Respiratory histopathology

Question 1

Normal Lung

Answer 1

lined by ciliated respiratory epithelium

Ciliated epithelium waft pathogen-containing mucous up the ‘mucociliary escalator’

The mucous is coughed up and swallowed (protective function)

The small airways are important for respiration

Alveoli are characterised by very fine capillaries lined by type 1 pneumocytes (short diffusion distance)

Question 2

pulmonary oedema definition

CXR

Associated with

Very common cause of what condition

Answer 2

Defined by the accumulation of fluid in the alveolar spaces either due to “leaky capillaries” or “backpressure” from a failing left ventricle. This leads to poor gas exchange, hypoxia and respiratory failure.

Radiologically, pulmonary oedema presents with very fluffy opacities.

Associated with HF (acute/chronic)

VERY COMMOM cause of acute and chronic respiratory failure in A+E and community

Common finding at post-mortem

Question 3

Causes of pulmonary oedema

Answer 3

Left heart failure (commonest cause)

Alveolar injury or capillary injury (drug, inhalation, pancreatitis)

Neurogenic (following head injury)

High altitude

Question 4

Pulmonary oedema pathology

Answer 4

Heavy, congested watery lungs

Intra-alveolar fluid on histology (often slightly fibrinous)

Question 5

Acute Lung Injury Pattern/Diffuse Alveolar Damage

Important cause of what condition

adults and neonates

Answer 5

Important cause of RAPID onset respiratory failure

Adults: Acute Respiratory Distress Syndrome (ARDS)

• ‘Shock lung’
• Numerous causes in adults:
  
  • Infection (local or generalised sepsis)
  • Aspiration
  • Trauma
  • Inhaled irritant gases
  • Shock
  • Blood transfusion
  • DIC
  • Drug overdose
  • Pancreatitis
  • Idiopathic

Neonates: Hyaline Membrane Disease of the Newborn (Respiratory Distress Syndrome)

• Insufficient surfactant production (surfactant needed for lung expansion at birth)
• Seen in premature babies (these babies aren’t yet producing surfactant)

White out in all lung fields CXR

Question 6

Acute Lung Injury Pattern/Diffuse Alveolar Damage pathology

Answer 6

This is acute respiratory failure NOT due to pulmonary oedema

It is caused by acute damage to the endothelium and/or alveolar epithelium (frequently both)

Basic pathology is the same in all cases: diffuse alveolar damage

The lungs are expanded and firm

On post-mortem examination, the lungs are plum-coloured, heavy (> 1 kg) and airless

Question 7

Acute Lung Injury Pattern/Diffuse Alveolar Damage pathophysiology

Answer 7

Initially, the capillaries are markedly dilated and congested

Following capillary and epithelial damage, there is fluid leakage into the air spaces (exudative phase)

Proteinaceous deposits line the alveolar walls

They will then develop hyaline membranes (serum proteins and dead cells that have leaked out and end up lining the alveolar spaces, making gas exchange very difficult

Eventually, you get organisation of the exudates to form granulation tissue sitting within the alveolar spaces (organising pneumonia) as the body attempts to repair the damage

Question 8

prognosis of diffuse alveolar damage

Answer 8

Death (in around 40%)

• Superimposed infection due to fluid accumulation (e.g. pneumonias)

Resolution (in some): lung function returns to normal

Residual fibrosis: leads to chronic respiratory impairment

Question 9

asthma definition

Answer 9

Chronic inflammatory airway disorder with recurrent episodes of widespread narrowing of the airways that changes in severity over short periods of time.

Prevalence increased in recent decades (10% = children, 5% = adults)

Presents with wheezing, chest tightness, shortness of breath, night-time cough

In a SEVERE attack, patients develop status asthmaticus

• extreme form of asthma exacerbation characterized by hypoxemia, hypercarbia, and secondary respiratory failure

It can be an atopic condition (genetic tendency to develop allergic reaction to common environmental antigens (e.g. house dust mite))

Non-atopic triggers:

• Air pollution
• Drugs (NSAIDs)
• Occupational (inhaled gases/fumes)
• Diet
• Genetic factors
• Physical exertion (“cold”)
• Intrinsic

Question 10

Asthma: acute and chronic changes

Answer 10

Acute Changes

• Bronchospasm
• Oedema (of the mucosa)
• Hyperaemia
• Inflammation

The trigger for acute changes is the binding of an antigen to the surface of the bronchi epithelium, and a dendritic cell (which presents it in turn to a T cell)  release of cytokines, recruitment of inflammatory cells etc. inflammatory mediators damage the airway epithelium and cause excess mucous production and muscular contraction.

Chronic change

• Muscular hypertrophy
• Airway narrowing
• Mucus plugging

NOTE: once you’ve plugged a large airway, the distal lung will collapse.

Question 11

mucus plug

Answer 11

This is a mucus plug coughed up by someone who had had a severe asthma attack.

When we look at the lungs of patients who have died from an acute asthma attack, they are pale and over-inflated.

Question 12

histological features of asthma

Answer 12

Very dilated and congested blood vessels (as is seen in any inflammatory reaction)

There are a lot of eosinophils and mast cells infiltrating the surface epithelium

You will also see goblet cell hyperplasia

Mucus plugs can be seen within the airway

The bronchial smooth muscle becomes thick and the blood vessels become dilated

Question 13

COPD definition

Answer 13

• Very common cause of chronic respiratory failure
• May present with acute exacerbations
• 80% are smokers
• Smoking causes inflammation leading to secondary damage to the airways and interstitium
• There is a mix of airway and alveolar pathology (chronic bronchitis and emphysema), resulting in progressive airway obstruction

We see a mixture of airway damage (bronchitis) and interstitial damage (damage to the terminal parts of the lungs i.e. emphysema).

Question 14

Chronic bronchitis definition, pathology and complications

Answer 14

Defined as a chronic cough productive of sputum, most days for at least 3 months over 2 consecutive years.

Chronic injury to the airways elicits reactive changes which predispose to further damage

Pathology

• Dilated airways
• Mucus gland hyperplasia
• Goblet cell hyperplasia
• Mild inflammation

Complications

• Recurrent infections (most common cause of admission and death)
• Chronic respiratory failure (with hypoxia and reduced exercise tolerance)
• Chronic hypoxia results in pulmonary hypertension and right heart failure (cor pulmonale)
• Increased risk of lung cancer (independent of smoking)

Patients may have acute infectious exacerbations with large amounts of pus sitting in the airways as a result of chronic bronchitis.

Question 15

Emphysema definition

Answer 15

Defined as a permanent loss of the alveolar parenchyma distal to the terminal bronchiole.

• This disease results in much more peripheral changes in the alveolar structure
• Damage to alveolar epithelium is secondary to inflammation
  
  • Smoking (most common cause)
  • Alpha-1 antitrypsin deficiency (anti-protease)
  • RARE: cadmium exposure, IVDU, connective tissue disorder

Neutrophils and macrophages that are activated by smoking, will release proteases which degrade tissues.

Question 16

emphysema pathophysiology

Answer 16

• Normal lung looks like a tightly packed sponge
• Emphysema lungs have a loss of the alveolar structure
• Destroyed alveoli results in large air spaces

Smoking causes inflammation within the lung (including neutrophil and macrophage activation)

• Smoking tends to cause centrilobular damage to the alveolar tissue due to protease activation

Most of the damage takes place in the airways that feed into the lung lobules

• Patients with alpha-1 antitrypsin deficiency have damage throughout the lung (panacinar)

Complications

• Bullae (large air spaces) – can rupture and cause pneumothorax
• Respiratory failure
• Pulmonary hypertension and right heart failure

Question 17

Bronchiectasis definition

Answer 17

Defined as a permanent abnormal dilation of the bronchi with inflammation and fibrosis extending into adjacent parenchyma.Bronchiectasis tends to affect the larger airways of the lung.

• Varies in site depending on cause (idiopathic often involves lower lobe)
• Lungs experience repeated infections -> inflammation and scarring
• Leads to inflamed and scarred lungs with dilated airways

We see that the airway is dilated (much larger than the size of the accompanying artery, which is normally around the same size). We see a lot of scarring and inflammation around the airways.

Question 18

Causes of bronchiectasis

Answer 18

Infection (most common cause)

• Post-infectious (especially in children or cystic fibrosis)
• Abnormal host defence (primary (hypogammaglobulinemia) or secondary (chemotherapy)
• Ciliary dyskinesia (primary (Kartagener’s syndrome) or secondary) situs inversus, chronic sinusitis, and bronchiectasis

Obstruction

Post-inflammatory (aspiration)

Secondary to bronchiolar disease and interstitial disease (e.g. sarcoidosis)

Systemic disease (connective tissue disorders)

Asthma

Congenital

Question 19

bronchiectasis complications

Answer 19

Recurrent infections

Haemoptysis (due to erosion into vessels by inflammation)

Pulmonary hypertension and right sided heart failure

Amyloidosis

Question 20

Cystic Fibrosis definition

Answer 20

An autosomal recessive (approximately 1/20 are carriers) inherited disease (commonest cause of bronchiectasis in the UK). Affects 1 in 2,500 live births.

• Chromosome 7q3 = CFTR gene (codes for a chloride ion transporter protein)
• There are over 1400 mutations, but the delta F508 mutation is the most common
• Abnormality leads to defective ion transport across cell membranes due to excessive resorption of water from secretions of exocrine glands

It is a generalised disorder of the exocrine glands resulting in abnormally thick mucus secretion in all organs.

• GI: meconium ileus, malabsorption
• Pancreas: pancreatitis, malabsorption
• Liver: cirrhosis
• Male reproductive system: infertility

Question 21

lung involvement in Cystic Fibrosis

Answer 21

Over 90% of patients have lung involvement

Recurrent infections (S. pneumoniae, H. influenzae, P. aeruginosa and B. cepacia)

Manifestations:

• Haemoptysis, pneumothorax, chronic respiratory failure, cor pulmonale, ABPA, atelectasis
• Bronchiectasis

Improved treatment means that most will survive 35-40 years

Improved treatment: physiotherapy, antibiotics, enzyme supplements, parenteral nutrition

Lung transplantation offers even longer survival

Question 22

Pulmonary infections

Answer 22

Common (community or hospital acquired)

Wide spectrum of infective agents

• Bacterial (including mycobacteria)
• Viral
• Mycoplasma
• Fungal & parasitic – think if history of foreign travel
• Opportunistic (CMV, pneumocystis, fungal) – think if history of immunosuppression

Symptoms: shortness of breath, cough, fever, purulent sputum

Question 23

bacterial pneumonia (3 types)

Answer 23

• Community-Acquired: Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma
• Hospital-Acquired: Gram-negatives (Klebsiella, Pseudomonas)
• Aspiration: Mixed aerobic and anaerobic

There are a variety of PATTERNS of lung involvement depending on the organism and other co-factors:

Question 24

Bronchopneumonia

location

causative organisms

pathologically

Answer 24

The infection and inflammation are centred around the airway

• Infection is centred around the airways (often leads to fatality)
• Compromised host defence (elderly)
• Often LOW virulence organisms (Staphylococcus, Haemophilus, Streptococcus, Pneumococcus)
• Patchy bronchial and peribronchial distribution often involving the lower lobes
• There is acute inflammation surrounding airways and within alveoli
• A lot of the lung looks relatively normal; but we see foci of infection
• Histopathologically: peribronchial distribution, acute inflammation surrounding airways within alveoli

Question 25

lobar pneumonia location causative organism

Answer 25

The whole lobe of the lung contains infective exudate. We do not see this as much anymore. * The infection is **focused in a lobe of the lung** * _Infrequent because of antibiotics_ * 90-95% are **S. pneumoniae** (often seen in association with quite a virulent organism) * **_Widespread fibrinosuppurative consolidation_** * There is a very pronounced pneumatic process when looking at the lung * Demarcation of the lobe; we see a complete infective **‘white-out’ of the affected** * With antibiotic treatment, the pneumonia very rarely progresses to this stage

Question 26

lobar pneumonia histopathology

Answer 26

Congestion (hyperaemia and intra-alveolar fluid) Red hepatisation (hyperaemia, intra-alveolar neutrophils) Grey hepatisation (intra-alveolar connective tissue) Resolution (restoration of normal tissue architecture)

Question 27

Complications of infection in lung

Answer 27

Abscess formation Pleuritis and pleural effusion * Infected pleural effusion (empyema) Fibrous scarring (resulting in respiratory impairment) Septicaemia

Question 28

Granulomatous infection what is a granuloma

Answer 28

A granuloma is a collection of **macrophages and multi-nucleate giant cells.** * It can be necrotising or non-necrotising * Must think of _TUBERCULOSIS_ * Other causes: fungi and parasites (travel history is important)

Question 29

Atypical pneumonia causative organisms what do we see in CMV histologically

Answer 29

**Mycoplasma, viruses (e.g. CMV, influenza), Coxiella and Chlamydia** Interstitial inflammation (pneumonitis) without accumulation of intra-alveolar inflammatory cells Chronic inflammatory cells within alveolar septa with oedema with or without viral inclusions NOTE: In CMV infections, we see **Owl’s eye inclusions** (big, eosinophilic viral inclusion).

Question 30

Pulmonary Thromboembolism definition where do most come from risk factors

Answer 30

The **occlusion of a pulmonary artery** (either a large artery or small, distal branch) by **thromboembolus.** Most come from DVTs – deep leg veins are a common site for clot formation (95%) **DVTs**: present with leg swelling and symptoms of spread to lungs (PE) The clot from the DVT can detach and embolise into the lung _Virchow's Triad:_ stasis, hypercoagulability, vessel wall damage (think of risk factors) Risk factors: * Advanced age * Female sex * Obesity * Immobility * Cardiac failure * Malignancy * Trauma * Surgery * Childbirth * Haemoconcentration * Polycythaemia * DIC * Contraceptive pill * Cannulation * Anti-phospholipid syndrome

Question 31

Effect depends on the SIZE of the thrombus

Answer 31

Small peripheral pulmonary arterial occlusion -\> _wedge-shaped haemorrhagic infarct_ NOTE: haemorrhagic infarct (lung has a dual blood supply – pulmonary and bronchial arteries) _Small emboli_ may present with **pleuritic chest pain** or chronic **progressive shortness of breath** * This is due to **pulmonary hypertension** * Repeated emboli cause increasing occlusion of the pulmonary vascular bed and pulmonary HTN _Large emboli_ may occlude the _main pulmonary trunk (saddle embolus)_ * This may present with **sudden death, acute right heart failure or cardiogenic shock** * In survivors, the embolus usually resolves, but 30% will develop a second embolus

Question 32

non-thrombotic emboli examples

Answer 32

Bone marrow (e.g. following fracture of a long bone) Amniotic fluid (during pregnancy or childbirth) Trophoblast Tumour Foreign body (seen in intravenous drug users) Air Fat

Question 33

Sites of lung tumours

Answer 33

Airways (mainly squamous cell carcinoma) Peripheral alveolar spaces (mainly adenocarcinoma) Small cell carcinoma can arise either centrally or peripherally Mesothelioma is a tumour of the pleura

Question 34

benign tumours

Answer 34

Do NOT metastasise Can cause local complications (e.g. airway obstruction) Example: chondroma

Question 35

malignant tumours: 2 types

Answer 35

Potential to metastasise – but variable clinical behaviour from indolent to aggressive Most common are _epithelial_ tumours (90-95%) Non-Small Cell Carcinoma * **Squamous cell carcinoma (30%**) – often seen in the large airways (central) * **Adenocarcinoma (30%)** – often seen in the periphery of the lung * **Large cell carcinoma (20%)** Small Cell Carcinoma (20%) * These are **particularly aggressive** – cause death within 6 – 18 months

Question 36

epidemiology of lung cancer

Answer 36

NOTE: incidence of lung cancer in **men is dropping and in women is risin**g (because women took longer to quit smoking). 1 in 7 new cancer cases per year (almost 40,000 cases of lung cancer in 2007) The male to female ratio is **4:3** (but increasing numbers of women) _Men: second commonest cancer after prostate cancer_ _Women: third commonest after breast and bowel cancer_ Global cancer

Question 37

lung cancer aetiology

Answer 37

25% of lung cancer in non-smokers is attributed to **passive smoking** Smoke contains * Tumour initiators (polycyclic aromatic hydrocarbons) * Tumour promoters (nicotine, nitrosamines, phenols) * Complete carcinogens (nickel, arsenic) Strongest association with **squamous cell carcinoma and small cell carcinoma** NOTE: _adenocarcinoma is more common in non-smokers_ **NOTE: Smoking cessation at any age does reduce the risk of lung cance**r.

Question 38

Other risk factors for lung cancer

Answer 38

25% of lung cancers are in non-smokers * Asbestos exposure (asbestos + smoking  50-fold increase risk) * Radiation (radon exposure, therapeutic radiation, uranium miners) * High levels of ambient radon gas within the South West of England and in Wales * Air pollution * Heavy metals (chromates, arsenic, nickel) * Genetics (familial lung cancers are rare) * Epidemiological evidence of increased risk for first degree relatives * Young age, non-smoking cases -\> think familial * Susceptibility genes * Chemical modification of carcinogens (polymorphisms in genes for cytochrome P450/CYP1A1 and glutathione S transferases, which play a role in eliminating carcinogens) * Susceptibility to chromosomal damage * Nicotine addiction susceptibility

Question 39

development of carcinoma

Answer 39

Multistep pathway includes: * Metaplasia -\> Dysplasia -\> Carcinoma in situ -\> Invasive carcinoma Associated with an accumulation of gene mutations leading to: * Disordered, unregulated growth * Tissue invasion * Angiogenesis There are different pathways for different tumour types For some lung tumours, a precursor lesion is not identifiable (e.g. small cell carcinoma)

Question 40

Squamous cell carcinoma

Answer 40

Normal airways are lined by ciliated respiratory epithelium Irritation of the epithelium (e.g. by smoking) causes a hyperplastic, regenerative response The body responds by a process of **metaplasia (squamous epithelium)** Squamous epithelium is much more resilient (tougher), but it **does NOT have cilia** This leads to a build-up of mucus) Within this mucus, you will get loads of carcinogens -\> accumulation of more mutations (dysplasia) A carcinoma in situ becomes an invasive carcinoma when it produces enzymes that enable invasion Invasive squamous carcinoma is responsible for about 35% of lung cancers **Closely associated with smoking** Traditionally **centrally** located arising from **bronchial epithelium** **Increasing incidence of peripheral** squamous cell carcinomas (possibly because modern cigarette smoke can be inhaled more deeply) **Spreads locally and metastasises late**

Question 41

Invasive squamous cell carcinoma

Answer 41

Frequency: 35% pulmonary carcinoma Risk factors: closely associated with **smoking** Behaviour: local spread, metastasise late Site: * Traditionally centrally located arising from bronchial epithelium * Increasing number of peripheral squamous cell carcinomas Histologically, we see evidence of **squamous differentiation and keratinisation** **Cytologically, we can identify SCCs from sputum samples (atypical squamous cells)**

Question 42

Adenocarcinoma

Answer 42

Tend to arise in the **periphery** of the lung (often around the **terminal airways**) **Precursor lesion: atypical adenomatous hyperplasia** (earliest phase of adenocarcinoma) * Proliferation of atypical cells lining the alveolar walls * Increases in size and eventually can become invasive Next to the terminal bronchioles, we may see well-defined proliferations of atypical cells They grow along the surface of the alveolar structure This is proliferation of atypical cells lining the alveolar walls This will increase in size and develops into a non-mucinous BAC (adenocarcinoma in situ – still not invasive) and then eventually into a mixed pattern adenocarcinoma (happens when a clone of cells develops the ability to break down the tissue and infiltrate the underlying interstitium The key event here is the **invasive phenotype (if you catch the cancer in the in-situ stage or before, you will cure the patient)**

Question 43

molecular pathways in the development of adenocarcinoma

Answer 43

Commonest type of cancer arising in **non-smokers** Tends to **occur peripherally** Often **multi-centric** (lots of little tumours at different stages of development) Behaviour: **Extra-thoracic metastases are common and occur early** (80% present with metastases) Histology: shows evidence of **glandular differentiation** Cytology: pleural fluid aspirate contains malignant cells, which have cytoplasmic **mucin vacuoles**

Question 44

large cell carcinoma

Answer 44

**Poorly differentiated tumours** composed of large cells **Peripheral or central** 10% of tumours There is no histological evidence of glandular or squamous differentiation Poor prognosis NOTE: on electron microscopy, there may be some evidence of glandular, squamous or neuroendocrine differentiation (probably very poorly differentiated adeno/squamous cell carcinomas)

Question 45

small cell carcinoma

Answer 45

Frequency: 20% of lung tumours Risk factors: Very close association with **SMOKING** Site: Often **CENTRAL** and near the bronchi Behaviour: * 80% will present with advanced disease * Although very chemosensitive, these have an abysmal prognosis * Very chemosensitive but **VERY POOR PROGNOSIS** * Most have metastases that have spread to bones/liver/brain at presentation * May cause paraneoplastic syndromes Histology: small, poorly differentiated cells Common mutations: p53 and RB1 Cytology: we see small, hyperchromatic malignant cells

Question 46

small cell and non-small cell lung cancer prognosis and treatment

Answer 46

Small Cell Lung Cancer * Survival 2-4 months if untreated * Survival 10-20 months on current treatment * Chemoradiotherapy is the mainstay (surgery is rarely performed because most cases would have spread by the time of diagnosis) Non-Small Cell Lung Cancer * Early stage 1 tumours have a 60% 5-year survival * Late stage 4 tumours have a 5% 5-year survival (many patients present in late stage) * 20-30% have early stage tumours suitable for surgical resection * **LESS chemosensitive**

Question 47

Adenocarcinoma vs squamous cell carcinoma

Answer 47

Molecular changes are important for adenocarcinoma; they can be targeted using specific therapies Main molecular changes (seen in adenocarcinoma, but not in SCCs: * EGFR mutation (responder or resistance) * ALK translocation * Ros1 translocation It is important to know the type of cancer because, for example, some patients with squamous cell carcinoma develop fatal haemorrhage with some new chemotherapeutic drugs (bevacizumab).

Question 48

role of the pathologist: how is the diagnosis made

Answer 48

Cytology: looking at cells * Sputum * Bronchial washings and brushings * Pleural fluid * Endoscopic fine needle aspiration of tumour/enlarged lymph nodes Histology: looking at tissues * Biopsy at bronchoscopy – central tumours * Percutaneous CT guided biopsy – peripheral tumours * Mediastinoscopy and lymph node biopsy – for staging * Open biopsy at time of surgery if lesion not accessible otherwise – frozen section * Resection specimen – confirm excision and staging

Question 49

stains that can subtype lung cancer tumours

Answer 49

**TTF-1 stain:** highlights a transcription factor that is expressed in alveolar epithelial cells (characteristic of an adenocarcinoma) **P40 stain:** identifies malignant squamous cell carcinoma cells Even with little amounts of tissue, we can sub-type the tumours and send them off for molecular analysis. You want to send adenocarcinomas off to look for mutation types (responder mutations, resistance mutations

Question 50

treatment of lung cancer

Answer 50

**Curative:** Surgery +/- radical radiotherapy +/- immunemodulatory therapy **Palliative:** Chemoradiotherapy, immunemodulatory, targeted therapy

Question 51

mesothelioma

Answer 51

Malignant tumour of the **pleura** (lining of the lung and chest wall) Frequency: \< 1% of cancer deaths but increasing incidence (peak predicted in around 2010-2020) Aetiology: Associated with **asbestos exposure** * There is a **_long lag_** (tumour may develop decades after exposure) * More common in **males** (3:1 ratio male to female) * **50-70 years** * Present with **shortness of breath and chest pain** Behaviour: Essentially **FATAL** (behaves very aggressively) Medicolegal implications because of compensation **POOR** prognosis Several histological types (two main types: epithelioid and sarcomatoid)