Nasal passages and sinuses

These constitute the upper respiratory tract. The nasal passages and sinuses are in continuity and are lined with respiratory mucosa. The hairs in the nose trap large particles of foreign material, thereby filtering the air. The air is also warmed and humidified as it passes through the nasal cavity. The middle ear, also lined with respiratory epithelium, connects with the nasal cavity via the Eustachian tube.

Larynx

The larynx connects the trachea to the pharynx. Consisting of a complicated system of cartilages and muscles, it allows air into the trachea, with the epiglottis preventing the passage of food into the lungs, and also produces sound for speaking. Part of the larynx, including the vocal cords and epiglottis, is covered with non-keratinising squamous epithelium similar to that lining the oral cavity, pharynx and oesophagus.

Lungs

The lower respiratory tract consists of the trachea, bronchi, bronchioles, alveolar ducts and alveoli (Fig. 14.2). (Table 14.2).

Fig. 14.2 Structure and nomenclature of the lower respiratory tract.

Table 14.2 Structure of the respiratory tree

The lungs develop from an outpouching of the anterior wall of the primitive foregut at about the fifth week of development. From this tube, two lateral outgrowths appear which eventually form the right and left lungs. These outgrowths are surrounded by mesenchyme from which forms the connective tissue of the respiratory tree. Thus the lungs, like the gastrointestinal tract, develop from endoderm, and developmental abnormalities such as cysts can therefore be lined by either respiratory or gastrointestinal mucosa.

The lungs are divided into lobes: the right lung has three lobes (upper, middle, lower); the left lung has only two lobes (upper and lower). Each lung is formed of 10 anatomically defined bronchopulmonary segments. Each segment is supplied by a segmental branches of the pulmonary artery and bronchus (the bronchovascular bundle). The veins draining adjacent segments often anastomose before they reach the hilum and run principally in the fibrous septae of the lungs.

The respiratory tree is designed to transport clean, humidified air into distal airways and alveoli, where the waste product of metabolism (CO₂) is exchanged for O₂.

Bronchioles branch until they form terminal bronchioles less than 2 mm in diameter. The respiratory system distal to the terminal bronchiole is called the acinus or terminal respiratory unit, where gas exchange occurs. Small airways, defined as having an internal diameter of less than 2 mm, consist of terminal and respiratory bronchioles. Respiratory bronchioles are involved with gas exchange, having alveoli in their walls. A group of three to five respiratory acini is called a lobule.

The alveoli are lined by flattened type I pneumocytes with occasional type II pneumocytes; the latter are rounded cells with surface microvilli and are believed to be the stem cell population for the alveolus. Type II cells secrete surfactant, and replicate quickly after injury to alveolar walls. Beneath the alveolar cells lie a basement membrane which is shared by the alveolar capillary epithelial cells and some interstitial matrix, including elastin fibres. The structure of the alveolar–capillary membrane permits rapid and efficient diffusion of oxygen and carbon dioxide.

The lung is encased by the visceral pleura which is a thin layer of fibroconnective tissue and elastin with overlying mesothelial cells. The lungs sit within the chest cavity surrounded by the parietal pleura, by the diaphragm, ribs and intercostal muscles, vertebral column and sternum.

Blood supply and lymphatic drainage

The lungs are perfused by a dual arterial blood supply. The trunk of the pulmonary artery arises from the right ventricle, splits into main right and left pulmonary arteries and thence follows the airways, forming the bronchovascular bundles. The bronchial arteries arise from the descending thoracic aorta and supply oxygenated blood to lung parenchyma around the hilum. Pulmonary veins take all the blood from the lungs back to the left atrium.

Pulmonary veins course along the interlobular septa with lymphatics.These lymphatic channels and those in the pleura drain into the thoracic duct.

Hyaline membrane disease or idiopathic respiratory distress syndrome

Complication of prematurity (less than 36 weeks’ gestation)

Due to deficiency of pulmonary surfactant

Tachypnoea, dyspnoea, expiratory grunting, cyanosis

Diffuse alveolar damage with hyaline membranes

Associated with maternal diabetes, multiple pregnancy, caesarean section, amniotic fluid aspiration

Many similarities to adult respiratory distress syndrome (ARDS)

Hyaline membrane disease (HMD) is almost always seen in premature infants of birth weight less than 2.5 kg. Infants are usually of less than 36 weeks’ gestation, and the incidence of HMD rises as the gestational age decreases. The risk of developing HMD may be decreased by giving mothers oral corticosteroids prior to delivery of the baby as this appears to stimulate surfactant production in the lungs.

Bronchopulmonary dysplasia

Bronchopulmonary dysplasia is the term used to describe the picture of lung organisation after HMD. Often, infants have been previously treated with high levels of oxygen, and it is not clear whether bronchopulmonary dysplasia is a separate disorder, solely related to oxygen toxicity, or merely a result of organisation after HMD. Certainly, the features are almost identical to those seen with organisation of ARDS; there is interstitial fibrosis, peribronchial fibrosis, and features of pulmonary hypertension. The airways may show extensive squamous metaplasia.

Viral and mycoplasma pneumonia

The clinical course is varied depending on the extent and severity of the disease. In fatal cases, the lungs appear heavy, red and consolidated, as in adult respiratory distress syndrome (ARDS). Histology shows interstitial inflammation consisting of lymphocytes, macrophages and plasma cells. Hyaline membranes of fibrinous exudate are prominent. The alveoli may be relatively free of cellular exudate. Secondary bacterial infection is, however, common and may be severe, for example staphylococcal pneumonia complicating flu.

Mycoplasma pneumonia tends to cause a more low-grade pneumonia, with interstitial inflammation and less exudation.

Legionnaires’ disease

Since the first well-described outbreak in 1976, in a group of American Legion conventioneers, this disease has become increasingly recognised; 201 cases were reported in 1996 in the United Kingdom. It is caused by a bacillus, Legionella pneumophila, transmitted in water droplets from contaminated air humidifiers and water cisterns. Patients may be previously well, although a proportion have an underlying chronic illness, such as heart failure or carcinoma. Symptoms include cough, dyspnoea and chest pain, together with more systemic features, such as myalgia, headache, confusion, nausea, vomiting and diarrhoea. About 5–20% of cases are fatal depending on the age of the population affected. At autopsy the lungs are very heavy and consolidated.

Pneumocystis jiroveci

Alveoli are filled with a bubbly pink exudate. Round or crescent-shaped organisms are seen using a silver impregnation stain. There may also be diffuse alveolar damage.

Fungi

Both Candida and Aspergillus species can cause widespread areas of necrosis (Fig. 14.9). Micro-abscesses contain the characteristic fungal filaments (hyphae).

Fig. 14.9 Aspergillus pneumonia. Lung at autopsy showing focal yellow areas of consolidation.

Viruses

Viral infection may produce diffuse alveolar damage and areas of lung necrosis. Characteristic intranuclear inclusions are seen with infections by cytomegalovirus (CMV) and herpes viruses.

HIV lung disease

Pulmonary disease accounts for up to 70% of AIDS-defining illnesses and is the cause of death in at least a third of all AIDS patients.

The lung is frequently involved with infections, the commonest globally being tuberculosis, although combinations of common bacteria, Pneumocystis jiroveci, viruses and even fungi are commonly seen in AIDS patients in Western society.

Cryptogenic organising pneumonia

Cryptogenic organising pneumonia is described in the Chronic interstitial diseases section (p. 341).

Aspiration pneumonia

Aspiration pneumonia occurs when fluid or food is aspirated into the lung, resulting in secondary inflammation and consolidation. Clinical situations where patients are at risk include sedation, operations, coma, stupor, laryngeal and oesophageal carcinoma, and severe debility. The parts of the lung affected vary according to the patient’s posture: lying on the back, the affected area is the apical segment of the lower lobe; lying on the right side, the posterior segment of the upper lobe is affected. Often, such areas of aspiration pneumonia contain anaerobic organisms, and a lung abscess containing foul material may ensue.

Lipid pneumonia

Lipid pneumonia may be endogenous, associated with airway obstruction causing distal collections of foamy macrophages and giant cells. This is often seen distal to bronchial carcinoma or an inhaled foreign body. Alternatively, lipid pneumonia may be exogenous, due to aspiration of material containing a high concentration of lipid. Such materials include liquid paraffin or oily nose drops. Vacuoles of lipid are ingested by foreign-body giant cells; there may be some interstitial fibrosis.

Eosinophilic pneumonia

Acute eosinophilic pneumonia is usually idiopathic and associated with a blood eosinophilia (Löffler’s syndrome); it is characterised by numerous eosinophils in the interstitium and alveoli. There is usually a swift response to steroid therapy.

Chronic eosinophilic pneumonia is less frequently associated with a peripheral eosinophilia. The lung shows extensive infiltration with eosinophils and the presence of organising exudates which may go on to give rise to fibrosis. The aetiology is often unclear but can be the result of allergic type reaction to drugs or other environmental agents.

Primary tuberculosis

The lungs are usually the initial site of contact between tubercle bacilli and humans. The focus of primary infection, which is usually asymptomatic, is called a Ghon focus. The pulmonary lesion is usually about 10 mm in diameter, and consists of a central zone of caseous necrosis surrounded by palisaded epithelioid histiocytes, the occasional Langhans’ giant cell and lymphocytes. Similar granulomas are seen in lymph nodes that drain the affected portion of the lung.

In almost all cases, a primary lesion will organise, leaving a fibrocalcific nodule in the lung, and there will be no clinical sequelae. However, tubercle bacilli may still be present within such scarred foci and may persist as viable organisms for years. In a few cases the infection may progress with systemic spread.

Secondary tuberculosis

As indicated above, most secondary TB represents re-activation of old primary infection. These lesions are nearly always located in the lung apices, sometimes bilaterally (Fig. 14.11). Histologically, typical granulomas are seen, most having central zones of caseous necrosis. Progression of the disease depends on the balance between host sensitivity and organism virulence. Most lesions are converted to fibrocalcific scars, a frequent finding in the lungs of elderly people at autopsy. However, as in primary TB, many complications can ensue.

Fig. 14.11 Secondary pulmonary tuberculosis. Lung at autopsy showing cavitation and scarring at the apex of the right upper lobe.

Miliary tuberculosis

Miliary TB may be a consequence of either primary or secondary TB in which there is severe impairment of host resistance. The disease becomes widely disseminated, resulting in numerous small granulomas in many organs. Lesions are commonly found in the lungs, meninges, kidneys, bone marrow and liver, but no organ is exempt. The granulomas often contain numerous mycobacteria, and the Mantoux test is frequently negative (see below). This is an acute medical emergency necessitating prompt treatment with antituberculous chemotherapy if a fatal outcome is to be averted.

Aetiology

Bronchiectasis arises as a result of chronic inflammation that damages the alveolated lung around the airways and the airway walls. The resulting scarring causes airway distortion and dilatation with further inflammatory process in the wall of the damaged airway due to secondary infection. Bronchiectasis can arise from a wide range of lung insults:

Clinical features

Usually, the lower lobes are affected, leading to pooling of bronchial secretions with further infection. Symptoms are usually a chronic cough with expectoration of large quantities of foul-smelling sputum, sometimes flecked with blood. Patients may have finger-clubbing. Recurrent respiratory tract infections result from the inability of the patient to clear pooled secretions. Infective processes may remain localised to the bronchi, or spread.

Morphology

There is dilatation of bronchi and bronchioles, with inflammatory infiltration, especially polymorphs, during acute exacerbations. The inflammation and associated fibrosis extend into the adjacent lung tissue. The dilated bronchi and bronchioles can appear cylindrical, saccular or fusiform; these terms are purely descriptive of the variable morphology and are of no aetiological or prognostic significance.

Venous congestion and pulmonary oedema

Pulmonary oedema can result from:

An initial increase in venous hydrostatic pressure leads to pulmonary venous congestion. Common causes are:

Secondary pulmonary venous hypertension follows, with congestion of alveolar wall capillaries. Fluid is then forced out of the venous circulation into the alveoli to form pulmonary oedema.

The lungs are heavy, congested and contain bubbly fluid. In chronic congestion, recurrent alveolar haemorrhages lead to the accumulation of haemosiderin-laden macrophages (heart-failure cells) with some interstitial fibrosis, so-called ‘brown induration of the lung’.

Clinically, there is dyspnoea with a cough, producing bubbly fluid. Auscultation reveals fine crackles in the chest due to air bubbling through numerous fluid-soaked airways. There is respiratory impairment with hypoxaemia. The boggy lungs are prone to secondary infection.

Pulmonary hypertension and ‘cor pulmonale’

Pulmonary hypertension may be:

All the above mechanisms may lead to ‘cor pulmonale’ or heart failure caused primarily by respiratory disease, which is manifested by pulmonary hypertension and right ventricular hypertrophy.

Pre-capillary pulmonary hypertension may be:

Capillary pulmonary hypertension is due to disease in the pulmonary vascular bed. Severe chronic obstructive airways disease may also cause pulmonary hypertension and ‘cor pulmonale’.

Post-capillary pulmonary hypertension is due to high pressure in the pulmonary venous system causing secondary back pressure into the arterial tree. Examples include mitral stenosis, left ventricular failure from any cause, and the rare pulmonary veno-occlusive disease.

Any cause of chronic hypoxaemia may lead to pulmonary hypertension, including living at high altitude. The Pickwickian syndrome is characterised by chronic hypoxaemia and pulmonary hypertension caused by poor respiration associated with gross obesity.

Obviously, the gross and microscopic pathology in each instance is determined by the underlying cause. There are also relatively constant changes seen in the pulmonary arterial tree, including muscular hypertrophy, intimal proliferation, capillary dilatation and, in severe cases, necrotising arteritis.

Pulmonary veno-occlusive disease

Pulmonary veno-occlusive disease is rare; it leads to chronic venous congestion with interstitial fibrosis and many haemosiderin-laden macrophages in alveolar spaces. The left heart is normal, and disease is caused by internal thickening and occlusion of pulmonary veins in the septa. The aetiology is largely unknown, although some cases have been reported in association with drugs and connective tissue disorders. Symptoms are of progressive dyspnoea and ‘cor pulmonale’.

Pulmonary arterial hypertension with right-to-left shunt

In patients with a congenital atrial septal defect (Ch. 13), often asymptomatic, who subsequently develop pulmonary hypertension, the raised right intra-atrial blood pressure causes blood to flow through the defect into the left atrium (right-to-left shunt). Right-to-left shunts may also occur in patients with longstanding left-to-right shunts (i.e. the shunt reverses), for example in ventricular septal defects following the development of secondary pulmonary hypertension (Eisenmenger’s syndrome).

This has two important consequences:

Chronic obstructive pulmonary disease (COPD)

COPD is a clinical syndrome that pathologically is associated with two patterns of disease in the lung—chronic bronchitis and emphysema. Although pathologically these are two distinct processes, they almost always co-exist to some degree. Together they rank fifth in the global burden of disease: in the UK COPD affects approximately 6% of men and 4% of women over the age of 45, and in the USA it is the fourth leading cause of death, claiming ~120 000 lives annually. COPD is closely linked with cigarette smoking and is associated with progressive loss of lung function: increasing breathlessness, hypoxia and respiratory failure with cor pulmonale.

Chronic bronchitis

Defined clinically as cough and sputum for 3 months in 2 consecutive years

Mucus hypersecretion with bronchial mucous gland hypertrophy

Respiratory bronchiolitis

Most cases caused by smoking

Emphysema

Defined anatomically as abnormal enlargement of alveolar airspaces

Usually seen in smokers in association with chronic bronchitis

There are various patterns of emphysema (Fig. 14.18). Although each category has a precise anatomical definition, it must be emphasised that in advanced cases there is usually a mixed picture, and an accurate classification in an individual patient is therefore not possible. Suffice to say that all forms of pulmonary emphysema show loss of distal lung parenchyma with resultant airspace enlargement (Fig. 14.19). The pathogenesis is poorly understood but may result from an imbalance of tissue remodelling favouring removal of connective tissue as a result of smoking-induced inflammation. The fact that there are different patterns present may, however, suggest that different pathogenetic process occur.

Fig. 14.18 Classification of emphysema. Emphysema is classified according to the pattern of distribution of lesions. These can, to some extent, be correlated with specific aetiological factors, e.g. centrilobular emphysema and cigarette smoke. A, alveolus; RB, respiratory bronchiole; TB, terminal bronchiole.

Fig. 14.19 Emphysema. This is severe emphysematous change characterised by large bullae at the pleural surface. Histology shows the presence of enlarged alveolar spaces characteristic of emphysema in comparison with that in a normal lung .

Asthma

Reversible small airways obstruction characterised by bronchospasm, inflammation and oedema

Paroxysmal attacks

Overdistended lungs

Mucous plugs in bronchi

Enlarged bronchial mucous glands

Asthma is defined as hyper-reactivity of the bronchial tree with paroxysmal narrowing of the small airways (Fig. 14.20), which may reverse spontaneously or after treatment. Asthma is increasingly common in many countries, but it is a relatively rare cause of death.

Fig. 14.20 Asthma. Tracheal mucous plug (arrowed) in death from status asthmaticus. Histological section of lung at autopsy showing occlusion of airways by oedema and mucous plugs (arrowed) accompanied by alveolar distension with entrapped gas.

There are five major clinical categories of asthma:

Each type has different predisposing factors, and is mediated in different ways. However, the resulting clinical symptoms and pathology are similar to those seen in atopic asthma. Any important differences are outlined below.

Atopic asthma

Atopic asthma is triggered by a variety of environmental agents, including dust, pollens, foods and animal danders, e.g. faecal pellets from housedust mites. There is often a family history of asthma, hay fever or atopic eczema. Patients with atopic asthma may also suffer from atopic disorders such as hay fever or eczema. Increased levels of endogenous nitric oxide (NO) produced by a variety of cells in the respiratory tract have been found in exhaled air from asthmatics when compared with normal controls; whether NO is merely a marker of airway irritation or has a more fundamental role in the pathogenesis of asthma is not known. Recently the gene labelled ADAM33 (a disintegrin and metalloproteinase) has been identified that may underlie the variation in bronchial hypersensitivity between individuals.

Bronchoconstriction is mediated by a type I hypersensitivity reaction (Ch. 9); bronchoconstriction leads to the clinical effects of wheezing, tachypnoea and dyspnoea (Fig. 14.21). Rarely, symptoms persist for days (status asthmaticus), leading to respiratory failure and even death. Release of histamine and slow-reacting substance of anaphylaxis (SRS-A) leads to bronchoconstriction, increased vascular permeability and mucus hypersecretion. Eosinophil chemotactic factor of anaphylaxis (ECF-A) attracts numerous eosinophils to the bronchial walls.

Fig. 14.21 Pathogenesis of allergic asthma. Inhalation of allergen (antigen) causes degranulation of mast cells bearing specific IgE molecules. Release of vasoactive substances from the mast cells causes bronchial constriction, oedema and mucus hypersecretion.

Platelet activating factor (PAF) leads to the aggregation of platelets with the release of further histamine and 5-hydroxytryptamine (5-HT) from their granules. The hypersensitivity reaction results in acute and chronic changes, with the former being identifiable during an acute episode and the latter being the result of airway remodelling following repeated attacks:

• Acute

– bronchial obstruction with distal overinflation or atelectasis (collapse)

– mucous plugging of bronchi

– bronchial inflammation with prominent numbers of eosinophils, lymphocytes and plasma cells

– bronchial epithelial shedding and subsequent regeneration

– Curschmann’s spirals: whorls of shed epithelium within mucous plugs

– Charcot

– Leyden crystals: crystals within aggregates of eosinophils

• Chronic

– mucous gland hypertrophy

– development of mucosa–associated lymphoid tissue

– bronchial wall smooth muscle hypertrophy

– thickening of bronchial basement membrane.

Radiation pneumonitis

The clinical effects of radiation toxicity to the lungs are highly dependent on the dose given (Ch. 6), the volume of lung irradiated and the length of treatment. If heavily exposed, a picture of diffuse alveolar damage may be seen as described above. If exposure is less severe and occurs over a longer period, progressive pulmonary fibrosis is seen with the typical restrictive defect of pulmonary function.

Diffuse intrapulmonary haemorrhage

Goodpasture’s syndrome is characterised by haemoptysis, haematuria, anaemia and pulmonary infiltrates. Most cases have circulating anti-glomerular basement membrane antibody in their blood. This antibody causes glomerulonephritis, and also acts on alveolar membranes leading to pulmonary haemorrhage.

Idiopathic pulmonary haemosiderosis is a rare condition presenting most often in children. Clinically, patients may present with recurrent episodes of intra-alveolar haemorrhage associated with haemoptysis, cough and dyspnoea; alternatively, they may present with insidious pulmonary fibrosis. The more acute form shows evidence of diffuse alveolar damage, with type II pneumocyte hyperplasia.

Idiopathic pulmonary fibrosis (IPF)

IPF is a progressive chronic pulmonary fibrosis of unknown aetiology, although approximately 20% of patients give a history of occupational exposure to metals and wood dusts. Most patients are aged over 60 years and present with increasing dyspnoea and a dry cough. Men are affected twice as often as women. The disease progresses to respiratory failure, with or without cor pulmonale, within about 5 years. Fatigue and considerable weight loss may occur, raising the clinical suspicion of malignancy. Examination often shows finger- and toe-clubbing; auscultation of the chest reveals dry crackles, reflecting the opening and closing of fibrotic airspaces. Signs of right ventricular strain or failure may be present. These patients also have an excess risk of carcinoma of the lung and ischaemic heart disease.

Pneumoconioses

Exposure to inhaled materials may have several potential consequences depending on the nature of the dust and the degree of exposure:

These conditions are often all regarded as ‘occupational’ or ‘industrial’ lung disease although it is important to remember that exposure can occur outwith the workplace. Pneumoconiosis is, however, defined as lung fibrosis secondary to inhaled inorganic dust (e.g. coal dust, silica, metals, etc.). In many industrial settings patients may be exposed to a wide variety of different dusts and identifying which dust might be responsible for lung disease may be difficult.

The distribution of lung disease depends on the physical properties of each separate type of dust, which determine where the particles settle in the lung. Only very small particles reach distal alveoli, as larger particles are trapped in the nose or excreted by mucociliary clearance from the larger airways.

Dust particles are phagocytosed by alveolar macrophages, which then collect and drain into peribronchiolar lymphatics and thence to hilar lymph nodes. Not surprisingly, dusts causing disease in the lungs are also often present in the sinuses of hilar lymph nodes.

Coal-worker’s pneumoconiosis

In coal-worker’s pneumoconiosis (CWP), coal dust is phagocytosed by alveolar macrophages (dust cells), which then aggregate around bronchioles; the degree of black pigment in the lung (anthracosis) is related to the amount of inhaled carbon. Anthracosis is also commonly seen in smokers and those living in urban environments. The consequences of coal-dust inhalation are variable, ranging from trivial to fatal.

Simple CWP is associated with minimal scarring and no significant disability. The predominant pattern is of dust macules consisting of focal aggregates of dust-laden macrophages in and around the walls of respiratory bronchioles, pulmonary arterioles and pulmonary veins. Similar cells are seen in lymphatics and hilar lymph nodes. There may be some associated airspace enlargement consistent with emphysema. To qualify as pneumoconiosis there must, however, be evidence of fibrosis and this is characterised by the development of fibrous nodules. This is usually regarded as a progression from the macular stage. In simple CWP nodules less than 10mm in diameter are seen in a background of macular CWP.

Complicated CWP or progressive massive fibrosis (PMF) is characterised by large, irregular nodules with scarring (Fig. 14.22); they are greater than 10 mm in diameter and can be very large. These fibrotic black nodules may show central liquefaction and, when cut at autopsy, exude viscid jet-black liquid. They may contract, leading to adjacent irregular emphysema. Large nodules are usually mid-zonal or in upper lobes, and may be bilateral. The associated emphysema is always severe, often with the formation of bullae. Progression of the disease leads to further scarring and lung destruction with respiratory failure, or cor pulmonale.

Fig. 14.22 Coal-worker’s pneumoconiosis. This transilluminated thin slice of lung shows several large black fibrotic nodules. which measure more than 10 mm, consistent with complicated coal-worker’s pneumoconiosis (progressive massive fibrosis). In some cases these may cavitate as shown in this example.

It is recognised that in a group of miners working at the same pit for the same length of time, some will develop PMF and die, while others develop little respiratory impairment. The reasons why only some miners develop PMF are unknown and some investigators believe that the determining factor is merely the amount of coal dust inhaled. It is clear, however, that PMF is seen more commonly in some coal fields compared with others, which may suggest that exposure to other dusts such as silica in the rocks may play a role. Whatever the cause, the progression of CWP to PMF is an ominous event.

Caplan’s syndrome is characterised by the presence of large pigmented necrobiotic nodules in patients with CWP. This occurs in the presence of seropositive rheumatoid disease, although lung nodules may precede the development of systemic features. The nodules may regress.

Asbestosis

The name ‘asbestos’ is derived from a Greek word meaning ‘inconsumable’, and, indeed, asbestos has been used for its fire-resistant qualities for many centuries. Asbestos is used for insulation and the manufacture of brake linings and other friction materials. There are several types of asbestos: amphiboles are the fibres that cause pulmonary disease in humans, and of these crocidolite (blue asbestos) is probably the most dangerous.

Inhaled asbestos fibres collect in alveoli at the lung bases. Many become coated in acid mucopolysaccharide and encrusted with haemosiderin to form ‘asbestos bodies’ or ‘ferruginous bodies’, appearing as characteristic beaded structures. The majority of fibres are, however, detectable only by electron microscopy.

Asbestosis is characterised by the development of a pattern of lung fibrosis that is essentially similar to UIP described above with destructive subpleural honeycomb changes (Fig. 14.23). It is usually seen only in patients with relatively heavy asbestos exposure and is therefore most common in those who have worked extensively with insulation materials, for example in shipyards or power stations. Disease progression is much slower and the prognosis in most cases considerably better than for IPF. Differentiation of asbestosis from IPF may be important in terms of compensation but can be difficult. Quantification of the number of asbestos fibres may be helpful in this regard but clearly the finding of fibres by itself only proves previous exposure, not causation of the disease present.

Fig. 14.23 Asbestosis. The fibrous reaction to inhaled asbestos has resulted in a ‘honeycomb’ lung.

Extrinsic allergic alveolitis (hypersensitivity pneumonitis)

Interstitial lung disease caused by inhalation of organic dusts results from the individual being sensitised (hypersensitive) to the inhaled antigen (see also occupational asthma). Many antigens have been described as causing an allergic interstitial lung disease known as extrinsic allergic alveolitis or hypersensitivity pneumonitis. These include: cotton fibres, causing byssinosis; sugar cane fibres, causing bagassosis; and bird faeces, causing bird fancier’s lung. Whilst many of these may be associated with occupational exposure and thus can be regarded as an ‘occupational lung disease’, exposure to antigens in the domestic environment and even drugs can give an identical pattern of disease in the lung.

The best known and most typical example of an occupational extrinsic allergic alveolitis is farmer’s lung. In this disorder, a fungus present in poorly stored, mouldy hay is inhaled by whoever disturbs the hay. If the individual is already sensitised to the organism, a type III immune complex hypersensitivity reaction follows. One of the earliest features is a bronchiolitis. Later, chronic inflammatory cells are seen in the interstitium, together with non-caseating granulomas. The inflammatory process may resolve on withdrawal of the antigen but if there is chronic exposure then pulmonary fibrosis will develop.

Clinically, there is acute dyspnoea and cough a few hours after inhalation of the antigen. Corticosteroid treatment helps to ameliorate the inflammatory reaction and to prevent the onset of pulmonary fibrosis.

Sarcoidosis

Sarcoidosis is a multisystem inflammatory disorder which most commonly involves the mediastinal lymph nodes and lung. The aetiology is unknown but it is possible that the granulomas arise as a result of an aberrant immune response due to abnormal T-cell–macrophage interactions. The possibility of an infective aetiology has been considered for many years but no convincing demonstration of an infective agent has been found. Clinical symptoms are variable depending on the extent of the disease. Many patients may be asymptomatic while others may have systemic upset with tiredness and cough. Common extrapulmonary manifestations include erythema nodosum, iritis and arthralgia. In most cases the disease is either self-limiting or responds to steroid therapy. In a minority of cases progression to end-stage pulmonary fibrosis occurs. Involvement of other organs, including the heart and central nervous system, occurs more rarely and can cause severe morbidity and death.

Histologically, sarcoid in the lung is characterised by the presence of relatively discrete non-caseating granulomas (Fig. 14.24) which may coalesce to form larger nodules. Predominantly they are found in relation the bronchovascular bundles, septae and the pleura. The principal differential diagnosis is that of infective disorders such as tuberculosis and histoplasmosis.

Fig. 14.24 Sarcoid. The histological feature of sarcoid is the presence of non-caseating granulomas in the lung.

Cryptogenic organising pneumonia (COP)

COP (or bronchiolitis obliterans organising pneumonia, BOOP) is a clinical syndrome characterised by mild systemic upset with possible cough, low-grade fever and breathlessness which radiologically shows evidence of focal lung consolidation that may ‘flit’ within the lungs over time. The pathogenesis is poorly understood. Pathologically, the lungs show nodular foci of organising exudates within alveolar spaces and terminal bronchioles, and variable, usually mild, interstitial inflammation. In most cases the condition responds well to steroid therapy and there is resolution with no significant fibrosis. Some patients may, however, relapse and more progressive cases with lung fibrosis have been described.

Langerhans’ cell histiocytosis (LCH)

Langerhans’ cell granulomatosis (previously known as histiocytosis X) is a disease principally of smokers, characterised by the proliferation of Langerhans’ cells. This is believed to occur as a response to cigarette smoke and increased numbers have been described in the lungs of smokers compared with non-smokers, even in the absence of LCH. The Langerhans’ cells are specialised histiocytes which are involved in antigen presentation. Inflammatory infiltrates are seen in the pulmonary interstitium with the Langerhans’ cells admixed with lymphocytes and eosinophils. These may form nodular masses with areas of cystic change. In most cases smoking cessation results in complete resolution of the nodules or healing, leaving small areas of fibrosis. In some cases, however, the disease may be progressive and result in end-stage pulmonary fibrosis.

Alveolar lipoproteinosis

Alveolar lipoproteinosis (or proteinosis) is a rare condition characterised by the accumulation of eosinophilic material within alveoli. In most instances the aetiology is unknown and the pathogenesis is uncertain but there appears to be an association with haematological disorders in some patients. Symptoms include dyspnoea and cough, when gelatinous material may be expectorated.

Connective tissue disorders and interstitial lung disease

Patients with connective tissue disorders such as rheumatoid arthritis and scleroderma may show a variety of pulmonary complications which fall into the ILD categories described above. The commonest pattern associated with these conditions is non-specific interstitial pneumonitis but patients may also develop cryptogenic organising pneumonia and usual interstitial pneumonitis. Drug treatments may also be associated with acute interstitial pneumonitis/ARDS (e.g. methotrexate), hypersensitivity reactions or opportunistic infection following immunosuppression. Other lung manifestations include rheumatoid nodules, Caplan’s syndrome, vasculitis and obliterative bronchiolitis.

Aetiology

Major risk factors for the development of lung cancer are:

Clinical features

Weight loss, cough and haemoptysis are common presenting features. Weight loss is often severe and may be due to humoral factors from the tumour. Dyspnoea and chest pain are also common; the latter is often pleuritic and due to obstructive changes. Patients may present with, or ultimately develop, metastases; common sites include lymph nodes, bone, brain, liver and adrenals. Paraneoplastic effects are common and are due to ectopic hormones: ACTH and ADH from small cell lung carcinomas, PTH from squamous cell carcinomas. Finger-clubbing and hypertrophic pulmonary osteoarthropathy are common (Fig. 14.25).

Fig. 14.25 Clinical features and complications of primary lung cancer.

Lung carcinomas may arise centrally in the lung or towards the periphery. Central tumours may cause airway obstruction with collapse or distal consolidation of a lobe or the whole lung. These tumours may infiltrate medially into the mediastinum at a relatively early stage and patients can present as a result of this rather than the lesion in the lung (e.g. hoarseness from involvement of the left recurrent laryngeal nerve). More peripheral tumours are often asymptomatic but pleural involvement may lead to pleural effusion or the tumour may extend into the chest wall causing pain. Larger tumours, especially squamous carcinomas, often cavitate. Small cell carcinoma has usually disseminated by the time of diagnosis and the primary lesion in the lung may be small compared to the bulky nodal deposits in the mediastinum and liver.

Morphology

Most tumours arise from bronchi close to the hilum (Fig. 14.26); usually an upper lobe or main bronchus is involved. Ulceration is common, so the sputum may be bloodstained and contain malignant cells which can be detected cytologically (Fig. 14.27) or by biopsy at bronchoscopy (Fig. 14.28). Distally, the lung may be consolidated with foamy macrophages, the usual result of proximal obstruction, and patients may present with what appears to be a pneumonia.

Fig. 14.26 Carcinoma of the lung. The tumour is arising at the hilum of the affected lobe and is invading the adjacent lung tissue.

Fig. 14.27 Carcinoma of the lung. Tumour cells found in diagnostic bronchial washings, the appearances of which are consistent with non-small cell carcinoma of the lung.

Fig. 14.28 Lung carcinoma. Histology of a poorly differentiated squamous cell carcinoma. Bronchial cartilage (left) is relatively resistant to neoplastic invasion.

Histological classification

There are four major types of lung cancer, classified according to their appearance on light microscopy; their approximate incidences are:

• squamous cell carcinoma (SqCC): 20–30%

• small cell lung carcinoma (SCLC): 15–20%

• adenocarcinoma (AC): 30–40%

• large cell undifferentiated carcinoma (LCUC): 10–15%

• carcinoid tumours: 5%.

The lung cancers are discussed below according to this classification. For practical purposes the tumours are often divided into non-small cell carcinomas (SqCC, AC and LCUC) and small cell carcinomas as this distinction largely directs management. About 20% of lung carcinomas may show evidence of a mixed pattern of differentiation, e.g. SqCC and SCLC, or AC and SqCC.

Squamous cell carcinoma.

This is the type of lung cancer most closely associated with cigarette smoking although the relative incidence has been decreasing over the last few years. The tumours are usually central in location and are thought to arise from areas of squamous metaplasia through increasing grades of dysplasia. There is often haemorrhage and necrosis with cavitation. Tumours may be well, moderately or poorly differentiated. SqCC tends to metastasise locally to hilar lymph nodes; distant metastases are a later feature.

Small cell lung carcinomas.

These tumours were previously also known as ‘oat cell’ carcinoma because the small nuclei were thought to resemble oat grains; SCLC usually arise in a hilar bronchus. Unlike non-small cell carcinomas, they metastasise very early, producing widespread bulky secondary deposits. Sometimes, the primary tumour can be small and difficult to find. The histology is of a highly cellular tumour composed of small cells with hyperchromatic nuclei and indistinct nucleoli. The cells are very delicate and the chromatin may appear smudged. The cells commonly express neuroendocrine markers, suggesting that this is a form of very poorly differentiated neuroendocrine carcinoma.

Adenocarcinomas.

These may be central or peripheral and can show a wide range of morphological patterns. The relative incidence of adenocarcinoma has been increasing over the last two decades and this type of tumour has overtaken squamous carcinoma as the most common subtype. Adenocarcinomas are usually single lesions but they can arise in a multifocal pattern, sometimes bilaterally. In this situation the tumour usually has a broncho-alveolar configuration where the cells grow along the alveolar walls, giving rise to areas that appear consolidated (Fig. 14.29). There is now some evidence to suggest that most peripheral adenocarcinomas may arise from an area of broncho-alveolar carcinoma and that this may therefore represent an early form of these tumours.

Fig. 14.29 Broncho-alveolar adenocarcinoma. The tumour cells diffusely infiltrate the alveolar spaces mimicking a pneumonic process clinically, radiologically and grossly.

Large cell undifferentiated carcinomas.

Usually central, these are highly aggressive and destructive lesions with necrosis and haemorrhage. Histologically, there is often gross nuclear pleomorphism with numerous bizarre mitoses. By definition no squamous or glandular differentiation is seen on light microscopy, although such evidence is often found ultrastructurally. Some of these tumours may have features suggesting neuroendocrine differentiation and the term large cell neuroendocrine carcinoma has been adopted to distinguish them from SCLC and carcinoid tumours.

Bronchial carcinoid tumours.

These are low-grade malignant tumours arising usually in the central airways. They are highly vascular and commonly present with haemoptysis or result in bronchial obstruction. These tumours generally have a good prognosis and, whilst metastatic spread to hilar lymph nodes can occur, this is rare and resection is usually curative. Some of these tumours may produce ACTH and are a rare cause of Cushing’s syndrome.

Benign tumours

Adenomas may arise from bronchial mucous glands. They present as polypoid or sessile lesions in a bronchus. Symptoms are related to obstruction.

Benign mesenchymal tumours may arise anywhere that mesenchyme (connective tissue) occurs. Thus, neurofibromas, lipomas, etc. may be found in the lung. More common is the chondroma. The lesion is hard, white and well circumscribed, and is discovered as an isolated ‘coin’ lesion on chest X-ray. It is composed of nodules of cartilage with infoldings and clefts lined with bronchial or bronchiolar epithelium.

Malignant tumours

Malignant mesenchymal tumours (sarcomas) are extremely rare but the commonest primary type is angiosarcoma.

Primary pulmonary lymphomas are rare tumours presenting as pulmonary disease with or without hilar lymph node involvement, but without clinical evidence of disease elsewhere. HIV/AIDS patients have an increased incidence of pulmonary lymphoma. These tumours arise from bronchus- and bronchiole-associated lymphoid tissue.