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Allergic rhinitis (hay fever) commonly affects the nose, paranasal sinuses and nasopharynx and can predispose to inflammatory nasal polyps ( Fig. 12.1 ). The sinonasal (Schneiderian) papilloma is particular to the nasal cavity and is usually unilateral ( Fig. 12.2 ). Malignant tumours of the nasal passages and sinuses are rare, but nasopharyngeal carcinoma ( Fig. 12.3 ) is of special interest because of its association with Epstein–Barr virus (EBV) infection.
Vocal cord polyps (laryngeal or singer’s nodule) arise as smooth nodules on the surface of the true vocal cords, usually as a result of persistent inflammation ( Fig. 12.4 ). The stratified squamous epithelium of the larynx may also contain a low risk HPV infection associated lesion, the benign squamous papilloma. Cigarette smoking and alcohol consumption predispose to the development of dysplasia and invasive squamous cell carcinoma of the larynx . ( Fig. 12.5 ).
E respiratory type epithelium Eo eosinophils M mucin-filled cysts N neutrophilic abscesses S oedematous stroma
C laryngeal cartilage B bone K keratinisation L lymphoid cells O oedematous submucosa S stratified squamous epithelium
The trachea and bronchi may become acutely inflamed due to infections by viruses or pyogenic bacteria to cause acute tracheobronchitis ( Fig. 12.6 ). Bacterial infections of airways are frequently complicated by extension of inflammation into the surrounding lung parenchyma to cause a pattern of lung infection known as bronchopneumonia ( Fig. 12.7 ), a common cause of illness and death in the debilitated and elderly. Another pattern of bacterial lung infection is lobar pneumonia , which involves a whole segment or lobe. In this setting, a more virulent bacterium such as the pneumococcus is usually involved and fit young people may be almost as susceptible as the elderly and debilitated. Lobar pneumonia illustrates many important principles of acute inflammation and the phenomenon of resolution and is discussed in Ch. 3 (Figs 3.3 and 3.7). In contrast, tuberculosis and sarcoidosis are classic examples of specific chronic inflammations and are discussed fully in Chapter 4, Chapter 5 . Recurrent or persistent suppurative bacterial infections of bronchi may lead to irreversible dilatation of airways with marked thickening and chronic inflammation of the walls, a condition known as bronchiectasis (see Fig. 4.3 ). Abscess formation in the lungs is a serious complication of certain pneumonias, particularly Staphylococcal and Klebsiella pneumonias. Lung abscesses may also result from septic emboli causing infarction of the lung, bronchiectasis, bronchial obstruction (e.g. by tumour or foreign body) or as a complication of pulmonary tuberculosis.
The term chronic obstructive pulmonary disease (COPD) refers to conditions characterised by chronic or recurrent obstruction of air flow and includes chronic bronchitis and emphysema. Recurrent episodes of acute bronchitis or persistent, non-infective irritation of bronchial mucosa (e.g. as a result of cigarette smoking) may produce chronic bronchitis ( Fig. 12.9 ), which is frequently associated with persistent dilatation of air spaces and destruction of their walls, a condition known as emphysema ( Fig. 12.8 ). Asthma ( Fig. 12.10 ) is a disorder of the airways characterised by reversible bronchoconstriction, often provoked by allergens in susceptible individuals, but also triggered by physical agents or infection. There is also increased secretion of bronchial mucus, leading to plugging of the bronchial lumina.
The massive capillary bed of the lungs makes them vulnerable to a variety of haemodynamic and other vascular disorders. Left ventricular failure results in engorgement of pulmonary capillaries and fluid transudation into the alveolar spaces causing pulmonary congestion and oedema ( Fig. 12.11 ). Two other common vascular disorders of great clinical importance are pulmonary embolism and its sequel pulmonary infarction , illustrated in Figs 9.4 and 10.4 respectively.
B bullae G mucinous glands In chronic inflammatory cells M mucosal smooth muscle P purulent exudate
A wide range of pathogenic stimuli may cause interstitial lung inflammation, i.e. inflammation primarily involving the alveolar walls. This contrasts with the pneumonic or intra-alveolar inflammation seen in pneumonia.
Acute interstitial inflammation is often called pneumonitis . The clinical picture may be of catastrophic acute respiratory distress as seen in adult respiratory distress syndrome (ARDS) , which has a wide range of causes including viral and atypical pneumonias, shock, drugs and hypersensitivity reactions. Respiratory distress syndrome of premature infants (IRDS) is a similar phenomenon and both the adult and infant forms are characterised by the formation of hyaline membranes which line the alveolar walls ( Fig. 12.12 ).
At the chronic end of the spectrum, interstitial lung disease usually presents as insidious onset of breathlessness secondary to pulmonary fibrosis ( Fig. 12.13 ). The development of pulmonary fibrosis again may be due to a wide range of agents and may be preceded by an acute phase. The common causative factors are inorganic dusts such as silica, coal dust and asbestos, organic dusts such as mouldy hay in ‘farmer’s lung’ and disorders of unknown cause such as sarcoidosis and idiopathic pulmonary fibrosis (see Fig. 4.5 ).
The disorders caused by inhalation of inorganic dusts are known as pneumoconioses and follow inhalation of mineral dusts (e.g. silica and asbestos), usually over a long period of industrial exposure, leading to fibrotic reactions in the lung. Inhalation of organic dusts (e.g. fungal spores and plant dusts) usually cause pulmonary fibrosis by the development of chronic allergic responses termed hypersensitivity pneumonitis .
The end result of these diseases is the development of interstitial fibrosis in the lungs. Pulmonary fibrosis of this type results in thickening of the barrier between blood and air causing reduced gas transfer. As the disease progresses, these may cause pulmonary hypertension and respiratory failure may develop. In most of these diseases, there are few clues to the causative agent when the fibrosis is well developed. Exceptions to this rule include silicosis ( Fig. 12.14 ), which has a distinctive pattern of fibrosis, asbestosis ( Fig. 12.15 ) where the presence of plentiful asbestos bodies is diagnostic and sarcoidosis where characteristic granulomas may be seen (see Fig. 4.8 ).
A alveolar wall G mucinous glands H hyaline membranes In inflammatory infiltrate M smooth muscle Mu mucus
A asbestos body F fibrous tissue G giant cell H hyaline centre
Genuinely benign lung tumours are rare. Most bronchial adenomas are in fact carcinoid tumours arising from lung neuroendocrine cells ( Fig. 12.22 ). These may be locally invasive and occasionally metastasise. Their histological appearance is similar to well differentiated neuroendocrine tumours in the gastrointestinal tract (see Fig. 13.13 ).
The great majority of primary malignant tumours of the lung are carcinomas that arise in the bronchi and are thus often called bronchogenic carcinomas . Carcinogens in cigarette smoke are the major aetiological agents. Other less important factors include exposure to radiation, asbestos (especially when combined with smoking), as well as other minerals such as nickel and chromium. Air pollution and genetic predisposition are other possible factors. Occasionally, tumours may arise in a pre-existing lung scar.
Bronchogenic carcinomas are of various histological types, but in broad terms they are divided into two main groups: small cell carcinoma ( Fig. 12.17 ) and non–small cell carcinomas . The current World Health Organization (WHO) Classification of lung tumours further divides non–small cell lung carcinomas into histological sub-groups, including squamous cell carcinoma ( Fig. 12.18 ), non-mucinous adenocarcinoma ( Figs 12.19 and 12.20 ), mucinous adenocarcinoma and large cell carcinoma ( Figs 12.21 and Table 12.1 ). There are further subcategories of tumours, the commonest of which are listed in Fig. 12.16 . The term non-small cell carcinoma, not otherwise specified (NOS), can be used in small biopsies where there are no morphological or immunohistochemical features of a specific tumour subtype. Neuroendocrine tumours of the lung are also discussed in Fig. 12.22 . It should also be noted that mixtures of these tumour types can occur, most often in the form of adenosquamous carcinoma. Metastatic tumours, usually blood-borne from distant organs, are also very common in the lungs (see Figs 7.16 and 12.23).
The pleura is the site of an uncommon but fatal tumour known as malignant mesothelioma ( Fig. 12.25 ). Mesothelioma occurs almost exclusively in those exposed to asbestos.
The diagnosis of lung carcinoma is usually first suspected due to symptoms such as weight loss, breathlessness and haemoptysis , often in patients who are cigarette smokers. Initial investigation typically involves obtaining a chest radiograph, followed by more detailed imaging using other modalities such as computed tomography scanning. If a lung mass is identified, formal diagnosis is usually made on the basis of small amounts of material obtained by minimally invasive techniques such as bronchoscopic biopsy or radiologically guided needle biopsy for peripherally situated lung masses. This is because management of lung carcinoma is highly dependent upon initial classification of histological type. During bronchoscopy, samples for cytological examination are often obtained, as well as small biopsies, because bronchial washings and brush cytology samples can allow retrieval of cells from sites that are not visible or accessible for biopsy. This means that both cytological and histological techniques have complementary roles in the pathological diagnosis of lung cancer. Cytological preparations are illustrated here alongside the biopsy findings for comparison.
B bronchus E bronchial epithelial cells K keratinisation In infiltration M moulding of nuclei T tumour cells
The majority of lung cancers are diagnosed using a combination of biopsy and cytology as described above. Acquiring biopsy tissue is therefore important to subtype the tumour accurately and to provide material for molecular testing (see clinical box ‘Molecular aspects of lung cancer’). Non–small cell carcinomas are broadly subdivided into squamous cell carcinoma or adenocarcinoma on the basis of the histological features described earlier. Some of these tumours are very poorly differentiated and do not show the diagnostic light microscopy features but, at a cellular level, will express proteins associated with these histological types.
|Squamous cell carcinoma||–||–||+||+|
|Squamous cell carcinoma||–||–||+||–|
|Non–small cell carcinoma (not otherwise specified)||–||–||–||–|
|Nose, nasopharynx and larynx|
|Nasal polyps||Oedematous, polypoid respiratory mucosa with vascular congestion, numerous eosinophils and plasma cells.||12.1|
|Sinonasal (Schneiderian) papilloma||Three main types (inverted, exophytic, oncocytic). Small risk of malignant transformation.||12.2|
|Nasopharyngeal carcinoma||Various types including keratinising squamous, non-keratinising squamous and undifferentiated carcinoma. EBV association.||12.3|
|Vocal cord polyp||Small, smooth nodule(s) on the vocal cords. Oedematous submucosa covered with stratified squamous epithelium.||12.4|
|Laryngeal carcinoma||Mostly squamous and well differentiated, strongly associated with smoking and alcohol consumption.||12.5|
|Inflammatory lung disease|
|Acute purulent bronchitis||Purulent exudate within lumina of bronchi and bronchioles, some surrounding oedema in parenchyma.||12.6|
|Bronchopneumonia||Extension of purulent material into alveolar spaces around bronchi, may become confluent (compare with lobar pneumonia, Fig. 3.3 ).||12.7|
|Emphysema||Abnormal permanent dilatation of airspaces with reduced alveolar area for gas exchange, peripheral bullae may form.||12.8|
|Chronic bronchitis||Clinical definition, histological changes include thickened bronchial wall due to inflammation, smooth muscle and bronchial gland hyperplasia.||12.9|
|Asthma||Paroxysmal bronchoconstriction, no acute changes but when chronic, smooth muscle hyperplasia, hypersensitivity pneumonitis||12.10|
|Pulmonary oedema||Alveolar spaces filled with fluid transudate due to altered Starling forces. May be foci of alveolar haemorrhage with haemosiderin in macrophages.||12.11|
|Interstitial lung disease|
|Hyaline membrane disease||Result of diffuse alveolar damage (DAD). Fibrin within alveolar exudate forms hyaline membranes. May be fatal, resolve or progress to fibrosis.||12.12|
|Pulmonary fibrosis||Deposition of collagen within alveolar walls, reducing gas exchange. Many causes, end stage of DAD and hypersensitivity pneumonitis.||12.13|
|Silicosis||Inorganic dust deposition resulting in collagenous scars with hyaline centre and surrounding fibrosis. Silica visible on polarisation.||12.14|
|Asbestosis||Complex silicate causing fibrosis in lower lobes, often subpleural. Asbestos bodies formed due to protein and iron encrustation.||12.15|
|Tumours of lung and pleura|
|Small cell carcinoma||Highly malignant but chemosensitive. Small cells with little cytoplasm showing nuclear moulding.||12.17|
|Squamous cell carcinoma||Central tumours arising from squamous metaplasia and dysplasia. Endobronchial growth may cause obstruction.||12.18|
|Adenocarcinoma||More often peripheral, some associated with scars. Glandular formations, often with mucin formation.||12.19, 12.20|
|Large cell carcinoma (or non-small cell carcinoma NOS)||No evidence of clear line of differentiation following light microscopy and immunohistochemistry.||12.21|
|Neuroendocrine tumours of lung||Carcinoid tumour, atypical carcinoid and large cell neuroendocrine tumour with evidence of neuroendocrine differentiation.||12.22|
|Lung metastases||Usually multiple and bilateral. Solitary lung lesions should be distinguished from a metastasis.||12.23|
|Malignant mesothelioma||Important association with asbestos. Epithelioid and spindle cell components. Spreads along pleural surfaces.||12.25|
A panel of immunohistochemical markers (see Ch. 1 ) can be used to detect these proteins and favour a histological type. This has led to an increase in patients being able to access targeted therapies for specific tumour types. The table above summarises a typical panel of markers used for diagnosis: + denotes a positive marker and – denotes a negative marker. TTF1 and Napsin are expressed in adenocarcinomas, whereas these markers are usually negative in squamous cell carcinoma, which expresses p40 and CK5/6.
A adenocarcinoma cells C undifferentiated malignant cells E bronchial epithelial cells G glandular formations NP neutrophil polymorphs V cytoplasmic vacuole
C bronchial cartilage G separate green and orange signals GL Malignant glands K karyorrhectic debris L lung parenchyma P peripheral palisading N normal fused yellow signal Ne necrosis O neuroendocrine tumour nests P peripheral palisading T tumour cell nuclei
Recently, molecular tests have been introduced into the routine pathological assessment of lung cancer specimens. Particular histological subtypes harbour molecular signatures, which, if detected, allow specific targeted therapies to be used. Three of these tests are outlined briefly although the repertoire of molecular tests available is likely to increase over the next few years, particularly with the introduction of next generation sequencing (see Ch. 1 ).
∗ EGFR mutation : Epidermal growth factor receptor (EGFR) mutations are the commonest driver mutations in lung adenocarcinoma and are associated with a poor prognosis. The mutation is typically found in tumours in young women, Asian ethnicity, light or never smokers and those with lepidic or micropapillary growth patterns. The EGFR gene codes for a cell surface protein tyrosine kinase receptor, which binds to EGF and activates downstream pathways (RAS/ PI3K) involved in cell replication and cell death. Mutation of the gene causes dysregulation of these pathways and is a key event in the development of lung cancer. Patients with certain EGFR mutations show an improved survival with specific tyrosine kinase inhibitors that block EGFR activity. EGFR mutations are most commonly detected by a PCR-based test for mutations in exons 18 to 21.
∗ ALK rearrangements : Anaplastic lymphoma kinase (ALK) gene rearrangements are most commonly associated with adenocarcinomas and are almost mutually exclusive with EGFR and KRAS mutations. Similar to EGFR mutations, ALK rearrangements are more common in younger patients who are light or never smokers. The most frequent abnormality is EML4-ALK fusion as a result of an inversion on the short arm of chromosome 2. ALK fusions are most commonly detected via fluorescence in situ hybridisation (FISH; see Fig. 12.24 ). Patients with ALK rearrangements show improved outcome with ALK inhibitors.
∗ PD-1/PD-L1 : Programmed death-1 is an immune checkpoint protein on the surface of cytotoxic T cells. Non-small cell lung cancers express PD-Ligand 1 and can bind with T lymphocytes to impair function and therefore suppress the immune response to the tumour. Immune checkpoint inhibitor drugs (usually monoclonal antibodies) bind to PD-1 or PD-L1 and allow the immune system to recognise and destroy the tumour cells, although the immune system is highly complex and there are often other pathways and signals at play. Immunohistochemistry for PD-L1 expression is now routinely used to assess possible tumour response to specific immunomodulatory drugs. PD-L1 testing is also likely to be used in other tumour types such as melanoma, genitourinary cancers and gastrointestinal cancers.
An accumulation of fluid within the pleural cavity is termed pleural effusion . Similar collections of fluid can also occur within the other serous cavities, described as ascites within the peritoneal cavity or as pericardial effusion when within the pericardium.
Such collections of fluid are divided into two broad groups on the basis of their protein content. Transudates have low protein content and their formation reflects altered hydrostatic or colloid osmotic pressures (Starling forces) . Common causes include congestive cardiac failure and hypoalbuminaemia. In contrast, exudates have high protein content and, in broad terms, are a result of damage to the integrity of the microvasculature, allowing leakage of plasma proteins across capillary walls. The causes of exudates are diverse but include infection, infarction, inflammation and malignancy.
Cytological examination of fluid from effusions is frequently used in clinical practice, often as a means of guiding further investigation. Malignant cells can be identified in such samples and the type of tumour can often be determined by a combination of morphological examination and use of immunostaining. Distinguishing carcinoma cells from reactive mesothelial cells and from malignant mesothelioma can be extremely challenging.
P papillary architecture PS pleural surface T tubular architecture
A 32-year-old man presents with weight loss, oral thrush and worsening cough with shortness of breath. A chest X-ray examination demonstrates bilateral pulmonary infiltrates. His condition deteriorates and he is admitted to critical care. A bronchoscopy and biopsy of the infiltrates is performed and is illustrated above. What is the underlying diagnosis? Select ONE answer.
Staphylococcus aureus pneumonia
Pneumocystis jirovecii pneumonia
Locally advanced bronchial adenocarcinoma
A 62-year-old woman with a history of alcohol excess is admitted with acute severe pancreatitis. She deteriorates during admission and requires increasing oxygen therapy to maintain her oxygen saturation. Despite supportive measures she dies the following day. Post mortem examination reveals that the lungs are heavy and oedematous and a histological section is illustrated above. What is the histological feature marked (A) ? Select ONE answer.
A) Oedema fluid
A 74-year-old man presents with haemoptysis and a cough over the last month. A chest X-ray examination demonstrates a suspicious hilar mass. Bronchoscopy and lung aspirate is performed and the cytology is illustrated above. What is the diagnosis?