Respiratory histopathology Flashcards
Normal Lung
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)
pulmonary oedema definition
CXR
Associated with
Very common cause of what condition
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
Causes of pulmonary oedema
Left heart failure (commonest cause)
Alveolar injury or capillary injury (drug, inhalation, pancreatitis)
Neurogenic (following head injury)
High altitude
Pulmonary oedema pathology
Heavy, congested watery lungs
Intra-alveolar fluid on histology (often slightly fibrinous)
Acute Lung Injury Pattern/Diffuse Alveolar Damage
Important cause of what condition
adults and neonates
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
Acute Lung Injury Pattern/Diffuse Alveolar Damage pathology
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
Acute Lung Injury Pattern/Diffuse Alveolar Damage pathophysiology
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
prognosis of diffuse alveolar damage
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
asthma definition
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
Asthma: acute and chronic changes
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.
mucus plug
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.
histological features of asthma
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
COPD definition
- 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).
Chronic bronchitis definition, pathology and complications
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.
Emphysema definition
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.
emphysema pathophysiology
- 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
Bronchiectasis definition
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.
Causes of bronchiectasis
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
bronchiectasis complications
Recurrent infections
Haemoptysis (due to erosion into vessels by inflammation)
Pulmonary hypertension and right sided heart failure
Amyloidosis
Cystic Fibrosis definition
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
lung involvement in Cystic Fibrosis
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
Pulmonary infections
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
bacterial pneumonia (3 types)
- 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:
Bronchopneumonia
location
causative organisms
pathologically
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
lobar pneumonia
location
causative organism
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
lobar pneumonia histopathology
Congestion (hyperaemia and intra-alveolar fluid)
Red hepatisation (hyperaemia, intra-alveolar neutrophils)
Grey hepatisation (intra-alveolar connective tissue)
Resolution (restoration of normal tissue architecture)
Complications of infection in lung
Abscess formation
Pleuritis and pleural effusion
- Infected pleural effusion (empyema)
Fibrous scarring (resulting in respiratory impairment)
Septicaemia
Granulomatous infection
what is a granuloma
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)
Atypical pneumonia causative organisms
what do we see in CMV histologically
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).
Pulmonary Thromboembolism definition
where do most come from
risk factors
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
Effect depends on the SIZE of the thrombus
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
non-thrombotic emboli examples
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
Sites of lung tumours
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
benign tumours
Do NOT metastasise
Can cause local complications (e.g. airway obstruction)
Example: chondroma
malignant tumours: 2 types
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
epidemiology of lung cancer
NOTE: incidence of lung cancer in men is dropping and in women is rising (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
lung cancer aetiology
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 cancer.
Other risk factors for lung cancer
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
development of carcinoma
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)
Squamous cell carcinoma
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
Invasive squamous cell carcinoma
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)
Adenocarcinoma
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)
molecular pathways in the development of adenocarcinoma
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
large cell carcinoma
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)
small cell carcinoma
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
small cell and non-small cell lung cancer prognosis and treatment
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
Adenocarcinoma vs squamous cell carcinoma
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).
role of the pathologist: how is the diagnosis made
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
stains that can subtype lung cancer tumours
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
treatment of lung cancer
Curative: Surgery +/- radical radiotherapy +/- immunemodulatory therapy
Palliative: Chemoradiotherapy, immunemodulatory, targeted therapy
mesothelioma
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)
