8. Lung Cancer Pathology Flashcards
What are the symptoms of lung cancer?
• Most patients are asymptomatic • Symptomatic - cough - haemoptysis - recurrent infections - chest wall pain
What can pathologists look at when determining lung cancer, in terms of cytology?
(study of individual cells) • sputum • bronchial washings and brushings • pleural fluid • endoscopic fine needle aspiration
What can pathologists look at when determining lung cancer, in terms of histology?
(study of tissues)
• Biopsy at bronchoscopy - central tymours
• Percutaneous CT guided biopsy - peripheral tumours
• Mediastinoscopy and lymph node biopsy - staging
• Open biopsy at time of surgery
• Resection specimen
What are the characteristics of a benign lung tumour?
- Don’t metastasise
* Local complications e.g. obstruction of airways
What are the characteristics of a malignant lung tumour?
- Potential to metastasise
- Invade adjacent tissues
- Most common: epithelial tumours (carcinomas)
What are the 3 types of Non-Small Cell Carcinoma
- Squamous Cell Carcinoma
- Adenocarcinoma (most common lung cancer among non-smokers)
- Large Cell Carcinoma
How is Small Cell Carcinoma different to Non-small Cell Carcinoma?
• Worst form of lung cancer
(• Worse prognosis than non-small cell)
• Unusual to find early stage - rapid and more aggressive
What are the trends in the incidence of Non-Small Cell Carcinoma?
- Incidence of Squamous Cell Carcinoma is decreasing (association with smoking)
- Incidence of adenocarcinoma is increasing (as incidence of smoking is decreasing, or less tar in cigarettes)
Where do squamous cell carcinomas and adenocarcinomas tend to arise?
- Squamous - near the mediastinum, in airways (there has been an increase in peripheral)
- Adenocarcinoma - periphery
What are the main causes of lung cancer?
• Smoking
- 75% of smokers and 25% of non smokers (passive smoking)
- Tumour initiators: polycyclic aromatic hydrocarbons
- Tumour promoters: N Nitrosamines, Nicotine, Phenols
- Complete carcinogens: Nickel, Arsenic
• Asbestos Exposure
• Radiation
• Rare metals
How do genes affect lung cancer?
• Familial lung cancers are very rare
• Susceptibility genes:
- Nicotine addiction
- Chemical modification of carcinogens (Cytochrome P450 enzymes and Glutathione S transferases)
• Susceptibility to chromosome breaks and DNA damage
How does a carcinoma generally develop?
- Disordered growth
- Loss of cell adhesion
- Invasion of tissue
- Stimulation of new vessel formation
How does a Squamous Cell Carcinoma develop?
- Airway epithelium toughens after irritation by cigarette smoke (hyperplasia)
- Repeated exposure - squamous metaplasia
- No cilia => mucus stays => carcinogens accumulate
- Squamous cells acquire mutations - dyplasia
- More disordered => carcinoma in sity
- Further mutations => invasive
Is Squamous Cell Carcinoma reversible?
- Remove exposure to the irritant up to the metaplastic squamous cell stage
- Can revert back to ciliated epithelial cells
- Further along the pathway, mutations are irreversible
Describe the cytology of Squamous Cancer Cells
- Large nuclei
* Keratin in the cytoplasm
Describe the histology of Squamous Cancer tissues
- Keratinisation
* Intracellular ‘prickles’ represent desmosomes
Describe the development of adenocarcinomas
• Forms from glandular epithelium
• Increasing in incidence because of deeper inhalation
• Precursor lesion - atypical adenomatous hyperplasia
- proliferation of atypical cells lining the alveolar walls
• Walls thicken
• Cells grow larger
• Cells form enzymes that break down the stroma (connective tissue)
• Inflammation
• Invasion
Describe the cytology of an adenocarcinoma
- Produces mucin
- Big atypical nuclei
- Rest of cytoplasm filled with mucin globule
Describe the histology of adenocarcinoma
- Multi-focal in the lungs
- Tends to spread early
- Glandular differentiation
What are the molecular pathways in adenocarcinoma?
• Smoker - K ras mutation (DNA methylation + P53)
- can’t respond to targeted therapy
• Non-Smoker - EGFR mutation/amplification
- responder mutation: almost complete regression to targeted therapy
- resistance mutation
Describe the histology of large cell carcinoma
• Poorly differentiated tumours
• No evidence of glandular, squamous or neuroendocrine differentiation
- apart from on electron microscopy
• Probably poorly differentiated adenocarcinoma or squamous cell carcinoma
• Poorer prognosis
Describe the cytology of small cell carcinoma
- Small cells
- Nuclei with a small amount of cytoplasm
- Look like lymphocytes
Describe the histology of small cell carcinoma
- Central near the bronchi
- 80% of cases present with advanced disease
- Lot of paraneoplastic syndromes (involves altered immune response)
- Lots of mitoses
- Often outgrows its blood supply and becomes necrotic
What is the prognosis like for small cell carcinoma?
- Chemosensitive due to high growth rate
* However, awful prognosis - can relapse after treatment
Compare the survival rate of small cell carcinoma with non-small cell carcinoma
Small cell carcinoma
• General survival of 2-4 months untreated
• General survival of 10-20 months with current treatment
(• Chemoradiotherapy)
Non-small cell carcinoma • Early Stage 1: 60% 5 year survival • Late Stage 4: 5% 5 year survival • 20-30% have early stage tumours suitable for surgical resection (• Less chemosensitive)
Why is it important to subtype Non-small cell carcinoma in terms of treatment?
- If treated with Bevacizumab and actually have squamous cell carcinoma - may develop fatal haemorrhage
- Some chemo e.g. Pemetrexed, works better in adenocarcinoma instead due to specific characteristics e.g. EGFR, ALK, ros, ret mutations
Give an example of a way you can predict the response to conventional chemotherapy
• Excision Repair Cross-Complimentation Group 1 Protein (ERCC1)
• This marker determines response to cisplatin
• Advanced stage non-small cell lung cancer:
- ERCC1 positive tumours have a poor response to cisplatin based chemotherpy
- ERCC1 protein removes drug-DNA adducts
How can EGFR (Epidermal Growth Factor Receptor) be used as a target for treatment?
- Membrane receptor Tyrosine Kinase
- Regulates angiogenesis, proliferation, apoptosis and migration
- Mutation/amplification of EGFR => adenocarcinoma (mainly non-smokers)
- Target of a Tyrosine Kinase Inhibitor
What is the ALK gene and what does a mutation in it lead to + treatment?
- Gene with instructions for production of ALK receptor tyrosine kinase (regulating cell growth)
- Mutation in the gene occurs in a small number of adenocarcinomas
- Stain to look for mutations
- Treated with anti-ALK mediation
What is PDL-1?
- Protein expressed by tumour cells
- Hides the tumour from cytotoxic T-cells
- Immunotherapy - medication can be used to block PDL-1 so the T-cell can recognise the tumour cells
Which of the following tumour staging is the gold standard:
• clinical
• radiological
• pathological
Pathological
What are the local effects of a bronchogenic carcinoma?
• Proximal tumour - squamous cell or small cell carcinoma
• Bronchial obstruction
- collapse of distal lung => shortness of breath
- impaired drainage of the bronchus => chest infection
• Invasion of local airways and vessels => haemoptysis
• Invasion around large vessels - Superior Vena Cava syndrome => venous congestion of the head and arm, oedema and ultimately circulatory collapse
• Dysphagia - difficulty swalling
• Horner’s syndrome - tumour on sympathetic nervous system => miosis (constricted pupil) and ptosis (weak, droopy eyelid)
What are the effects when bronchogenic carcinoma extends through the pleura/pericardium?
- Pleuritis or pericarditis with effusions => breathlessness
- Cardiac compromise => effusion can affect cardiac function
- Diffuse lymphatic spread within lung => shortness of breath, poor prognostic features
What are the systemic effects of bronchogenic carcinoma?
- Brain => fits
- Skin => lumps
- Liver => pain, deranged function tests
- Bone => pain, fracture
- Paraneoplastic Syndrome => abnormal expression of factors by tumour cells, not normally expressed by the tissue it came from
Give examples of endocrine paraneoplastic syndromes
- Anti-diuretic hormone (ADH) => SIADH (high ADH) - hyponatremia
- Low adrenocorticotropic hormone (ACTH) => Cushing’s Syndrome (especially small cell carcinoma)
- Parathyroid hormone-related peptides => hypercalcaemia (especially squamous cell carcinoma)
- Calcitonin => Hypocalcaemia
- Gonadotrophins => Gynaecomastia
- Seratonin => Carcinoid Syndrome
What do non-endocrine paraneoplastic syndromes affect?
- Haematologic/coagulation defects
- Skin
- Muscular
- Miscellaneous
What is the cause of mesothelioma (a malignant pleural tumour) and how does it present?
- Asbestos
- Currently a peak in incidence
- Fatal
- Long lag time (develops decades after exposure)
- More common in males
- Shortness of breath, chest pain
- Awful prognosis
