically, it is characterised by the following features
- Patchy and bronchiolocentric location of smokers’ macrophages similar to those seen in DIP.
- Peribronchial infiltrate of lymphocytes and histiocytes.
- There may be mild peribronchial fibrosis.
- Centriacinar emphysema may coexist.
Chronic Restrictive Lung Disease:
- Chronic restrictive lung diseases are diffuse lung diseases having reduced expansion of lung parenchyma.
- These may be due to chest wall disorders or interstitial lung diseases (ILDs); the latter are more common.
- Pneumoconioses are occupational lung diseases due to dust.
- The commonest form of occupational lung disease is coal workers’ pneumoconiosis which evolves through anthracosis, simple coal workers’ pneumoconiosis and progressive massive fibrosis.
- Silicosis appears after prolonged exposure to silica dust and the lung is studded with well-circumscribed, hard, fibrotic nodules.
- Asbestos exposure for more than a decade can lead to asbestosis, non-neoplastic pleural disease and some tumours (e.g. bronchogenic carcinoma, mesothelioma).
- In addition to pneumoconioses, two other common entities with interstitial fibrosis of unknown aetiology are idiopathic pulmonary fibrosis (or usual interstitial pneumonia) and cryptogenic organising pneumonia (or bronchiolitis obliterans organising pneumonia i.e. BOOP).
- A group of ILDs are associated with granulomatous inflammation e.g. sarcoidosis, Wegener’s granulomatosis etc.
- ILDs associated with immunologic lung diseases are hypersensitivity pneumonitis, pulmonary infiltrate with eosinophilia, Goodpasture’s syndrome and alveolar proteinosis.
- Various connective tissue diseases may develop ILD during the course of the disease.
- Smoking-related ILDs are desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis
Tumours Of Lungs
A number of benign and malignant tumours occur in the lungs but primary lung cancer, commonly termed bronchogenic carcinoma, is the most common (95% of all primary lung
tumours).
The lung is also the commonest site for metastasis from carcinomas and sarcomas.
A revised WHO classification of lung tumours (2015).
1. Epithelial tumours:
1. Benign
- Papilloma, squamous cell (exophytic, inverted)
- Adenomas
- Mixed squamous and glandular papilloma
2. Malignant
- Adenocarcinoma (Major types: lepidic, acinar, papillary, micropapillary, solid, mucinous, pre-invasive)
- Squamous cell carcinoma (Major types: keratinising, non-keratinising, basaloid, pre-invasive)
- Neuroendocrine tumours (Major types: small cell, large cell, carcinoid, pre-invasive)
- Large cell carcinoma
- Adenosquamous carcinoma
- Sarcomatoid carcinoma
- Other and unclassified carcinomas
- Salivary gland-type tumours
2. Mesenchymal tumours
- Pulmonary hamartoma
- Chondroma
- PEComas
- A myofibroblastic tumour (congenital, inflammatory)
- Rare tumours
3. Lymphohistiocytic tumours
- MALToma
- Diffuse large cell lymphoma
- Pulmonary Langerhans cell histiocytosis
4. Tumours of ectopic origin
- Germ cell tumours
- Intrapulmonary thymoma
5. Metastatic tumours
Lung Cancer:
The term lung cancer and bronchogenic carcinoma are used synonymously. The WHO defines lung cancer as tumours arising from the respiratory epithelium (bronchi, bronchioles, and
alveoli).
Incidence And Classification;
Lung cancer is the most common primary malignant tumour in men and accounts for nearly 30% of all cancer deaths in both sexes in developing countries.
Cancer of the lung is a disease of middle and late life with a peak incidence in 55-65 years of age, after which there is a gradual fall in its incidence.
Of late, there has been a slight decline in lung cancer deaths in males due to smoking cessation efforts which started in the West in the 1980s and have started yielding results.
However, worldwide the scene on its incidence and prognosis is quite grim; data from International Agency for Research on Cancer estimate that worldwide by the year 2030, there would be about 10 million deaths per year from lung cancer.
Etiology:
The high incidence of lung cancer is associated with a number of etiologic factors, notably cigarette smoking.
1. Smoking: The most important factor for the high incidence of all forms of bronchogenic carcinoma is tobacco smoking.
About 80% of the lung cancer occurs in active smokers. A number of evidence support the positive relationship between lung cancer with tobacco smoking
Total dose: There is a direct statistical correlation between the death rate from lung cancer and the total amount of cigarettes smoked e.g.
An average active smoker has 13 times higher risk while a passive smoker has 1.5 times risk of lung cancer than a non-smoker.
The risk of smokers of more than 2 packs (40 cigarettes) per day for 20 years is 60-70 times greater than a non-smoker.
Cessation of smoking by a regular smoker results in a gradual decline in the chances of developing lung cancer.
After 10 years of abstinence from smoking, the risk declines but never returns to the non-smoker level.
Pipe and cigar smokers, though have a higher risk than non-smokers but are at lesser risk than cigarette smokers.
Histologic alterations: The association of tobacco smoking is strongest for squamous cell carcinoma and small cell carcinoma of the lung.
More than 90% of smokers have sequential epithelial changes in the respiratory tract in the form of squamous metaplasia, dysplasia and carcinoma in situ.
Mechanism: How tobacco smoking causes lung cancer is not quite clear. However, the following facts have been observed
Analysis of the tar from cigarette smoke has revealed a number of known carcinogens (e.g. polycyclic aromatic hydrocarbons, nitrosamines) and tumour promoters (e.g. phenol derivatives).
In experimental animal studies, it has been possible to induce cancer by skin painting experiments with smoke tar.
However, it has not been possible to reproduce a pattern of human respiratory tract cancer, probably because of the difficulty in reproducing human smoking methods in animals.
2. Other Factors: Although smoking is the dominant etiologic factor in lung cancer, 15% of cases of lung cancer occur in non-smokers, more so in women probably related to hormonal factors.
A few other factors implicated in lung cancer are as follows:
Radiation exposure: Long-term exposure to radon or patients receiving thoracic radiation has an increased risk of lung cancer.
Atmospheric pollution: There is an increased risk of developing bronchogenic carcinoma in non-smokers living in industrialised and smoky cities than in less polluted rural areas.
It is possible that specific industrial pollutants may be at fault as evidenced by high rates of lung
cancer in people living in the neighborhood of petrochemical industries.
Occupational causes: There are a number of well-established occupational causes of lung cancer.
These include workers exposed to asbestos, bis-ethers, nickel, beryllium, arsenic, metallic iron and iron oxide. Some industrial carcinogens and cigarette smoking have a carcinogenic effect, particularly in uranium mines and asbestos workers.
Dietary factors: Susceptibility to respiratory cancers is increased in vitamin A deficiency.
Smokers with low vitamin A intake have a greater risk of lung cancer than those with a vitamin A-rich diet. The incidence of lung cancer is inversely related to socioeconomic level reflecting their dietary pattern.
Chronic scarring Peripheral adenocarcinomas occur more frequently in areas of chronic scarring caused by chronic inflammatory changes, old tuberculosis, asbestosis, chronic interstitial fibrosis, old infarcts and in scleroderma.
Molecular Pathogenesis:
Molecular studies have revealed that there are several genetic alterations in cancer stem cells which produce clones of malignant cells to form tumour masses.
Following genetic changes have been found:
1. Activation of growth-promoting oncogenes: Mutation in the K-RAS oncogene has been seen as the dominant change in lung cancer.
Besides, there is a mutation in the tyrosine kinase domain of EGFR oncogene in cases of adenocarcinoma lung in non-smokers. Other mutations include BRAF, PIK3CA and MYC family, and overexpression of bcl-2 and other anti-apoptotic proteins.
2. Inactivation of tumour-suppressor genes: Inactivation of tumour-suppressor genes has been found as another molecular mechanism in lung cancer.
Many tumour suppressor genes have been found on chromosome 3p in lung cancer cases. These include the inactivation of the p53 and the Rb gene.
Besides, some tumour-acquired promoter genes have been identified in lung cancer e.g. p16, RASSFIA etc, which cause loss of normal function of growth-regulatory tumour suppressor genes.
3. Autocrine growth factors: Studie has shown that lung cancer is a multistep process initiator carcinogen causing mutation, followed by the action of tumour promoters. Nicotine acts as both initiator as well a promoter carcinogen.
Derivatives of nicotine in smoke unmask and expresses nicotine acetylcholine receptors which activate the signalling pathway in the tumour, blocking apoptosis.
Promoters also include several hormones which are elaborated by lung cancer by autocrine pathway as part of paraneoplastic syndrome.
4. Inherited predisposition: Although not common, there are a few examples of inheritance of lung cancer
Patients of Li-Fraumeni syndrome who inherit the p53 mutation may develop lung cancer.
Clinical cases of retinoblastoma having a mutation in the Rb gene are predisposed to develop lung cancer if they live up to adulthood.
First-degree relatives of lung cancer patients have a 2-3 fold higher risk of developing lung cancer in their lifetime.
Mutations of the cytochrome P450 system have been identified in lung cancer patients; P450 metabolises chemical carcinogens in tobacco smoke.
5. Molecular targets for therapy and survival prediction: Knowledge of the insight into molecular biology and pathogenesis of lung cancer has stratified cases into specific histologic types which is useful for targeted therapy and for predicting response to treatment and survival:
- EGFR mutations It has been reported that 70% of cases of advanced adenocarcinoma have overexpression of EGFR protein or amplification of the EGFR gene.
- EGFR belonging to the ERBB(HER) family of proto-oncogenes through mutation in its tyrosine kinase (TK) domain plays a role in both extracellular and intracellular signalling resulting in tumour cell proliferation, metastasis and anti-apoptotic action.
- Targeted molecular therapy against these mutations in EGFR includes EGFR-TK inhibitor oral therapy.
Anaplastic lymphoma kinase (ALK) rearrangement ALK mutation is common in advanced adenocarcinoma lung; ALK-positive cases receive ALK-inhibitor therapy.
VEGF and monoclonal therapy Although not mutated, VEGF is excessively produced in lung cancer and contributes to tumour angiogenesis.
Monoclonal antibody therapy against EGFR in conjunction with chemotherapy has been used for curtailing tumour angiogenesis in lung cancer.
Morphologic Features:
Grossly, based on location lung cancer may be hilar or peripheral:
1. Hilar type: Hilar location of lung cancer is more common (most often squamous cell carcinomas) where it arises in either the main bronchus or one of its segmental branches in the hilar parts of the lung, more often on the right side.
The tumour begins as a small roughened area on the bronchial mucosa at the bifurcation. As the tumour enlarges, it thickens the bronchial mucosa producing a nodular or ulcerated surface.
As the nodules coalesce, the carcinoma grows into a friable spherical mass, 1 to 5 cm in diameter, narrowing and occluding the lumen.
The cut surface of the tumour is yellowish-white with foci of necrosis and haemorrhages which may produce cavitary lesions sums up a list of common conditions having pulmonary cavitary lesions or ‘honey-comb lung’ during the course of different lung diseases.
It is common to find secondary changes in bronchogenic carcinoma of the lung such as bronchopneumonia, abscess formation and bronchiectasis as a result of obstruction and intercurrent infections.
The tumour soon spreads within the lungs by direct extension or by lymphatics, and to distant sites by lymphatic or haematogenous routes, as described later.
2. Peripheral type: These tumours are in subpleural location, chiefly adenocarcinomas.
They originate from a small peripheral bronchiole but the exact site of origin may not be discernible.
The tumour may be a single nodule in a scar tissue or multiple nodules in the periphery of the lung producing pneumonia-like consolidation of a large part of the lung. The cut surface of the tumour is greyish and mucoid.
Histologically, various types of lung tumours; however, the most common are the following four histologic types of malignant epithelial lung tumours:
- Adenocarcinoma ((~50%)
- Squamous cell carcinoma (~20%)
- Small cell carcinoma (~20%)
- Large cell carcinoma (~10%)
As per reports on international data for the last 25 years, while there has been a decline in the incidence of small cell carcinoma, the incidence of adenocarcinoma of the lung has risen and is the most frequent histologic subtype of lung cancer, accounting for almost half of all lung cancers.
In view of different natural history and therapeutic approaches, lung cancer is distinguished into the following two groups
- Small cell lung carcinomas (SCLC) comprise 20-25% of cases.
- Non-small cell lung carcinomas, (NSCLC) comprise 70-75%; these include 3 histologic types: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma Major differences between SCLC and NSCLC are summed
1. Adenocarcinoma: Adenocarcinoma, also called peripheral (subpleural) carcinoma due to its location and scar carcinoma due to its association with areas of chronic scarring.
Recent estimates on lung cancer place adenocarcinoma as the most frequent histologic subtype of lung cancer.
A preinvasive stage and minimally invasive adenocarcinoma (≤ 3 cm lepidic tumour with ≤ 5 mm invasion) have also been categorised.
Invasive adenocarcinoma is further subclassified into 5 types:
Acinar-predominant adenocarcinoma has a predominance of glandular pattern or duct-like appearance and often occurs in the larger bronchi (17.43, A, B).
Papillary predominant adenocarcinoma has a pronounced macro papillary configuration and is frequently peripherally located in the lungs and is found in relation to pulmonary scars (scar carcinoma).
Lepidic predominant (formerly called bronchioloalveolar carcinoma) is characterised by cuboidal to tall columnar and mucus-secreting epithelial cells growing along the existing alveoli (lepidic = hobnail-like cells spreading along a surface).
Ultrastructurally, these tumour cells resemble Clara cells or less often type II pneumocytes.
Solid predominant carcinoma is a poorly-differentiated adenocarcinoma lacking acini, tubules or papillae but having mucus-containing vacuoles in many tumour cells.
Micropapillary predominant adenocarcinoma has tumour cells growing in tiny papillary tufts lacking fibrovascular core.
2. Squamous cell (epidermoid) carcinoma: This has been the most common histologic subtype of bronchogenic carcinoma until recently and is found more commonly in men, often
with a history of tobacco smoking.
These tumours usually arise in a large bronchus and are prone to massive necrosis and cavitation. The tumour is diagnosed microscopically by identification of either intercellular bridges or keratinisation.
The tumour may show varying histologic grades of differentiation such as well-differentiated, moderately-differentiated and poorly-differentiated.
Occasionally, a variant of squamous cell carcinoma, spindle cell carcinoma, having a biphasic pattern of growth due to the presence of a component of squamous cell carcinoma and the other sarcoma-like spindle cell component, is found.
Usually, the spread of squamous cell carcinoma is more rapid than the other histologic types of NSCC.
Frequently, the edge of the growth and the adjoining uninvolved bronchi show squamous metaplasia, epithelial dysplasia and carcinoma in situ.
3. Small cell carcinoma: Small cell carcinomas originate from neuroendocrine cells and are highly malignant tumours. They are frequently hilar or central in location and have a strong relationship to cigarette smoking.
They are most often associated with ectopic hormone production because of the presence of neurosecretory granules in the majority of tumour cells having originated from argentaffin or Kulchitsky cells found in bronchial epithelium.
By immunohistochemistry, these tumour cells are positive for neuroendocrine markers chromogranin, neuron-specific enolase (NSE) and synaptophysin.
Small cell carcinomas have 2 subtypes:
Pure small cell carcinoma is composed of uniform, small (or oat-like) cells, larger than lymphocytes with dense, round or oval nuclei having diffuse chromatin, inconspicuous nucleoli and very sparse cytoplasm (oat = a form of grain).
These cells are organised into cords, aggregates and ribbons or around small blood vessels forming pseudorosettes. The tumour shows frequent and extensive necrosis.
Combined small cell carcinoma is a tumour in which there is a definite component of small cell carcinoma with a component of another non-small lung carcinoma such as squamous cell and/or adenocarcinoma.
4. Large cell carcinoma: These are undifferentiated carcinomas which lack the specific features by which they could be assigned into squamous cell carcinoma or adenocarcinoma.
Large cell carcinomas are more common in men, have a strong association with cigarette smoking and are highly malignant tumours.
The tumour cells have large nuclei, prominent nucleoli, abundant cytoplasm and well-defined cell borders.
Variants of large cell undifferentiated carcinomas include giant cell carcinoma with a prominence of highly pleomorphic multinucleate cells and clear cell carcinoma composed of cells with clear or foamy cytoplasm without mucin.
Spread:
1. Infections
- Pulmonary tuberculosis
- Primary lung abscess (e.g. due to aspiration)
- Secondary lung abscess (e.g. preceding pneumonia, pyaemia, sepsis)
- Bronchiectasis
- Fungal infections (e.g. aspergillosis, mucormycosis)
- Actinomycosis
- Nocardiosis
2. Non-Infectious Causes
-
- Pneumoconiosis (e.g. simple coal-workers’ pneumoconiosis, silicosis, asbestosis)
- Bronchogenic carcinoma
- Metastatic lung tumours
- Wegener’s granulomatosis
- Pulmonary infarction
- Congenital cysts
- Idiopathic pulmonary fibrosis
Bronchogenic carcinoma can invade the adjoining structures directly or may spread by lymphatic and haematogenous routes.
1. Direct spread: The tumour extends directly by invading through the wall of the bronchus and destroys and replaces the peribronchial lung tissue.
As it grows further, it spreads to the opposite bronchus and lung, into the pleural cavity, the pericardium and the myocardium and along the great vessels of the heart causing their constriction.
Extension of cancer located at the apex of the lung into the thoracic cage may involve the brachial plexus and the sympathetic chain causing pain and sensory disturbances, so-called Pancoast’s syndrome.
2. Lymphatic spread: Initially, hilar lymph nodes are affected. Later, lymphatic metastases occur in the other groups leading to the spread to mediastinal, cervical, supraclavicular and paraaortic lymph nodes. Invasion of the thoracic duct may produce chylous ascites.
3. Haematogenous spread: Distant metastases via the bloodstream are widespread and early.
The sites affected, in descending order of involvement, are the liver, adrenals, bones, pancreas, brain, opposite lung, kidneys and thyroid.
Clinical Features:
Symptoms of lung cancer are quite variable and result from local effects, effects due to occlusion of a bronchus, direct and distant metastases, and paraneoplastic syndromes.
Diagnostic aids include the radiologic examination and CT scan of the chest, cytologic examination of the sputum, bronchial washings and bronchioalveolar lavage.
1. Local Symptoms: Most common local complaints are cough, chest pain, dyspnoea and haemoptysis (A list of various causes of haemoptysis is summed.
2. Bronchial Obstructive Symptoms: Occlusion of a bronchus may result in bronchopneumonia, lung abscess, and bronchiectasis in the lung tissue distal to the site of obstruction and cause their attendant symptoms like fever, productive cough, pleural effusion, and weight loss.
3. Symptoms Due To Metastases: Distant spread may produce varying features and sometimes these are the first manifestation of lung cancer.
These include superior vena cava syndrome, painful bony lesions, paralysis of recurrent nerve and other neurologic manifestations resulting from brain metastases.
4. Paraneoplastic Syndromes: A number of paraneoplastic syndromes are associated with lung cancer.
These include the following:
- Ectopic hormone production Different hormonal syndromes are characteristic of different histologic types of lung cancer. Small cell carcinomas are associated most often with ectopic hormone production.
The various hormones elaborated by lung cancer are as follows:
- ACTH, producing Cushing’s syndrome.
- ADH, inducing hyponatremia.
1. Inflammatory
- Bronchitis
- Bronchiectasis
- Tuberculosis
- Lung abscess
- Pneumonias
2. Neoplastic
- Primary and metastatic lung cancer
- Bronchial adenoma
3. Others
- Pulmonary thromboembolism
- Left ventricular failure
- Mitral stenosis
- Trauma
- Foreign bodies
- Primary pulmonary hypertension
- Hemorrhagic diathesis
- Parathormone, causing hypercalcemia.
- Calcitonin-producing hypocalcemia.
- Gonadotropins cause gynecomastia.
- Serotonin is associated with carcinoid syndrome.
Other systemic manifestations include the following:
- Neuromuscular e.g. polymyositis, myopathy, peripheral neuropathy, and subacute cerebellar degeneration.
- Skeletal e.g. clubbing and hypertrophic osteoarthropathy.
- Cutaneous e.g. acanthosis nigricans and dermatomyopathy.
- Cardiovascular e.g. migratory thrombophlebitis (Trousseau’s syndrome), nonbacterial thrombotic endocarditis.
- Haematologic e.g. abnormalities in coagulation and leukemoid reaction.
Staging And Prognosis:
The widely accepted clinical staging of lung cancer is according to the TNM classification, combining features of primary Tumours, Nodal involvement, and distant Metastases.
TNM staging divides all lung cancers into the following 4 stages:
Occult: Malignant cells in the bronchopulmonary secretions but no evidence of primary tumor or metastasis.
Stage 1: Tumour less than 3 cm, with or without ipsilateral nodal involvement, no distant metastasis.
Stage 2: Tumour larger than 3 cm, with ipsilateral hilar lymph node involvement, no distant metastasis.
Stage 3: Tumour of any size, involving adjacent structures, involving contralateral lymph nodes, or distant metastasis.
In general, a tumor size larger than 5 cm has a worse prognosis.
Symptomatic patients, particularly those with systemic symptoms, fare far more badly than nonsymptomatic patients.
Current WHO classification has laid emphasis on additional tools for diagnosis, planning therapy, and determining prognosis based on expanded use of immunohistochemistry (for categorizing lung cancer into SCLC and NSCLC) and recommended molecular testing for EGFR mutation and ALK rearrangement (for targeted therapy). The overall prognosis of bronchogenic carcinoma is dismal.
However, 5-year survival rate with surgery combined with radiotherapy or chemotherapy in the last 30 years has doubled from its earlier rate of about 9% to the present rate of 15%.
Adenocarcinoma and squamous cell carcinoma which are localized, are resectable, and have a slightly better prognosis.
Small cell carcinoma has the worst prognosis since surgical treatment is ineffective though the tumor is sensitive to radiotherapy and chemotherapy.
Other Lung Tumours:
Carcinoid Tumour:
Neuroendocrine tumors of the lung represent a continuum spectrum of lung tumors with progressively increasing aggressiveness which includes typical carcinoid (least aggressive), atypical carcinoid, large cell endocrine carcinoma, and also small cell carcinoma (most
aggressive).
All these tumors arise from neuroendocrine (Kulchitsky) cells of the bronchial mucosa.
Formerly, bronchial carcinoids used to be classified as ‘bronchial adenomas’ but now it is known that they are locally invasive and have the capacity to metastasize.
Bronchial carcinoids tend to occur at a younger age than bronchogenic carcinoma, often appearing below the age of 40 years, and are not related to cigarette smoking.
Morphologic Features: Bronchial carcinoids resemble their intestinal counterparts.
Grossly, bronchial carcinoids most commonly arise from a major bronchus and project into the bronchial lumen as a spherical polypoid mass, 3-4 cm in diameter.
Less commonly, the tumor may grow into the bronchial wall and produce collar-button-like lesions. The overlying bronchial mucosa is usually intact. The cut surface of the tumor is yellow-tan in color.
Histologically, the tumor is composed of uniform cuboidal cells forming aggregates, trabeculae or ribbons separated by fine fibrous septa.
The tumor cells have abundant, finely granular cytoplasm and oval central nuclei with clumped nuclear chromatin. Mitoses are rare and necrosis is uncommon.
The secretory granules of bronchial carcinoids resemble those of other foregut carcinoids and stain positively with argyrophilic stains in which an exogenous reducing agent is added for the reaction.
Immunohistochemically, markers for neuroendocrine are stained positive e.g. NSE, chromogranin, synaptophysin, and neurofilaments.
Clinical Features: Bronchial carcinoids occur at a relatively early age and have equal sex incidence.
Most of the symptoms in bronchial carcinoids occur as a result of bronchial obstruction such as cough, hemoptysis, atelectasis and secondary infection.
About 5-10% of bronchial carcinoids metastasize to the liver and these cases are capable of producing carcinoid syndrome.
Pulmonary Hamartoma:
Hamartoma is a tumor-like lesion composed of an abnormal admixture of pulmonary tissue components and is discovered incidentally as a coin lesion in the chest X-ray.
Pulmonary hamartomas are of 2 types: chondromatous and leiomyomatous.
Chondromatous hamartoma is more common and usually asymptomatic.
It forms a solitary, spherical mass, 2-5 cm in diameter, usually at the periphery of the lung.
Typically, it shows nodules of cartilage associated with fibrous and adipose tissue admixed with bronchial epithelium.
Leiomyomatous hamartoma has a prominent smooth muscle component and bronchiolar structures.
They are frequently multiple, 1-2 mm in diameter, and are more commonly located near the pleura.
Metastatic Lung Tumours:
Secondary tumors of the lungs are more common than primary pulmonary tumors.
Metastases from carcinomas, as well as sarcomas arising from anywhere in the body, may spread to the lung by hematogenous or lymphatic routes, or by direct extension.
Blood-borne metastases are the most common since emboli of tumor cells from any malignant tumor entering the systemic venous circulation are likely to be lodged in the lungs.
Metastases are most common in the peripheral part of the lung forming single or multiple, discrete nodular lesions which appear radiologically as cannon-ball secondaries.
Less frequently, the metastatic growth is confined to peribronchiolar and perivascular locations which is due to spread via lymphatics.
The most common sources of metastases in the lungs are carcinomas of the bowel, breast, thyroid, kidney, pancreas, lung (ipsilateral or contralateral), and liver.
Other tumors which frequently metastasize to the lungs are osteogenic sarcoma, neuroblastoma, Wilms’ tumor, melanoma, lymphomas, and leukemias.
Tumors of Lungs:
- Lung cancer or bronchogenic carcinoma arises from the respiratory epithelium (the bronchi, bronchioles, and alveoli).
- The most important factor in the etiology of all forms of bronchogenic carcinoma is tobacco smoking. About 80% of the lung cancer occurs in active smokers.
- Lung cancer may have two main locations: hilar (most commonly squamous cell carcinoma) and peripheral (most often adenocarcinoma).
- Histologically, four main types of lung cancer are distinguished: adenocarcinoma (~50%), squamous cell carcinoma (~20%), small cell carcinoma (~20%), and large cell carcinoma (~10%).
- Clinically they are divided into 2 types: small cell and non-small cell carcinomas (includes three histologic types: adenocarcinoma, squamous cell carcinoma, and large cell
carcinoma). - Immunohistochemistry is used for categorising lung cancer into SCLC and NSCLC while molecular testing for EGFR and ALK is recommended for targeted therapy.
- Lung cancer may spread directly, or to distant sites by lymphohaematogenous route Clinically, lung cancer frequently produces haemoptysis and may be associated with paraneoplastic syndrome of ectopic hormone production.
- Bronchial carcinoid arises from neuroendocrine cells and is associated with carcinoid syndrome.
- Pulmonary hamartoma is a tumor-like lesion that may be predominantly chondromatous or leiomyomatosis.
- Metastatic tumours in the lung are more common than primary tumours.
- Common cancers metastatic in the lungs may arise from cancer of the bowel, breast, thyroid, kidney, pancreas etc.
Diseases Of Pleura
Normal Structure Visceral pleura covers the lungs and extends into the fissures while the parietal pleura limits the mediastinum and covers the dome of the diaphragm and the inner aspect of the chest wall.
The two layers between them enclose a pleural cavity that contains less than 15 ml of clear serous fluid.
Microscopically, both the pleural layers are lined by a single layer of flattened mesothelial cells facing each other. Underneath the lining cells is a thin layer of connective tissue.
Diseases affecting the pleura are nearly always secondary to some other underlying disease.
Broadly, they fall into inflammations, non-inflammatory pleural effusions, pneumothorax, and tumors.
Inflammations:
Inflammatory involvement of the pleura is commonly termed pleuritis or pleurisy.
Depending upon the character of the resultant exudate, it can be divided into serous, fibrinous, and serofibrinous,
suppurative or empyema, and hemorrhagic pleuritis.
1. Serous, Fibrinous And Serofibrinous Pleuritis: Acute inflammation of the pleural sac (acute pleuritis) can result in serous, serofibrinous and fibrinous exudate.
Most of the causes of such pleuritis are infective in origin, particularly within the lungs, such as tuberculosis, pneumonia, pulmonary infarcts, lung abscesses, and bronchiectasis.
Other causes include a few collagen diseases (e.g. rheumatoid arthritis and disseminated lupus erythematosus), uremia, metastatic involvement of the pleura, irradiation of lung tumors, and diffuse systemic infections (e.g. typhoid fever, tularaemia, blastomycosis, and coccidioidomycosis).
Pleurisy causes pain in the chest on breathing and a friction rub is audible on auscultation.
In most patients, the exudate is minimal and is resorbed resulting in resolution. Repeated attacks of pleurisy may result in the organization leading to fibrous adhesions and obliteration of the pleural cavity.
2. Suppurative Pleuritis (Empyema Thoracic): Bacterial or mycotic infection of the pleural cavity that converts a serofibrinous effusion into purulent exudate is termed suppurative pleuritis or empyema thoracic.
The most common cause is the direct spread of pyogenic infection from the lung.
Other causes are a direct extension from a subdiaphragmatic abscess or liver abscess and penetrating injuries to the chest wall.
Occasionally, the spread may occur by hematogenous or lymphatic routes.
In empyema, the exudate is yellow-green, creamy pus that accumulates in large volumes.
Empyema is eventually replaced by granulation tissue and fibrous tissue.
In time, fibro collagenic adhesions develop which obliterate the cavity, and with the passage of years, calcification may occur.
The effect of these is serious respiratory difficulty due to inadequate pulmonary expansion.
3. Haemorrhagic Pleuritis: Haemorrhagic pleuritis differs from haemothorax in having inflammatory cells or exfoliated tumor cells in the exudate. The causes of hemorrhagic pleuritis are metastatic involvement of the pleura, bleeding disorders, and rickettsial diseases.
Non-Inflammatory Pleural Effusions:
These include fluid collections in the pleural cavity such as hydrothorax, haemothorax, and chylothorax.
1. Hydrothorax: Hydrothorax is a non-inflammatory accumulation of serous fluid within the pleural cavities.
Hydrothorax may be unilateral or bilateral depending upon the underlying cause.
Occasionally, an effusion is limited to part of a pleural cavity by pre-existing pleural adhesions.
The most common cause of hydrothorax, often bilateral, is congestive heart failure.
Other causes are renal failure, cirrhosis of the liver, Meigs’ syndrome, pulmonary edema, and primary and secondary tumors of the lungs.
The non-inflammatory serous effusion in hydrothorax is clear and straw-colored and has the characteristics of transudate with a specific gravity of <1.012, protein content <1 gm/dl, and little cellular content.
If the fluid collection in the pleural cavity is less than 300 ml (normal is <15 ml), no signs or symptoms are produced and may be apparent in chest X-ray in standing posture as the obliterated costodiaphragmatic angle.
If the pleural cavity contains abundant fluid, it imparts a characteristic opaque radiographic appearance to the affected side with a deviation of the trachea to the opposite side.
In such cases, symptoms such as respiratory embarrassment and dyspnoea are produced which are promptly relieved on withdrawal of fluid.
2. Haemothorax: Accumulation of pure blood in the pleural cavity is termed haemothorax.
The most common causes of haemothorax are trauma to the chest wall or to the thoracic viscera and rupture of aortic aneurysm. It is important to remove the blood from the pleural cavity as early as possible.
Otherwise, the blood will clot and organize, resulting in fibrous adhesions and obliteration of the pleural cavity.
3. Chylothorax: Chylothorax is an uncommon condition in which there is an accumulation of milky fluid of lymphatic origin into the pleural cavity.
Chylothorax results most commonly from rupture of the thoracic duct by trauma or obstruction of the thoracic duct such as by malignant tumors, most often malignant lymphomas. Chylothorax is more often confined to the left side. Chylous effusion is milky due to the high content of finely emulsified fats in the chyle.
Pneumothorax:
An accumulation of air in the pleural cavity is called pneumothorax.
It may occur in one of three circumstances: spontaneous, traumatic, and therapeutic.
Spontaneous pneumothorax occurs due to spontaneous rupture of alveoli in any form of pulmonary disease. Most commonly, spontaneous pneumothorax occurs in association with emphysema, asthma, and tuberculosis.
Other causes include chronic bronchitis in an old patient, bronchiectasis, pulmonary infarction, and bronchial cancer.
In young patients, recurrent spontaneous rupture of peripheral subpleural blebs may occur without any cause resulting in a disabling condition termed spontaneous idiopathic pneumothorax.
Traumatic pneumothorax is caused by trauma to the chest wall or lungs, ruptured esophagus or stomach, and surgical operations of the thorax.
Therapeutic (artificial) pneumothorax used to be employed formerly in the treatment of chronic pulmonary tuberculosis in which air was introduced into the pleural sac so as to collapse the lung and limit its respiratory movements.
The effects of pneumothorax due to any cause depend upon the amount of air collected in the pleural cavity.
If the quantity of air in the pleura is small, it is resorbed. The larger volume of air collection in the pleural cavity causes dyspnoea and pain in the chest.
Pneumothorax causes lung collapse and pulls the mediastinum to the unaffected side.
Occasionally, the defect in the lungs is such that it acts as a flap valve and allows entry of air during inspiration but does not permit its escape during expiration, creating tension pneumothorax which requires urgent relief of pressure so as to relieve severe dyspnoea and circulatory failure.
Tumours Of Pleura:
Pleural tumors may be primary or secondary. In line with pulmonary tumours, secondary tumours in the pleura are more common.
Major primary tumors in the pleura are solitary fibrous tumours and mesothelioma.
Solitary Fibrous Tumour:
The solitary fibrous tumour is a benign mesenchymal tumour of the fibroblastic type that occurs in the pleura and as an extrapulmonary tumour at other sites such as the mediastinum, pericardium, retroperitoneum, abdominal cavity, head and neck (especially orbit) etc.
Grossly, it is a firm, circumscribed, encapsulated tumour which is attached to the pleura with a pedicle.
Microscopically, it is composed of keloid-like collagen without any arrangement and has pronounced perivascular hyalinisation.
Thus, the tumour has haemangiopericytoma-like vascular pattern.
Malignant Mesothelioma:
Mesothelioma is an uncommon malignant tumour arising from the mesothelial lining of serous cavities, most often in the pleural cavity, and rarely in the peritoneal cavity and pericardial sac.
Malignant mesothelioma grows diffusely and is a highly malignant tumor associated with high mortality.
The tumour is significant in view of its recognised association with occupational exposure to asbestos (particularly crocidolite) for a number of years, usually 20 to 40 years.
About 90% of malignant mesotheliomas are asbestos-related. The mechanism of carcinogenicity by asbestos is not quite clear but it appears that prolonged exposure to amphibole type of asbestos is capable of inducing oncogenic mutation in the mesothelium.
However, prolonged asbestos exposure is considered more significant rather than heavy exposure as documented by the occurrence of malignant mesothelioma in the family members of asbestos workers.
Although the combination of cigarette smoking and asbestos exposure greatly increases the risk to develop bronchogenic carcinoma, there is no such extra increased risk of developing mesothelioma in asbestos workers who smoke.
The role of SV40 (simian vacuolating virus) antigen has also been implicated in the etiology of mesothelioma.
Grossly, the tumor is characteristically diffuse, forming a thick, white, fleshy coating over the parietal and visceral surfaces.
Microscopically, malignant mesothelioma may have epithelial, sarcomatoid or biphasic patterns.
The epithelioid pattern resembles an adenocarcinoma, consisting of tubular and tubulopapillary formations. The tumor cells are usually well-differentiated, cuboidal, flattened or columnar cells.
The tumor can be distinguished from adenocarcinoma by positive immunostaining for calretinin, WT-1, and cytokeratin 5/6.
The sarcomatoid pattern consists of spindle cell sarcoma resembling fibrosarcoma.
The tumor cells are arranged in a storiform pattern with abundant collagen between them.
The mixed pattern shows mixed growth having epithelial as well as sarcomatoid patterns.
Usually, there are slit-like or gland-like spaces lined by neoplastic mesothelial cells separated by proliferating spindle-shaped tumor cells.
Asbestos bodies are found in the lungs of most patients with malignant mesothelioma of any histologic type.
Clinical manifestations include chest pain, dyspnoea, pleural effusion, and infections.
The tumor spreads rapidly by direct invasion into the lung and by lymphatic spread into hilar lymph nodes and pericardium. Sometimes distant metastases, particularly to the liver, occur.
The prognosis is poor; 50% of patients die within one year of diagnosis.
Secondary Pleural Tumours:
Metastatic malignancies in the pleura are more common than the primary tumors and appear as small nodules scattered over the lung surface.
The most frequent primary malignant tumors metastasizing to the pleura are of the lung and breast through lymphatics, and ovarian cancers via the hematogenous route.
Diseases of Pleura:
- Inflammatory involvement of the pleura is called pleuritis or pleurisy.
- It may be serous, fibrinous, serofibrinous, suppurative, or hemorrhagic.
- Non-inflammatory pleural effusions may be hydrothorax, haemothorax, and chylothorax.
- Pneumothorax is an accumulation of air in the pleural cavity. It may be spontaneous, traumatic or therapeutic.
- Primary tumours of pleura are solitary fibrous tumors and malignant mesothelioma.
- Malignant mesothelioma has a strong association with asbestos exposure.
- It is a diffuse tumour and may be epithelial, sarcomatoid or mixed type.
- Metastatic pleural tumors are more common and generally arise from the lung and breast
Leave a Reply