What are some origins of pollutants that can cause lung disease?
combustion (exhaust, cigarettes)
indoor (cleaning products
What are some possible patterns of exposure to lung pollutants?
magnitude of exposure (insidious vs accidental?)
persistence (acute? chronic?)
duration (steady? intermittent? diurnal?)
conditions (exertion? PPE?)
What 3 factors determine the lung response to an inhaled pollutant?
Biological activity of the substance
What determines the deposition of noxious gases and particles in the respiratory tract?
- depends on solubility (henry's constant, e.g. gas:liquid ratio)
- higher gas:liquid deposits in the alveoli
- lower gas:liquid deposits in nasopharynx/upper resp (e.g. ammonia)
- depends mostly on particle size (sizes: thoracic, coarse, fine, ultrafine). Exhaust and cigarette smoke is ultrafine
What are the 3 patterns of deposition and what do they depend on? How could a pollutant be absorbed systemically?
Impaction (large airwyas, upper airways)
Sedimentation: (small airways)
Diffusion (alvoeli) ***may be able to enter the blood through this route and be absorbed systemically**
What are the lung's natural defences?
What determines whether a pollutant is cleared/detoxified from the lungs?
the site of deposition
the health of natural lung defences
What are some pathophysiologic mechanisms by which pollutants cause lung disease?
Non-specific chemical reactivity
strong acid or base
Specific toxic effects
- DNA mutation
- invoke allergic response
- change O2 carrying capacity
What are some disease states that can caused (and exacerbated) by pollutant exposure?
Upper resp tract:
- interstitial disease
What are some strategies to diagnose an occupational/environmental disease?
acquire MSDS to know what you could be dealing with
take a thorough history
can send patient home with a spirometer and have them do PEF several times a day to establish whether the symptoms aer due to work exposure
How to minimize the incidence of diseases caused by environmental exposure?
Good industrial hygiene:
- Engineering controls
- administrative controls
- surveilllance for sentinel cases
Classification of lung malignancies
Small-cell carcinoma (15%)
Non small cell carcinoma (85%)
- squamous cell carcinoma
- large cell carcinoma
Pathologic characteristics of squamous cell carcinoma
Pathologic features of adenocarcinoma
2/3 peripheral, 1/3 central
gland formation +/- mucin production (PAS stain)
What is bronchoalveolar carcinoma? AKA?
AKA: adenocarcinoma in-situ (preferred name)
Tumour cells grow along the surface of the alveoli, BUT can have mixed AIS and invasive adenocarcinoma.
What are the pathologic features of small cell carcinoma?
small, dark cells with hyperchromatic nucleus (salt and pepper chromatin)
What are the pathologic features of large cell carcinoma?
large polygonal cells, poorly differentiated
Why do we group lung cancers in small cell vs. non-small cell?
Within NSCLC, how and why do we group into squamous and non-squamous?
SCLC vs. NSCLC:
- Non-small cancers are treated primarly by surgical resection.
- Small cell cancers are more disseminated and are treated by chemotherapy
Squamous vs. Non-squamous
- subtype using TTF-1 and p63 expression
- no targeted therapy is available for squamous.
What targeted therapy is available for adenocarcinomas?
eGFR mutation positive --> tyrosine kinase inhibitor
ALK mutation positive --> crizotinib
**these are almost always mutually exclusive, and are not found in all patients**
What type of syndromes can local spread of lung cancer cause?
superior vena caval syndrome (facial swelling, cyanosis, protrusion of neck veins)
pancoast tumour (brachial plexus compression --> arm pain)
Horner syndrome (compression of cervical sympathetic chain --> unilateral ptosis, miosis, anhidrosis
What is the usual lymph node spread of lung cancer?
intrapulmonary--?hilar nodes-->tracheobronchial nodes -->mediastinal nodes-->cervical, supraclavicular, axillary, distance nodes
What are the most common metastasis in lung cancer? How are they spread?
They are spread hematogenously
- adrenals (50%)
- liver (30-50%)
- brain (20%)
- bone (20%)
What are the clinical procedures used to acquire tissue to make a diagnosis of lung cancer?
For central (squamous and small cell) can often do cytology on the sputum
Bronchoscopy: lavage, brush, biopsy and do cytology/histology on each.
Trans-throacic fine needle aspirate
Trans-thoracic core needle aspirate
Are primary or metastatic tumours of the lung or pleura more common?
Metastatic tumours are more common for both
Define mesothelioma. What is it associated with? What are it's pathologic features?
Mesothioloma is a primary tumour involving the pleura, often associated with asbestos exposure. Distant metastasis occur late, but poor prognosis.
It encases the lung, and can invade the thoracic wall (***it doesn't usually invade the lung itself)
It has three microscopic patterns: epithelial (gland like), sarcomatoid, mixed.
What is the differential for a pulmonary nodule?
granuloma (TB, fungal)
How to differentiate mesothelioma and adenocarcinoma?
Have to sub-type. Adenocarcinoma will be TTF-1 positive,
What is the differential for mesothelioma?
bronchogenic carcinoma invading the pleura
Describe the diagnostic algorithm or pathway in detection/diagnosis of lung cancer using imaging.
Nodule or mass discovered (CXR or CT)
Nodule or mass tissue needs to be characterized (CT)
Resectability of the mass needs to be determined (local tissue involvement) (CT, MR) (MR is good for determining if vessels are encased and if there is chest wall invasion)
Search for distant metastases (PET-CT) (MR and CT aren't good at differentiating nodes enlarged by infection or metastatic disease) (Use MR for brain mets)
How to differentiate malignant from benign masses or nodules using imaging
CXR with contrast allows you to see vascularization of the mass/nodule
compare with previous CXR to see if it is growing
is it obvisouly calcified? CT will differentiate between fat (harmatoma), calcium (TB/fungal) and soft tissue (neoplasm?)
Are the margins smooth (more likely benign) or spiculated ( more like neoplastic)?
Does it have satellite nodules? More likely past infection.
When is a lung cancer unresectable?
Stage IIIb or higher:
- mediastinal involvement
- contralateral nodes/masses
- spinal cord involvement
- distant metastasis
- malignant pleural effusion
Where does the pleural fluid come from?
From intercostal microvessels and bronchial microvessels
How does the Starling equation relate to the formation of pleural fluid in the normal physiologic state
Flow= K (change in hydrostatic pressure-change in oncotic pressure)
Transudation and absorption of fluid within the pleural space normally follow the Starling equation, which depends on hydrostatic, colloid, and tissue pressures in addition to permeability of the pleural membrane.
**net flow of fluid is from parietal to visceral pleura**
Define exudative vs. transudative effusions
They can be distinguished by using Light's criteria.
- results from an inflammatory process
- contains high protein
- contains high LDH
- low protein, LDH
- leaks across an intact membrane
- results from low increased hydrostatic pressure or decreased oncotic pressure in the the pleural space.
What is the mnemonic for transudative effusions?
Liver (hepatic hydrothorax)
Kidney (low protein state)
Iatrogenic (e.g. central line into pleural space)
What are 3 causes of exudative pleural effusion?
serositis due to connective tissue disease
What are 3 mechanisms by which lung cancer can cause pleural effusion?
Can be direct or indirect
- tumour blocking lymphatic drainage
- inflitration of vasculature -->leaky (cytokine production?)
- superior vena caval syndrome
- infiltration of cancer cells into the pleural space
How long does it take nicotine to reach the brain when inhaled? What is it's half-life? What is it's major metabolite? What is it's oral bioavailability?
10 s to reach the brain
metabolized by CYP2A6 into continine (used as a serum marker for nicotine
has very poor oral bioavailablity
How is nicotine addictive?
It is a nicotinic receptor agonist. It causes dopamine release, is a stimulant, and activates the reward pathway of the brain.
Long term use result in nicotinic receptor upregulation
What are the withdrawal symptoms for nicotine?
What kinds of nicotine replacement therapies are availability and what are the side effects/drawbacks?
- craving rescue
- gastric irritant
- craving rescue
- gastric irritant
- nicotine maintenance
- local irritation
- night-time waking because of continous delivery of nicotine
- mimics behaviour of smoking
- cough/local irritation
- faster absorption
What is Champix, how does it work, what are its main side effects and what is its safety?
- partial agonist at nicotinic receptor
- provides small amount of stimulation
- reduces reward from smoking because it competes for receptors with nicotine, but only has partial activity
- S/E: nausea
- may cause anxiety/depression/suicide
- increases risk of CV event in people with CV history
What is Zyban, how does it work, what is its main side effects and what is its safety?
- dopamine reuptake inhibitor
- S/E: dry mouth, insomnia, nausae
- Safety: not safe if Hx of seizures (may cause these), and welbutrin=zyban, and suicidal behaviour in youth
What is nortriptyline, what is its MOA, what are its main side-effects?
- inhibits serotonin and NE reuptake
- anticholinergic side-effects
What is the efficacy of NRT, verenicline and bupropion?
all NRT types more effective than placebo, but no clear advantage of one type over another
bupropion works about the same as NRT, verenicline works better.
success is still only ~20%
What is a carcinoid?
A type of neuroendocrine tumour. Usually benign and slow growing. Often found in GI tract and lungs.
What are common genomic alterations in lung cancer? Which ones are tested for and why?
- Bcl-2, C-kit, MMP, VEGF
- The usual culprits...targeted therapy has failed though
- eGFR gain of function mutation
- KRAS gain of function mutation (mutually exclusive of eGFR mutation, found dowstream)
- EML4-ALK fusion (driver mutation, mutually exclusive with eGFR, poor prognostic variable)
We test for eGFR and ALK mutations in NSCLC because targeted drug therapy improves patient outcomes
What are the different kinds of head and neck cancers? What kind of carcinoma are they usually? Is there targeted therapy for these?
primary cancer of unknown origin
Usually squamous cell carcinoma. NPC is squamous, but morphologically different and associated with EBV
EGFR is overexpressed in 80% of head and neck cancers, so can use cetuximab. No testing, they just use it.
What are the risks for oral cancer?
Sex (HPV 16)